IL-11 ANTIBODIES

Abstract

IL-11 antibodies are disclosed. Also disclosed are compositions comprising the IL-11 antibodies, and methods using the IL-11 antibodies.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority under 35 USC .sctn. 119(a)-(d) to United Kingdom Application No. 1709535.7, filed Jun. 15, 2017 and United Kingdom Application No. 1621446.2, filed Dec. 16, 2016, the entire contents of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to antibodies that bind to interleukin 11 (IL-11).

BACKGROUND TO THE INVENTION

[0003] Many fatal and incurable diseases are caused by organ failure due to excessive and maladaptive fibrosis (Rockey et al., 2015 Journal of Infectious Diseases 214, jiw176). Fibrotic disorders include both rare, genetically-driven diseases such as scleroderma, idiopathic pulmonary fibrosis and hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and common diseases like atrial fibrillation, ventricular fibrillation, non-alcoholic fatty liver disease and diabetic kidney disease. Due to the significant impact on world-wide morbidity and mortality, there is a need to develop therapeutics to inhibit the fibrotic response (Nanthakumar et al., 2015 Nat Rev Drug Discov 14, 693-720).

[0004] A major hallmark of fibrosis is the pathologic activation of resident fibroblasts that drives their transition from a quiescent state to proliferating, secretory and contractile myofibroblasts (Hinz et al., 2010 Am J Pathology 170, 1807-1816). Stimuli such as mechanical stress and pro-fibrotic cytokines can activate fibroblasts. The TGF.beta.1 pathway is considered to be of central importance for the fibrotic response (Leask and Abraham, 2004 The FASEB Journal 18, 816-827) and its inhibition is a therapeutic strategy that is under investigation (Gourdie et al., 2016 Nature Reviews Drug Discovery 15, 620-638). However, direct inhibition of multi-functional TGF.beta.1 is associated with severe side effects such as inflammation and cancer susceptibility.

SUMMARY OF THE INVENTION

[0005] In one aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, wherein the antibody or antigen binding fragment is a fully human antibody or antigen binding fragment and is capable of inhibiting IL-11 trans signalling.

[0006] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising the amino acid sequences i) to vi):

TABLE-US-00001 i) LC-CDR1: (SEQ ID NO: 239) X.sub.1X.sub.2DX.sub.3GX.sub.4YX.sub.5Y; (SEQ ID NO: 240) X.sub.6SNX.sub.7GX.sub.8X.sub.9X.sub.10; (SEQ ID NO: 241) QX.sub.11X.sub.12SSX.sub.13; (SEQ ID NO: 242) X.sub.14GX.sub.15IASNX.sub.16; (SEQ ID NO: 101) QDVGRY; or (SEQ ID NO: 161) SLRGYY; ii) LC-CDR2: (SEQ ID NO: 243) DVX.sub.17; (SEQ ID NO: 244) X.sub.18NX.sub.19; (SEQ ID NO: 245) X.sub.20AS; (SEQ ID NO: 246) X.sub.21DX.sub.22; (SEQ ID NO: 247) EVX.sub.23; or (SEQ ID NO: 248) DX.sub.24X.sub.25; iii) LC-CDR3: (SEQ ID NO: 249) X.sub.26SYTX.sub.27X.sub.28X.sub.29X.sub.30X.sub.31VX.sub.32; (SEQ ID NO: 250) X.sub.33SYAX.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39X.sub.40X.sub.4- 1X.sub.42X.sub.43X.sub.44X.sub.45X.sub.46X.sub.47X.sub.48X.sub.49; (SEQ ID NO: 251) X.sub.50X.sub.51WDX.sub.52X.sub.53LX.sub.54X.sub.55X.sub.56V; (SEQ ID NO: 252) QQX.sub.57X.sub.58X.sub.59PX.sub.60X.sub.61X.sub.62X.sub.63X.sub.64X.sub.6- 5X.sub.66X.sub.67X.sub.68X.sub.69X.sub.70X.sub.71X.sub.72; (SEQ ID NO: 253) Q5YX.sub.73X.sub.74SX.sub.75X.sub.76X.sub.77X.sub.78; (SEQ ID NO: 254) X.sub.79SYX.sub.80SSX.sub.81X.sub.82X.sub.83VX.sub.84; (SEQ ID NO: 169) NSYVTGNNWA; or (SEQ ID NO: 163) DSRGRSGDHWL; iv) HC-CDR1: (SEQ ID NO: 255) GFTFSSYX.sub.85; (SEQ ID NO: 256) GX.sub.88X.sub.87X.sub.88X.sub.89SYG; (SEQ ID NO: 257) X.sub.90X.sub.91X.sub.92X.sub.93X.sub.94SYA; (SEQ ID NO: 204) WIFLKSYA; (SEQ ID NO: 180) VSSNSAAWN; (SEQ ID NO: 220) GGSISSSNW; or (SEQ ID NO: 183) GFTFSGAY; v) HC-CDR2: (SEQ ID NO: 258) ISYDGSX.sub.95K; (SEQ ID NO: 210) IIPIFGTA; (SEQ ID NO: 181) YRSKWYN; (SEQ ID NO: 229) ISAYNGNT; or (SEQ ID NO: 221) IYHSGST; vi) HC-CDR3: (SEQ ID NO: 197) AKLSGPNGVDY; (SEQ ID NO: 259) AKX.sub.96X.sub.97X.sub.98GX.sub.99X.sub.100X.sub.101X.sub.102DY; (SEQ ID NO: 260) ARDX.sub.103GYSSGWYFDY; (SEQ ID NO: 261) ARLX.sub.104X.sub.105X.sub.106X.sub.107X.sub.108X.sub.109X.sub.110X.sub.11- 1X.sub.112X.sub.113X.sub.114X.sub.115X.sub.116X.sub.117 X.sub.118X.sub.119X.sub.120AFDI; (SEQ ID NO: 199) ARIMGYDYGDYDVVDY; (SEQ ID NO: 262) ARIX.sub.121X.sub.122X.sub.123X.sub.124X.sub.125X.sub.126DX.sub.127X.sub.1- 28X.sub.129X.sub.130; (SEQ ID NO: 205) ARVGFSSWYPDLYYFDY; (SEQ ID NO: 263) X.sub.131X.sub.132X.sub.133X.sub.134RGYX.sub.135DY; (SEQ ID NO: 194) ARITHDYGDFSDAFDI; (SEQ ID NO: 264) ARX.sub.136GVLX.sub.137DY; (SEQ ID NO: 235) AKGSYYFDY; (SEQ ID NO: 206) ARLYSGYPSRYYYGMDV; (SEQ ID NO: 216) ARVQSGEPESDY; (SEQ ID NO: 187) AKIGATDPLDY; (SEQ ID NO: 185) ARDLYAFDI; (SEQ ID NO: 203) ARPDDDY; (SEQ ID NO: 207) AKGGKSYYGFDY; (SEQ ID NO: 231) ARADSSAGGGPYYYGMDV; (SEQ ID NO: 233) ARVYYDSSGTQGDSFDY; (SEQ ID NO: 230) ARVVAAARSYYYYMDV; (SEQ ID NO: 224) ARGGGPYYDFWSGYYTEFDY; (SEQ ID NO: 218) ARMVNLYYGDAFDI; (SEQ ID NO: 211) ARGLITGTTP; (SEQ ID NO: 198) ARGQNVDL; (SEQ ID NO: 222) ARVQNLGGGSYYVGAFDY; or (SEQ ID NO: 219) ARLVGATADDY;

[0007] or a variant thereof in which one or two or three amino acids in one or more of the sequences i) to vi) are replaced with another amino acid;

wherein X.sub.1=S or I, X.sub.2=S or R, X.sub.3=V or I, X.sub.4=G, A or N, X.sub.5=N, E, K or D, X.sub.6=S or Y, X.sub.7=I or V, X.sub.8=S, N or Y, X.sub.9=N, Y or D, X.sub.10=L, T or A, X.sub.11=G, S or I, X.sub.12=S, I or V, X.sub.13=Y or N, X.sub.14=S or T, X.sub.15=S or N, X.sub.16=Y or R, X.sub.17=S, T or G, X.sub.18=R, I or G, X.sub.19=N or D, X.sub.20=A or G, X.sub.21=E, D or N, X.sub.22=N or D, X.sub.23=S, F or N, X.sub.24=N or V, X.sub.25=H or T, X.sub.26=S, N or G, X.sub.27=S or T, X.sub.28=S or G, X.sub.29=S, N, G or I, X.sub.30=T or S, X.sub.31=W, L, V or Q, X.sub.32=absent or V, X.sub.33=C or S, X.sub.34=G or D, X.sub.35=S, Y, N or T, X.sub.36=Y or N, X.sub.37=T or N, X.sub.38=W or F, X.sub.39=V, G or L, X.sub.40=absent or V, X.sub.41=absent or R, X.sub.42=absent or R, X.sub.43=absent or R, X.sub.44=absent or D, X.sub.45=absent or R, X.sub.46=absent or A, X.sub.47=absent or D, X.sub.48=absent or R, X.sub.49=absent or P, X.sub.50=A or G, X.sub.51=A or T, X.sub.52=D, G or S, X.sub.53=S or G, X.sub.54=S, K or N, X.sub.55=G or A, X.sub.56=W, G or H, X.sub.57=S or Y, X.sub.59=Y, R or N, X.sub.59=S or N, X.sub.60=T, A or W, X.sub.61=L or T, X.sub.62=Y, A, W or T, X.sub.63=T, absent or F, X.sub.64=absent or G, X.sub.65=absent or G, X.sub.66=absent or G, X.sub.67=absent or T, X.sub.68=absent or K, X.sub.69=absent or V, X.sub.70=absent or E, X.sub.71=absent or F, X.sub.72=absent or K, X.sub.73=D or N, X.sub.74=S or Y, X.sub.75=K, S or N, X.sub.76=V or L, X.sub.77=I, V or W, X.sub.78=absent or V, X.sub.79=T or N, X.sub.80=T or S, X.sub.81=T or S, X.sub.82=P or T, X.sub.83=Y or L, X.sub.84=absent or A, X.sub.95=A or G, X.sub.86=F or Y, X.sub.87=S or T, X.sub.99=L or F, X.sub.99=G, R, T, S or N, X.sub.90=G or I, X.sub.91=G, F or L, X.sub.62=T, S or P, X.sub.93=F or S, X.sub.64=S or D, X.sub.95=N or D, X.sub.96=L, F or D, X.sub.97=Y, A or L, X.sub.98=S or R, X.sub.99=S, V or L, X.sub.100=S, or P, X.sub.101=N, L or I, X.sub.102=F or I, X.sub.103=S or V, X.sub.104=H or A, X.sub.105=S, Q or F, X.sub.106=S or G, X.sub.107=absent or Y, X.sub.108=absent or S, X.sub.109=absent, R or S, X.sub.110=Q, N or S, X.sub.111=W or Y, X.sub.112=absent, Y or F, X.sub.113=absent or E, X.sub.114=absent or W, X.sub.115=absent or E, X.sub.116=absent or P, X.sub.117=absent, G or S, X.sub.118=absent, R or T, X.sub.119=G, E or I, X.sub.120=D or H, X.sub.121=A or G, X.sub.122=A or G, X.sub.123=A or Y, X.sub.124=D or absent, X.sub.125=G or D, X.sub.126=F, M or R, X.sub.127=V, Y or A, X.sub.128=absent or F, X.sub.129=absent or D, X.sub.130=absent or I, X.sub.131=absent or A, X.sub.132=absent or R, X.sub.133=A or G, X.sub.134=R or T, X.sub.135=F or G, X.sub.136=absent or S, X.sub.137=absent or F.

[0008] In some embodiments, HC-CDR1 is one of VSSNSAAWN (SEQ ID NO:180), GFTFSGAY (SEQ ID NO:183), GFTFSSYG (SEQ ID NO:186), GFTFSSYA (SEQ ID NO:190), GFSFRSYG (SEQ ID NO:193), GFTFRSYG (SEQ ID NO:196), GFSFSSYA (SEQ ID NO:212), WIFLKSYA (SEQ ID NO:204), GFSLNSYG (SEQ ID NO:217), GGTFSSYA (SEQ ID NO:209), GGSISSSNW (SEQ ID NO:220), GFSLSSYG (SEQ ID NO:201), GGTFSSYA (SEQ ID NO:209), ILPSDSYA (SEQ ID NO:226), GYTFTSYG (SEQ ID NO:228), GFTFGSYG (SEQ ID NO:234) or GFSLGSYG (SEQ ID NO:238).

[0009] In some embodiments, HC-CDR2 is one of YRSKWYN (SEQ ID NO:181), ISYDGSNK (SEQ ID NO:184), ISYDGSDK (SEQ ID NO:188), IIPIFGTA (SEQ ID NO:210), IYHSGST (SEQ ID NO:221), or ISAYNGNT (SEQ ID NO:229).

[0010] In some embodiments, HC-CDR3 is one of ARGTRGYFDY (SEQ ID NO:182), ARDLYAFDI (SEQ ID NO:185), AKIGATDPLDY (SEQ ID NO:187), AKDLSGLPIIDY (SEQ ID NO:189), ARRGYFDY (SEQ ID NO:191), ARIAAADGMDV (SEQ ID NO:192), ARITHDYGDFSDAFDI (SEQ ID NO:194), AKLYSGSSNFDY (SEQ ID NO:195), AKLSGPNGVDY (SEQ ID NO:197), ARGQNVDL (SEQ ID NO:198), ARIMGYDYGDYDVVDY (SEQ ID NO:199), ARRGYGDY (SEQ ID NO:213), ARVGFSSWYPDLYYFDY (SEQ ID NO:205), AKFARGVYLFDY (SEQ ID NO:215), ARVQSGEPESDY (SEQ ID NO:216), ARMVNLYYGDAFDI (SEQ ID NO:218), ARLVGATADDY (SEQ ID NO:219), AKLSGPNGVDY (SEQ ID NO:197), ARGLITGTTP (SEQ ID NO:211), ARVQNLGGGSYYVGAFDY (SEQ ID NO:222), ARLHFSQYFSTIDAFDI (SEQ ID NO:223), ARDVGYSSGWYFDY (SEQ ID NO:200), ARLAQSYSSSWYEWEPGREHAFDI (SEQ ID NO:202), ARPDDDY (SEQ ID NO:203) AKLSGPNGVDY (SEQ ID NO:197), ARLYSGYPSRYYYGMDV (SEQ ID NO:206), AKGGKSYYGFDY (SEQ ID NO:207), ARLHSGRNWGDAFDI (SEQ ID NO:208), ARGGGPYYDFWSGYYTEFDY (SEQ ID NO:224), ARDSGYSSGWYFDY (SEQ ID NO:225), ARIAAAGRDAFDI (SEQ ID NO:227), ARVVAAARSYYYYMDV (SEQ ID NO:230), ARADSSAGGGPYYYGMDV (SEQ ID NO:231), ARIGGYDDFDY (SEQ ID NO:232), ARVYYDSSGTQGDSFDY (SEQ ID NO:233), AKGSYYFDY (SEQ ID NO:235), ARGVLFDY (SEQ ID NO:236) or ARSGVLDY (SEQ ID NO:237).

[0011] In some embodiments, LC-CDR1 is one of QDVGRY (SEQ ID NO:101), TGNIASNR (SEQ ID NO:104), SSDVGGYNY (SEQ ID NO:107), SSDVGAYNY (SEQ ID NO:110), SSDIGAYNY (SEQ ID NO:114), SSNIGSNY (SEQ ID NO:116), ISDVGGYNY (SEQ ID NO:122), SSNIGNNL (SEQ ID NO:126), SSDVGGYDY (SEQ ID NO:128), QSVSSN (SEQ ID NO:137), SSNIGNNY (SEQ ID NO:140), YSNVGSNL (SEQ ID NO:144), SSNIGSNT (SEQ ID NO:147), SRDVGGYNY (SEQ ID NO:150), SGSIASNY (SEQ ID NO:152), QIISSY (SEQ ID NO:155), SSDVGGYEY (SEQ ID NO:159), SLRGYY (SEQ ID NO:161), SSNIGSYY (SEQ ID NO:164), SSDVGAYNY (SEQ ID NO:167), SSNIGYDA (SEQ ID NO:170), QGSSSY (SEQ ID NO:173), SSDVGGYKY (SEQ ID NO:175) or SSDVGNYKY (SEQ ID NO:178).

[0012] In some embodiments, LC-CDR2 is one of AAS (SEQ ID NO:102), DNH (SEQ ID NO:105), DVS (SEQ ID NO:108), EVS (SEQ ID NO:111), RNN (SEQ ID NO:117), DVT (SEQ ID NO:123), DVH (SEQ ID NO:129), DVG (SEQ ID NO:133), EVN (SEQ ID NO:135), DVT (SEQ ID NO:123), GAS (SEQ ID NO:138), DNT (SEQ ID NO:141), EDD (SEQ ID NO:145), INN (SEQ ID NO:148), DDN (SEQ ID NO:153), EDN (SEQ ID NO:157), GNN (SEQ ID NO:162), RND (SEQ ID NO:165), EVF (SEQ ID NO:168) or NDN (SEQ ID NO:171).

[0013] In some embodiments, LC-CDR3 is one of QQYRSAPLA (SEQ ID NO:103), QSYDYSSVI (SEQ ID NO:106), SSYTSSSSWV (SEQ ID NO:109), SSYTSSNTLV (SEQ ID NO:112), SSYTSSSTVV (SEQ ID NO:113), SSYTTSSTVV (SEQ ID NO:115), AAWDGSLSGWV (SEQ ID NO:118), SSYTSSSTWV (SEQ ID NO:119), CSYAGSYTFV (SEQ ID NO:120), NSYTSSTPYV (SEQ ID NO:121), SSYAGSYTWV (SEQ ID NO:124), GSYTSSNTQV (SEQ ID NO:125), AAWDDSLSAGV (SEQ ID NO:127), SSYTSSITWV (SEQ ID NO:130), CSYAGSYTWV (SEQ ID NO:131), GSYTSSSTWV (SEQ ID NO:132), SSYTSGSTWV (SEQ ID NO:134), SSYAGTNNFVV (SEQ ID NO:136), QQYNNWPLTFGGGTKVEFK (SEQ ID NO:139), GTWDSSLSGGV (SEQ ID NO:142), SSYAGSYTWGVRRRDRADRP (SEQ ID NO:143), AAWDDSLKGHV (SEQ ID NO:146), AAWDDSLNGWV (SEQ ID NO:149), CSYADYYTWV (SEQ ID NO:151), QSYDSSNLWV (SEQ ID NO:154), QQSYSTPTWT (SEQ ID NO:156), QSYNSSKVV (SEQ ID NO:158), NSYTSSGTLVV (SEQ ID NO:160), DSRGRSGDHWL (SEQ ID NO:163), ATWDDGLSGWV (SEQ ID NO:166), NSYVTGNNWA (SEQ ID NO:169), AAWDDSLSGWV (SEQ ID NO:172), QQSYSTPLYT (SEQ ID NO:174), CSYAGNYTWL (SEQ ID NO:176), TSYSSSSTLVA (SEQ ID NO:177) or SSYTSSSTLVV (SEQ ID NO:179).

[0014] In some embodiments, the antibody or antigen binding fragment has at least one heavy chain variable region incorporating the following CDRs:

TABLE-US-00002 (SEQ ID NO: 180) HC-CDR1: VSSNSAAWN (SEQ ID NO: 181) HC-CDR2: YRSKWYN (SEQ ID NO: 182) HC-CDR3: ARGTRGYFDY; or (SEQ ID NO: 183) HC-CDR1: GFTFSGAY (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 185) HC-CDR3: ARDLYAFDI; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 187) HC-CDR3: AKIGATDPLDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 188) HC-CDR2: ISYDGSDK (SEQ ID NO: 189) HC-CDR3: AKDLSGLPIIDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 191) HC-CDR3: ARRGYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 192) HC-CDR3: ARIAAADGMDV; or (SEQ ID NO: 193) HC-CDR1: GFSFRSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 194) HC-CDR3: ARITHDYGDFSDAFDI; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 195) HC-CDR3: AKLYSGSSNFDY; or (SEQ ID NO: 196) HC-CDR1: GFTFRSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 194) HC-CDR3: ARITHDYGDFSDAFDI; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 198) HC-CDR3: ARGQNVDL; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 199) HC-CDR3: ARIMGYDYGDYDVVDY; or (SEQ ID NO: 212) HC-CDR1: GFSFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 199) HC-CDR3: ARIMGYDYGDYDVVDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 213) HC-CDR3: ARRGYGDY; or (SEQ ID NO: 204) HC-CDR1: WIFLKSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 205) HC-CDR3: ARVGFSSWYPDLYYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 215) HC-CDR3: AKFARGVYLFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 216) HC-CDR3: ARVQSGEPESDY; or (SEQ ID NO: 217) HC-CDR1: GFSLNSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 195) HC-CDR3: AKLYSGSSNFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 205) HC-CDR3: ARVGFSSWYPDLYYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 218) HC-CDR3: ARMVNLYYGDAFDI; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 219) HC-CDR3: ARLVGATADDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 209) HC-CDR1: GGTFSSYA (SEQ ID NO: 210) HC-CDR2: IIPIFGTA (SEQ ID NO: 211) HC-CDR3: ARGLITGTTP; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or

(SEQ ID NO: 220) HC-CDR1: GGSISSSNW (SEQ ID NO: 221) HC-CDR2: IYHSGST (SEQ ID NO: 222) HC-CDR3: ARVQNLGGGSYYVGAFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 223) HC-CDR3: ARLHFSQYFSTIDAFDI; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 199) HC-CDR3: ARIMGYDYGDYDVVDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 200) HC-CDR3: ARDVGYSSGWYFDY; or (SEQ ID NO: 201) HC-CDR1: GFSLSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 202) HC-CDR3: ARLAQSYSSSWYEWEPGREHAFDI; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 203) HC-CDR3: ARPDDDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 204) HC-CDR1: WIFLKSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 205) HC-CDR3: ARVGFSSWYPDLYYFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 206) HC-CDR3: ARLYSGYPSRYYYGMDV; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 207) HC-CDR3: AKGGKSYYGFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 208) HC-CDR3: ARLHSGRNWGDAFDI; or (SEQ ID NO: 209) HC-CDR1: GGTFSSYA (SEQ ID NO: 210) HC-CDR2: IIPIFGTA (SEQ ID NO: 224) HC-CDR3: ARGGGPYYDFWSGYYTEFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 225) HC-CDR3: ARDSGYSSGWYFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 225) HC-CDR3: ARDSGYSSGWYFDY; or (SEQ ID NO: 226) HC-CDR1: ILPSDSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 227) HC-CDR3: ARIAAAGRDAFDI; or (SEQ ID NO: 228) HC-CDR1: GYTFTSYG (SEQ ID NO: 229) HC-CDR2: ISAYNGNT (SEQ ID NO: 230) HC-CDR3: ARVVAAARSYYYYMDV; or (SEQ ID NO: 209) HC-CDR1: GGTFSSYA (SEQ ID NO: 210) HC-CDR2: IIPIFGTA (SEQ ID NO: 231) HC-CDR3: ARADSSAGGGPYYYGMDV; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 215) HC-CDR3: AKFARGVYLFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 232) HC-CDR3: ARIGGYDDFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 233) HC-CDR3: ARVYYDSSGTQGDSFDY; or (SEQ ID NO: 234) HC-CDR1: GFTFGSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 235) HC-CDR3: AKGSYYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 238) HC-CDR1: GFSLGSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 235) HC-CDR3: AKGSYYFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 236) HC-CDR3: ARGVLFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 237) HC-CDR3: ARSGVLDY.

[0015] In some embodiments, the antibody or antigen binding fragment has at least one light chain variable region incorporating the following CDRs:

TABLE-US-00003 (SEQ ID NO: 101) LC-CDR1: QDVGRY (SEQ ID NO: 102) LC-CDR2: AAS (SEQ ID NO: 103) LC-CDR3: QQYRSAPLA; or (SEQ ID NO: 104) LC-CDR1: TGNIASNR (SEQ ID NO: 105) LC-CDR2: DNH (SEQ ID NO: 106) LC-CDR3: QSYDYSSVI; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 109) LC-CDR3: SSYTSSSSWV; or (SEQ ID NO: 110) LC-CDR1: SSDVGAYNY (SEQ ID NO: 111) LC-CDR2: EVS (SEQ ID NO: 112) LC-CDR3: SSYTSSNTLV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 113) LC-CDR3: SSYTSSSTVV; or (SEQ ID NO: 114) LC-CDR1: SSDIGAYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 115) LC-CDR3: SSYTTSSTVV; or (SEQ ID NO: 116) LC-CDR1: SSNIGSNY (SEQ ID NO: 117) LC-CDR2: RNN (SEQ ID NO: 118) LC-CDR3: AAWDGSLSGWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 119) LC-CDR3: SSYTSSSTWV; or (SEQ ID NO: 116) LC-CDR1: SSNIGSNY (SEQ ID NO: 117) LC-CDR2: RNN (SEQ ID NO: 118) LC-CDR3: AAWDGSLSGWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 120) LC-CDR3: CSYAGSYTFV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 121) LC-CDR3: NSYTSSTPYV; or (SEQ ID NO: 122) LC-CDR1: ISDVGGYNY (SEQ ID NO: 123) LC-CDR2: DVT (SEQ ID NO: 124) LC-CDR3: SSYAGSYTWV; or (SEQ ID NO: 122) LC-CDR1: ISDVGGYNY (SEQ ID NO: 123) LC-CDR2: DVT (SEQ ID NO: 124) LC-CDR3: SSYAGSYTWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 125) LC-CDR3: GSYTSSNTQV; or (SEQ ID NO: 126) LC-CDR1: SSNIGNNL (SEQ ID NO: 117) LC-CDR2: RNN (SEQ ID NO: 127) LC-CDR3: AAWDDSLSAGV; or (SEQ ID NO: 128) LC-CDR1: SSDVGGYDY (SEQ ID NO: 129) LC-CDR2: DVH (SEQ ID NO: 130) LC-CDR3: SSYTSSITWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 131) LC-CDR3: CSYAGSYTWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 119) LC-CDR3: SSYTSSSTWV; or (SEQ ID NO: 126) LC-CDR1: SSNIGNNL (SEQ ID NO: 117) LC-CDR2: RNN (SEQ ID NO: 127) LC-CDR3: AAWDDSLSAGV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 131) LC-CDR3: CSYAGSYTWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 113) LC-CDR3: SSYTSSSTVV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 132) LC-CDR3: GSYTSSSTWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 133) LC-CDR2: DVG (SEQ ID NO: 134) LC-CDR3: SSYTSGSTWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 135) LC-CDR2: EVN (SEQ ID NO: 136) LC-CDR3: SSYAGTNNFVV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 123) LC-CDR2: DVT (SEQ ID NO: 131) LC-CDR3: CSYAGSYTWV; or

(SEQ ID NO: 137) LC-CDR1: QSVSSN (SEQ ID NO: 138) LC-CDR2: GAS (SEQ ID NO: 139) LC-CDR3: QQYNNWPLTFGGGTKVEFK; or (SEQ ID NO: 140) LC-CDR1: SSNIGNNY (SEQ ID NO: 141) LC-CDR2: DNT (SEQ ID NO: 142) LC-CDR3: GTWDSSLSGGV; or (SEQ ID NO: 122) LC-CDR1: ISDVGGYNY (SEQ ID NO: 123) LC-CDR2: DVT (SEQ ID NO: 143) LC-CDR3: SSYAGSYTWGVRRRDRADRP; or (SEQ ID NO: 144) LC-CDR1: YSNVGSNL (SEQ ID NO: 145) LC-CDR2: EDD (SEQ ID NO: 146) LC-CDR3: AAWDDSLKGHV; or (SEQ ID NO: 147) LC-CDR1: SSNIGSNT (SEQ ID NO: 148) LC-CDR2: INN (SEQ ID NO: 149) LC-CDR3: AAWDDSLNGWV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 131) LC-CDR3: CSYAGSYTWV; or (SEQ ID NO: 150) LC-CDR1: SRDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 151) LC-CDR3: CSYADYYTWV; or (SEQ ID NO: 126) LC-CDR1: SSNIGNNL (SEQ ID NO: 117) LC-CDR2: RNN (SEQ ID NO: 127) LC-CDR3: AAWDDSLSAGV; or (SEQ ID NO: 152) LC-CDR1: SGSIASNY (SEQ ID NO: 153) LC-CDR2: DDN (SEQ ID NO: 154) LC-CDR3: QSYDSSNLWV; or (SEQ ID NO: 155) LC-CDR1: QIISSY (SEQ ID NO: 102) LC-CDR2: AAS (SEQ ID NO: 156) LC-CDR3: QQSYSTPTWT; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 119) LC-CDR3: SSYTSSSTWV; or (SEQ ID NO: 152) LC-CDR1: SGSIASNY (SEQ ID NO: 157) LC-CDR2: EDN (SEQ ID NO: 158) LC-CDR3: QSYNSSKVV; or (SEQ ID NO: 159) LC-CDR1: SSDVGGYEY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 160) LC-CDR3: NSYTSSGTLVV; or (SEQ ID NO: 159) LC-CDR1: SSDVGGYEY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 160) LC-CDR3: NSYTSSGTLVV; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 131) LC-CDR3: CSYAGSYTWV; or (SEQ ID NO: 161) LC-CDR1: SLRGYY (SEQ ID NO: 162) LC-CDR2: GNN (SEQ ID NO: 163) LC-CDR3: DSRGRSGDHWL; or (SEQ ID NO: 164) LC-CDR1: SSNIGSYY (SEQ ID NO: 165) LC-CDR2: RND (SEQ ID NO: 166) LC-CDR3: ATWDDGLSGWV; or (SEQ ID NO: 110) LC-CDR1: SSDVGAYNY (SEQ ID NO: 168) LC-CDR2: EVF (SEQ ID NO: 169) LC-CDR3: NSYVTGNNWA; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 119) LC-CDR3: SSYTSSSTWV; or (SEQ ID NO: 170) LC-CDR1: SSNIGYDA (SEQ ID NO: 171) LC-CDR2: NDN (SEQ ID NO: 172) LC-CDR3: AAWDDSLSGWV; or (SEQ ID NO: 173) LC-CDR1: QGSSSY (SEQ ID NO: 102) LC-CDR2: AAS (SEQ ID NO: 174) LC-CDR3: QQSYSTPLYT; or (SEQ ID NO: 175) LC-CDR1: SSDVGGYKY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 176) LC-CDR3: CSYAGNYTWL; or (SEQ ID NO: 173) LC-CDR1: QGSSSY (SEQ ID NO: 102) LC-CDR2: AAS (SEQ ID NO: 174) LC-CDR3: QQSYSTPLYT; or (SEQ ID NO: 107) LC-CDR1: SSDVGGYNY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 177) LC-CDR3: TSYSSSSTLVA; or (SEQ ID NO: 178) LC-CDR1: SSDVGNYKY (SEQ ID NO: 108) LC-CDR2: DVS (SEQ ID NO: 179) LC-CDR3: SSYTSSSTLVV.

[0016] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, having at least one heavy chain variable region incorporating the following CDRs:

TABLE-US-00004 (SEQ ID NO: 180) HC-CDR1: VSSNSAAWN (SEQ ID NO: 181) HC-CDR2: YRSKWYN (SEQ ID NO: 182) HC-CDR3: ARGTRGYFDY; or (SEQ ID NO: 183) HC-CDR1: GFTFSGAY (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 185) HC-CDR3: ARDLYAFDI; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 187) HC-CDR3: AKIGATDPLDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 188) HC-CDR2: ISYDGSDK (SEQ ID NO: 189) HC-CDR3: AKDLSGLPIIDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 191) HC-CDR3: ARRGYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 192) HC-CDR3: ARIAAADGMDV; or (SEQ ID NO: 193) HC-CDR1: GFSFRSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 194) HC-CDR3: ARITHDYGDFSDAFDI; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 195) HC-CDR3: AKLYSGSSNFDY; or (SEQ ID NO: 196) HC-CDR1: GFTFRSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 194) HC-CDR3: ARITHDYGDFSDAFDI; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 198) HC-CDR3: ARGQNVDL; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 199) HC-CDR3: ARIMGYDYGDYDVVDY; or (SEQ ID NO: 212) HC-CDR1: GFSFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 199) HC-CDR3: ARIMGYDYGDYDVVDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 213) HC-CDR3: ARRGYGDY; or (SEQ ID NO: 204) HC-CDR1: WIFLKSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 205) HC-CDR3: ARVGFSSWYPDLYYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 215) HC-CDR3: AKFARGVYLFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 216) HC-CDR3: ARVQSGEPESDY; or (SEQ ID NO: 217) HC-CDR1: GFSLNSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 195) HC-CDR3: AKLYSGSSNFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 205) HC-CDR3: ARVGFSSWYPDLYYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 218) HC-CDR3: ARMVNLYYGDAFDI; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 219) HC-CDR3: ARLVGATADDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 209) HC-CDR1: GGTFSSYA (SEQ ID NO: 210) HC-CDR2: IIPIFGTA (SEQ ID NO: 211) HC-CDR3: ARGLITGTTP; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or

(SEQ ID NO: 220) HC-CDR1: GGSISSSNW (SEQ ID NO: 221) HC-CDR2: IYHSGST (SEQ ID NO: 222) HC-CDR3: ARVQNLGGGSYYVGAFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 223) HC-CDR3: ARLHFSQYFSTIDAFDI; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 199) HC-CDR3: ARIMGYDYGDYDVVDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 200) HC-CDR3: ARDVGYSSGWYFDY; or (SEQ ID NO: 201) HC-CDR1: GFSLSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 202) HC-CDR3: ARLAQSYSSSWYEWEPGREHAFDI; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 203) HC-CDR3: ARPDDDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 204) HC-CDR1: WIFLKSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 205) HC-CDR3: ARVGFSSWYPDLYYFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 206) HC-CDR3: ARLYSGYPSRYYYGMDV; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 207) HC-CDR3: AKGGKSYYGFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 208) HC-CDR3: ARLHSGRNWGDAFDI; or (SEQ ID NO: 209) HC-CDR1: GGTFSSYA (SEQ ID NO: 210) HC-CDR2: IIPIFGTA (SEQ ID NO: 224) HC-CDR3: ARGGGPYYDFWSGYYTEFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 225) HC-CDR3: ARDSGYSSGWYFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 225) HC-CDR3: ARDSGYSSGWYFDY; or (SEQ ID NO: 226) HC-CDR1: ILPSDSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 227) HC-CDR3: ARIAAAGRDAFDI; or (SEQ ID NO: 228) HC-CDR1: GYTFTSYG (SEQ ID NO: 229) HC-CDR2: ISAYNGNT (SEQ ID NO: 230) HC-CDR3: ARVVAAARSYYYYMDV; or (SEQ ID NO: 209) HC-CDR1: GGTFSSYA (SEQ ID NO: 210) HC-CDR2: IIPIFGTA (SEQ ID NO: 231) HC-CDR3: ARADSSAGGGPYYYGMDV; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 215) HC-CDR3: AKFARGVYLFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 232) HC-CDR3: ARIGGYDDFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 233) HC-CDR3: ARVYYDSSGTQGDSFDY; or (SEQ ID NO: 234) HC-CDR1: GFTFGSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 235) HC-CDR3: AKGSYYFDY; or (SEQ ID NO: 186) HC-CDR1: GFTFSSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 197) HC-CDR3: AKLSGPNGVDY; or (SEQ ID NO: 238) HC-CDR1: GFSLGSYG (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 235) HC-CDR3: AKGSYYFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 236) HC-CDR3: ARGVLFDY; or (SEQ ID NO: 190) HC-CDR1: GFTFSSYA (SEQ ID NO: 184) HC-CDR2: ISYDGSNK (SEQ ID NO: 237) HC-CDR3: ARSGVLDY;

and

[0017] having at least one light chain variable region arrived at following light chain shuffling.

[0018] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain and a heavy chain variable region sequence, wherein:

[0019] the light chain comprises a LC-CDR1, LC-CDR2, LC-CDR3, having at least 85% overall sequence identity to LC-CDR1: one of X.sub.1X.sub.2DX.sub.3GX.sub.4YX.sub.5Y (SEQ ID NO:239), X.sub.6SNX.sub.7GX.sub.8X.sub.9X.sub.10 (SEQ ID NO:240), QX.sub.11X.sub.12SSX.sub.13 (SEQ ID NO:241), X.sub.14GX.sub.151 ASNX.sub.16 (SEQ ID NO:242), QDVGRY (SEQ ID NO:101), or SLRGYY (SEQ ID NO:161); LC-CDR2: one of DVX.sub.17 (SEQ ID NO:243), X.sub.18NX.sub.19 (SEQ ID NO:244), X.sub.20AS (SEQ ID NO:245), X.sub.21DX.sub.22 (SEQ ID NO:246), EVX.sub.23 (SEQ ID NO:247), or DX.sub.24X.sub.25 (SEQ ID NO:248); LC-CDR3: one of X.sub.26SYTX.sub.27X.sub.28X.sub.20X.sub.30X.sub.31VX.sub.32 (SEQ ID NO:249), X.sub.335 YAX.sub.34X.sub.38X.sub.36X.sub.37X.sub.38X.sub.39X.sub.40X.sub.41X.sub.4- 2X.sub.43X.sub.44X.sub.48X.sub.46X.sub.47X.sub.48X.sub.49 (SEQ ID NO:250), X.sub.50X.sub.51NDX.sub.52X.sub.53LX.sub.54X.sub.55X.sub.56V (SEQ ID NO:251), QQX.sub.57X.sub.58X.sub.59PX.sub.60X.sub.61X.sub.62X.sub.63X.sub- .64X.sub.65X.sub.66X.sub.67X.sub.68X.sub.69X.sub.70X.sub.71X.sub.72 (SEQ ID NO:252), QSYX.sub.73X.sub.74SX.sub.75X.sub.76X.sub.77X.sub.78 (SEQ ID NO:253), X.sub.70SYX.sub.80SSX.sub.81X.sub.82X.sub.83VX.sub.84 (SEQ ID NO:254), NSYVTGNNWA (SEQ ID NO:169), or DSRGRSGDHWL (SEQ ID NO:163); and

[0020] the heavy chain comprises a HC-CDR1, HC-CDR2, HC-CDR3, having at least 85% overall sequence identity to HC-CDR1: one of GFTFSSYX.sub.85 (SEQ ID NO:255), GX.sub.88X.sub.87X.sub.88X.sub.88SYG (SEQ ID NO:256), X.sub.90X.sub.91X.sub.92X.sub.93X.sub.94SYA (SEQ ID NO:257), WIFLKSYA (SEQ ID NO:204), VSSNSAAWN (SEQ ID NO:180), GGSISSSNW (SEQ ID NO:220), or GFTFSGAY (SEQ ID NO:183); HC-CDR2: one of ISYDGSX.sub.95K (SEQ ID NO:258), IIPIFGTA (SEQ ID NO:210), YRSKWYN (SEQ ID NO:181), ISAYNGNT (SEQ ID NO:229), or IYHSGST (SEQ ID NO:221); HC-CDR3: one of AKLSGPNGVDY (SEQ ID NO:197), AKX.sub.96X.sub.97X.sub.98GX.sub.99X.sub.100X.sub.101X.sub.102DY (SEQ ID NO:259), ARDX.sub.103GYSSGWYFDY (SEQ ID NO:260), ARI-X.sub.104X.sub.105X.sub.106X.sub.107X.sub.108X.sub.109X.sub.110X.sub.- 111X.sub.112X.sub.113X.sub.114X.sub.115X.sub.116X.sub.117X.sub.118X.sub.11- 9X.sub.120ARDI (SEQ ID NO:261), ARIMGYDYGDYDVVDY (SEQ ID NO:199), ARIX.sub.121X.sub.122X.sub.123X.sub.124X.sub.125X.sub.126DX.sub.127X.sub.- 128X.sub.129X.sub.130 (SEQ ID NO:262), ARVGFSSWYPDLYYFDY (SEQ ID NO:205), X.sub.131X.sub.132X.sub.133X.sub.134RGYX.sub.135DY (SEQ ID NO:263), ARITHDYGDFSDAFDI (SEQ ID NO:194), ARX.sub.136GVLX.sub.137DY (SEQ ID NO:264), AKGSYYFDY (SEQ ID NO:235), ARLYSGYPSRYYYGMDV (SEQ ID NO:206), ARVQSGEPESDY (SEQ ID NO:216), AKIGATDPLDY (SEQ ID NO:187), ARDLYAFDI (SEQ ID NO:185), ARPDDDY (SEQ ID NO:203), AKGGKSYYGFDY (SEQ ID NO:207), ARADSSAGGGPYYYGMDV (SEQ ID NO:231), ARVYYDSSGTQGDSFDY (SEQ ID NO:233), ARVVAAARSYYYYMDV (SEQ ID NO:230), ARGGGPYYDFWSGYYTEFDY (SEQ ID NO:224), ARMVNLYYGDAFDI (SEQ ID NO:218), ARGLITGTTP (SEQ ID NO:211), ARGQNVDL (SEQ ID NO:198), ARVQNLGGGSYYVGAFDY (SEQ ID NO:222), or ARLVGATADDY (SEQ ID NO:219); wherein X.sub.1=S or I, X.sub.2=S or R, X.sub.3=V or I, X.sub.4=G, A or N, X.sub.5=N, E, K or D, X.sub.6=S or Y, X.sub.7=I or V, X.sub.8=S, N or Y, X.sub.9=N, Y or D, X.sub.10=L, T or A, X.sub.11=G, S or I, X.sub.12=S, I or V, X.sub.13=Y or N, X.sub.14=S or T, X.sub.15=S or N, X.sub.16=Y or R, X.sub.17=S, T or G, X.sub.18=R, I or G, X.sub.19=N or D, X.sub.20=A or G, X.sub.21=E, D or N, X.sub.22=N or D, X.sub.23=S, F or N, X.sub.24=N or V, X.sub.25=H or T, X.sub.26=S, N or G, X.sub.27=S or T, X.sub.28=S or G, X.sub.29=S, N, G or I, X.sub.30=T or S, X.sub.31=W, L, V or Q, X.sub.32=absent or V, X.sub.33=C or S, X.sub.34=G or D, X.sub.35=S, Y, N or T, X.sub.36=Y or N, X.sub.37=T or N, X.sub.38=W or F, X.sub.39=V, G or L, X.sub.40=absent or V, X.sub.41=absent or R, X.sub.42=absent or R, X.sub.43 absent or R, X.sub.44=absent or D, X.sub.45=absent or R, X.sub.46=absent or A, X.sub.47=absent or D, X.sub.48=absent or R, X.sub.49=absent or P, X.sub.50=A or G, X.sub.51=A or T, X.sub.52=D, G or S, X.sub.53=S or G, X.sub.54=S, K or N, X.sub.55=G or A, X.sub.56=W, G or H, X.sub.57=S or Y, X.sub.58=Y, R or N, X.sub.59=S or N, X.sub.60=T, A or W, X.sub.61=L or T, X.sub.62=Y, A, W or T, X.sub.63T, absent or F, X.sub.64=absent or G, X.sub.65=absent or G, X.sub.66=absent or G, X.sub.67=absent or T, X.sub.68=absent or K, X.sub.69=absent or V, X.sub.70=absent or E, X.sub.71=absent or F, X.sub.72=absent or K, X.sub.73=D or N, X.sub.74=S or Y, X.sub.75=K, S or N, X.sub.76=V or L, X.sub.77=I, V or W, X.sub.78=absent or V, X.sub.79=T or N, X.sub.80=T or S, X.sub.81=T or S, X.sub.82=P or T, X.sub.83=Y or L, X.sub.84=absent or A, X.sub.85=A or G, X.sub.86=F or Y, X.sub.87=S or T, X.sub.88=L or F, X.sub.89=G, R, T, S or N, X.sub.90=G or I, X.sub.91=G, F or L, X.sub.92=T, S or P, X.sub.93=F or S, X.sub.94=S or D, X.sub.95=N or D, X.sub.96=L, F or D, X.sub.97=Y, A or L, X.sub.98=S or R, X.sub.99=S, V or L, X.sub.100=S, or P, X.sub.101=N, L or I, X.sub.102=F or I, X.sub.103=S or V, X.sub.104=H or A, X.sub.105=S, Q or F, X.sub.106=S or G, X.sub.107=absent or Y, X.sub.108=absent or S, X.sub.109=absent, R or S, X.sub.110=Q, N or S, X.sub.111=W or Y, X.sub.112=absent, Y or F, X.sub.113=absent or E, X.sub.114=absent or W, X.sub.115=absent or E, X.sub.116=absent or P, X.sub.117=absent, G or S, X.sub.118=absent, R or T, X.sub.119=G, E or I, X.sub.120=D or H, X.sub.121=A or G, X.sub.122=A or G, X.sub.123=A or Y, X.sub.124=D or absent, X.sub.125=G or D, X.sub.126=F, M or R, X.sub.127=V, Y or A, X.sub.128=absent or F, X.sub.129=absent or D, X.sub.130=absent or I, X.sub.131=absent or A, X.sub.132=absent or R, X.sub.133=A or G, X.sub.134=R or T, X.sub.135=F or G, X.sub.136=absent or S, X.sub.137=absent or F.

[0021] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain and a heavy chain variable region sequence, wherein:

[0022] the light chain sequence has at least 85% sequence identity to the light chain sequence of one of SEQ ID NOs:1 to 50, and;

[0023] the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence of one of SEQ ID NOs:51 to 100.

[0024] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, which is capable of inhibiting IL-11 trans signalling, optionally wherein the antibody or antigen binding fragment is an antibody or antigen binding fragment according to the present invention.

[0025] In some embodiments in accordance with the various aspects of the present invention, the antibody or antigen binding fragment is conjugated to a drug moiety or a detectable moiety.

[0026] In another aspect, the present invention provides a complex, optionally an in vitro complex and/or optionally isolated, comprising an antibody or antigen binding fragment according to the present invention bound to IL-11.

[0027] In another aspect, the present invention provides a composition comprising the antibody or antigen binding fragment according to the present invention, and at least one pharmaceutically-acceptable carrier.

[0028] In another aspect, the present invention provides an isolated nucleic acid encoding the antibody or antigen binding fragment according to the present invention.

[0029] In some embodiments, the nucleic acid comprises a sequence having at least 60%, 70%, 80%, 90%, 95%, or greater sequence identity to one of SEQ ID NOs:476 to 539, or an equivalent sequence as a result of codon degeneracy. In some embodiments, the nucleic acid comprises a sequence having at least 60%, 70%, 80%, 90%, 95%, or greater sequence identity to one of SEQ ID NOs:571 to 580, or an equivalent sequence as a result of codon degeneracy.

[0030] In another aspect, the present invention provides a vector comprising the nucleic acid according to the present invention.

[0031] In another aspect, the present invention provides a host cell comprising the vector according to the present invention.

[0032] In another aspect, the present invention provides a method for making an antibody or antigen binding fragment according to the present invention, comprising culturing the host cell according to the present invention under conditions suitable for the expression of the antibody or antigen binding fragment, and recovering the antibody or antigen binding fragment.

[0033] In another aspect, the present invention provides an antibody, antigen binding fragment, or composition according to the present invention for use in therapy, or in a method of medical treatment.

[0034] In another aspect, the present invention provides an antibody, antigen binding fragment, or composition according to the present invention for use in the treatment or prevention of fibrosis, or a disease/disorder characterised by fibrosis.

[0035] In another aspect, the present invention provides an antibody, antigen binding fragment, or composition according to the present invention for use in the treatment of a cancer.

[0036] In another aspect, the present invention provides the use of an antibody, antigen binding fragment, or composition according to the present invention in the manufacture of a medicament for use in the treatment or prevention of fibrosis or a disease/disorder characterised by fibrosis.

[0037] In another aspect, the present invention provides the use of an antibody, antigen binding fragment, or composition according to the present invention in the manufacture of a medicament for use in the treatment or prevention of a cancer.

[0038] In another aspect, the present invention provides a method of treating fibrosis comprising administering an antibody, antigen binding fragment, or composition according to the present invention to a subject suffering from fibrosis or a disease/disorder characterised by fibrosis.

[0039] In another aspect, the present invention provides a method of treating cancer comprising administering an antibody, antigen binding fragment, or composition according to the present invention to a subject suffering from a cancer.

[0040] In another aspect, the present invention provides an antibody or antigen binding fragment for use in a method of treating a disease in which IL-11 mediated signalling is implicated in the pathology of the disease, wherein the antibody or antigen binding fragment is capable of inhibiting IL-11 trans signalling.

[0041] In another aspect, the present invention provides the use of an antibody or antigen binding fragment in the manufacture of a medicament for use in the treatment of a disease in which IL-11 mediated signalling is implicated in the pathology of the disease, wherein the antibody or antigen binding fragment is capable of inhibiting IL-11 trans signalling.

[0042] In another aspect, the present invention provides a method of treating a disease in which IL-11 mediated signalling is implicated in the pathology of the disease, comprising administering an antibody or antigen binding fragment to a subject suffering from the disease, wherein the antibody or antigen binding fragment is capable of inhibiting IL-11 trans signalling.

[0043] In another aspect, the present invention provides a method comprising contacting a sample containing, or suspected to contain, IL-11 with an antibody or antigen binding fragment according to the present invention and detecting the formation of a complex of the antibody or antigen binding fragment with IL-11.

[0044] In another aspect, the present invention provides a method of diagnosing a disease or condition in a subject, the method comprising contacting, in vitro, a sample from the subject with an antibody or antigen binding fragment according to the present invention and detecting the formation of a complex of the antibody or antigen binding fragment with IL-11.

[0045] In another aspect, the present invention provides a method of selecting or stratifying a subject for treatment with an IL-11-targeted agent, the method comprising contacting, in vitro, a sample from the subject with the antibody or antigen binding fragment according to the present invention and detecting the formation of a complex of the antibody or antigen binding fragment with IL-11.

[0046] In another aspect, the present invention provides the use of an antibody or antigen binding fragment according to the present invention for the detection of IL-11 in vitro or in vivo.

[0047] In another aspect, the present invention provides the use of an antibody or antigen binding fragment according to the present invention as an in vitro or in vivo diagnostic or prognostic agent.

[0048] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising the amino acid sequences i) to vi):

TABLE-US-00005 i) LC-CDR1: (SEQ ID NO: 393) X.sub.138X.sub.139DVGGYX.sub.140X.sub.141, (SEQ ID NO: 394) SSDVX.sub.142X.sub.143YX.sub.144Y, (SEQ ID NO: 395) X.sub.145X.sub.146DX.sub.147GAYNY, (SEQ ID NO: 396) SSDIGX.sub.148YNY, (SEQ ID NO: 397) X.sub.149SDVGAYDY, (SEQ ID NO: 398) SGDVGTYX.sub.150Y, (SEQ ID NO: 399) QX.sub.151IX.sub.152SY, (SEQ ID NO: 400) QSX.sub.153SSSY, (SEQ ID NO: 401) RX.sub.154DX.sub.155GGYDX.sub.156, (SEQ ID NO: 284) SSNVGGYNY, (SEQ ID NO: 349) GSNVGGYNY or (SEQ ID NO: 359) QSVNSAY; ii) LC-CDR2: (SEQ ID NO: 402) DVX.sub.157 or (SEQ ID NO: 403) X.sub.158A5; iii) LC-CDR3: (SEQ ID NO: 404) X.sub.159SYAGX.sub.160X.sub.161X.sub.162WX.sub.163, (SEQ ID NO: 405) SSYTX.sub.164X.sub.165X.sub.166X.sub.167WV, (SEQ ID NO: 406) QQSYSX.sub.168PX.sub.169WT, (SEQ ID NO: 407) SSFX.sub.170X.sub.171SX.sub.172X.sub.173WV, (SEQ ID NO: 362) NSYTSGSTWV, (SEQ ID NO: 334) ASYTRSSVWV, (SEQ ID NO: 357) QQSSTSPTWA, or (SEQ ID NO: 282) SSYRSGSTLGVRRRDQADRPR; iv) HC-CDR1: (SEQ ID NO: 409) GFTFX.sub.174SYX.sub.175; v) HC-CDR2: (SEQ ID NO: 410) ISYDGSNX.sub.176 ; vi) HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY, (SEQ ID NO: 199) ARIMGYDYGDYDVVDY, (SEQ ID NO: 197) AKLSGPNGVDY or (SEQ ID NO: 411) AKGX.sub.177X.sub.178SYYX.sub.179FDY;



[0049] or a variant thereof in which one or two or three amino acids in one or more of the sequences i) to vi) are replaced with another amino acid; wherein X.sub.138=S, N or I, X.sub.139=S or R, X.sub.140=N, E or D, X.sub.141=Y or F, X.sub.142=G or A, X.sub.143=D, G or T, X.sub.144=N or D, X.sub.145=S or N, X.sub.146=N, T or S, X.sub.147=V or I, X.sub.148=V or G, X.sub.149=S or G, X.sub.150=N or D, X.sub.151=A or I, X.sub.162=N or S, X.sub.153=F or V, X.sub.154=S or R, X.sub.155=I or V, X.sub.156=Y or F, X.sub.157=S, T, N, G, V or D, X.sub.168=A or G, X.sub.159=C, S, A or N, X.sub.160=S, R, N, G, T or F, X.sub.161=Y or H, X.sub.162=T, N, I, S or V, X.sub.163=V, M or I, X.sub.164=S or N, X.sub.165=S or N, X.sub.166=T, I, S or R, X.sub.167=T or S, X.sub.165=T or D, X.sub.163=S, R or T, X.sub.170=T or A, X.sub.171=T or S, X.sub.172=I or T, X.sub.173=A or T, X.sub.174=S or G, X.sub.175=G or A, X.sub.176=K or R, X.sub.177=absent or G, X.sub.178=absent or K, and X.sub.179=absent or G.

[0050] In some embodiments HC-CDR1 is one of GFTFSSYG (SEQ ID NO:186), GFTFSSYA (SEQ ID NO:190) or GFTFGSYG (SEQ ID NO:234).

[0051] In some embodiments HC-CDR2 is one of ISYDGSNK (SEQ ID NO:184) or ISYDGSNR (SEQ ID NO:381).

[0052] In some embodiments HC-CDR3 is one of AKIGATDPLDY (SEQ ID NO:187), ARIMGYDYGDYDVVDY (SEQ ID NO:199), AKGGKSYYGFDY (SEQ ID NO:207), AKGSYYFDY (SEQ ID NO:235) or AKLSGPNGVDY (SEQ ID NO:197).

[0053] In some embodiments LC-CDR1 is one of SSDVGGYNF (SEQ ID NO:294), SSDVGGYEY (SEQ ID NO:159), SRDVGGYNY (SEQ ID NO:150), NSDVGGYNY (SEQ ID NO:300), SSDVGGYDY (SEQ ID NO:128), SSDVGGYNY (SEQ ID NO:107), ISDVGGYNY (SEQ ID NO:122), SSDVGDYDY (SEQ ID NO:317), SSDVAGYNY (SEQ ID NO:330), SSDVGTYNY (SEQ ID NO:344), NTDVGAYNY (SEQ ID NO:272), SNDIGAYNY (SEQ ID NO:306), SSDVGAYNY (SEQ ID NO:110), SSDIGVYNY (SEQ ID NO:347), SSDIGGYNY (SEQ ID NO:326), SSDVGAYDY (SEQ ID NO:333), GSDVGAYDY (SEQ ID NO:322), SGDVGTYNY (SEQ ID NO:298), SGDVGTYDY (SEQ ID NO:302), QAINSY (SEQ ID NO:352), QIISSY (SEQ ID NO:155), QSFSSSY (SEQ ID NO:356), QSVSSSY (SEQ ID NO:367), RSDIGGYDY (SEQ ID NO:290), RRDVGGYDF (SEQ ID NO:339), SSNVGGYNY (SEQ ID NO:284), GSNVGGYNY (SEQ ID NO:349) or QSVNSAY (SEQ ID NO:359).

[0054] In some embodiments LC-CDR2 is one of DVS (SEQ ID NO:108), DVV (SEQ ID NO:275), DVT (SEQ ID NO:123), DVD (SEQ ID NO:295), DVN (SEQ ID NO:291), DVG (SEQ ID NO:133), AAS (SEQ ID NO:102) or GAS (SEQ ID NO:138).

[0055] In some embodiments LC-CDR3 is one of CSYAGSYTWV (SEQ ID NO:131), SSYAGSYTWV (SEQ ID NO:124), CSYAGSYSWV (SEQ ID NO:273), CSYAGGYTWV (SEQ ID NO:276), NSYAGSYTWV (SEQ ID NO:278), CSYAGSYVWV (SEQ ID NO:285), CSYAGRYTWI (SEQ ID NO:296), CSYAGRYTWM (SEQ ID NO:336), CSYAGTYTWV (SEQ ID NO:340), CSYAGFYTWV (SEQ ID NO:345), CSYAGSHIWV (SEQ ID NO:308), CSYAGRYTWV (SEQ ID NO:313), CSYAGNYTWM (SEQ ID NO:315), CSYAGSYTWI (SEQ ID NO:324), ASYAGNYNWV (SEQ ID NO:304), SSYAGGYTWV (SEQ ID NO:364), SSYTNSRTWV (SEQ ID NO:292), SSYTSNTTWV (SEQ ID NO:311), SSYTSNTTWV (SEQ ID NO:320), SSYTSSSSWV (SEQ ID NO:109), SSYTSSISWV (SEQ ID NO:288), SSYTSSITWV (SEQ ID NO:130), QQSYSTPSWT (SEQ ID NO:354), QQSYSDPRWT (SEQ ID NO:360), QQSYSTPTWT (SEQ ID NO:156), SSFTTSIAWV (SEQ ID NO:268), SSFTSSTTWV (SEQ ID NO:281), SSFATSISWV (SEQ ID NO: 408), NSYTSGSTWV (SEQ ID NO:362), ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357) or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO:282).

[0056] In some embodiments the antibody or antigen binding fragment has at least one heavy chain variable region incorporating the following CDRs:

TABLE-US-00006 HC-CDR1: (SEQ ID NO: 186) GFTFSSYG HC-CDR2: (SEQ ID NO: 184) ISYDGSNK HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY; or HC-CDR1: (SEQ ID NO: 190) GFTFSSYA HC-CDR2: (SEQ ID NO: 184) ISYDGSNK HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY; or HC-CDR1: (SEQ ID NO: 234) GFTFGSYG HC-CDR2: (SEQ ID NO: 184) ISYDGSNK HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY; or HC-CDR1: (SEQ ID NO: 186) GFTFSSYG HC-CDR2: (SEQ ID NO: 381) ISYDGSNR HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY; or HC-CDR1: (SEQ ID NO: 186) GFTFSSYG HC-CDR2: (SEQ ID NO: 184) ISYDGSNK HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY; or HC-CDR1: (SEQ ID NO: 186) GFTFSSYG HC-CDR2: (SEQ ID NO: 184) ISYDGSNK HC-CDR3: (SEQ ID NO: 207) AKGGKSYYGFDY; or HC-CDR1: (SEQ ID NO: 234) GFTFGSYG HC-CDR2: (SEQ ID NO: 184) ISYDGSNK HC-CDR3: (SEQ ID NO: 235) AKGSYYFDY; or HC-CDR1: (SEQ ID NO: 186) GFTFSSYG HC-CDR2: (SEQ ID NO: 184) ISYDGSNK HC-CDR3: (SEQ ID NO: 197) AKLSGPNGVDY.

[0057] In some embodiments the antibody or antigen binding fragment has at least one light chain variable region incorporating the following CDRs:

TABLE-US-00007 LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 268) SSFTTSIAWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 124) SSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 272) NTDVGAYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 273) CSYAGSYSWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 275) DVV LC-CDR3: (SEQ ID NO: 276) CSYAGGYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 278) NSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 150) SRDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 281) SSFTSSTTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 282) SSYRSGSTLGVRRRDQADRPR; or LC-CDR1: (SEQ ID NO: 284) SSNVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 285) CSYAGSYVWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 276) CSYAGGYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 288) SSYTSSISWV; or LC-CDR1: (SEQ ID NO: 290) RSDIGGYDY LC-CDR2: (SEQ ID NO: 291) DVN LC-CDR3: (SEQ ID NO: 130) SSYTSSITWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 292) SSYTNSRTWV; or LC-CDR1: (SEQ ID NO: 294) SSDVGGYNF LC-CDR2: (SEQ ID NO: 295) DVD LC-CDR3: (SEQ ID NO: 296) CSYAGRYTWI; or LC-CDR1: (SEQ ID NO: 298) SGDVGTYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 278) NSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 300) NSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 302) SGDVGTYDY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 278) NSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 284) SSNVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 304) ASYAGNYNWV; or LC-CDR1: (SEQ ID NO: 306) SNDIGAYNY

LC-CDR2: (SEQ ID NO: 291) DVN LC-CDR3: (SEQ ID NO: 273) CSYAGSYSWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 308) CSYAGSHIWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 273) CSYAGSYSWV; or LC-CDR1: (SEQ ID NO: 128) SSDVGGYDY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 311) SSYTSNTTWV; or LC-CDR1: (SEQ ID NO: 128) SSDVGGYDY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 313) CSYAGRYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 315) CSYAGNYTWM; or LC-CDR1: (SEQ ID NO: 317) SSDVGDYDY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 320) SSYTSSTTWV; or LC-CDR1: (SEQ ID NO: 322) GSDVGAYDY LC-CDR2: (SEQ ID NO: 291) DVN LC-CDR3: (SEQ ID NO: 408) SSFATSISWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 324) CSYAGSYTWI; or LC-CDR1: (SEQ ID NO: 326) SSDIGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 294) SSDVGGYNF LC-CDR2: (SEQ ID NO: 291) DVN LC-CDR3: (SEQ ID NO: 276) CSYAGGYTWV; or LC-CDR1: (SEQ ID NO: 159) SSDVGGYEY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 330) SSDVAGYNY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY LC-CDR2: (SEQ ID NO: 291) DVN LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 333) SSDVGAYDY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 334) ASYTRSSVWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 291) DVN LC-CDR3: (SEQ ID NO: 336) CSYAGRYTWM; or LC-CDR1: (SEQ ID NO: 122) ISDVGGYNY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 124) SSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 339) RRDVGGYDF LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 340) CSYAGTYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 133) DVG

LC-CDR3: (SEQ ID NO: 276) CSYAGGYTWV; or LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 344) SSDVGTYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 345) CSYAGFYTWV; or LC-CDR1: (SEQ ID NO: 347) SSDIGVYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 349) GSNVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 340) CSYAGTYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 124) SSYAGSYTWV; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 108) DVS LC-CDR3: (SEQ ID NO: 109) SSYTSSSSWV; or LC-CDR1: (SEQ ID NO: 352) QAINSY LC-CDR2: (SEQ ID NO: 102) AAS LC-CDR3: (SEQ ID NO: 354) QQSYSTPSWT; or LC-CDR1: (SEQ ID NO: 356) QSFSSSY LC-CDR2: (SEQ ID NO: 138) GAS LC-CDR3: (SEQ ID NO: 357) QQSSTSPTWA; or LC-CDR1: (SEQ ID NO: 359) QSVNSAY LC-CDR2: (SEQ ID NO: 138) GAS LC-CDR3: (SEQ ID NO: 360) QQSYSDPRWT; or LC-CDR1: (SEQ ID NO: 155) QIISSY LC-CDR2: (SEQ ID NO: 102) AAS LC-CDR3: (SEQ ID NO: 156) QQSYSTPTWT; or LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY LC-CDR2: (SEQ ID NO: 291 DVN LC-CDR3: (SEQ ID NO: 362) NSYTSGSTWV; or LC-CDR1: (SEQ ID NO: 122) ISDVGGYNY LC-CDR2: (SEQ ID NO: 123) DVT LC-CDR3: (SEQ ID NO: 364) SSYAGGYTWV; or LC-CDR1: (SEQ ID NO: 155) QIISSY LC-CDR2: (SEQ ID NO: 102) AAS; or LC-CDR1: (SEQ ID NO: 367) QSVSSSY LC-CDR2: (SEQ ID NO: 138) GAS LC-CDR3: (SEQ ID NO: 156) QQSYSTPTWT.

[0058] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain and a heavy chain variable region sequence, wherein:

[0059] the light chain comprises a LC-CDR1, LC-CDR2, LC-CDR3, having at least 85% overall sequence identity to LC-CDR1: one of X.sub.138X.sub.139DVGGYX.sub.140X.sub.141 (SEQ ID NO:393), SSDVX.sub.142X.sub.143YX.sub.144Y (SEQ ID NO:394), X.sub.145X.sub.146DX.sub.147GAYNY (SEQ ID NO:395), SSDIGX.sub.148YNY (SEQ ID NO:396), X.sub.149SDVGAYDY (SEQ ID NO:397), SGDVGTYX.sub.150Y (SEQ ID NO:398), QX.sub.1511 X.sub.152SY (SEQ ID NO:399), QSX.sub.153SSSY (SEQ ID NO:400), RX.sub.154DX.sub.155GGYDX.sub.156 (SEQ ID NO:401), SSNVGGYNY (SEQ ID NO:284), GSNVGGYNY (SEQ ID NO:214) or QSVNSAY (SEQ ID NO:359); LC-CDR2: one of DVX.sub.157 (SEQ ID NO:402) or X.sub.158AS (SEQ ID NO:403); LC-CDR3: one of X.sub.159SYAGX.sub.160X.sub.161X.sub.162WX.sub.163 (SEQ ID NO:404), SSYTX.sub.164X.sub.165X.sub.166X.sub.167WV (SEQ ID NO:405), QQSYSX.sub.168PX.sub.169WT (SEQ ID NO:406), SSFX.sub.170X.sub.171SX.sub.172X.sub.173WV (SEQ ID NO:407), NSYTSGSTWV (SEQ ID NO:362), ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357), or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO:282); and

[0060] the heavy chain comprises a HC-CDR1, HC-CDR2, HC-CDR3, having at least 85% overall sequence identity to HC-CDR1: GFTFX.sub.174SYX.sub.175 (SEQ ID NO:409); HC-CDR2: ISYDGSNX.sub.176 (SEQ ID NO:410); HC-CDR3: AKIGATDPLDY (SEQ ID NO:187), ARIMGYDYGDYDVVDY (SEQ ID NO:199), AKLSGPNGVDY (SEQ ID NO:197) or AKGX.sub.177X.sub.178SYYX.sub.179FDY (SEQ ID NO:411); wherein X.sub.138=S, N or I, X.sub.139=S or R, X.sub.140=N, E or D, X.sub.141=Y or F, X.sub.142=G or A, X.sub.143=D, G or T, X.sub.144=N or D, X.sub.145=S or N, X.sub.146=N, T or S, X.sub.147=V or I, X.sub.148=V or G, X.sub.149=S or G, X.sub.150=N or D, X.sub.151=A or I, X.sub.152=Nor S, X.sub.153=F or V, X.sub.154=S or R, X.sub.155=I or V, X.sub.156=Y or F, X.sub.157=S, T, N, G, V or D, X.sub.158=A or G, X.sub.159=C, S, A or N, X.sub.160=S, R, N, G, T or F, X.sub.161=Y or H, X.sub.162=T, N, I, S or V, X.sub.163=V, M or I, X.sub.164=S or N, X.sub.165=S or N, X.sub.166=T, I, S or R, X.sub.167=T or S, X.sub.165=T or D, X.sub.163=S, R or T, X.sub.170=T or A, X.sub.171=T or S, X.sub.172=I or T, X.sub.173=A or T, X.sub.174=S or G, X.sub.175=G or A, X.sub.176=K or R, X.sub.177=absent or G, X.sub.178=absent or K, and X.sub.179=absent or G.

[0061] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain and a heavy chain variable region sequence, wherein:

[0062] the light chain sequence has at least 85% sequence identity to the light chain sequence of one of SEQ ID NOs: 267, 269, 270, 271, 274, 277, 279, 280, 540, 283, 286, 287, 289, 353, 293, 297, 299, 301, 303, 305, 307, 309, 310, 312, 314, 316, 318, 319, 321, 323, 325, 327, 328, 329, 331, 332, 335, 337, 338, 341, 342, 343, 346, 348, 214, 350, 13, 3, 351, 355, 358, 35, 361, 363, 365, 366, or 20; and the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence of one of

[0063] SEQ ID NOs: 53, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 85, 390, 73, 391, or 392.

[0064] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising an amino acid sequence having at least 85% sequence identity to the sequence of one of SEQ ID NOs: 412 to 475.

[0065] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising the amino acid sequences i) to vi):

TABLE-US-00008 i) LC-CDR1: (SEQ ID NO: 555) ENVVTY, (SEQ ID NO: 558) QSIGTS, (SEQ ID NO: 562) QSLLYNSSQKNY or (SEQ ID NO: 565) QDVGTA; ii) LC-CDR2: (SEQ ID NO: 569) X.sub.184AS; iii) LC-CDR3: (SEQ ID NO: 570) X.sub.185QX.sub.186X.sub.187SX.sub.188X.sub.189X.sub.190T; iv) HC-CDR1: (SEQ ID NO: 567) GYTFTX.sub.180YX.sub.181; v) HC-CDR2: (SEQ ID NO: 568) INPX.sub.182NGGX.sub.183 or (SEQ ID NO: 552) IYPRSSNT; vi) HC-CDR3: (SEQ ID NO: 544) ARGELGHWYFDV, (SEQ ID NO: 547) AREGPYGYTWFAY, (SEQ ID NO: 550) ARNPSLYDGYLDC or (SEQ ID NO: 553) ARANWVGYFDV;



[0066] or a variant thereof in which one or two or three amino acids in one or more of the sequences i) to vi) are replaced with another amino acid; wherein X.sub.180=D or S, X.sub.181=N or G, X.sub.182=H, D or N, X.sub.183=P, T or I, X.sub.184=G, Y or W, X.sub.185=Q or G X.sub.186=Y, G or S, X.sub.187=Y, N or S, X.sub.188=Y or W, X.sub.189=P or absent, and X.sub.190=L, Y or R.

[0067] In some embodiments HC-CDR1 is one of GYTFTDYN (SEQ ID NO:542) or GYTFTSYG (SEQ ID NO:228).

[0068] In some embodiments HC-CDR2 is one of INPHNGGP (SEQ ID NO:543), INPDNGGT (SEQ ID NO:546), INPNNGGI (SEQ ID NO:549) or IYPRSSNT (SEQ ID NO:552).

[0069] In some embodiments HC-CDR3 is one of ARGELGHWYFDV (SEQ ID NO:544), AREGPYGYTWFAY (SEQ ID NO:547), ARNPSLYDGYLDC (SEQ ID NO:550) or ARANWVGYFDV (SEQ ID NO:553).

[0070] In some embodiments LC-CDR1 is one of ENVVTY (SEQ ID NO:555), QSIGTS (SEQ ID NO:558), QSLLYNSSQKNY (SEQ ID NO:562) or QDVGTA (SEQ ID NO:565).

[0071] In some embodiments LC-CDR2 is one of GAS (SEQ ID NO:138), YAS (SEQ ID NO:559) or WAS (SEQ ID NO:563).

[0072] In some embodiments LC-CDR3 is one of GQGYSYPYT (SEQ ID NO:556), QQSNSWPLT (SEQ ID NO:560), QQYYSYPLT (SEQ ID NO:563) or QQYSSYRT (SEQ ID NO:566).

[0073] In some embodiments the antibody or antigen binding fragment has at least one heavy chain variable region incorporating the following CDRs:

TABLE-US-00009 HC-CDR1: (SEQ ID NO: 542) GYTFTDYN HC-CDR2: (SEQ ID NO: 543) INPHNGGP HC-CDR3: (SEQ ID NO: 544) ARGELGHWYFDV; or HC-CDR1: (SEQ ID NO: 542) GYTFTDYN HC-CDR2: (SEQ ID NO: 546) INPDNGGT HC-CDR3: (SEQ ID NO: 547) AREGPYGYTWFAY; or HC-CDR1: (SEQ ID NO: 542) GYTFTDYN HC-CDR2: (SEQ ID NO: 549) INPNNGGI HC-CDR3: (SEQ ID NO: 550) ARNPSLYDGYLDC; or HC-CDR1: (SEQ ID NO: 228) GYTFTSYG HC-CDR2: (SEQ ID NO: 552) IYPRSSNT HC-CDR3: (SEQ ID NO: 553) ARANWVGYFDV.

[0074] In some embodiments the antibody or antigen binding fragment has at least one heavy chain variable region incorporating the following CDRs:

TABLE-US-00010 LC-CDR1: (SEQ ID NO: 555) ENVVTY LC-CDR2: (SEQ ID NO: 138) GAS LC-CDR3: (SEQ ID NO: 556) GQGYSYPYT; or LC-CDR1: (SEQ ID NO: 558) QSIGTS LC-CDR2: (SEQ ID NO: 559) YAS LC-CDR3: (SEQ ID NO: 560) QQSNSWPLT; or LC-CDR1: (SEQ ID NO: 562) QSLLYNSSQKNY LC-CDR2: (SEQ ID NO: 563) WAS LC-CDR3: (SEQ ID NO: 581) QQYYSYPLT; or LC-CDR1: (SEQ ID NO: 565) QDVGTA LC-CDR2: (SEQ ID NO: 563) WAS LC-CDR3: (SEQ ID NO: 566) QQYSSYRT.

[0075] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain and a heavy chain variable region sequence, wherein:

[0076] the light chain comprises a LC-CDR1, LC-CDR2, LC-CDR3, having at least 85% overall sequence identity to LC-CDR1: one of ENVVTY (SEQ ID NO:555), QSIGTS (SEQ ID NO:558), QSLLYNSSQKNY (SEQ ID NO:562) or QDVGTA (SEQ ID NO:565); LC-CDR2: X.sub.184AS (SEQ ID NO:569); LC-CDR3: X.sub.185QX.sub.186X.sub.187SX.sub.188X.sub.189X.sub.190T (SEQ ID NO:570); and

[0077] the heavy chain comprises a HC-CDR1, HC-CDR2, HC-CDR3, having at least 85% overall sequence identity to HC-CDR1: GYTFTX.sub.180YX.sub.181 (SEQ ID NO:567); HC-CDR2: one of INPX.sub.182NGGX.sub.183 (SEQ ID NO:568) or IYPRSSNT (SEQ ID NO:552); HC-CDR3: one of ARGELGHWYFDV (SEQ ID NO:544), AREGPYGYTWFAY (SEQ ID NO:547), ARNPSLYDGYLDC (SEQ ID NO:550) or ARANWVGYFDV (SEQ ID NO:553); wherein X.sub.180=D or S, X.sub.181=N or G, X.sub.182=H, D or N, X.sub.183=P, T or I, X.sub.184=G, Y or W, X.sub.185=Q or G X.sub.186=Y, G or S, X.sub.187=Y, N or S, X.sub.188=Y or W, X.sub.189=P or absent, and X.sub.190=L, Y or R.

[0078] In another aspect, the present invention provides an antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain and a heavy chain variable region sequence, wherein:

[0079] the light chain sequence has at least 85% sequence identity to the light chain sequence of one of SEQ ID NOs:554, 557, 561 or 564; and

[0080] the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence of one of SEQ ID NOs:541, 545, 548 or 551.

DESCRIPTION

[0081] The present invention relates to antibodies with specificity for interleukin-11 (IL-11). The present disclosure describes the identification of IL-11/IL-11R signalling as a key mediator of fibrosis, and the generation and functional characterisation of anti-IL-11 antibodies. Therapeutic and diagnostic uses of the antibodies is also described.

[0082] IL-11 and IL-11 Mediated Signalling

[0083] The antibodies and fragments of the present invention bind to interleukin 11. Interleukin 11 (IL-11), also known as adipogenesis inhibitory factor, is a pleiotropic cytokine and a member of the IL-6 family of cytokines that includes IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF) and neuropoetin (NP-1).

[0084] IL-11 is transcribed with a canonical signal peptide that ensures efficient secretion from cells. The immature form of human IL-11 is a 199 amino acid polypeptide whereas the mature form of IL-11 encodes a protein of 178 amino acid residues (Garbers and Scheller., Biol. Chem. 2013; 394(9):1145-1161). The human IL-11 amino acid sequence is available under UniProt accession no. P20809 (P20809.1 GI:124294). Recombinant human IL-11 (oprelvekin) is also commercially available. IL-11 from other species, including mouse, rat, pig, cow, several species of bony fish and primates, have also been cloned and sequenced.

[0085] In this specification "IL-11" refers to an IL-11 from any species and includes isoforms, fragments, variants or homologues of an IL-11 from any species.

[0086] In some embodiments, the IL-11 is mammalian IL-11 (e.g. cynomolgous, human and/or rodent (e.g. rat and/or murine) IL-11). Isoforms, fragments, variants or homologues of an IL-11 may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of immature or mature IL-11 from a given species, e.g. human. Isoforms, fragments, variants or homologues of an IL-11 may optionally be characterised by ability to bind IL-11R.alpha. (preferably from the same species) and stimulate signal transduction in cells expressing IL-11R.alpha. and gp130 (e.g. as described in Curtis et al. Blood, 1997, 90(11); or Karpovich et al. Mol. Hum. Reprod. 2003 9(2): 75-80). A fragment of IL-11 may be of any length (by number of amino acids), although may optionally be at least 25% of the length of mature IL-11 and may have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of mature IL-11. A fragment of IL-11 may have a minimum length of 10 amino acids, and a maximum length of one of 15, 20, 25, 30, 40, 50, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 195 amino acids.

[0087] IL-11 signals through a homodimer of the ubiquitously expressed .beta.-receptor glycoprotein 130 (gp130; also known as glycoprotein 130, IL-6ST, IL-6-beta or CD130). Gp130 is a transmembrane protein that forms one subunit of the type I cytokine receptor with the IL-6 receptor family. Specificity is gained through an individual IL-11 .alpha.-receptor (IL-11R.alpha.), which does not directly participate in signal transduction, although the initial cytokine binding event to the .alpha.-receptor leads to the final complex formation with the 6-receptors. IL-11 activates a downstream signalling pathway, which is predominantly the mitogen-activated protein kinase (MAPK)-cascade and the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway (Garbers and Scheller, supra).

[0088] Human IL-11R.alpha. is a 422 amino acid polypeptide (Genbank accession no. NP 001136256.1 GI:218505839) and shares .about.85% nucleotide and amino acid sequence identity with the murine IL-11R.alpha. (Du and Williams., Blood Vol, 89, No, 11, Jun. 1, 1997). Two isoforms of IL-11R.alpha. have been reported, which differ in the cytoplasmic domain (Du and Williams, supra). In some embodiments as used herein, the IL-11R.alpha. may be IL-11R.alpha. isoform 1 or IL-11R.alpha. isoform 2.

[0089] The IL-11 receptor .alpha.-chain (IL-11R.alpha.) shares many structural and functional similarities with the IL-6 receptor .alpha.-chain (IL-6R.alpha.). The extracellular domain shows 24% amino acid identity including the characteristic conserved Trp-Ser-X-Trp-Ser (WSXWS) motif. The short cytoplasmic domain (34 amino acids) lacks the Box 1 and 2 regions that are required for activation of the JAK/STAT signalling pathway.

[0090] IL-11R.alpha. binds its ligand with a low affinity (Kd.about.10 nmol/L) and alone is insufficient to transduce a biological signal. The generation of a high affinity receptor (Kd.about.400 to 800 pmol/L) capable of signal transduction requires co-expression of the IL-11R.alpha. and gp130 (Curtis et al (Blood 1997 Dec. 1; 90 (11):4403-12; Hilton et al., EMBO J 13:4765, 1994; Nandurkar et al., Oncogene 12:585, 1996). Binding of IL-11 to cell-surface IL-11R.alpha. induces heterodimerization, tyrosine phosphorylation, activation of gp130 and MAPK and/or Jak/STAT signalling as described above.

[0091] The receptor binding sites on murine IL-11 have been mapped and three sites--I, II and III--identified. Binding to gp130 is reduced by substitutions in the site II region and by substitutions in the site III region. Site III mutants show no detectable agonist activity and have IL-11R.alpha. antagonist activity (Cytokine Inhibitors Chapter 8; edited by Gennaro Ciliberto and Rocco Savino, Marcel Dekker, Inc. 2001).

[0092] In principle, a soluble IL-11R.alpha. can also form biologically active soluble complexes with IL-11 (Pflanz et al., 1999 FEBS Lett, 450, 117-122) raising the possibility that, similar to IL-6, IL-11 may in some instances bind soluble IL-11R.alpha. prior to binding cell-surface gp130 (Garbers and Scheller, supra). Curtis et al (Blood 1997 Dec. 1; 90 (11):4403-12) describe expression of a soluble murine IL-11 receptor alpha chain (sIL-11R.alpha.) and examined signalling in cells expressing gp130. In the presence of gp130 but not transmembrane IL-11R the sIL-11R mediated IL-11 dependent differentiation of M1 leukemic cells and proliferation in Ba/F3 cells and early intracellular events including phosphorylation of gp130, STATS and SHP2 similar to signalling through transmembrane IL-11R.

[0093] Activation of signalling through cell-membrane bound gp130 by IL-11 bound to soluble IL-11R.alpha. has recently been demonstrated (Lokau et al., 2016 Cell Reports 14, 1761-1773). This so-called IL-11 trans signalling may be a very important component of IL-11 mediated signalling, and may even be the most common form of IL-11 mediated signalling, because whilst the expression of IL-11R.alpha. is restricted to a relatively small subset of cell types, gp130 is expressed on a wide range of cell types.

[0094] As used herein, `IL-11 trans signalling` is used to refer to signalling which is triggered by binding of IL-11 bound to IL-11R.alpha., to gp130. The IL-11 may be bound to IL-11R.alpha. as a non-covalent complex. The gp130 is membrane-bound and expressed by the cell in which signalling occurs following binding of the IL-11:IL-11Ra complex to gp130. In some embodiments the IL-11R.alpha. may be a soluble IL-11R.alpha.. In some embodiments, the soluble IL-11R.alpha. is a soluble (secreted) isoform of IL-11R.alpha. (e.g. lacking a transmembrane domain). In some embodiments, the soluble IL-11R.alpha. is the liberated product of proteolytic cleavage of the extracellular domain of cell membrane bound IL-11R.alpha.. In some embodiments, the IL-11R.alpha. may be cell membrane-bound, and signalling through gp130 may be triggered by binding of IL-11 bound to cell-membrane-bound IL-11R.alpha..

[0095] In this specification an IL-11 receptor (IL-11R) refers to a polypeptide capable of binding IL-11 and inducing signal transduction in cells expressing gp130. An IL-11 receptor may be from any species and includes isoforms, fragments, variants or homologues of an IL-11 receptor from any species. In preferred embodiments the species is human (Homo sapiens). In some embodiments the IL-11 receptor may be IL-11Ra. Isoforms, fragments, variants or homologues of an IL-11R.alpha. may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of IL-11R.alpha. from a given species, e.g. human. Isoforms, fragments, variants or homologues of an IL-11R.alpha. may optionally be characterised by ability to bind IL-11 (preferably from the same species) and stimulate signal transduction in cells expressing IL-11R.alpha. and gp130 (e.g. as described in Curtis et al. Blood, 1997, 90(11) or Karpovich et al. Mol. Hum. Reprod. 2003 9(2): 75-80). A fragment of an IL-11 receptor may be of any length (by number of amino acids), although may optionally be at least 25% of the length of the mature IL-11R.alpha. and have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the mature IL-11R.alpha.. A fragment of an IL-11 receptor fragment may have a minimum length of 10 amino acids, and a maximum length of one of 15, 20, 25, 30, 40, 50, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 400, or 415 amino acids.

[0096] TGF.beta.1 has been shown to induce IL-11 expression in fibroblasts (Elias et al., 1994 J. Immunol. 152, 2421-2429).

[0097] IL-11 has been proposed to function mainly as a thrombopoietic growth factor, which underpinned the use of recombinant IL-11 (Neumega (Oprelvekin)) as a therapeutic agent to increase platelet count.

[0098] The role of IL-11 in fibrosis is not clear. The majority of studies suggest an anti-fibrotic function for IL-11 in the heart (Obana et al., 2010 Circulation 121, 684-691; Obana et al., 2012 Heart and Circulatory Physiology 303, H569-77) and kidney (Ham et al., 2013 Anesthesiology 119, 1389-1401; Stangou et al., 2011 J. Nephrol. 24, 106-111). Kurahara et al., J. Smooth Muscle Res. 2016; 52: 78-92 describes IL-11 as an anti-fibrotic cytokine, and suggests that IL-11 supresses .alpha.SMA expression.

[0099] IL-11 has also been suggested to be an anti-inflammatory factor in several tissues and chronic inflammatory diseases (Trepicchio and Dorner, 1998 Expert Opin Investig Drugs 7, 1501-1504; Zhu et al., 2015 PLoS ONE 10, e0126296). These studies suggest that the observed secretion of IL-11 in response to TGF.beta.1 is a protective mechanism.

[0100] On the other hand, it has been suggested that IL-11 signalling may be involved in pathology of diseases of the lung. Inhibition of IL-11 either via antibodies or a mutated recombinant IL-11 in a model of tuberculosis revealed a positive feedback loop in vivo and diminished histopathology of the lung (Kapina et al., 2011 PLoS ONE 6, e21878; Shepelkova et al., 2016 Journal of Infectious Diseases 214, jiw176), fibrosis of the murine airway has been associated with IL-11 expression (Tang et al., 1996 The Journal of Clinical Investigation 98, 2845-2853). When the pro-fibrotic function of IL-13 in lung tissue was investigated in IL-11 RA-/- mice, IL-11 signalling was implicated in the mechanism (Chen et al., 2005 J. Immunol. 174, 2305-2313).

[0101] IL-11 was also found to be elevated in the airway of patients with severe asthma (Minshall et al., 2000 Respiratory Research 14, 1-14), is overexpressed in the lungs of IPF patients (Lindahl et al., 2013 Respiratory Research 14, 1-14) and is elevated in skin lesions in atopic dermatitis patients (Toda et al., 2003 J Allergy Clin Immun 111, 875-881). It is uncertain whether these associations are due to increased IL-11 gene/protein expression as a response to disease processes, or whether IL-11 is an effector of disease processes.

[0102] Antibodies and Antigen-Binding Fragments

[0103] Antibodies and antigen-binding fragments according to the present invention bind to IL-11 (interleukin 11). In some embodiments, the antibody/fragment binds to human IL-11. In some embodiments, the antibody/fragment binds to non-human primate IL-11. In some embodiments, the antibody/fragment binds to murine IL-11.

[0104] By "antibody" we include fragments and derivatives thereof, or a synthetic antibody or synthetic antibody fragment. As used herein, an antibody is a polypeptide capable of binding specifically to the relevant target molecule (i.e. the antigen for which the antibody is specific). Antibodies according to the present invention may be provided in isolated form.

[0105] In view of contemporary techniques in relation to monoclonal antibody technology, antibodies can be prepared to most antigens. The antigen-binding portion may be a part of an antibody (for example a Fab fragment) or a synthetic antibody fragment (for example a single chain Fv fragment [ScFv]). Suitable monoclonal antibodies to selected antigens may be prepared by known techniques, for example those disclosed in "Monoclonal Antibodies: A manual of techniques", H Zola (CRC Press, 1988) and in "Monoclonal Hybridoma Antibodies: Techniques and Applications", J G R Hurrell (CRC Press, 1982). Chimeric antibodies are discussed by Neuberger et al (1988, 8th International Biotechnology Symposium Part 2, 792-799).

[0106] Monoclonal antibodies (mAbs) are useful in the methods of the invention and are a homogenous population of antibodies specifically targeting a single epitope on an antigen.

[0107] Antigen binding fragments of antibodies, such as Fab and Fab.sub.2 fragments may also be used/provided as can genetically engineered antibodies and antibody fragments. The variable heavy (V.sub.H) and variable light (V.sub.L) domains of the antibody are involved in antigen recognition, a fact first recognised by early protease digestion experiments. Further confirmation was found by "humanisation" of rodent antibodies. Variable domains of rodent origin may be fused to constant domains of human origin such that the resultant antibody retains the antigenic specificity of the rodent parent antibody (Morrison et al (1984) Proc. Natl. Acad. Sd. USA 81, 6851-6855).

[0108] In some embodiments, the antibody/fragment is a fully human antibody/fragment. A fully human antibody/fragment is encoded by human nucleic acid sequence(s). Fully human antibodies/fragments are devoid of non-human amino acid sequences.

[0109] The two most commonly employed techniques to the production of fully human antibodies are (i) phage display, in which human antibody genes are expressed in phage display libraries, and (ii) production of antibodies in transgenic mice engineered to have human antibody genes (described in Park and Smolen Advances in Protein Chemistry (2001) 56: 369-421). Briefly, in the human antibody gene-phage display technique, genes encoding the VH and VL chains are generated by PCR amplification and cloning from "naive" human lymphocytes, and assembled into a library from which they can be expressed either as disulfide-linked Fab fragments or as single-chain Fv (scFv) fragments. The Fab- or scFv-encoding genes are fused to a surface coat protein of filamentous bacteriophage and Fab or scFv capable of binding to the target of interest can then be identified by screening the library with antigen. Molecular evolution or affinity maturation procedures can be employed to enhance the affinity of the Fab/scFv fragment. In the transgenic mouse technique, mice in which the endogenous murine Ig gene loci have been replaced by homologous recombination with their human homologues are immunized with antigen, and monoclonal antibody is prepared by conventional hybridoma technology, to yield fully human monoclonal antibody.

[0110] In some embodiments, the antibody/fragment according to the present invention is a murine antibody/fragment. The antibody/fragment may be prepared by phage display using a human nave antibody gene library.

[0111] In some embodiments, the antibody/fragment is a mouse/human chimeric antibody/fragment (e.g., an antibody/antigen binding fragment comprising murine variable domains and human constant regions). In some embodiments, the antibody/fragment is a humanised antibody/fragment (e.g., an antibody/antigen binding fragment comprising murine CDRs and human framework and constant regions).

[0112] A mouse/human chimeric antibody/antigen binding fragment can be prepared from a mouse monoclonal antibody by the process of chimerisation, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 8 thereof, in particular section 3 of Chapter 8.

[0113] A humanised antibody/antigen binding fragment can be prepared from a mouse antibody by the process of chimerisation, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 7 thereof, in particular section 3.1 of Chapter 7 entitled `Antibody Humanization`.

[0114] That antigenic specificity is conferred by variable domains and is independent of the constant domains is known from experiments involving the bacterial expression of antibody fragments, all containing one or more variable domains. These molecules include Fab-like molecules (Better et al (1988) Science 240, 1041); Fv molecules (Skerra et al (1988) Science 240, 1038); single-chain Fv (ScFv) molecules where the V.sub.H and V.sub.Lpartner domains are linked via a flexible oligopeptide (Bird et al (1988) Science 242, 423; Huston et al (1988) Proc. Natl. Acad. Sd. USA 85, 5879) and single domain antibodies (dAbs) comprising isolated V domains (Ward et al (1989) Nature 341, 544). A general review of the techniques involved in the synthesis of antibody fragments which retain their specific binding sites is to be found in Winter & Milstein (1991) Nature 349, 293-299.

[0115] By "ScFv molecules" we mean molecules wherein the V.sub.H and V.sub.L partner domains are covalently linked, e.g. by a flexible oligopeptide.

[0116] Fab, Fv, ScFv and dAb antibody fragments can all be expressed in and secreted from E. coli, thus allowing the facile production of large amounts of the said fragments.

[0117] Whole antibodies, and F(ab').sub.2 fragments are "bivalent". By "bivalent" we mean that the said antibodies and F(ab').sub.2 fragments have two antigen combining sites. In contrast, Fab, Fv, ScFv and dAb fragments are monovalent, having only one antigen combining site.

[0118] The present invention provides an antibody or antigen binding fragment which is capable of binding to IL-11. In some embodiments, the antibody or antigen binding fragment may be isolated.

[0119] An antigen-binding fragment according to the present invention may be any fragment of a polypeptide which is capable of binding to an antigen.

[0120] In some embodiments, an antigen binding fragment comprises at least three light chain CDRs (i.e. LC-CDR1, LC-CDR2 and LC-CDR3; also referred to herein as LC-CDRs 1-3) and three heavy chain CDRs (i.e. HC-CDR1, HC-CDR2 and HC-CDR3; also referred to herein as HC-CDRs 1-3) which together define the antigen binding region of an antibody or antigen binding fragment. In some embodiments, an antigen binding fragment may comprise the light chain variable domain and heavy chain variable domain of an antibody or antigen binding fragment. In some embodiments, an antigen binding fragment may comprise the light chain polypeptide and heavy chain polypeptide of an antibody or antigen binding fragment.

[0121] The present invention also provides a chimeric antigen receptor (CAR) capable of binding to IL-11, comprising one or more antigen binding fragments or polypeptides according to the present invention. Chimeric Antigen Receptors (CARs) are recombinant receptors that provide both antigen-binding and T cell activating functions. CAR structure and engineering is reviewed, for example, in Dotti et al., Immunol Rev (2014) 257(1), hereby incorporated by reference in its entirety. Antigen-binding fragments according to the present invention are provided herein as the antigen-binding domain of a chimeric antigen receptor (CAR). In some embodiments, the CAR comprises a VL domain and a VH domain according to any embodiment of an antibody, antigen binding fragment or polypeptide described herein. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors or cytokines to further enhance T cell potency, specificity and safety (Sadelain et al., The basic principles of chimeric antigen receptor (CAR) design. Cancer Discov. 2013 April; 3(4): 388-398. doi:10.1158/2159-8290.CD-12-0548, specifically incorporated herein by reference). Also provided is a cell comprising a CAR according to the invention. The CAR according to the present invention may be used to generate T cells. Engineering of CARs into T cells may be performed during culture, in vitro, for transduction and expansion, such as happens during expansion of T cells for adoptive T cell therapy.

[0122] Also provided in the present invention are bispecific antibodies and bispecific antigen binding fragments comprising an antibody or antigen binding fragment according to the present invention. The bispecific antibodies or bispecific antigen binding fragments may comprise (i) an antibody or antigen binding fragment according to the present invention, and (ii) an antibody or antigen binding fragment specific for a target other than IL-11.

[0123] Bispecific antibodies/fragments may be provided in any suitable format, such as those formats described in Kontermann MAbs 2012, 4(2): 182-197, which is hereby incorporated by reference in its entirety. For example, a bispecific antibody or bispecific antigen binding fragment may be a bispecific antibody conjugate (e.g. an IgG2, F(ab').sub.2 or CovX-Body), a bispecific IgG or IgG-like molecule (e.g. an IgG, scFv.sub.4-Ig, IgG-scFv, scFv-IgG, DVD-Ig, IgG-sVD, sVD-IgG, 2 in 1-IgG, mAb.sup.2, or Tandemab common LC), an asymmetric bispecific IgG or IgG-like molecule (e.g. a kih IgG, kih IgG common LC, CrossMab, kih IgG-scFab, mAb-Fv, charge pair or SEED-body), a small bispecific antibody molecule (e.g. a Diabody (Db), dsDb, DART, scDb, tandAbs, tandem scFv (taFv), tandem dAb/VHH, triple body, triple head, Fab-scFv, or F(ab').sub.2-scFv.sub.2), a bispecific Fc and C.sub.H3 fusion protein (e.g. a taFv-Fc, Di-diabody, scDb-C.sub.H3, scFv-Fc-scFv, HCAb-VHH, scFv-kih-Fc, or scFv-kih-C.sub.H3), or a bispecific fusion protein (e.g. a scFv.sub.2-albumin, scDb-albumin, taFv-toxin, DNL-Fab.sub.3, DNL-Fab.sub.4-IgG, DNL-Fab.sub.4-IgG-cytokine.sub.2). See in particular FIG. 2 of Kontermann MAbs 2012, 4(2): 182-19.

[0124] Methods for producing bispecific antibodies include chemically crosslinking of antibodies or antibody fragments, e.g. with reducible disulphide or non-reducible thioether bonds, for example as described in Segal and Bast, 2001. Production of Bispecific Antibodies. Current Protocols in Immunology. 14:IV:2.13:2.13.1-2.13.16, which is hereby incorporated by reference in its entirety. For example, N-succinimidyl-3-(-2-pyridyldithio)-propionate (SPDP) can be used to chemically crosslink e.g. Fab fragments via hinge region SH-- groups, to create disulfide-linked bispecific F(ab).sub.2 heterodimers. Other methods include fusing antibody-producing hybridomas e.g. with polyethylene glycol, to produce a quadroma cell capable of secreting bispecific antibody, for example as described in D. M. and Bast, B. J. 2001. Production of Bispecific Antibodies. Current Protocols in Immunology. 14:IV:2.13:2.13.1-2.13.16. Bispecific antibodies and bispecific antigen binding fragments can also be produced recombinantly, by expression from e.g. a nucleic acid construct encoding polypeptides for the antigen binding molecules, for example as described in Antibody Engineering: Methods and Protocols, Second Edition (Humana Press, 2012), at Chapter 40: Production of Bispecific Antibodies: Diabodies and Tandem scFv (Hornig and Farber-Schwarz), or French, How to make bispecific antibodies, Methods Mol. Med. 2000; 40:333-339, the entire contents of both of which are hereby incorporated by reference.

[0125] Antibodies may be produced by a process of affinity maturation in which a modified antibody is generated that has an improvement in the affinity of the antibody for antigen, compared to an unmodified parent antibody. Affinity-matured antibodies may be produced by procedures known in the art, e.g., Marks et al., Rio/Technology 10:779-783 (1992); Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):331 0-15 9 (1995); and Hawkins et al, J. Mol. Biol. 226:889-896 (1992).

[0126] The present invention provides antibodies described herein which have further undergone the process of chain shuffling, e.g. light chain shuffling and/or heavy chain shuffling. Chain shuffling to improve antibody affinity is described in detail in Marks, Antibody Affinity Maturation by Chain Shuffling, Antibody Engineering Methods and Protocols, Humana Press (2004) Vol. 248, pp 327-343, which is hereby incorporated by reference in its entirety--in particular, light chain shuffling is described in detail at sections 3.1 and 3.2 thereof. In light chain shuffling, heavy chain variable regions of antibodies are combined with a repertoire of light chain variable region partners to identify new VLNH combinations having high affinity for the target protein of interest. In this way, the antibody/fragment is optimised for very high binding affinity.

[0127] In some aspects, the antibody/fragment of the present invention comprises the CDRs (i.e. CDRs 1-3) of the VH and/or VL domains of an IL-11-binding antibody clone described herein, or a variant thereof. In some embodiments, the antibody/fragment of the present invention comprises HC-CDRs 1-3 of an IL-11-binding antibody clone described herein, or a variant thereof. In some embodiments, the antibody/fragment of the present invention comprises LC-CDRs 1-3 of an IL-11-binding antibody clone described herein, or a variant thereof.

[0128] HC-CDRs 1-3 and LC-CDRs 1-3 of the antibody clones of the present disclosure are defined according to VBASE2, as described in Retter et al., Nucl. Acids Res. (2005) 33 (suppl 1): D671-D674, which is hereby incorporated by reference in its entirety.

[0129] As used herein, a variant of a CDR may comprise e.g. 1 or 2 or 3 substitutions in the amino acid sequence of the CDR. As used herein, a variant of a VL or VH domain may comprise e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substitutions in the amino acid sequence of the domain.

[0130] In some embodiments, the antibody/fragment of the present invention comprises HC-CDRs 1-3 of an IL-11-binding antibody clone described herein, or a variant thereof, and LC-CDRs 1-3 of an IL-11-binding antibody clone described herein, or a variant thereof.

[0131] In some aspects, the antibody/fragment of the present invention comprises the CDRs of the VH and/or VL domains of an IL-11-binding antibody clone described herein, or a variant thereof. In some aspects, the antibody/fragment of the present invention comprises the VH and/or VL domains of an IL-11-binding antibody clone described herein, or a variant thereof.

[0132] In some aspects, the antibody/fragment of the present invention comprises the CDRs of the VH and/or VL domains of a clone, or a variant thereof, selected from YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU45-G1, YU45-B2, YU45-C2/A7/B10, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-E3, YU45-C8/E8, YU45-F8, YU45-G8/H6, YU45-H8, YU45-F9, YU45-H10, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-03/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU45-B4, YU45-H4, YU45-B6, YU45-D6, YU45-E7, YU45-F5, YU45-H7/B5, YU45-B8, YU45-C1, YU46-G1, YU46-A2, YU46-A8, YU46-B2, YU46-B6, YU46-C1, YU46-D7, YU46-E3, YU46-E7, YU46-H8, YU46-G9, YU46-G8, YU46-B7 or YU46-D3; e.g. selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU46-G8.

[0133] In some aspects, the antibody/fragment of the present invention comprises the VH and/or VL domains of a clone, or a variant thereof, selected from YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU45-G1, YU45-B2, YU45-C2/A7/B10, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-E3, YU45-C8/E8, YU45-F8, YU45-G8/H6, YU45-H8, YU45-F9, YU45-H10, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-03/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU45-B4, YU45-H4, YU45-B6, YU45-D6, YU45-E7, YU45-F5, YU45-H7/B5, YU45-B8, YU45-C1, YU46-G1, YU46-A2, YU46-A8, YU46-B2, YU46-B6, YU46-C1, YU46-D7, YU46-E3, YU46-E7, YU46-H8, YU46-G9, YU46-G8, YU46-B7 or YU46-D3; e.g. selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU46-G8.

[0134] In some aspects, the antibody/fragment of the present invention comprises the CDRs of the VH and/or VL domains of a clone, or a variant thereof, selected from BSN-1H2, BSN-1H7, BSN-2E1, BSN-2F5, BSN-2G6, BSN-3C6, BSN-3C11, BSN-5A6, BSN-5B8, BSN-5F6, BSN-6F3, BSN-7D4, BSN-7E4, BSN-7F9, BSN-8C4 or BSN-8H11, e.g. selected from one of BSN-2E1, BSN-2G6, BSN-3C6, BSN-5A6 or BSN-5B8; or selected from one of BSN-2G6, BSN-3C6, BSN-5B8 or BSN-7D4; or BSN-3C6.

[0135] In some aspects, the antibody/fragment of the present invention comprises the VH and/or VL domains of a clone, or a variant thereof, selected from BSN-1H2, BSN-1H7, BSN-2E1, BSN-2F5, BSN-2G6, BSN-3C6, BSN-3C11, BSN-5A6, BSN-5B8, BSN-5F6, BSN-6F3, BSN-7D4, BSN-7E4, BSN-7F9, BSN-8C4 or BSN-8H11, e.g. selected from one of BSN-2E1, BSN-2G6, BSN-3C6, BSN-5A6 or BSN-5B8; or selected from one of BSN-2G6, BSN-3C6, BSN-5B8 or BSN-7D4; or BSN-3C6.

[0136] In some aspects, the antibody/fragment of the present invention comprises HC-CDRs 1-3 of the VH domain of an IL-11-binding antibody clone described herein, or a variant thereof. In some aspects, the antibody/fragment of the present invention comprises the VH domain of a clone, or a variant thereof.

[0137] In some aspects, the antibody/fragment of the present invention comprises LC-CDRs 1-3 of the VL domain of an IL-11-binding antibody clone described herein, or a variant thereof. In some aspects, the antibody/fragment of the present invention comprises the VL domain of a clone, or a variant thereof.

[0138] In some embodiments the antibody/fragment of the present invention comprises HC-CDRs 1-3 of the VH domain, or the VH domain, of an IL-11-binding antibody clone selected from YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU45-G1, YU45-B2, YU45-C2/A7/B10, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-E3, YU45-C8/E8, YU45-F8, YU45-G8/H6, YU45-H8, YU45-F9, YU45-H10, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-03/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU45-B4, YU45-H4, YU45-B6, YU45-D6, YU45-E7, YU45-F5, YU45-H7/B5, YU45-B8, YU45-C1, YU46-G1, YU46-A2, YU46-A8, YU46-B2, YU46-B6, YU46-C1, YU46-D7, YU46-E3, YU46-E7, YU46-H8, YU46-G9, YU46-G8, YU46-B7 or YU46-D3; e.g. selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU46-G8. In some embodiments, the antibody/fragment comprises a VL domain which is arrived at following light chain shuffling.

[0139] In some embodiments the antibody/fragment of the present invention comprises LC-CDRs 1-3 of the VL domain, or the VL domain, of an IL-11-binding antibody clone selected from YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU45-G1, YU45-B2, YU45-C2/A7/B10, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-E3, YU45-C8/E8, YU45-F8, YU45-G8/H6, YU45-H8, YU45-F9, YU45-H10, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-03/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU45-B4, YU45-H4, YU45-B6, YU45-D6, YU45-E7, YU45-F5, YU45-H7/B5, YU45-B8, YU45-C1, YU46-G1, YU46-A2, YU46-A8, YU46-B2, YU46-B6, YU46-C1, YU46-D7, YU46-E3, YU46-E7, YU46-H8, YU46-G9, YU46-G8, YU46-B7 or YU46-D3; e.g. selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU46-G8 or YU46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU46-G8. In some embodiments, the antibody/fragment comprises a VH domain which is arrived at following heavy chain shuffling.

[0140] The amino acid sequences of the VL domains of the human anti-human IL-11-binding antibody clones YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU45-G1, YU45-B2, YU45-C2/A7/B10, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-E3, YU45-C8/E8, YU45-F8, YU45-G8/H6, YU45-H8, YU45-F9, YU45-H10, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-03/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU45-B4, YU45-H4, YU45-B6, YU45-D6, YU45-E7, YU45-F5, YU45-H7/B5, YU45-B8, YU45-C1, YU46-G1, YU46-A2, YU46-A8, YU46-B2, YU46-B6, YU46-C1, YU46-D7, YU46-E3, YU46-E7, YU46-H8, YU46-G9, YU46-G8, YU46-B7 and YU46-D3 are shown in FIG. 15, as are the LC-CDRs 1-3, defined using VBASE2 (described in Retter et al., Nucl. Acids Res. (2005) 33 (suppl 1): D671-D674). The amino acid sequences of the VH domains for these human anti-human IL-11-binding antibody clones are shown in FIG. 16, as are the HC-CDRs 1-3, defined using VBASE2.

[0141] In some aspects, the antibody/fragment of the present invention comprises the CDRs of the VH and/or VL domains of a clone, or a variant thereof, selected from YU100-A10, YU100-A11, YU100-A12, YU100-601, YU100-1303, YU100-1306, YU100-1307, YU100-1308, YU100-1309, YU100=B12, YU100-002, YU100-004, YU100-005, YU100-C10, YU100-C11, YU100-C12, YU100-D01, YU100-D02, YU100-D05, YU100-D07, YU100-D11, YU100-E01, YU100-E04, YU100-E05, YU100-E06, YU100-E07, YU100-E08, YU100-E09, YU100-E10, YU100-E11, YU100-E12, YU100-F01, YU100-F02, YU100-F05, YU100-F06, YU100-F07, YU100-F11, YU100-G01, YU100-G07, YU100-G08, YU100-G09, YU100-G10, YU100-G11, YU100-H01, YU100-H02, YU100-H04, YU100-H05, YU100-H06, YU100-H09, YU100-H11, YU112-A07, YU112-B06, YU112-C03, YU112-C05, YU112-C09, YU112-D08, YU112-E07, YU112-E08, YU112-F05, YU112-G01, YU112-G06, YU112-G09, YU112-H01 or YU112-H02. The amino acid sequences of the VL domains and LC-CDRs 1-3 (defined using VBASE2) for these human anti-human IL-11-binding antibody clones are shown in FIG. 44, and the amino acid sequences of the VH domains and HC-CDRs 1-3 (defined using VBASE2) for these human anti-human IL-11-binding antibody clones are shown in FIG. 45.

[0142] Antibodies according to the present invention may comprise VL and/or VH chains comprising an amino acid sequence that has a high percentage sequence identity to one or more of the VL and/or VH amino acid sequences described herein. For example, antibodies according to the present invention include antibodies that bind IL-11 and have a VL chain that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the VL chain amino acid sequence of one of SEQ ID NOs:1 to 50. Antibodies according to the present invention include antibodies that bind IL-11 and have VH chain that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the VH chain amino acid sequence of one of SEQ ID NOs:51 to 100.

[0143] Antibodies according to the present invention include antibodies that bind IL-11 and have a VL chain that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the VL chain amino acid sequence of one of SEQ ID NOs: 267, 269, 270, 271, 274, 277, 279, 280, 540, 283, 286, 287, 289, 353, 293, 297, 299, 301, 303, 305, 307, 309, 310, 312, 314, 316, 318, 319, 321, 323, 325, 327, 328, 329, 331, 332, 335, 337, 338, 341, 342, 343, 346, 348, 214, 350, 13, 3, 351, 355, 358, 35, 361, 363, 365, 366, or 20. Antibodies according to the present invention include antibodies that bind IL-11 and have VH chain that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the VH chain amino acid sequence of one of SEQ ID NOs: 53, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 85, 390, 73, 391, or 392.

[0144] In some embodiments the antibody/fragment of the present invention comprises HC-CDRs 1-3 of the VH domain, or the VH domain, of an IL-11-binding antibody clone selected from BSN-2E1, BSN-3C6, BSN-5A6_1 BSN-2G6, BSN-5A6_2 or BSN-5B8; e.g. BSN-3C6.

[0145] In some embodiments the antibody/fragment of the present invention comprises LC-CDRs 1-3 of the VL domain, or the VL domain, of an IL-11-binding antibody clone selected from BSN-2E1, BSN-3C6, BSN-5A6_1 BSN-2G6, BSN-5A6_2 or BSN-5B8; e.g. BSN-3C6.

[0146] The amino acid sequences of the VH domains of the anti-human IL-11-binding antibody clones BSN-2E1, BSN-3C6, BSN-5A6_1 BSN-2G6, BSN-5A6_2 and BSN-5B8 are shown in FIG. 68, as are the HC-CDRs 1-3, defined using VBASE2 (described in Retter et al., Nucl. Acids Res. (2005) 33 (suppl 1): D671-D674). The amino acid sequences of the VL domains for these anti-human IL-11-binding antibody clones are shown in FIG. 69, as are the LC-CDRs 1-3, defined using VBASE2.

[0147] In some aspects, the antibody/fragment of the present invention comprises the CDRs of the VH and/or VL domains of a clone, or a variant thereof, selected from BSN-2E1, BSN-3C6, BSN-5A6_1 BSN-2G6, BSN-5A6_2 or BSN-5B8; e.g. BSN-3C6.

[0148] Antibodies according to the present invention include antibodies that bind IL-11 and have a VL chain that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the VL chain amino acid sequence of one of SEQ ID NOs:554, 557, 561 or 564. Antibodies according to the present invention include antibodies that bind IL-11 and have VH chain that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the VH chain amino acid sequence of one of SEQ ID NOs: 541, 545, 548 or 551.

[0149] The light and heavy chain CDRs disclosed herein may also be particularly useful in conjunction with a number of different framework regions. Accordingly, light and/or heavy chains having LC-CDR1-3 or HC-CDR1-3 may possess an alternative framework region. Suitable framework regions are well known in the art and are described for example in M. Lefranc & G. Le:franc (2001) "The Immunoglobulin FactsBook", Academic Press, incorporated herein by reference.

[0150] Antibodies according to the present invention may be detectably labelled or, at least, capable of detection. For example, the antibody may be labelled with a radioactive atom or a coloured molecule or a fluorescent molecule or a molecule which can be readily detected in any other way. Suitable detectable molecules include fluorescent proteins, luciferase, enzyme substrates, radiolabels and binding moieties. Labelling may be by conjugation to the antibody/fragment. The antigen binding molecule may be directly labelled with a detectable label or it may be indirectly labelled. In some embodiments, the label may be selected from: a radio-nucleotide, positron-emitting radionuclide (e.g. for positron emission tomography (PET)), MRI contrast agent or fluorescent label.

[0151] Antibodies and antigen binding fragments according to the present invention may be conjugated to a drug moiety, e.g. a cytotoxic small molecule. Such conjugates are useful for the targeted killing of cells expressing the antigen molecule.

[0152] Also provided by the present invention are isolated heavy chain variable region polypeptides, and isolated light chain variable region polypeptides.

[0153] In some aspects an isolated heavy chain variable region polypeptide is provided, comprising the HC-CDRs 1-3 of any one of the anti-IL-11 antibody clones described herein. In some aspects an isolated heavy chain variable region polypeptide is provided, comprising an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the heavy chain variable region of any one of the anti-IL-11 antibody clones described herein.

[0154] In some aspects an isolated light chain variable region polypeptide is provided, comprising the LC-CDRs 1-3 of any one of the anti-IL-11 antibody clones described herein. In some aspects an isolated light chain variable region polypeptide is provided, comprising an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the light chain variable region of any one of the anti-IL-11 antibody clones described herein.

[0155] Antibodies according to the present invention include antibodies that bind IL-11 and comprise an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of one of SEQ ID NOs: 412 to 475.

[0156] Functional Properties of the Antibodies/Fragments

[0157] The IL-11 antibodies and fragments of the present invention may be characterised by reference to certain functional properties. In particular, an IL-11 antibody or antigen binding fragment according to the present invention may possess one or more of the following properties:

[0158] a) Specific binding to IL-11 (e.g. human IL-11 and/or mouse IL-11);

[0159] b) Binding to IL-11 (e.g. human IL-11) with an affinity of binding of EC50=less than 1000 ng/ml, e.g. as determined by ELISA;

[0160] c) Inhibition of interaction between IL-11 and IL-11R.alpha.;

[0161] d) Inhibition of interaction between IL-11 and gp130;

[0162] e) Inhibition of interaction between IL-11 and IL-11Ra:gp130 receptor complex;

[0163] f) Inhibition of interaction between IL-11:IL-11R.alpha. complex and gp130;

[0164] g) Inhibition of signalling mediated by IL-11;

[0165] h) Inhibition of signalling mediated by binding of IL-11 to IL-11Ra:gp130 receptor complex;

[0166] i) Inhibition of signalling mediated by binding of IL-11:IL-11R.alpha. complex to gp130 (i.e. IL-11 trans signalling);

[0167] j) Inhibition of fibroblast proliferation;

[0168] k) Inhibition of myofibroblast generation from fibroblasts;

[0169] l) Inhibition of a pathological process mediated by IL-11;

[0170] m) Inhibition of fibrosis;

[0171] n) Inhibition of gene or protein expression in fibroblasts of one or more of collagen, fibronectin, periostin, IL-6, IL-11, .alpha.SMA, TIMP1, MMP2, e.g. following stimulation with a profibrotic factor;

[0172] o) Inhibition of extracellular matrix production by fibroblasts

[0173] p) Inhibition of proliferation and/or survival of cells of a cancer;

[0174] q) Inhibition of tumour growth.

[0175] Herein, `inhibition` refers to a reduction, decrease or lessening relative to a control condition. For example, inhibition of a process by an antibody/fragment refers to a reduction, decrease or lessening of the extent/degree of that process in the absence of the antibody/fragment, and/or in the presence of an appropriate control antibody/fragment.

[0176] Inhibition may herein also be referred to as neutralisation or antagonism. That is, an IL-11 binding antibody/fragment which is capable of inhibiting a function or process (e.g. interaction, signalling or other activity mediated by IL-11 or an IL-11-containing complex) may be said to be a `neutralising` or `antagonist` antibody/fragment with respect to the relevant function or process. For example, antibody/fragment which is capable of inhibiting IL-11 mediated signalling may be referred to as an antibody/fragment which is capable of neutralising IL-11 mediated signalling, or may be referred to as an antagonist of IL-11 mediated signalling.

[0177] The skilled person is able to identify an appropriate control condition for a given assay. For example, a control antibody/fragment may be an antibody/fragment directed against a target protein which is known not to have a role involved in the property being investigated in the assay. A control antibody/fragment may be of the same isotype as the ant-IL-11 antibody/fragment being analysed, and may e.g. have the same constant regions.

[0178] An antibody/fragment that specifically binds to a target molecule preferably binds the target with greater affinity, and/or with greater duration than it binds to other, non-target molecules. In some embodiments the present antibodies/fragments may bind with greater affinity to IL-11 than to one or more members of the IL-6 cytokine family. In some embodiments the present antibodies/fragments may bind with greater affinity to IL-11 than to one or more of IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF), and cardiotrophin-like cytokine (CLC).

[0179] In some embodiments, the extent of binding of an antibody to an non-target is less than about 10% of the binding of the antibody to the target as measured, e.g., by ELISA, SPR, Bio-Layer Interferometry (BLI), MicroScale Thermophoresis (MST), or by a radioimmunoassay (RIA). Alternatively, the binding specificity may be reflected in terms of binding affinity, where the anti-IL-11 antibody/fragment of the present invention binds to IL-11 with a K.sub.D that is at least 0.1 order of magnitude (i.e. 0.1.times.10.sup.n, where n is an integer representing the order of magnitude) greater than the K.sub.D towards another, non-target molecule. This may optionally be one of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, or 2.0.

[0180] Binding affinity of an antibody or antigen-binding fragment for its target is often described in terms of its dissociation constant (K.sub.D). Binding affinity can be measured by methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty et al., Methods Mol Biol (2012) 907:411-442; or Rich et al., Anal Biochem. 2008 Feb. 1; 373(1):112-20), Bio-Layer Interferometry (see e.g. Lad et al., (2015) J Biomol Screen 20(4): 498-507; or Concepcion et al., Comb Chem High Throughput Screen. 2009 September; 12(8):791-800), MicroScale Thermophoresis (MST) analysis (see e.g. Jerabek-Willemsen et al., Assay Drug Dev Technol. 2011 August; 9(4): 342-353), or by a radiolabelled antigen binding assay (RIA) performed with the Fab version of the antibody and antigen molecule.

[0181] In some embodiments, the antibody/fragment according to the present invention binds to IL-11 with a K.sub.D of 5 .mu.M or less, preferably one of .ltoreq.1 .mu.M, .ltoreq.500 nM, .ltoreq.100 nM, .ltoreq.75 nM, .ltoreq.50 nM, .ltoreq.40 nM, .ltoreq.30 nM, .ltoreq.20 nM, .ltoreq.15 nM, .ltoreq.12.5 nM, .ltoreq.10 nM, .ltoreq.9 nM, .ltoreq.8 nM, .ltoreq.7 nM, .ltoreq.6 nM, .ltoreq.5 nM, .ltoreq.4 nM, .ltoreq.3 nM, .ltoreq.2 nM, .ltoreq.1 nM, .ltoreq.500 pM.

[0182] In some embodiments, the antibody/fragment according to the present invention binds to IL-11 with an affinity of binding (e.g. as determined by ELISA) of EC50=1000 ng/ml or less, preferably one of .ltoreq.900 ng/ml, .ltoreq.800 ng/ml, .ltoreq.700 ng/ml, .ltoreq.600 ng/ml, .ltoreq.500 ng/ml, ng/ml, .ltoreq.300 ng/ml, .ltoreq.200 ng/ml, .ltoreq.100 ng/ml, .ltoreq.90 ng/ml, E30 ng/ml, .ltoreq.70 ng/ml, .ltoreq.60 ng/ml, .ltoreq.50 ng/ml, ng/ml, .ltoreq.30 ng/ml, .ltoreq.20 ng/ml, .ltoreq.15 ng/ml, .ltoreq.10 ng/ml, .ltoreq.7.5 ng/ml, .ltoreq.5 ng/ml, .ltoreq.2.5 ng/ml, or .ltoreq.1 ng/ml.

[0183] Affinity of binding to IL-11 by an antibody/fragment may be analysed in vitro by ELISA assay. Suitable assays are well known in the art and can be performed by the skilled person, for example, as described in Antibody Engineering, vol. 1 (2.sup.nd Edn), Springer Protocols, Springer (2010), Part V, pp 657-665. For example, the affinity of binding to IL-11 by an antibody/fragment may be analysed according to the methodology described herein in the experimental examples.

[0184] The ability of an antibody/fragment to inhibit interaction between two proteins can be determined for example by analysis of interaction in the presence of, or following incubation of one or both of the interaction partners with, the antibody/fragment. An example of a suitable assay to determine whether a given antibody/fragment is capable of inhibiting interaction between two interaction partners is a competition ELISA assay.

[0185] An antibody/fragment which is capable of inhibiting a given interaction (e.g. between IL-11 and IL-11R.alpha., or between IL-11 and gp130, or between IL-11 and IL-11Ra:gp130, or between IL-11:IL-11R.alpha. and gp130) is identified by the observation of a reduction/decrease in the level of interaction between the interaction partners in the presence of or following incubation of one or both of the interaction partners with the antibody/fragment, as compared to the level of interaction in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). Suitable analysis can be performed in vitro, e.g. using recombinant interaction partners or using cells expressing the interaction partners. Cells expressing interaction partners may do so endogenously, or may do so from nucleic acid introduced into the cell. For the purposes of such assays, one or both of the interaction partners and/or the antibody/fragment may be labelled or used in conjunction with a detectable entity for the purposes of detecting and/or measuring the level of interaction.

[0186] Ability of an antibody/fragment to inhibit interaction between two binding partners can also be determined by analysis of the downstream functional consequences of such interaction, e.g. receptor signalling. For example, downstream functional consequences of interaction between IL-11 and IL-11Ra:gp130 or between IL-11:IL-11R.alpha. and gp130 may include proliferation of fibroblasts, myofibroblast generation from fibroblasts, or gene or protein expression of one or more of collagen, fibronectin, periostin, IL-6, IL-11, .alpha.SMA, TIMP1, MMP2.

[0187] Fibroblasts according to the present disclosure may be derived from any tissue, including liver, lungs, kidney, heart, blood vessels, eye, skin, pancreas, spleen, bowel (e.g. large or small intestine), brain, and bone marrow. In particular embodiments, for the purposes of analysis of the antibody/fragment, the fibroblasts may be cardiac fibroblasts (e.g. atrial fibroblasts), skin fibroblasts, lung fibroblasts, kidney fibroblasts or liver fibroblasts. Fibroblasts may be characterised by gene or protein expression of one or more of COL1A, ACTA2, prolyl-4-hydroxylase, MAS516, and FSP1.

[0188] Gene expression can be measured by various means known to those skilled in the art, for example by measuring levels of mRNA by quantitative real-time PCR (qRT-PCR), or by reporter-based methods. Similarly, protein expression can be measured by various methods well known in the art, e.g. by antibody-based methods, for example by western blot, immunohistochemistry, immunocytochemistry, flow cytometry, ELISA, ELISPOT, or reporter-based methods.

[0189] In some embodiments, the antibody/fragment according to the present invention may inhibit protein expression of one or more markers of fibrosis, e.g. protein expression of one or more of collagen, fibronectin, periostin, IL-6, IL-11, .alpha.SMA, TIMP1, MMP2.

[0190] The ability of an antibody/fragment to inhibit interaction between IL-11 and IL-11R.alpha.:gp130 can, for example, be analysed by stimulating fibroblasts with TGF.beta.1, incubating the cells in the presence of the antibody/fragment and analysing the proportion of cells having .alpha.SMA-positive phenotype after a defined period of time. In such example, inhibition of interaction between IL-11 and IL-11R.alpha.:gp130 can be identified by observation of a lower proportion of cells having an .alpha.SMA-positive phenotype as compared to positive control condition in which cells are treated with TGF.beta.1 in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment), or in the presence of an appropriate control antibody/fragment.

[0191] Such assays are also suitable for analysing the ability of antibody/fragment to inhibit IL-11-mediated signalling.

[0192] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting interaction between IL-11 and IL-11R.alpha. to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of interaction between IL-11 and IL-11R.alpha. in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting interaction between IL-11 and IL-11R.alpha. to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of interaction between IL-11 and IL-11R.alpha. in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0193] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting interaction between IL-11 and gp130 to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of interaction between IL-11 and gp130 in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting interaction between IL-11 and gp130 to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of interaction between IL-11 and gp130 in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0194] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting interaction between IL-11 and IL-11R.alpha.:gp130 to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of interaction between IL-11 and IL-11R.alpha.:gp130 in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting interaction between IL-11 and IL-11R.alpha.:gp130 to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of interaction between IL-11 and IL-11R.alpha.:gp130 in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0195] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting interaction between IL-11:IL-11R.alpha. complex and gp130 to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of interaction between IL-11:IL-11R.alpha. complex and gp130 in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of inhibiting interaction between IL-11:IL-11R.alpha. complex and gp130 to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of interaction between IL-11:IL-11R.alpha. complex and gp130 in the absence of the antibody/fragment.

[0196] Inhibition of IL-11 mediated signalling can also be analysed using .sup.3H-thymidine incorporation and/or Ba/F3 cell proliferation assays such as those described in e.g. Curtis et al. Blood, 1997, 90(11) and Karpovich et al. Mol. Hum. Reprod. 2003 9(2): 75-80. Ba/F3 cells co-express IL-11R.alpha. and gp130.

[0197] As used herein, IL-11 mediated signalling and/or processes mediated by IL-11 includes signalling mediated by fragments of IL-11 and polypeptide complexes comprising IL-11 or fragments thereof. IL-11 mediated signalling may be signalling mediated by human IL-11 and/or mouse IL-11. Signalling mediated by IL-11 may occur following binding of IL-11 or an IL-11 containing complex to a receptor to which IL-11 or said complex binds.

[0198] In some embodiments, antibodies and fragments according to the present invention are capable of inhibiting the biological activity of IL-11 or an IL-11-containing complex. In some embodiments, the antibody/fragment binds to IL-11 or the IL-11-containing complex in a region which is important for binding to a receptor for the IL-11 or IL-11-containing complex, e.g. gp130 or IL-11R.alpha., and thereby disrupts binding to and/or signalling through the receptor.

[0199] In some embodiments, the antibody/fragment according to the present invention is an antagonist of one or more signalling pathways which are activated by signal transduction through receptors comprising IL-11R.alpha. and/or gp130, e.g. IL-11R.alpha.:gp130. In some embodiments, the antibody/fragment is capable of inhibiting signalling through one or more immune receptor complexes comprising IL-11R.alpha. and/or gp130, e.g. IL-11R.alpha.:gp130.

[0200] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting IL-11-mediated signalling to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of signalling in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing IL-11 mediated signalling to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of signalling in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0201] In some embodiments, the IL-11 mediated signalling may be signalling mediated by binding of IL-11 to IL-11R.alpha.:gp130 receptor. Such signalling can be analysed e.g. by treating cells expressing IL-11R.alpha. and gp130 with IL-11, or by stimulating IL-11 production in cells which express IL-11R.alpha. and gp130.

[0202] The IC.sub.50 for antibody/fragment for inhibition of IL-11 mediated signalling may be determined, e.g. by culturing Ba/F3 cells expressing IL-11R.alpha. and gp130 in the presence of human IL-11 and the IL-11 binding agent, and measuring .sup.3H-thymidine incorporation into DNA.

[0203] In some embodiments, the antibody/fragment of the present invention may exhibit an IC.sub.50 of 10 .mu.g/ml or less, preferably one of .ltoreq.5 .mu.g/ml, .ltoreq.4 .mu.g/ml, .ltoreq.3.5 .mu.g/ml, .ltoreq.3 .mu.g/ml, .ltoreq.2 .mu.g/ml, .ltoreq.1 .mu.g/ml, .ltoreq.0.9 .mu.g/ml, .ltoreq.0.8 .mu.g/ml, .ltoreq.0.7 .mu.g/ml, .ltoreq.0.6 .mu.g/ml, or 0.5 .mu.g/ml in such an assay.

[0204] In some embodiments, the IL-11 mediated signalling may be signalling mediated by binding of IL-11:IL-11Ra complex to gp130. In some embodiments, the IL-11:IL-11R.alpha. complex may be soluble, e.g. complex of extracellular domain of IL-11R.alpha. and IL-11, or complex of soluble IL-11R.alpha. isoform/fragment, and IL-11. In some embodiments, the soluble IL-11R.alpha. is a soluble (secreted) isoform of IL-11R.alpha., or is the liberated product of proteolytic cleavage of the extracellular domain of cell membrane bound IL-11R.alpha..

[0205] In some embodiments, the IL-11:IL-11R.alpha. complex may be cell-bound, e.g. complex of cell-membrane bound IL-11R.alpha. and IL-11. Signalling mediated by binding of IL-11:IL-11R.alpha. complex to gp130 can be analysed by treating cells expressing gp130 with IL-11:IL-11R.alpha. complex, e.g. recombinant fusion protein comprising IL-11 joined by a peptide linker to the extracellular domain of IL-11R.alpha. (e.g. hyper IL-11 as described herein).

[0206] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting signalling mediated by binding of IL-11:IL-11R.alpha. complex to gp130, and is also capable of inhibiting signalling mediated by binding of IL-11 to IL-11R.alpha.:gp130 receptor.

[0207] In some embodiments, the antibody/fragment is capable of inhibiting fibroblast proliferation. Proliferation of fibroblasts can be determined by analysing cell division over a period of time. Cell division for a given population of fibroblasts can be analysed, for example, by in vitro analysis of incorporation of .sup.3H-thymidine or by CFSE dilution assay, e.g. as described in Fulcher and Wong, Immunol Cell Biol (1999) 77(6): 559-564, hereby incorporated by reference in entirety. Proliferating cells (e.g. proliferating fibroblasts) may also be identified by analysis of incorporation of 5-ethynyl-2'-deoxyuridine (EdU) by an appropriate assay, as described e.g. in Buck et al., Biotechniques. 2008 June; 44(7):927-9, and Sali and Mitchison, PNAS USA 2008 Feb. 19; 105(7): 2415-2420, both hereby incorporated by reference in their entirety.

[0208] Fibroblasts according to the present disclosure may be derived from any tissue, including liver, lungs, kidney, heart, blood vessels, eye, skin, pancreas, spleen, bowel (e.g. large or small intestine), brain, and bone marrow. In particular embodiments, for the purposes of analysis of the antibody/fragment, the fibroblasts may be cardiac fibroblasts (e.g. atrial fibroblasts), skin fibroblasts, lung fibroblasts, kidney fibroblasts or liver fibroblasts.

[0209] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting fibroblast proliferation to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of fibroblast proliferation in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing fibroblast proliferation to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, times, .ltoreq.0.85 times, times, .ltoreq.0.85 times, .ltoreq.0.75 times, times, .ltoreq.0.65 times, times, .ltoreq.0.55 times, times, .ltoreq.0.45 times, times, .ltoreq.0.35 times, times, .ltoreq.0.25 times, times, .ltoreq.0.15 times, times the level of fibroblast proliferation in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0210] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting a pathological process mediated by IL-11, e.g. following stimulation with a profibrotic factor (e.g. TGF.beta.1). Pathological processes mediated by IL-11 include fibrosis, and can be evaluated either in vitro or in vivo.

[0211] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting fibrosis. Fibrosis may be of a particular tissue or several tissues, e.g. liver, lung, kidney, heart, blood vessel, eye, skin, pancreas, spleen, bowel (e.g. large or small intestine), brain, or bone marrow. Fibrosis may be measured by means well known to the skilled person, for example by analysing gene or protein expression of one or more myofibroblast markers and/or gene or protein expression of one or more markers of fibrosis in a given tissue or tissues.

[0212] Myofibroblast markers may include one or more of increased .alpha.SMA, vimentin, palladin, cofilin or desmin. Markers of fibrosis include increased level of collagen, fibronectin, periostin, IL-6, IL-11, .alpha.SMA, TIMP1 and MMP2, extracellular matrix components, number/proportion of myofibroblasts, and organ weight.

[0213] Inhibition of fibrosis can be measured in vitro or in vivo. For example, whether an antibody/fragment is capable of inhibiting fibrosis in a given tissue can be analysed in vitro by treating fibroblasts derived from that tissue with a profibrotic stimulus, and then analysing whether the antibody can reduce myofibroblast generation from the fibroblasts (or e.g. some other marker of fibrosis). Whether an antibody/fragment is capable of inhibiting fibrosis can be analysed in vivo, for example, by administering the antibody/fragment to a subject (e.g. a subject that has been exposed to a profibrotic stimulus), and analysing tissue(s) for one or more markers of fibrosis.

[0214] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting fibrosis to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of fibrosis in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing fibrosis to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, times, .ltoreq.0.85 times, times, .ltoreq.0.85 times, .ltoreq.0.75 times, times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of fibrosis in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0215] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting myofibroblast generation from fibroblasts, e.g. following exposure of the fibroblasts to profibrotic factor. Myofibroblast generation from fibroblasts can be investigated by analysis for myofibroblast markers. A profibrotic factor according to the present disclosure may be e.g. TGF.beta.1, IL-11, IL-13, PDGF, ET-1, oncostatin M (OSM) or ANG2 (AngII).

[0216] In some embodiments, the antibody/fragment is capable of inhibiting gene or protein expression in fibroblasts, or fibroblast-derived cells (e.g. myofibroblasts), of one or more of collagen, fibronectin, periostin, IL-6, IL-11, .alpha.SMA, TIMP1, MMP2, e.g. following stimulation with a profibrotic factor. In some embodiments, the antibody/fragment is capable of inhibiting gene or protein expression in fibroblasts, or fibroblast-derived cells (e.g. myofibroblasts), of one or more extracellular matrix components, e.g. following stimulation with a profibrotic factor.

[0217] In the experimental examples herein, myofibroblast generation from fibroblasts is analysed by measuring .alpha.SMA protein expression levels using Operetta High-Content Imaging System following stimulation of the fibroblasts with TGF.beta.1.

[0218] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting myofibroblast generation from fibroblasts to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of myofibroblast generation from fibroblasts in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing myofibroblast generation from fibroblasts to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of myofibroblast generation from fibroblasts in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0219] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting gene or protein expression in fibroblasts of one or more of collagen, fibronectin, periostin, IL-6, IL-11, .alpha.SMA, TIMP1, MMP2, e.g. following stimulation with a profibrotic factor (e.g. TGF.beta.1). In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting gene or protein expression to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of gene or protein expression in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing gene or protein expression to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of gene or protein expression in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0220] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting extracellular matrix production by fibroblasts, e.g. following stimulation with a profibrotic factor (e.g. TGF.beta.1). Extracellular matrix production can be evaluated, for example, by measuring the level of an extracellular matrix component. Extracellular matrix components according to the present invention include e.g. proteoglycan, heparan sulphate, chondroitin sulphate, keratan sulphate, hyaluronic acid, collagen, periostin, fibronectin, vitronectin, elastin, fibronectin, laminin, nidogen, gelatin and aggrecan.

[0221] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting extracellular matrix production by fibroblasts to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of extracellular matrix production by fibroblasts in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing extracellular matrix production by fibroblasts to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of extracellular matrix production in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0222] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting proliferation and/or survival of cells of a cancer. The skilled person is able to determine whether an antibody/fragment is capable of inhibiting proliferation and/or survival of cells of a cancer for example by analysing the effect of the antibody/fragment on cells of the cancer. For example, proliferation of cells can be measured as described herein, e.g. by .sup.3H thymidine incorporation or CFSE dilution assays. Cell survival can be analysed by measuring cells for markers of cell viability/cell death following treatment with the antibody/fragment.

[0223] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting proliferation and/or survival of cells of a cancer to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of proliferation and/or survival of cells of a cancer in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing proliferation and/or survival of cells of a cancer to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of proliferation and/or survival of cells of a cancer in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0224] In some embodiments, the antibody/fragment according to the present invention is capable of inhibiting tumour growth to less than 100%, e.g. one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of tumour growth in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibody/fragment is capable of reducing tumour growth to less than 1 times, e.g. one of .ltoreq.0.99 times, .ltoreq.0.95 times, .ltoreq.0.9 times, .ltoreq.0.85 times, .ltoreq.0.8 times, .ltoreq.0.85 times, .ltoreq.0.75 times, .ltoreq.0.7 times, .ltoreq.0.65 times, .ltoreq.0.6 times, .ltoreq.0.55 times, .ltoreq.0.5 times, .ltoreq.0.45 times, .ltoreq.0.4 times, .ltoreq.0.35 times, .ltoreq.0.3 times, .ltoreq.0.25 times, .ltoreq.0.2 times, .ltoreq.0.15 times, .ltoreq.0.1 times the level of tumour growth in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

[0225] In some embodiments, the antibody/fragment according to the present invention has one or more improved properties as compared to a prior art anti-IL-11 antibody/fragment. In some embodiments the prior art anti-IL-11 antibody/antigen binding fragment may be, or may comprise the CDRs and/or VL and VH sequences of, monoclonal mouse anti-human IL-11 antibody clone #22626; Catalog No. MAB218 (R&D Systems, MN, USA).

[0226] In some embodiments, the antibody/fragment of the present invention displays one or more of the following properties as compared to a prior art antibody/antigen binding fragment (e.g. monoclonal mouse antibody clone #22626; Catalog No. MAB218):

[0227] (i) binds to IL-11 with greater specificity relative to one or more of IL-6, LIF, OSM, CT-1, CNTF, and CLC (i.e. reduced cross-reactivity for proteins of the IL-6 cytokine family other than IL-11);

[0228] (ii) binds to IL-11 (e.g. human IL-11) with greater affinity (e.g. has lower EC50 as determined by ELISA);

[0229] (iii) inhibits interaction between IL-11 and IL-11R.alpha. to a greater extent;

[0230] (iv) inhibits interaction between IL-11 and gp130 to a greater extent;

[0231] (v) inhibits interaction between IL-11 and IL-11R.alpha.:gp130 receptor complex to a greater extent;

[0232] (vi) inhibits interaction between IL-11:IL-11R.alpha. complex and gp130 to a greater extent;

[0233] (vii) inhibits signalling mediated by IL-11 to a greater extent;

[0234] (viii) inhibits signalling mediated by binding of IL-11 to IL-11R.alpha.:gp130 receptor complex to a greater extent;

[0235] (ix) inhibits signalling mediated by binding of IL-11:IL-11R.alpha. complex to gp130 (i.e. IL-11 trans signalling) to a greater extent;

[0236] (x) inhibits fibroblast proliferation to a greater extent;

[0237] (xi) inhibits myofibroblast generation from fibroblasts to a greater extent;

[0238] (xii) inhibits a pathological process mediated by IL-11 to a greater extent;

[0239] (xiii) inhibits fibrosis to a greater extent;

[0240] (xiv) inhibits gene or protein expression in fibroblasts of one or more of collagen, fibronectin, periostin, IL-6, IL-11, .alpha.SMA, TIMP1, MMP2, e.g. following stimulation with a profibrotic factor to a greater extent;

[0241] (xv) inhibits extracellular matrix production by fibroblasts to a greater extent;

[0242] (xvi) inhibits proliferation and/or survival of cells of a cancer to a greater extent; or

[0243] (xvii) inhibits tumour growth to a greater extent.

[0244] In some embodiments, "greater specificity" or "greater affinity" or "inhibition to a greater extent" herein is, respectively, a level of specificity, affinity or inhibition which is greater than 1 times, e.g. .gtoreq.1.01 times, .gtoreq.1.02 times, .gtoreq.1.03 times, .gtoreq.1.04 times, .gtoreq.1.05 times, .gtoreq.1.06 times, .gtoreq.1.07 times, .gtoreq.1.08 times, .gtoreq.1.09 times, .gtoreq.1.1 times, 21.2 times, .gtoreq.1.3 times, .gtoreq.1.4 times, .gtoreq.1.5 times, .gtoreq.1.6 times, .gtoreq.1.7 times, .gtoreq.1.8 times, .gtoreq.1.9 times, .gtoreq.2 times, .gtoreq.2.1 times, .gtoreq.2.2 times, .gtoreq.2.3 times, .gtoreq.2.4 times, .gtoreq.2.5 times, .gtoreq.2.6 times, .gtoreq.2.7 times, .gtoreq.2.8 times, .gtoreq.2.9 times, .gtoreq.3 times, .gtoreq.3.5 times, .gtoreq.4 times, .gtoreq.4.5 times, .gtoreq.5 times, .gtoreq.6 times, .gtoreq.7 times, .gtoreq.8 times, .gtoreq.9 times, .gtoreq.10 times, .gtoreq.15 times, .gtoreq.20 times, .gtoreq.25 times, .gtoreq.30 times, .gtoreq.35 times, .gtoreq.40 times, .gtoreq.45 times, .gtoreq.50 times, .gtoreq.60 times, .gtoreq.70 times, 280 times, .gtoreq.90 times, .gtoreq.100 times, .gtoreq.200 times, .gtoreq.300 times, .gtoreq.400 times, .gtoreq.500 times, .gtoreq.600 times, .gtoreq.700 times, 2800 times, .gtoreq.900 times, .gtoreq.1000 times the specificity or affinity or level of inhibition displayed by the prior art antibody/antigen binding fragment in a comparable assay.

[0245] Therapeutic Applications

[0246] Antibodies and antigen binding fragments according to the present invention and compositions comprising such agents may be provided for use in methods of medical treatment or prevent of a disease/disorder, or alleviation of the symptoms of a disease/disorder. The antibodies/fragments of the present invention may be administered to subjects having a disease/condition in need of treatment, and/or to subjects at risk of such developing or contracting the disease/disorder.

[0247] Treatment, prevention or alleviation of fibrosis according to the present invention may be of fibrosis that is associated with an upregulation of IL-11 and/or IL-11R.alpha., e.g. an upregulation of IL-11 and/or IL-11R.alpha. in cells or tissue in which the disease/disorder occurs or may occur, or upregulation of extracellular IL-11 or IL-11R.alpha.. In some embodiments, IL-11 or IL-11R expression is locally or systemically upregulated in the subject.

[0248] Treatment or alleviation of a disease/disorder may be effective to prevent progression of the disease/disorder, e.g. to prevent worsening of the condition or to slow the rate of development. In some embodiments treatment or alleviation may lead to an improvement in the disease/disorder, e.g. a reduction in the symptoms of the disease/disorder or reduction in some other correlate of the severity/activity of the disease/disorder.

[0249] Prevention of a disease/disorder may refer to prevention of a worsening of the condition or prevention of the development of the disease/disorder, e.g. preventing an early stage disease/disorder developing to a later, chronic, stage.

[0250] The antibodies/fragments of the present invention are preferably able to bind to and inhibit the biological activity of IL-11 and IL-11-containing molecules/complexes (e.g. IL-11:IL-11R.alpha. complex). Accordingly, the antibodies/fragments of the present invention find use in the treatment or prevention of diseases and disorders in which IL-11 is implicated in the pathology of the disease/disorder. That is, the antibodies/fragments of the present invention find use in the treatment or prevention of diseases and disorders associated with IL-11/IL-11R signalling.

[0251] In some embodiments, the disease/disorder may be associated with increased IL-11, IL-11R.alpha. and/or gp130 gene or protein expression, e.g. as compared to the control (i.e. non-diseased) state. In some embodiments, the disease/disorder may be associated with an increased level of IL-11-mediated signalling as compared to the control state. In some embodiments, the disease/disorder may be associated with an increased level of signalling through ERK and/or STAT3 pathways as compared to the control state. In some embodiments, the increased expression/activity of IL-11, IL-11R.alpha. and/or gp130, and/or the increased level of IL-11-mediated signalling, may be observed in effector cells of the disease/disorder (e.g. for a cancer, the cancerous cells). In some embodiments, the increased expression/activity of IL-11, IL-11R.alpha. and/or gp130, and/or the increased level of IL-11-mediated signalling, may be observed in cells other than the effector cells.

[0252] Signalling through ERK can be measured e.g. using an assay for ERK phosphorylation such as an assay described in Assay Guidance Manual: Phospho-ERK Assays, Kim E. Garbison, Beverly A. Heinz, Mary E. Lajiness, Jeffrey R. Weidner, and G. Sitta Sittampalam, E H Lilly & Company, Sittampalam GS, Coussens N P, Nelson H, et al., editors Bethesda (Md.): E H Lilly & Company and the National Center for Advancing Translational Sciences; 2004. Signalling through STAT3 can be measured e.g. using an assay for phosphorylation of STAT3, such as the Phospho-STAT3 (Tyr705) Cellular Assay Kit (Cisbio Assays).

[0253] In some embodiments, the treatment is of a disease/disorder for which a reduction in IL-11 mediated signalling is therapeutic. In some embodiments, the treatment is of a disease/disorder associated with excess ERK and/or STAT3 signalling. In some embodiments, the treatment is of a disease/disorder associated with excess proliferation or hyperactivation of fibroblasts, or associated with an excess of myofibroblasts.

[0254] In some embodiments, the treatment may be aimed at preventing or treating a disease/disorder by decreasing the number or proportion of myofibroblasts or .alpha.SMA-positive fibroblasts.

[0255] In some embodiments, the disease/disorder may be fibrosis, a fibrotic condition, or a disease/disorder characterised by fibrosis. As used herein, "fibrosis" refers to the formation of excess fibrous connective tissue as a result of the excess deposition of extracellular matrix components, for example collagen. Fibrous connective tissue is characterised by having extracellular matrix (ECM) with a high collagen content. The collagen may be provided in strands or fibers, which may be arranged irregularly or aligned. The ECM of fibrous connective tissue may also include glycosaminoglycans.

[0256] As used herein, "excess fibrous connective tissue" refers to an amount of connective tissue at a given location (e.g. a given tissue or organ, or part of a given tissue or organ) which is greater than the amount of connective tissue present at that location in the absence of fibrosis, e.g. under normal, non-pathological conditions. As used herein, "excess deposition of extracellular matrix components" refers to a level of deposition of one or more extracellular matrix components which is greater than the level of deposition in the absence of fibrosis, e.g. under normal, non-pathological conditions.

[0257] The cellular and molecular mechanisms of fibrosis are described in Wynn, J. Pathol. (2008) 214(2): 199-210, and Wynn and Ramalingam, Nature Medicine (2012) 18:1028-1040, which are hereby incorporated by reference in their entirety. The main cellular effectors of fibrosis are myofibroblasts, which produce a collagen-rich extracellular matrix.

[0258] In response to tissue injury, damaged cells and leukocytes produce pro-fibrotic factors such as TGF8, IL-13 and PDGF, which activate fibroblasts to .alpha.SMA-expressing myofibroblasts, and recruit myofibroblasts to the site of injury. Myofibroblasts produce a large amount of extracellular matrix, and are important mediators in aiding contracture and closure of the wound. However, under conditions of persistent infection or during chronic inflammation there can be overactivation and recruitment of myofibroblasts, and thus over-production of extracellular matrix components, resulting in the formation of excess fibrous connective tissue.

[0259] In some embodiments fibrosis may be triggered by pathological conditions, e.g. conditions, infections or disease states that lead to production of pro-fibrotic factors such as TGF.beta.1. In some embodiments, fibrosis may be caused by physical injury/stimuli, chemical injury/stimuli or environmental injury/stimuli. Physical injury/stimuli may occur during surgery, e.g. iatrogenic causes. Chemical injury/stimuli may include drug induced fibrosis, e.g. following chronic administration of drugs such as bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine, gold and nitrofurantoin (Daba et al., Saudi Med J 2004 June; 25(6): 700-6). Environmental injury/stimuli may include exposure to asbestos fibres or silica.

[0260] Fibrosis can occur in many tissues of the body. For example, fibrosis can occur in the lung, liver (e.g. cirrhosis), kidney, heart, blood vessels, eye, skin, pancreas, spleen, bowel (e.g. large or small intestine), brain, and bone marrow. Fibrosis may also occur in multiple organs at once.

[0261] In embodiments herein, fibrosis may involve an organ of the gastrointestinal system, e.g. of the liver, small intestine, large intestine, or pancreas. In some embodiments, fibrosis may involve an organ of the respiratory system, e.g. the lungs. In embodiments, fibrosis may involve an organ of the cardiovascular system, e.g. of the heart or blood vessels. In some embodiments, fibrosis may involve the skin. In some embodiments, fibrosis may involve an organ of the nervous system, e.g. the brain. In some embodiments, fibrosis may involve an organ of the urinary system, e.g. the kidneys. In some embodiments, fibrosis may involve an organ of the musculoskeletal system, e.g. muscle tissue.

[0262] In some preferred embodiments, the fibrosis is cardiac or myocardial fibrosis, hepatic fibrosis, or renal fibrosis. In some embodiments cardiac or myocardial fibrosis is associated with dysfunction of the musculature or electrical properties of the heart, or thickening of the walls or valves of the heart. In some embodiments fibrosis is of the atrium and/or ventricles of the heart. Treatment or prevention of atrial or ventricular fibrosis may help reduce risk or onset of atrial fibrillation, ventricular fibrillation, or myocardial infarction.

[0263] In some preferred embodiments hepatic fibrosis is associated with chronic liver disease or liver cirrhosis. In some preferred embodiments renal fibrosis is associated with chronic kidney disease.

[0264] Diseases/disorders characterised by fibrosis in accordance with the present invention include but are not limited to: respiratory conditions such as pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, obliterative bronchiolitis, Hermansky-Pudlak syndrome, asbestosis, silicosis, chronic pulmonary hypertension, AIDS associated pulmonary hypertension, sarcoidosis, tumor stroma in lung disease, and asthma; chronic liver disease, primary biliary cirrhosis (PBC), schistosomal liver disease, liver cirrhosis; cardiovascular conditions such as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), fibrosis of the atrium, atrial fibrillation, fibrosis of the ventricle, ventricular fibrillation, myocardial fibrosis, Brugada syndrome, myocarditis, endomyocardial fibrosis, myocardial infarction, fibrotic vascular disease, hypertensive heart disease, arrhythmogenic right ventricular cardiomyopathy (ARVC), tubulointerstitial and glomerular fibrosis, atherosclerosis, varicose veins, cerebral infarcts; neurological conditions such as gliosis and Alzheimer's disease; muscular dystrophy such as Duchenne muscular dystrophy (DMD) or Becker's muscular dystrophy (BMD); gastrointestinal conditions such as Chron's disease, microscopic colitis and primary sclerosing cholangitis (PSC); skin conditions such as scleroderma, nephrogenic systemic fibrosis and cutis keloid; arthrofibrosis; Dupuytren's contracture; mediastinal fibrosis; retroperitoneal fibrosis; myelofibrosis; Peyronie's disease; adhesive capsulitis; kidney disease (e.g., renal fibrosis, nephritic syndrome, Alport's syndrome, HIV associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus); progressive systemic sclerosis (PSS); chronic graft versus host disease; diseases/disorders of the eye and associated processes, such as Grave's opthalmopathy, epiretinal fibrosis (e.g. diabetic retinopathy (DR)), glaucoma, subretinal fibrosis (e.g, associated with macular degeneration (e.g. wet age-related macular degeneration (AMD))), macular edema, drusen formation, post-surgical fibrosis (e.g. of the posterior capsule following cataract surgery, or of the bleb following trabeculectomy for glaucoma), conjunctival fibrosis, subconjunctival fibrosis; arthritis; fibrotic pre-neoplastic and fibrotic neoplastic disease; and fibrosis induced by chemical or environmental insult (e.g., cancer chemotherapy, pesticides, radiation/cancer radiotherapy).

[0265] It will be appreciated that many of the diseases/conditions listed above are interrelated. For example, fibrosis of the ventricle may occur post myocardial infarction, and is associated with DCM, HCM and myocarditis.

[0266] In particular embodiments, the disease/disorder may be one of pulmonary fibrosis, atrial fibrillation, ventricular fibrillation, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), non-alcoholic steatohepatitis (NASH), cirrhosis, chronic kidney disease, scleroderma, systemic sclerosis, keloid, cystic fibrosis, Chron's disease, post-surgical fibrosis or retinal fibrosis, e.g. associated with wet age-related macular degeneration (AMD).

[0267] Fibrosis can lead directly or indirectly to, and/or increase susceptibility to development of, diseases/disorders. For example, more than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers (Affo et al. 2016, Annu Rev Pathol.), suggesting an important role for liver fibrosis in the premalignant environment (PME) of the liver.

[0268] Accordingly, the antibodies/fragments of the present invention find use in methods for the treatment and prevention of diseases/disorders associated with fibrosis, and/or for which fibrosis is a risk factor. In some embodiments, the disease/disorder associated with fibrosis, or for which fibrosis is a risk factor, is a cancer, e.g. cancer of the liver (e.g. hepatocellular carcinoma).

[0269] IL-11 is also implicated in the pathology of other diseases/disorders, and the antibodies and fragments of the present invention accordingly find use in methods to treat, prevent and/or alleviate the symptoms of these diseases/disorders also.

[0270] IL-11 has been implicated in the development and progression of various cancers. Studies suggest that IL-11 is important for promoting chronic gastric inflammation and associated gastric, colonic, hepatocellular and breast cancer tumorogenesis through excessive activation of STAT3 (Ernst M, et al. J Olin Invest. (2008); 118:1727-1738), that IL-11 may promote tumorigenesis by triggering the JAK-STAT intracellular signalling pathway, and may also promote metastasis via signalling through the PI3K-AKT-mTORC1 pathway (Xu et al., Cancer Letters (2016) 373(2): 156-163). Through STAT3, IL-11 promotes survival, proliferation, invasion angiogenesis and metastasis, the IL-11/GP130/JAK/STAT3 signalling axis may be rate-limiting for the progression of gastrointestinal tumors, and elevated IL-11 expression is associated with poor prognosis of breast cancer patients (Johnstone et al., Cytokine & Growth Reviews (2015) 26(5): 489-498). IL-11 has also been shown to influence breast cancer stem cell dynamics and tumor heterogeneity (Johnstone et al., Cytokine & Growth Reviews (2015) 26(5); 489-498). Recently, IL-11 signalling has been implicated in chemoresistance of lung adenocarcinoma; cancer associated fibroblasts were found to upregulate IL-11, and confer chemoresistance to lung cancer cells through activation of the IL-11/IL-11RISTAT3 anti-apoptotic signalling pathway (Tao et al. 2016, Sci Rep. 6; 6:38408). IL-11 signalling may promote the fibroblast-to-myofibroblast transition and extracellular matrix production by fibroblasts in the premalignant environment (PME) and tumour micro-environment (TME).

[0271] In some embodiments, the antibodies/fragments of the present invention are provided for use in methods to treat/prevent a cancer. In some embodiments, the cancer may be a cancer which leads directly or indirectly to inflammation and/or fibrosis.

[0272] A cancer may be any unwanted cell proliferation (or any disease manifesting itself by unwanted cell proliferation), neoplasm or tumor or increased risk of or predisposition to the unwanted cell proliferation, neoplasm or tumor. The cancer may be benign or malignant and may be primary or secondary (metastatic). A neoplasm or tumor may be any abnormal growth or proliferation of cells and may be located in any tissue.

[0273] In some embodiments, the antibodies/fragments of the present invention are provided for use in methods to treat/prevent a cancer, e.g. an epithelial cell cancer, breast cancer, gastrointestinal cancer (e.g. esophageal cancer, stomach cancer, pancreatic cancer, liver cancer (e.g. HOC), gallbladder cancer, colorectal cancer, anal cancer, gastrointestinal carcinoid tumor), and lung cancer (e.g. non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC))). In some embodiments, the cancer is a cancer for which acute and/or chronic inflammation is a risk factor. In some embodiments, the cancer is a cancer for which a disease/disorder characterised by fibrosis (e.g. as described herein) is a risk factor.

[0274] In some embodiments, the cancer may be associated with increased IL-11, IL-11R.alpha. and/or gp130 gene or protein expression. For example, cells of the cancer may have increased expression of IL-11, IL-11R.alpha. and/or gp130 as compared to comparable, non-cancerous cells, or may be associated with increased expression of IL-11, IL-11R.alpha. and/or gp130 by other cells (e.g. non-cancerous cells) as compared to the level of expression by comparable cells in the absence of a cancer (e.g. in a healthy control subject). In some embodiments, cells of the cancer may be determined to have an increased level of signalling through ERK and/or STATS pathways as compared to comparable non-cancerous cells.

[0275] In some embodiments, the cancer may be associated with a mutation in IL-11, IL-11R.alpha. and/or gp130. In some embodiments, such mutation may be associated with increased level of gene or protein expression, or may be associated with an increased level of IL-11/IL-11R signalling relative to the level of expression/signalling observed in the absence of the mutation.

[0276] IL-11 has also been implicated in diseases/disorders characterised by inflammation. Intra-articular injection of IL-11 has been shown to cause joint inflammation (Wong et al., Cytokine (2005) 29:72-76), and IL-11 has been shown to be proinflammatory at sites of IL-13-mediated tissue inflammation (Chen et al., J Immunol (2005) 174:2305-2313). IL-11 expression has also been observed to be significantly increased in chronic skin lesions in atopic dermatitis, and is known to be involved in bronchial inflammation (Toda et al., J Allergy Clin Immunol (2003) 111:875-881). IL-11-mediated signalling is implicated in inflammatory bowel disease (IBD) and asthma (Putoczki and Ernst, J Leuko Biol (2010) 88(6)1109-1117). IL-11 has also been identified as a risk factor for multiple sclerosis; IL-11 is elevated in the cerebrospinal fluid of patients with clinically isolated syndrome (CIS) as compared to control subjects, and serum levels of IL-11 are higher during relapses for patients with relapsing-remitting multiple sclerosis, and IL-11 may promote differentiation of CD4+ T cells to a T.sub.H17 phenotype T.sub.H17 cells are important cells in the pathogenesis of multiple sclerosis (Zhang et al., Oncotarget (2015) 6(32): 32297-32298).

[0277] In some embodiments, the antibodies/fragments of the present invention are provided for use in methods to treat/prevent a disease/disorder characterised by inflammation. In some embodiments, a disease or disorder characterised by inflammation may be a disease/disorder which leads directly or indirectly to a cancer and/or fibrosis. Diseases characterised by inflammation include e.g. allergic inflammation such as allergic asthma and bronchial inflammation, atopic dermatitis, allergic rhinitis and ocular allergic diseases, and autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, chronic active hepatitis, type 1 diabetes mellitus, celiac disease, Grave's disease, uveitis, pemphigus, psoriasis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, anaemia and autoimmune thyroiditis.

[0278] In some embodiments, the antibodies/fragments of the present invention are provided for use in methods to treat/prevent a disease/disorder associated with infection, in particular where infection leads directly or indirectly to fibrosis, cancer or inflammation. A disease associated with infection may be a disease which is caused or exacerbated by infection with the relevant infectious agent, or may be a disease for which infection with the relevant infectious agent is a risk factor.

[0279] An infection may be any infection or infectious disease, e.g. bacterial, viral, fungal, or parasitic infection. In particular embodiments, the disease/disorder may be associated with a viral infection. In some embodiments it may be particularly desirable to treat chronic/persistent infections, e.g. where such infections are associated with inflammation, cancer and/or fibrosis.

[0280] The infection may be chronic, persistent, latent or slow, and may be the result of bacterial, viral, fungal or parasitic infection. As such, treatment may be provided to patients having a bacterial, viral or fungal infection. Examples of bacterial infections include infection with Helicobacter pylori and Mycobacterium tuberculosis infection of the lung. Examples of viral infections include infection with EBV, HPV, HIV, hepatitis B or hepatitis C.

[0281] The treatment may involve ameliorating, treating, or preventing the disease/disorder by inhibiting the biological activity of IL-11 or an IL-11-containing complex. Such methods may include the administration of the antibodies/fragments/compositions according to the present invention to bind to and inhibit the biological activity of IL-11 or an IL-11-containing complex. Herein, inhibiting the biological activity of IL-11 or an IL-11-containing complex may be referred to as `neutralising`.

[0282] Methods of treatment may optionally include the co-administration of biological adjuvants (e.g., interleukins, cytokines, Bacillus Comette-Guerin, monophosphoryl lipid A, etc.) in combination with conventional therapies for treating cancer such as treatment with an agent for treating cancer (e.g. chemotherapy), radiation, or surgery. Methods of medical treatment may also involve in vivo, ex vivo, and adoptive immunotherapies, including those using autologous and/or heterologous cells or immortalized cell lines.

[0283] The treatment may be aimed at prevention of a disease/disorder associated with overactive/elevated IL-11 mediated signalling. As such, the antibodies, antigen binding fragments and polypeptides may be used to formulate pharmaceutical compositions or medicaments and subjects may be prophylactically treated against development of a disease state. This may take place before the onset of symptoms of the disease state, and/or may be given to subjects considered to be at greater risk of the disease or disorder.

[0284] Administration of an antibody, antigen binding fragment or polypeptide is preferably in a "therapeutically effective amount", this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins.

[0285] Formulating Pharmaceutically Useful Compositions and Medicaments

[0286] Antibodies and antigen binding fragments according to the present invention may be formulated as pharmaceutical compositions or medicaments for clinical use and may comprise a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0287] The composition may be formulated for topical, parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, oral or transdermal routes of administration which may include injection or infusion. Suitable formulations may comprise the antibody/fragment in a sterile or isotonic medium. Medicaments and pharmaceutical compositions may be formulated in fluid, including gel, form. Fluid formulations may be formulated for administration by injection or via catheter to a selected region of the human or animal body.

[0288] In accordance with the present invention methods are also provided for the production of pharmaceutically useful compositions, such methods of production may comprise one or more steps selected from: isolating an antibody or antigen binding fragment as described herein; and/or mixing an isolated antibody or antigen binding fragment as described herein with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.

[0289] For example, a further aspect of the present invention relates to a method of formulating or producing a medicament or pharmaceutical composition for use in a method of medical treatment, the method comprising formulating a pharmaceutical composition or medicament by mixing an antibody or antigen binding fragment as described herein with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.

[0290] Methods of Detection

[0291] Antibodies, or antigen binding fragments, described herein may be used in methods that involve the binding of the antibody or antigen binding fragment to IL-11. Such methods may involve detection of the bound complex of antibody, or antigen binding fragment, and IL-11. As such, in one embodiment a method is provided, the method comprising contacting a sample containing, or suspected to contain, IL-11 with an antibody or antigen binding fragment as described herein and detecting the formation of a complex of antibody, or antigen binding fragment, and IL-11.

[0292] Suitable method formats are well known in the art, including immunoassays such as sandwich assays, e.g. ELISA. The method may involve labelling the antibody/antigen binding fragment or IL-11, or both, with a detectable label, e.g. fluorescent, luminescent or radio-label. IL-11 expression may be measured by immunohistochemistry (IHC), for example of a tissue sample obtained by biopsy. In some embodiments, the label may be selected from: a radio-nucleotide, positron-emitting radionuclide (e.g. for positron emission tomography (PET)), MRI contrast agent or fluorescent label.

[0293] Analysis in vitro or in vivo of processes mediated by IL-11 may involve analysis by positron emission tomography (PET), magnetic resonance imaging (MRI), or fluorescence imaging, e.g. by detection of appropriately labelled species.

[0294] Methods of this kind may provide the basis of a method of diagnosis of a disease or condition requiring detection and or quantitation of IL-11 or an IL-11-containing complex. Such methods may be performed in vitro on a subject sample, or following processing of a subject sample. Once the sample is collected, the subject is not required to be present for the in vitro method of diagnosis to be performed and therefore the method may be one which is not practised on the human or animal body.

[0295] Such methods may involve determining the amount of IL-11 or IL-11-containing complex present in a subject sample. The method may further comprise comparing the determined amount against a standard or reference value as part of the process of reaching a diagnosis. Other diagnostic tests may be used in conjunction with those described here to enhance the accuracy of the diagnosis or prognosis or to confirm a result obtained by using the tests described here.

[0296] The level of IL-11 or IL-11-containing complex present in a subject sample may be indicative that a subject may respond to treatment with an anti-IL-11 antibody/fragment, e.g. an anti-IL-11 antibody/fragment or composition according to the present invention. The presence of a high level of IL-11 or IL-11-containing complex in a sample may be used to select a subject for treatment with an anti-IL-11 antibody/fragment or composition described herein. The antibodies of the present invention may therefore be used to select a subject for treatment with anti-IL-11 therapy.

[0297] Detection in a sample of IL-11 or IL-11-containing complex may be used for the purpose of diagnosis of an infectious disease, autoimmune disorder or a cancerous condition in the subject, diagnosis of a predisposition to an infectious disease, autoimmune disorder or a cancerous condition or for providing a prognosis (prognosticating) of an infectious disease, autoimmune disorder or a cancerous condition. The diagnosis or prognosis may relate to an existing (previously diagnosed) infectious, inflammatory or autoimmune disease/disorder or cancerous condition.

[0298] A sample may be taken from any tissue or bodily fluid. The sample may comprise or may be derived from: a quantity of blood; a quantity of serum derived from the individual's blood which may comprise the fluid portion of the blood obtained after removal of the fibrin clot and blood cells; a tissue sample or biopsy; pleural fluid; cerebrospinal fluid (CSF); or cells isolated from said individual. In some embodiments, the sample may be obtained or derived from a tissue or tissues which are affected by the disease/disorder (e.g. tissue or tissues in which symptoms of the disease manifest, or which are involved in the pathogenesis of the disease/disorder).

[0299] Methods according to the present invention may preferably be performed in vitro. The term "in vitro" is intended to encompass experiments with cells in culture whereas the term "in vivo" is intended to encompass experiments with and/or treatment of intact multi-cellular organisms.

[0300] Combination Therapies

[0301] Antibodies, antigen binding fragments and compositions according to the present invention may be administered alone or in combination with other treatments. Administration of such combination may be simultaneous or sequential, depending on the disease/disorder to be treated. The other treatment with which the antibody/fragment or composition is administered may be aimed at treating or preventing the disease/disorder. In some embodiments, the other treatment with which the antibody/fragment or composition is administered may be aimed at treating or preventing e.g. infection, inflammation and/or cancer.

[0302] Simultaneous administration refers to administration of the antibody, antigen binding fragment or polypeptide and therapeutic agent together, for example as a pharmaceutical composition containing both agents (combined preparation), or immediately after each other and optionally via the same route of administration, e.g. to the same artery, vein or other blood vessel.

[0303] Sequential administration refers to administration of one of the antibody, antigen binding fragment or polypeptide or therapeutic agent followed after a given time interval by separate administration of the other agent. It is not required that the two agents are administered by the same route, although this is the case in some embodiments. The time interval may be any time interval.

[0304] In some embodiments, treatment with an antibody, antigen binding fragment or composition of the present invention may be accompanied by an agent for treating or preventing infection (e.g. an antibiotic, anti-viral, anti-fungal or anti-parasitic agent). In some embodiments, treatment with an antibody, antigen binding fragment or composition of the present invention may be accompanied by an agent for treating or preventing inflammation (e.g. a non-steroidal anti-inflammatory drug (NSAID). In some embodiments, treatment with an antibody, antigen binding fragment or composition of the present invention may be accompanied by radiotherapy (i.e. treatment with ionising radiation, e.g. X-rays or .gamma.-rays) and/or an agent for treating or preventing cancer (e.g. a chemotherapeutic agent). In some embodiments, the antibody, antigen binding fragment or composition of the present invention may be administered as part of a combination treatment with an immunotherapy.

[0305] A treatment may involve administration of more than one drug. A drug may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

[0306] Routes of Administration

[0307] Antibodies, antigen binding fragments, medicaments and pharmaceutical compositions according to aspects of the present invention may be formulated for administration by a number of routes, including but not limited to, parenteral, intravenous, intra-arterial, intraocular, intraconjunctival, intramuscular, subcutaneous, intradermal, intratumoral injection or infusion, and oral administration. Antibodies, antigen binding fragments, polypeptides and other therapeutic agents, may be formulated in fluid or solid form. Fluid formulations may be formulated for administration by injection or infusion to a selected region of the human or animal body.

[0308] Kits

[0309] In some aspects of the present invention a kit of parts is provided. In some embodiments the kit may have at least one container having a predetermined quantity of the antibody, fragment, or composition. The kit may provide the antibody/fragment in the form of a medicament or pharmaceutical composition, and may be provided together with instructions for administration to a subject in order to treat a specified disease/disorder. The antibody, fragment or composition may be formulated so as to be suitable for injection or infusion to a tumor or to the blood.

[0310] In some embodiments the kit may further comprise at least one container having a predetermined quantity of another therapeutic agent (e.g. anti-infective agent or chemotherapy agent). In such embodiments, the kit may also comprise a second medicament or pharmaceutical composition such that the two medicaments or pharmaceutical compositions may be administered simultaneously or separately such that they provide a combined treatment for the specific disease or condition. The therapeutic agent may also be formulated so as to be suitable for injection or infusion to a tumor or to the blood.

[0311] Subjects

[0312] The subject to be treated may be any animal or human. The subject is preferably mammalian, more preferably human. The subject may be a non-human mammal, but is more preferably human. The subject may be male or female. The subject may be a patient. A subject may have been diagnosed with a disease or condition requiring treatment, or be suspected of having such a disease or condition.

[0313] In some embodiments the subject may be at risk of developing/contracting a disease or disorder.

[0314] Protein Expression

[0315] Molecular biology techniques suitable for producing the proteins (e.g. the antibodies/fragments) according to the invention in cells are well known in the art, such as those set out in Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989

[0316] The polypeptide may be expressed from a nucleotide sequence. The nucleotide sequence may be contained in a vector present in a cell, or may be incorporated into the genome of the cell.

[0317] A "vector" as used herein is an oligonucleotide molecule (DNA or RNA) used as a vehicle to transfer exogenous genetic material into a cell. The vector may be an expression vector for expression of the genetic material in the cell. Such vectors may include a promoter sequence operably linked to the nucleotide sequence encoding the gene sequence to be expressed. A vector may also include a termination codon and expression enhancers. Any suitable vectors, promoters, enhancers and termination codons known in the art may be used to express polypeptides from a vector according to the invention. Suitable vectors include plasmids, binary vectors, viral vectors and artificial chromosomes (e.g. yeast artificial chromosomes).

[0318] In this specification the term "operably linked" may include the situation where a selected nucleotide sequence and regulatory nucleotide sequence (e.g. promoter and/or enhancer) are covalently linked in such a way as to place the expression of the nucleotide sequence under the influence or control of the regulatory sequence (thereby forming an expression cassette). Thus a regulatory sequence is operably linked to the selected nucleotide sequence if the regulatory sequence is capable of effecting transcription of the nucleotide sequence. Where appropriate, the resulting transcript may then be translated into a desired protein or polypeptide.

[0319] Any cell suitable for the expression of polypeptides may be used for producing polypeptides according to the invention. The cell may be a prokaryote or eukaryote. Suitable prokaryotic cells include E. coli. Examples of eukaryotic cells include a yeast cell, a plant cell, insect cell or a mammalian cell (e.g. Chinese Hamster Ovary (CHO) cells). In some cases the cell is not a prokaryotic cell because some prokaryotic cells do not allow for the same post-translational modifications as eukaryotes. In addition, very high expression levels are possible in eukaryotes and proteins can be easier to purify from eukaryotes using appropriate tags. Specific plasmids may also be utilised which enhance secretion of the protein into the media.

[0320] Methods of producing a polypeptide of interest may involve culture or fermentation of a cell modified to express the polypeptide. The culture or fermentation may be performed in a bioreactor provided with an appropriate supply of nutrients, air/oxygen and/or growth factors. Secreted proteins can be collected by partitioning culture media/fermentation broth from the cells, extracting the protein content, and separating individual proteins to isolate secreted polypeptide. Culture, fermentation and separation techniques are well known to those of skill in the art.

[0321] Bioreactors include one or more vessels in which cells may be cultured. Culture in the bioreactor may occur continuously, with a continuous flow of reactants into, and a continuous flow of cultured cells from, the reactor. Alternatively, the culture may occur in batches. The bioreactor monitors and controls environmental conditions such as pH, oxygen, flow rates into and out of, and agitation within the vessel such that optimum conditions are provided for the cells being cultured.

[0322] Following culture of cells that express the polypeptide of interest, that polypeptide is preferably isolated. Any suitable method for separating polypeptides from cell culture known in the art may be used. In order to isolate a polypeptide of interest from a culture, it may be necessary to first separate the cultured cells from media containing the polypeptide of interest. If the polypeptide of interest is secreted from the cells, the cells may be separated from the culture media that contains the secreted polypeptide by centrifugation. If the polypeptide of interest collects within the cell, it will be necessary to disrupt the cells prior to centrifugation, for example using sonification, rapid freeze-thaw or osmotic lysis. Centrifugation will produce a pellet containing the cultured cells, or cell debris of the cultured cells, and a supernatant containing culture medium and the polypeptide of interest.

[0323] It may then be desirable to isolate the polypeptide of interest from the supernatant or culture medium, which may contain other protein and non-protein components. A common approach to separating polypeptide components from a supernatant or culture medium is by precipitation. Polypeptides/proteins of different solubility are precipitated at different concentrations of precipitating agent such as ammonium sulfate. For example, at low concentrations of precipitating agent, water soluble proteins are extracted. Thus, by adding increasing concentrations of precipitating agent, proteins of different solubility may be distinguished. Dialysis may be subsequently used to remove ammonium sulfate from the separated proteins.

[0324] Other methods for distinguishing different polypeptides/proteins are known in the art, for example ion exchange chromatography and size chromatography. These may be used as an alternative to precipitation, or may be performed subsequently to precipitation.

[0325] Once the polypeptide of interest has been isolated from culture it may be necessary to concentrate the protein. A number of methods for concentrating a protein of interest are known in the art, such as ultrafiltration or lyophilisation.

[0326] Sequence Identity

[0327] Alignment for purposes of determining percent amino acid or nucleotide sequence identity can be achieved in various ways known to a person of skill in the art, for instance, using publicly available computer software such as ClustalW 1.82. T-coffee or Megalign (DNASTAR) software. When using such software, the default parameters, e.g. for gap penalty and extension penalty, are preferably used. The default parameters of ClustalW 1.82 are: Protein Gap Open Penalty=10.0, Protein Gap Extension Penalty=0.2, Protein matrix=Gonnet, Protein/DNA ENDGAP=-1, Protein/DNA GAPDIST=4.

[0328] The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0329] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0330] Aspects and embodiments of the present invention will now be illustrated, by way of example, with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0331] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0332] It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.

BRIEF DESCRIPTION OF THE FIGURES

[0333] Embodiments and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures, in which:

[0334] FIG. 1. Graph showing read depth for whole transcriptome sequencing of human atrial fibroblasts from 160 individuals with and without stimulation with TGF.beta.1.

[0335] FIGS. 2A to 2E. Graphs showing expression of endothelial, cardiomyocyte and fibroblast marker genes as determined by RNA-seq of the tissue of origin (human atrial tissues samples, n=8) and primary, unstimulated fibroblast cultures. (FIG. 2A) PECAM1, (FIG. 2B) MYH6 (FIG. 2C) TNNT2, (FIG. 2D) COL1A2, and (FIG. 2E) ACTA2.

[0336] FIGS. 3A to 3E. Graphs showing upregulation of IL-11 expression in fibroblasts in response to stimulation with TGF.beta.1. (FIG. 3A and FIG. 3B) Graphs showing fold change in gene expression in fibrosis; IL-11 is the most upregulated gene in response to TGF.beta.1 treatment. (FIG. 3C) IL-11 secretion by fibroblasts in response to stimulation with TGF.beta.1. (FIG. 3D) Comparison of IL-11 gene expression in tissues of healthy individuals and in atrial fibroblasts, with or without TGF.beta.1 stimulation. (FIG. 3E) Correspondence of fold change in IL-11 expression as determined by RNA-seq vs. qPCR.

[0337] FIGS. 4A to 4D. Graphs showing induction of IL-11 secretion in primary fibroblasts by various profibrotic cytokines, as determined by ELISA. (FIG. 4A) TGF.beta.1, ET-1, AngII, PDGF, OSM and IL-13 induce IL-11 secretion, and IL-11 also induces IL-11 expression in a positive feedback loop. (FIG. 4B) Graph showing that the ELISA only detects native IL-11 secreted from cells, and does not detect recombinant IL-11 used for the IL-11 stimulation condition. (FIG. 4C) and (FIG. 4D) Cells were stimulated with recombinant IL-11, IL-11RNA was measured and the native IL-11 protein level was measured in the cell culture supernatant by ELISA at the indicated time points.

[0338] FIGS. 5A to 5F. Graphs and images showing myofibroblast generation from, and production of ECM and cytokine expression by, atrial fibroblasts in response to stimulation with TGF.beta.1 or IL-11. (FIG. 5A) myofibroblast generation and ECM production by primary atrial fibroblasts following stimulation with TGF.beta.1 or IL-11, as measured by fluorescence microscopy following staining for a .alpha.-SMA, collagen or periostin. (FIG. 5B) Collagen content of cell culture supernatant as determined by Sirius Red staining. Secretion of the fibrosis markers (FIG. 5C) IL-6, (FIG. 5D) TIMP1 and (FIG. 5E) MMP2 as measured by ELISA. (FIG. 5F) Activation of murine fibroblasts by stimulation with human or mouse recombinant IL-11. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 [Mean.+-.SD, Dunnett].

[0339] FIGS. 6A to 6C. Graphs showing the profibrotic effect of IL-11. (FIG. 6A) Mouse fibroblasts from different tissues of origin can be activated by IL-11 and display increased ECM production. [Mean.+-.SD, Dunnett]. Injection of mice with recombinant IL-11 or AngII results in (FIG. 6B) an increase in organ weight [Mean.+-.SEM], and (FIG. 6C) an increase in collagen content (as determined by HPA assay). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 [Mean.+-.SD, Dunnett].

[0340] FIGS. 7A to 7F. Graphs and images showing that IL-11 is required the pro-fibrotic effects of TGF.beta.1 on fibroblasts. (FIG. 7A) myofibroblast generation and ECM production by primary atrial fibroblasts, with or without stimulation with TGF.beta.1, and in the presence/absence of neutralising anti-IL-11 antibody or isotype control IgG, as measured by fluorescence microscopy following staining for (FIG. 7A) .alpha.-SMA, (FIG. 7B) EdU or (FIG. 7C) Periostin. (FIGS. 7D to 7F) Secretion of the fibrosis markers (FIG. 7D) IL-6, (FIG. 7E) TIMP1, and (FIG. 7F) MMP2 was analysed by ELISA. Fluorescence was normalized to the control group without stimulation. [Mean.+-.SD, Dunnett]*P<0.05, **P<0.01, ***P<0.001 or ****P<0.0001.

[0341] FIGS. 8A and 8B. Graphs and images showing the effect of neutralisation of IL-11 on collagen production triggered by TGF.beta.1. Collagen production by cardiac fibroblasts with or without stimulation with TGF.beta.1, and in the presence/absence of neutralising anti-IL-11 antibody or isotype control IgG, as determined by (FIG. 8A) Operetta assay or (FIG. 8B) Sirius Red staining. [Mean.+-.SD, Dunnett]*P<0.05, **P<0.01, ***P<0.001 or ****P<0.0001.

[0342] FIG. 9. Graphs showing the ability of various IL-11 and IL-11R.alpha. antagonists to inhibit fibrosis. Human atrial fibroblasts were treated with neutralizing antibody against IL-11, neutralizing antibody against IL-11R.alpha., decoy IL-11 receptor molecule that binds to IL-11, siRNA that downregulates IL-11 expression or siRNA that downregulates IL-11RA expression and the effect on the TGF.beta.1-driven pro-fibrotic response in fibroblasts in vitro was analysed. [Mean.+-.SD, Dunnett]*P<0.05, **P<0.01, ***P<0.001 or ****P<0.0001.

[0343] FIGS. 10A to 10D. Bar charts showing the response of fibroblasts from IL-11-RA knockout mice to pro-fibrotic treatment. Fibroblasts derived from IL-11RA WT (+/+), Heterozygous (+/-) and Homozygous null (-/-) mice were incubated for 24 h with TGF.beta.1, IL-11 or AngII (5 ng/ml). (FIG. 10A) Percentage of myofibroblasts as determined by analysis .alpha.SMA content, (FIG. 10B) Percentage proliferating cells as determined by staining for EdU, (FIG. 10C) Collagen content and (FIG. 10D) ECM production as measured by detection of periostin [Mean.+-.SD].

[0344] FIGS. 11A and 11B. Graphs showing the effect of IL-11 neutralisation on fibrosis in response to various pro-fibrotic stimuli. Fibroblasts were cultured in vitro in the presence/absence of various different pro-fibrotic factors, and in the presence/absence of neutralising anti-IL-11 antibody or pan anti-TGF6 antibody (FIG. 11A) Collagen production and (FIG. 11B) myofibroblast generation as determined by analysis of .alpha.SMA expression. [Mean.+-.SD, Dunnett]*P<0.05, **P<0.01, ***P<0.001 or ****P<0.0001.

[0345] FIGS. 12A to 12D. Bar charts showing expression of markers of fibrosis in the atrium and heart of WT and IL-11RA (-/-) animals following treatment with AngII treatment. (FIG. 12A) Collagen content, as measured by hydroxyproline assay. (FIG. 12B) Collagen (Col1A2) expression. (FIG. 12C) .alpha.SMA (ACTA2) expression. (FIG. 12D) Fibronectin (Fn1) expression.

[0346] FIGS. 13A to 13C. Schematics of the experimental procedures for analysing fibrosis in (FIG. 13A) lung, (FIG. 13B) skin and (FIG. 13C) eye for IL-11RA-/- mice as compared to IL-11RA+/+ mice.

[0347] FIGS. 14A and 14B. Scatterplots showing fold change in gene expression. (FIG. 14A) Fold changes in gene expression in fibroblasts following stimulation with TGF.beta.1, IL-11 or TGF.beta.1 and IL-11. (FIG. 14B) Fold changes in gene expression in fibroblasts obtained from IL-11RA+/+ and IL-11RA-/- mice following stimulation with TGF.beta.1.

[0348] FIG. 15. Light chain variable domain sequences for human anti-IL-11 antibody clones. CDRs are underlined and shown separately.

[0349] FIG. 16. Heavy chain variable domain sequences for human anti-IL-11 antibody clones. CDRs are underlined and shown separately.

[0350] FIG. 17. Table showing light chain CDR sequences for human anti-IL-11 antibody clones.

[0351] FIG. 18. Table showing heavy chain CDR sequences for human anti-IL-11 antibody clones.

[0352] FIGS. 19A to 19C. Tables showing light chain CDR sequences for human anti-IL-11 antibody clones and consensus sequences, for (FIG. 19A) LC-CDR1, (FIG. 19B) LC-CDR2 and (FIG. 19C) LC-CDR3.

[0353] FIGS. 20A to 20C. Tables showing heavy chain CDR sequences for human anti-IL-11 antibody clones and consensus sequences, for (FIG. 20A) HC-CDR1, (FIG. 20B) HC-CDR2 and (FIG. 20C) HC-CDR3.

[0354] FIG. 21. Table summarising panning strategies used to identify human anti-human IL-11 antibodies capable of binding to both human IL-11 and mouse IL-11.

[0355] FIG. 22. Scatterplot showing strength of binding signal to human IL-11 and mouse IL-11 as determined by ELISA assay for 86 human anti-IL-11 antibody candidates.

[0356] FIG. 23. Table summarising the 56 human anti-human IL-11 antibody clones.

[0357] FIGS. 24A and 24B. Bar charts showing inhibition by the human anti-IL-11 antibodies of signalling mediated by IL-11 in vitro in human atrial fibroblasts, as determined by fold change in the percentage of .alpha.SMA positive cells as compared to control (unstimulated) fibroblasts, following stimulation with TGF.beta.1, in the presence of the human anti-IL-11 antibodies. (FIG. 24A) Bar chart showing fold change in proportion of .alpha.SMA-positive cells relative to unstimulated cells (=1). (FIG. 24B) Bar chart showing the percentage of .alpha.SMA-positive cells (activated fibroblasts).

[0358] FIGS. 25A and 25B. Bar chart showing inhibition by the human anti-IL-11 antibodies of signalling mediated by IL-11 in vitro in (FIG. 25A) mouse atrial fibroblasts and (FIG. 25B) mouse dermal fibroblasts, as determined by fold change in the percentage of .alpha.SMA positive cells as compared to control (unstimulated) fibroblasts, following stimulation with TGF.beta.1, in the presence of the human anti-IL-11 antibodies.

[0359] FIG. 26. Bar chart showing inhibition by the human anti-IL-11 antibodies of IL-11 trans signalling mediated by hyper IL-11 in vitro in human atrial fibroblasts, as determined by fold change in the percentage of .alpha.SMA positive cells as compared to control (unstimulated) fibroblasts, following stimulation with hyper IL-11, in the presence of the human anti-IL-11 antibodies.

[0360] FIG. 27. Table summarising the fold-change data of FIGS. 24 to 26 for the 56 human anti-IL-11 antibodies. Antibody candidates numbered 1 to 56 correspond to clone designations as indicated in FIG. 23. Industry standard is monoclonal mouse anti-IL-11 IgG2A; Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA.

[0361] FIGS. 28A to 28F. Graphs showing binding of human anti-IL-11 antibodies to human IL-11 as determined by ELISA analysis. (FIG. 28A) ELISA for clones YU45-A3, YU45-A10, YU45-D11, YU45-E11, YU45-D12 and YU33-A2(IgG). (FIG. 28B) ELISA for clones YU45-G1, YU45-B2, YU45-A5, YU45-E3, YU45-F8 and YU33-H3(IgG). (FIG. 28C) ELISA for clones YU45-G8, YU45-F9, YU45-H10, YU45-F2, YU45-H3 and YU33-E3(IgG). (FIG. 28D) ELISA for clones YU45-A8, YU45-B5, YU45-D9, YU45-G7, YU45-B6 and YU45-F9. (FIG. 28E) ELISA for clones YU45-F5, YU46-B5, YU45-C1, YU46-A8, YU46-B6 and YU45-F9. (FIG. 28F) ELISA for clones YU46-E3, YU46-G8, YU46-D3, YU45-B6, YU45-C1 and YU45-F9.

[0362] FIG. 29. Table summarising EC.sub.50 values determined for binding of human anti-IL-11 antibodies to IL-11 as determined by ELISA analysis.

[0363] FIG. 30. Schematic representation of the process of antibody light chain shuffling.

[0364] FIG. 31. Table summarising the 16 mouse anti-human IL-11 antibody clones.

[0365] FIG. 32. Bar chart showing inhibition by the mouse anti-IL-11 antibodies of signalling mediated by IL-11 in vitro in human atrial fibroblasts, as determined by fold change in the percentage of .alpha.SMA positive cells as compared to control (unstimulated) fibroblasts, following stimulation with TGF.beta.1, in the presence of the mouse anti-IL-11 antibodies.

[0366] FIG. 33. Bar chart showing inhibition by the mouse anti-IL-11 antibodies of signalling mediated by IL-11 in vitro in mouse atrial fibroblasts, as determined by fold change in the percentage of .alpha.SMA positive cells as compared to control (unstimulated) fibroblasts, following stimulation with TGF.beta.1, in the presence of the mouse anti-IL-11 antibodies.

[0367] FIG. 34. Bar chart showing inhibition by the mouse anti-IL-11 antibodies of IL-11 trans signalling mediated by hyper IL-11 in vitro in human atrial fibroblasts, as determined by fold change in the amount of MMP2 in the cell culture supernatant as compared to control (unstimulated) fibroblasts, following stimulation with hyper IL-11, in the presence of the mouse anti-IL-11 antibodies.

[0368] FIG. 35. Table summarising the fold-change data of FIGS. 32 to 34 for the 16 mouse anti-IL-11 antibodies. Antibody candidates numbered 1 to 16 correspond to clone designations as indicated in FIG. 31. Industry standard is monoclonal mouse anti-IL-11 IgG2A; Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA.

[0369] FIGS. 36A and 36B. Table and bar chart showing binding of mouse-anti-IL-11 antibodies to human IL-11, as determined by iQue analysis (FIG. 36A) Table summarising the results of the experiments. (FIG. 36B) Bar chart showing strength of binding relative to the positive control anti-FLAG antibody (100%); numbers correspond to the clones as indicated in FIG. 35.

[0370] FIG. 37. Graphs showing the effect of IL-11RA knockout on folate-induced kidney fibrosis as measured by collagen content in kidney tissue.

[0371] FIGS. 38A and 38B. Photographs showing the effect of IL-11RA knockout on wound healing and fibrosis in the eye following trabeculectomy (filtration surgery). (FIG. 38A) Eye sections of IL-11RA+/+(WT) and IL-11 RA-/- (KO) animals 7 days after filtration surgery. (FIG. 38B) Maturation of collagen fibres as evaluated by picro-sirius red/polarization light technique (Szendroi et al. 1984, Acta Morphol Hung 32, 47-55); more fibrosis is observed in WT mice than KO mice.

[0372] FIGS. 39A to 39D. Graphs showing that IL-11 is required the pro-fibrotic effects of TGF.beta.1 in liver fibroblasts. Activation and proliferation of primary human liver fibroblasts, with or without stimulation with TGF.beta.1, and in the presence/absence of neutralising anti-IL-11 antibody or isotype control IgG, as measured by analysis of the proportion of (FIG. 39A) .alpha.-SMA positive cells, and (FIG. 39B) EdU positive cells, (FIG. 39C) Collagen positive cells and (FIG. 39D) Periostin positive cells as compared to the unstimulated cells (Baseline). [Mean.+-.SD, Dunnett]*P<0.05, **P<0.01, ***P<0.001 or ****P<0.0001.

[0373] FIG. 40. Bar chart showing that IL-11 is required for the pro-fibrotic effects of TGF.beta.1 in skin fibroblasts. Activation of mouse skin fibroblasts, with or without stimulation with TGF.beta.1, and in the presence/absence of neutralising anti-IL-11 antibody, as measured by analysis of the percentage of .alpha.-SMA positive cells (activated fibroblasts).

[0374] FIG. 41. Bar chart showing lung fibroblast cell migration with and without IL-11 signalling. Migration of lung fibroblasts from IL-11RA+/+(WT) and IL-11RA-/- (KO) animals was analysed in an in vitro scratch assay without stimulus, or in the presence of TGF.beta.1 or IL-11.

[0375] FIGS. 42A and 42B. Graphs showing fibroblast activation in response to hyper IL-11. Cells were stimulated with the indicated amount (in ng/ml) of hyper IL-11 or recombinant IL-11, and fibroblast activation was measured by analysis of the percentage of .alpha.-SMA positive cells. (FIG. 42A) and (FIG. 42B) present the results of two different experiments.

[0376] FIG. 43. Graph showing induction of IL-11 secretion in primary fibroblasts by hyper IL-11. Cells were stimulated with hyper IL-11, and IL-11RNA and native IL-11 protein levels were measured in the cell culture supernatant by ELISA at the indicated time points.

[0377] FIG. 44. Light chain variable domain sequences for human anti-IL-11 antibody clones after light chain shuffling. CDRs are underlined and shown separately.

[0378] FIG. 45. Heavy chain variable domain sequences for human anti-IL-11 antibody clones after light chain shuffling. CDRs are underlined and shown separately.

[0379] FIG. 46. Table showing light chain CDR sequences for human anti-IL-11 antibody clones after light chain shuffling.

[0380] FIG. 47. Table showing heavy chain CDR sequences for human anti-IL-11 antibody clones after light chain shuffling.

[0381] FIGS. 48A to 48C. Tables showing light chain CDR sequences for human anti-IL-11 antibody clones after light chain shuffling, and consensus sequences, for (FIG. 48A) LC-CDR1, (FIG. 48B) LC-CDR2 and (FIG. 48C) LC-CDR3.

[0382] FIGS. 49A to 49C. Tables showing heavy chain CDR sequences for human anti-IL-11 antibody clones after light chain shuffling, and consensus sequences, for (FIG. 49A) HC-CDR1, (FIG. 49B) HC-CDR2 and (FIG. 49C) HC-CDR3.

[0383] FIG. 50. Single-chain variable antibody fragment (ScFv) amino acid sequences for human anti-IL-11 antibody clones after light chain shuffling.

[0384] FIG. 51. Nucleotide sequences encoding scFv for human anti-IL-11 antibody clones after light chain shuffling.

[0385] FIG. 52. Table summarising panning strategies used to identify human anti-human IL-11 antibodies capable of binding to both human IL-11 and mouse IL-11, after light chain shuffling.

[0386] FIG. 53. Scatterplot showing binding signal to human IL-11 and mouse IL-11 as determined by ELISA assay for light chain-shuffled human anti-IL-11 antibodies. 66 antibodies displaying cross-reactive binding to human IL-11 and mouse IL-11 were identified (black circles). Antibodies displaying binding to mouse IL-11 only are indicated by grey circles.

[0387] FIGS. 54A and 54B. Bar chart (FIG. 54A) and Table (FIG. 54B) showing binding signal to human IL-11 and mouse IL-11 as determined by ELISA assay for the 64 unique light chain-shuffled human anti-IL-11 antibodies.

[0388] FIG. 55. Bar chart showing EC50 values in ng/ml for binding of the indicated light-chain shuffled anti-IL-11 antibodies to human IL-11, as determined by ELISA.

[0389] FIGS. 56A and 56B. Bar chart showing the effect of anti-IL-11 antibodies on MMP2 secretion by human cardiac atrial fibroblasts in response to TGF.beta.1 FIGS. 56A and 56B show the results of two separate experiments. Cells were cultured in the presence of TGF.beta.1 (5 ng/ml) for 24 hours, in the presence of the indicated light chain shuffled anti-IL-11 antibodies, or in the presence of human IgG1 isotype control. Basal MMP2 secretion by the cells in culture was measured by culture in the absence of TGF.beta.1, in the presence of human IgG1 isotype control. Horizontal lines show basal MMP2 secretion by cardiac atrial human fibroblasts cultured for 24 hours in the presence of human IgG1 isotype control antibody in the absence of TGF.beta.1 (NEG); and MMP2 secretion by cardiac atrial human fibroblasts cultured for 24 hours in the presence of 5 ng/ml TGF.beta. and the human IgG1 isotype control antibody (POS).

[0390] FIG. 57. Table summarising the results of FIGS. 55 and 56 relating to functional characterisation of the indicated light-chain shuffled anti-IL-11 antibody clones. N.D=not determined.

[0391] FIGS. 58A and 58B. Images and graph showing the results of histological analysis of kidney sections from mice subjected to different treatments in a mouse model of kidney fibrosis. Kidney fibrosis was induced by intraperitoneal (IP) injection of folic acid (FA, 180 mg/kg) in vehicle (0.3M NaHCO.sub.3) mice; control mice were administered vehicle alone. Mice were administered isotype control IgG2 (20 mg/kg, 3.times. per week, intraperitoneal), anti-IL-11 antibody (20 mg/kg, 3.times. per week, intraperitoneally) from day 1 post folic acid injury and for the duration of the experiment. Animals were sacrificed 28 days after folic acid-induced kidney damage and analysed for fibrosis histologically using Masson's Trichrome stain. (FIG. 58A) Images of Masson's Trichrome stained kidney sections. Fibrotic areas containing collagen appear darker as compared to healthy areas that appear lighter. (FIG. 58B) Graphs showing semi-quantitative analysis of collagen area expressed as a percentage (%) of the total kidney area (graph). ***, P<0.001 compared to FA+IgG, ANOVA.

[0392] FIG. 59. Graph showing the urinary albumin/creatine ratio in mice subjected to different treatments in a mouse model of kidney fibrosis. Kidney fibrosis was induced by intraperitoneal (IP) injection of folic acid (FA, 180 mg/kg) in vehicle (0.3M NaHCO.sub.3) mice; control mice were administered vehicle alone. FA treated mice were administered isotype control IgG2 (20 mg/kg, 3.times. per week, intraperitoneal) or anti-IL11 antibody (20 mg/kg, 3.times. per week, intraperitoneal) from day 1 post folic acid injury and for the duration of the experiment. Mice were placed in metabolic cages and urinary creatinine and albumin measured using commercial assays (Abcam) according to the manufacturer's instructions. ***, P<0.001 compared to FA+IgG, ANOVA.

[0393] FIG. 60. Graph showing total collagen in kidney tissue in mice subjected to different treatments in a mouse model of kidney fibrosis. Kidney fibrosis was induced by intraperitoneal (IP) injection of folic acid (FA, 180 mg/kg) in vehicle (0.3M NaHCO.sub.3) mice; control mice were administered vehicle alone. From day one of the experiment, mice in the treatment groups were given isotype control IgG2 (20 mg/kg, 3.times. per week) or neutralizing anti-IL11 antibody at varying doses: 20 mg/kg.times.3/week; 10 mg/kg.times.3/week; 10 mg/kg.times.2/week; 5 mg/kg.times.3/week; 5 mg/kg.times.2/week; 1 mg/kg.times.2/week), all intraperitoneal. Animals were sacrificed 28 days post-injection and kidney analysed for fibrosis (micrograms/g (.mu.g/g)) by hydroxyproline assay using Quickzyme Total Collagen assay kit (Quickzyme Biosciences) according to the manufacturer's protocol. **, P<0.01; ***, P<0.001 compared to FA+IgG, ANOVA.

[0394] FIGS. 61A and 61B. Images and graph showing the results of histological analysis of kidney sections from mice subjected to different treatments in a mouse model of acute renal injury. (FIG. 61A) Mice were treated by sham operation or ureteric obstruction of one ureter. Mice received IgG, anti-IL-11 antibody (20 mg/kg on surgical days -1, 1, 3, 5) and injured kidneys (UUO IgG, IL-11) or contralateral (Con) uninjured kidneys (Con IgG, IL-11) were harvested on day 7 post surgery. (FIG. 61B) Semi-quantitative assessment of tubular injury was determined by histological analysis of casts, tubular atrophy or tubular expansion blinded to experimental conditions (Tubular injury score: 0, none; 1, minimal; 2, mild; 3, moderate; 4, severe). *, P<0.05 compared to UUO IgG, ANOVA.

[0395] FIG. 62. Image showing the results of ELISA western blot for IL-11 of human liver samples. Liver samples obtained from patients undergoing liver surgery were used for western blot analysis. Blotting of GAPDH was used as a loading control. Samples from normal human liver (NHL) had low levels of IL-11 protein, whereas samples from patients with fibrotic liver diseases including alcoholic liver disease (ALD), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) or non-alcoholic steatohepatitis (NASH) had higher levels of IL-11.

[0396] FIG. 63. Bar chart showing the results of ELISA analysis of secretion of IL-11 by human PCLS subjected to different treatments.

[0397] FIGS. 64A and 64B. Images and graph showing the results of analysis of liver tissue from mice subjected to different treatments in a mouse model of nonalcoholic steatohepatitis. Diabetic mice (db/db; deficient for the leptin receptor) were maintained for 8 weeks on a normal chow diet (left, round symbols) or on a NASH-inducing (methionine/choline deficient (MCD)) diet. In a subset of animals neutralizing anti-IL11 antibody was administered (20 mg/kg, 3.times./week, intraperitoneal) for the final 3 weeks of the 8 week NASH diet. Liver samples were photographed (FIG. 64A) and assessed for collagen content per mg of liver tissue (FIG. 64B); each symbol represents an individual animal. P values shown on graph, ANOVA.

[0398] FIGS. 65A and 65B. Bar chart and images showing the results of analysis of eye fibrosis from mice subjected to different treatments in a mouse model of retinal fibrosis. Mice (10 per group) were subjected to laser-induced retinal damage (4 burns per retina) and administered intraocularly with 0.5 .mu.g of anti-IL-11 antibody or IgG control antibody on days 1, 7, 14 and 21. Eyes were harvested for histological analyses on day 28. The area of fibrosis at burn sites were measured by Masson's Trichrome staining. (FIG. 65A) Bar cahrt showing quantification of the fibrosis areas in control (IgG) or anti-IL11 (IL11) treated mice. (FIG. 65B) representative images showing staining of fibrotic areas in control antibody treated eyes (IGG, top panel) or anti-IL11 treated eyes (IL11, bottom panel).

[0399] FIGS. 66A to 66C. Schematic, images and bar chart relating to analysis of skin fibrosis in mice subjected to different treatments in a mouse model of skin fibrosis. (FIG. 66A) Schematic representation of experimental procedures for different treatment groups. Groups 1 and 2 were treated with bleomycin (BLM), and either anti-IL-11 antibody (Group 1) or IgG control antibody (Group 2). Group 3 were injected with vehicle (PBS) only and do not develop fibrosis. (FIG. 66B) Images showing Masson's trichrome staining of skin section at equal distances from the injection site. Dermal thickness is indicated by the black bar. (FIG. 66C) Bar chart showing the results of analysis of dermal thickness (blinded for treatment groups). Average dermal thickness was determined from the bottom of epithelial layer to top of dermal white adipose tissue layer across 40 fields of view per sample. Each point indicates an animal. P value was calculated using an unpaired two-tailed t-test.

[0400] FIG. 67. Images showing the results of histological analysis of heart fibrosis in mice subjected to different treatments in a mouse model of cardiac fibrosis. Mice (C57616, male, 8-12 weeks old) were subjected to fibrosis-inducing transverse aortic constriction (TAC) or sham operations. TAC-treated animals received either control antibody (20 mg/kg, 3x/week, intraperitoneal) or neutralizing anti-IL-11 antibody (20 mg/kg, 3x/week, intraperitoneal). After two weeks hearts were harvested and assessed for fibrosis extent using Masson's Trichrome stain.

[0401] FIG. 68. Heavy chain variable domain sequences for mouse anti-IL-11 antibody clones. CDRs are underlined and shown separately.

[0402] FIG. 69. Light chain variable domain sequences for mouse anti-IL-11 antibody clones. CDRs are underlined and shown separately.

[0403] FIG. 70. Table showing heavy chain CDR sequences for mouse anti-IL-11 antibody clones.

[0404] FIG. 71. Table showing light chain CDR sequences for mouse anti-IL-11 antibody clones.

[0405] FIGS. 72A to 72C. Tables showing heavy chain CDR sequences for mouse anti-IL-11 antibody clones, and consensus sequences, for (FIG. 72A) HC-CDR1, (FIG. 72B) HC-CDR2 and (FIG. 72C) HC-CDR3.

[0406] FIGS. 73A to 73C. Tables showing light chain CDR sequences for mouse anti-IL-11 antibody clones, and consensus sequences, for (FIG. 73A) LC-CDR1, (FIG. 73B) LC-CDR2 and (FIG. 73C) LC-CDR3.

[0407] FIG. 74. Nucleotide sequences encoding mouse anti-IL-11 antibody clone heavy chains and light chains.

EXAMPLES

[0408] In the following Examples, the inventors identify a role for IL-11/IL-11R signalling in fibrosis in a variety of tissues, and described the generation of anti-human IL-11 antibodies, and in vitro and in vivo functional characterisation of the antibodies.

Example 1: A Role for IL-11 in Fibrosis

[0409] 1.1 IL-11 is Upregulated in Fibrosis

[0410] To understand the molecular processes underlying the transition of fibroblasts to activated myofibroblasts, atrial tissue was obtained from more than 200 patients that underwent cardiac bypass surgery at the National Heart Centre Singapore. Cells were cultured in vitro at low passage (passage <4), and either not stimulated or stimulated with TGF.beta.1 for 24h. We subsequently performed high-throughput RNA sequencing (RNA-seq) analysis of unstimulated fibroblasts and cells stimulated with the prototypic pro-fibrotic stimulus TGF.beta.1 across 160 individuals; average read depth was .about.70M reads per sample (paired-end 100 bp; FIG. 1).

[0411] To ensure the purity of the atrial fibroblast cell cultures, we analysed expression of endothelial cell, cardiomyocyte and fibroblast cell type marker genes from the atrium (Hsu et al., 2012 Circulation Cardiovasc Genetics 5, 327-335) in the RNA-seq dataset.

[0412] The results are shown in FIGS. 2A to 2E, and confirm the purity of the atrial fibroblast cultures.

[0413] Gene expression was assessed by RNA-seq of the tissue of origin (human atrial tissues samples, n=8) and primary, unstimulated fibroblast cultures. No/very low expression of the endothelial cell marker PECAM1 (FIG. 2A), and the cardiomyocyte markers MYH6 (FIG. 2B) and TNNT2 (FIG. 2C) was detected in the fibroblast cell culture samples. Markers for fibroblasts COL1A2 (FIG. 2D) and ACTA2 (FIG. 2E) were highly expressed compared to the tissue of origin.

[0414] Next, the RNA-seq data was analysed to identify genes whose expression was increased or decreased upon stimulation with TGF.beta.1, and this information was integrated with the large RNA-seq dataset across 35+ human tissues provided by the GTEx project (The GTEx Consortium, 2015 Science 348, 648-660). This enabled the identification of gene expression signatures that were specific to the fibroblast-myofibroblast transition.

[0415] The results are shown in FIGS. 3A to 3E. Across the 10000+ genes expressed in the fibroblasts, IL-11 was the most strongly upregulated gene in response to stimulation with TGF.beta.1, and on average across the 160 individuals was upregulated more than 10-fold (FIG. 3B).

[0416] Upregulation of IL-11 expression was confirmed by ELISA analysis of the cell culture supernatant of TGF.beta.1 stimulated fibroblasts (FIG. 3C). As compared to the level of expression level of IL-11 in other tissues of healthy individuals, this response was observed to be highly specific to activated fibroblasts (FIG. 3D). Various fold changes of IL-11RNA expression were also confirmed by qPCR analysis (FIG. 3E).

[0417] Next, fibroblasts were cultured in vitro and stimulated with several other known pro-fibrotic factors: ET-1, ANGII, PDGF, OSM and IL-13, and also with human recombinant IL-11. For analysing upregulation of IL-11 produced in response to stimulation with IL-11, it was confirmed that the ELISA was only able to detect native IL-11 secreted from cells and does not detect recombinant IL-11 used for the stimulations (FIG. 4B).

[0418] The results are shown in FIG. 4A. Each factor was found to significantly induce IL-11 secretion from fibroblasts. IL-11 is shown to act in an autocrine loop in fibroblasts, which can result in an upregulation of IL-11 protein as much as 100-fold after 72 hours (FIG. 4D).

[0419] Interestingly, this autocrine loop for IL-11 is similar to the autocrine production of IL-6. IL-6 is from the same cytokine family and also signals via the gp130 receptor (Garbers and Scheller, 2013 Biol Chem 394, 1145-1161), which is proposed to ensure the continued survival and growth of lung and breast cancer cells (Grivennikov and Karin, 2008 Cancer Cell 13, 7-9).

[0420] No increase in IL-11RNA level was detected in response to stimulation with IL-11 (FIG. 4D). Unlike TGF.beta.1, which increases IL-11 expression at both the RNA and protein level, therefore IL-11 seems to upregulate IL-11 expression only at the post-transcriptional level.

[0421] 1.2 IL-11 has a Profibrotic Role in Fibrosis of Heart Tissue

[0422] To explore whether the autocrine production of IL-11 is pro- or anti-fibrotic, fibroblasts were cultured in vitro with recombinant IL-11, and the fraction of myofibroblasts (.alpha.SMA-positive cells) and extracellular matrix production was analysed.

[0423] The expression of .alpha.SMA, collagen and periostin was monitored with the Operetta High-Content Imaging System in an automated, high-throughput fashion. In parallel, secretion of fibrosis marker proteins such as MMP2, TIMP1 and IL-6 was analysed by ELISA assays, and the levels of collagen were confirmed by calorimetric Sirius Red analysis of the cell culture supernatant.

[0424] Briefly, atrial fibroblasts derived from 3 individuals were incubated in 2 wells each for 24 h without stimulation, with TGF.beta.1 (5 ng/ml), or with IL-11 (5 ng/ml). Following incubation, cells were stained to analyse .alpha.-SMA content to estimate the fraction of myofibroblasts, and for collagen and periostin to estimate ECM production. Fluorescence was measured in 7 fields per well. The supernatant of 2 wells per individual was also assessed for collagen content by Sirius Red staining. The signal was normalized to the control group without stimulation. Secretion of the fibrosis markers IL-6, TIMP1 and MMP2 was analysed via ELISA.

[0425] The results are shown in FIGS. 5A to 5F. TGF.beta.1 activated fibroblasts and increased ECM production (FIG. 5A). Unexpectedly, and in contrast with the anti-fibrotic role described for IL-11 in heart tissue in the scientific literature, recombinant IL-11 caused an increase in the fraction of myofibroblasts in fibroblast cultures, and also promoted the production of extracellular matrix proteins collagen and periostin to the same extent as TGF.beta.1 (FIG. 5A). Both of IL-11 and TGF.beta.1 cytokines also significantly increased the secretion of pro-fibrotic markers IL-6, TIMP1 and MMP2 (FIGS. 5B to 5E), and to a similar level.

[0426] The inventors hypothesized that the contradiction between the present finding that IL-11 is profibrotic in heart tissue and the antifibrotic role described in the literature might be related to the use of human IL-11 in rodents in those previous studies (Obana et al., 2010, 2012; Stangou et al., 2011; Trepicchio and Dorner, 1998).

[0427] To investigate this hypothesis, serial dilutions of both human and mouse IL-11 were performed, and the activation of human atrial fibroblasts was monitored (FIG. 5F). No activation of fibroblasts was observed at low concentrations of human IL-11 on mouse cells, suggesting that previous insights into IL-11 function may in part be due to IL-11-non-specific observations.

[0428] 1.3 IL-11 has a Profibrotic Role in Fibrosis of a Variety of Tissues

[0429] To test whether the profibrotic action of IL-11 was specific to atrial fibroblasts, human fibroblasts derived from several different tissues (heart, lung, skin, kidney and liver) were cultured in vitro, stimulated with human IL-11, and fibroblast activation and ECM production was analysed as described above. Increased fibroblast activation and production of ECM was observed as compared to non-stimulated cultures in fibroblasts derived from each of the tissues analysed.

[0430] 1.3.1 Liver Fibrosis

[0431] To test whether IL-11 signalling is important in liver fibrosis, human primary liver fibroblasts (Cell Biologics, Cat#: H-6019) were cultured at low passage in wells of 96-well plates and either not stimulated, stimulated with TGF.beta.1 (5 ng/ml, 24h), IL-11 (5 ng/ml, 24h) or incubated with both TGF.beta.1 (5 ng/ml) and a neutralising IL-11 antibody (2 .mu.g/ml), or TGF.beta.1 (5 ng/ml) and an Isotype control antibody. Fibroblast activation (.alpha.SMA positive cells), cell proliferation (EdU positive cells) and ECM production (Periostin and Collagen) was analysed using the Operetta platform.

[0432] The results of the experiments with primary human liver fibroblasts are shown in FIGS. 39A to 39D. IL-11 was found to activate liver fibroblasts, and IL-11 signalling was found to be necessary for the profibrotic action of TGF.beta.1 in liver fibroblasts. Both activation and proliferation of fibroblasts was inhibited by neutralising anti-IL-11 antibody.

[0433] 1.3.2 Skin Fibrosis

[0434] To test whether IL-11 signalling is important in skin fibrosis, primary mouse skin fibroblasts were cultured at low passage in wells of 96-well plates and either not stimulated, stimulated with TGF.beta.1 (5 ng/ml, 24h) or incubated for 24 h with both TGF.beta.1 (5 ng/ml) and a neutralising IL-11 antibody (2 .mu.g/ml). Fibroblast activation (.alpha.SMA positive cells) was then analysed using the Operetta platform.

[0435] The results are shown in FIG. 40. TGF.beta.1-mediated activation of skin fibroblasts was inhibited by neutralising anti-IL-11 antibody.

[0436] 1.3.3 Fibrosis in Multiple Organs

[0437] Next, mouse recombinant IL-11 was injected (100 .mu.g/kg, 3 days/week, 28 days) into mice to test whether IL-11 can drive global tissue fibrosis in vivo.

[0438] The results are shown in FIGS. 6A to 6C. Compared to injection of AngII (a cytokine that causes an elevation in blood pressure and hypertrophy of the heart), IL-11 also increased the heart weight but also kidney, lung and liver weight indexed to body weight (FIG. 6B). Assessing collagen content in these issues by hydroxyproline assay revealed an upregulation of collagen production in these tissues, indicating fibrosis as the likely cause for the increase in organ weight (FIG. 6C). Expression of fibrosis marker genes ACTA2 (=.alpha.SMA), Col1a1, Col3a1, Fn1, Mmp2 and Timp1 was also detected by qPCR analysis of RNA isolated from heart, kidney, lung and liver tissues of these animals

Example 2: Therapeutic Potential of IL-11/IL-11R Antagonism

[0439] 2.1 Inhibition of the Fibrotic Response Using Neutralising Antagonists of IL-11/IL-11R

[0440] Next it was investigated whether the autocrine loop of IL-11 secretion was required for the pro-fibrotic effect of TGF.beta.1 on fibroblasts.

[0441] IL-11 was inhibited using a commercially available neutralizing antibody (Monoclonal Mouse IgG2A; Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA). Fibroblasts were treated with TGF.beta.1 in the presence or absence of the antibody, and fibroblast activation, the proportion of proliferating cells and ECM production and markers of the fibrotic response were measured.

[0442] Briefly, atrial fibroblasts derived from 3 individuals were incubated for 24 h with TGF.beta.1 (5 ng/ml) or TGF.beta.1 in the presence of neutralising anti-IL-11 antibody or isotype control antibody. Following incubation, cells were stained for .alpha.SMA to determine the fraction of myofibroblasts, the proportion of proliferating cells was determined by analysing the cells for EdU incorporation, and periostin was measured to determine ECM production. Fluorescence was measured with the Operetta platform for 14 fields across 2 wells for each individual. Secretion of the fibrosis markers IL-6, TIMP1 and MMP2 was also analysed by ELISA. Fluorescence was normalized to the control group without stimulation.

[0443] The results are shown in FIGS. 7A to 7F. IL-11 inhibition was found to ameliorate TGF.beta.1-induced fibrosis, and it was shown that IL-11 is essential for the pro-fibrotic effect of TGF.beta.1. Inhibition of IL-11 was found to `rescue` the TGF.beta.1 phenotype at the protein level.

[0444] Collagen production was also analysed. Cardiac fibroblasts derived from 3 individuals were incubated for 24 h with TGF.beta.1 (5 ng/ml) or TGF.beta.1 and a neutralizing IL-11 antibody. Following incubation the cells were stained for collagen using the Operetta assay and florescence was quantified as described above. Secreted collagen levels in the cell culture supernatant were assessed by Sirius Red staining.

[0445] The results are shown in FIGS. 8A and 8B, and confirm the anti-fibrotic effect of inhibition of IL-11 using a neutralising antibody.

[0446] Next, the ability of several other IL-11/IL-11R antagonists to inhibit fibrosis was analysed in vitro using the atrial fibroblast, TGF.beta.1-induced myofibroblast transition assay described herein above.

[0447] Briefly, human atrial fibroblasts cells were cultured in vitro, stimulated for 24 h with TGF.beta.1 (5 ng/ml) or left unstimulated, in the presence/absence of: (i) neutralising anti-IL-11 antibody, (ii) a IL-11RA-gp130 fusion protein (iii) neutralising anti-IL-11RA antibody, (iv) treatment with siRNA directed against IL-11 or (v) treatment with siRNA directed against IL-11RA. The proportion of activated fibroblasts (myofibroblasts) was analysed by evaluating .alpha.SMA content as described above.

[0448] The results are shown in FIG. 9. Each of the antagonists of IL-11/IL-11R signalling was found to be able to abrogate TGF.beta.1-mediated profibrotic response.

Example 3: In Vivo Confirmation of a Profibrotic Role for IL-11/IL-11R Signalling

[0449] 3.1 In Vitro Studies Using Cells Derived from IL-11RA Gene Knock-Out Mice

[0450] All mice were bred and housed in the same room and provided food and water ad libitum. Mice lacking functional alleles for IL-11R.alpha. (IL-11RA1 KO mice) were on C57131/6 genetic background. Mice were of 9-11 weeks of age and the weight of animals did not differ significantly.

[0451] To further confirm the anti-fibrotic effect of inhibition of IL-11 signalling, primary fibroblasts were generated from IL-11RA gene knock-out mice and incubated with primary fibroblast cells harvested from IL-11RA+/+(i.e. wildtype), IL-11RA+/-(i.e. heterozygous knockout) and IL-11RA-/- (i.e. homozygous knockout) animals with TGF.beta.1, IL-11 or AngII. Activation and proliferation of fibroblasts and ECM production was analysed.

[0452] Fibroblasts derived from IL-11RA+/+, IL-11RA+/- and IL-11RA-/- mice were incubated for 24 hours with TGF.beta.1, IL-11 or AngII (5 ng/ml). Following incubation, cells were stained for .alpha.SMA content to estimate the fraction of myofibroblasts, for EdU to identify the fraction of proliferating cells, and for collagen and periostin to estimate ECM production. Fluorescence was measured using the Operetta platform.

[0453] The results are shown in FIGS. 10A to 10D. IL-11RA-/- mice were found not to respond to pro-fibrotic stimuli. These results suggested that IL-11 signalling is also required for AngII-induced fibrosis.

[0454] Next, it was investigated whether this was also true for other pro-fibrotic cytokines.

[0455] Briefly, fibroblasts were cultured in vitro in the presence/absence of various different pro-fibrotic factors (ANG2, ET-1 or PDGF), and in the presence/absence of neutralising anti-IL-11 antibody or pan anti-TGF.beta. antibody. After 24 hours, collagen production by the cells was determined by analysis using the Operetta system as described above, and myofibroblast generation was determined by analysis of .alpha.SMA expression as described above.

[0456] The results are shown in FIGS. 11A and 11B. IL-11 was found to be required for fibrosis downstream of various profibrotic stimuli, and was thus identified as a central mediator of fibrosis induced by a variety of different profibrotic factors.

[0457] In a further experiment, the role of IL-11 signalling was investigated in lung fibrosis, using an in vitro scratch assay of migration of lung fibroblasts. In response to pro-fibrotic stimuli, fibroblasts are activated and migrate within the fibrotic niche in the body. The migration rate of cells is a measure of cell-cell and cell-matrix interactions and a model for wound healing in vivo (Liang et al., 2007; Nat Protoc. 2(2):329-33).

[0458] Fibroblasts derived from lung tissue from both wild type (WT) and also homozygous IL-11RA (-/-) knockout mice were grown at low passage on a plastic surface until they formed a uniform cell monolayer. A scratch was then created in the cell layer, and cell migration close to the scratch was monitored, either in the absence of stimulation, or in the presence of TGF.beta.1 or IL-11. Images captured at images at the two time points of immediately after creating the scratch and at 24 h were used to determine the area covered by cells, and the rate of migration was compared between WT and KO fibroblasts. Cell migration (area in the scratch covered by cells after 24h) was normalized to the migration rate of WT cells without stimulus.

[0459] The results are shown in FIG. 41. Lung fibroblasts derived from WT mice were shown to migrate faster in the presence of TGF.beta.1 and IL-11, indicating a pro-fibrotic effect of both cytokines in lung fibroblasts. Cells lacking IL-11 signalling derived from KO mice migrated more slowly as compared to WT cells. They also did not migrate faster in the presence of TGF.beta.1. The scratch assay revealed that lung fibroblasts lacking IL-11 signalling have a decrease cell migration rate both in the presence of TGF.beta.1 or IL-11, and at baseline. Thus, inhibition of IL-11 signalling is anti-fibrotic in the lung.

[0460] 3.2 Heart Fibrosis

[0461] The efficacy of IL-11 inhibition to treat fibrotic disorders was investigated in vivo. A mouse model for cardiac fibrosis, in which fibrosis is induced by treatment with AngII, was used to investigate whether IL-11RA-/- mice were protected from cardiac fibrosis.

[0462] Briefly, a pump was implanted, and wildtype (WT) IL-11RA(+/+) and knockout (KO) IL-11RA(-/-) mice were treated with AngII (2 mg/kg/day) for 28 days. At the end of the experiment, collagen content was assessed in the atria of the mice using a calorimetric hydroxyproline-based assay kit, and the level of RNA expression of the markers or fibrosis Col1A2, .alpha.SMA (ACTA2) and fibronectin (Fn1) were analysed by qPCR.

[0463] The results are shown in FIGS. 12A to 12D. The IL-11RA-/- mice were found to be protected from the profibrotic effects of AngII.

[0464] 3.3 Kidney Fibrosis

[0465] A mouse model for kidney fibrosis was established in wildtype (WT) IL-11RA(+/+) and knockout (KO) IL-11 RA(-/-) mice by intraperitoneal injection of folic acid (180 mg/kg) in vehicle (0.3M NaHCO.sub.3); control mice were administered vehicle alone.

[0466] Kidneys were removed 28 days post-injection, weighed and either fixed in 10% neutral-buffered formalin for Masson's trichrome and Sirius staining or snap-frozen for collagen assay, RNA, and protein studies.

[0467] Total RNA was extracted from the snap-frozen kidney using Trizol reagent (Invitrogen) and Qiagen TissueLyzer method followed by RNeasy column (Qiagen) purification. The cDNA was prepared using iScript.TM. cDNA synthesis kit, in which each reaction contained 1 .mu.g of total RNA, as per the manufacturer's instructions. Quantitative RT-PCR gene expression analysis was performed on triplicate samples with either TaqMan (Applied Biosystems) or fast SYBR green (Qiagen) technology using StepOnePlus.TM. (Applied Biosystem) over 40 cycles. Expression data were normalized to GAPDH mRNA expression level and we used the 2-.DELTA..DELTA.Ct method to calculate the fold-change. The snap-frozen kidneys were subjected to acid hydrolysis by heating in 6M HCl at a concentration of 50 mg/ml (95.degree. C., 20 hours). The amount of total collagen in the hydrolysate was quantified based on the colorimetric detection of hydroxyproline using Quickzyme Total Collagen assay kit (Quickzyme Biosciences) as per the manufacturer's instructions.

[0468] The results of the analysis are shown in FIG. 37. Folate-induced kidney fibrosis is shown to be dependent on IL-11 mediated signalling. A significant increase in collagen content in kidney tissue was observed in IL-11 RA+/+ mice, indicative of kidney fibrosis. No significant increase in collagen content was observed in IL-11 RA-/- mice. Animals deficient for IL-11 signalling had significantly less collagen deposition in kidneys after toxic injury as compared to wild type animals.

[0469] 3.4 Lung Fibrosis

[0470] IL-11 is confirmed as a key mediator of fibrosis in the lung, skin and eye in further in vivo models using the IL-11RA-/- knockout mice. Schematics of the experiments are shown in FIGS. 13A to 13C.

[0471] To analyse pulmonary fibrosis, IL-11RA-/- mice and IL-11RA+/+ mice are treated by intratracheal administration of bleomycin on day 0 to establish a fibrotic response in the lung (pulmonary fibrosis). Fibrosis of the lung develops by 21 days, at which point animals are sacrificed and analysed for differences in fibrosis markers between animals with and without IL-11 signalling. IL-11RA-/- mice have a reduced fibrotic response in lung tissue as compared to IL-11RA+/+ mice, as evidenced by reduced expression of markers of fibrosis.

[0472] 3.5 Skin Fibrosis

[0473] To analyse fibrosis of the skin, IL-11RA-/- mice and IL-11RA+/+ mice are treated by subcutaneous administration of bleomycin on day 0 to establish a fibrotic response in the skin. Fibrosis of the skin develops by 28 days, at which point animals are sacrificed and analysed for differences in fibrosis markers between animals with and without IL-11 signalling. IL-11RA-/- mice have a reduced fibrotic response in skin tissue as compared to IL-11RA+/+ mice, as evidenced by reduced expression of markers of fibrosis.

[0474] 3.6 Eye Fibrosis

[0475] To analyse fibrosis in the eye, IL-11RA-/- mice and IL-11RA+/+ mice underwent trabeculectomy (filtration surgery) on day 0 to initiate a wound healing response in the eye. This mouse model of glaucoma filtration surgery has been shown to be an efficient model to evaluate the wound healing response in the eye (Khaw et al. 2001, Curr Opin Ophthalmol 12, 143-148; Seet et al. 2011, Mol. Med. 17, 557-567) and has successfully shown the beneficial effect of fibrotic modulators in vivo (Mead et al. 2003, Invest. Ophthalmol. Vis. Sci. 44, 3394-3401; Wong et al. 2003 Invest. Ophthalmol. Vis. Sci. 44, 1097-1103; Wong et al. 2005, Invest. Ophthalmol. Vis. Sci. 46, 2018-2022).

[0476] Briefly, the conjunctiva was dissected to expose the underlying sclera, after which an incision was made through the sclera into the anterior chamber of the eye using a 30-gauge needle. The created fistula allowed aqueous humor to exit into and underneath the conjunctiva. The dissected conjunctiva was then secured and closed at the limbus by a 10-0 (0.2 metric) Ethilon black monofilament nylon scleral suture. Fucithalmic ointment was instilled at the end of the procedure. The surgery was performed under anaesthesia by intraperitoneal injection of a 0.1 ml ketamine/xylazine mixture, as well as topical application of one drop per eye of 1% xylocaine. Fucithalmic ointment was instilled post-surgery to prevent infection. Surgery was performed with 70% propyl alcohol sterilized surgical scissors and forceps and sterile needles.

[0477] The accumulated fluid underneath the sutured conjunctiva was observed as a conjunctival bleb. Mice were euthanized on day 7 post-surgery for analyses. For qualitative immune-histological analyses, eyes from mice will be harvested by enucleation and then sectioned. Maturation of collagen fibres was evaluated with using the picro-sirius red/polarization light technique (Szendroi et al. 1984, Acta Morphol Hung 32, 47-55); orange-red indicated mature collagen, and yellow/green indicated newly formed immature collagen.

[0478] The results of the experiment are shown in FIGS. 38A and 38B. IL-11RA-/- mice were found to have a reduced fibrotic response in eye tissue as compared to IL-11RA+/+ mice.

[0479] 3.7 Other Tissues

[0480] The effect of IL-11RA knockout on fibrosis is also analysed in mouse models of fibrosis for other tissues, such as the liver, bowel, and is also analysed in a model relevant to multiorgan (i.e. systemic) fibrosis. The fibrotic response is measured and compared between the IL-11RA-/- mice and IL-11RA+/+ mice. IL-11RA-/- mice have a reduced fibrotic response as compared to IL-11RA+/+ mice, as evidenced by reduced expression of markers of fibrosis.

Example 4: Analysis of the Molecular Mechanisms Underlying IL-11-Mediated Induction of Fibrosis

[0481] The canonical mode of action of IL-11 is thought to be regulation of RNA expression via STAT3-mediated transcription (Zhu et al., 2015 PLoS ONE 10, e0126296), and also through activation of ERK.

[0482] STAT3 activation is observed following stimulation with IL-11 However, when fibroblasts are incubated with TGF.beta.1, only activation of the canonical SMACK pathway and ERK pathways is seen, and activation of STAT3 is not observed, even in spite of the fact that IL-11 is secreted in response to TGF.beta.1. Only ERK activation is common to both TGF.beta.1 and IL-11 signal transduction.

[0483] Cross-talk between TGF.beta.1 and IL-6 signalling has previously been described, wherein TGF.beta.1 blocks the activation of STAT3 by IL-6 (Walla et al., 2003 FASEB J. 17, 2130-2132). Given the dose relationship between IL-6 and IL-11, similar cross-talk may be observed for IL-11 mediated signalling.

[0484] The inventors investigated by RNA-seq analysis whether regulation of RNA abundance was the underlying mechanism for the increased expression of fibrosis marker proteins in response to IL-11, which would suggest STAT3 as the underlying signalling pathway for IL-11 mediated profibrotic processes. Fibroblasts were incubated for 24 hours either without stimulus, or in the presence of TGF.beta.1, IL-11 or TGF.beta.1 and IL-11, The results are shown in FIG. 14A. TGF.beta.1 induced the expression of collagen, ACTA2 (.alpha.SMA) and other fibrosis marker at the RNA level. However, IL-11 did not regulate the expression of these genes, but a different set of genes.

[0485] Gene ontology analysis suggests that a pro-fibrotic effect in fibroblasts is driven by IL-11-regulated RNA expression. Both TGF.beta.1 and IL-11 regulate an almost completely different set of genes on the RNA level.

[0486] Whilst TGF.beta.1 increases IL-11 secretion, the target genes of IL-11 are not regulated when both TGF.beta.1 and IL-11 are present. This suggests that TGF.beta.1 upregulates IL-11 and simultaneously blocks the canonical IL-11-driven regulation of RNA expression via STAT3, similar to what is known about the interaction of TGF.beta.1 and IL-6 pathways (Walia et al., 2003 FASEB J. 17, 2130-2132).

[0487] We also analysed whether RNA expression differences induced by TGF.beta.1 are dependent on IL-11 signalling, by analysing changes in RNA expression in fibroblasts obtained from IL-11RA-/- mice as compared to IL-11RA+4 mice. RNA expression regulated by TGF.beta.1 is still observed when IL-11RA knockout cells were stimulated with TGF.beta.1, and RNA levels of .alpha.SMA, collagen etc. were still upregulated in the absence of IL-11 signalling (in IL-11RA-/- fibroblasts). When the pro-fibrotic effect of IL-11 and the anti-fibrotic effect of IL-11 inhibition was investigated in vitro, reduced expression of markers of fibrosis was only observed at the protein level, not at the transcriptional level as determined by qPCR.

[0488] The activation of non-canonical pathways (e.g. ERK signal transduction) is known to be crucial for the pro-fibrotic action of TGF.beta.1 (Guo and Wang, 2008 Cell Res 19, 71-88). It is likely that non-canonical pathways are likely to be important for signalling for all known pro-fibrotic cytokines, and that IL-11 is a post-transcriptional regulator which is essential for fibrosis.

Example 5: Human Anti-Human IL-11 Antibodies

[0489] Fully human anti-human IL-11 antibodies were developed via phage display.

[0490] Recombinant human IL-11 (Cat. No. Z03108-1) and recombinant murine IL-11 (Cat. No. Z03052-1) were obtained from GenScript (NJ, USA). Recombinant human IL-11 was expressed in CHO cells, both as an Fc-tagged version and a tag-free version. Tag-free murine IL-11 was expressed in HEK293 cells.

[0491] IL-11 bioactivity of recombinant human IL-11 and mouse IL-11 was confirmed by in vitro analysis using primary fibroblast cell cultures.

[0492] Recombinant, biotinylated human IL-11 and murine IL-11 were also prepared by biotinylation of the recombinant human IL-11 and murine IL-11 molecules, according to standard methods.

[0493] Antibodies capable of binding to both human IL-11 and murine IL-11 (i.e. cross-reactive antibodies) were identified by phage display using a human nave library by panning using biotinylated and non-biotinylated recombinant human and murine IL-11, based on 16 different panning strategies as summarised in FIG. 21. The phage display identified 175 scFv binders, as `first hits`. Sequence analysis of the CDR sequences from these 175 scFv identified 86 unique scFv.

[0494] The soluble scFv were produced by recombinant expression in E. coli, and analysed for their ability to bind to human IL-11 and murine IL-11 by ELISA. Briefly, the respective antigen was coated to wells of an ELISA plate, the cell culture supernatant containing the respective scFv was added at a 1:2 dilution, and binding was detected.

[0495] The results of the ELISA analysis of binding to human IL-11 and murine IL-11 are shown in FIG. 22. The analysis revealed:

[0496] 8 scFV capable of binding only to human IL-11;

[0497] 6 scFv capable of binding to murine IL-11 only;

[0498] 32 scFv displaying only weak binding to human/murine IL-11, with a high signal to noise ratio, and;

[0499] 40 scFv having cross-reactivity for both human IL-11 and murine IL-11.

[0500] From these 86 scFV, 56 candidates were selected for further functional characterisation. For further analyses, the scFV were cloned into scFV-Fc format in E. coli.

[0501] The antibody clone designations are shown in FIG. 23.

[0502] The amino acid sequence information for the antibodies is shown in FIGS. 15 to 20.

[0503] The VH and VL sequences of the antibodies were cloned into expression vectors for the generation of scFv-Fc (human IgG1) antibodies. The vectors were transiently expressed in mammalian cells cultured in serum-free media, and isolated by protein A purification.

Example 6: Functional Characterisation of Human Anti-Human Antibodies

[0504] The antibodies described in Example 5 were analysed in in vitro assays for their ability to

(i) inhibit human IL-11-mediated signalling, (ii) inhibit mouse IL-11-mediated signalling, and (iii) inhibit IL-11 trans signalling, by IL-11 in complex with IL-11RA. The affinity of the antibodies for human IL-11 was also analysed by ELISA.

[0505] 6.1 Ability to Inhibit Human IL-11 Mediated Signalling

[0506] To investigate ability to neutralise human IL-11-mediated signalling, cardiac atrial human fibroblasts were cultured in wells of 96-well plates in the presence of TGF.beta.1 (5 ng/ml) for 24 hours, in the presence or absence of the anti-IL-11 antibodies. TGF.beta.1 promotes the expression of IL-11, which in turn drives the transition of quiescent fibroblasts to activated, .alpha.SMA-positive fibroblasts. It has previously been shown that neutralising IL-11 prevents TGF.beta.1-induced transition to activated, .alpha.SMA-positive fibroblasts.

[0507] Expression of .alpha.SMA was analysed with the Operetta High-Content Imaging System in an automated high-throughput fashion.

[0508] In non-stimulated cultures, .about.29.7% (=1) of the fibroblasts were .alpha.SMA-positive, activated fibroblasts at the end of the 24 hour culture period, whilst .about.52% (=1.81) of fibroblasts were .alpha.SMA-positive in cultures that were stimulated with TGF.beta.1 in the absence of anti-IL-11 antibodies.

[0509] Anti-IL-11 antibodies (2 .mu.g/ml) were added to fibroblast cultures that were stimulated with TGF.beta.1, and at the end of the 24 hour culture period, the percentage of .alpha.SMA-positive fibroblasts was determined. The percentages were normalised based on the percentage of .alpha.SMA-positive fibroblasts observed in cultures of fibroblasts which had not been stimulated with TGF.beta.1.

[0510] The results of the experiments are shown in FIGS. 24A, 24B and 27. 28 of the antibodies were demonstrated to be capable of neutralising signalling mediated by human IL-11.

[0511] A commercial monoclonal mouse anti-IL-11 antibody (Monoclonal Mouse IgG2A; Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA) was also analysed for ability to inhibit signalling by human IL-11 in the experiments. This antibody was found to be able to reduce the percentage of activated fibroblasts to 28.3% (=0.99).

[0512] Several of the clones neutralised signalling by human IL-11 to a greater extent than the commercially available mouse anti-IL-11 antibody (industry standard): YU45-C11/A10 (#6), YU45-G1 (#11), YU45-E3 (#16), YU45-F8 (#18), YU45-F9 (#21), YU45-H10 (#22), YU45-F2 (#24), YU45-H3 (#25), YU45-G7 (#33), YU45-B6 (#36), YU45-C1 (#42), YU46-B6 (#47), YU46-E3 (#50), YU46-G8 (#54) and YU46-D3 (#56).

[0513] 6.2 Ability to Inhibit Mouse IL-11 Mediated Signalling

[0514] The ability of the human antibodies to inhibit mouse IL-11-mediated signalling was also investigated, following the same procedure as described in section 6.1 above, but using mouse atrial fibroblasts instead of human atrial fibroblasts.

[0515] After 24 hours in culture, about 31.8% (=1) of non-stimulated cells in culture were activated fibroblasts. Stimulation with TGF.beta.1 resulted in a .about.2-fold increase in the percentage of activated fibroblasts (68.8%=2.16) as compared to non-stimulated cultures.

[0516] The results of the experiments are shown in FIGS. 25 and 27. The antibodies were demonstrated to be capable of neutralising signalling mediated by mouse IL-11. Monoclonal Mouse IgG2A clone #22626, catalog No. MAB218 anti-IL-11 antibody was also analysed for ability to inhibit signalling by mouse IL-11. This antibody was found to be able to reduce the percentage of activated fibroblasts to 39.4% (=1.24).

[0517] Several of the clones neutralised signalling by IL-11 in mouse atrial fibroblasts to a greater extent than the commercially available mouse anti-IL-11 antibody (industry standard): YU33-B4/YU45-G2/A3 (#3), YU45-H11/D12 (#9), YU45-G1 (#11), YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5 (#14), YU45-B3 (#15), YU45-F8 (#18), YU45-H10 (#22), YU46-A10 (#23), YU45-A8/C6 (#27), YU45-D9/D3 (#31), YU45-B6 (#36), YU45-C1 (#42), YU46-A8 (#45), YU46-C1 (#48), YU46-H8 (#52), YU46-G8 (#54) and YU46-D3 (#56).

[0518] The ability of the human antibodies to inhibit mouse IL-11-mediated signalling was also investigated using mouse skin fibroblasts.

[0519] The results of the experiments are shown in FIG. 27. The antibodies were demonstrated to be capable of neutralising signalling mediated by mouse IL-11.

[0520] Several of the clones neutralised signalling by IL-11 in mouse skin fibroblasts to a greater extent than the commercially available mouse anti-IL-11 antibody (industry standard): YU45-B6 (#36), YU45-C1 (#42), and YU46-H8 (#52).

[0521] 6.3 Ability to Inhibit IL-11 Trans Signalling, by IL-11 in Complex with IL-11RA

[0522] Trans signalling is recognised as a major aspect of IL-6 signalling, where a complex of IL-6 and soluble IL-6R.alpha. can activate cells that express gp130, but lack the IL-6 receptor (Hunter and Jones, 2015 Nature Immunology 16, 448-457).

[0523] It has recently been suggested that trans signalling by a complex of IL-11 and soluble IL-11RA is also important for IL-11 biology (Lokau et al., Cell Reports (2016) 14, 1761-1773). Using a recombinant fusion protein of IL-11 and IL-11R.alpha. (as described in Pflanz et al., Febs Lett (1999) 450: 117-122), anti-IL-11 antibodies were screened for the ability to inhibit trans signalling mediated by IL-11:IL-11R.alpha. complex.

[0524] Importantly, antibodies which are capable of inhibiting both classical IL-11 mediated signalling and IL-11 trans signalling by IL-11:IL-11R.alpha. complex are able to inhibit all known modes of IL-11/IL-11R signalling.

[0525] The IL-11:IL-11R.alpha. fusion protein (hereafter referred to as hyper IL-11) consists of the extracellular domain of the IL-11 receptor alpha (IL-11R.alpha.) linked to IL-11.

[0526] Hyper IL-11 was found to be a more potent activator of human fibroblasts than recombinant IL-11 protein. Briefly, in two separate experiments human fibroblasts were cultured without stimulation (Baseline), in the presence of different amounts of hyper IL-11 (0.008 ng/ml, 0.04 ng/ml, 0.2 ng/ml, 1 ng/ml and 5 ng/ml), or 5 ng/ml recombinant human IL-11 obtained from a commercial source, and fibroblast activation was analysed by determining the percentage of .alpha.SMA-positive cells as described herein. The results are shown in (FIGS. 42A and 42B). Hyper-IL-11 activated fibroblasts in a dose-dependent fashion, and was a more potent activator than IL-11.

[0527] The IL-11:IL-11R.alpha. fusion protein was prepared as follows:

[0528] DNA encoding IL-11:IL-11R.alpha. fusion protein (i.e. SEQ ID NO:265) was cloned into pTT5 vector, and transfected into 293-6E cells in culture in serum-free FreeStyle.TM. 293 Expression Medium (Thermo Fisher Scientific).

[0529] Cells were maintained in Erlenmeyer Flasks (Corning Inc.) at 37.degree. C. with 5% CO.sub.2 on an orbital shaker (VWR Scientific).

[0530] Cell culture supernatants were collected on day 6 were used for purification.

[0531] Cell culture supernatant was loaded onto an affinity purification column.

[0532] After washing and elution with appropriate buffer, the eluted fractions were pooled and buffer exchanged to final formulation buffer.

[0533] The purified IL-11:IL-11R.alpha. fusion protein was analyzed by SDS-PAGE, Western blot to confirm molecular weight and purity.

TABLE-US-00011

[0533] DNA encoding IL-11: IL-11R.alpha. fusion protein: (SEQ ID NO: 265) GAATTCCCGCCGCCACCATGGGCTGGTCCTGCATCATCCTGTTTCTGGTG GCCACAGCCACCGGCGTGCACTCTCCACAGGCTTGGGGACCTCCAGGCGT GCAGTATGGCCAGCCTGGCAGATCCGTGAAGCTGTGCTGTCCTGGCGTGA CAGCTGGCGACCCTGTGTCCTGGTTCAGAGATGGCGAGCCCAAGCTGCTG CAGGGCCCAGATTCTGGACTGGGCCACGAACTGGTGCTGGCCCAGGCCGA TTCTACCGACGAGGGCACCTACATCTGCCAGACCCTGGATGGCGCCCTGG GCGGAACAGTGACACTGCAGCTGGGCTACCCTCCCGCCAGACCTGTGGTG TCTTGTCAGGCCGCCGACTACGAGAACTTCAGCTGCACATGGTCCCCCAG CCAGATCAGCGGCCTGCCCACCAGATACCTGACCAGCTACCGGAAGAAAA CCGTGCTGGGCGCCGACAGCCAGAGAAGAAGCCCTTCTACAGGCCCCTGG CCCTGCCCTCAGGATCCTCTGGGAGCTGCCAGATGTGTGGTGCACGGCGC CGAGTTCTGGTCCCAGTACCGGATCAACGTGACCGAAGTGAACCCCCTGG GCGCCTCCACAAGACTGCTGGATGTGTCCCTGCAGAGCATCCTGCGGCCC GATCCTCCACAGGGCCTGAGAGTGGAAAGCGTGCCCGGCTACCCCAGAAG GCTGAGAGCCAGCTGGACATACCCCGCCTCTTGGCCTTGCCAGCCCCACT TCCTGCTGAAGTTTCGGCTGCAGTACCGGCCAGCCCAGCACCCTGCTTGG AGCACAGTGGAACCTGCCGGCCTGGAAGAAGTGATCACAGACGCCGTGGC CGGACTGCCTCATGCTGTGCGGGTGTCCGCCAGAGACTTTCTGGATGCCG GCACCTGGTCTACCTGGTCCCCAGAAGCCTGGGGCACACCTTCTACTGGC GGACCTGCTGGACAGTCTGGCGGAGGCGGAGGAAGTGGCGGAGGATCAGG GGGAGGATCTGTGCCTGGACCTCCTCCAGGACCCCCTAGAGTGTCCCCAG ATCCTAGGGCCGAGCTGGACTCTACCGTGCTGCTGACCAGATCCCTGCTG GCCGACACAAGGCAGCTGGCTGCCCAGCTGAGAGACAAGTTCCCCGCCGA CGGCGACCACAACCTGGATAGCCTGCCTACCCTGGCCATGTCTGCTGGCG CACTGGGGGCTCTGCAGCTGCCTGGGGTGCTGACTAGACTGAGAGCCGAC CTGCTGAGCTACCTGCGGCATGTGCAGTGGCTGAGAAGGGCTGGCGGCAG CAGCCTGAAAACCCTGGAACCTGAGCTGGGCACACTGCAGGCCAGACTGG ACAGACTGCTGCGCAGACTGCAGCTGCTGATGAGCAGACTGGCTCTGCCC CAGCCTCCTCCTGACCCTCCTGCTCCTCCACTGGCTCCTCCAAGCTCTGC TTGGGGCGGAATTAGAGCCGCCCACGCCATTCTGGGAGGCCTGCACCTGA CACTGGATTGGGCAGTGCGGGGCCTGCTGCTGCTGAAAACCAGACTGCAC CACCACCATCACCACTGATAAGCTT Amino acid sequence of IL-11: IL-11R.alpha. fusion protein: (SEQ ID NO: 266) MGWSCIILFLVATATGVHSPQAWGPPGVQYGQPGRSVKLCCPGVTAGDPV SWFRDGEPKLLQGPDSGLGHELVLAQADSTDEGTYICQTLDGALGGTVTL QLGYPPARPVVSCQAADYENFSCTWSPSQISGLPTRYLTSYRKKTVLGAD SQRRSPSTGPWPCPQDPLGAARCVVHGAEFWSQYRINVTEVNPLGASTRL LDVSLQSILRPDPPQGLRVESVPGYPRRLRASWTYPASWPCQPHFLLKFR LQYRPAQHPAWSTVEPAGLEEVITDAVAGLPHAVRVSARDFLDAGTWSTV VSPEAWGTPSTGGPAGQSGGGGGSGGGSGGGSVPGPPPGPPRVSPDPRAE LDSTVLLTRSLLADTRQLAAQLRDKFPADGDHNLDSLPTLAMSAGALGAL QLPGVLTRLRADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRLLR RLQLLMSRLALPQPPPDPPAPPLAPPSSAWGGIRAAHAILGGLHLTLDWA VRGLLLLKTRLHHHHHH

[0534] Fibroblasts cultured in vitro and stimulated with hyper IL-11 were shown to upregulate IL-11 protein expression, as determined by ELISA (FIG. 43). Interestingly, an increase in IL-11RNA level was not detected in response to stimulation with hyper IL-11. Unlike TGF.beta.1, which increases IL-11 expression at both the RNA and the protein level, hyper IL-11 seems to upregulate IL-11 expression only post-transcriptionally, at the protein level.

[0535] The ability of the human antibodies to inhibit signalling mediated by hyper IL-11 was investigated.

[0536] Human atrial fibroblasts derived from 3 individuals were incubated for 24 h with hyper IL-11 (0.2 ng/ml) in the presence of neutralising anti-IL-11 antibody or isotype control antibody. Following incubation, cells were stained for .alpha.SMA to determine the fraction of myofibroblasts.

[0537] After 24 hours in culture, about 26.5.% (=1) of non-stimulated cells in culture were activated fibroblasts. Stimulation with hyper IL-11 resulted in a .about.2-fold increase in the percentage of activated fibroblasts (56.4%=2.13) as compared to non-stimulated cultures.

[0538] The results of the experiments are shown in FIGS. 26 and 27. The antibodies were demonstrated to be capable of neutralising signalling mediated by hyper IL-11 (i.e. IL-11 trans signalling).

[0539] Monoclonal Mouse IgG2A clone #22626, catalog No. MAB218 anti-IL-11 antibody was also analysed for ability to inhibit signalling by hyper IL-11. This antibody was found to be able to reduce the percentage of activated fibroblasts to 33.8% (=1.28).

[0540] Clone YU33-B4/YU45-G2/A3 (#3) neutralised IL-11 trans signalling by hyper IL-11 to a greater extent than the commercially available mouse anti-IL-11 antibody (industry standard).

[0541] The results of the experimental procedures described in hereinabove identified antibody clones which possess functional properties which are relevant for their pre-clinical and clinical development of antibodies capable of inhibiting IL-11/IL-11-R signalling.

[0542] Clones YU33-B4/YU45-G2/A3 (#3), YU45-E3 (#16), YU45-F2 (#24), YU45-F5 (#39), YU46-A8 (#45) and YU46-G8 (#54) were identified as particularly promising candidates, showing good ability to inhibit signalling by both human and mouse IL-11, and good inhibition of IL-11 trans signalling.

[0543] 6.4 Analysis of Antibody Affinity for Human IL-11

[0544] The human anti-human IL-11 antibodies were analysed for their affinity of binding to human IL-11 by ELISA assay.

[0545] Recombinant human IL-11 was obtained from Genscript and Horseradish peroxidase (HRP)-conjugated anti-human IgG (Fc-specific) antibody was obtained from Sigma. Corning 96-well ELISA plates were obtained from Sigma. Pierce 3,3',5,5'-tetramethylbenzidine (TMB) ELISA substrate kit was obtained from Life Technologies (0.4 g/mL TMB solution, 0.02% hydrogen peroxide in citric acid buffer). Bovine serum albumin and sulphuric acid was obtained from Sigma. Wash buffer comprised 0.05% Tween-20 in phosphate buffered saline (PBS-T). ScFv-Fc antibodies were generated as described in Example 5. Purified mouse and human IgG controls were purchased from Life Technologies. Tecan Infinite 200 PRO NanoQuant was used to measure absorbance.

[0546] Criss-cross serial dilution analysis was performed as described by Hornbeck et al., (2015) Curr Protoc Immunol 110, 2.1.1-23) to determine the optimal concentration of coating antigen, primary and secondary antibodies.

[0547] An indirect ELISA was performed to assess the binding affinity of primary ScFv-Fc antibodies at 50% of effective concentration (EC.sub.50) as previously described (Unverdorben et al., (2016) MAbs 8, 120-128.). ELISA plates were coated with 1 .mu.g/mL of recombinant human IL-11 overnight at 4.degree. C. and remaining binding sites were blocked with 2% BSA in PBS. ScFv-Fc antibodies were diluted in 1% BSA in PBS, titrated to obtain working concentrations of 800, 200, 50, 12.5, 3.125, 0.78, 0.195, and 0.049 ng/mL, and incubated in duplicates for 2 hours at room temperature. Detection of antigen-antibody binding was performed with 15.625 ng/mL of HRP-conjugated anti-human IgG (Fc-specific) antibody. Following 2 hours of incubation with the detection antibody, 100 .mu.l of TMB substrate was added for 15 mins and chromogenic reaction stopped with 100 .mu.l of 2 M H.sub.2SO.sub.4. Absorbance reading was measured at 450 nm with reference wavelength correction at 570 nm. Data were fitted with Graph Pad Prism software with log transformation of antibody concentrations followed by non-linear regression analysis with the asymmetrical (five-parameter) logistic dose-response curve to determine individual EC50 values.

[0548] The same materials and procedures as described above were performed to determine the affinity of binding for the murine monoclonal anti-IL-11 antibodies, with the exception that HRP-conjugated anti-mouse IgG (H&L) was used instead of HRP-conjugated anti-human IgG.

[0549] The same materials and procedures as described above were performed to determine the affinity of binding for the human monoclonal anti-IL-11 antibodies and murine monoclonal anti-IL-11 antibodies to recombinant murine IL-11 obtained from Genscript.

[0550] The results of the ELISA assays are shown in FIG. 28A to 28F, and were used to determine EC.sub.50 values for the antibodies which are shown in FIG. 29.

[0551] 6.5 Ability to Inhibit Human IL-11 Mediated Signalling in a Variety of Tissues

[0552] Ability of the antibodies to neutralise IL-11-mediated signalling and trans signalling in fibroblasts obtained from a variety of different tissues is investigated, essentially as described in sections 6.1 and 6.3 except that instead of cardiac atrial human fibroblasts, human fibroblasts derived from liver, lung, kidney, eye, skin, pancreas, spleen, bowel, brain, and bone marrow are used for the experiments.

[0553] Anti-IL-11 antibodies are demonstrated to be capable of neutralising signalling in fibroblasts derived from the various different tissues, as determined by observation of a relative decrease in the proportion of .alpha.SMA-positive fibroblasts at the end of the 24 h culture period in the presence of the anti-IL-11 antibodies as compared to culture in the absence of the antibodies.

Example 7: Light Chain Shuffling of Human Anti-Human IL-11 Antibodies

[0554] Human IL-11 antibodies are affinity-matured by light chain shuffling to obtain antibodies having improved affinity for IL-11.

[0555] Chain shuffling to improve antibody affinity is a well-known technique in the field of antibody technology, and is described in detail in Marks, Antibody Affinity Maturation by Chain Shuffling, Antibody Engineering Methods and Protocols, Humana Press (2004) Vol. 248, pp 327-343, incorporated by reference herein. In particular, Light chain shuffling is described in detail at sections 3.1 and 3.2 thereof.

[0556] The heavy chain variable regions of the human anti-human IL-11 antibodies are combined with a repertoire of light chain variable region partners to identify new VLNH combinations having high affinity for IL-11.

[0557] A schematic representation of light chain shuffling is shown in FIG. 30. Briefly, nucleic acid encoding the VH domain for an antibody is cloned into a phage display vector comprising a repertoire of VL chains, and scFv comprising new VH/VL combinations are analysed for binding to human IL-11 by ELISA.

[0558] The scFv having VH/VL combinations displaying the strongest binding affinity for IL-11 are then analysed for cross-reactivity against murine IL-11.

[0559] The VH/VL sequences of the scFv are then cloned into expression vectors for the generation of scFv-Fc (human IgG1) antibodies, the vectors are transiently expressed in mammalian cells cultured in serum-free media, and isolated by protein A purification.

Example 8: Mouse Monoclonal Anti-Human IL-11 Antibodies

[0560] Mouse monoclonal antibodies directed against human IL-11 protein were also generated, as follows.

[0561] cDNA encoding the amino acid for human IL-11 was cloned into expression plasmids (Aldevron GmbH, Freiburg, Germany).

[0562] Mice were immunised by intradermal application of DNA-coated gold-particles using a hand-held device for particle-bombardment ("gene gun"). Serum samples were collected from mice after a series of immunisations, and tested in flow cytometry on HEK cells which had been transiently transfected with human IL-11 expression plasmids (cell surface expression of human IL-11 by transiently transfected HEK cells was confirmed with anti-tag antibodies recognising a tag added to the N-terminus of the IL-11 protein).

[0563] Antibody-producing cells were isolated from the mice and fused with mouse myeloma cells (Ag8) according to standard procedures.

[0564] Hybridomas producing antibodies specific for IL-11 were identified by screening for ability to bind to IL-11 expressing HEK cells by flow cytometry.

[0565] Cell pellets of positive hybridomas cells were prepared using an RNA protection agent (RNAlater, cat. #AM7020 by ThermoFisher Scientific) and further processed for sequencing of the variable domains of the antibodies.

[0566] In total, 16 mouse monoclonal anti-human IL-11 antibodies were prepared (FIG. 31).

Example 9: Functional Characterisation of Mouse Monoclonal Anti-Human IL-11 Antibodies

[0567] 9.1 Ability to Inhibit Human IL-11 Mediated Signalling

[0568] The ability of the murine monoclonal anti-human IL-11 antibodies to inhibit signalling mediated by human IL-11 was investigated using the same assay as described in Example 6.1 above.

[0569] The results of the Experiments are shown in FIGS. 32 and 35. The antibodies were demonstrated to be capable of neutralising signalling mediated by human IL-11.

[0570] A commercial monoclonal mouse anti-IL-11 antibody (Monoclonal Mouse IgG2A; Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA) was also analysed for ability to inhibit signalling by human IL-11 in the experiments. This antibody was found to be able to reduce the percentage of activated fibroblasts to 0.89 times.

[0571] Clone A7 (BSN-3C11) was found to neutralise signalling by human IL-11 to a greater extent than the commercially available mouse anti-IL-11 antibody (industry standard).

[0572] 9.2 Ability to Inhibit Mouse IL-11 Mediated Signalling

[0573] The ability of the murine monoclonal anti-human IL-11 antibodies to inhibit signalling mediated by murine IL-11 was investigated using the same assay as described in Example 6.2 above, but using mouse atrial fibroblasts instead of mouse dermal fibroblasts.

[0574] The results of the Experiments are shown in FIGS. 33 and 35. The antibodies were demonstrated to be capable of neutralising signalling mediated by murine IL-11.

[0575] A commercial monoclonal mouse anti-IL-11 antibody (Monoclonal Mouse IgG2A; Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA) was also analysed for ability to inhibit signalling by human IL-11 in the experiments. This antibody was found to be able to reduce the percentage of activated fibroblasts to 43.0% (=1.44).

[0576] Several of the clones neutralised signalling by murine IL-11 to a greater extent than the commercially available mouse anti-IL-11 antibody (industry standard): A3 (BSN-2E1), A5 (BSN-2G6) and A6 (BSN-3C6).

[0577] 9.3 Ability of Mouse Anti-IL-11 Antibodies to Inhibit IL-11 Trans Signalling, by IL-11 in Complex with IL-11RA

[0578] The ability of the mouse anti-IL-11 antibodies to inhibit signalling mediated by hyper IL-11 was investigated.

[0579] Human atrial fibroblasts were incubated for 24 h with hyper IL-11 (0.2 ng/ml) in the presence of anti-IL-11 antibodies (2 .mu.g/ml) or isotype control antibody. Following incubation, cell culture supernatant was analysed for MMP2. Stimulation with hyper IL-11 results in an increase in the secretion of MMP2 as compared to non-stimulated cultures.

[0580] The results of the experiments are shown in FIGS. 34 and 35. The mouse anti-IL-11 antibodies were found to be capable of neutralising signalling mediated by hyper IL-11 (i.e. IL-11 trans signalling), and several were found to be capable of inhibiting trans signalling to a greater extent than the commercial monoclonal mouse anti-IL-11 antibody (Monoclonal Mouse IgG2A; Clone #22626; Catalog No. MAB218; R&D Systems, MN, USA): BSN-2G6 (A5), BSN-3C6 (A6), BSN-5B8 (A9) and BSN-7D4 (A12).

[0581] Clone BSN-3C6 (A6) was identified as a particularly promising candidate for further development (highlighted in FIG. 35), showing good ability to inhibit both human IL-11 and mouse IL-11 mediated signalling, and good inhibition of IL-11 trans signalling.

[0582] 9.4 Screening for Ability of Mouse Anti-IL-11 Antibodies to Bind IL-11

[0583] The mouse hybridomas producing anti-human IL-11 antibodies were sub-cloned, and cell culture supernatant from the subcloned hybridomas was analysed by "mix-and-measure" iQue assay for (i) ability to bind to human IL-11, and (ii) cross reactivity for antigen other than IL-11.

[0584] Briefly, labelled control cells (not expressing IL-11 at the cell surface) and unlabelled target cells expressing human IL-11 at their surface (following transient transfection with a plasmid encoding a FLAG-tagged human IL-11) were mixed together with the cell culture supernatant (containing mouse-anti-IL-11 antibodies) and secondary detection antibodies (fluorescently-labelled anti-mouse IgG antibody).

[0585] The cells were then analysed using the HTFC Screening System (iQue) for the two labels (i.e. the cell label and the label on the secondary antibody). Detection of the secondary antibody on the unlabelled, IL-11 expressing cells indicated ability of the mouse-anti-IL-11 antibodies to bind to IL-11. Detection of the secondary antibody on the labelled, control cells indicated cross-reactivity of the mouse-anti-IL-11 antibodies for target other than IL-11.

[0586] As a positive control condition, labelled and unlabelled cells were incubated with a mouse anti-FLAG tag antibody as the primary antibody.

[0587] The results are shown in FIGS. 36A and 36B. The majority of the subcloned hybridomas expressed antibody which was able to bind to human IL-11, and which recognised this target with high specificity. Clones BSN-2G6, BSN-5B8 and BSN-7F9 displayed some binding to cells not expressing IL-11, and so may have cross-reactivity for target(s) other than IL-11. Antibody produced by subcloned BSN-3C11 was found not to bind to human IL-11.

[0588] 13 of the 16 antibodies displayed stronger signal for binding to IL-11 than signal for the positive control anti-tag antibody for the tag, indicating that these antibodies bind to IL-11 with high affinity.

Example 10: Chimeric and Humanised Versions of the Mouse Anti-Human IL-11 Antibodies

[0589] Mouse/human chimeric and humanised versions of the mouse monoclonal anti-human IL-11 antibodies of Example 8 are prepared according to standard methods.

[0590] 10.1 Mouse/Human Chimeric Antibodies

[0591] Mouse/human chimeric antibodies are prepared from the mouse monoclonal anti-human IL-11 antibodies as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 8 thereof.

[0592] Briefly, the DNA sequences encoding the VH and VL of hybridomas producing the mouse anti-human IL-11 antibodies are determined, and combined with DNA sequence encoding human immunoglobulin constant regions to produce a mouse/human chimeric antibody sequence, from which a chimeric mouse/human antibody is expressed in mammalian cells.

[0593] 10.2 Humanised Antibodies

[0594] Humanised antibodies are prepared from the mouse monoclonal anti-human IL-11 antibodies as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 7 thereof, in particular at section 3.1 of Chapter 7 entitled `Antibody Humanization`.

[0595] Briefly, the DNA sequences encoding the VH and VL of hybridomas producing the mouse anti-human IL-11 antibodies are determined, and inserted into DNA sequence encoding human antibody variable region framework regions and immunoglobulin constant regions, to produce a humanised antibody sequence, from which a humanised antibody is expressed in mammalian cells.

Example 11: Further Biochemical Analysis of Anti-IL-11 Antibodies

[0596] The antibodies described above are subjected to further biochemical analysis.

[0597] The antibodies are analysed by BIAcore, Biolayer interferometry (BLI) and MicroScale Thermophoresis (MST) analysis to determine the affinity of binding to human IL-11 and mouse IL-11.

[0598] BIAcore determination of antibody affinity by surface plasmon resonance (SPR) analysis is performed as described in Rich et al., Anal Biochem. 2008 Feb. 1; 373(1):112-20.

[0599] Biolayer interferometry analysis of antibody affinity is performed as described in Concepcion et al., Comb Chem High Throughput Screen. 2009 September; 12(8):791-800.

[0600] MicroScale Thermophoresis analysis of antibody affinity is performed as described in Jerabek-Willemsen et al., Assay Drug Dev Technol. 2011 August; 9(4): 342-353.

[0601] Aggregation of the antibodies is analysed by size exclusion chromatography (SEC), as described in lacob et al., J Pharm Sci. 2013 December; 102(12): 4315-4329.

[0602] Hydophobicity of the antibodies is analysed by Hydrophobic interaction chromatography (HIC) as described in Haverick et al., MAbs. 2014 July-August; 6(4):852-8.

[0603] The melting temperature of the antibodies is analysed by Differential scanning fluorimetry (DSF) as described in Menzen and Friess, J Pharm Sci. 2013 February; 102(2):415-28.

Example 12: Inhibition of Fibrosis In Vivo Using Anti-IL-11 Antibodies

[0604] The therapeutic utility of the anti-human IL-11 antibodies is demonstrated in in vivo mouse models of fibrosis for various different tissues. The mice used in the experiments are wildtype (i.e. IL-11RA+/+) mice.

[0605] 12.1 Heart Fibrosis

[0606] A pump is implanted, and mice are treated with AngII (2 mg/kg/day) for 28 days.

[0607] Neutralising anti-IL-11 antibodies, or control antibodies, are administered to different groups of mice by intravenous injection. At the end of the experiment, collagen content is assessed in the atria of the mice using a calorimetric hydroxyproline-based assay kit, and the level of RNA expression of the markers or fibrosis Col1A2, .alpha.SMA (ACTA2) and fibronectin (Fn1) were analysed by qPCR.

[0608] Mice treated with neutralising anti-IL-11 antibodies have a reduced fibrotic response in heart tissue as compared to mice treated with control antibodies, as evidenced by reduced expression of markers of fibrosis.

[0609] 12.2 Kidney Fibrosis

[0610] A mouse model for kidney fibrosis is established, in which fibrosis is induced by intraperitoneal injection of folic acid (180 mg/kg) in vehicle (0.3M NaHCO.sub.3); control mice were administered vehicle alone.

[0611] Neutralising anti-IL-11 antibodies, or control antibodies, are administered to different groups of mice by intravenous injection. Kidneys are removed at day 28, weighed and either fixed in 10% neutral-buffered formalin for Masson's trichrome and Sirius staining or snap-frozen for collagen assay, RNA, and protein studies.

[0612] Total RNA is extracted from the snap-frozen kidney using Trizol reagent (Invitrogen) and Qiagen TissueLyzer method followed by RNeasy column (Qiagen) purification. The cDNA is prepared using iScript.TM. cDNA synthesis kit, in which each reaction contained 1 .mu.g of total RNA, as per the manufacturer's instructions. Quantitative RT-PCR gene expression analysis is performed on triplicate samples with either TaqMan (Applied Biosystems) or fast SYBR green (Qiagen) technology using StepOnePlus.TM. (Applied Biosystem) over 40 cycles. Expression data are normalized to GAPDH mRNA expression level and the 2-.DELTA..DELTA.Ct method is used to calculate the fold-change. The snap-frozen kidneys are subjected to acid hydrolysis by heating in 6M HCl at a concentration of 50 mg/ml (95.degree. C., 20 hours). The amount of total collagen in the hydrolysate is quantified based on the colorimetric detection of hydroxyproline using Quickzyme Total Collagen assay kit (Quickzyme Biosciences) as per the manufacturer's instructions.

[0613] Mice treated with neutralising anti-IL-11 antibodies have a reduced fibrotic response in kidney tissue as compared to mice treated with control antibodies, as evidenced by reduced expression of markers of fibrosis.

[0614] 12.3 Lung Fibrosis

[0615] Mice are treated by intratracheal administration of bleomycin on day 0 to establish a fibrotic response in the lung (pulmonary fibrosis).

[0616] Neutralising anti-IL-11 antibodies, or control antibodies, are administered to different groups of mice by intravenous injection. Mice are sacrificed at day 21, and analysed for differences in fibrosis markers.

[0617] Mice treated with neutralising anti-IL-11 antibodies have a reduced fibrotic response in lung tissue as compared to mice treated with control antibodies, as evidenced by reduced expression of markers of fibrosis.

[0618] 12.4 Skin Fibrosis

[0619] Mice are treated by subcutaneous administration of bleomycin on day 0 to establish a fibrotic response in the skin.

[0620] Neutralising anti-IL-11 antibodies, or control antibodies, are administered to different groups of mice by intravenous injection. Mice are sacrificed at day 21, and analysed for differences in fibrosis markers.

[0621] Mice treated with neutralising anti-IL-11 antibodies have a reduced fibrotic response in skin tissue as compared to mice treated with control antibodies, as evidenced by reduced expression of markers of fibrosis.

[0622] 12.5 Eye Fibrosis

[0623] Mice undergo trabeculectomy procedure as described in Example 3.6 above to initiate a wound healing response in the eye.

[0624] Neutralising anti-IL-11 antibodies, or control antibodies, are administered to different groups of mice by intravenous injection, and fibrosis is monitored in the eye tissue.

[0625] Mice treated with neutralising anti-IL-11 antibodies have a reduced fibrotic response in eye tissue as compared to mice treated with control antibodies, as evidenced by reduced expression of markers of fibrosis.

[0626] 12.6 Other Tissues

[0627] The effect of treatment with neutralising anti-IL-11 antibodies on fibrosis is also analysed in mouse models of fibrosis for other tissues, such as the liver, kidney, bowel, and is also analysed in a model relevant to multiorgan (i.e. systemic) fibrosis.

[0628] The fibrotic response is measured and compared between mice treated with neutralising anti-IL-11 antibodies and mice treated with control antibodies. Mice treated with neutralising anti-IL-11 antibodies have a reduced fibrotic response as compared to mice treated with control antibodies, as evidenced by reduced expression of markers of fibrosis.

Example 13: Treatment of Cancer In Vivo Using Anti-IL-11 Antibodies

[0629] The effect of treatment with neutralising anti-IL-11 antibodies on cancer is analysed in mouse models of cancer.

[0630] Models of breast, lung, and gastrointestinal cancers are established in mice, the mice are treated by administration of neutralising anti-IL-11 antibodies, or control antibodies, and the development/progression of cancer is monitored.

[0631] An anti-cancer effect is observed for the neutralising anti-IL-11 antibodies, as evidenced by reduced symptoms of cancer and/or increased survival as compared to mice treated with control antibodies.

Example 14: Treatment of AMD Using Anti-IL-11 Antibodies

[0632] The effect of treatment with neutralising anti-IL-11 antibodies is investigated in wet age-related macular degeneration (AMD).

[0633] Neutralising anti-IL-11 antibody is administered to subjects having wet AMD. In some treatment conditions, subjects are administered with VEGF antagonist therapy (e.g. ranibizumab, bevacizumab, pegaptanib, brolucizumab or aflibercept), PDGF antagonist therapy (e.g. pegpleranib), or are treated by laser coagulation therapy in addition to treatment with anti-IL-11 antibody.

[0634] A reduction in wet AMD pathology and/or improvement in the symptoms of wet AMD is observed in subjects treated with anti-IL-11 antibody as compared to subjects not treated with anti-IL-11 antibody.

Example 15: Light Chain Shuffled Antibodies

[0635] Light chain shuffling was performed as represented schematically in FIG. 30.

[0636] The heavy chains of the following IL-11-binding antibody clones were used for light chain shuffling: YU45-E03, YU45-F02, YU45-F05, YU45-G02, YU46-A08, YU46-G08.

[0637] Variable regions of the heavy chains were amplified by PCR, and the resulting amplicons were pooled and cloned into phagemid vectors (phagemids) each containing a specific VL chain, and representing nave lambda and kappa light chain library repertoires. The VH and VL containing phagemids were used to produce a new library of antibody-phages, which was used to select clones displaying binding to IL-11 under stringent conditions (i.e. antigen limitation, large number washing steps).

[0638] Antibodies capable of binding to both human IL-11 and murine IL-11 (i.e. cross-reactive antibodies) were identified by phage display by panning using biotinylated and non-biotinylated recombinant human and murine IL-11, based on the panning strategy shown in FIG. 52.

[0639] The analysis identified 66 cross-reactive antibodies (FIG. 53). Sequence analysis identified 64 unique antibody clones, the amino acid sequences of which are shown in FIG. 50, and the nucleotide sequences of which are shown in FIG. 51.

[0640] The 64 antibody clones were analysed for binding signal to human IL-11 and murine IL-11 in an ELISA assay. The results are shown in FIGS. 54A and 54B.

Example 16: Functional Characterisation of the Light Chain Shuffled Antibodies

[0641] 54 of the light chain shuffled antibodies were analysed for their ability to bind IL-11 and inhibit IL-11 mediated signalling.

[0642] 16.1 Binding to Human IL-11

[0643] The light chain shuffled anti-IL-11 antibodies were analysed to determine the EC50 for binding to human IL-11 by ELISA according to standard methods. Briefly, wells of microtiter plates were coated with recombinant human IL-11 (100 ng/well), scFv-Fc comprising the VH and VL domains of the clones were added in a dilution series and antibody binding was detected using a polyclonal antibody detection system.

[0644] The results of the ELISA assays were used to calculate EC50 values (ng/ml) for the light chain shuffled antibody clones, and these are shown in FIG. 55.

[0645] 16.2 Ability to Inhibit Human IL-11 Mediated Signalling

[0646] To investigate the ability of light chain shuffled antibody clones to neutralise human IL-11-mediated signalling, cardiac atrial human fibroblasts were cultured in wells of 96-well plates in the presence of TGF.beta.1 (5 ng/ml) for 24 hours, in the presence of anti-IL-11 antibodies in scFv-human IgG1-Fc format, or in the presence of human IgG1 isotype control antibody, at a final concentration of 2 mg/ml. Levels of the pro-fibrotic marker MMP2 in the cell culture supernatant were then measured by ELISA. Basal MMP2 secretion by the cells in culture was measured by culture in the absence of TGF.beta.1, in the presence of human IgG1 isotype control (2 mg/ml).

[0647] The results of two separate experiments are shown in FIGS. 56A and 56B. Horizontal lines in the bar charts represent the basal MMP2 secretion by cardiac atrial human fibroblasts cultured for 24 hours in the presence of human IgG1 isotype control antibody in the absence of TGF.beta.1 stimulation (`NEG` in FIGS. 56A and 56B), and MMP2 secretion by cardiac atrial human fibroblasts cultured for 24 hours in the presence of 5 ng/ml TGF.beta. and the human IgG1 isotype control antibody (`POS` in FIGS. 56A and 56B).

[0648] The light chain shuffled anti-IL-11 antibodies were shown to be able to bind to human IL-11, and to inhibit IL-11 mediated signalling.

Example 17: Inhibition of Kidney Fibrosis Using Anti-IL-11 Antibodies

[0649] 10-12 week old littermate mice of similar weight had kidney fibrosis induced by intraperitoneal (i.p.) injection of folic acid (180 mg kg.sup.-1) in vehicle (0.3 M NaHCO.sub.3); control mice were administered vehicle alone.

[0650] Anti-IL11 antibody clone BSN-3C6 was administered one day after folic acid treatment and then 3 times per week at a dose of 20 mg/kg. Mice were euthanized 28 days post-injection.

[0651] The mouse plasma levels of urea and creatinine were quantified using urea assay kit (ab83362, Abcam) and creatinine assay kit (ab65340, Abcam), respectively according to the manufacturer's instructions. The amount of total collagen in the kidney was quantified on the basis of colourimetric detection of hydroxyproline using a Quickzyme Total Collagen assay kit (Quickzyme Biosciences). All colourimetric assays were performed according to the manufacturer's instructions.

[0652] Tissues were paraffin-embedded, and kidneys were sectioned at 3 .mu.m. For paraffin sections, tissues were fixed for 24 h, at room temperature in 10% neutral-buffered formalin (Sigma-Aldrich), dehydrated and embedded in paraffin. For cryosections, freshly dissected organs were embedded with Tissue-Tek Optimal Cutting Temperature compound (VWR International). Cryomoulds were then frozen in a metal beaker with isopentane cooled in liquid nitrogen and sections were stored in 80.degree. C. Total collagen was stained with Masson's trichrome stain kit (HT15, Sigma-Aldrich) according to the manufacturer's instructions. Images of the sections were captured and blue-stained fibrotic areas were semi-quantitatively determined with ImageJ software (version 1.49). For immunohistochemistry, the tissue sections were incubated with anti-ACTA2 antibody (ab5694, Abcam). Primary antibody staining was visualized using an ImmPRESS HRP Anti-Rabbit IgG Polymer Detection kit (Vector Laboratories) with ImmPACT DAB Peroxidase Substrate (Vector Laboratories) as the chromogen. The sections were then counterstained with Mayer's haematoxylin (Merck).

[0653] FIGS. 58A and 58B show that mice treated with anti-IL11 antibody were found to have significantly reduced staining for collagen, indicating that anti-IL-11 antibody treatment had inhibited kidney fibrosis.

[0654] FIG. 59 shows that the urinary albumin/creatine ratio was significantly reduced by treatment with anti-IL11 antibody, indicating a reduced level of kidney damage in mice treated with anti-IL-11 antibody.

[0655] FIG. 60 shows that treatment with the anti-IL-11 antibody inhibited folic acid-induced kidney fibrosis in a dose-dependent fashion.

[0656] In another experiment a mouse model of acute renal injury was induced by unilateral ureteric obstruction (UUO). Briefly, mice were treated by sham operation or ureteric obstruction of one ureter. Mice received IgG, anti-IL-11 antibody clone BSN-3C6 (20 mg/kg; on surgical days -1, 1, 3, 5) and injured kidneys NUM or contralateral uninjured kidneys (Con) were harvested on day 7 post surgery.

[0657] Semi-quantitative assessment of tubular injury was performed by histological analysis of casts, tubular atrophy or tubular expansion blinded to experimental conditions (Tubular injury score: 0, none; 1, minimal; 2, mild; 3, moderate; 4, severe).

[0658] FIGS. 61A and 61B show that treatment with anti-IL-11 antibody reduced tubular damage in a mouse model of acute renal injury.

Example 18: IL-11 and Liver Fibrosis

[0659] Protein expression of IL-11 in healthy and diseased livers was confirmed by western blots in matched samples of human livers. Matched frozen liver samples were prepared for western blotting and levels of IL11 determined using Human IL-11 Antibody Monoclonal Mouse IgG2A Clone #22626, catalog number MAB218 from R&D Systems. Film images were generated.

[0660] The results are shown in FIG. 62. Increased expression of IL-11 was detected in most diseased tissue as compared to normal healthy livers.

[0661] To determine whether IL-11 expression changed with disease, an ELISA was performed on media from Precision Cut Liver Slices (PCLS) was performed using Human IL-11 DuoSet 15 plate kit, catalog number DY218 from R&D Systems.

[0662] Human PCLS were cut and incubated with media treatments after a 24 h rest period for acclimatisation to media plates. Samples were treated with media only (control), media with LPS, a combination of profibrogenic stimuli inducing TGF.beta.1, or a combination of profibrogenic stimuli inducing TGF.beta.1 and the TGF.beta.1 inhibitor ALK5.

[0663] The results are shown in FIG. 63. The profibrogenic stimuli induced upregulation of IL-11 protein expression, and ALK5 inhibitor was found to inhibit TGF.beta.1 receptor signalling, which reduced the expression of IL-11 protein down to control levels.

[0664] 18.1 Inhibition of Liver Fibrosis Using Anti-IL-11 Antibodies in a Preclinical Model of NASH

[0665] Diabetic mice (db/db; deficient for the leptin receptor) were maintained for 8 weeks on a normal chow diet or on a NASH-inducing (methionine/choline deficient (MCD)) diet. To test the efficacy of neutralizing anti-IL11 antibodies, we administered anti-IL-11 antibody clone BSN-3C6 (20 mg/kg, 3x/week, intraperitoneally) for the final 3 weeks of the 8 week NASH diet (FIG. 64A, bottom panels). Gross liver histology was assessed at time of euthanasia, and collagen content of the liver was analysed by hydroxyproline assay.

[0666] The results are shown in FIGS. 64A and 64B. Inhibition of IL-11 mediated signalling by anti-IL-11 antibody treatment improved liver histology in a mouse model of nonalcoholic steatohepatitis (FIG. 64A) as evidenced by partial restoration of liver morphology and texture in anti-IL-11 antibody-treated animals on NASH diet as compared to untreated animals on NASH diet. Livers from mice treated with anti-IL-11 antibody on NASH diet were also found to have reduced collagen content as compared to untreated animals on NASH diet (FIG. 64B).

Example 19: Inhibition of Eye Fibrosis Using Anti-IL-11 Antibodies

[0667] The anti-fibrotic effect of anti-IL-11 antibody treatment was assessed in a mouse model of retinal fibrosis in which Bruch's membrane is disrupted, as described in Caballero et al., Exp Eye Res. (2009) March; 88(3):367-77.

[0668] Briefly, mice were subjected to laser-induced retinal damage (4 burns per retina) and were then treated by intraocular administration of antibodies (0.5 .mu.g of either IgG control or anti-IL11 antibody clone BSN-3C6) on days 1, 7, 14 and 21. Eyes were harvested for histological analyses on day 28. The area of fibrosis at burn sites was measured using Masson's Trichrome staining, blinded to treatment.

[0669] The results are shown in FIGS. 65A and 65B. The area of fibrosis was significantly greater in control IgG-treated mice as compared to anti-IL11 antibody treated mice.

Example 20: Inhibition of Skin Fibrosis Using Anti-IL-11 Antibodies

[0670] The anti-fibrotic effect of anti-IL-11 antibody treatment was analysed in a mouse model of skin fibrosis stablished by subcutaneous injection of bleomycin (BLM, Sigma B2434, 50 .mu.g/day).

[0671] Briefly, the fur on the middle of the back of the mice (.about.9 cm.sup.2) was trimmed using a scissors, and hair removal cream was applied to remove fur completely. Subcutaneous injections of 100 .mu.L of bleomycin dissolved in PBS at a concentration of 0.5 mg/ml were performed on the top half of the injection site. Subcutaneous injections of 60 .mu.L of anti-IL11 antibody clone BSN-3C6 or control IgG antibody were subsequently performed on the bottom half of the injection site (dosage=15 mg/kg/day). Injections were performed daily for 21 days and animals were sacrificed one day after the final injection and analysed histologically for dermal thickness and collagen content (by Masson's trichrome staining).

[0672] FIGS. 66B and 66C show that dermal thickness was significantly reduced in mice treated with neutralising anti-IL-11 antibody as compared to control IgG-treated mice. Increased collagen staining can also be seen for the control IgG-treated group (FIG. 66B, middle panel).

Example 21: Inhibition of Heart Fibrosis Using Anti-IL-11 Antibodies

[0673] The anti-fibrotic effect of anti-IL-11 antibody treatment was analysed in a mouse model of cardiac fibrosis. Briefly, transverse aortic constriction (TAC) was performed in male mice as described previously (Tarnayski, O. et al. Mouse cardiac surgery: comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies. Physiol. Genomics 16, 349-360 (2004)). Age-matched mice underwent a sham operative procedure without TAC. Trans-thoracic two-dimensional Doppler echocardiography was used to confirm increased pressure gradients (>40 mm Hg), indicative of successful TAC.

[0674] Mice were euthanized at 2 weeks post-TAC for histological and molecular assessment. Anti-IL-11 antibody clone BSN-3C6 or control IgG antibody were administered intraperitoneally 3 times per week at a dose of 20 mg/kg. After two weeks hearts were harvested and assessed for fibrosis extent using Masson's Trichrome stain kit (HT15, Sigma-Aldrich), in accordance with the manufacturer's instructions.

[0675] The results of the analysis is shown in FIG. 67. Mice treated with neutralising anti-IL-11 antibody were found to have reduced levels of fibrosis in the epicardium, endocardium and in perivascular regions as compared to mice treated with IgG control antibody.

Sequence CWU 1

1

5811107PRTArtificial SequenceYU33-A2 1Asp Val Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Gly Arg Tyr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Val Gly Lys Val Pro Arg Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Thr Ala Ser Glu Thr Ser Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Ser Tyr Tyr Cys Gln Gln Tyr Arg Ser Ala Pro Leu 85 90 95 Ala Phe Gly Gly Gly Thr Gly Val Glu Ile Lys 100 105 2110PRTArtificial SequenceYU33-B3/H3 2Leu Pro Val Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Arg 1 5 10 15 Thr Val Thr Ile Ser Cys Thr Arg Asn Thr Gly Asn Ile Ala Ser Asn 20 25 30 Arg Val Gln Trp Tyr Gln Gln Arg Pro Ala Ser Ala Pro Thr Val Val 35 40 45 Ile Tyr Asp Asn His Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Ile Asp Thr Ser Pro Asn Ser Ala Tyr Leu Thr Ile Ser Gly 65 70 75 80 Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Tyr 85 90 95 Ser Ser Val Ile Phe Gly Gly Gly Thr Gln Leu Thr Val Leu 100 105 110 3110PRTArtificial SequenceYU33-B4/YU45-G2/A3 3Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Phe Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 4110PRTArtificial SequenceYU33-E6 4Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser His Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Asn Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 5110PRTArtificial SequenceYU45-C11/A10 5Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 6110PRTArtificial SequenceYU45-D11/F11 6Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser His Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Ala Ala Ser Leu Thr Ile Ser Gly Val 65 70 75 80 Gln Ala Glu Asp Gly Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Ser 85 90 95 Ser Thr Val Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu 100 105 110 7110PRTArtificial SequenceYU45-E11/E12 7Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Gly Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 8110PRTArtificial SequenceYU45-H11/D12 8Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 9110PRTArtificial SequenceYU45-A12/G10 9Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Gly Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 10110PRTArtificial SequenceYU45-G1 10Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 11110PRTArtificial SequenceYU45-C2/A7/B10 11Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Arg Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Ser 85 90 95 Thr Pro Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110 12110PRTArtificial SequenceYU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5 12Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ile Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Gly Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu 100 105 110 13110PRTArtificial SequenceYU45-E3 13Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ile Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Gly Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu 100 105 110 14110PRTArtificial SequenceYU45-C8/E8 14Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Val Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Thr Ser Ser 85 90 95 Asn Thr Gln Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 15110PRTArtificial SequenceYU45-F8 15Gln Pro Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Leu Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Ala Leu 100 105 110 16110PRTArtificial SequenceYU45-G8/H6 16Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu 35 40 45 Met Ile Ser Asp Val His Asn Arg Pro Leu Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ile Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 17110PRTArtificial SequenceYU45-F9 17Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Arg Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 18110PRTArtificial SequenceYU45-H10 18Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 19110PRTArtificial SequenceYU46-A10 19Gln Pro Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Leu Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Ala Leu 100 105 110 20110PRTArtificial SequenceYU45-F2 20Gln Pro Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Val 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90

95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 21110PRTArtificial SequenceYU45-H3 21Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 22110PRTArtificial SequenceYU45-A1 22Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 23110PRTArtificial SequenceYU45-A8/C6 23Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Gly Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Gly 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 24111PRTArtificial SequenceYU45-B5/A4 24Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Thr 85 90 95 Asn Asn Phe Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 25110PRTArtificial SequenceYU45-C3/A6 25Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 26107PRTArtificial SequenceYU45-D1 26Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Phe Lys 100 105 27110PRTArtificial SequenceYU45-D9/D3 27Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Glu Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Thr Glu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Arg Ser Gly Thr Ser Val Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 28110PRTArtificial SequenceYU45-E5 28Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ile Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Gly Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Gly Val Arg Arg Arg Asp Arg Ala Asp Arg Pro 100 105 110 29110PRTArtificial SequenceYU45-G7 29Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Arg 1 5 10 15 Thr Val Thr Ile Ser Cys Ser Gly Ser Tyr Ser Asn Val Gly Ser Asn 20 25 30 Leu Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Val 35 40 45 Ile Tyr Glu Asp Asp Lys Arg Leu Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Lys Gly His Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu 100 105 110 30110PRTArtificial SequenceYU45-B4 30Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ile Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Thr Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 31110PRTArtificial SequenceYU45-H4 31Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Ala Leu 100 105 110 32110PRTArtificial SequenceYU45-B6 32Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Glu Ala Pro Lys Leu 35 40 45 Met Ile Phe Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Asp Tyr 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 33110PRTArtificial SequenceYU45-D6 33Gln Pro Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Leu Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Ala Leu 100 105 110 34111PRTArtificial SequenceYU45-E7 34Leu Pro Val Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys 1 5 10 15 Thr Val Thr Ile Ser Cys Thr Gly Ser Ser Gly Ser Ile Ala Ser Asn 20 25 30 Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Thr Thr Val 35 40 45 Ile Tyr Asp Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly 65 70 75 80 Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser 85 90 95 Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 35108PRTArtificial SequenceYU45-F5 35Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ile Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Thr 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 36110PRTArtificial SequenceYU45-H7/46-B5 36Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 37110PRTArtificial SequenceYU46-G1 37Leu Pro Val Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys 1 5 10 15 Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn 20 25 30 Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val 35 40 45 Ile Tyr Glu Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly 65 70 75 80 Leu Arg Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asn Ser 85 90 95 Ser Lys Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 38111PRTArtificial SequenceYU46-A2 38Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Glu Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Ser 85 90 95 Gly Thr Leu Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 39111PRTArtificial SequenceYU46-A8 39Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Glu Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Ser 85 90 95 Gly Thr Leu Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 40110PRTArtificial SequenceYU46-B2 40Gln Pro Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75

80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 41108PRTArtificial SequenceYU46-B6 41Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Gly Tyr Tyr Ala 20 25 30 Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Val Val Met Tyr 35 40 45 Gly Asn Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asp Ser Arg Gly Arg Ser Gly Asp His 85 90 95 Trp Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 42110PRTArtificial SequenceYU46-C1 42Gln Ala Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Ser Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Tyr 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Val Pro Gly Thr Ala Pro Lys Ile Leu 35 40 45 Ile Tyr Arg Asn Asp Glu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala His Tyr Tyr Cys Ala Thr Trp Asp Asp Gly Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 43110PRTArtificial SequenceYU46-D7 43Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Ala Gly Thr Ser Ser Asp Val Gly Ala Tyr 20 25 30 Asn Tyr Val Ala Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Ser Glu Val Phe Arg Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Thr Ala Phe Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala Asp Asp Glu Ala Val Tyr Phe Cys Asn Ser Tyr Val Thr Gly 85 90 95 Asn Asn Trp Ala Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 44110PRTArtificial SequenceYU46-E3 44Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 45110PRTArtificial SequenceYU46-E7 45Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Tyr Asp 20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Val 35 40 45 Ile Ser Asn Asp Asn Arg Arg Pro Ser Gly Val Pro Ala Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Tyr Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 46108PRTArtificial SequenceYU46-H8 46Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ser Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 47110PRTArtificial SequenceYU46-G9 47Gln Pro Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Lys Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Glu Leu 35 40 45 Ile Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Asn 85 90 95 Tyr Thr Trp Leu Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 48108PRTArtificial SequenceYU46-G8 48Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ser Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 49111PRTArtificial SequenceYU46-B7 49Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Thr Ser Tyr Ser Ser Ser 85 90 95 Ser Thr Leu Val Ala Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 50111PRTArtificial SequenceYU46-D3 50Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asn Tyr 20 25 30 Lys Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 51118PRTArtificial SequenceYU33-A2 51Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr Leu 1 5 10 15 Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn Ser Ala 20 25 30 Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu Trp Leu 35 40 45 Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Val Ser 50 55 60 Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Thr Leu Gln Leu Asn Ser Val Thr Pro Asp Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Thr Arg Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 52116PRTArtificial SequenceYU33-B3/H3 52Glu Val Gln Leu Val Glu Ser Gly Gly Gly Phe Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Ser Ile Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Ala 20 25 30 Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Tyr Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 53118PRTArtificial SequenceYU33-B4/YU45-G2/A3 53Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 54119PRTArtificial SequenceYU33-E6 54Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Leu Ser Gly Leu Pro Ile Ile Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 55115PRTArtificial SequenceYU45-C11/A10 55Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 56118PRTArtificial SequenceYU45-D11/F11 56Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Ala Ala Ala Asp Gly Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 57123PRTArtificial SequenceYU45-E11/E12 57Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Leu Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Gly Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Thr His Asp Tyr Gly Asp Phe Ser Asp Ala Phe Asp Ile 100 105 110 Trp Gly Gln Gly Thr Met Val Ala Val Ser Ser 115 120 58119PRTArtificial SequenceYU45-H11/D12 58Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Arg Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Tyr Ser Gly Ser Ser Asn Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 59123PRTArtificial SequenceYU45-A12/G10 59Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Leu Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Gly Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Thr His Asp Tyr Gly Asp Phe Ser Asp Ala Phe Asp Ile 100 105 110 Trp Gly Gln Gly Thr Met Val Ala Val

Ser Ser 115 120 60118PRTArtificial SequenceYU45-G1 60Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 61115PRTArtificial SequenceYU45-C2/A7/B10 61Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gln Asn Val Asp Leu Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 62123PRTArtificial SequenceYU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5 62Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 63123PRTArtificial SequenceYU45-E3 63Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 64115PRTArtificial SequenceYU45-C8/E8 64Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Gly Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 65124PRTArtificial SequenceYU45-F8 65Arg Ser Ala Ala Gly Gly Val Trp Gly Arg Arg Gly Pro Ala Trp Glu 1 5 10 15 Val Pro Glu Thr Leu Leu Cys Ser Leu Trp Ile Phe Leu Lys Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Phe Ser Ser Trp Tyr Pro Asp Leu Tyr Tyr Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 66119PRTArtificial SequenceYU45-G8/H6 66Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Phe Ala Arg Gly Val Tyr Leu Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 67119PRTArtificial SequenceYU45-F9 67Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gln Ser Gly Glu Pro Glu Ser Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 68119PRTArtificial SequenceYU45-H10 68Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Arg Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Asn Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Tyr Ser Gly Ser Ser Asn Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 69124PRTArtificial SequenceYU46-A10 69Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Phe Ser Ser Trp Tyr Pro Asp Leu Tyr Tyr Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 70118PRTArtificial SequenceYU45-F2 70Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 71121PRTArtificial SequenceYU45-H3 71Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Val Asn Leu Tyr Tyr Gly Asp Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 72118PRTArtificial SequenceYU45-A1 72Gln Leu Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Val Gly Ala Thr Ala Asp Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 73118PRTArtificial SequenceYU45-A8/C6 73Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 74124PRTArtificial SequenceYU45-B5/A4 74Ser Glu Gln Glu Asn Cys Glu Gln Val Gln Leu Val Gln Ser Gly Ala 1 5 10 15 Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser 20 25 30 Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro 35 40 45 Gly Gln Gly Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr 50 55 60 Ala Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp 65 70 75 80 Glu Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu 85 90 95 Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Leu Ile Thr Gly Thr Thr 100 105 110 Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 75118PRTArtificial SequenceYU45-C3/A6 75Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 76126PRTArtificial SequenceYU45-D1 76Ala Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser 1 5 10 15 Gly Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser 20 25 30 Ser Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Val Gln Asn Leu Gly Gly Gly Ser Tyr Tyr Val Gly Ala 100 105 110 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 77124PRTArtificial SequenceYU45-D9/D3 77Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu His Phe Ser Gln Tyr Phe Ser Thr Ile Asp Ala Phe Asp 100 105 110 Ile Trp Gly Gln Gly Thr Met Val Thr Ile Ser Ser 115 120 78123PRTArtificial SequenceYU45-E5 78Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 79121PRTArtificial SequenceYU45-G7 79Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Val Gly Tyr Ser Ser Gly Trp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 80131PRTArtificial SequenceYU45-B4 80Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Ala Gln Ser Tyr Ser Ser Ser Trp Tyr Glu Trp Glu Pro 100 105 110 Gly Arg Glu His Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr 115 120 125 Val Ser Ser 130 81114PRTArtificial SequenceYU45-H4 81Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Asp Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser 82118PRTArtificial SequenceYU45-B6 82Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 83124PRTArtificial SequenceYU45-D6 83Arg Ser Ala Ala Gly Gly Val Trp Gly Arg Arg Gly Pro Ala Trp Glu 1 5 10 15 Val Pro Glu Thr Leu Leu Cys Ser Leu Trp Ile Phe Leu Lys Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Thr Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Phe Ser Ser Trp Tyr Pro Asp Leu Tyr Tyr Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 84124PRTArtificial SequenceYU45-E7 84Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Tyr Ser Gly Tyr Pro Ser Arg Tyr Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 85118PRTArtificial SequenceYU45-F5 85Val Thr Leu Lys Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 35 40 45 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Gly Gly Lys Ser Tyr Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 86122PRTArtificial SequenceYU45-H7/46-B5 86Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu His Ser Gly Arg Asn Trp Gly Asp Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 87126PRTArtificial SequenceYU46-G1 87Gln Val Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser 1 5 10 15 Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala 20 25 30 Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly 35 40 45 Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln 50 55 60 Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met 65 70 75 80 Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Gly Gly Pro Tyr Tyr Asp Phe Trp Ser Gly Tyr Tyr Thr Glu 100 105 110 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 88121PRTArtificial SequenceYU46-A2 88Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gly Tyr Ser Ser Gly Trp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 89121PRTArtificial SequenceYU46-A8 89Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gly Tyr Ser Ser Gly Trp Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 90120PRTArtificial SequenceYU46-B2 90Gly Ala Ala Gly Gly Val Trp Gly Arg Arg Gly Pro Ala Trp Glu Val 1 5 10 15 Pro Glu Thr Leu Leu Cys Ser Leu Trp Ile Leu Pro Ser Asp Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Ala Ala Ala Gly Arg Asp Ala Phe Asp Ile Trp Gly Gln 100 105 110 Gly Thr Met Val Thr Val Ser Ser 115 120 91123PRTArtificial SequenceYU46-B6 91Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Val Ala Ala Ala Arg Ser Tyr Tyr Tyr Tyr Met Asp Val 100 105 110 Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 115 120 92125PRTArtificial SequenceYU46-C1 92Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Asp Ser Ser Ala Gly Gly Gly Pro Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 93119PRTArtificial SequenceYU46-D7 93Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Phe Ala Arg Gly Val Tyr Leu Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 94118PRTArtificial SequenceYU46-E3 94Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Gly Gly Tyr Asp Asp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 95124PRTArtificial SequenceYU46-E7 95Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Tyr Tyr Asp Ser Ser Gly Thr Gln Gly Asp Ser Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 96116PRTArtificial SequenceYU46-H8 96Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25

30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 97118PRTArtificial SequenceYU46-G9 97Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 98116PRTArtificial SequenceYU46-G8 98Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 99115PRTArtificial SequenceYU46-B7 99Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Val Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 100115PRTArtificial SequenceYU46-D3 100Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ser Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Gly Val Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 1016PRTArtificial SequenceYU33-A2 LC-CDR 1 101Gln Asp Val Gly Arg Tyr 1 5 1023PRTArtificial SequenceYU33-A2 LC-CDR 2 102Ala Ala Ser 1 1039PRTArtificial SequenceYU33-A2 LC-CDR 3 103Gln Gln Tyr Arg Ser Ala Pro Leu Ala 1 5 1048PRTArtificial SequenceYU33-B3/H3 LC-CDR 1 104Thr Gly Asn Ile Ala Ser Asn Arg 1 5 1053PRTArtificial SequenceYU33-B3/H3 LC-CDR 2 105Asp Asn His 1 1069PRTArtificial SequenceYU33-B3/H3 LC-CDR 3 106Gln Ser Tyr Asp Tyr Ser Ser Val Ile 1 5 1079PRTArtificial SequenceYU33-B4/YU45-G2/A3 LC-CDR 1 107Ser Ser Asp Val Gly Gly Tyr Asn Tyr 1 5 1083PRTArtificial SequenceYU33-B4/YU45-G2/A3 LC-CDR 2 108Asp Val Ser 1 10910PRTArtificial SequenceYU33-B4/YU45-G2/A3 LC-CDR 3 109Ser Ser Tyr Thr Ser Ser Ser Ser Trp Val 1 5 10 1109PRTArtificial SequenceYU33-E6 LC-CDR 1 110Ser Ser Asp Val Gly Ala Tyr Asn Tyr 1 5 1113PRTArtificial SequenceYU33-E6 LC-CDR 2 111Glu Val Ser 1 11210PRTArtificial SequenceYU33-E6 LC-CDR 3 112Ser Ser Tyr Thr Ser Ser Asn Thr Leu Val 1 5 10 11310PRTArtificial SequenceYU45-C11/A10 LC-CDR 3 113Ser Ser Tyr Thr Ser Ser Ser Thr Val Val 1 5 10 1149PRTArtificial SequenceYU45-D11/F11 LC-CDR 1 114Ser Ser Asp Ile Gly Ala Tyr Asn Tyr 1 5 11510PRTArtificial SequenceYU45-D11/F11 LC-CDR 3 115Ser Ser Tyr Thr Thr Ser Ser Thr Val Val 1 5 10 1168PRTArtificial SequenceYU45-E11/E12 LC-CDR 1 116Ser Ser Asn Ile Gly Ser Asn Tyr 1 5 1173PRTArtificial SequenceYU45-E11/E12 LC-CDR 2 117Arg Asn Asn 1 11811PRTArtificial SequenceYU45-E11/E12 LC-CDR 3 118Ala Ala Trp Asp Gly Ser Leu Ser Gly Trp Val 1 5 10 11910PRTArtificial SequenceYU45-H11/D12 LC-CDR 3 119Ser Ser Tyr Thr Ser Ser Ser Thr Trp Val 1 5 10 12010PRTArtificial SequenceYU45-G1 LC-CDR 3 120Cys Ser Tyr Ala Gly Ser Tyr Thr Phe Val 1 5 10 12110PRTArtificial SequenceYU45-C2/A7/B10 LC-LCDR 3 121Asn Ser Tyr Thr Ser Ser Thr Pro Tyr Val 1 5 10 1229PRTArtificial SequenceYU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5 LC-CDR 1 122Ile Ser Asp Val Gly Gly Tyr Asn Tyr 1 5 1233PRTArtificial SequenceYU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5 LC-CDR 2 123Asp Val Thr 1 12410PRTArtificial SequenceYU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5 LC-CDR 3 124Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Val 1 5 10 12510PRTArtificial SequenceYU45-C8/E8 LC-CDR 3 125Gly Ser Tyr Thr Ser Ser Asn Thr Gln Val 1 5 10 1268PRTArtificial SequenceYU45-F8YU45-F8 LC-CDR 1 126Ser Ser Asn Ile Gly Asn Asn Leu 1 5 12711PRTArtificial SequenceYU45-F8YU45-F8 LC-CDR 3 127Ala Ala Trp Asp Asp Ser Leu Ser Ala Gly Val 1 5 10 1289PRTArtificial SequenceYU45-G8/H6 LC-CDR 1 128Ser Ser Asp Val Gly Gly Tyr Asp Tyr 1 5 1293PRTArtificial SequenceYU45-G8/H6 LC-CDR 2 129Asp Val His 1 13010PRTArtificial SequenceYU45-G8/H6 LC-CDR 3 130Ser Ser Tyr Thr Ser Ser Ile Thr Trp Val 1 5 10 13110PRTArtificial SequenceYU45-F9 LC-CDR 3 131Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val 1 5 10 13210PRTArtificial SequenceYU45-A1 LC-CDR 3 132Gly Ser Tyr Thr Ser Ser Ser Thr Trp Val 1 5 10 1333PRTArtificial SequenceYU45-A8/C6 LC-CDR 2 133Asp Val Gly 1 13410PRTArtificial SequenceYU45-A8/C6 LC-CDR 3 134Ser Ser Tyr Thr Ser Gly Ser Thr Trp Val 1 5 10 1353PRTArtificial SequenceYU45-B5/A4 LC-CDR 2 135Glu Val Asn 1 13611PRTArtificial SequenceYU45-B5/A4 LC-CDR 3 136Ser Ser Tyr Ala Gly Thr Asn Asn Phe Val Val 1 5 10 1376PRTArtificial SequenceYU45-D1 LC-CDR 1 137Gln Ser Val Ser Ser Asn 1 5 1383PRTArtificial SequenceYU45-D1 LC-CDR 2 138Gly Ala Ser 1 13919PRTArtificial SequenceYU45-D1 LC-CDR 3 139Gln Gln Tyr Asn Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 1 5 10 15 Glu Phe Lys 1408PRTArtificial SequenceYU45-D9/D3 LC-CDR 1 140Ser Ser Asn Ile Gly Asn Asn Tyr 1 5 1413PRTArtificial SequenceYU45-D9/D3 LC-CDR 2 141Asp Asn Thr 1 14211PRTArtificial SequenceYU45-D9/D3 LC-CDR 3 142Gly Thr Trp Asp Ser Ser Leu Ser Gly Gly Val 1 5 10 14320PRTArtificial SequenceYU45-E5 LC-CDR 3 143Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Gly Val Arg Arg Arg Asp Arg 1 5 10 15 Ala Asp Arg Pro 20 1448PRTArtificial SequenceYU45-G7 LC-CDR 1 144Tyr Ser Asn Val Gly Ser Asn Leu 1 5 1453PRTArtificial SequenceYU45-G7 LC-CDR 2 145Glu Asp Asp 1 14611PRTArtificial SequenceYU45-G7 LC-CDR 3 146Ala Ala Trp Asp Asp Ser Leu Lys Gly His Val 1 5 10 1478PRTArtificial SequenceYU45-B4 LC-CDR 1 147Ser Ser Asn Ile Gly Ser Asn Thr 1 5 1483PRTArtificial SequenceYU45-B4 LC-CDR 2 148Ile Asn Asn 1 14911PRTArtificial SequenceYU45-B4 LC-CDR 3 149Ala Ala Trp Asp Asp Ser Leu Asn Gly Trp Val 1 5 10 1509PRTArtificial SequenceYU45-B6 LC-CDR 1 150Ser Arg Asp Val Gly Gly Tyr Asn Tyr 1 5 15110PRTArtificial SequenceYU45-B6 LC-CDR 3 151Cys Ser Tyr Ala Asp Tyr Tyr Thr Trp Val 1 5 10 1528PRTArtificial SequenceYU45-E7 LC-CDR 1 152Ser Gly Ser Ile Ala Ser Asn Tyr 1 5 1533PRTArtificial SequenceYU45-E7 LC-CDR 2 153Asp Asp Asn 1 15410PRTArtificial SequenceYU45-E7 LC-CDR 3 154Gln Ser Tyr Asp Ser Ser Asn Leu Trp Val 1 5 10 1556PRTArtificial SequenceYU45-F5 LC-CDR 1 155Gln Ile Ile Ser Ser Tyr 1 5 15610PRTArtificial SequenceYU45-F5 LC-CDR 3 156Gln Gln Ser Tyr Ser Thr Pro Thr Trp Thr 1 5 10 1573PRTArtificial SequenceYU46-G1 LC-CDR 2 157Glu Asp Asn 1 1589PRTArtificial SequenceYU46-G1 LC-CDR 3 158Gln Ser Tyr Asn Ser Ser Lys Val Val 1 5 1599PRTArtificial SequenceYU46-A2 LC-CDR 1 159Ser Ser Asp Val Gly Gly Tyr Glu Tyr 1 5 16011PRTArtificial SequenceYU46-A2 LC-CDR 3 160Asn Ser Tyr Thr Ser Ser Gly Thr Leu Val Val 1 5 10 1616PRTArtificial SequenceYU46-B6 LC-CDR 1 161Ser Leu Arg Gly Tyr Tyr 1 5 1623PRTArtificial SequenceYU46-B6 LC-CDR 2 162Gly Asn Asn 1 16311PRTArtificial SequenceYU46-B6 LC-CDR 3 163Asp Ser Arg Gly Arg Ser Gly Asp His Trp Leu 1 5 10 1648PRTArtificial SequenceYU46-C1 LC-CDR 1 164Ser Ser Asn Ile Gly Ser Tyr Tyr 1 5 1653PRTArtificial SequenceYU46-C1 LC-CDR 2 165Arg Asn Asp 1 16611PRTArtificial SequenceYU46-C1 LC-CDR 3 166Ala Thr Trp Asp Asp Gly Leu Ser Gly Trp Val 1 5 10 1679PRTArtificial SequenceYU46-D7 LC-CDR 1 167Ser Ser Asp Val Gly Ala Tyr Asn Tyr 1 5 1683PRTArtificial SequenceYU46-D7 LC-CDR 2 168Glu Val Phe 1 16910PRTArtificial SequenceYU46-D7 LC-CDR 3 169Asn Ser Tyr Val Thr Gly Asn Asn Trp Ala 1 5 10 1708PRTArtificial SequenceYU46-E7 LC-CDR 1 170Ser Ser Asn Ile Gly Tyr Asp Ala 1 5 1713PRTArtificial SequenceYU46-E7 LC-CDR 2 171Asn Asp Asn 1 17211PRTArtificial SequenceYU46-E7 LC-CDR 3 172Ala Ala Trp Asp Asp Ser Leu Ser Gly Trp Val 1 5 10 1736PRTArtificial SequenceYU46-H8 LC-CDR 1 173Gln Gly Ser Ser Ser Tyr 1 5 17410PRTArtificial SequenceYU46-H8 LC-CDR 3 174Gln Gln Ser Tyr Ser Thr Pro Leu Tyr Thr 1 5 10 1759PRTArtificial SequenceYU46-G9 LC-CDR 1 175Ser Ser Asp Val Gly Gly Tyr Lys Tyr 1 5 17610PRTArtificial SequenceYU46-G9 LC-CDR 3 176Cys Ser Tyr Ala Gly Asn Tyr Thr Trp Leu 1 5 10 17711PRTArtificial SequenceYU46-B7 LC-CDR 3 177Thr Ser Tyr Ser Ser Ser Ser Thr Leu Val Ala 1 5 10 1789PRTArtificial SequenceYU46-D3 LC-CDR 1 178Ser Ser Asp Val Gly Asn Tyr Lys Tyr 1 5 17911PRTArtificial SequenceYU46-D3 LC-CDR 3 179Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val Val 1 5 10 1809PRTArtificial SequenceYU33-A2 LC-CDR 1 180Val Ser Ser Asn Ser Ala Ala Trp Asn 1 5 1817PRTArtificial SequenceYU33-A2 LC-CDR 2 181Tyr Arg Ser Lys Trp Tyr Asn 1 5 18210PRTArtificial SequenceYU33-A2 LC-CDR 3 182Ala Arg Gly Thr Arg Gly Tyr Phe Asp Tyr 1 5 10 1838PRTArtificial SequenceYU33-B3/H3 LC-CDR 1 183Gly Phe Thr Phe Ser Gly Ala Tyr 1 5 1848PRTArtificial SequenceYU33-B3/H3 LC-CDR 2 184Ile Ser Tyr Asp Gly Ser Asn Lys 1 5 1859PRTArtificial SequenceYU33-B3/H3 LC-CDR 3 185Ala Arg Asp Leu Tyr Ala Phe Asp Ile 1 5 1868PRTArtificial SequenceYU33-B4/YU45-G2/A3 LC-CDR 1 186Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 18711PRTArtificial SequenceYU33-B4/YU45-G2/A3 LC-CDR 3 187Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr 1 5 10 1888PRTArtificial SequenceYU33-E6 LC-CDR 2 188Ile Ser Tyr Asp Gly Ser Asp Lys 1 5 18912PRTArtificial SequenceYU33-E6 LC-CDR 3 189Ala Lys Asp Leu Ser Gly Leu Pro Ile Ile Asp Tyr 1 5 10 1908PRTArtificial SequenceYU45-C11/A10 LC-CDR 1 190Gly Phe Thr Phe Ser Ser Tyr Ala 1 5 1918PRTArtificial SequenceYU45-C11/A10 LC-CDR 2 191Ala Arg Arg Gly Tyr Phe Asp Tyr 1 5 19211PRTArtificial SequenceYU45-C11/A10 LC-CDR 3 192Ala Arg Ile Ala Ala Ala Asp Gly Met Asp Val 1 5 10 1938PRTArtificial SequenceYU45-E11/E12 LC-CDR 1 193Gly Phe Ser Phe Arg Ser Tyr Gly 1 5 19416PRTArtificial SequenceYU45-E11/E12 LC-CDR 3 194Ala Arg Ile Thr His Asp Tyr Gly Asp Phe Ser Asp Ala Phe Asp Ile 1 5 10 15 19512PRTArtificial SequenceYU45-H11/D12 LC-CDR 3 195Ala Lys Leu Tyr Ser Gly Ser Ser Asn Phe Asp Tyr 1 5 10 1968PRTArtificial SequenceYU45-A12/G10 LC-CDR 1 196Gly Phe Thr Phe Arg Ser Tyr Gly 1 5 19711PRTArtificial SequenceYU45-G1 LC-CDR 3 197Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr 1 5 10 1988PRTArtificial SequenceYU45-C2/A7/B10 LC-CDR 3 198Ala Arg Gly Gln Asn Val Asp Leu 1 5 19916PRTArtificial SequenceYU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5 LC-CDR 3 199Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 1 5 10 15 20014PRTArtificial SequenceYU45-G7 LC-CDR 3 200Ala Arg Asp Val Gly Tyr Ser Ser Gly Trp Tyr Phe Asp Tyr 1 5 10 2018PRTArtificial SequenceYU45-B4 LC-CDR 1 201Gly Phe Ser Leu Ser Ser Tyr Gly 1 5 20224PRTArtificial SequenceYU45-B4 LC-CDR 3 202Ala Arg Leu Ala Gln Ser Tyr Ser Ser Ser Trp Tyr Glu Trp Glu Pro 1 5 10 15 Gly Arg Glu His Ala Phe Asp Ile 20 2037PRTArtificial SequenceYU45-H4 HC-CDR3 Family Consensus 203Ala Arg Pro Asp Asp Asp Tyr 1 5 2048PRTArtificial SequenceYU45-F8 HC-CDR 1 204Trp Ile Phe Leu Lys Ser Tyr Ala 1 5 20517PRTArtificial SequenceYU45-F8 HC-CDR 3 205Ala Arg Val Gly Phe Ser Ser Trp Tyr Pro Asp Leu Tyr Tyr Phe Asp 1 5 10 15 Tyr 20617PRTArtificial SequenceYU45-E7 HC-CDR 3 206Ala Arg Leu Tyr Ser Gly Tyr Pro Ser Arg Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val 20712PRTArtificial SequenceYU45-F5 HC-CDR 3 207Ala Lys Gly Gly Lys Ser Tyr Tyr Gly Phe Asp Tyr 1 5 10 20815PRTArtificial SequenceYU45-H7/B5 HC-CDR 3 208Ala Arg Leu His Ser Gly Arg Asn Trp Gly Asp Ala Phe Asp Ile 1 5 10 15 2098PRTArtificial SequenceYU45-B5/A4 HC-CDR 1 209Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 2108PRTArtificial SequenceYU45-B5/A4 HC-CDR 2 210Ile Ile Pro Ile Phe Gly Thr Ala 1 5 21110PRTArtificial

SequenceYU45-B5/A4 HC-CDR 3 211Ala Arg Gly Leu Ile Thr Gly Thr Thr Pro 1 5 10 2128PRTArtificial SequenceYU45-E3 HC-CDR 1 212Gly Phe Ser Phe Ser Ser Tyr Ala 1 5 2138PRTArtificial SequenceYU45-C8/E8 HC-CDR 3 213Ala Arg Arg Gly Tyr Gly Asp Tyr 1 5 214110PRTArtificial SequenceYU100-H06 214Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 21512PRTArtificial SequenceYU45-G8/H6 HC-CDR3 215Ala Lys Phe Ala Arg Gly Val Tyr Leu Phe Asp Tyr 1 5 10 21612PRTArtificial SequenceYU45-F9 HC-CDR 3 216Ala Arg Val Gln Ser Gly Glu Pro Glu Ser Asp Tyr 1 5 10 2178PRTArtificial SequenceYU45-H10 HC-CDR 1 217Gly Phe Ser Leu Asn Ser Tyr Gly 1 5 21814PRTArtificial SequenceYU45-H3 HC-CDR 3 218Ala Arg Met Val Asn Leu Tyr Tyr Gly Asp Ala Phe Asp Ile 1 5 10 21911PRTArtificial SequenceYU45-A1 HC-CDR 3 219Ala Arg Leu Val Gly Ala Thr Ala Asp Asp Tyr 1 5 10 2209PRTArtificial SequenceYU45-D1 HC-CDR 1 220Gly Gly Ser Ile Ser Ser Ser Asn Trp 1 5 2217PRTArtificial SequenceYU45-D1 HC-CDR 2 221Ile Tyr His Ser Gly Ser Thr 1 5 22218PRTArtificial SequenceYU45-D1 HC-CDR 3 222Ala Arg Val Gln Asn Leu Gly Gly Gly Ser Tyr Tyr Val Gly Ala Phe 1 5 10 15 Asp Tyr 22317PRTArtificial SequenceYU45-D9/D3 HC-CDR 3 223Ala Arg Leu His Phe Ser Gln Tyr Phe Ser Thr Ile Asp Ala Phe Asp 1 5 10 15 Ile 22420PRTArtificial SequenceYU46-G1 HC-CDR 3 224Ala Arg Gly Gly Gly Pro Tyr Tyr Asp Phe Trp Ser Gly Tyr Tyr Thr 1 5 10 15 Glu Phe Asp Tyr 20 22514PRTArtificial SequenceYU46-A2 HC-CDR 3 225Ala Arg Asp Ser Gly Tyr Ser Ser Gly Trp Tyr Phe Asp Tyr 1 5 10 2268PRTArtificial SequenceYU46-B2 HC-CDR 1 226Ile Leu Pro Ser Asp Ser Tyr Ala 1 5 22713PRTArtificial SequenceYU46-B2 HC-CDR 3 227Ala Arg Ile Ala Ala Ala Gly Arg Asp Ala Phe Asp Ile 1 5 10 2288PRTArtificial SequenceYU46-B6 HC-CDR 1 228Gly Tyr Thr Phe Thr Ser Tyr Gly 1 5 2298PRTArtificial SequenceYU46-B6 HC-CDR 2 229Ile Ser Ala Tyr Asn Gly Asn Thr 1 5 23016PRTArtificial SequenceYU46-B6 HC-CDR 3 230Ala Arg Val Val Ala Ala Ala Arg Ser Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 23118PRTArtificial SequenceYU46-C1 HC-CDR 3 231Ala Arg Ala Asp Ser Ser Ala Gly Gly Gly Pro Tyr Tyr Tyr Gly Met 1 5 10 15 Asp Val 23211PRTArtificial SequenceYU46-E3 HC-CDR 3 232Ala Arg Ile Gly Gly Tyr Asp Asp Phe Asp Tyr 1 5 10 23317PRTArtificial SequenceYU46-E7 HC-CDR 3 233Ala Arg Val Tyr Tyr Asp Ser Ser Gly Thr Gln Gly Asp Ser Phe Asp 1 5 10 15 Tyr 2348PRTArtificial SequenceYU46-H8 HC-CDR 1 234Gly Phe Thr Phe Gly Ser Tyr Gly 1 5 2359PRTArtificial SequenceYU46-H8 HC-CDR 3 235Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr 1 5 2368PRTArtificial SequenceYU46-B7 HC-CDR 3 236Ala Arg Gly Val Leu Phe Asp Tyr 1 5 2378PRTArtificial SequenceYU46-D3 HC-CDR 3 237Ala Arg Ser Gly Val Leu Asp Tyr 1 5 2388PRTArtificial SequenceYU46-G8 HC-CDR 1 238Gly Phe Ser Leu Gly Ser Tyr Gly 1 5 2399PRTArtificial SequenceLC-CDR1-1 Family consensusMISC_FEATURE(1)..(1)X = S or IMISC_FEATURE(2)..(2)X = S or RMISC_FEATURE(4)..(4)X = V or IMISC_FEATURE(6)..(6)X = G, A or NMISC_FEATURE(8)..(8)X = N, E, K or D 239Xaa Xaa Asp Xaa Gly Xaa Tyr Xaa Tyr 1 5 2408PRTArtificial SequenceLC-CDR1-2 Family consensusMISC_FEATURE(1)..(1)X = S or YMISC_FEATURE(4)..(4)X = I or VMISC_FEATURE(6)..(6)X = S, N or YMISC_FEATURE(7)..(7)X = N, Y or DMISC_FEATURE(8)..(8)X = L, Y, T or A 240Xaa Ser Asn Xaa Gly Xaa Xaa Xaa 1 5 2416PRTArtificial SequenceLC-CDR1-3 Family ConsensusMISC_FEATURE(2)..(2)X= G, S or IMISC_FEATURE(3)..(3)X= S, I or VMISC_FEATURE(6)..(6)X= Y or N 241Gln Xaa Xaa Ser Ser Xaa 1 5 2428PRTArtificial SequenceLC-CDR1-4 Family consensusMISC_FEATURE(1)..(1)X= S or TMISC_FEATURE(3)..(3)X = S or NMISC_FEATURE(8)..(8)X = Y or R 242Xaa Gly Xaa Ile Ala Ser Asn Xaa 1 5 2433PRTArtificial SequenceLC-CDR2-1 Family consensusMISC_FEATURE(3)..(3)X = S, T or G 243Asp Val Xaa 1 2443PRTArtificial SequenceLC-CDR2-2 Family consensusMISC_FEATURE(1)..(1)X = R, I or GMISC_FEATURE(3)..(3)X = N or D 244Xaa Asn Xaa 1 2453PRTArtificial SequenceLC-CDR2-3 Family consensusMISC_FEATURE(1)..(1)X = A or G 245Xaa Ala Ser 1 2463PRTArtificial SequenceLC-CDR2-4 Family consensusMISC_FEATURE(1)..(1)X = E, D or NMISC_FEATURE(3)..(3)X = N or D 246Xaa Asp Xaa 1 2473PRTArtificial SequenceLC-CDR2-5 Family consensusMISC_FEATURE(3)..(3)X = S, F or N 247Glu Val Xaa 1 2483PRTArtificial SequenceLC-CDR2-6 Family consensusMISC_FEATURE(2)..(2)X = N or VMISC_FEATURE(3)..(3)X = H or T 248Asp Xaa Xaa 1 24911PRTArtificial SequenceLC-CDR3-1 Family consensusMISC_FEATURE(1)..(1)X = S, N or GMISC_FEATURE(5)..(5)X = S or TMISC_FEATURE(6)..(6)X = S or GMISC_FEATURE(7)..(7)X = S, N, G or IMISC_FEATURE(8)..(8)X = T or SMISC_FEATURE(9)..(9)X = W, L, V or QMISC_FEATURE(11)..(11)X = absent or V 249Xaa Ser Tyr Thr Xaa Xaa Xaa Xaa Xaa Val Xaa 1 5 10 25020PRTArtificial SequenceLC-CDR3-2 Family consensusMISC_FEATURE(1)..(1)X = C or SMISC_FEATURE(5)..(5)X = G or DMISC_FEATURE(6)..(6)X = S, Y, N or TMISC_FEATURE(7)..(7)X = Y or NMISC_FEATURE(8)..(8)X = T or NMISC_FEATURE(9)..(9)X = W or FMISC_FEATURE(10)..(10)X = V, G or LMISC_FEATURE(11)..(11)X = absent or VMISC_FEATURE(12)..(12)X = absent or RMISC_FEATURE(13)..(13)X = absent or RMISC_FEATURE(14)..(14)X = absent or RMISC_FEATURE(15)..(15)X = absent or DMISC_FEATURE(16)..(16)X = absent or RMISC_FEATURE(17)..(17)X = absent or AMISC_FEATURE(18)..(18)X = absent or DMISC_FEATURE(19)..(19)X = absent or RMISC_FEATURE(20)..(20)X = absent or P 250Xaa Ser Tyr Ala Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa 20 25111PRTArtificial SequenceLC-CDR3-3 Family consensusMISC_FEATURE(1)..(1)X = A or GMISC_FEATURE(2)..(2)X = A or TMISC_FEATURE(5)..(5)X = D, G or SMISC_FEATURE(6)..(6)X = S or GMISC_FEATURE(8)..(8)X = S, K or NMISC_FEATURE(9)..(9)X = G or AMISC_FEATURE(10)..(10)X = W, G or H 251Xaa Xaa Trp Asp Xaa Xaa Leu Xaa Xaa Xaa Val 1 5 10 25219PRTArtificial SequenceLC-CDR3-4 Family consensusMISC_FEATURE(3)..(3)X = S or YMISC_FEATURE(4)..(4)X = Y, R or NMISC_FEATURE(5)..(5)X = S or NMISC_FEATURE(7)..(7)X = T, A or WMISC_FEATURE(8)..(8)X = L or TMISC_FEATURE(9)..(9)X = Y, A, W or TMISC_FEATURE(10)..(10)X = T, absent or FMISC_FEATURE(11)..(11)X = absent or GMISC_FEATURE(12)..(12)X = absent or GMISC_FEATURE(13)..(13)X = absent or GMISC_FEATURE(14)..(14)X = absent or TMISC_FEATURE(15)..(15)X = absent or KMISC_FEATURE(16)..(16)X = absent or VMISC_FEATURE(17)..(17)X = absent or EMISC_FEATURE(18)..(18)X = absent or FMISC_FEATURE(19)..(19)X = absent or K 252Gln Gln Xaa Xaa Xaa Pro Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa 25310PRTArtificial SequenceLC-CDR3-5 Family consensusMISC_FEATURE(4)..(4)X = D or NMISC_FEATURE(5)..(5)X = S or YMISC_FEATURE(7)..(7)X = K, S or NMISC_FEATURE(8)..(8)X = V or LMISC_FEATURE(9)..(9)X = I, V or WMISC_FEATURE(10)..(10)X = absent or V 253Gln Ser Tyr Xaa Xaa Ser Xaa Xaa Xaa Xaa 1 5 10 25411PRTArtificial SequenceLC-CDR3-6 Family consensusMISC_FEATURE(1)..(1)X = T or NMISC_FEATURE(4)..(4)X = T or SMISC_FEATURE(7)..(7)X = T or SMISC_FEATURE(8)..(8)X = P or TMISC_FEATURE(9)..(9)X = Y or LMISC_FEATURE(11)..(11)X = absent or A 254Xaa Ser Tyr Xaa Ser Ser Xaa Xaa Xaa Val Xaa 1 5 10 2558PRTArtificial SequenceHC-CDR1-1 Familyl consensusMISC_FEATURE(8)..(8)X = A or G 255Gly Phe Thr Phe Ser Ser Tyr Xaa 1 5 2568PRTArtificial SequenceHC-CDR1-2 Family consensusMISC_FEATURE(2)..(2)X = F or YMISC_FEATURE(3)..(3)X = S or TMISC_FEATURE(4)..(4)X = L or FMISC_FEATURE(5)..(5)X = G, R, T, S or N 256Gly Xaa Xaa Xaa Xaa Ser Tyr Gly 1 5 2578PRTArtificial SequenceHC-CDR1-3 Family consensusMISC_FEATURE(1)..(1)X = G or IMISC_FEATURE(2)..(2)X = G, F or LMISC_FEATURE(3)..(3)X = T, S or PMISC_FEATURE(4)..(4)X = F or SMISC_FEATURE(5)..(5)X = S or D 257Xaa Xaa Xaa Xaa Xaa Ser Tyr Ala 1 5 2588PRTArtificial SequenceHC-CDR2-1 Family consensusMISC_FEATURE(7)..(7)X = N or D 258Ile Ser Tyr Asp Gly Ser Xaa Lys 1 5 25912PRTArtificial SequenceHC-CDR3-2 Family consensusMISC_FEATURE(3)..(3)X = L, F or DMISC_FEATURE(4)..(4)X =Y, A or LMISC_FEATURE(5)..(5)X = S or RMISC_FEATURE(7)..(7)X = S, V or LMISC_FEATURE(8)..(8)X = S, Y or PMISC_FEATURE(9)..(9)X = N, L or IMISC_FEATURE(10)..(10)X = F or I 259Ala Lys Xaa Xaa Xaa Gly Xaa Xaa Xaa Xaa Asp Tyr 1 5 10 26014PRTArtificial SequenceHC-CDR3-3 Family consensusMISC_FEATURE(4)..(4)X = S or V 260Ala Arg Asp Xaa Gly Tyr Ser Ser Gly Trp Tyr Phe Asp Tyr 1 5 10 26124PRTArtificial SequenceHC-CDR3-4 Family consensusMISC_FEATURE(4)..(4)X = H or AMISC_FEATURE(5)..(5)X = S, Q or FMISC_FEATURE(6)..(6)X = S or GMISC_FEATURE(7)..(7)X = absent or YMISC_FEATURE(8)..(8)X = absent or SMISC_FEATURE(9)..(9)X = absent, R or SMISC_FEATURE(10)..(10)X = Q, N or SMISC_FEATURE(11)..(11)X = W or YMISC_FEATURE(12)..(12)X = absent, Y or FMISC_FEATURE(13)..(13)X = absent or EMISC_FEATURE(14)..(14)X = absent or WMISC_FEATURE(15)..(15)X = absent or EMISC_FEATURE(16)..(16)X = absent or PMISC_FEATURE(17)..(17)X = absent, G or SMISC_FEATURE(18)..(18)X = absent, R or TMISC_FEATURE(19)..(19)X = G, E or IMISC_FEATURE(20)..(20)X = D or H 261Ala Arg Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Ala Phe Asp Ile 20 26214PRTArtificial SequenceHC-CDR3-6 Family consensusMISC_FEATURE(4)..(4)X = A or GMISC_FEATURE(5)..(5)X = A or GMISC_FEATURE(6)..(6)X = A or YMISC_FEATURE(7)..(7)X = D or absentMISC_FEATURE(8)..(8)X = G or DMISC_FEATURE(9)..(9)X = F, M or RMISC_FEATURE(11)..(11)X = V, Y or AMISC_FEATURE(12)..(12)X = absent or FMISC_FEATURE(13)..(13)X = absent or DMISC_FEATURE(14)..(14)X = absent or I 262Ala Arg Ile Xaa Xaa Xaa Xaa Xaa Xaa Asp Xaa Xaa Xaa Xaa 1 5 10 26310PRTArtificial SequenceHC-CDR3-8 Family consensusMISC_FEATURE(1)..(1)X = absent or AMISC_FEATURE(2)..(2)X = absent or RMISC_FEATURE(3)..(3)X = A or GMISC_FEATURE(4)..(4)X = R or TMISC_FEATURE(8)..(8)X = F or G 263Xaa Xaa Xaa Xaa Arg Gly Tyr Xaa Asp Tyr 1 5 10 2649PRTArtificial SequenceHC-CDR3-10 Family consensusMISC_FEATURE(3)..(3)X = absent or SMISC_FEATURE(7)..(7)X = absent or F 264Ala Arg Xaa Gly Val Leu Xaa Asp Tyr 1 5 2651575DNAArtificial SequenceDNA encoding IL-11IL-11Ralpha fusion protein 265gaattcccgc cgccaccatg ggctggtcct gcatcatcct gtttctggtg gccacagcca 60ccggcgtgca ctctccacag gcttggggac ctccaggcgt gcagtatggc cagcctggca 120gatccgtgaa gctgtgctgt cctggcgtga cagctggcga ccctgtgtcc tggttcagag 180atggcgagcc caagctgctg cagggcccag attctggact gggccacgaa ctggtgctgg 240cccaggccga ttctaccgac gagggcacct acatctgcca gaccctggat ggcgccctgg 300gcggaacagt gacactgcag ctgggctacc ctcccgccag acctgtggtg tcttgtcagg 360ccgccgacta cgagaacttc agctgcacat ggtcccccag ccagatcagc ggcctgccca 420ccagatacct gaccagctac cggaagaaaa ccgtgctggg cgccgacagc cagagaagaa 480gcccttctac aggcccctgg ccctgccctc aggatcctct gggagctgcc agatgtgtgg 540tgcacggcgc cgagttctgg tcccagtacc ggatcaacgt gaccgaagtg aaccccctgg 600gcgcctccac aagactgctg gatgtgtccc tgcagagcat cctgcggccc gatcctccac 660agggcctgag agtggaaagc gtgcccggct accccagaag gctgagagcc agctggacat 720accccgcctc ttggccttgc cagccccact tcctgctgaa gtttcggctg cagtaccggc 780cagcccagca ccctgcttgg agcacagtgg aacctgccgg cctggaagaa gtgatcacag 840acgccgtggc cggactgcct catgctgtgc gggtgtccgc cagagacttt ctggatgccg 900gcacctggtc tacctggtcc ccagaagcct ggggcacacc ttctactggc ggacctgctg 960gacagtctgg cggaggcgga ggaagtggcg gaggatcagg gggaggatct gtgcctggac 1020ctcctccagg accccctaga gtgtccccag atcctagggc cgagctggac tctaccgtgc 1080tgctgaccag atccctgctg gccgacacaa ggcagctggc tgcccagctg agagacaagt 1140tccccgccga cggcgaccac aacctggata gcctgcctac cctggccatg tctgctggcg 1200cactgggggc tctgcagctg cctggggtgc tgactagact gagagccgac ctgctgagct 1260acctgcggca tgtgcagtgg ctgagaaggg ctggcggcag cagcctgaaa accctggaac 1320ctgagctggg cacactgcag gccagactgg acagactgct gcgcagactg cagctgctga 1380tgagcagact ggctctgccc cagcctcctc ctgaccctcc tgctcctcca ctggctcctc 1440caagctctgc ttggggcgga attagagccg cccacgccat tctgggaggc ctgcacctga 1500cactggattg ggcagtgcgg ggcctgctgc tgctgaaaac cagactgcac caccaccatc 1560accactgata agctt 1575266516PRTArtificial SequenceAmino acid sequence of IL-11IL-11Ralpha fusion protein 266Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser Pro Gln Ala Trp Gly Pro Pro Gly Val Gln Tyr Gly Gln 20 25 30 Pro Gly Arg Ser Val Lys Leu Cys Cys Pro Gly Val Thr Ala Gly Asp 35 40 45 Pro Val Ser Trp Phe Arg Asp Gly Glu Pro Lys Leu Leu Gln Gly Pro 50 55 60 Asp Ser Gly Leu Gly His Glu Leu Val Leu Ala Gln Ala Asp Ser Thr 65 70 75 80 Asp Glu Gly Thr Tyr Ile Cys Gln Thr Leu Asp Gly Ala Leu Gly Gly 85 90 95 Thr Val Thr Leu Gln Leu Gly Tyr Pro Pro Ala Arg Pro Val Val Ser 100 105 110 Cys Gln Ala Ala Asp Tyr Glu Asn Phe Ser Cys Thr Trp Ser Pro Ser 115 120 125 Gln Ile Ser Gly Leu Pro Thr Arg Tyr Leu Thr Ser Tyr Arg Lys Lys 130 135 140 Thr Val Leu Gly Ala Asp Ser Gln Arg Arg Ser Pro Ser Thr Gly Pro 145 150 155 160 Trp Pro Cys Pro Gln Asp Pro Leu Gly Ala Ala Arg Cys Val Val His 165 170 175 Gly Ala Glu Phe Trp Ser Gln Tyr Arg Ile Asn Val Thr Glu Val Asn 180 185 190 Pro Leu Gly Ala Ser Thr Arg Leu Leu Asp Val Ser Leu Gln Ser Ile 195 200 205 Leu Arg Pro Asp Pro Pro Gln Gly Leu Arg Val Glu Ser Val Pro Gly 210 215 220 Tyr Pro Arg Arg Leu Arg Ala Ser Trp Thr Tyr Pro Ala Ser Trp Pro 225 230 235 240 Cys Gln Pro His Phe Leu Leu Lys Phe Arg Leu Gln Tyr Arg Pro Ala 245 250 255 Gln His Pro Ala Trp Ser Thr Val Glu Pro Ala Gly Leu Glu Glu Val 260 265 270 Ile Thr Asp Ala Val Ala Gly Leu Pro His Ala Val Arg Val Ser Ala 275 280 285 Arg Asp Phe Leu Asp Ala Gly Thr Trp Ser Thr Trp Ser Pro Glu Ala 290 295 300 Trp Gly Thr Pro Ser Thr Gly Gly Pro Ala Gly Gln Ser Gly Gly Gly 305 310 315 320 Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Val Pro Gly Pro Pro 325 330 335 Pro Gly Pro Pro Arg Val Ser Pro Asp Pro Arg Ala Glu Leu Asp Ser 340 345 350 Thr Val Leu Leu Thr Arg Ser Leu Leu Ala Asp Thr Arg Gln

Leu Ala 355 360 365 Ala Gln Leu Arg Asp Lys Phe Pro Ala Asp Gly Asp His Asn Leu Asp 370 375 380 Ser Leu Pro Thr Leu Ala Met Ser Ala Gly Ala Leu Gly Ala Leu Gln 385 390 395 400 Leu Pro Gly Val Leu Thr Arg Leu Arg Ala Asp Leu Leu Ser Tyr Leu 405 410 415 Arg His Val Gln Trp Leu Arg Arg Ala Gly Gly Ser Ser Leu Lys Thr 420 425 430 Leu Glu Pro Glu Leu Gly Thr Leu Gln Ala Arg Leu Asp Arg Leu Leu 435 440 445 Arg Arg Leu Gln Leu Leu Met Ser Arg Leu Ala Leu Pro Gln Pro Pro 450 455 460 Pro Asp Pro Pro Ala Pro Pro Leu Ala Pro Pro Ser Ser Ala Trp Gly 465 470 475 480 Gly Ile Arg Ala Ala His Ala Ile Leu Gly Gly Leu His Leu Thr Leu 485 490 495 Asp Trp Ala Val Arg Gly Leu Leu Leu Leu Lys Thr Arg Leu His His 500 505 510 His His His His 515 267110PRTArtificial SequenceYU100-A10 267Leu Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Glu Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Thr Thr Ser 85 90 95 Ile Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 26810PRTArtificial SequenceYU100-A10 LC-CDR3 268Ser Ser Phe Thr Thr Ser Ile Ala Trp Val 1 5 10 269110PRTArtificial SequenceYU100-A11 269Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 270110PRTArtificial SequenceYU100-A12 270Leu Pro Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asp Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 271110PRTArtificial SequenceYU100-B01 271Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Asn Thr Asp Val Gly Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Tyr Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 2729PRTArtificial SequenceYU100-B01 LC-CDR1 272Asn Thr Asp Val Gly Ala Tyr Asn Tyr 1 5 27310PRTArtificial SequenceYU100-B01 LC-CDR3 273Cys Ser Tyr Ala Gly Ser Tyr Ser Trp Val 1 5 10 274120PRTArtificial SequenceYU100-B03 274Gln Ser Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Arg 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Thr Leu Tyr Asp Val Val Lys Arg Pro Ser Gly Val Pro Asp Arg Tyr 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Gly 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Cys Ser 100 105 110 Tyr Ala Gly Ser Tyr Ser Trp Val 115 120 2753PRTArtificial SequenceYU100-B03 LC-CDR2 275Asp Val Val 1 27610PRTArtificial SequenceYU100-B03 LC-CDR3 276Cys Ser Tyr Ala Gly Gly Tyr Thr Trp Val 1 5 10 277110PRTArtificial SequenceYU100-B06 277Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 27810PRTArtificial SequenceYU100-B06 LC-CDR3 278Asn Ser Tyr Ala Gly Ser Tyr Thr Trp Val 1 5 10 279110PRTArtificial SequenceYU100-B07 279Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Met Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln His His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Glu Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 280110PRTArtificial SequenceYU100-B08 280Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Val Pro Arg Leu 35 40 45 Leu Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Thr Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Gly Glu Asp Glu Ala Glu Tyr Tyr Cys Ser Ser Phe Thr Ser Ser 85 90 95 Thr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 28110PRTArtificial SequenceYU100-B08 LC-CDR3 281Ser Ser Phe Thr Ser Ser Thr Thr Trp Val 1 5 10 28221PRTArtificial SequenceYU100-B09 LC-CDR3 282Ser Ser Tyr Arg Ser Gly Ser Thr Leu Gly Val Arg Arg Arg Asp Gln 1 5 10 15 Ala Asp Arg Pro Arg 20 283110PRTArtificial SequenceYU100-C02 283Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asn Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Val Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 2849PRTArtificial SequenceYU100-C02 LC-CDR1 284Ser Ser Asn Val Gly Gly Tyr Asn Tyr 1 5 28510PRTArtificial SequenceYU100-C02 LC-CDR3 285Cys Ser Tyr Ala Gly Ser Tyr Val Trp Val 1 5 10 286110PRTArtificial SequenceYU100-C04 286Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln His His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Glu Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Gly 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 287110PRTArtificial SequenceYU100-C05 287Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ile Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 28810PRTArtificial SequenceYU100-C05 LC-CDR3 288Ser Ser Tyr Thr Ser Ser Ile Ser Trp Val 1 5 10 289110PRTArtificial SequenceYU100-C10 289Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Arg Ser Asp Ile Gly Gly Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Glu Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ile Thr Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 2909PRTArtificial SequenceYU100-C10 LC-CDR1 290Arg Ser Asp Ile Gly Gly Tyr Asp Tyr 1 5 2913PRTArtificial SequenceYU100-C10 LC-CDR3 291Asp Val Asn 1 29210PRTArtificial SequenceYU100-C11 LC-CDR3 292Ser Ser Tyr Thr Asn Ser Arg Thr Trp Val 1 5 10 293110PRTArtificial SequenceYU100-D01 293Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Asp Val Asp Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Arg Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Thr Glu Asp Glu Ala Lys Tyr Tyr Cys Cys Ser Tyr Ala Gly Arg 85 90 95 Tyr Thr Trp Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 2949PRTArtificial SequenceYU100-D01 LC-CDR1 294Ser Ser Asp Val Gly Gly Tyr Asn Phe 1 5 2953PRTArtificial SequenceYU100-D01 LC-CDR2 295Asp Val Asp 1 29610PRTArtificial SequenceYU100-D01 LC-CDR3 296Cys Ser Tyr Ala Gly Arg Tyr Thr Trp Ile 1 5 10 297110PRTArtificial SequenceYU100-D02 297Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Gly Asp Val Gly Thr Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Phe Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 2989PRTArtificial SequenceYU100-D02 LC-CDR1 298Ser Gly Asp Val Gly Thr Tyr Asn Tyr 1 5 299110PRTArtificial SequenceYU100-D05 299Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Leu Ile Thr Ile Ser Cys Thr Gly Thr Asn Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 3009PRTArtificial SequenceYU100-D05 LC-CDR1 300Asn Ser Asp Val Gly Gly Tyr Asn Tyr 1 5 301110PRTArtificial SequenceYU100-D07 301Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Gly Asp Val Gly Thr Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val

Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 3029PRTArtificial SequenceYU100-D07 LC-CDR1 302Ser Gly Asp Val Gly Thr Tyr Asp Tyr 1 5 303110PRTArtificial SequenceYU100-D11 303Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asn Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asn Tyr Tyr Cys Ala Ser Tyr Ala Gly Asn 85 90 95 Tyr Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 30410PRTArtificial SequenceYU100-D11 LC-CDR3 304Ala Ser Tyr Ala Gly Asn Tyr Asn Trp Val 1 5 10 305110PRTArtificial SequenceYU100-E01 305Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Asn Asp Ile Gly Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 3069PRTArtificial SequenceYU100-E01 LC-CDR1 306Ser Asn Asp Ile Gly Ala Tyr Asn Tyr 1 5 307110PRTArtificial SequenceYU100-E04 307Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Thr Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp His Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 His Ile Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 30810PRTArtificial SequenceYU100-E04 LC-CDR3 308Cys Ser Tyr Ala Gly Ser His Ile Trp Val 1 5 10 309110PRTArtificial SequenceYU100-E05 309Gln Ala Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 310126PRTArtificial SequenceYU100-E06 310Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Phe Pro Glu Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Asn 85 90 95 Thr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 115 120 125 31110PRTArtificial SequenceYU100-E06 LC-CDR3 311Ser Ser Tyr Thr Ser Asn Thr Thr Trp Val 1 5 10 312110PRTArtificial SequenceYU100-E07 312Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Glu Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Ala Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Arg 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 31310PRTArtificial SequenceYU100-E07 LC-CDR3 313Cys Ser Tyr Ala Gly Arg Tyr Thr Trp Val 1 5 10 314110PRTArtificial SequenceYU100-E08 314Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Arg Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Asn 85 90 95 Tyr Thr Trp Met Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 31510PRTArtificial SequenceYU100-E08 LC-CDR3 315Cys Ser Tyr Ala Gly Asn Tyr Thr Trp Met 1 5 10 316110PRTArtificial SequenceYU100-E09 316Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Arg Gly Thr Lys Leu Thr Val Leu 100 105 110 3179PRTArtificial SequenceYU100-E09 LC-CDR1 317Ser Ser Asp Val Gly Asp Tyr Asp Tyr 1 5 318110PRTArtificial SequenceYU100-E10 318Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Phe Asp Val Ser Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Ala Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 319110PRTArtificial SequenceYU100-E12 319Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Thr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 32010PRTArtificial SequenceYU100-E12 LC-CDR3 320Ser Ser Tyr Thr Ser Ser Thr Thr Trp Val 1 5 10 321110PRTArtificial SequenceYU100-F01 321Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Gly Ser Asp Val Gly Ala Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Glu Tyr Tyr Cys Ser Ser Phe Ala Thr Ser 85 90 95 Ile Ser Trp Val Phe Gly Gly Gly Thr Arg Leu Thr Val Leu 100 105 110 3229PRTArtificial SequenceYU100-F01 LC-CDR1 322Gly Ser Asp Val Gly Ala Tyr Asp Tyr 1 5 323110PRTArtificial SequenceYU100-F02 323Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 32410PRTArtificial SequenceYU100-F02 LC-CDR3 324Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Ile 1 5 10 325110PRTArtificial SequenceYU100-F05 325Gln Ala Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Ser Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Met Thr Val Leu 100 105 110 3269PRTArtificial SequenceYU100-F05 LC-CDR1 326Ser Ser Asp Ile Gly Gly Tyr Asn Tyr 1 5 327110PRTArtificial SequenceYU100-F06 327Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Phe Val Ser Trp Tyr Arg Gln His Pro Gly Glu Ala Pro Lys Leu 35 40 45 Val Ile Phe Asp Val Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Thr Glu Asp Glu Ala Asp Tyr Phe Cys Cys Ser Tyr Ala Gly Gly 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 110 328110PRTArtificial SequenceYU100-F07 328Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Glu Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Gly Glu Asp Ala Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Thr Val Thr Val Leu 100 105 110 329110PRTArtificial SequenceYU100-F11 329Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Ser Ser Ser Asp Val Ala Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu 100 105 110 3309PRTArtificial SequenceYU100-F11 LC-CDR1 330Ser Ser Asp Val Ala Gly Tyr Asn Tyr 1 5 331110PRTArtificial SequenceYU100-G01 331Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Ala Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Leu Tyr Asp Val Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Arg Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 332110PRTArtificial SequenceYU100-G07 332Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Tyr Thr Arg Ser

85 90 95 Ser Val Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 3339PRTArtificial SequenceYU100-G07 LC-CDR1 333Ser Ser Asp Val Gly Ala Tyr Asp Tyr 1 5 33410PRTArtificial SequenceYU100-G07 LC-CDR3 334Ala Ser Tyr Thr Arg Ser Ser Val Trp Val 1 5 10 335110PRTArtificial SequenceYU100-G08 335Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Leu Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln His Tyr Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Phe Asp Val Asn Glu Arg Ser Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Arg 85 90 95 Tyr Thr Trp Met Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 33610PRTArtificial SequenceYU100-G08 LC-CDR3 336Cys Ser Tyr Ala Gly Arg Tyr Thr Trp Met 1 5 10 337110PRTArtificial SequenceYU100-G09 337Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ile Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Gly Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 338110PRTArtificial SequenceYU100-G10 338Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Ser Ile Thr Met Ser Cys Thr Gly Thr Arg Arg Asp Val Gly Gly Tyr 20 25 30 Asp Phe Val Ser Trp Tyr Gln Gln Tyr Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Thr Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Thr 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110 3399PRTArtificial SequenceYU100-G10 LC-CDR1 339Arg Arg Asp Val Gly Gly Tyr Asp Phe 1 5 34010PRTArtificial SequenceYU100-G10 LC-CDR3 340Cys Ser Tyr Ala Gly Thr Tyr Thr Trp Val 1 5 10 341110PRTArtificial SequenceYU100-G11 341Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Thr Leu Tyr Asp Val Gly Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Gly 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Val Thr Val Val 100 105 110 342110PRTArtificial SequenceYU100-H01 342Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 343110PRTArtificial SequenceYU100-H02 343Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Arg Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Phe 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 3449PRTArtificial SequenceYU100-H02 LC-CDR1 344Ser Ser Asp Val Gly Thr Tyr Asn Tyr 1 5 34510PRTArtificial SequenceYU100-H02 LC-CDR3 345Cys Ser Tyr Ala Gly Phe Tyr Thr Trp Val 1 5 10 346110PRTArtificial SequenceYU100-H04 346Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Val Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 3479PRTArtificial SequenceYU100-H04 LC-CDR1 347Ser Ser Asp Ile Gly Val Tyr Asn Tyr 1 5 348110PRTArtificial SequenceYU100-H05 348Gln Ala Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Gly Ser Asn Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Gln Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Thr 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 3499PRTArtificial SequenceYU100-H05 LC-CDR1 349Gly Ser Asn Val Gly Gly Tyr Asn Tyr 1 5 350110PRTArtificial SequenceYU100-H09 350Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 351108PRTArtificial SequenceYU112-C03 351Asp Ser Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Asn Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 3526PRTArtificial SequenceYU112-C03 LC-CDR1 352Gln Ala Ile Asn Ser Tyr 1 5 353110PRTArtificial SequenceYU100-C11 353Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Pro Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Asn Ser 85 90 95 Arg Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 35410PRTArtificial SequenceYU112-C03 LC-CDR3 354Gln Gln Ser Tyr Ser Thr Pro Ser Trp Thr 1 5 10 355109PRTArtificial SequenceYU112-C09 355Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Arg Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Thr Ser Pro 85 90 95 Thr Trp Ala Phe Gly Arg Gly Thr Lys Val Glu Val Lys 100 105 3567PRTArtificial SequenceYU112-C09 LC-CDR1 356Gln Ser Phe Ser Ser Ser Tyr 1 5 35710PRTArtificial SequenceYU112-C09 LC-CDR2 357Gln Gln Ser Ser Thr Ser Pro Thr Trp Ala 1 5 10 358109PRTArtificial SequenceYU112-E07 358Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Asn Ser Ala 20 25 30 Tyr Leu Ala Trp Tyr Gln His Lys Pro Gly Gln Pro Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Arg Arg Val Thr Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Asp Pro 85 90 95 Arg Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 3597PRTArtificial SequenceYU112-E07 LC-CDR1 359Gln Ser Val Asn Ser Ala Tyr 1 5 36010PRTArtificial SequenceYU112-E07 LC-CDR3 360Gln Gln Ser Tyr Ser Asp Pro Arg Trp Thr 1 5 10 361110PRTArtificial SequenceYU112-F05 361Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Ala Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Gly 85 90 95 Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 36210PRTArtificial SequenceYU112-F05 LC-CDR3 362Asn Ser Tyr Thr Ser Gly Ser Thr Trp Val 1 5 10 363110PRTArtificial SequenceYU112-G06 363Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ile Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr Lys Arg Arg Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Gly Tyr Tyr Cys Ser Ser Tyr Ala Gly Gly 85 90 95 Tyr Thr Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu 100 105 110 36410PRTArtificial SequenceYU112-G06 LC-CDR3 364Ser Ser Tyr Ala Gly Gly Tyr Thr Trp Val 1 5 10 36597PRTArtificial SequenceYU112-G09 365Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ile Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Gly Arg Phe Cys Asn Leu Leu Leu Ser Thr Glu Leu Gln Tyr Pro His 85 90 95 Val 366109PRTArtificial SequenceYU112-H01 366Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro 85 90 95 Thr Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 3677PRTArtificial SequenceYU112-H01 LC-CDR1 367Gln Ser Val Ser Ser Ser Tyr 1 5 368118PRTArtificial SequenceYU100-A11 368Glu Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 369118PRTArtificial SequenceYU100-A12 369Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 370118PRTArtificial SequenceYU100-B01 370Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 371118PRTArtificial SequenceYU100-B06 371Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 372118PRTArtificial SequenceYU100-B08 372Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 373123PRTArtificial SequenceYU100-B12 373Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 374118PRTArtificial SequenceYU100-C10 374Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Ile Thr Val Ser Ser 115 375123PRTArtificial SequenceYU100-C12 375Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 376123PRTArtificial SequenceYU100-D01 376Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 377118PRTArtificial SequenceYU100-D02 377Gln Val Arg Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 378118PRTArtificial SequenceYU100-D05 378Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 379123PRTArtificial SequenceYU100-D07 379Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 380118PRTArtificial SequenceYU100-E07 380Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 3818PRTArtificial SequenceYU100-E07 LC-CDR2 381Ile Ser Tyr Asp Gly Ser Asn Arg 1 5 382123PRTArtificial SequenceYU100-E08 382Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 383123PRTArtificial SequenceYU100-E09 383Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 384123PRTArtificial SequenceYU100-E11 384Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 385123PRTArtificial SequenceYU100-H02 385Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 386118PRTArtificial SequenceYU112-A07 386Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 387119PRTArtificial SequenceYU112-C03 387Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55

60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Gly Lys Ser Tyr Tyr Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 388116PRTArtificial SequenceYU112-C09 388Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 389118PRTArtificial SequenceYU112-D08 389Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 390118PRTArtificial SequenceYU112-F05 390Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 391118PRTArtificial SequenceYU112-G06 391Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 392116PRTArtificial SequenceYU112-H01 392Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 3939PRTArtificial SequencematLC-CDR1-1 Family consensusMISC_FEATURE(1)..(1)X = S, N or IMISC_FEATURE(2)..(2)X = S or RMISC_FEATURE(8)..(8)X = N, E or DMISC_FEATURE(9)..(9)X = Y or F 393Xaa Xaa Asp Val Gly Gly Tyr Xaa Xaa 1 5 3949PRTArtificial SequencematLC-CDR1-2 Family consensusMISC_FEATURE(5)..(5)X = G or AMISC_FEATURE(6)..(6)X = D, G or TMISC_FEATURE(8)..(8)X = N or D 394Ser Ser Asp Val Xaa Xaa Tyr Xaa Tyr 1 5 3959PRTArtificial SequencematLC-CDR1-3 Family consensusMISC_FEATURE(1)..(1)X = S or NMISC_FEATURE(2)..(2)X = N, T or SMISC_FEATURE(4)..(4)X = V or I 395Xaa Xaa Asp Xaa Gly Ala Tyr Asn Tyr 1 5 3969PRTArtificial SequencematLC-CDR1-4 Family consensusMISC_FEATURE(6)..(6)X = V or G 396Ser Ser Asp Ile Gly Xaa Tyr Asn Tyr 1 5 3979PRTArtificial SequencematLC-CDR1-5 Family consensusMISC_FEATURE(1)..(1)X = S or G 397Xaa Ser Asp Val Gly Ala Tyr Asp Tyr 1 5 3989PRTArtificial SequencematLC-CDR1-6 Family consensusMISC_FEATURE(8)..(8)X = N or D 398Ser Gly Asp Val Gly Thr Tyr Xaa Tyr 1 5 3996PRTArtificial SequencematLC-CDR1-7 Family consensusMISC_FEATURE(2)..(2)X = A or IMISC_FEATURE(4)..(4)X = N or S 399Gln Xaa Ile Xaa Ser Tyr 1 5 4007PRTArtificial SequencematLC-CDR1-8 Family consensusMISC_FEATURE(3)..(3)X = F or V 400Gln Ser Xaa Ser Ser Ser Tyr 1 5 4019PRTArtificial SequencematLC-CDR1-9 Family consensusMISC_FEATURE(2)..(2)X = S or RMISC_FEATURE(4)..(4)X = I or VMISC_FEATURE(9)..(9)X = Y or F 401Arg Xaa Asp Xaa Gly Gly Tyr Asp Xaa 1 5 4023PRTArtificial SequencematLC-CDR2-1 Family consensusMISC_FEATURE(3)..(3)X = S, T, N, G, V or D 402Asp Val Xaa 1 4033PRTArtificial SequencematLC-CDR2-2 Family consensusMISC_FEATURE(1)..(1)X = A or G 403Xaa Ala Ser 1 40410PRTArtificial SequencematLC-CDR3-1 Family consensusMISC_FEATURE(1)..(1)X = C, S, A or NMISC_FEATURE(6)..(6)X = S, R, N, G, T or FMISC_FEATURE(7)..(7)X = Y or HMISC_FEATURE(8)..(8)X = T, N, I, S or VMISC_FEATURE(10)..(10)X = V, M or I 404Xaa Ser Tyr Ala Gly Xaa Xaa Xaa Trp Xaa 1 5 10 40510PRTArtificial SequencematLC-CDR3-2 Family consensusMISC_FEATURE(5)..(5)X = S or NMISC_FEATURE(6)..(6)X = S or NMISC_FEATURE(7)..(7)X = T, I, S or RMISC_FEATURE(8)..(8)X = T or S 405Ser Ser Tyr Thr Xaa Xaa Xaa Xaa Trp Val 1 5 10 40610PRTArtificial SequencematLC-CDR3-3 Family consensusMISC_FEATURE(6)..(6)X = T or DMISC_FEATURE(8)..(8)X = S, R or T 406Gln Gln Ser Tyr Ser Xaa Pro Xaa Trp Thr 1 5 10 40710PRTArtificial SequencematLC-CDR3-4 Family consensusMISC_FEATURE(4)..(4)X = T or AMISC_FEATURE(5)..(5)X = T or SMISC_FEATURE(7)..(7)X = I or TMISC_FEATURE(8)..(8)X = A or T 407Ser Ser Phe Xaa Xaa Ser Xaa Xaa Trp Val 1 5 10 40810PRTArtificial SequenceYU100-F01 LC-CDR3 408Ser Ser Phe Ala Thr Ser Ile Ser Trp Val 1 5 10 4098PRTArtificial SequencematHC-CDR1-1 Family consensusMISC_FEATURE(5)..(5)X = S or GMISC_FEATURE(8)..(8)X = G or A 409Gly Phe Thr Phe Xaa Ser Tyr Xaa 1 5 4108PRTArtificial SequencematHC-CDR2-1 Family consensusMISC_FEATURE(8)..(8)X = K or R 410Ile Ser Tyr Asp Gly Ser Asn Xaa 1 5 41112PRTArtificial SequencematHC-CDR3-4 Family consensusMISC_FEATURE(4)..(4)X = absent or GMISC_FEATURE(5)..(5)X = absent or KMISC_FEATURE(9)..(9)X = absent or G 411Ala Lys Gly Xaa Xaa Ser Tyr Tyr Xaa Phe Asp Tyr 1 5 10 412262PRTArtificial SequenceYU100-A10 412Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Leu Pro Val Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Ala Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Glu Leu Met Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Phe Thr Thr Ser Ile Ala Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 413262PRTArtificial SequenceYU100-A11 413Glu Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 414262PRTArtificial SequenceYU100-A12 414Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Leu Pro Val Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asp Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 415262PRTArtificial SequenceYU100-B01 415Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Asn Thr Asp Val Gly Ala Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 Tyr Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Ser Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 416262PRTArtificial SequenceYU100-B03 416Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40

45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Val Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Arg Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Thr Leu Tyr Asp Val Val Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Tyr Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Gly Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 417262PRTArtificial SequenceYU100-B06 417Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Asn Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 418262PRTArtificial SequenceYU100-B07 418Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Met Ser Cys Thr Gly 145 150 155 160 Thr Ser Arg Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln His 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Glu Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 419262PRTArtificial SequenceYU100-B08 419Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Val Pro Arg Leu Leu Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Thr Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Gly Glu Asp Glu Ala Glu Tyr 210 215 220 Tyr Cys Ser Ser Phe Thr Ser Ser Thr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 420262PRTArtificial SequenceYU100-B09 420Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asp Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Arg Ser Gly Ser Thr Leu Gly Val Arg Arg Arg 225 230 235 240 Asp Gln Ala Asp Arg Pro Arg Ser Ala Gln Gly Cys Pro Leu Gly His 245 250 255 Ser Val Pro Ala Leu Leu 260 421267PRTArtificial SequenceYU100-B12 421Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 422262PRTArtificial SequenceYU100-C02 422Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asn Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Val Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 423262PRTArtificial SequenceYU100-C04 423Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln His 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Ala Ile Ser Gly Leu Gln Ala Glu Glu Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Gly Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 424262PRTArtificial SequenceYU100-C05 424Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu

Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Thr Ser Ser Ile Ser Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 425262PRTArtificial SequenceYU100-C10 425Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Ile Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Arg Ser Asp Ile Gly Gly Tyr Asp Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Glu Tyr 210 215 220 Tyr Cys Ser Ser Tyr Thr Ser Ser Ile Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 426262PRTArtificial SequenceYU100-C11 426Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 Arg Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Asp Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Thr Asn Ser Arg Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 427267PRTArtificial SequenceYU100-C12 427Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 428267PRTArtificial SequenceYU100-D01 428Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Phe Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 180 185 190 Asp Val Asp Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Arg Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Thr Glu 210 215 220 Asp Glu Ala Lys Tyr Tyr Cys Cys Ser Tyr Ala Gly Arg Tyr Thr Trp 225 230 235 240 Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Ile Leu Phe Pro Pro Ser Ser 260 265 429262PRTArtificial SequenceYU100-D02 429Gln Val Arg Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Gly Asp Val Gly Thr Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Phe Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Asn Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 430262PRTArtificial SequenceYU100-D05 430Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Leu Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Asn Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 431267PRTArtificial SequenceYU100-D07 431Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Leu Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Gly Asp Val Gly Thr Tyr Asp Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Thr 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 432262PRTArtificial SequenceYU100-D11 432Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asn Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asn Tyr 210 215 220 Tyr Cys Ala Ser Tyr Ala Gly Asn Tyr Asn Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 433262PRTArtificial SequenceYU100-E01 433Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr

100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Asn Asp Ile Gly Ala Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Val Asn Asn Arg 180 185 190 Pro Ser Gly Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Ser Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Asn Pro Thr Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 434262PRTArtificial SequenceYU100-E04 434Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Thr Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp His Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser His Ile Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 435262PRTArtificial SequenceYU100-E05 435Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ala Val Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Ser Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 436262PRTArtificial SequenceYU100-E06 436Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Phe Pro Glu Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asp Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Thr Ser Asn Thr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Arg Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 437262PRTArtificial SequenceYU100-E07 437Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asp Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Glu Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Ala Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Arg Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 438267PRTArtificial SequenceYU100-E08 438Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Arg Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Asn Tyr Thr Trp 225 230 235 240 Met Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 439267PRTArtificial SequenceYU100-E09 439Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Tyr Asp Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr 180 185 190 Asp Val Thr Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Arg Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Thr 260 265 440262PRTArtificial SequenceYU100-E10 440Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Phe Asp Val Ser Gln Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Ala Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 441267PRTArtificial SequenceYU100-E11 441Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265

442262PRTArtificial SequenceYU100-E12 442Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Thr Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Thr Ser Ser Thr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 443262PRTArtificial SequenceYU100-F01 443Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Gly Ser Asp Val Gly Ala Tyr Asp Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Glu Tyr 210 215 220 Tyr Cys Ser Ser Phe Ala Thr Ser Ile Ser Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Arg Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 444262PRTArtificial SequenceYU100-F02 444Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Asp Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Ile Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 445262PRTArtificial SequenceYU100-F05 445Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ala Val Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Ile Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Thr Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Ser Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Met Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 446267PRTArtificial SequenceYU100-F06 446Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Ser Ser Ser Asp Val Gly Gly Tyr Asn Phe Val 165 170 175 Ser Trp Tyr Arg Gln His Pro Gly Glu Ala Pro Lys Leu Val Ile Phe 180 185 190 Asp Val Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Thr Glu 210 215 220 Asp Glu Ala Asp Tyr Phe Cys Cys Ser Tyr Ala Gly Gly Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 447267PRTArtificial SequenceYU100-F07 447Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Val Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Glu Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Gly Glu 210 215 220 Asp Ala Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Thr Val Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 448262PRTArtificial SequenceYU100-F11 448Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Ser Ser Ser Asp Val Ala Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Gln Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 449262PRTArtificial SequenceYU100-G01 449Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Ala Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Ala Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Leu Tyr Asp Val Asn Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Arg Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 450262PRTArtificial SequenceYU100-G07 450Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150

155 160 Thr Ser Ser Asp Val Gly Ala Tyr Asp Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ala Ser Tyr Thr Arg Ser Ser Val Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Ser Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 451262PRTArtificial SequenceYU100-G08 451Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Leu Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln His 165 170 175 Tyr Pro Gly Lys Ala Pro Lys Leu Met Ile Phe Asp Val Asn Glu Arg 180 185 190 Ser Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Arg Tyr Thr Trp Met Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 452262PRTArtificial SequenceYU100-G09 452Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ile Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Gly Tyr 210 215 220 Tyr Cys Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 453262PRTArtificial SequenceYU100-G10 453Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Leu Gly Gln Ser Ile Thr Met Ser Cys Thr Gly 145 150 155 160 Thr Arg Arg Asp Val Gly Gly Tyr Asp Phe Val Ser Trp Tyr Gln Gln 165 170 175 Tyr Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Thr Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Thr Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 454267PRTArtificial SequenceYU100-G11 454Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Thr Leu Tyr 180 185 190 Asp Val Gly Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Gly Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Val Thr Val Val Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 455267PRTArtificial SequenceYU100-H01 455Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Glu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 456267PRTArtificial SequenceYU100-H02 456Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Arg Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Phe Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 457267PRTArtificial SequenceYU100-H04 457Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Val Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 458262PRTArtificial SequenceYU100-H05 458Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ala Val Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Gly Ser Asn Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Gln Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Thr Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 459262PRTArtificial SequenceYU100-H06 459Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Ile Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 460267PRTArtificial SequenceYU100-H09 460Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 461262PRTArtificial SequenceYU100-H11 461Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 462262PRTArtificial SequenceYU112-A07 462Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ile Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Gly Tyr 210 215 220 Tyr Cys Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Glu Leu Thr Val Leu Ser Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 463262PRTArtificial SequenceYU112-B06 463Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Ala 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Phe Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ser Ser Tyr Thr Ser Ser Ser Ser Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 464253PRTArtificial SequenceYU112-C03 464Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Gly Lys Ser Tyr Tyr Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu 115 120 125 Glu Gly Glu Phe Ser Glu Ala Arg Val Asp Ser Val Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Gln Ala Ile Asn Ser Tyr Leu Asn Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln 180 185 190 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Tyr Ser Thr Pro Ser Trp Thr Phe Gly Gln Gly Thr 225 230 235 240 Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 245 250 465267PRTArtificial SequenceYU112-C05 465Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Met Gly Tyr Asp Tyr Gly Asp Tyr Asp Val Val Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala 115 120 125 Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala 130 135 140 Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr 145 150 155 160 Ile Ser Cys Thr Gly Thr Ile Ser Asp Val Gly Gly Tyr Asn Tyr Val 165 170 175 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 180 185 190 Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 210 215 220 Asp Glu Ala Gly Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser Tyr Thr Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Ser Gln Pro Lys Ala 245 250 255 Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser 260 265 466251PRTArtificial SequenceYU112-C09 466Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu Gly Glu 115 120 125 Phe Ser Glu Ala Arg Val Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr 130 135 140 Leu Ser Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser 145 150 155 160 Gln Ser Phe Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Pro Gly 180 185 190 Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu 195 200 205 Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln 210 215 220 Gln Ser Ser Thr Ser Pro Thr Trp Ala Phe Gly Arg Gly Thr Lys Val 225 230 235 240 Glu Val Lys Arg Thr Val Ala Ala Pro Ser Val 245 250 467262PRTArtificial SequenceYU112-D08 467Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ile Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala

Gly Tyr 210 215 220 Tyr Cys Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Glu Leu Thr Val Leu Ser Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 468251PRTArtificial SequenceYU112-E07 468Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu Gly Glu 115 120 125 Phe Ser Glu Ala Arg Val Glu Ile Val Met Thr Gln Ser Pro Asp Ser 130 135 140 Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser 145 150 155 160 Gln Ser Val Asn Ser Ala Tyr Leu Ala Trp Tyr Gln His Lys Pro Gly 165 170 175 Gln Pro Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Val Thr Gly 180 185 190 Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Ser Tyr Ser Asp Pro Arg Trp Thr Phe Gly Gln Gly Thr Lys Val 225 230 235 240 Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 245 250 469252PRTArtificial SequenceYU112-E08 469Val Thr Leu Lys Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 35 40 45 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Gly Gly Lys Ser Tyr Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Phe Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ile Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Thr Trp Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 245 250 470262PRTArtificial SequenceYU112-F05 470Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr Asp Val Asn Asn Arg 180 185 190 Pro Ser Gly Val Ser Asn Arg Phe Ser Ala Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Asn Ser Tyr Thr Ser Gly Ser Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 471262PRTArtificial SequenceYU112-G01 471Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ile Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Gly Tyr 210 215 220 Tyr Cys Ser Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Glu Leu Thr Val Leu Ser Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 472262PRTArtificial SequenceYU112-G06 472Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ile Gly Ala Thr Asp Pro Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Ser Ala Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ile Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Thr Lys Arg 180 185 190 Arg Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Gly Tyr 210 215 220 Tyr Cys Ser Ser Tyr Ala Gly Gly Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Glu Leu Thr Val Leu Ser Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 473233PRTArtificial SequenceYU112-G09 473Val Thr Leu Lys Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 35 40 45 Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Gly Gly Lys Ser Tyr Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Phe Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ile Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Gly Arg Phe Cys Asn Leu Leu Leu 210 215 220 Ser Thr Glu Leu Gln Tyr Pro His Val 225 230 474251PRTArtificial SequenceYU112-H01 474Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu Gly Glu 115 120 125 Phe Ser Glu Ala Arg Val Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr 130 135 140 Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser 145 150 155 160 Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly 180 185 190 Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Ser Tyr Ser Thr Pro Thr Trp Thr Phe Gly Gln Gly Thr Lys Val 225 230 235 240 Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 245 250 475262PRTArtificial SequenceYU112-H02 475Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gly Pro Asn Gly Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Ser Ala Ser Ala Pro Lys Leu Glu Glu 115 120 125 Gly Glu Phe Ser Glu Ala Arg Val Gln Pro Val Leu Thr Gln Pro Arg 130 135 140 Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly 145 150 155 160 Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln 165 170 175 His Pro Gly Lys Ala Pro Lys Val Met Ile Tyr Asp Val Ser Lys Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr 195 200 205 Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Trp Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr 245 250 255 Leu Phe Pro Pro Ser Ser 260 476786DNAArtificial SequenceYU100-A10 476gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtact gcctgtgctg 420actcagcccg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgc ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccgaac tcatgattta tgatgtcagt aatcggccct ccggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca gcctgaggac 660gaggctgatt attactgcag ctcatttacg accagcatcg cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786477786DNAArtificial SequenceYU100-A11 477gaggtgcagc tgcagcagtc gggggggggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt

attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctaca cttgggtatt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786478786DNAArtificial SequenceYU100-A12 478caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtact gcctgtgctg 420actcagcccc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcga cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgttc ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786479786DNAArtificial SequenceYU100-B01 479caggtgcagc tggtgcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accaacactg atgttggtgc ttataactat gtctcctggt accaacagta cccaggcaaa 540gcccccaaac tcatcattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctact cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccg 780tcctct 786480786DNAArtificial SequenceYU100-B03 480caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgtgctg 420actcagcccc gctcagtgtc cgggtctcct gggcggtcag tcaccatctc atgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaag 540gcccccaaac tcacacttta tgatgtcgtt aagcggccct caggggtccc tgatcgctac 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggccgatt attactgctg ctcatatgca ggcggctaca cttgggtgtt cggcggaggg 720accaaggtga ccgtcgttgg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786481786DNAArtificial SequenceYU100-B06 481caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagagccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagtagtg acgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgcaa ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786482786DNAArtificial SequenceYU100-B07 482caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatacg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatgtc ctgcactgga 480accagcagag atgttggtgg ttataattat gtctcctggt accaacatca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgagctcca ggctgaggat 660gaggctgatt attactgttg ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786483786DNAArtificial SequenceYU100-B08 483gaggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct gggcagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540gtccccagac tcttgattta tgatgtcagt aaccggccct caggggtttc tactcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca gggtgaggac 660gaggctgagt attactgcag ttcatttacg agtagtacca cttgggtgtt cggcggaggg 720accaagctga ccgtcctggg tcagcccaag gctgccccct cggtcactct gttcccaccg 780tcctct 786484787DNAArtificial SequenceYU100-B09 484caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac ttatgattta tgatgtcagt gatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca gcctgaggac 660gaggctgatt attactgcag ttcatataga agcggcagca ctttgggtgt tcggcggagg 720gaccaagctg accgtcctag gtcagcccaa ggctgccccc tcggtcactc tgttcccgcc 780ctcctct 787485801DNAArtificial SequenceYU100-B12 485caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaaggaccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtt ggtggttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggcag ctacacttgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccctcctc t 801486786DNAArtificial SequenceYU100-C02 486caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggccgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagta atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600agtggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctacg tttgggtgtt cggcggaggg 720accaagctga ccgtcctcgg tcagcccaag gctgccccct cggtcactct gttcccgccg 780tcctct 786487786DNAArtificial SequenceYU100-C04 487caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcttgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacacca cccaggcaaa 540gcccccaaac tcataattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctggccatct ctgggctcca ggctgaggaa 660gaggctgatt attactgctg ctcatatgca ggcgggtaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccg 780tcctct 786488786DNAArtificial SequenceYU100-C05 488caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggggg ttataattat gtctcctggt atcaacaaca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aatcggccct cagggatttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggac 660gaggctgatt attactgcag ctcatacaca agcagcattt cttgggtgtt cggcggaggg 720accaaactga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786489786DNAArtificial SequenceYU100-C10 489caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcggt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctga tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480acccgcagtg acattggtgg ttatgactat gtctcctggt atcaacagca cccaggcaaa 540gcccccaaac tcatgattta tgacgtcaat aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggac 660gaggctgagt attactgctc ctcatataca agcagcatca cttgggtgtt cggcggaggg 720accaaggtga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786490786DNAArtificial SequenceYU100-C11 490caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgg ttataactat gtctcctggt accaacagcg cccaggcaag 540gcccccaaac tcatgattta tgatgtcagt aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca gcctgacgac 660gaggctgatt attactgcag ctcatataca aacagcagga cttgggtgtt cggcggaggg 720accaagttga ccgtcctaag tcagcccaag gctgccccct cggtcactct gttcccaccg 780tcctct 786491801DNAArtificial SequenceYU100-C12 491gaggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtt ggtggttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggcag ctacacttgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccgtcctc t 801492801DNAArtificial SequenceYU100-D01 492caggtgcagc tgcagcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctccctcc gcgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtc ggtggttaca actttgtctc ctggtatcaa 540caacaccccg gcaaagcccc caaactcttg atttatgatg tcgataagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcagaacgg cctccctgac catctctggg 660ctccagactg aggatgaggc taaatattat tgctgctcat atgcaggcag gtacacttgg 720atattcggcg gagggaccaa gctgaccgtc ctcggtcagc ccaaggctgc cccctcggtc 780attctgttcc caccgtcctc t 801493786DNAArtificial SequenceYU100-D02 493caggtgcggc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcggtg atgttggtac ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcatgatttt tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgcaa ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786494786DNAArtificial SequenceYU100-D05 494caggtgcagc tgcagcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga

agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagttga tcaccatctc ctgcactgga 480accaacagtg acgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccg 780tcctct 786495801DNAArtificial SequenceYU100-D07 495caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg actcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cggtgatgtt ggtacttatg actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgcaactcat atgcaggcag ctacacttgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaagactgc cccctcggtc 780actctgttcc cgccctcctc t 801496786DNAArtificial SequenceYU100-D11 496caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagta atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaagat 660gaggctaatt attactgcgc ctcatatgca ggcaactaca attgggtgtt cggcggaggg 720accaagctga ccgtccttgg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786497786DNAArtificial SequenceYU100-E01 497caggtgcagc tgcagcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcaatg acataggtgc ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcctgattta tgatgtcaat aatcggccct caggggtttc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctact cttgggtgtt cggcggaggg 720accaaactga ccgtcctagg tcagcccaag gccaacccca ctgtcactct gttcccaccc 780tcctct 786498786DNAArtificial SequenceYU100-E04 498caggtgcagc tgcagcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540acccccaaac tcatgattta tgatgtcact aagcggccct caggggtccc tgatcacttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagtcaca tttgggtgtt cggcggaggg 720accaagttga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786499786DNAArtificial SequenceYU100-E05 499gaggtgcagc tggtgcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca ggctgtgctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctact cctgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786500786DNAArtificial SequenceYU100-E06 500caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtttcct gaacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgg ttatgactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctggcctcca acctgaggac 660gaggctgatt attattgcag ctcatataca agcaacacca cttgggtgtt cggcggaggg 720accaagctga ccgtcctacg tcagcccaag gctgccccct cggtcactct gttcccaccg 780tcctct 786501786DNAArtificial SequenceYU100-E07 501caggtgcagc tgcaggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa tagatactat 180gcagactccg tgaagggccg attcgccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttatgactat gtctcctggt accaacagca cccaggcaaa 540gcccccgaac tcatgattta tgatgtcact aagcggccct caggggtcgc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcaggtaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786502801DNAArtificial SequenceYU100-E08 502caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtt ggtggttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaggcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggcaa ttacacttgg 720atgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccgtcctc t 801503801DNAArtificial SequenceYU100-E09 503caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctgggtt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtt ggtgattatg actatgtctc ctggtaccaa 540caacacccag gcaaagcccc caaactcatt atttatgatg tcactaaacg gccctcaggg 600atccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggcag ttacacttgg 720gtgttcggca gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccctccac t 801504786DNAArtificial SequenceYU100-E10 504caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcatgatttt tgatgtcagt cagcggccct caggggtccc tgatcgcttc 600tctgcctcca agtccggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786505801DNAArtificial SequenceYU100-E11 505caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtt ggtggttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggcag ctacacttgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccctcctc t 801506786DNAArtificial SequenceYU100-E12 506caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgg ttataactat gtctcctggt accaacagca cccaggcaca 540gcccccaaac tcatgattta tgatgtcagt aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggac 660gaggctgatt attactgcag ctcatataca agcagcacca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786507786DNAArtificial SequenceYU100-F01 507caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accggcagtg acgttggtgc ttatgactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcaat aatcggccct caggagtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca agctgaggac 660gaggctgaat attactgcag ttcatttgca actagcattt cttgggtgtt cggcggaggg 720accagactga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786508786DNAArtificial SequenceYU100-F02 508gaggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgacgat 660gaggctgatt attactgctg ctcatatgca ggcagctaca cttggatatt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786509786DNAArtificial SequenceYU100-F05 509caggtgcagc tgcagcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca ggccgtgctg 420actcagcccg cctccgtgtc tgggtctcct ggacagtcga tcaccatttc ctgcactgga 480accagcagtg acattggtgg ttataactat gtctcctggt accagcaaca cccaggcaca 540gcccccaaac tcatgattta tgatgtcagt agtcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggac 660gaggctgatt attactgctg ctcatatgca ggcagttaca cttgggtgtt cggcggaggg 720accaagatga ccgtcctggg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786510801DNAArtificial SequenceYU100-F06 510caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggatccag cagtgatgtt ggtggttata actttgtctc ctggtaccga 540caacacccag gcgaagcccc caaactcgtg atttttgatg tcaataagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctcaggg 660ctgcaaactg aggatgaggc tgattatttc tgctgctcat atgcaggcgg ctacacttgg 720gtgttcggcg gagggaccaa ggtgaccgtc gttggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccctcctc t 801511801DNAArtificial SequenceYU100-F07 511caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgtgt ctcctggaca gtcagtcacc

480atctcctgca ctggaaccag cagtgacgtt ggcggttatg aatatgtctc ctggtaccaa 540caacacccag gcaaagcccc caaactcatg atttatgatg tcactaagag gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccagggtg aagatgcggc tgattattac tgctgttcat atgcaggctc ttacacttgg 720gtattcggcg gaggcaccac ggtgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccgtcctc t 801512786DNAArtificial SequenceYU100-F11 512caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactggg 480agcagtagtg acgttgctgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagttaca cttgggtttt cggcggaggg 720acccagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccg 780tcctct 786513786DNAArtificial SequenceYU100-G01 513caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgcgtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgc ttataactat gtctcctggt accaacaaca ccccggcaaa 540gcccccaaac tcatgcttta tgatgtcaat aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctaggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786514786DNAArtificial SequenceYU100-G07 514caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgc ttatgactat gtctcctggt atcaacaaca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggac 660gaggctgatt attactgcgc ctcatacaca cgcagcagcg tttgggtgtt cggcggaggg 720accaaactga ccgtcttagg tcagcccaag gctgcctcct cggtcactct gttcccaccc 780tcctct 786515786DNAArtificial SequenceYU100-G08 515caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccctctc ctgtactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacacta cccaggcaaa 540gcccccaaac tcatgatttt tgatgtcaat gagcggtcct caggagtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcaggtaca cttggatgtt cggcggaggg 720accaaagtga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786516786DNAArtificial SequenceYU100-G09 516gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accatcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctggtt attactgctc ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786517786DNAArtificial SequenceYU100-G10 517caggtgcagc tggtgcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggtaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctctt ggacagtcga tcaccatgtc ctgcactgga 480accagaagag acgttggtgg ttatgacttt gtctcctggt accaacagta ccccggcaaa 540gcccccaagc tcatcattta cgatgtcagc aatcggccct cgggggtttc taatcgcttc 600actggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcacctaca cttgggtgtt cggcggaggg 720accaaggtga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786518801DNAArtificial SequenceYU100-G11 518caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctgggca gtcagtcacc 480atctcatgca ctggaaccag cagtgatgtt ggtggttata actatgtctc ctggtaccaa 540cagcacccag gcaaggcccc caaactcacg ctttatgatg tcggtaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggcgg ctacacttgg 720gtgttcggcg gagggaccaa ggtgaccgtc gtaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccctcctc t 801519801DNAArtificial SequenceYU100-H01 519caggtgcagc tggtgcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtt ggtgcttata actatgtctc ctggtaccag 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtgagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggcag ctacacttgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccgtcctc t 801520801DNAArtificial SequenceYU100-H02 520caggtgcagc tgcagcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccaggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccag cagtgatgtt ggtacttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcaggctt ctacacttgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc caccgtcctc t 801521801DNAArtificial SequenceYU100-H04 521caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctgcctcc gtgtctgggt ctcctggaca gtcgatcacc 480atctcctgca cgggaaccag cagtgacatt ggtgtttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tgattattac tgctgctcat atgcgggcag ctacacctgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc cgccctcctc t 801522786DNAArtificial SequenceYU100-H05 522caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca ggctgtgctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcaa tcaccatctc ctgcactgga 480accggcagta atgttggtgg ttataactat gtctcctggt atcaacaaca cccaggccaa 540gcccccaaac tcatgattta tgatgtcagt aagaggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attattgctg ctcatatgca ggcacctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786523786DNAArtificial SequenceYU100-H06misc_feature(405)..(405)n is a, c, g, or t 523caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgnataca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaat tgatgattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaagat 660gaggctgatt attattgctc ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786524801DNAArtificial SequenceYU100-H09 524caggtgcagc tggtgcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gattactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctgcctcc gtgtctgggt ctcctggaca gtcgatcacc 480atctcctgca ctggaaccag cagtgacgtt ggtggttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcagtaatcg gccctcaggg 600gtttctaatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggacgaggc tgattattac tgctgttcat atgcaggcag ctacacttgg 720gtgttcggcg gagggaccaa gctgaccgtc ctaggtcagc ccaaggctgc cccctcggtc 780actctgttcc cgccgtcctc t 801525786DNAArtificial SequenceYU100-H11 525caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccaccc 780tcctct 786526786DNAArtificial SequenceYU112-A07 526caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180acagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accatcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctggtt attactgctc ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accgagctga ccgtcctgag tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786527786DNAArtificial SequenceYU112-B06 527caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctg cctccgtgtc tgggtctcct ggacagtcga tcaccatctc ctgcactgga 480accagcagtg acgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcagt aatcggccct caggggtttc taatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ttgggctcca ggctgaggac 660gaggctgatt attactgcag ctcatataca agcagtagca gttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786528759DNAArtificial SequenceYU112-C03 528caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggggg 300aagagctact acggatttga ctactggggc cagggaaccc tggtcaccgt ctcctcaggg 360agtgcatccg ccccaaagct tgaagaaggt gaattttcag aagcacgcgt agacagcgtg 420atgacccagt ctccatcctc cctgtctgca tctgtagggg acagagtcac catcacttgc 480cgggcaagtc aggccattaa cagctattta aattggtatc

agcagaaacc agggaaagcc 540cctaagctcc tgatctatgc tgcatccagt ttgcagagtg gggtcccatc aaggttcagt 600ggcagtggat ctgggacaga tttcactctc accatcagcg gtctgcaacc tgaagatttt 660gcaacttact actgtcaaca gagttacagt accccttcgt ggacgttcgg ccaagggacc 720aaggtggaaa tcaaacgaac tgtggctgca ccatctgtc 759529801DNAArtificial SequenceYU112-C05 529gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatgcta tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcaa taaatactac 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gagaatcatg 300ggctatgact acggtgacta cgacgtagtt gactactggg gccagggaac cctggtcacc 360gtctcctcag ggagtgcatc cgccccaaag cttgaagaag gtgaattttc agaagcacgc 420gtacagtctg ccctgactca gcctcgctca gtgtccgggt ctcctggaca gtcagtcacc 480atctcctgca ctggaaccat cagtgatgtt ggtggttata actatgtctc ctggtaccaa 540cagcacccag gcaaagcccc caaactcatg atttatgatg tcactaagcg gccctcaggg 600gtccctgatc gcttctctgg ctccaagtct ggcaacacgg cctccctgac catctctggg 660ctccaggctg aggatgaggc tggttattac tgctcctcat atgcaggcag ctacacttgg 720gtgttcggcg gagggaccga gctgaccgtc ctgagtcagc ccaaggctgc cccctcggtc 780actctgttcc cgccctcctc t 801530753DNAArtificial SequenceYU112-C09 530caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcggt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaggttcg 300tactactttg actactgggg ccagggaacc ctggtcaccg tctcctcagg gagtgcatcc 360gccccaaagc ttgaagaagg tgaattttca gaagcacgcg tagaaacgac actcacgcag 420tctccagcca ccctgtctgt gtctccaggg gaaagagcca ccctctcctg cagggccagt 480cagagtttta gcagcagcta cttagcctgg taccagcaga aacctggcca ggctcccagg 540ctcctcatct atggtgcatc cagaagagcc cctggcatcc cagacaggtt cagtggcagt 600gggtctggga cagacttcag tctcaccatc agcagactgg agcctgaaga ttttgcagtg 660tattactgtc agcagtctag cacctcaccc acgtgggcgt tcggccgagg gaccaaggtg 720gaagtcaaac gaactgtggc tgcaccatct gtc 753531786DNAArtificial SequenceYU112-D08 531caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tggagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accatcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctggtt attactgctc ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accgagctga ccgtcctgag tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786532753DNAArtificial SequenceYU112-E07 532caggtgcagc tggtgcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcggt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaggttcg 300tactactttg actactgggg ccagggaacc ctggtcaccg tctcctcagg gagtgcatcc 360gccccaaagc ttgaagaagg tgaattttca gaagcacgcg tagaaattgt gatgactcag 420tctccagact ccctggctgt gtctctgggc gagagggcca ccatcaactg caagtccagc 480cagagtgtta acagcgccta cttagcctgg taccagcaca aacctggcca gcctcccaga 540ctcctcattt atggtgcatc tcgcagggtc actggcgtcc cagacaggtt cagtggcagt 600gggtctggga cagacttcac tctcaccatc agcagtctgc aaccagaaga ttttgcaact 660tactactgtc aacagagtta cagtgaccct cggtggacgt tcggccaagg gaccaaggtg 720gaaatcaaac gaactgtggc tgcaccatct gtc 753533759DNAArtificial SequenceYU112-E08 533taggtcacct tgaaggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggggg 300aagagctact acggatttga ctactggggc cagggaaccc tggtcaccgt ctcctcaggg 360agtgcatccg ccccaaagct tgaagaaggt gaattttcag aagcacgcgt agacatccag 420atgacccagt ctccatcctt cctgtctgca tctgtaggag acagagtcac catcacttgc 480cgggcaagtc agatcattag cagctattta aattggtatc agcagaaacc agggaaagcc 540cctaaactcc tgatctatgc tgcatccagt ttgcaaagtg gggtcccatc aaggttcagt 600ggcagtggat ctgggacaga tttcactctc accatcagca gtctgcaacc tgaagatttt 660gcaacttact actgtcaaca gagttacagt acccccacgt ggacgttcgg ccaagggacc 720aaggtggaaa tcaaacgaac tgtggctgca ccatctgtc 759534786DNAArtificial SequenceYU112-F05 534gaggtgcagc tggtgcagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcggt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaac tcatcattta tgatgtcaat aatcggccct caggggtttc taatcgcttc 600tctgcctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggac 660gaggctgatt attactgcaa ctcatataca agcggtagca cttgggtctt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786535786DNAArtificial SequenceYU112-G01 535caggtgcagc tggtggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctgggtt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaactttcc 300gggcccaacg gtgtggacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accatcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctggtt attactgctc ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accgagctga ccgtcctgag tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786536786DNAArtificial SequenceYU112-G06 536caggtgcagc tgcaggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacactgtac 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaatagga 300gctactgacc cccttgacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gtctgccctg 420actcagcctc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accatcagtg atgttggtgg ttataactat gtctcctggt accaacagca cccaggcaaa 540gcccccaaac tcatgattta tgatgtcact aagcggcgct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctggtt attactgctc ctcatatgca ggcggctaca cttgggtgtt cggcggaggg 720accgagctga ccgtcctgag tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786537702DNAArtificial SequenceYU112-G09 537taggtcacct tgaaggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggggg 300aagagctact acggatttga ctactggggc cagggaaccc tggtcaccgt ctcctcaggg 360agtgcatccg ccccaaagct tgaagaaggt gaattttcag aagcacgcgt agacatccag 420atgacccagt ctccatcctt cctgtctgca tctgtaggag acagagtcac catcacttgc 480cgggcaagtc agatcattag cagctattta aattggtatc agcagaaacc agggaaagcc 540cctaaactcc tgatctatgc tgcatccagt ttgcaaagtg gggtcccatc aaggttcagt 600ggcagtggat ctgggacaga tttcactctc accatcagca gtctgcaacc tggaagattt 660tgcaacttac tactgtcaac agagttacag tacccccacg tg 702538753DNAArtificial SequenceYU112-H01 538caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcggt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaggttcg 300tactactttg actactgggg ccagggaacc ctggtcaccg tctcctcagg gagtgcatcc 360gccccaaagc ttgaagaagg tgaattttca gaagcacgcg tagaaacgac actcacgcag 420tctccaggca ccctgtcttt gtctccaggg gaaagagcca ccctctcctg cagggccagt 480cagagtgtta gcagcagcta cttagcctgg taccagcaga aacctggcca ggctcccagg 540ctcctcatct atggtgcatc cagcagggcc actggcatcc cagacaggtt cagtggcagt 600gggtctggga cagacttcac tctcaccatc agcagtctgc aacctgatga ttttgcaact 660tactactgtc aacagagtta cagcactcct acgtggacat tcggccaagg gaccaaggtg 720gaaatcaaac gaactgtggc tgcaccatct gtc 753539786DNAArtificial SequenceYU112-H02 539caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaactttcc 300gggcccaacg gtgtggacta ctggggccag ggaaccctgg tcaccgtctc ctcagggagt 360gcatccgccc caaagcttga agaaggtgaa ttttcagaag cacgcgtaca gcctgtgctg 420actcagcccc gctcagtgtc cgggtctcct ggacagtcag tcaccatctc ctgcactgga 480accagcagtg atgttggtgg ttataactat gtctcctggt accaacaaca cccaggcaaa 540gcccccaaag tcatgattta tgatgtcagt aagcggccct caggggtccc tgatcgcttc 600tctggctcca agtctggcaa cacggcctcc ctgaccatct ctgggctcca ggctgaggat 660gaggctgatt attactgctg ctcatatgca ggcagctaca cttgggtgtt cggcggaggg 720accaagctga ccgtcctagg tcagcccaag gctgccccct cggtcactct gttcccgccc 780tcctct 786540111PRTArtificial SequenceYU100-B09 540Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Arg Ser Gly 85 90 95 Ser Thr Leu Gly Val Arg Arg Arg Asp Gln Ala Asp Arg Pro Arg 100 105 110 541119PRTArtificial SequenceBSN-2E1 541Gln Val Gln Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Pro Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro His Asn Gly Gly Pro Ile Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Glu Leu Gly His Trp Tyr Phe Asp Val Trp Gly Thr Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 5428PRTArtificial SequenceBSN-2E1 HC-CDR1 542Gly Tyr Thr Phe Thr Asp Tyr Asn 1 5 5438PRTArtificial SequenceBSN-2E1 HC-CDR2 543Ile Asn Pro His Asn Gly Gly Pro 1 5 54412PRTArtificial SequenceBSN-2E1 HC-CDR3 544Ala Arg Gly Glu Leu Gly His Trp Tyr Phe Asp Val 1 5 10 545120PRTArtificial SequenceBSN-2G6 545Gln Val Gln Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Pro Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asn Ile Asn Pro Asp Asn Gly Gly Thr Ile Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Gly Pro Tyr Gly Tyr Thr Trp Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Asp Thr Val Ser Ala 115 120 5468PRTArtificial SequenceBSN-2G6 HC-CDR2 546Ile Asn Pro Asp Asn Gly Gly Thr 1 5 54713PRTArtificial SequenceBSN-2G6 HC-CDR3 547Ala Arg Glu Gly Pro Tyr Gly Tyr Thr Trp Phe Ala Tyr 1 5 10 548120PRTArtificial SequenceBSN-5A6 548Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Pro Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asn Ile Asn Pro Asn Asn Gly Gly Ile Ile Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Val Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Pro Ser Leu Tyr Asp Gly Tyr Leu Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser 115 120 5498PRTArtificial SequenceBSN-5A6 HC-CDR2 549Ile Asn Pro Asn Asn Gly Gly Ile 1 5 55013PRTArtificial SequenceBSN-5A6 HC-CDR3 550Ala Arg Asn Pro Ser Leu Tyr Asp Gly Tyr Leu Asp Cys 1 5 10 551118PRTArtificial SequenceBSN-5B8 551Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Tyr Pro Arg Ser Ser Asn Thr Tyr Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Asp Tyr Phe Cys 85 90 95 Ala Arg Ala Asn Trp Val Gly Tyr Phe Asp Val Trp Gly Thr Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 5528PRTArtificial SequenceBSN-5B8 HC-CDR2 552Ile Tyr Pro Arg Ser Ser Asn Thr 1 5 55311PRTArtificial SequenceBSN-5B8 HC-CDR3 553Ala Arg Ala Asn Trp Val Gly Tyr Phe Asp Val 1 5 10 554107PRTArtificial SequenceBSN-2E1 554Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly 1 5 10 15 Glu Arg Val Thr Leu Thr Cys Lys Ala Ser Glu Asn Val Val Thr Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser

Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Gly Tyr Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 5556PRTArtificial SequenceBSN-2E1 LC-CDR1 555Glu Asn Val Val Thr Tyr 1 5 5569PRTArtificial SequenceBSN-2E1 LC-CDR3 556Gly Gln Gly Tyr Ser Tyr Pro Tyr Thr 1 5 557107PRTArtificial SequenceBSN-2G6 557Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Ser 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Ser Asn Ser Trp Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 5586PRTArtificial SequenceBSN-2G6 LC-CDR1 558Gln Ser Ile Gly Thr Ser 1 5 5593PRTArtificial SequenceBSN-2G6 LC-CDR2 559Tyr Ala Ser 1 5609PRTArtificial SequenceBSN-2G6 LC-CDR3 560Gln Gln Ser Asn Ser Trp Pro Leu Thr 1 5 561113PRTArtificial SequenceBSN-5A6_2 561Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Asn 20 25 30 Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Asn Leu Glu Leu 100 105 110 Lys 56212PRTArtificial SequenceBSN-5A6_2 LC-CDR1 562Gln Ser Leu Leu Tyr Asn Ser Ser Gln Lys Asn Tyr 1 5 10 5633PRTArtificial SequenceBSN-5A6_2 LC-CDR2 563Trp Ala Ser 1 564106PRTArtificial SequenceBSN-5B8 564Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg Leu Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr Ile Asn Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Arg Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 5656PRTArtificial SequenceBSN-5B8 LC-CDR1 565Gln Asp Val Gly Thr Ala 1 5 5668PRTArtificial SequenceBSN-5B8 LC-CDR3 566Gln Gln Tyr Ser Ser Tyr Arg Thr 1 5 5678PRTArtificial SequencemHC-CDR1-1 family consensusMISC_FEATURE(6)..(6)Xaa = D or SMISC_FEATURE(8)..(8)Xaa = N or G 567Gly Tyr Thr Phe Thr Xaa Tyr Xaa 1 5 5688PRTArtificial SequencemHC-CDR2-1 family consensusMISC_FEATURE(4)..(4)Xaa = H, D or NMISC_FEATURE(8)..(8)Xaa = P, T or I 568Ile Asn Pro Xaa Asn Gly Gly Xaa 1 5 5693PRTArtificial SequencemLC-CDR2-1 family consensusMISC_FEATURE(1)..(1)Xaa = G, Y or W 569Xaa Ala Ser 1 5709PRTArtificial SequencemLC-CDR3-1 family consensusMISC_FEATURE(1)..(1)Xaa = Q or GMISC_FEATURE(3)..(3)Xaa = Y, G or SMISC_FEATURE(4)..(4)Xaa = Y, N or SMISC_FEATURE(6)..(6)Xaa = Y or WMISC_FEATURE(7)..(7)Xaa = P or absentMISC_FEATURE(8)..(8)Xaa = L, Y or R 570Xaa Gln Xaa Xaa Ser Xaa Xaa Xaa Thr 1 5 571357DNAArtificial SequenceBSN-2E1_VH 571caggtccagc tgcaggagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata 60ccctgcaagg cttctggata cacattcact gactacaaca tggactgggt gaagcagagc 120catggaaaga gccttgagtg gattggagat attaatcctc acaatggtgg tcctatctac 180aaccagaagt tcacgggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240atggagctcc gcagcctgac atctgaggac actgcagtct attactgtgc aagaggggaa 300ctgggtcact ggtacttcga tgtctggggc acagggacca cggtcaccgt ctcctca 357572321DNAArtificial SequenceBSN-2E1_VL 572aacattgtaa tgacccaatc tcccaaatcc atgtccatgt cagtaggaga gagggtcacc 60ttgacctgca aggccagtga gaatgtggtt acttatgttt cctggtatca acagaaacca 120gagcagtctc ctaaactgct gatatacggg gcatccaacc ggtacactgg ggtccccgat 180cgcttcacag gcagtggatc tgcaacagat ttcactctga ccatcagcag tgtgcaggct 240gaagaccttg cagattatca ctgtggacag ggttacagct atccgtacac gttcggaggg 300gggaccaagc tggaaataaa a 321573360DNAArtificial SequenceBSN-2G6_VH 573caggtccagc tgcaggagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata 60ccctgcaagg cttctggata cacgttcact gactacaaca tggactgggt gaagcagagc 120catggaaaga gccttgagtg gattggaaat attaatcctg acaatggtgg tactatctac 180aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240atggagctcc gcagcctgac atctgaggac actgcagtct atttctgtgc aagagagggg 300ccttatggtt acacctggtt tgcttactgg ggccaaggga ctctggacac tgtctctgca 360574321DNAArtificial SequenceBSN-2G6_VL 574gacatcttgc tgactcagtc tccagccatc ctgtctgtga gtccaggaga aagagtcagt 60ttctcctgca gggccagtca gagcattggc acaagcatac actggtatca gcaaagaaca 120aatggttctc caaggcttct cataaagtat gcttctgagt ctatctctgg gatcccttcc 180aggtttagtg gcagtggatc agggacagat tttactctta gcatcaacag tgtggagtct 240gaagatattg cagattatta ctgtcaacaa agtaatagct ggccgctcac gttcggtgct 300gggaccaagc tggagctgaa a 321575321DNAArtificial SequenceBSN-3C6_VL 575aacattgtaa tgacccaatc tcccaaatcc atgtccatgt cagtaggaga gagggtcacc 60ttgacctgca aggccagtga gaatgtggtt acttatgttt cctggtatca acagaaacca 120gagcagtctc ctaaactgct gatatacggg gcatccaacc ggtacactgg ggtccccgat 180cgcttcacag gcagtggatc tgcaacagat ttcactctga ccatcagcag tgtgcaggct 240gaagaccttg cagattatca ctgtggacag ggttacagct atccgtacac gttcggaggg 300gggaccaagc tggaaataaa a 321576360DNAArtificial SequenceBSN-5A6_VH 576gaggtccagc tgcaacagtc tggacctgaa ctggtgaagc ctggggcttc agtgaagata 60ccctgcaagg cttctggata cacattcact gactacaaca tggactgggt gaagcagagc 120catggaaaga gccttgagtg gattggaaat attaatccta acaatggtgg tattatctac 180aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240atggtactcc gcagcctgac atctgaggac actgcagtct attactgtgc aagaaaccca 300agtctctatg atggttacct tgactgctgg ggccaaggca ccactctcac agtctcctca 360577321DNAArtificial SequenceBSN-5A6_VL1 577aacattgtaa tgacccaatc tcccaaatcc atgtccatgt cagtaggaga gagggtcacc 60ttgacctgca aggccagtga gaatgtggtt acttatgttt cctggtatca acagaaacca 120gagcagtctc ctaaactgct gatatacggg gcatccaacc ggtacactgg ggtccccgat 180cgcttcacag gcagtggatc tgcaacagat ttcactctga ccatcagcag tgtgcaggct 240gaagaccttg cagattatca ctgtggacag ggttacagct atccgtacac gttcggaggg 300gggaccaagc tggaaataaa a 321578339DNAArtificial SequenceBSN-5A6_VL2 578gacattgtga tgtcacagtc tccatcctcc ctagctgtgt cagttggaga gaaggttact 60atgaactgca agtccagtca gagcctttta tataatagca gtcaaaagaa ctacttggcc 120tggtaccagc agaaaccagg gcagtctcct aaattgctga tttactgggc atccactagg 180gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 240atcagcagtg tgaaggctga agacctggca gtttattact gtcagcaata ttatagttat 300ccgctcacgt tcggtgctgg gaccaacctg gagctgaaa 339579354DNAArtificial SequenceBSN-5B8_VH 579caggtccagc tgcagcagtc tggagctgag ctggcgaggc ctgggacttc agtgaaactg 60tcctgcaagg cttctggcta caccttcaca agctatggta taagctgggt gaaacagaga 120actggacagg gccttgagtg gattggagaa atttatcctc gaagtagtaa tacttactac 180aatgagaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcgtac 240atggagctcc gcagcctgac atctgaggac tctgcggact atttctgtgc aagggctaac 300tgggtagggt acttcgatgt ctggggcaca gggaccacgg tcaccgtctc ctca 354580318DNAArtificial SequenceBSN-5B8_VL 580gacattgtga tgacccagtc tcacaaattc atgtccacat cagtcggaga cagggtcacc 60atcacctgca aggccagtca ggatgtgggt actgctgtag cctggtatca acagaaacca 120ggacaatctc ctaaactact gatttactgg gcatccaccc ggctcactgg agtccctgat 180cgcttcacag gcagtggatc tgggacatat ttcactctca ccattaacaa tgtgcagtct 240gaagacttgg cagattattt ctgtcagcaa tatagcagct atcggacgtt cggtggaggc 300accaagctgg aaatcaag 3185819PRTArtificial SequenceBSN-5A6_2 LC-CDR3 581Gln Gln Tyr Tyr Ser Tyr Pro Leu Thr 1 5

Claims

1-99. (canceled)

100. An antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain variable region sequence and a heavy chain variable region sequence, wherein: the light chain variable region sequence has at least 85% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and the heavy chain variable region sequence has at least 85% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.

101. The antibody or antigen binding fragment according to claim 100, wherein: the light chain variable region sequence has at least 90% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and the heavy chain variable region sequence has at least 90% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.

102. The antibody or antigen binding fragment according to claim 100, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00012 i) LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY, (SEQ ID NO: 107) SSDVGGYNY or (SEQ ID NO: 330) SSDVAGYNY; ii) LC-CDR2: (SEQ ID NO: 108) DVS, (SEQ ID NO: 291) DVN or (SEQ ID NO: 123) DVT; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV or (SEQ ID NO: 336) CSYAGRYTWM;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00013 iv) HC-CDR1: (SEQ ID NO: 190) GFTFSSYA or (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY or (SEQ ID NO: 187) AKIGATDPLDY.

103. The antibody or antigen binding fragment according to claim 100, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00014 i) LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY; ii) LC-CDR2: (SEQ ID NO: 108) DVS; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00015 iv) HC-CDR1: (SEQ ID NO: 190) GFTFSSYA; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; vi) HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY.

104. The antibody or antigen binding fragment according to claim 100, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00016 i) LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY; ii) LC-CDR2: (SEQ ID NO: 291) DVN; and iii) LC-CDR3: (SEQ ID NO: 336) CSYAGRYTWM;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00017 iv) HC-CDR1: (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY.

105. The antibody or antigen binding fragment according to claim 100, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00018 i) LC-CDR1: (SEQ ID NO: 330) SSDVAGYNY; ii) LC-CDR2: (SEQ ID NO: 123) DVT and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00019 iv) HC-CDR1: (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY.

106. The antibody or antigen binding fragment according to claim 100, which is capable of inhibiting IL-11 trans signalling.

107. The antibody or antigen binding fragment according claim 100, conjugated to a drug moiety or a detectable moiety.

108. A method of treating fibrosis or a disease/disorder characterised by fibrosis, comprising administering an antibody or antigen binding fragment to a subject suffering from fibrosis or a disease/disorder characterised by fibrosis, wherein the antibody or antigen binding fragment is capable of binding to IL-11, and comprises a light chain variable region sequence and a heavy chain variable region sequence, wherein: the light chain variable region sequence has at least 85% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and the heavy chain variable region sequence has at least 85% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.

109. The method according to claim 108, wherein: the light chain variable region sequence has at least 90% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and the heavy chain variable region sequence has at least 90% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.

110. The method according to claim 108, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00020 i) LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY, (SEQ ID NO: 107) SSDVGGYNY or (SEQ ID NO: 330) SSDVAGYNY; ii) LC-CDR2: (SEQ ID NO: 108) DVS, (SEQ ID NO: 291) DVN or (SEQ ID NO: 123) DVT; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV or (SEQ ID NO: 336) CSYAGRYTWM;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00021 iv) HC-CDR1: (SEQ ID NO: 190) GFTFSSYA or (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY or (SEQ ID NO: 187) AKIGATDPLDY.

111. The method according to claim 108, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00022 i) LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY; ii) LC-CDR2: (SEQ ID NO: 108) DVS; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00023 iv) HC-CDR1: (SEQ ID NO: 190) GFTFSSYA; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; vi) HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY.

112. The method according to claim 108, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00024 i) LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY; ii) LC-CDR2: (SEQ ID NO: 291) DVN; and iii) LC-CDR3: (SEQ ID NO: 336) CSYAGRYTWM;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00025 iv) HC-CDR1: (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY.

113. The method according to claim 108, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00026 i) LC-CDR1: (SEQ ID NO: 330) SSDVAGYNY; ii) LC-CDR2: (SEQ ID NO: 123) DVT; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00027 iv) HC-CDR1: (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY.

114. A method of treating cancer, comprising administering an antibody or antigen binding fragment to a subject suffering from cancer, wherein the antibody or antigen binding fragment is capable of binding to IL-11, and comprises a light chain variable region sequence and a heavy chain variable region sequence, wherein: the light chain variable region sequence has at least 85% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and the heavy chain variable region sequence has at least 85% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.

115. The method according to claim 114, wherein: the light chain variable region sequence has at least 90% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and the heavy chain variable region sequence has at least 90% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.

116. The method according to claim 114, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00028 i) LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY, (SEQ ID NO: 107) SSDVGGYNY or (SEQ ID NO: 330) SSDVAGYNY; ii) LC-CDR2: (SEQ ID NO: 108) DVS, (SEQ ID NO: 291) DVN or (SEQ ID NO: 123) DVT; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV or (SEQ ID NO: 336) CSYAGRYTWM;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00029 iv) HC-CDR1: (SEQ ID NO: 190) GFTFSSYA or (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY or (SEQ ID NO: 187) AKIGATDPLDY.

117. The method according to claim 114, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00030 i) LC-CDR1: (SEQ ID NO: 110) SSDVGAYNY; ii) LC-CDR2: (SEQ ID NO: 108) DVS; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00031 iv) HC-CDR1: (SEQ ID NO: 190) GFTFSSYA; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; vi) HC-CDR3: (SEQ ID NO: 199) ARIMGYDYGDYDVVDY.

118. The method according to claim 114, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00032 i) LC-CDR1: (SEQ ID NO: 107) SSDVGGYNY; ii) LC-CDR2: (SEQ ID NO: 291) DVN; and iii) LC-CDR3: (SEQ ID NO: 336) CSYAGRYTWM;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00033 iv) HC-CDR1: (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY.

119. The method according to claim 114, wherein the light chain variable region sequence comprises the following CDRs: TABLE-US-00034 i) LC-CDR1: (SEQ ID NO: 330) SSDVAGYNY; ii) LC-CDR2: (SEQ ID NO: 123) DVT; and iii) LC-CDR3: (SEQ ID NO: 131) CSYAGSYTWV;

and wherein the heavy chain variable region sequence comprises the following CDRs TABLE-US-00035 iv) HC-CDR1: (SEQ ID NO: 186) GFTFSSYG; v) HC-CDR2: (SEQ ID NO: 184) ISYDGSNK; and vi) HC-CDR3: (SEQ ID NO: 187) AKIGATDPLDY.