RECOMBINANT ANTIBODIES FOR TREATMENT OF RESPIRATORY SYNCYTIAL VIRUS INFECTIONS

Abstract

Disclosed are novel polyclonal antibodies, which target respiratory syncytial virus (RSV), as well as novel high affinity antibody molecules reactive with RSV. The polyclonal antibodies may comprise antibody molecules which are reactive with both RSV protein F and RSV protein G, and preferably the polyclonal antibodies target a variety of epitopes on these proteins. The antibody molecules of the invention have shown superior efficacy in vitro and/or in vivo. Also disclosed are methods of producing the antibodies of the invention as well as methods of their use in treatment or prevention of RSV infection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No. 12/073,538, filed Mar. 6, 2008, which claims the benefit of the filing date of U.S. Provisional Appl. No. 60/971,387, filed Sep. 11, 2007, Danish Appl. No. PA 2007 01291, filed Sep. 7, 2007, and International Appl. No. PCT/DK2007/000113, filed Mar. 6, 2007, each of which is incorporated by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB

[0002] The content of the electronically submitted sequence listing in ASCII text file (Name: 24880120002_SequenceListing.txt: Size: 311,496 bytes, and Date of Creation: Dec. 20, 2010) filed with the application is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of The Invention

[0003] The present invention relates to specific recombinant mono- and polyclonal antibody compositions for prevention, treatment or amelioration of one or more symptoms associated with respiratory syncytial virus infections. The invention also relates to polyclonal expression cell lines producing anti-RSV recombinant polyclonal antibody (anti-RSV rpAb). Further, the application describes diagnostic and pharmacological compositions comprising anti-RSV rpAb and use in prevention, treatment or amelioration of one or more symptoms associated with a RSV infection.

[0004] Respiratory syncytial virus (RSV) is a major cause for lower respiratory tract disease in infants and small children. Premature infants and children with an underlying health problem such as chronic lung disease or congenital heart disease are at the greatest risk for serious illness such as bronchiolitis and pneumonia following RSV infection. Recently, RSV was also recognized as an important pathogen in certain high-risk adults, such as immunocompromised adults, particularly bone marrow transplant recipients, elderly individuals and individuals with chronic pulmonary disease.

[0005] Human RSV is a member of the Pneumovirus subfamily of the family Paramyxoviridae, and exists as an A and B subtype. RSV is an enveloped, non-segmented, negative-sense RNA virus. The viral genome codes for at least 11 proteins of which three are the envelope associated proteins, F (fusion glycoprotein), G (receptor-binding glycoprotein), and SH (small hydrophobic protein). The envelope proteins are present on the viral surface, and to some extent also on the surface of infected cells. The F protein promotes fusion of the viral and cell membranes, thereby allowing penetration of the viral RNA into the cell cytoplasm. The F protein consists of two disulfide-linked subunits, F₁ and F₂, produced by proteolytical cleavage of an inactive, N-glycosylated precursor of 574 amino acids. The G protein is a type II trans-membrane glycoprotein of 289-299 amino acids (depending on the virus strain). The precursor form is 32 kDa, which matures to a protein of 80-90 kDa upon addition of both N- and O-linked oligosaccharides. The RSV G protein is responsible for the attachment of virions to the target cells. In addition to the membrane-bound form of the G protein, a truncated, soluble form is also produced. It has been suggested that the function of this is to redirect the immune response away from the virus and infected cells. Further it has been shown that the G protein is associated with a number of pro-inflammatory effects such as modification of chemokine and cytokine expression as well as leukocyte recruitment. The SH protein is a protein of 64-65 amino acids that is present in very low amounts on the surface of purified RSV particles, but is abundantly expressed on the surface of RSV-infected cells. The function of the SH protein has not been defined, but it is possible that it may aid virus protein transport through the Golgi complex (Rixon et al 2004, J. Gen. Virol. 85:1153-1165). Blocking the function of the G and F proteins is believed to be relevant in prevention of RSV infection.

[0006] The prevention and treatment of RSV infection has received considerable attention during the last decades, and include vaccine development, antiviral compounds (Ribavirin approved for treatment), antisense drugs, RNA interference (RNAi) technology and antibody products such as immunoglobulin and monoclonal antibodies (all reviewed in Maggon and Batik, 2004, Rev. med. Virol. 14:149-168). Of these approaches, the intravenous immunoglobulin, RSV-IVIG, and the monoclonal antibody, Palivizumab, have been approved for RSV prophylaxis in high-risk children.

[0007] Immunoglobulin products such as RSV-IVIG (RespiGam) are, however, known to have several drawbacks such as low specific activity resulting in need for injection of large volumes, which is difficult in children with limited venous access due to prior intensive therapy. Further, there is also the risk of transmission of viral diseases from serum-derived immunoglobulin products, as well as problems with batch-to-batch variations. Finally, it is difficult to obtain sufficient donors to meet the needs for hyperimmune RSV immunoglobulin production, since only approximately 8% of normal donors have RSV neutralizing antibody titers that are high enough.

[0008] Monoclonal antibodies against the F protein or the G protein have been shown to have neutralizing effect in vitro and prophylactic effects in vivo (e.g. Beeler and Coelingh 1989. J. Virol. 63:2941-50; Garcia-Barreno et al. 1989. J. Virol. 63:925-32; Taylor et al. 1984. Immunology 52: 137-142; Walsh et al. 1984, Infection and Immunity 43:756-758; U.S. Pat. No. 5,842,307 and U.S. Pat. No. 6,818,216). Today the monoclonal antibody Palivizumab has almost substituted the use of RSV-IVIG completely. Neutralization assays show that Palivizumab and RSV-IVIG perform equally well against RSV subtype B, whereas Palivizumab perform better against subtype A (Johnson et al. 1997. J. Infect. Dis. 176:1215-24.). However, despite the good neutralizing and prophylactic effects of monoclonal antibodies as illustrated by products like Palivizumab and Numax, these may also be associated with certain drawbacks due to the nature of the RSV virus.

[0009] RSV exists in two distinct antigenic groups or subtypes, A and B. Most of the RSV proteins are highly conserved between the two subgroups, with the F protein showing 91% amino acid similarity. However, the G protein displays extensive sequence variability, with only 53% amino acid similarity between the A and B subgroups (Sullender 2000. Clin. Microbiol. Rev. 13:1-15). Most of the proteins also show some limited intra subgroup variation, except for the G protein, which differs by up to 20% within subgroup A and 9% within subgroup B on amino acid level. The A and B virus subtypes co-circulate in most RSV epidemics, with the relative frequency varying between different years. Thus, a monoclonal antibody must be carefully selected such that it is capable of neutralizing both subtypes as well as intra subtype variations.

[0010] In addition to the issue of the two RSV subtypes and intra-subtype diversity, human RSV, like most RNA viruses, has the capacity of undergoing rapid mutations under selective pressure. The selection of RSV escape mutants in vitro using mAb is well documented (e.g. Garcia-Barreno et al. 1989. J. Virol. 63:925-32). Importantly, it was recently discovered that Palivizumab also selects for escape mutants, in vitro as well as in vivo, and that some of the isolated mutants are completely resistant to Palivizumab prophylaxis in cotton rats (Zhao and Sullender 2005. J. Virol. 79:3962-8 and Zhao et al. 2004. J. Infect. Dis. 190:1941-6.). Further, wild type RSV strains that are intrinsically resistant to Palivizumab may also exist, as demonstrated by the failure of the murine antibody, which Palivizumab originates from, to neutralize one clinical isolate (Beeler and Coelingh 1989. J. Virol. 63:2941-50). Furthermore, one apparently resistant virus has also been identified following Palivizumab prophylaxis in immunocompetent cotton rats (Johnson et al. 1997. J. Infect. Dis. 176:1215-24). Thus, under certain conditions, the use of a single, monospecific antibody may not be adequate or sufficient for the treatment of RSV disease, since escape mutants exist or may develop over time as a result of treatment.

[0011] A further consideration in relation to the utility of the RSV-IVIG and Palivizumab is the dose needed for efficient treatment. Serum concentrations of greater than 30 μg/ml have been shown to be necessary to reduce pulmonary RSV replication by 100 fold in the cotton rat model of RSV infection. For RSV-IVIG a monthly dose of 750 mg total protein/kg administrated intravenously was effective in reducing the incidence of RSV hospitalization in high-risk children, whereas for Palivizumab monthly intramuscular doses of 15 mg/kg proved effective. However, the administration of multiple intravenous or intramuscular large doses is inconvenient for the patient, and impedes the broad use of these products for the prophylaxis and treatment of the large group of adults at risk for RSV infection.

[0012] Thus, a need exists for an antibody product which is not dependent on the donor availability, and which binds immunospecifically to one or more RSV antigens covering subtypes A and B as well as any escape mutants arising due to virus mutations, is highly potent, have an improved pharmacokinetic profile, and thus have an overall improved therapeutic profile, and therefore requires less frequent administration and/or administration of a lower dose.

[0013] It is therefore the objective of the present invention to provide a highly potent alternative anti-RSV immunoglobulin product which is produced recombinantly and shows reactivity to subtypes A and B of the respiratory syncytial virus as well as to multiple epitopes on at least one of the major surface antigens to limit the possibility of escape mutations.

[0014] The invention also has as an objective to provide novel human anti-RSV antibody molecules as well as derivatives thereof, where the antibody molecules or derivatives exhibit improved characteristics over existing monoclonal anti-RSV antibodies and antibody derivatives.

DESCRIPTION OF THE INVENTION

[0015] The invention relates to antibodies capable of competing in binding with antibody 824 as defined herein or with its Fab fragment. Antibody 824 binds poorly to recombinant protein but with very high affinity to human cells infected with RSV, resulting in very potent neutralization of RSV. By providing antibody 824 the inventors have identified an epitope, which results in more efficient in vitro and in vivo neutralization than seen before for any single RSV epitope. By providing antibody 824, the inventors have also enabled the identification of further antibodies which bind to the same epitope. These further antibodies may be of any origin and includes binding fragments as well as affinity matured antibodies. Antibodies capable of competing with antibody 824 may be identified in a cellular competition assay (determination of relative epitope specificities) as described in Example 1, section g-4.

[0016] In further aspects the invention relates to an anti-RSV antibody comprising a CDRH3 having the following formula: CAX₁X₂X₃X₄X₅X₆PX₇X₈X₉X₁- 0X₁₁W

where X₁ to X₁₁ are selected individually from the groups of amino acids listed below

X₁═R or K;

X₂=D, E, N or Q;

X₃═S, T, G or A;

X₄═S, T, G or A;

X₅═N, Q, D or E;

X₆═W, Y, F or H;

X₇=A, G, V, or S;

X₈=G, A, V, or S;

X₉═Y, F, W or H;

X₁₀=E or D; and

X₁₁=E, N or Q;

[0017] and a CDRL3 described by the following formula: CX₁X₂X₃X₄X₅X₆PX₇TF where X₁ to X₇ are selected individually from the groups of amino acids listed below:

X₁=Q or H;

X₂=Q, E or H;

X₃═F, Y, W or H;

X₄═N, Q or H;

X₅=T, S, G or A;

X₆═Y, F, W or H; and

X₇═F, Y, W or H.

[0018] Antibodies comprising these CDR sequences based on antibody 824 are expected to result in very efficient virus neutralization both in vitro and in vivo as they are expected to bind the same epitope. In further aspects, the invention relates to nucleic acids encoding these CDR sequences, to nucleic acid encoding VL and VH sequences of antibody 824, to expression vectors encoding such antibodies and CDRs and to cells expressing these.

[0019] Preferably, the anti-RSV antibody comprises the CDR1, and CDR2 regions from the VH and VL pair of antibody 824 as set forth in SEQ ID NOs: 232, 317, 487, and 572, and a CDRH3 region having the formula CAR₁D2S₃S₄N₅W₆PA₇G₈Y₉E₁₀D.su- b.11W (SEQ ID NO 402), and a CDRL3 region having the formula CQ₁Q2F3N4T₅Y₆ PF7TF (SEQ ID NO 657).

[0020] In a further aspect the invention relates to an antibody composition comprising an antibody based on the CDR sequences above and one or more additional anti-RSV antibodies.

[0021] The invention also relates to an antibody composition comprising distinct members comprising heavy chain and light chain CDR1, CDR2 and CDR3 regions selected from the group of VH and VL pairs listed in Table 6, wherein the distinct members are the distinct members of one of antibody compositions 2 to 56 in Table 9 herein.

[0022] In further aspects the invention relates to a method of preventing, treating or ameliorating one or more symptoms associated with a RSV infection in a mammal, comprising administering an effective amount of an anti-RSV antibody according to the invention.

[0023] The use of a polyclonal antibody composition targeting multiple epitopes on RSV is expected to minimize the development of escape mutants and can also provide protection against diverse, naturally circulating viruses. In contrast to serum-derived RSV-IVIG, a polyclonal antibody of the present invention does not contain antibody molecules, which bind to non-RSV antigens.

[0024] The present invention provides a polyclonal anti-RSV antibody. Preferably, the polyclonal anti-RSV antibody is obtained from cells which do not naturally produce antibodies. Such an antibody is termed a recombinant polyclonal antibody (rpAb). An anti-RSV rpAb of the present invention is directed against multiple epitopes on the F or G protein. In particular an anti-RSV rpAb which is directed against multiple epitopes on both the G and F proteins is preferred. Preferably, G protein epitopes belonging to the conserved group and potentially also the subtype-specific group and the strain-specific group are covered by the anti-RSV rpAb. Further, antibodies with reactivity against the third envelope protein, small hydrophobic (SH) protein is a desired component of an anti-RSV rpAb of the present invention.

[0025] Further, the present invention provides pharmaceutical compositions where the active ingredient is an anti-RSV polyclonal antibody, as well as uses of such compositions for the prevention, amelioration or treatment of RSV infections.

[0026] The present invention further provides procedures for mirroring the humoral immune response raised upon infection with RSV, by isolating the original V_H and V_L gene pairs from such challenged individuals, and producing antibodies maintaining this original paring.

DEFINITIONS

[0027] The term "antibody" describes a functional component of serum and is often referred to either as a collection of molecules (antibodies or immunoglobulin) or as one molecule (the antibody molecule or immunoglobulin molecule). An antibody molecule is capable of binding to or reacting with a specific antigenic determinant (the antigen or the antigenic epitope), which in turn may lead to induction of immunological effector mechanisms. An individual antibody molecule is usually regarded as monospecific, and a composition of antibody molecules may be monoclonal (i.e., consisting of identical antibody molecules) or polyclonal (i.e., consisting of different antibody molecules reacting with the same or different epitopes on the same antigen or on distinct, different antigens). Each antibody molecule has a unique structure that enables it to bind specifically to its corresponding antigen, and all natural antibody molecules have the same overall basic structure of two identical light chains and two identical heavy chains. Antibodies are also known collectively as immunoglobulin. The terms antibody or antibodies as used herein is used in the broadest sense and covers intact antibodies, chimeric, humanized, fully human and single chain antibodies, as well as binding fragments of antibodies, such as Fab, Fv fragments or scFv fragments, as well as multimeric forms such as dimeric IgA molecules or pentavalent IgM. In some instances, the present application uses the term "synthetic or semi-synthetic antibody analogue", which specifically refers to non-naturally occurring molecules which exhibit antibody characteristics (by exhibiting specific binding to RSV antigens) and includes CDRs from naturally occurring antibodies--such analogues are e.g. represented by scFv fragments, unibodies, diabodies etc, but could e.g. also be seemingly naturally occurring antibodies which are engineered to include the CDRs (e.g. by grafting techniques known in the art) from an anti-RSV antibody molecule disclosed herein--for instance, such an antibody analogue could comprise CDRs disclosed herein incorporated into an antibody molecule of another animal species or into a different antibody isotype or class from the same species.

[0028] The term "anti-RSV recombinant polyclonal antibody" or "anti-RSV rpAb" describes a composition of recombinantly produced diverse antibody molecules, where the individual members are capable of binding to at least one epitope on a respiratory syncytial virus, and where the polyclonal composition as a whole is capable of neutralizing RSV. Preferably, an anti-RSV rpAb composition neutralizes both RSV subtype A and B. Even more preferred the anti-RSV rpAb further comprise binding reactivity towards the G and F protein. Preferably, the composition is produced from a single polyclonal manufacturing cell line.

[0029] The term "cognate V_H and V_L coding pair" describes an original pair of V_H and V_L coding sequences contained within or derived from the same cell. Thus, a cognate V_H and V_L pair represents the V_H and V_L pairing originally present in the donor from which such a cell is derived. The term "an antibody expressed from a V_H and V_L coding pair" indicates that an antibody or an antibody fragment is produced from a vector, plasmid or similar containing the V_H and V_L coding sequence. When a cognate V_H and V_L coding pair is expressed, either as a complete antibody or as a stable fragment thereof, they preserve the binding affinity and specificity of the antibody originally expressed from the cell they are derived from. A library of cognate pairs is also termed a repertoire or collection of cognate pairs, and may be kept individually or pooled.

[0030] The terms "a distinct member of a recombinant polyclonal antibody" denotes an individual antibody molecule of the recombinant polyclonal antibody composition, comprising one or more stretches within the variable regions, which are characterized by differences in the amino acid sequence compared to the other individual members of the polyclonal protein. These stretches are in particular located in the CDR1, CDR2 and CDR 3 regions.

[0031] The term "epitope" is commonly used to describe a proportion of a larger molecule or a part of a larger molecule (e.g. antigen or antigenic site) having antigenic or immunogenic activity in an animal, preferably a mammal, and most preferably in a human. An epitope having immunogenic activity is a portion of a larger molecule that elicits an antibody response in an animal. An epitope having antigenic activity is a portion of a larger molecule to which an antibody immunospecifically binds as determined by any method well known in the art, for example, by the immunoassays described herein. Antigenic epitopes need not necessarily be immunogenic. An antigen is a substance to which an antibody or antibody fragment immunospecifically binds, e.g. toxin, virus, bacteria, proteins or DNA. An antigen or antigenic site often has more than one epitope, unless they are very small, and is often capable of stimulating an immune response. Antibodies binding to different epitopes on the same antigen can have varying effects on the activity of the antigen they bind depending on the location of the epitope. An antibody binding to an epitope in an active site of the antigen may block the function of the antigen completely, whereas another antibody binding at a different epitope may have no or little effect on the activity of the antigen alone. Such antibodies may however still activate complement and thereby result in the elimination of the antigen, and may result in synergistic effects when combined with one or more antibodies binding at different epitopes on the same antigen. In the present invention the larger molecule which the epitope is a proportion of is preferably a proportion of an RSV polypeptide. Antigens of the present invention are preferably RSV associated proteins, polypeptides or fragments thereof to which an antibody or antibody fragment immunospecifically binds. A RSV associated antigen may also be an analog or derivative of a RSV polypeptide or fragment thereof to which an antibody or antibody fragment immunospecifically binds.

[0032] The term "fully human" used for example in relation to DNA, RNA or protein sequences describes sequences which are between 98 to 100% human.

[0033] The term "immunoglobulin" commonly is used as a collective designation of the mixture of antibodies found in blood or serum, but may also be used to designate a mixture of antibodies derived from other sources.

[0034] The term "mirrors the humoral immune response" when used in relation to a polyclonal antibody refers to an antibody composition where the nucleic acid sequences encoding the individual antibody members are derived from a donor with an increased frequency of plasma cells producing anti-RSV specific antibodies. Such a donor may either be recovering from a RSV infection, has had close contact with an RSV infected individual, or has been subject to RSV vaccination (for examples of RSV vaccines see for example Maggon and Batik, 2004, Rev. med. Virol. 14:149-168). In order to mirror the affinity and specificity of antibodies raised in a donor upon infection or challenge, the sequences encoding the variable heavy chain (V_H) and the variable light chain (V_L) should be maintained in the gene pairs or combinations originally present in the donor (cognate pairs) when they are isolated. In order to mirror the diversity of a humoral immune response in a donor all the sequences encoding antibodies which bind to RSV are selected based on a screening procedure. The isolated sequences are analyzed with respect to diversity of the variable regions, in particular the CDR regions, but also with respect to the V_H and V_L family. Based on these analyses a population of cognate pairs representing the overall diversity of the RSV binding antibodies are selected. Such a polyclonal antibody typically have at least 5, 10, 20, 30, 40, 50, 100, 1000 or 10⁴ distinct members.

[0035] A composition is said to be "pharmacologically acceptable" if its administration can be tolerated by a recipient patient--the same of course applies to excipients, vehicles carriers and diluents being part of a composition.

[0036] The term "polyclonal antibody" describes a composition of different (diverse) antibody molecules which is capable of binding to or reacting with several different specific antigenic determinants/epitopes on the same or on different antigens, where each individual antibody in the composition is capable of reacting with a particular epitope. Usually, the variability of a polyclonal antibody is located in the so-called variable regions of the polyclonal antibody, in particular in the CDR1, CDR2 and CDR3 regions. In the present invention a polyclonal antibody may either be produced in one pot from a polyclonal cell line, or it may be a mixture of different polyclonal antibodies. A mixture of monoclonal antibodies is not as such considered a polyclonal antibody, since they are produced in individual batches and not necessarily from the same cell line which will result in e.g. post translational modification differences. However, if a mixture of monoclonal antibodies provide the same antigen/epitope coverage as a polyclonal antibody of the present invention it will be considered as an equivalent of the polyclonal antibody. When stating that a member of a polyclonal antibody specifically binds to or has specific reactivity against an antigen/antigenic site/epitope, it is herein meant that the binding constant is below 100 nM, preferably below 10 nM, even more preferred below 1 nM.

[0037] The term "recombinant antibody" is used to describe an antibody molecule or several molecules that is/are expressed from a cell or cell line transfected with an expression vector comprising the coding sequence of the antibody which is not naturally associated with the cell. If the antibody molecules in a recombinant antibody composition are diverse or different, the term "recombinant polyclonal antibody" or "rpAb" applies in accordance with the definition of a polyclonal antibody.

[0038] The term "recombinant polyclonal cell line" or "polyclonal cell line" refers to a mixture/population of protein expressing cells that are transfected with a repertoire of variant nucleic acid sequences (e.g. a repertoire of antibody encoding nucleic acid sequences), which are not naturally associated with the transfected cells. Preferably, the transfection is performed such that the individual cells, which together constitute the recombinant polyclonal cell line, each carry a transcriptionally active copy of a single distinct nucleic acid sequence of interest, which encodes one member of the recombinant polyclonal antibody of interest. Even more preferred, only a single copy of the distinct nucleic acid sequence is integrated at a specific site in the genome. The cells constituting the recombinant polyclonal cell line are selected for their ability to retain the integrated copy (copies) of the distinct nucleic acid sequence of interest, for example by antibiotic selection. Cells which can constitute such a polyclonal cell line can be for example bacteria, fungi, eukaryotic cells, such as yeast, insect cells, plant cells or mammalian cells, especially immortal mammalian cell lines such as CHO cells, COS cells, BHK cells, myeloma cells (e.g., Sp2/0 cells, NS0), NIH 3T3, YB2/0 and immortalized human cells, such as HeLa cells, HEK 293 cells, or PER.C6.

[0039] The terms "sequences encoding V_H and V_L pairs" or "V_H and V_L encoding sequence pairs" indicate nucleic acid molecules, where each molecule comprise a sequence that code for the expression of a variable heavy chain and a variable light chain, such that these can be expressed as a pair from the nucleic acid molecule if suitable promoter and/or IRES regions are present and operably linked to the sequences. The nucleic acid molecule may also code for part of the constant regions or the complete constant region of the heavy chain and/or the light chain, allowing for the expression of a Fab fragment, a full-length antibody or other antibody fragments if suitable promoter and/or IRES regions are present and operably linked to the sequences.

[0040] A recombinant polyclonal antibody is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significant, e.g. prevents or attenuates an RSV infection in an animal or human.

DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1: (A) Alignment of the amino acid sequences of the whole G protein from the prototypic strains, Long (subtype A) and 18537 (subtype B). The signal/trans-membrane region is boxed with a dotted line. The two variable domains between amino acid 101-133 and 208-299 as identified by Cane et al. 1991 J. Gen. Virol. 72:2091-2096 are identified with an underline. The central fragment of the G protein has been expressed as a fusion protein in E. coli and is boxed in black. The 2 amino acid sequences are set forth in SEQ ID NOs: 711 (subtype A) and 712 (Subtype B). (B) Alignment of the central fragment, as indicated in (A). The location of the 13-aa conserved region (a.a. residue 164-176) and the G protein cysteine-rich region (GCRR) are indicated with brackets. The disulphide bridges in the GCRR (identical for both subtypes) are indicated with square brackets. The 2 amino acid sequences are set forth in SEQ ID NOs: 713 (Subtype A) and 714 (subtype B).

[0042] FIG. 2: Schematic outline of the multiplex overlap-extension RT-PCR (A) and the cloning steps (B). (A) Two sets of primers, CH+VH 1-8 and VK1-6+CK1, specific for V_H and V_L gene families, respectively, were used for the first PCR step. A homologous region between the V_H or V.sub.κ primers results in the generation of an overlap PCR product. In the second step this product is amplified in the nested PCR. The primers also include recognition sites for restriction enzymes that facilitate cloning. (B) The generated cognate linked V_H and V_L coding pairs are pooled and inserted into a mammalian IgG expression vector (e.g. FIG. 3) by the use of the flanking XhoI and NotI restriction sites. Subsequently a bi-directional promoter is inserted into the AscI-NheI restriction site between the linked V_H and V_L coding sequences to facilitate expression of full length antibodies. PCR primers used are indicated by horizontal arrows. CH1: heavy chain constant domain 1, CL: constant domain, LC: light chain; Ab: antibody; P1-P2: bi-directional promoters.

[0043] FIG. 3: Schematic presentation of a mammalian full-length antibody expression vector 00-VP-530. The vector comprises the following elements: Amp and Amp pro=ampicillin resistance gene and its promoter. pUC origin=pUC origin of replication. P1=mammalian promoter driving the expression of the light chain. P2=mammalian promoter driving the expression of the heavy chain, Leader IGHV=genomic human heavy chain leader. VH=heavy chain variable region encoding sequence. IgG1=Sequence encoding genomic immunoglobulin isotype G1 heavy chain constant region. Rabbit B-globin A=rabbit beta-globin polyA sequence. Kappa leader=sequence encoding for murine kappa leader. LC=Sequence of light chain encoding sequence. SV40 term=Simian virus 40 terminator sequence. FRT=A Flp recognition target site. Neo=neomycin resistance gene. SV40 poly A=Simian virus 40 poly A signal sequence

[0044] FIG. 4: Characterization of the epitope specificity of antibody obtained from clone 801 (Ab801) using Biacore analysis. Antibody 801 binding was tested in pair-wise competition for binding to protein F, using three antibodies, 9c5 (2), 133-h (3) and Palivizumab (4), which bind to antigenic site F1, C and II, respectively. The reference cell illustrates binding to protein F of uncompeted Ab801 (1). Injection times of the four antibodies are indicated by an arrow. The response is indicated in relative resonance units (RU). The long double headed arrow indicates the magnitude of the uncompeted response and the short double headed arrow indicates the magnitude of the 9c5 inhibited response.

[0045] FIG. 5: Shows results from in vitro neutralization of RSV subtype A and B strains. Dilutions of anti-F antibody mixtures were tested for their ability to neutralize RSV Long (Panel A) and RSV B1 (Panel B) strains. Antibody mixture, anti-F(I), obtained from clones 810, 818, 819, 825 and 827 is shown as triangles (.tangle-solidup.) and antibody mixture, anti-F(II), obtained from clones 735, 800, 810, 818, 819, 825, 827, 863, 880, 884 and 894 is shown as squares (.box-solid.). Palivizumab is shown as diamonds (.diamond-solid.), and an isotype-matched negative control (anti-Rhesus D) antibody is shown as circles ( ). The absorbance was measured at 490 nm and correlates with RSV replication.

[0046] FIG. 6: Shows results from an in vitro RSV fusion inhibition assay. Dilutions of antibody mixtures were tested for their ability to neutralize RSV B1 strain. Antibody mixture, anti-F(I)G, obtained from clones 810, 818, 819, 825, 827, 793, 796, 838, 841, 856 and 888 is shown as open squares (quadrature) and antibody mixture, anti-F(II)G, obtained from clones 735, 800, 810, 818, 819, 825, 827, 863, 880, 884, 894, 793, 796, 838, 841, 856 and 888 is shown as open triangles (Δ). Palivizumab is shown as diamonds (.diamond-solid.). The absorbance was measured at 490 nm and correlates with RSV replication.

[0047] FIG. 7: Shows results from an in vitro neutralization of RSV by combinations of anti-G antibody clones as measured by the PRNT in the presence of active complement. Dilutions of individual antibody compositions (described in Table 9) were incubated with RSV strain Long in the presence of rabbit complement and afterwards allowed to infect HEp-2 cells. After 24 hours of incubation, the degree of infection was detected using immunodetection of RSV-specific plaques. Anti-RSV rpAb 13 is shown as open triangles (Δ), anti-RSV rpAb 35 as triangles (.tangle-solidup.), anti-RSV rpAb 36 as squares (.box-solid.), anti-RSV rpAb 41 as circles ( ) and anti-RSV rpAb 45 as open squares (quadrature). Data are presented as % infection compared to control±SD.

[0048] FIG. 8. The pharmacokinetics profile of anti-RSV rpAb 33 and rpAb 56 in mice. BALB/c mice were treated with the anti-RSV rpAb 33 and anti-RSV rpAb 56 (antibody compositions of Table 9) at a dose of 15 mg/kg. Serum samples were taken at a number of time points ranging from day 0 (before inoculation) until day 29. Each point represents the mean human IgG1 level in serum at sampling time±standard deviation.

DETAILED DESCRIPTION OF THE INVENTION

Target Antigens and Polyclonal Antibody Compositions

[0049] A polyclonal antibody of the present invention is composed of a number of distinct antibody molecules in the same composition. Each molecule is selected based on its ability to bind an RSV associated antigen. A polyclonal antibody of the present invention comprises binding reactivity corresponding to the compiled binding reactivity of the distinct antibody molecules constituting the polyclonal antibody composition.

[0050] An anti-RSV polyclonal antibody of the present invention preferably comprise a compiled binding reactivity against both the G and F proteins and even more preferred against multiple epitopes to minimize the risk of development of escape mutants and achieve highest possible neutralizing capacity. At least five major antigenic sites that are recognized by neutralizing antibodies have been identified on the F protein (Lopez et al. 1998. J. Virol. 72:6922-8). All the antigenic sites have been mapped to the F₁ chain, and include site I, II, IV, V and VI, where site I and II also may be termed B and A, respectively. Site II is located in a protease-resistant region in the N-terminal segment, and sites IV, V and VI in the C-terminal end of the cysteine-rich region of the protein. Site I is located in the middle of this cysteine cluster. A further antigenic site on the F protein is site C in which the epitope F2 including amino acid positions 241 and 242 is located. Additionally, there are monoclonal antibodies binding to an antigenic site termed F1, comprising the epitopes termed F1a, F1b and F1c. Currently this antigenic site has not been mapped to a particular site on the F protein, but it seems to be overlapping with site I. The majority of these sites/epitopes give rise to broadly neutralizing antibodies, but some antibodies specific for antigenic site I have been shown to be subtype A-specific. Antibodies binding to site I also have a marginal effect in virus neutralization. The epitope recognized by Palivizumab is located in antigenic site II as judged by the localization of the selected escape mutations in amino acid position 272 (Zhao et al. 2004. J. Infect. Dis. 190:1941-6). Furthermore, three types of epitopes have been identified on the G protein: i) conserved epitopes that are present in all RSV strains, ii) group-specific epitopes that are present in all viruses belonging to the same subtype, and iii) strain-specific or variable epitopes that are present only in a subset of strains belong to the same subtype. The conserved and group-specific epitopes have been mapped to the central part of the G protein containing a cluster of four cysteines (amino acid residue 173, 176, 182 and 186) and a short amino acid segment (residues 164-176) of identical sequence among all human RSV isolates. The cysteine cluster is held by disulfide bonds between position 173-183 and 176-182 and constitutes the central part of the G protein cysteine-rich region (GCRR) ranging from amino acid residue 171-187, thereby the GCRR is overlapping with the 13 amino acid conserved region. The G glycoprotein appears to play a role in both induction of protective immunity and disease pathogenesis. For example, studies in mice have shown that the G glycoprotein primes for a Th2 CD4+ T cell response, characterized by production of IL-4, IL-5, IL-13 and pulmonary eosinophilia. Eosinophil recruitment and activation are promoted by several factors, such as IL-4 and IL-5. Further, expression of RSV G protein during acute infection in mice has been associated with a modified innate immune response characterized by decreased Th1 cytokine expression (e.g., IL-2 and gamma interferon), altered chemokine mRNA expression (e.g., MIP-1 alpha, MIP-1 beta, MIP-2, IP-10, MCP-1), and decreased NK cell trafficking to the infected lung. In particular the GCRR has been shown to play an important role in modulating the innate inflammatory response, thereby potentially delaying RSV clearance (Polack et al. 2005. PNAS 102:8996-9001). The GCRR comprise a CX3C motif at amino acid positions 182 to 186. Reduction in respiratory rates in RSV infected mice has been shown to be associated with the CX3C motif, since antibodies against this motif abolish the reduction in the respiratory rates (Tripp et al. 2003. J. Virol. 77:6580-6584 and US 2004/0009177 (application Ser. No. 10/420,387)). The strain-specific epitopes are preferentially localized in the variable C-terminal third of the G polypeptide, although a strain-specific epitope has been mapped to a variable region N-terminal to the cysteine cluster in the G protein ectodomain (Martinez et al. 1997. J. Gen. Virol. 78:2419-29). FIG. 1 shows an alignment of the G proteins from the Long strain (subtype A) and the 18537 strain (subtype B), indicating the various regions of the G protein. Generally, monoclonal anti-G protein antibodies have marginal effects on RSV neutralization. However, it has been reported that mixtures of monoclonal anti-G antibodies enhance neutralization of RSV in vitro as well as in vivo (Walsh et al. 1989. J. Gen. Virol. 70:2953-61 and Martinez and Melero 1998 J. Gen. Virol. 79:2215-20). The greatest effect of combining monoclonal anti-G antibodies is apparently achieved when the antibodies bind different epitopes, although a fraction of the virus still remained resistant to neutralization. Further, it has been shown that combinations of two different anti-F antibodies with different epitope specificities as well as combinations of one anti-F and one anti-G specific antibody showed an enhanced in vitro neutralizing effect on RSV (Anderson et al. 1988. J. Virol. 62: 4232-4238). Some of the advantages obtained by mixing monoclonal antibodies seem to be due to the individual properties of the monoclonal antibodies, such as an antagonistic effect, e.g. by blockage of the active site. Other effects seem to be synergistic for reasons that currently are not understood.

[0051] The mechanisms of RSV neutralization are complex and not completely understood. The large number of different epitopes, conserved, subtype specific as well as strain specific epitopes, identified on the F and G proteins alone, as well as the potential generation of escape mutants suggests that a wide spectrum of antibody specificities is needed to address all the neutralization mechanisms that may play a role in the prevention of RSV infection. Thus, it would be very difficult, in a rational way, to select the mixture of monoclonal antibodies that is capable of preventing RSV infection with RSV strain of both subtype A and B, as well as escape mutants and new strains arising from the RSV strains known today.

[0052] An aspect of the present invention is to provide a polyclonal anti-RSV antibody with a considerable diversity and broad anti-RSV specificity. The polyclonal anti-RSV antibody of the present invention is not dependent on the donor availability at the time of production and the batch to batch variation is considerably lower than observed for donor-derived anti-RSV immunoglobulin products (e.g. RSV IVIG). In a polyclonal anti-RSV antibody of the present in invention all the individual antibody members are capable of binding a RSV associated antigen and the polyclonal antibody is capable of neutralizing RSV subtype A and B. It is preferred that each distinct antibody of the polyclonal antibody binds an epitope which is not bound by any of the other members of the polyclonal antibody. A polyclonal anti-RSV antibody of the present invention will bind to RSV antigens in a multivalent manner, which usually results in synergistic neutralization, improved phagocytosis of infected cells by macrophages and improved antibody-dependent cellular cytotoxicity (ADCC) against infected cells as well as increased complement activation. Further, a polyclonal antibody of the present invention is not "diluted" by non-binding protein which is the case for RSV IVIG, where a dose of 750 mg total protein/kg is needed to be efficient. The percentage of RSV-specific antibodies within the 750 mg total protein is not known, but it is not likely to constitute more than maximally 1%, and most likely less. Thus, when the in vitro potency of Palivizumab was estimated to be 25-30 times higher than that of RSV IVIG (Johnson et al. 1997. J. Infect. Dis. 176:1215-24), this is offset by a reduced specific activity of the RSV IVIG. Thus, if only 1% of the immunoglobulin molecules contained in the RSV-IVIG are specific for RSV, then the active dose of the RSV-IVIG polyclonal antibody is only 7.5 mg/kg which is lower than that of the monoclonal antibody Palivizumab.

[0053] For these reasons a recombinant polyclonal RSV-specific antibody of the present invention is expected to be significantly more potent than a monoclonal antibody, and it will therefore be possible to administer a smaller dose of a polyclonal antibody of the present invention, compared to the effective doses of Palivizumab and RSV IVIG. Thus, a polyclonal anti-RSV antibody of the present invention is also considered suitable for the prophylaxis and treatment of high-risk adults, in particular bone marrow transplant recipients, elderly individuals and individuals with chronic pulmonary disease. A further advantage of a polyclonal anti-RSV antibody of the present invention, is that the concentration of the individual antibody members is significantly lower than the concentration of a monoclonal antibody (even if the dose used is the same), hence the possibility that the individual antibody will be recognized as foreign by the immune system of the individual under treatment is decreased, and even if one individual antibody is eliminated by an immune response in the patient, this is not likely to affect the neutralizing capability or the clearance rate of the polyclonal anti-RSV antibody, since the remaining antibody members remain intact.

[0054] An embodiment of the present invention is a recombinant polyclonal anti-RSV antibody capable of neutralizing RSV subtype A and B, and where said polyclonal antibody comprises distinct antibody members which in union specifically binds at least three different epitopes on at least one RSV envelope protein. Preferably, the F protein is bound specifically by at least three distinct antibody members, and said epitopes are preferably located at different antigenic sites.

[0055] A further embodiment of the present invention is a recombinant polyclonal anti-RSV antibody capable of neutralizing RSV subtype A and B, and where said polyclonal antibody comprises distinct antibody members which in union provide specific reactivity against at least two RSV envelope proteins. The two envelope proteins can be selected from the RSV G protein, RSV F protein and RSV SH protein. Preferably, the polyclonal anti-RSV antibody of the present invention comprises anti-G and anti-F reactivity. The anti-G and anti-F reactivity of such a polyclonal antibody is preferably comprised of at least two distinct anti-G antibodies and at least one distinct anti-F antibody. Preferably, at least three distinct antibodies bind to different epitopes, thereby covering at least three different epitopes, and together the antibodies are capable of neutralizing RSV subtype A and subtype B strains equally well. Even more preferred the anti-G and anti-F reactivity of a polyclonal anti-RSV antibody of the present invention is comprised of any combination of the anti-G and anti-F reactivities described below. Most preferred a polyclonal anti-RSV antibody of the present invention is comprised of anti-G and anti-F reactivity against all the antigenic sites/epitopes mentioned below. To obtain the broadest specificity possible of a polyclonal anti-RSV antibody of the present invention, it is desired that one or more, preferably all the antigenic sites are covered by more than one distinct antibody. Consequently, it is preferred that several epitopes on the same antigen or antigenic site are bound by distinct members of a polyclonal antibody of the present invention.

[0056] With respect to the anti-G reactivity of a polyclonal anti-RSV antibody of the present invention, this reactivity is preferably directed against conserved epitopes. Even more preferred the anti-G reactivity is comprised of a first anti-G antibody capable of specifically binding a conserved epitope on the G-protein, and a second anti-G antibody capable of specifically binding the G protein cysteine-rich region (GCRR) The polyclonal anti-RSV antibody preferably comprise at least two distinct anti-G antibodies, where at least one first antibody is capable of specifically binding a conserved epitope on the G-protein, and at least one second antibody is capable of specifically binding a different conserved epitope or a group-specific epitope recognizing either with subtype A or subtype B. Preferably, the polyclonal antibody comprise at least three distinct anti-G antibodies where the first antibody is capable of specifically binding a conserved epitope on the G-protein, and the second antibody is capable of specifically binding a G protein of subtype A and the third antibody is capable of specifically binding a G protein of subtype B. The G protein cysteine-rich region (GCRR) partially overlaps with the upstream 13 amino acid region where the conserved epitopes are located and a region where the group specific epitopes are located. Thus, antibodies capable of specifically binding a conserved epitope as well as group specific antibodies may bind the GCRR if the epitope that they recognize is located in the GCRR. Preferably, at least one of the distinct antibodies characterized by their binding to a conserved epitope or a strain specific epitope also recognizes the GCRR. Antibodies binding to the CX3C motif of the GCRR are especially preferred from a virus neutralization point of view. However, antibodies binding to CX3C motifs may also bind a number of other unrelated human antigens, such as fractalkine and other human CX3C chemokines and thus produce undesired side-effects meaning that it will be a rational approach to test such antibodies for cross-reactivity (e.g. as demonstrated for certain antibodies in the examples) and later to test the same antibodies in suitable model systems. At any rate, it will always be necessary to test a given pharmaceutical, such as an antibody of the present invention, in a clinical trial before it can be established with a degree of certainty that side effects are absent, minor or at least acceptable. In addition to the conserved and group-specific anti-G reactivity additional anti-G reactivity directed against strain specific epitopes may also be comprised in the polyclonal anti-RSV antibody of the present invention. Strain-specific anti-G reactivity directed against the most abundant strain-specific epitopes present on virus strains which have resulted in RSV infection within the last five years is preferred. In the current invention strain-specific epitopes are understood as epitopes which only are present on a limited number of RSV strains. The addition of group-specific and/or strain specific anti-G antibodies can provide additional diversity to an anti-RSV antibody of the present invention, and may induce synergy when combined with antibodies with reactivity to the conserved region of the G protein. Preferably, the anti-G antibodies of the present invention neutralize RSV directly, block entry of the virus into the cell, prevent cell migration, inhibit inflammatory responses and/or prevent syncytia formation.

[0057] With respect to the anti-F reactivity of a polyclonal anti-RSV antibody of the present invention, this reactivity is preferably directed against at least one epitope on one or more of the antigenic sites I, II, IV, V, VI, C or F1. In further embodiments of the present invention at least two, three, four, five, six or all these antigenic sites/epitopes are covered by distinct antibodies in a polyclonal anti-RSV antibody of the present invention. Preferably, the anti-F antibodies of the present invention neutralize RSV directly and/or block entry of the virus into the cell and/or prevent syncytia formation.

[0058] In polyclonal anti-RSV antibody compositions of the present invention where the composition does not comprise binding reactivity directed against all the antigenic sites on the F protein, the presence of at least one distinct anti-F antibody which specifically binds an epitope of antigenic site II is preferred. Even more preferred the site II-specific anti-F antibody binds to the same epitope or antigenic site as the antibody Palivizumab. In addition to the site II-specific antibodies one or more distinct site IV-specific anti-F antibodies are desired, such an antibody preferably binds to the same epitope as RSVF2-5.

[0059] Subtype-specific anti-F antibodies are also known in the art. However, since the F protein shows 91% amino acid similarity between the two subgroups A and B, the subtype-specific anti-F antibodies are less abundant than for anti-G antibodies. Such strain-specific anti-F antibodies will, however, contribute to obtaining as broad specificity as possible, and are therefore also desired components of a polyclonal anti-RSV antibody of the present invention.

[0060] In addition to the RSV G and F protein antigens mentioned above, the RS virus expresses a third envelope protein, the small hydrophobic (SH) protein. Hyperimmune sera raised against peptides from the SH proteins have been shown to be unable to neutralize RSV in vitro (Akerlind-Stopner et al. 1993 J. Med. Virol. 40:112-120). However, since the protein is mainly expressed on infected cells, we believe that antibodies against the SH protein will have an effect on fusion inhibition and potentially be relevant for in vivo protection against RSV infections. This is supported by the fact that RSV strains lacking the SH gene replicate 10-fold less efficient in the upper respiratory tract (Bukreyev et al. 1997 J. Virol. 71:8973-82).

[0061] An additional embodiment of the present invention is a polyclonal anti-RSV antibody capable of neutralizing RSV subtype A and B and comprising anti-SH reactivity, and anti-G or anti-F reactivity. The C-terminus ranging from amino acid 41 to 64/65 (subtype A/B) of the SH protein is exposed on the cell surface. Hence, anti-SH reactivity against an epitope located in this area is desired. The C-terminus of the SH protein varies from subtype A and B, and it is therefore desired to include anti-SH reactivity against both subtype A and B in a polyclonal antibody of the present invention. This SH reactivity can be provided by at least two distinct anti-SH antibodies where the first antibody is capable of specifically binding SH subtype A and the second antibody is capable of specifically binding SH subtype B.

[0062] In one embodiment of the present invention a polyclonal anti-RSV antibody comprises specific reactivity against SH subtype A and/or B as well as specific reactivity against the G protein. The reactivity against the G protein can be composed of any of the reactivities mentioned above.

[0063] In an alternative embodiment the specific reactivity against SH subtype A and/or B can be combined with any of the anti-F reactivities described in the above to constitute a polyclonal anti-RSV antibody.

[0064] In a preferred embodiment of the present invention a polyclonal anti-RSV antibody comprises reactivity against all three of the envelope proteins, F, G and SH.

[0065] The reactivity comprised in a polyclonal anti-RSV antibody of the present invention may constitute any possible combination of distinct antibodies with specific binding reactivity against the antigens/antigenic sites and/or epitopes summarized in Table 1, as long as the combination is capable of neutralizing RSV subtype A and B. Preferably, the combination contains reactivity against at least two RSV envelope proteins.

[0066] Preferably, the individual distinct antibody members of a polyclonal antibody according to the present invention, have neutralizing and/or anti-inflammatory properties on their own. Antibodies without these particular properties may however also play a role in RSV clearance for example through complement activation.

TABLE-US-00001 TABLE 1 Summary of RSV associated antigens, antigenic sites and epitopes Antigen Antigenic site/epitope F Protein Antigenic site I Antigenic site II Antigenic site IV Antigenic site V Antigenic site VI Antigenic site C F1 epitope G Protein Conserved region (a.a. 164-176) Subtype A specific Subtype B specific GCRR (a.a. 171-187) (conserved as well as strain specific) CX3C motif (a.a. 182-186) Strain specific SH protein Subtype A Subtype B

[0067] Preferably, a polyclonal antibody of the present invention is produced as a single batch or a few batches from a polyclonal cell line which is not naturally expressing antibody molecules (also termed recombinant polyclonal antibody expression). One of the advantages of producing a recombinant polyclonal antibody compared to mixing monoclonal antibodies, is the ability to produce an unlimited number of distinct antibody molecules at the same time (at a cost similar to that of producing a single monoclonal antibody). Thus, it is possible to include antibodies with reactivity towards a large number of RSV associated antigens, without increasing the cost of the end product significantly. In particular with a target as complex as the RSV, where the biology is not completely understood, individual antibodies which have not been shown to neutralize or protect against RSV alone, may when combined with other antibodies induce a synergistic effect. Thus, it can be an advantage to include distinct antibodies, in addition to those described above, in a polyclonal antibody composition, where the only criterion is that the individual antibody binds to an RSV associated antigen (e.g. assessed by binding to RSV infected cells). Preferably all the polyclonal anti-RSV antibody compositions described above are recombinant polyclonal anti-RSV antibody (anti-RSV rpAb) compositions.

[0068] One way to acquire potentially relevant antibodies that bind RSV target antigens which have not been verified as relevant antigens, but nonetheless may be so, is to generate a polyclonal antibody composition which is composed of individual antibodies raised by the immune response of a donor which has been infected with RSV (full immune response). In addition to obtaining antibodies representing a full immune response against RSV, a positive selection for antibodies binding to antigens that are likely to be of particular relevance in the protection, neutralization, and/or elimination of RSV infections, can be performed. Further, if antibodies to a particular antigen, antigenic site or epitope which is believed to be of relevance in the protection, neutralization and/or elimination of RSV are not identified in the full immune response of the donor, such antibodies may be raised by immunization/vaccination of a donor with that particular antigen (selected immune response). Generally, neutralization is assessed by in vitro neutralization assays such as plaque reduction, microneutralization or fusion-inhibition assays (e.g. Johnson et al. 1997. J. Infect. Dis. 176:1215-24). Hence, an antibody or antibody composition having a significant effect in one of these assays, when compared to a negative control are considered to be neutralizing. Protection is generally assessed by in vivo challenge experiments in e.g. the cotton rat model (e.g. Johnson et al. 1997. J. Infect. Dis. 176:1215-24) or the murine model (e.g. Taylor et al. 1984. Immunology 52, 137-142 and Mejias, et al. 2005. Antimicrob. Agents Chemother. 49: 4700-4707). The in vivo challenge experiments can either be performed in a prophylactic fashion, where the antibodies are administered prior to the viral challenge or as a treatment, where the antibodies are administered after viral challenge or as a combination of both.

[0069] A polyclonal antibody composition of the present invention can be composed of antibodies capable of binding a RSV antigen which is not necessarily known or not necessarily an envelope protein (the antibody binds to infected cells, but not to selected antigens or antigenic sites), but where the antibodies are acquired from a full immune response following a RSV infection, e.g. by obtaining nucleic acid sequences encoding the distinct antibodies from one or more donors with a RSV infection or recovering from a RSV infection. Secondly, antibodies from the same full immune response, which have been selected, based on their ability to bind a particular antigen, antigenic site and/or epitope, can be included in a polyclonal antibody of the present invention. Thirdly, distinct antibodies encoded from V_H and V_L pairs obtained from one or more donors which have been immunized/vaccinated with a particular RSV related antigen thereby raising a "selected" immune response in these donors, can be included in a polyclonal antibody composition of the present invention. Thus, antibodies derived by any of the mentioned techniques in the present invention may be combined into a single polyclonal antibody. Preferably the nucleic acids encoding the antibodies of the present invention are obtained from human donors and the antibodies produced are fully human antibodies.

[0070] The motivation behind the polyclonal antibody compositions of the present invention is: if a donor infected with RSV, raises a humoral immune response against an antigen, these antibodies are likely, at least to some extent, to contribute to viral clearance, and thereby qualify for inclusion in a polyclonal antibody product.

[0071] A further aspect of the present invention is to produce an anti-RSV rpAb wherein the composition of distinct antibody members mirrors the humoral immune response with respect to diversity, affinity and specificity against RSV envelope antigens. Preferably, the mirror of the humoral response is established by ensuring that one or more of the following are fulfilled i) the nucleic acid sequences coding for the V_H and V_L regions of the individual antibody members in such an anti-RSV rpAb are derived from a donor(s) who has raised a humoral immune response against RSV, for example following RSV infection; ii) the V_H and V_L coding sequences are isolated from the donor(s) such that the original pairing of the V_H and V_L coding sequences present in the donor(s) is maintained, iii) the V_H and V_L pairs, coding for the individual members of the rpAb, are selected such that the CDR regions are as diverse as possible; or iv) the specificity of the individual members of the anti-RSV rpAb are selected such that the antibody composition collectively binds antigens that elicit significant antibody responses in mammals. Preferably, the antibody composition collectively binds antigens, antigenic sites and/or epitopes which produce significant antibody titers in a serum sample from said donor(s). Such antigens, antigenic sites and/or epitopes are summarized in Table 1 above, but may also constitute unknown antigens, antigenic sites and/or epitopes as well as non-envelope antigens, as described above. Preferably, the donors are human, and the polyclonal antibody is a fully human antibody.

[0072] The present invention has identified a series of V_H and V_L pairs that can be expressed as full-length antibodies, Fab fragment or other antibody fragments that have binding specificity to a RSV associated antigen. The specific V_H and V_L pairs are identified by clone number in Table 6 in Example 2. An antibody containing a V_H and V_L pair as identified in Table 6 is preferably a fully human antibody. However, if desired, chimeric antibodies may also be produced.

[0073] A preferred anti-RSV recombinant polyclonal antibody of the present invention is composed of distinct members comprising heavy chain and light chain CDR1, CDR2 and CDR3 regions selected from the group of V_H and V_L pairs listed in Table 6. Preferably, the CDR regions are maintained in the pairing indicated in Table 6 and inserted into a desired framework. Alternatively, CDR regions from the heavy chain (CDRH) of a first clone are combined with the CDR regions from the light chain (CDRL) of a second clone (scrambling of V_H and V_L pairs). The CDR regions may also be scrambled within the light chain or heavy chain, for example by combining the CDRL1 region from a first clone with the CDRL2 and CDRL3 region from a second clone. Such scrambling is preferably performed among clones that bind the same antigen. The CDR regions of the present invention may also be subjected to affinity maturation, e.g. by point mutations.

Preferred Antibody Compositions

[0074] Particularly preferred antibody compositions comprising more than one distinct human antibody molecule have been identified by the present inventors. These include antibody compositions which are efficacious in virus neutralization assays (Table 9) and in vivo (Tables 10-11).

[0075] One particularly preferred antibody composition is an antibody composition comprising antibody 824 or an antibody derived therefrom as described herein and one or more additional anti-RSV antibodies. Antibody 824 on its own is a very potent antibody and when combined with other antibodies--in particular with antibodies directed against the G-protein--have a very high potency in vitro and in vivo.

[0076] The one or more additional anti-RSV antibodies may be selected from the group consisting of human antibodies, humanized antibodies, and chimeric human-mouse antibodies.

[0077] Preferably, the one or more additional anti-RSV antibodies are selected from the group consisting of the antibody molecules set forth in Table 6 herein, or a specifically binding fragment of said antibody molecule or a synthetic or semi-synthetic antibody analogue, said binding fragment or analogue comprising at least the complementarity-determining regions (CDRs) of said isolated antibody molecule, except an antibody having the CDRs of clone 824.

[0078] A preferred antibody composition is composed of distinct members comprising heavy chain and light chain CDR1, CDR2 and CDR3 regions selected from the group of V_H and V_L pairs listed in Table 6, wherein the distinct members are the distinct members of one of antibody compositions 2 to 56 in Table 9 herein. Such antibody compositions have shown to be potent in neutralizing one or more RSV strains in vitro.

[0079] Preferably the antibody composition is capable of neutralizing RSV subtype A in a virus neutralization assay, more preferably the composition is also capable of neutralizing RSV subtype B in a virus neutralization assay. Suitable assays include the Plaque reduction and microneutralization assays described herein.

[0080] Particularly preferred compositions have demonstrated in vivo potency and comprise the distinct members selected from the distinct members of one of antibody compositions 2, 9, 13, 17, 18, 28, 33, and 56 of Table 9 herein.

[0081] In some embodiments the antibody composition does not contain anti-RSV antibodies in addition to antibodies with the CDRs of the distinct members described for each composition 2-56 in Table 9 herein.

Isolation and Selection of Variable Heavy Chain and Variable Light Chain Coding Pairs

[0082] The process of generating an anti-RSV recombinant polyclonal antibody composition involves the isolation of sequences coding for variable heavy chains (V_H) and variable light chains (V_L) from a suitable source, thereby generating a repertoire of V_H and V_L coding pairs. Generally, a suitable source for obtaining V_H and V_L coding sequences are lymphocyte containing cell fractions such as blood, spleen or bone marrow samples from an animal or human which is infected with RSV or recovering from an RSV infection, or from an animal or human immunized/vaccinated with an RSV strain or proteins or DNA derived from such a strain. Preferably, lymphocyte containing fractions are collected from humans or transgenic animals with human immunoglobulin genes. The collected lymphocyte containing cell fraction may be enriched further to obtain a particular lymphocyte population, e.g. cells from the B lymphocyte linage. Preferably, the enrichment is performed using magnetic bead cell sorting (MACS) and/or fluorescence activated cell sorting (FACS), taking advantage of lineage-specific cell surface marker proteins for example for B cells, plasma blast and/or plasma cells. Preferably, the lymphocyte containing cell fraction is enriched with respect to B cells, plasma blasts and/or plasma cells. Even more preferred, cells with high CD38 expression and intermediate CD19 and/or CD45 expression are isolated from blood. These cells are sometimes termed circulating plasma cells, early plasma cells or plasma blasts. For ease, they are just termed plasma cells in the present invention, although the other terms may be used interchangeably.

[0083] The isolation of V_H and V_L coding sequences can either be performed in the classical way where the V_H and V_L coding sequences are combined randomly in a vector to generate a combinatorial library of V_H and V_L coding sequences pairs. However, in the present invention it is preferred to mirror the diversity, affinity and specificity of the antibodies produced in a humoral immune response upon RSV infection. This involves the maintenance of the V_H and V_L pairing originally present in the donor, thereby generating a repertoire of sequence pairs where each pair encodes a variable heavy chain (V_H) and a variable light chain (V_L) corresponding to a V_H and V_L pair originally present in an antibody produced by the donor from which the sequences are isolated. This is also termed a cognate pair of V_H and V_L encoding sequences and the antibody is termed a cognate antibody. Preferably, the V_H and V_L coding pairs of the present invention, combinatorial or cognate, are obtained from human donors, and therefore the sequences are completely human.

[0084] There are several different approaches for the generation of cognate pairs of V_H and V_L encoding sequences, one approach involves the amplification and isolation of V_H and V_L encoding sequences from single cells sorted out from a lymphocyte-containing cell fraction. The V_H and V_L encoding sequences may be amplified separately and paired in a second step or they may be paired during the amplification (Coronella et al. 2000. Nucleic Acids Res. 28: E85; Babcook et al 1996. PNAS 93: 7843-7848 and WO 2005/042774). A second approach involves in-cell amplification and pairing of the V_H and V_L encoding sequences (Embleton et al. 1992. Nucleic Acids Res. 20: 3831-3837; Chapal et al. 1997. BioTechniques 23: 518-524). A third approach is selected lymphocyte antibody method (SLAM) which combines a hemolytic plaque assay with cloning of V_H and V_L cDNA (Babcook et al. 1996. PNAS 93:7843-7848). In order to obtain a repertoire of V_H and V_L encoding sequence pairs which resemble the diversity of V_H and V_L sequence pairs in the donor, a high-throughput method with as little scrambling (random combination) of the V_H and V_L pairs as possible, is preferred, e.g. as described in WO 2005/042774 (hereby incorporated by reference).

[0085] In a preferred embodiment of the present invention a repertoire of V_H and V_L coding pairs, where the member pairs mirror the gene pairs responsible for the humoral immune response resulting from a RSV infection, is generated according to a method comprising the steps i) providing a lymphocyte-containing cell fraction from a donor infected with RSV or recovering from a RSV infection; ii) optionally enriching B cells or plasma cells from said cell fraction; iii) obtaining a population of isolated single cells, comprising distributing cells from said cell fraction individually into a plurality of vessels; iv) amplifying and effecting linkage of the V_H and V_L coding pairs, in a multiplex overlap extension RT-PCR procedure, using a template derived from said isolated single cells and v) optionally performing a nested PCR of the linked V_H and V_L coding pairs. Preferably, the isolated cognate V_H and V_L coding pairs are subjected to a screening procedure as described below.

[0086] Once the V_H and V_L sequence pairs have been generated, a screening procedure to identify sequences encoding V_H and V_L pairs with binding reactivity towards an RSV associated antigen is performed. Preferably, the RSV associated antigen is a RSV envelope protein, in particular RSV G protein, RSV F protein and RSV SH protein. If the V_H and V_L sequence pairs are combinatorial a phage display procedure can be applied to enrich for V_H and V_L pairs coding for antibody fragments binding to RSV prior to screening.

[0087] In order to mirror the diversity, affinity and specificity of the antibodies produced in a humoral immune response upon infection with RSV, the present invention has developed a screening procedure for the cognate pairs, in order to obtain the broadest diversity possible. For screening purposes the repertoire of cognate V_H and V_L coding pairs are expressed individually either as antibody fragments (e.g. scFv or Fab) or as full-length antibodies using either a bacterial or mammalian screening vector transfected into a suitable host cell. The repertoire of Fabs/antibodies is screened for reactivity to virus particles of one or more RSV strains. Preferably, at least two strains, one of subtype A and one of subtype B are used. Subtype A strains are for example Long (ATCC VR-26), A2 (ATCC VR-1540) or more recent Long-like subtype A isolates. Subtype B strains are for example 18537 (ATCC VR-1580), B1 (ATCC VR-1400), 9320 (ATCC VR-955) or more recent 18537-like isolates. In parallel, the repertoire of Fabs/antibodies is screened against selected antigens such as recombinant G protein, recombinant F protein and peptides derived from RSV antigens. The antigenic peptides can for example be selected from the conserved region of the G protein (amino acids 164-176) and the cysteine core region (amino acids 171-187 of subtype A as well as subtype B strains) of the G protein and, the extracellular region of the SH-protein (amino acids 42-64 of subtype A and 42-65 of subtype B). Preferably the peptides are biotinylated to facilitate immobilization onto beads or plates during screening. Alternative immobilization means may be used as well. The antigens are selected based on the knowledge of the RSV biology and the expected neutralizing and/or protective effect antibodies capable of binding to these antigens potentially can provide. This screening procedure can likewise be applied to a combinatorial phage display library. The recombinant G and/or F proteins used for screening can be expressed in bacteria, insect cells, mammalian cells or another suitable expression system. The G and/or F protein may either be expressed as a soluble protein (without the transmembrane region) or they may be fused to a third protein, to increase stability. If the G and/or F protein is expressed with a fusion tag, the fusion partner may be cleaved off prior to screening. Preferably, G and/or F proteins representative of both the subtype A and subtype B are expressed and used for screening. Additionally, strain-specific G proteins may be expressed and used for screening. In addition to the primary screening described above, a secondary screening may be performed, in order to ensure that none of the selected sequences encode false positives. In the second screening all the RSV/antigen binding V_H and V_L pairs identified in the first screening are screened again against both the virus strains and the selected antigens. Generally, immunological assays are suitable for the screening performed in the present invention. Such assays are well know in the art and constitute for example ELISPOTS, ELISA, FLISA, membrane assays (e.g. Western blots), arrays on filters, and FACS. The assays can either be performed without any prior enrichment steps, utilizing polypeptides produced from the sequences encoding the V_H and V_L pairs. In the event that the repertoire of V_H and V_L coding pairs are cognate pairs, no enrichment by e.g. phage display is needed prior to the screening. However, in the screening of combinatorial libraries, the immunoassays are preferably performed in combination with or following enrichment methods such as phage display, ribosome display, bacterial surface display, yeast display, eukaryotic virus display, RNA display or covalent display (reviewed in FitzGerald, K., 2000. Drug Discov. Today 5, 253-258).

[0088] The V_H and V_L pair encoding sequences selected in the screening are generally subjected to sequencing, and analyzed with respect to diversity of the variable regions. In particular the diversity in the CDR regions is of interest, but also the V_H and V_L family representation is of interest. Based on these analyses, sequences encoding V_H and V_L pairs representing the overall diversity of the RSV binding antibodies isolated from one or more donors are selected. Preferably, sequences with differences in all the CDR regions (CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2 and CDRL3) are selected. If there are sequences with one or more identical or very similar CDR regions which belong to different V_H or V_L families, these are also selected. Preferably, at least the CDR3 region of the variable heavy chain (CDRH3) differs among the selected sequence pairs. Potentially, the selection of V_H and V_L sequence pairs can be based solemnly on the variability of the CDRH3 region. During the priming and amplification of the sequences, mutations may occur in the framework regions of the variable region, in particular in the first framework region. Preferably, the errors occurring in the first framework region are corrected in order to ensure that the sequences correspond completely or at least 98% to those of the donor, e.g. such that the sequences are fully human.

[0089] When it is ensured that the overall diversity of the collection of selected sequences encoding V_H and V_L pairs is highly representative of the diversity seen at the genetic level in a humoral response to a RSV infection, it is expected that the overall specificity of antibodies expressed from a collection of selected V_H and V_L coding pairs also are representative with respect to the specificity of the antibodies produced in the RSV infected donors. An indication of whether the specificity of the antibodies expressed from a collection of selected V_H and V_L coding pairs are representative of the specificity of the antibodies raised by infected donors can be obtained by comparing the antibody titers towards the virus strains as well as the selected antigens of the donor blood with the specificity of the antibodies expressed from a collection of selected V_H and V_L coding pairs. Additionally, the specificity of the antibodies expressed from a collection of selected V_H and V_L coding pairs can be analyzed further. The degree of specificity correlates with the number of different antigens towards which binding reactivity can be detected. In a further embodiment of the present invention the specificity of the individual antibodies expressed from a collection of selected V_H and V_L coding pairs is analyzed by epitope mapping.

[0090] Epitope mapping may be performed by a number of methodologies, which do not necessarily exclude each other. One way to map the epitope-specificity of an antibody clone is to assess the binding to peptides of varying lengths derived from the primary structure of the target antigen. Such peptides may be both linear and conformational and may be used in a number of assay formats, including ELISA, FLISA and surface plasmon resonance (SPR, Biacore). Furthermore, the peptides may be rationally selected using available sequence and structure data to represent e.g. extracellular regions or conserved regions of the target antigen, or the may be designed as a panel of overlapping peptides representing a selected part or all of the antigen (Meloen R H, Puijk W C, Schaaper W M M. Epitope mapping by PEPSCAN. In: Immunology Methods Manual. Ed Iwan Lefkovits 1997, Academic Press, pp 982-988). Specific reactivity of an antibody clone with one or more such peptides will generally be an indication of the epitope specificity. However, peptides are in many cases poor mimics of the epitopes recognized by antibodies raised against proteinaceous antigens, both due to a lack of conformation and due to the generally larger buried surface area of interaction between an antibody and a protein antigen as compared to an antibody and a peptide. A second method for epitope mapping, which allows for the definition of specificities directly on the protein antigen, is by selective epitope masking using existing, well defined antibodies. Reduced binding of a second, probing antibody to the antigen following blocking is generally indicative of shared or overlapping epitopes. Epitope mapping by selective masking may be performed by a number of immunoassays, including, but not restricted to, ELISA and Biacore, which are well known in the art (e.g. Ditzel et al. 1997. J. Mol. Biol. 267:684-695; Aldaz-Carroll et al. 2005. J. Virol. 79: 6260-6271). Yet another potential method for the determination of the epitope specificity of anti-virus antibodies is the selection of viral escape mutants in the presence of antibody. Sequencing of the gene(s) of interest from such escape mutants will generally reveal which amino acids in the antigen(s) that are important for the recognition by the antibody and thus constitute (part of) the epitope.

[0091] Preferably, individual members to be comprised in an anti-RSV rpAb of the present invention are selected such that the specificity of the antibody composition collectively covers both RSV subtype A and B, as well as the RSV associated antigens protein F and G, and preferably also SH.

Production of a Recombinant Polyclonal Antibody from Selected V_H and V_L Coding Pairs

[0092] A polyclonal antibody of the present invention is produced from a polyclonal expression cell line in one or a few bioreactors or equivalents thereof. Following this approach the anti-RSV rpAb can be purified from the reactor as a single preparation without having to separate the individual members constituting the anti-RSV rpAb during the process. If the polyclonal antibody is produced in more than one bioreactor, the supernatants from each bioreactor can be pooled prior to the purification, or the purified anti-RSV rpAb can be obtained by pooling the antibodies obtained from individually purified supernatants from each bioreactor.

[0093] One way of producing a recombinant polyclonal antibody is described in WO 2004/061104 and WO 2006/007850 (PCT/DK2005/000501) (these references are hereby incorporated by reference). The method described therein, is based on site-specific integration of the antibody coding sequence into the genome of the individual host cells, ensuring that the V_H and V_L protein chains are maintained in their original pairing during production. Furthermore, the site-specific integration minimizes position effects and therefore the growth and expression properties of the individual cells in the polyclonal cell line are expected to be very similar. Generally, the method involves the following: i) a host cell with one or more recombinase recognition sites; ii) an expression vector with at least one recombinase recognition site compatible with that of the host cell; iii) generation of a collection of expression vectors by transferring the selected V_H and V_L coding pairs from the screening vector to an expression vector such that a full-length antibody or antibody fragment can be expressed from the vector (such a transfer may not be necessary if the screening vector is identical to the expression vector); iv) transfection of the host cell with the collection of expression vectors and a vector coding for a recombinase capable of combining the recombinase recognition sites in the genome of the host cell with that in the vector; v) obtaining/generating a polyclonal cell line from the transfected host cell and expressing and collecting the polyclonal antibody from the polyclonal cell line.

[0094] Preferably mammalian cells such as CHO cells, COS cells, BHK cells, myeloma cells (e.g., Sp2/0 or NS0 cells), fibroblasts such as NIH 3T3, and immortalized human cells, such as HeLa cells, HEK 293 cells, or PER.C6, are used. However, non-mammalian eukaryotic or prokaryotic cells, such as plant cells, insect cells, yeast cells, fungi, E. coli etc., can also be employed. A suitable host cell comprises one or more suitable recombinase recognition sites in its genome. The host cell should also contain a mode of selection which is operably linked to the integration site, in order to be able to select for integrants, (i.e., cells having an integrated copy of an anti-RSV Ab expression vector or expression vector fragment in the integration site). The preparation of cells having an FRT site at a pre-determined location in the genome was described in e.g. U.S. Pat. No. 5,677,177. Preferably, a host cell only has a single integration site, which is located at a site allowing for high expression of the integrant (a so-called hot-spot).

[0095] A suitable expression vector comprises a recombination recognition site matching the recombinase recognition site(s) of the host cell. Preferably the recombinase recognition site is linked to a suitable selection gene different from the selection gene used for construction of the host cell. Selection genes are well known in the art, and include glutamine synthetase gene (GS), dihydrofolate reductase gene (DHFR), and neomycin, where GS or DHFR may be used for gene amplification of the inserted V_H and V_L sequence. The vector may also contain two different recombinase recognition sites to allow for recombinase-mediated cassette exchange (RMCE) of the antibody coding sequence instead of complete integration of the vector. RMCE is described in Langer et al 2002. Nucleic Acids Res. 30, 3067-3077; Schlake and Bode 1994. Biochemistry 33, 12746-12751 and Belteki et al 2003. Nat. biotech. 21, 321-324. Suitable recombinase recognition sites are well known in the art, and include FRT, 10× and attP/attB sites. Preferably the integrating vector is an isotype-encoding vector, where the constant regions (preferably including introns) are present in the vector prior to transfer of the V_H and V_L coding pair from the screening vector (or the constant regions are already present in the screening vector if screening is performed on full-length antibodies). The constant regions present in the vector can either be the entire heavy chain constant region (CH₁ to CH₃ or to CH₄) or the constant region encoding the Fc part of the antibody (CH₂ to CH₃ or to CH₄). The light chain Kappa or Lambda constant region may also be present prior to transfer. The choice of the number of constant regions present, if any, depends on the screening and transfer system used. The heavy chain constant regions can be selected from the isotypes IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD and IgE. Preferred isotypes are IgG1 and/or IgG3. Further, the expression vector for site-specific integration of the anti-RSV antibody-encoding nucleic acid contains suitable promoters or equivalent sequences directing high levels of expression of each of the V_H and V_L chains. FIG. 3 illustrates one possible way to design the expression vector, although numerous other designs are possible.

[0096] The transfer of the selected V_H and V_L coding pairs from the screening vector can be performed by conventional restriction enzyme cleavage and ligation, such that each expression vector molecule contain one V_H and V_L coding pair. Preferably, the V_H and V_L coding pairs are transferred individually, they may, however, also be transferred in-mass if desired. When all the selected V_H and V_L coding pairs are transferred to the expression vector a collection or a library of expression vectors is obtained. Alternative ways of transfer may also be used if desired. If the screening vector is identical to the expression vector, the library of expression vectors is constituted of the V_H and V_L sequence pairs selected during screening, which are situated in the screening/expression vector.

[0097] Methods for transfecting a nucleic acid sequence into a host cell are known in the art. To ensure site-specific integration, a suitable recombinase must be provided to the host cell as well. This is preferably accomplished by co-transfection of a plasmid encoding the recombinase. Suitable recombinases are for example Flp, Cre or phage ΦC31 integrase, used together with a host cell/vector system with the corresponding recombinase recognition sites. The host cell can either be transfected in bulk, meaning that the library of expression vectors is transfected into the cell line in one single reaction thereby obtaining a polyclonal cell line. Alternatively, the collection of expression vectors can be transfected individually into the host cell, thereby generating a collection of individual cell lines (each cell line produce an antibody with a particular specificity). The cell lines generated upon transfection (individual or polyclonal) are then selected for site specific integrants, and adapted to grow in suspension and serum free media, if they did not already have these properties prior to transfection. If the transfection was performed individually, the individual cell lines are analyzed further with respect to their grow properties and antibody production. Preferably, cell lines with similar proliferation rates and antibody expression levels are selected for the generation of the polyclonal cell line. The polyclonal cell line is then generated by mixing the individual cell lines in a predefined ratio. Generally, a polyclonal master cell bank (pMCB), a polyclonal research cell bank (pRCB) and/or a polyclonal working cell bank (pWCB) is laid down from the polyclonal cell line. The polyclonal cell line is generated by mixing the individual cell lines in a predefined ratio. The polyclonal cell line is distributed into ampoules thereby generating a polyclonal research cell bank (pRCB) or master cell bank (pMCB) from which a polyclonal working cell bank (pWCB) can be generated by expanding cells from the research or master cell bank. The research cell bank is primarily for proof of concept studies, in which the polyclonal cell line may not comprise as many individual antibodies as the polyclonal cell line in the master cell bank. Normally, the pMCB is expanded further to lay down a pWCB for production purposes. Once the pWCB is exhausted a new ampoule from the pMCB can be expanded to lay down a new pWCB.

[0098] One embodiment of the present invention is a polyclonal cell line capable of expressing a recombinant polyclonal anti-RSV antibody of the present invention.

[0099] A further embodiment of the present invention is a polyclonal cell line wherein each individual cell is capable of expressing a single V_H and V_L coding pair, and the polyclonal cell line as a whole is capable of expressing a collection of V_H and V_L encoding pairs, where each V_H and V_L pair encodes an anti-RSV antibody. Preferably the collection of V_H and V_L coding pairs are cognate pairs generated according to the methods of the present invention.

[0100] A recombinant polyclonal antibody of the present invention is expressed by culturing one ampoule from a pWCB in an appropriate medium for a period of time allowing for sufficient expression of antibody and where the polyclonal cell line remains stable (The window is approximately between 15 days and 50 days). Culturing methods such as fed batch or perfusion may be used. The recombinant polyclonal antibody is obtained from the culture medium and purified by conventional purification techniques. Affinity chromatography combined with subsequent purification steps such as ion-exchange chromatography, hydrophobic interactions and gel filtration has frequently been used for the purification of IgG. Following purification, the presence of all the individual members in the polyclonal antibody composition is assessed, for example by ion-exchange chromatography. The characterization of a polyclonal antibody composition is described in detail in WO 2006/007853 (PCT/DK2005/000504) (hereby incorporated by reference).

[0101] An alternatively method of expressing a mixture of antibodies in a recombinant host is described in WO 2004/009618. This method produces antibodies with different heavy chains associated with the same light chain from a single cell line. This approach may be applicable if the anti-RSV rpAb is produced from a combinatorial library.

Therapeutic Compositions

[0102] Another aspect of the invention is a pharmaceutical composition comprising as an active ingredient an anti-RSV rpAb or anti-RSV recombinant polyclonal Fab or another anti-RSV recombinant polyclonal antibody fragment. Preferably, the active ingredient of such a composition is an anti-RSV recombinant polyclonal antibody as described in the present invention. Such compositions are intended for prevention and/or treatment of RSV infections. Preferably, the pharmaceutical composition is administered to a human, a domestic animal, or a pet.

[0103] The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0104] Anti-RSV rpAb or polyclonal fragments thereof may be administered within a pharmaceutically-acceptable diluent, carrier, or excipient, in unit dosage form. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer to patients infected with RSV, or to patients who may be at high risk if infected with RSV. In a preferred embodiment the administration is prophylactic. In another preferred embodiment the administration is therapeutic, meaning that it is administered after the onset of symptoms relating to RSV infection. Any appropriate route of administration may be employed, for example, administration may be parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intraperitoneal, intranasal, aerosol, suppository, or oral administration. For example, pharmaceutical formulations may be in the form of, liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets, capsules, chewing gum or pasta, and for intranasal formulations, in the form of powders, nasal drops, or aerosols.

[0105] The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example, by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see for example, in Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins, Philadelphia, Pa. and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, N.Y.).

[0106] Preferably solutions or suspensions of the active ingredient, and especially isotonic aqueous solutions or suspensions, are used to prepare pharmaceutical compositions of the present invention. In the case of lyophilized compositions that comprise the active ingredient alone or together with a carrier, for example mannitol, such solutions or suspensions may, if possible, be produced prior to use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

[0107] The injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing of the containers.

[0108] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating the resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, pills, or capsules, which may be coated with shellac, sugar or both. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.

[0109] The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, tablets, pills, or capsules. The formulations can be administered to human individuals in therapeutically or prophylactically effective amounts (e.g., amounts which prevent, eliminate, or reduce a pathological condition) to provide therapy for a disease or condition. The preferred dosage of therapeutic agent to be administered is likely to depend on such variables as the severity of the RSV infection, the overall health status of the particular patient, the formulation of the compound excipients, and its route of administration.

Therapeutic Uses of the Compositions According to the Invention

[0110] The pharmaceutical compositions according to the present invention may be used for the treatment, amelioration or prophylaxis of a disease in a mammal. Conditions that can be treated or prevented with the present pharmaceutical compositions include prevention, and treatment of patients infected with RSV, or at risk of becoming infected with RSV, in particular patients who may be at high risk if infected with RSV. High-risk patients are for example infants and small children. In particular premature infants and children with an underlying problem such as chronic lung disease or congenital heart disease are at the greatest risk for serious illness such as bronchiolitis and pneumonia following RSV infection. Also high-risk adults, such as immunocompromised adults, particularly bone marrow transplant recipients, elderly individuals and individuals with chronic pulmonary disease, can preferably be subjected to prophylactic or therapeutic treatment with a pharmaceutical composition according to the present invention.

[0111] One embodiment of the present invention is a method of preventing, treating or ameliorating one or more symptoms associated with a RSV infection in a mammal, comprising administering an effective amount of an anti-RSV recombinant polyclonal antibody of the present invention to said mammal.

[0112] A further embodiment of the present invention is the use of an anti-RSV recombinant polyclonal antibody of the present invention for the preparation of a composition for the treatment, amelioration or prevention of one or more symptoms associated with a RSV infection in a mammal.

[0113] The effective amount may be at most 100 mg of the antibody per kg of body weight, such as at most 90, at most 80, at most 70, at most 60, at most 50, at most 40, at most 30, at most 20, at most 10, at most 9, at most 8, at most 7, at most 6, at most 5, at most 4, at most 3, at most 2, at most 1, at most 0.9, at most 0.8, at most 0.7, at most 0.6, at most 0.5, at most 0.4, at most 0.3, at most 0.2 and at most 0.1 mg per kg of body weight.

[0114] In other embodiments the effective amount is at least 0.01 mg of the antibody per kg of body weight, such as at least 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8.

[0115] Preferably the effective amount is between 0.1-50 mg antibody per kg of body weight. More preferably the effective amount is between 1 and 20 mg antibody per kg of body weight.

[0116] The antibody may be administered at least 1 time per year, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 times per year.

[0117] In particular, the antibody may be administered at regular intervals during the period of the year where there is an increased risk of attracting an RSV infection. The regular intervals may be weekly, bi-weekly, monthly, or bi-monthly.

[0118] Preferably, the mammal in the embodiments above is a human, domestic animal or a pet.

[0119] In a further embodiment the mammal, subject to the method of preventing treating or ameliorating one or more symptoms associated with a RSV infection, preferably has a body weight above 40 kg.

[0120] In embodiments where the subject is a human, it is preferably a premature infant, a child with chronic lung disease or congenital heart disease. In alternative embodiments the human is an immunocompromised adult, in particularly a bone marrow transplant recipient, an elderly individual or an individual with chronic pulmonary disease.

Diagnostic Use

[0121] Another embodiment of the invention is directed to diagnostic kits. Kits according to the present invention comprise an anti-RSV rpAb prepared according to the invention which protein may be labeled with a detectable label or non-labeled for non-label detection. The kit may be used to identify individuals infected with RSV.

[0122] An antibody-based diagnostic kit generally comprises the following: a) a capture antibody, b) a detector antibody, c) a positive control, and d) a negative control. Depending on the detection method, a single reagent may be used both as capture and detector antibody. A method based on surface plasmon resonance (SPR) is one example were a single antibody will suffice both for capture and specific detection of the antigen of interest. The anti-RSV rpAb of the invention may be used both as capture antibody and as detector antibody. As capture antibody, the non-labeled anti-RSV rpAb is adsorbed onto a solid support, e.g. the surface of the wells of an ELISA plate or microbeads, for subsequent capture of RSV particles or antigens in patient samples. Captured antigen is then detected using a different antibody (detector), which is either directly labeled or detected using a secondary conjugated antibody or reagent of sufficient specificity. As detector antibody, the anti-RSV rpAb of the invention may be used labeled or non-labeled and the amount of bound antibody detected directly (labeled rpAb) or using a secondary antibody or reagent (unlabeled rpAb).

[0123] The read-out of the diagnostic kit may e.g. be based on detection of fluorescence from an attached fluorogenic label or absorbance of an added chromogenic substrate catalyzed by an enzyme conjugated to the detector antibody or the secondary antibody (enzyme immunoassay). In a method based on SPR, the amount of bound antigen is detected in real-time by the changes in the local index of refraction as it binds to the adsorbed capture antibody. Independent of the read-out, by comparing the intensity of the signal to a standard curve generated using the positive control, the quantity of antigen present in the sample may be determined.

Antibody Molecules of the Present Invention and Aspects Related Thereto

[0124] It should be noted that the novel antibody molecules disclosed herein are believed to contribute to the state of the art in their own right. Hence, the present invention also relates to any one of the antibody molecules disclosed herein as well as to fragments and analogues of these antibodies, where said fragments or analogues at least incorporate the CDRs of the antibodies disclosed herein.

[0125] For instance it has been found by the present inventors that some of the fully human antibody molecules which have been isolated from human donors include binding sites that exhibit extremely high improved kinetic profiles over known prior art monoclonal antibodies when it comes to antigen binding. Thus, even though much focus is put on polyclonal antibody compositions in the present disclosure, all subject matter relating to utilization of polyclonal antibodies set forth herein is also relevant for any one of the single antibody molecules disclosed herein--i.e. all disclosures relating to formulation, dosage, administration etc. which relate to polyclonal antibody compositions of the present invention apply mutatis mutandis to the individual antibody molecules, antibody fragments and antibody analogues disclosed herein, preferably also the framework sequences.

[0126] Hence, the present invention also relates to an isolated human anti RSV-antibody molecule selected from the antibody molecules set forth in Table 6 herein, or a specifically binding fragment of said antibody molecule or a synthetic or semi-synthetic antibody analogue, said binding fragment or analogue comprising at least the complementarity-determining regions (CDRs) of said isolated antibody molecule. Often, framework regions from the variable regions of the native human antibody will be included too in the fragments or analogues, since the antigen specificity of antibodies are known to be dependent on the 3D organisation of CDRs and framework regions.

[0127] The expression "isolated antibody molecule" is intended to denote a collection of distinct antibodies which are isolated from natural contaminants, and which exhibit the same amino acid sequence (i.e. identical variable and constant regions).

[0128] Typically, the antibody molecule, fragment or analogue is derived from the antibodies listed in Table 6, or includes the heavy chain CDR amino acid sequences included in one of SEQ ID Nos: 1-44 and in the accompanying light chain CDR amino acid sequences having a SEQ ID NO which is 88 higher than the amino acid sequence selected from SEQ ID NOs. 144. This means that the antibody molecule, fragment or analogue will include the cognate pairs of variable regions found in the same out of the 44 clones discussed above.

[0129] As mentioned above, a number of the present antibody molecules exhibit very high affinities, so the invention also pertains to an isolated antibody molecule, an antibody fragment or a synthetic or semi-synthetic antibody analogue, which comprises CDRs identical to the CDRs in an Fab derived from a human antibody, said Fab having a dissociation constant, K_D, for the RSV G protein of at most 500 nM when measured performing surface plasmon resonance analysis on a Biacore 3000, using recombinant RSV G protein immobilized onto the sensor surface at very low density to avoid limitations in mass transport. The isolated antibody molecule, antibody fragment or synthetic or semi-synthetic antibody typically exhibit a lower K_D of at most, 400 nM, such as at most 300 nM, at most 200 nM, at most 100 nM, at most 1 nM, at most 900 pM, at most 800 pM, at most 700, pM, at most 600 pM, at most 500 pM, at most 400 pM, at most 300 pM, at most 200 pM, at most 100 pM, at most 90 pM, and at most 80 pM. Details concerning the Biocore measurements are provided in the examples.

[0130] Another embodiment of the invention relates to an isolated antibody molecule, an antibody fragment or a synthetic or semi-synthetic antibody, which comprises an antigen binding site identical to the antigen binding site in an Fab derived from a human antibody, said Fab having a dissociation constant, K_D, for the RSV F protein of at most 500 nM when measured performing surface plasmon resonance analysis on a Biacore 3000, using recombinant RSV F protein immobilized onto the sensor surface at very low density to avoid limitations in mass transport. This isolated antibody, antibody fragment or synthetic or semi-synthetic antibody typically exhibits a KD of at most, 400 nM, such as at most 300 nM, at most 200 nM, at most 100 nM, at most 1 nM, at most 900 pM, at most 800 pM, at most 700, pM, at most 600 pM, at most 500 pM, at most 400 pM, at most 300 pM, at most 200 pM, at most 100 pM, at most 90 pM, at most 80 pM, at most 70 pM, at most 60 pM, at most 50 pM, at most 40 pM, at most 30 pM, at most 25 pM at most 20 pM, at most 15 pM, at most 10 pM, at most 9 pM, at most 8 pM, at most 7 pM, at most 6 pM, and at most 5 pM.

[0131] A specially useful antibody molecule or specifically binding fragment or synthetic or semi-synthetic antibody analogue comprises the CDRs of a human antibody produced in clone No. 810, 818, 819, 824, 825, 827, 858 or 894.

[0132] As mentioned above, these useful antibody molecules of the present invention may be formulated in the same way and for the same applications as the polyclonal formulations of the present invention. Hence, the present invention relates to an antibody composition comprising an antibody molecule, specifically binding fragment or synthetic or semi-synthetic antibody analogue discussed in this section in admixture with a pharmaceutically acceptable carrier, excipient, vehicle or diluent. The composition may comprise more than one binding specificity, and may e.g. include 2 distinct antibody molecules of the invention and/or specifically binding fragments and/or synthetic or semi-synthetic antibody analogues of the invention. The composition may even comprise at least 3 distinct antibody molecules and/or antibody fragments and/or synthetic or semisynthetic antibody analogues, specifically binding fragments or synthetic or semi-synthetic antibody analogues of the invention, and may therefore constitute a composition comprising at 4, 5, 6, 7, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 distinct antibody molecules and/or fragments and/or synthetic or semi-synthetic antibody analogues.

[0133] Especially interesting compositions include at least one antibody molecule, fragment or analogue of the invention which binds the RSV F protein and at least one antibody, fragment or analogue of the invention which binds the RSV G protein.

[0134] Also a part of the present invention is an isolated nucleic acid fragment which encodes the amino acid sequence of at least one CDR defined of an antibody molecule of the present invention, such as a nucleic acid fragment, which at least encodes the CDRs of an antibody produced by one of the clones listed in table 6. The nucleic acid fragment is typically DNA, but can also be RNA.

[0135] Another embodiment is an isolated nucleic acid fragment, which encodes the CDR sequences of a heavy chain amino acid sequence set forth in any one of SEQ ID NOs 1-44, or an isolated nucleic acid fragment, which encodes the CDR sequences of a light chain amino acid sequence set forth in any one of SEQ ID NOs 89-132. Preferred nucleic acid fragments of the invention encode the CDR sequences of a heavy chain amino acid sequence set forth in any one of SEQ ID NOs 1-44 and set forth in the accompanying light chain CDR amino acid sequences having a SEQ ID NO which is 88 higher than the amino acid sequence selected from SEQ ID NOs. 144. This of course means that the nucleic acid fragment will encode the cognate pairs of variable regions found in the same out of the 44 clones discussed above. The nucleic acid fragment may therefor include coding sequences comprised in SEQ ID NOs: 45-88 and/or 133-176.

[0136] Conveniently the nucleic acid fragments are introduced in a vector, which is also part of the present invention. Such a vector may be capable of autonomous replication, and is typically selected from the group consisting of a plasmid, a phage, a cosmid, a mini-chromosome, and a virus.

[0137] In the event the vector of the invention is an expression vector, it will preferably have the following outline (cf. also an exemplary vector in FIG. 3): (a) in the 5'→3' direction and in operable linkage at least one promoter for driving expression of a first nucleic acid fragment discussed above, which encodes at least one light chain CDR together with any necessary framework regions, optionally a nucleic acid sequence encoding a leader peptide, said first nucleic acid fragment, optionally a nucleic acid sequence encoding constant regions of an antibody, and optionally a nucleic acid sequence encoding a first terminator, and/or (b) in the 5'→3' direction and in operable linkage at least one promoter for driving expression of a second nucleic acid fragment of the invention, which encodes at least one heavy chain CDR together with any necessary framework regions, optionally a nucleic acid sequence encoding a leader peptide, said second nucleic acid fragment, optionally a nucleic acid sequence encoding constant regions, and optionally a nucleic acid sequence encoding a second terminator.

[0138] Such a vector is especially useful if it can be used to stably transform a host cell, which can subsequently be cultured in order to obtain the recombinant expression product. So, the preferred vector is one, which, when introduced into a host cell, is integrated in the host cell genome.

[0139] Hence, the invention also pertains to a transformed cell carrying the vector of the invention discussed in this section and also to a stable cell line which carries this vector and which expresses the nucleic acid fragment of the invention discussed in this section. Both the transformed cell and the cell line optionally secretes or carries its recombinant expression product (i.e. the inventive antibody molecule, antibody fragment or analogue) on its surface.

mAb 824 and Analogues

[0140] The present section relates to the monoclonal antibody 824 (mAb 824) and its analogues. The light chain of antibody 824 has the amino acid sequence set forth in SEQ ID NO 107. The variable region of the heavy chain has the amino acid sequence set forth in SEQ ID NO 19.

[0141] The invention relates to antibodies capable of competing in binding with antibody 824 as defined herein or with its Fab fragment. The antibody encoded by clone 824 as defined herein does not bind recombinant RSV antigen with particularly high affinity or potency. On the other hand, in virus neutralization assays (see Table 8) antibody 824 has a particularly low EC50 value against several different RSV isolates. When tested in an in vivo model of RSV infection (mouse challenge model, Example 1, k-1), mAb824 showed a significantly higher reduction in virus load than Synagis (Table 11b).

[0142] By providing antibody 824 the inventors have identified an epitope, which results in more efficient in vitro and in vivo neutralization than seen before for any single RSV epitope. By providing antibody 824, the inventors have also enabled the identification of further antibodies which bind to the same epitope. These further antibodies may be of any origin and includes binding fragments as well as affinity matured antibodies. Antibodies capable of competing with antibody 824 may be identified in a cellular competition assay (determination of relative epitope specificities) as described in Example 1, section g-4.

[0143] A preferred antibody being capable of competing with antibody 824 is an anti-RSV antibody comprising a CDRH3 having the following formula:

CAX₁X₂X₃X₄X₅X₆PX₇X₈X₉X₁₀X₁₁W

where X₁ to X₁₁ are selected individually from the groups of amino acids listed below X₁═R or K (i.e. positively charged at physiological pH); X₂=D, E, N or Q (i.e. fairly bulky, polar amino acids); X₃═S, T, G or A (i.e. small, preferably polar amino acids); X₄═S, T, G or A (i.e. small, preferably polar amino acids); X₅═N, Q, D or E (i.e. fairly bulky, polar amino acids); X₆═W, Y, F or H (i.e. bulky, aromatic amino acids); X₇=A, G, V, or S (i.e. small amino acids); X₈=G, A, V, or S (i.e. small amino acids); X₉═Y, F, W or H (i.e. bulky, aromatic amino acids); X₁₀=E or D (i.e. negatively charged at physiological pH); and X₁₁=D, E, N or Q (i.e. fairly bulky, polar amino acids); and a CDRL3 described by the following formula: CX₁X₂X₃X₄X₅X₆PX₇TF where X₁ to X₁₁ are selected individually from the groups of amino acids listed below: X₁=Q or H (i.e. bulky, polar amino acids); X₂=Q, E or H (i.e. bulky, polar amino acids); X₃═F, Y, W or H (i.e. bulky, aromatic amino acids); X₄═N, Q or H (i.e. fairly bulky, polar amino acids); X₅=T, S, G or A (i.e. small, preferably polar amino acids); X₆═Y, F, W or H (i.e. bulky, aromatic amino acids); and X₇═F, Y, W or H (i.e. bulky, aromatic amino acids).

[0144] The binding specificity of antibodies is determined primarily by the CDR3 region of the heavy and light chain. As is known in the art certain substitutions can be made in an amino acid sequence without altering the 3-D structure of the protein. It is thus expected that mutations as outlined above can be made to the CDR3 sequences of antibody 824 as defined herein while conserving the binding specificity and the potency of antibody 824.

[0145] The introduction of amino acid changes in a protein is known in the art. Antibodies with altered CDR3s compared to antibody 824 can be made and they can be tested in the virus neutralization assays as described in the examples. Conservation of the binding specificity can be verified in a competition assay with antibody 824.

[0146] Preferably, the anti-RSV antibody comprises the CDR1, and CDR2 regions from the VH and VL pair of antibody 824 as set forth in SEQ ID NOs: 232, 317, 487, and 572, and a CDRH3 region having the formula CAR₁D₂S₃S₄N₅W₆PA₇G₈Y₉E₁- 0D₁₁W (SEQ ID NO 402), and a CDRL3 region having the formula CQ1Q2F3N4T₅Y6 PF₇TF (SEQ ID NO 657).

[0147] In preferred embodiments the CDRH3 has the amino acid sequence set forth in SEQ ID NO: 402 and/or the CDRL3 has the amino acid sequence set forth in SEQ ID NO: 657.

[0148] In one embodiment the antibody comprises the VH region (SEQ ID NO: 19) of antibody 824. The monoclonal antibody may also comprise the VL region (amino acids 1 to 107 of SEQ ID NO: 107) of antibody 824.

[0149] Preferably, the antibody comprises the light chain (SEQ ID NO: 107) of antibody 824.

[0150] The antibody may comprise the CH as defined in SEQ ID NO: 178. Other constant regions for the heavy chain may be used.

[0151] Preferably, the monoclonal antibody is capable of neutralizing subtypes A and B of RSV in a virus neutralization assay. The neutralization potency of the monoclonal antibody is preferably comparable to the potency of mAb824.

[0152] Preferably, the antibody is capable of providing a significant reduction of RSV virus load in the lungs of a mammal infected with RSV. Preferably this reduction is significant compared to the reduction provided by Synagis, and more preferably the reduction is comparable to the reduction provided by mAb824.

[0153] Antibody mAb824 and antibodies based on the CDR sequences of mAb824 may be combined with and one or more additional anti-RSV antibodies to provide a polyclonal antibody. Such polyclonal antibody or antibody mixture(s) may be less susceptible to escape mutants.

[0154] The one or more additional anti-RSV antibodies may be selected from the group consisting of human antibodies, humanized antibodies, and chimeric human-mouse antibodies. For example the additional antibody may be palivizumab (Synagis) or MEDI-524 (Numax).

[0155] Preferably, the one or more additional anti-RSV antibodies is selected from the group consisting of the antibody molecules set forth in Table 6 herein, or a specifically binding fragment of said antibody molecule or a synthetic or semi-synthetic antibody analogue, said binding fragment or analogue comprising at least the complementarity-determining regions (CDRs) of said isolated antibody molecule, except an antibody having the CDRs of clone 824.

[0156] Also provided are isolated nucleic acids comprising a sequence encodes an amino acid sequence of at least one CDR defined in this section.

[0157] The isolated nucleic acid fragment may encode the CDR sequences of a heavy chain amino acid sequence set forth in SEQ ID NO: 19. The isolated nucleic acid fragment may encode the CDR sequences of the light chain amino acid sequence set forth in SEQ ID NO: 107.

[0158] Preferably the isolated nucleic acid fragment encodes the CDR sequences of the heavy chain amino acid sequence set forth in SEQ ID NO: 19 and in the accompanying light chain CDR amino acid sequences having SEQ ID NO: 107. In another preferred embodiment the nucleic acid fragment includes coding sequences comprised in SEQ ID NO: 63 and/or 151.

[0159] The isolated nucleic acids and fragments may be inserted in to a vector.

[0160] The vector may be capable of autonomous replication and could be selected from the group consisting of a plasmid, a phage, a cosmid, a mini-chromosome, and a virus.

[0161] In another embodiment the vector comprises,

(a) in the 5'→3' direction and in operable linkage at least one promoter for driving expression of a first nucleic acid fragment as described in this section, which encodes at least one light chain CDR derived from clone 824 together with necessary framework regions, optionally a nucleic acid sequence encoding a leader peptide, said first nucleic acid fragment, optionally a nucleic acid sequence encoding constant regions, and optionally a nucleic acid sequence encoding a first terminator, and/or (b) in the 5'→3' direction and in operable linkage at least one promoter for driving expression of a second nucleic acid fragment as described in this section, which encodes at least one heavy chain CDR derived from clone 824 together with necessary framework regions, optionally a nucleic acid sequence encoding a leader peptide, said second nucleic acid fragment, optionally a nucleic acid sequence encoding constant regions, and optionally a nucleic acid sequence encoding a second terminator.

[0162] The vector when introduced into a host cell, may be integrated in the host cell genome.

[0163] Also provided is as transformed cell carrying the vector as described in this section, and a stable cell line which carries the vector as described in this section and which expresses a nucleic acid fragment as described in this section, and which optionally secretes or carries its recombinant expression product on its surface.

Example 1

[0164] This example is a collection of the methods applied to illustrate the present invention.

a. Sorting of Lambda-Negative Plasma Blasts from Donor Blood

[0165] The peripheral blood mononuclear cells (PBMC) were isolated from blood drawn from donors using Lymphoprep (Axis Shield) and gradient centrifugation according to the manufacturer's instructions. The isolated PBMC were either cryopreserved in FCS; 10% DMSO at -150° C. or used directly. The B cell fraction was labeled with anti-CD19 antibody and isolated from the PBMC fraction using magnetic cell sorting (MACS). The PBMC (1×10⁶ cells) were incubated with anti-CD19-FITC conjugated antibody (BD Pharmingen) for 20 min at 4° C. Cells were washed twice in, and re-suspended in MACS buffer (Miltenyi Biotec). Anti-FITC MicroBeads (Miltenyi Biotec) were mixed with the labeled cells and incubated for 15 min at 4° C. The washing procedure was repeated before the cell-bead suspension was applied to a LS MACS column (Miltenyi Biotec). The CD19 positive cell fraction was eluted from the column according to the manufactures instructions and either stored in FCS-10% DMSO, or single-cell sorted directly.

[0166] Plasma blasts were selected from the CD19.sup.+ B cell fraction by fluorescence activated cell sorting (FACS) based on the expression profile of CD19, CD38, and CD45 cell surface proteins. CD19 is a B-cell marker that is also expressed on plasma cell precursors, while CD38 is highly expressed on plasma blasts and plasma cells. The plasma blasts apparently have a somewhat lower expression of CD19 and CD45 than the rest of the CD19.sup.+ cells, which allows for the separation of a discrete population. The cells were washed in FACS buffer (PBS; 1% BSA) and stained for 20 min with anti-CD19-FITC, anti-CD38-APC, anti-Lambda-PE (BD Pharmingen). The Lambda-light chain staining was included in order to allow exclusion of cells that cannot serve as template for the PCR (see Section c). The stained cells were washed and re-suspended in FACS buffer.

[0167] The flow rate of the cells during the FACS was set at approximately 200 events/sec and the cell concentration was 5×10⁵/ml to obtain a high plasma cell rescue.

[0168] The following set of gates was used. Each gate is a daughter of the former.

[0169] Gate 1: FSC/SSC gate. The lymphocyte population having the highest FSC was selected, thereby ensuring sorting of living cells.

[0170] Gate 2: SSCh/SSCw. This gate ensured sorting of single cells (doublet discrimination).

[0171] Gate 3: Events representing the plasma blasts were gated in the CD38/CD19 dot plot as CD38 High/CD19 intermediate.

[0172] Gate 4: Since the PCR procedure described in Section c only amplifies Kappa light chains, Lambda-negative events were gated in a Lambda/CD19 dot plot.

[0173] As an alternative or in addition to gate 3, the plasma blasts could also be identified as CD38 high and CD45 intermediate in a CD45/CD38 dot plot. This will require staining of the cells with anti-CD45-PerCP.

[0174] The resulting population that fulfilled these four criteria was single-cell sorted into 96-well PCR plates containing a sorting buffer (see Section c). The plates containing the cells were stored at -80° C.

b. ELISpot

[0175] ELISpot was used to estimate the percentage of plasma blasts expressing anti-RSV antibodies in obtained cell samples, i.e., PBMC, MACS-purified CD19.sup.+ cells, or a population of FACS sorted plasma blasts. 96-well plates with a nitrocellulose surface (Millipore) were coated with a solution of 25 μg/ml inactivated RSV Long particles (HyTest). The wells were blocked by incubation with RPMI, 2% milk powder and left at 4° C. for approximately 5 h followed by 1 h incubation at 37° C. Plates were washed and the cell samples were added in RPMI culture medium to each well followed by incubation at standard tissue culture conditions for 24 h. The secreted RSV-specific antibodies will bind to the immobilized virus particles surrounding the antibody producing cell. The cells were removed by washing three times in PBS; 0.01% Tween 20 and three times in PBS. HRP-conjugated anti-human IgG (H+L) (CalTag) and HRP-conjugated anti-human IgA (Serotec) were added and allowed to react with the immobilized antibodies for 1 h at 37° C. The washing procedure was repeated and the chromogen substrate (3-amino-9-ethylcarbazole solubilized in N,N-DMF (di-methyl formamide)) was added. The color development was terminated after 4 min by addition of H₂O. Red spots were identified at the sites where antigen-specific antibody-secreting cells had been located.

c. Linkage of Cognate V_H and V_L Pairs

[0176] The linkage of V_H and V_L coding sequences was performed on the single cells obtained as described in Section a, facilitating cognate pairing of the V_H and V_L coding sequences. The procedure utilized a two step PCR procedure based on a one-step multiplex overlap-extension RT-PCR followed by a nested PCR. The primer mixes used in the present example only amplify Kappa light chains. Primers capable of amplifying Lambda light chains could, however, be added to the multiplex primer mix and nested PCR primer mix if desired. If Lambda primers are added, the sorting procedure in Section a should be adapted such that Lambda positive cells are not excluded. The principle for linkage of cognate V_H and V_L sequences is illustrated in FIG. 2.

[0177] The 96-well PCR plates produced in Section a, were thawed and the sorted cells served as template for the multiplex overlap-extension RT-PCR. The sorting buffer added to each well before the single-cell sorting contained reaction buffer (OneStep RT-PCR Buffer; Qiagen), primers for RT-PCR (see Table 2) and RNase inhibitor (RNasin, Promega). This was supplemented with OneStep RT-PCR Enzyme Mix (25× dilution; Qiagen) and dNTP mix (200 μM each) to obtain the given final concentration in a 20-μl reaction volume.

[0178] The plates were incubated for 30 min at 55° C. to allow for reverse transcription of the RNA from each cell. Following the RT, the plates were subjected to the following PCR cycle: 10 min at 94° C., 35×(40 sec at 94° C., 40 sec at 60° C., 5 min at 72° C.), 10 min at 72° C.

[0179] The PCR reactions were performed in H20BIT Thermal cycler with a Peel Seal Basket for 24 96-well plates (ABgene) to facilitate a high-throughput. The PCR plates were stored at -20° C. after cycling.

TABLE-US-00002 TABLE 2 RT-PCR multiplex overlap-extension primer mix Final Primer Conc. SEQ ID name nM Sequence NO: VH set CH-IgG 0.2 GACSGATGGGCCCTTGGTGG 179 CH-IgA 0.2 GAGTGGCTCCTGGGGGAAGA 180 VH-1 0.04 TATTCCCATGGCGCGCCCAGRTGCAGCTGGTGCART 181 VH-2 0.04 TATTCCCATGGCGCGCCSAGGTCCAGCTGGTRCAGT 182 VH-3 0.04 TATTCCCATGGCGCGCCCAGRTCACCTTGAAGGAGT 183 VH-4 0.04 TATTCCCATGGCGCGCCSAGGTGCAGCTGGTGGAG 184 VH-5 0.04 TATTCCCATGGCGCGCCCAGGTGCAGCTACAGCAGT 185 VH-6 0.04 TATTCCCATGGCGCGCCCAGSTGCAGCTGCAGGAGT 186 VH-7 0.04 TATTCCCATGGCGCGCCGARGTGCAGCTGGTGCAGT 187 VH-8 0.04 TATTCCCATGGCGCGCCCAGGTACAGCTGCAGCAGTC 188 LC set CK1 0.2 ATATATATGCGGCCGCTTATTAACACTCTCCCCTGTTG 189 VL-1 0.04 GGCGCGCCATGGGAATAGCTAGCCGACATCCAGWTGACCCAGTCT 190 VL-2 0.04 GGCGCGCCATGGGAATAGCTAGCCGATGTTGTGATGACTCAGTCT 191 VL-3 0.04 GGCGCGCCATGGGAATAGCTAGCCGAAATTGTGWTGACRCAGTCT 192 VL-4 0.04 GGCGCGCCATGGGAATAGCTAGCCGATATTGTGATGACCCACACT 193 VL-5 0.04 GGCGCGCCATGGGAATAGCTAGCCGAAACGACACTCACGCAGT 194 VL-6 0.04 GGCGCGCCATGGGAATAGCTAGCCGAAATTGTGCTGACTCAGTCT 195 W = A/T, R = A/G, S = G/C

[0180] For the nested PCR step, 96-well PCR plates were prepared with the following mixture in each well (20-μl reactions) to obtain the given final concentration: 1× FastStart buffer (Roche), dNTP mix (200 μM each), nested primer mix (see Table 3), Phusion DNA Polymerase (0.08 U; Finnzymes) and FastStart High Fidelity Enzyme Blend (0.8 U; Roche). As template for the nested PCR, 1 μl was transferred from the multiplex overlap-extension PCR reactions. The nested PCR plates were subjected to the following PCR cycle: 35×(30 sec at 95° C., 30 sec at 60° C., 90 sec at 72° C.), 10 min at 72° C.

[0181] Randomly selected reactions were analyzed on a 1% agarose gel to verify the presence of an overlap-extension fragment of approximately 1070 bp.

[0182] The plates were stored at -20° C. until further processing of the PCR fragments.

TABLE-US-00003 TABLE 3 Nested primer set Final Primer Conc. name nM Sequence SEQ ID CK2 0.2 ACCGCCTCCACCGGCGGCCGCTTATTAACAC 196 TCTCCCCTGTTGAAGCTCTT PJ 1-2 0.2 GGAGGCGCTCGAGACGGTGACCAGGGTGCC 197 PJ 3 0.2 GGAGGCGCTCGAGACGGTGACCATTGTCCC 198 PJ 4-5 0.2 GGAGGCGCTCGAGACGGTGACCAGGGTTCC 199 PJ 6 0.2 GGAGGCGCTCGAGACGGTGACCGTGGTCCC 200

d. Insertion of Cognate V_H and V_L Coding Pairs into a Screening Vector

[0183] In order to identify antibodies with binding specificity to RSV particles or antigens, the V_H and V_L coding sequences obtained as described in Section c were expressed as full-length antibodies. This involved insertion of the repertoire of V_H and V_L coding pairs into an expression vector and transformation into a host cell.

[0184] A two-step cloning procedure was employed for generation of a repertoire of expression vectors containing the linked V_H and V_L coding pairs. Statistically, if the repertoire of expression vectors contains ten times as many recombinant plasmids as the number of cognate paired V_H and V_L PCR products used for generation of the screening repertoire, there is 99% likelihood that all unique gene pairs are represented. Thus, if 400 overlap-extension V-gene fragments were obtained in Section c, a repertoire of at least 4000 clones was generated for screening.

[0185] Briefly, the repertoires of linked V_H and V_L coding pairs from the nested PCR in Section c were pooled (without mixing pairs from different donors). The PCR fragments were cleaved with XhoI and NotI DNA endonucleases at the recognition sites introduced into the termini of PCR products. The cleaved and purified fragments were ligated into an XhoI/NotI digested mammalian IgG expression vector (FIG. 3) by standard ligation procedures. The ligation mix was electroporated into E. coli and added to 2×YT plates containing the appropriated antibiotic and incubated at 37° C. over night. The amplified repertoire of vectors was purified from cells recovered from the plates using standard DNA purification methods (Qiagen). The plasmids were prepared for insertion of promoter-leader fragments by cleavage using AscI and NheI endonucleases. The restriction sites for these enzymes were located between the V_H and V_L coding gene pairs. Following purification of the vector, an AscI-NheI digested bi-directional mammalian promoter-leader fragment was inserted into the AscI and NheI restriction sites by standard ligation procedures. The ligated vector was amplified in E. coli and the plasmid was purified using standard methods. The generated repertoire of screening vectors was transformed into E. coli by conventional procedures. Colonies obtained were consolidated into 384-well master plates and stored. The number of arrayed colonies exceeded the number of input PCR products by at least 3-fold, thus giving 95% percent likelihood for presence of all unique V-gene pairs obtained in Section c.

e. Screening

[0186] The bacterial colonies arrayed in Section d were inoculated into culture medium in similar 384-well plates and grown overnight. DNA for transfection was prepared from each well in the cell culture plate. The day prior to transfection 384-well plates were seeded with CHO Flp-In cells (Invitrogen) at 3000 cells/well in 20 μl culture medium. The cells were transfected with the DNA using Fugene6 (Roche) according to the manufactures instructions. After 2-3 days incubation the full-length antibody-containing supernatants were harvested and stored for screening purposes.

[0187] Screening was performed using the Applied Biosystems 8200 FMAT® System, a homogeneous bead-based soluble capture FLISA (fluorescent linked immunosorbent assay) (Swartzman et al. 1999, Anal. Biochem. 271:143-151). A number of antigens, including virus particles, recombinant G protein and biotinylated peptides derived from RSV antigens, were used for the screening. The peptides were derived from the conserved region (amino acids 164-176) and the cysteine core region (amino acids 171-187, strain Long and 18537) of the G protein and the extracellular region of the SH-protein (amino acids 42-64 of the A2 strain and 42-65 of the 18537 strain). Inactivated virus particles of RSV strain Long (HyTest) were immobilized on polystyrene beads by incubating 300 μl 5% w/v beads (6.79 μm diameter, Spherotech Inc.) with 300 μl virus stock (protein concentration: 200 μg/ml). Soluble recombinant G protein (amino acids 66-292 of the 18537 strain sequence) was similarly immobilized directly on polystyrene beads, whereas the biotinylated peptides were captured on precoated streptavidin polystyrene beads (6.0-8.0 μm diameter, Gerlinde Kisker) at saturating concentrations. The coating mixture was incubated overnight and washed twice in PBS. Beads were re-suspended in 50 ml PBS containing 1% bovine serum albumin (PBS/BSA) and 5 μl goat-anti-human IgG Alexa 647 conjugate (Molecular probes). Ten μl of re-suspended coating mixture was added to 20 μl antibody-containing supernatant in FMAT-compatible 384-well plates and incubated for approximately 12 h, after which the fluorescence at the bead surface in individual wells was measured. A fluorescence event was recognized as positive if its intensity was at least six standard deviations above the background baseline.

[0188] The clones resulting in primary hits were retrieved from the original master plates and collected in new plates. DNA was isolated from these clones and submitted for DNA sequencing of the V-genes. The sequences were aligned and all the unique clones were selected.

[0189] The selected clones were further validated. Briefly, 2×10⁶ Freestyle 293 cells (Invitrogen) were transfected with 1.7 μg DNA from the selected clones and 0.3 μg pAdVAntage plasmid (Promega) in 2 ml Freestyle medium (Invitrogen) according to the manufacturers' instructions. After two days, supernatants were tested for IgG expression and reactivity with the different antigens used for the primary screening as well as recombinant purified F protein and an E. coli produced fragment of the G protein (amino acids 127-203 of the 18537 strain sequence) by FLISA and/or ELISA. Antibody supernatants were tested in serial dilutions allowing for a ranking of clones according to antigen reactivity.

f. Clone Repair

[0190] When using a multiplex PCR approach as described in Section c, a certain degree of intra- and inter-V-gene family cross-priming is expected due to the high degree of homology. The cross-priming introduces amino acids that are not naturally occurring in the immunoglobulin framework with several potential consequences, e.g. structural changes and increased immunogenicity, all resulting in a decreased therapeutic activity.

[0191] In order to eliminate these drawbacks and to ensure that selected clones mirror the natural humoral immune response, such cross-priming mutations were corrected in a process called clone repair.

[0192] In the first step of the clone repair procedure, the V_H sequence was PCR amplified with a primer set containing the sequence corresponding to the V_H-gene the clone of interest originated from, thereby correcting any mutations introduced by cross-priming. The PCR fragment was digested with XhoI and AscI and ligated back into the XhoI/AscI digested mammalian expression vector (FIG. 3) using conventional ligation procedures. The ligated vector was amplified in E. coli and the plasmid was purified by standard methods. The V_H sequence was sequenced to verify the correction and the vector was digested with NheI/NotI to prepare it for insertion of the light chain.

[0193] In the second step the complete light chain was PCR amplified with a primer set containing the sequence corresponding to the V_L-gene the clone of interest originated from, thereby correcting any mutations introduced by cross-priming. The PCR fragment was digested with 1VheI/NotI and ligated into the V_H containing vector prepared above. The ligation product was amplified in E. coli and the plasmid was purified by standard methods. Subsequently, the light chain was sequenced to verify the correction.

[0194] In the case where the Kappa constant region of a selected clone contained mutations, introduced during the amplification of the genes as described in Section c, it was replaced by an unmutated constant region. This was done in an overlap PCR where the repaired V_L-gene (amplified without the constant region) was fused to a constant region with correct sequence (obtained in a separate PCR). The whole sequence was amplified and cloned into the V_H containing vector as described above and the repaired light chain was sequenced to verify the correction.

g. Generation of a Polyclonal Cell Line

[0195] The generation of a polyclonal expression cell line producing a recombinant polyclonal antibody is a multi-step procedure involving the generation of individual expression cell lines which each express a unique antibody from a single V_H and V_L gene sequence. The polyclonal cell line is obtained by mixing the individual cell lines and distributing the mixture into ampoules thereby generating a polyclonal research cell bank (pRCB) or master cell bank (pMCB) from which a polyclonal working cell bank (pWCB) can be generated by expanding cells from the research or master cell bank. Generally, the polyclonal cell lines from the pRCB are used directly without generating a pWCB.

[0196] The individual steps in the process of generating a polyclonal cell line are described below.

g-1 Transfection And Selection of Mammalian Cell Lines

[0197] The Flp-In CHO cell line (Invitrogen) was used as starting cell line. In order to obtain a more homogenous cell line the parental Flp-In CHO cell line was sub-cloned by limited dilution and several clones were selected and expanded. Based on growth behavior one clone, CHO-Flp-In (019), was selected as starting cell line. The CHO-Flp-In (019) cells were cultured as adherent cells in HAM-F12 with 10% fetal calf serum (FCS).

[0198] The individual plasmid preparations each containing a selected and repaired V_H and V_L coding pair obtained in Section f, were co-transfected with Flp recombinase encoding plasmid into ˜19×10⁶ CHO-Flp-In (019) cells (for further details, see WO 04/061104) in a T175 flask using Fugene6 (Roche). Cells were trypsinated after 24 h and transferred to a 2-layer (1260 cm²) cell factory (Nunc). Recombinant cell lines were selected by culturing in the presence of 500 μg/ml Geneticin, which was added 48 h after transfection. Approximately two weeks later clones appeared. Clones were counted and cells were trypsinated and hereafter cultured as pools of clones expressing one of the RSV-specific antibodies.

g-2 Adaptation to Serum Free Suspension Culture

[0199] The individual adherent anti-RSV antibody expressing cell cultures were trypsinated, centrifuged and transferred to separate shaker flasks (250 ml) with 1.15×10⁶ cells/ml in appropriate serum free medium (Excell302, JRH Biosciences; 500 μg/ml Geneticin, anti-clumping agent (1:250) and 4 mM L-glutamin). Growth and cell morphology were followed over several weeks. After 4-6 weeks the cell lines usually showed good and stable growth behavior with doubling times below 30 h and the adapted individual cell lines were then cryopreserved in multiple ampoules.

[0200] The individual antibodies expressed during adaptation were purified from the supernatants using the method described in Section i). The purified antibody was used for the characterization of antigen specificity and biochemical properties as described below.

g-3 Characterization of Cell Lines

[0201] All the individual cell lines were characterized with respect to antibody production and proliferation. This was performed with the following assays:

Production:

[0202] The production of recombinant antibodies of the individual expression cell lines were followed during the adaptation by Kappa specific ELISA. ELISA plates were coated overnight with goat-anti-human Fc purified antibody (Serotec) in carbonate buffer, pH 9.6. Plates were washed 6 times with washing buffer (PBS; 0.05% Tween 20) and blocked by incubation for 1 h in washing buffer containing 2% skim milk. Cell culture media supernatants were added and the incubated extended for 1 h. Plates were washed 6 times in washing buffer and secondary antibodies (goat-anti-human Kappa HRP, Serotec) were added and the incubation repeated. After vigorous washing the ELISA was developed with TMB substrate and reaction stopped by addition of H₂SO₄. Plates were read at 450 nm.

[0203] Further, intracellular staining was used to determine the general expression level as well as to determine the homogeneity of the cell population in relation to expression of recombinant antibody. 5×10⁵ cells were washed in cold FACS buffer (PBS; 2% FCS) before fixation by incubation in CellFix (BD-Biosciences) for 20 min. Cells were pelleted and permeabilized in ice cold methanol for 10 min and washed twice in FACS buffer. The suspension was fluorescently tagged antibody (Goat F(ab')₂ Fragment, Anti-human IgG(H+L)-PE, Beckman Coulter) was added. After 20 min on ice the cells were washed and re-suspended in FACS buffer followed by FACS analysis.

Proliferation:

[0204] Aliquots of the cell suspensions were taken two to three times a week and cell number, cell size and viability was determined by Vi-Cell XR (Cell viability analyzer, Beckman Coulter) analysis. The doubling time for the cell cultures was calculated using the cell numbers derived from Vi-Cell measurements.

g-4 Characterization of the Antigen Specificity of the Individual Antibodies

[0205] The antigen and epitope specificity of the individually expressed antibodies was assessed in order to allow for the generation of an anti-RSV rpAb with a well-characterized specificity. As already described in Section e, the antibodies identified during screening were validated by assessing their binding specificity to single RSV antigens (recombinant G protein, recombinant or purified F protein) or peptide fragments thereof (conserved region and cysteine-core motif of protein G, subtype A and B, known linear epitopes on protein F, and the extracellular domain of SH protein, subtype A and B) by FLISA, ELISA and surface plasmon resonance (SPR; Biacore). The epitope specificities were determined in ELISA by competition with well-characterized commercial antibodies, some of which are shown in Table 4. Not necessarily all the antibodies shown in Table 4 were used in the characterization of each individual antibody of the present invention, and potentially other antibodies or antibody fragments which have been characterized with respect to the antigen, antigenic site and/or epitope they bind may also be used. Briefly, the antibodies or antibody fragments used for epitope blocking were incubated with the immobilized antigen (RSV Long particles, HyTest) in large excess, i.e. concentrations 100 times the ones giving 75% maximum binding, as determined empirically (Ditzel et al., J. Mol. Biol. 1997, 267:684-695). Following washing, the individual antibody clones were incubated with the blocked antigen at various concentrations and any bound human IgG was detected using a Goat-anti-Human HRP conjugate (Serotec) according to standard ELISA protocols. Epitope specificities were further characterized by pair-wise competition between different antibody clones in Biacore using saturating concentrations (empirically determined) of both blocking and probing antibodies. Purified F or G protein immobilized by direct amine coupling (Biacore) was used as antigen. In both the ELISA- and Biacore-based epitope mapping, the reduced binding following epitope blocking was compared to the uncompeted binding.

TABLE-US-00004 TABLE 4 Monoclonal antibodies for epitope mapping of anti-F and anti-G antibodies Antigenic MAb/Fab Antigen Site Epitope (aa) Ref. 131-2a F F1 F1a 1, 2 9C5 F F1 F1a 5 92-11c F F1 F1b 1, 2 102-10b F F1 F1c 1, 2 133-1h F C F2.sup. 1, 2, 3 130-8f F C F2 (241/421) 1, 2, 3, 4 143-6c F A/II F3.sup. 1, 2, 3 Palivizumab F A/II (272) 8 1153 F A/II (262) 3, 4 1142 F A/II 3 1200 F A/II (272) 2, 4 1214 F A/II (276) 3, 4 1237 F A/II (276) 3, 4 1129 F A/II (275) 3, 4 1121 F A/II 3 1112 F B/I (389) 3, 6 1269 F B/I (389) 3, 6 1243 F C (241/421) 3, 6 Fab 19 F A/II (266) 7 RSVF2-5 F IV (429) 4 Mab19 F IV (429) 12 7.936 F V (432-447) 13 9.432 F VI (436) 13 63-10f G (A) G11 GCRR (A171-187) 1, 2 130-6d G (A) G12 (A174-214).sup. 1, 2, 9 131-2g G (A + B) G13 (150-173) 1, 2, 9 143-5a G (A + B) G5a 2 L9 G (A + B) A1/B1 Conserved 14, 15 (164-176) 8C5 G ND 5 1C2 G (A) ND GCRR (A172-188) 10, 11 3F4 G (A) ND 10, 11 4G4 G (A) ND GCRR (A172-188) 10, 11

[0206] The column "Antigen" indicates the RSV associated antigen bound by the Mab/Fab, and if a subtype specificity is known this is indicated in ( ). The column "Epitope (aa)" indicates the name of the epitope recognized by the MAb/Fab, further in ( ) amino acid positions resulting in RSV escape mutants, or peptides/protein fragments towards which binding has been show, are indicated. The numbered references (Ref.) given in Table 4 correspond to: [0207] 1. Anderson et al., J. Clin. Microbiol. 1986, 23:475-480. [0208] 2. Anderson et al., J. Virol. 1988, 62:1232-4238. [0209] 3. Beeler & van Wyke Coelingh, J. Virol. 1989, 63:2941-2950. [0210] 4. Crowe et al., JID 1998, 177:1073-1076. [0211] 5. Sominina et al., Vestn Ross Akad Med Nauk 1995, 9:49-54. [0212] 6. Collins et al., Fields Virology, p. 1313-1351. [0213] 7. Crowe et al., Virology 1998, 252:373-375. [0214] 8. Zhao & Sullender, J. Virol. 2004, 79:3962-3968. [0215] 9. Sullender, Virology 1995, 209:70-79. [0216] 10. Morgan et al., J. Gen. Virol. 1987, 68:2781-2788. [0217] 11. McGill et al., J. Immunol. Methods 2005, 297:143-152. [0218] 12. Arbiza et al., J. Gen. Virol. 1992, 73:2225-2234. [0219] 13. Lopez et al. J. Virol. 1998, 72:6922-6928. [0220] 14. Walsh et al., J. Gen. Virol. 1989, 70:2953-2961. [0221] 15. Walsh et al., J. Gen. Virol. 1998, 79:479-487.

[0222] Furthermore, the antibody clones were also characterized in terms of binding to human laryngeal epithelial HEp-2 cells (ATCC CLL-23) infected with different RSV strains (Long, B1, or 18537) by FACS and/or ELISA. Binding to mock-infected HEp-2 cells was similarly analyzed.

[0223] Briefly, for the FACS assay, HEp-2 cells were infected with either the RSV Long (ATCC number VR-26) strain or the RSV B1 (ATCC number VR-1400) strain in serum-free medium at a ratio of 0.1 pfu/cell for 24 (Long strain) or 48 h (B1 strain). Following detachment and wash the cells were dispensed in 96-well plates and incubated with dilutions (4 pM-200 μM) of the individual anti-RSV antibodies for 1 h at 37° C. The cells were fixed in 1% formaldehyde and cell surface-bound antibody was detected by incubation with goat F(ab)₂ anti-human IgG-PE conjugate (Beckman Coulter) for 30 min at 4° C.

[0224] For the ELISA assay, HEp-2 cells were infected with either the RSV Long strain or the RSV 18537 strain (ATCC number VR-1580) in serum-free medium at a ratio of 0.01 pfu/cell. After two hours of incubation, medium with 10% fetal calf serum was added and the cells were incubated for additional 45 hours (Long strain) or 70 hours (18537 strain). Following wash, the cells were incubated with dilutions of the individual anti-RSV (0.1 μM-0.03 nM) antibodies for 1 hour at room temperature. The cell surface-bound antibody was detected by incubation with goat F(ab)₂ anti-human IgG-HRP conjugate (Jackson ImmunoResearch) for 1 hour at room temperature, followed by addition of TMB^PLUS (Kem-En-Tec). After 10 min of incubation the reaction was terminated by H₂SO₄ and the absorbance measured. These cellular assays may also be used as a competition assay for determination of relative epitope specificities as described for the virus particle ELISA and SPR assay described above.

[0225] Selected clones identified as protein G-specific were also tested for cross-reactivity with recombinant human fractalkine (CX3CL1; R&D systems) by ELISA. Anti-human CX3CL1/Fractalkine monoclonal antibody (R&D systems) was used as a positive control.

g-5 Characterization of Binding Kinetics of the Individual Antibodies

[0226] Kinetic analysis of the antibodies of the invention was performed using surface plasmon resonance analysis on a Biacore 3000 (Biacore AB, Uppsala, Sweden), using recombinant antigens immobilized onto the sensor surface at very low density to avoid limitations in mass transport. The analysis was performed with Fab fragments prepared from individual antibody clones using the ImmunoPure Fab preparation Kit (Pierce). Briefly, a total of 200 resonance units (RU) recombinant protein F or a total of 50 RU recombinant protein G was conjugated to a CM5 chip surface using the Amine Coupling Kit (Biacore) according to the manufacturer's instructions. The Fab fragments were injected over the chip surface in serial dilutions, starting at an optimized concentration that did not result in RUmax values above 25 when tested on the chip with immobilized protein. The association rate constant (ka) and dissociation constant (kd) were evaluated globally using the predefined 1.1 (Langmuir) association and dissociation models in the BIAevaluation 4.1 software (BIAcore).

[0227] By performing the kinetic analyses on Fab fragments, it is ensured that the data obtained truly reflects the binding affinities towards RSV protein. If one used complete antibodies, the data would reflect binding avidities, which cannot readily be translated into a meaningful measure of the exact nature of the antibodies' binding characteristics vs. the antigen.

g-6 Characterization of the Biochemical Properties of Individual Antibodies

[0228] Heterogeneity is a common phenomenon in antibodies and recombinant proteins. Antibody modifications typically occur during expression, e.g. a post-translational modifications like N-glycosylation, proteolytic fragmentation, and N- and C-terminal heterogeneity resulting in size or charge heterogeneity. In addition, modifications like methionine oxidation and deamidation can occur during subsequent short or long term storage. Since these parameters need to be well-defined for therapeutic antibodies, they were analyzed prior to the generation of the polyclonal cell line.

[0229] The methods used for characterization of purified individual antibodies (see Section i) included SDS-PAGE (reducing and non-reducing conditions), weak cation exchange chromatography (IEX), size exclusion chromatography (SEC), and RP-HPLC (reducing and non-reducing conditions). The SDS-PAGE analysis under reducing and non-reducing conditions and SEC indicated that the purified antibodies were indeed intact with minute amounts of fragmented and aggregated forms. IEX profile analysis of the purified antibodies resulted in profiles with single peaks or chromatograms with multiple peaks, indicating charge heterogeneity in these particular antibodies. Antibody preparations resulting in multiple peaks in the IEX analysis and/or aberrant migration of either the light or heavy chain in SDS gels, or unusual RP-HPLC profiles were analyzed in detail for intact N-termini by N-terminal sequencing and for heterogeneity caused by differences in the oligosaccharide profiles. In addition, selected antibodies were analyzed for the presence of additional N-glycosylation sites in the variable chains using enzymatic treatment and subsequent SDS-PAGE analysis.

g-7 Establishment of a Polyclonal Cell Line for Anti-RSV Recombinant Polyclonal Antibody Production

[0230] From the collection of established expression cell lines, a subset is selected to be mixed for the generation of a polyclonal cell line and the polyclonal research/master cell bank (pRCB/pMCB). The selection parameters can be defined according to the use of the polyclonal antibody to be produced from the polyclonal cell line and the performance of the individual cell lines. Generally the following parameters are considered: [0231] Cell line characteristics; to optimize the stability of the polyclonal cell line, individual cell lines with doubling times between 21 and 30 hours and antibody productivity above 1 pg/cell/day are preferred. [0232] Reactivity; the antigens/antigenic sites and epitopes which the anti-RSV rpAb shall exert reactivity against are carefully considered. [0233] Protein chemistry; preferably antibodies with well-defined biochemical characteristics are included in the final anti-RSV rpAb.

[0234] The selected individual cell lines each expressing a recombinant anti-RSV antibody are thawed and expanded at 37° C. in serum free medium in shaker flasks to reach at least 4×10⁸ cells of each clone having a population doubling time of 21-34 hours. The viabilities are preferably in the range of 93% to 96%. The polyclonal cell line is prepared by mixing 2×10⁶ cells from each cell line. The polyclonal cell line is distributed into freeze ampoules containing 5.6×10⁷ cells and cryopreserved. This collection of vials with a polyclonal cell line is termed the polyclonal research/master cell bank (pRCB/pMCB) from which the polyclonal working cell bank (pWCB) can be generated by expanding one ampoule from the pRCB/pMCB to reach a sufficient number of cells to lay down a polyclonal working cell bank (pWCB) of approximately 200 ampoules with the same cell density as the ampoules of the pRCB/pMCB. Samples from the cell banks are tested for mycoplasma and sterility.

h. Expression of a Recombinant Polyclonal Anti-RSV Antibody

[0235] Recombinant polyclonal anti-RSV antibody batches are produced in 5 liter bioreactors (B. Braun Biotech International, Melsungen, Germany). Briefly, vials from the pRCB or pWCB are thawed and expanded in shaker flasks (Corning). Cells in seed train are cultured in ExCell 302 medium with G418 and with anti-clumping agent at 37° C., 5% CO₂. The bioreactors are inoculated with 0.6×10⁶ cells/ml suspended in 3 1 ExCell 302 medium without G418 and without anti-clumping agent. The cell numbers/viable cells are monitored daily by CASY or ViCell counting. At 50 h, 2000 ml ExCell 302 medium is supplemented and after 92 h a temperature downshift from 37° C. to 32° C. is performed. The cell culture supernatant is harvested after 164 h and subjected to purification as described in Section i).

i. Purification of Individual Anti-RSV Antibodies and Polyclonal Anti-RSV Antibodies

[0236] The antibodies expressed as described in Section g.g-2 and h, all of the IgG1 isotype, were affinity purified using a MabSelect SuRe column (Protein-A). The individual antibodies interacted with immobilized Protein A at pH 7.4, whereas contaminating proteins were washed from the column. The bound antibodies were subsequently eluted from the column by lowering of the pH to 2.7. The fractions containing antibodies, determined from absorbance measurements at 280 nm, were pooled and buffer changed using a G-25 column into 5 mM sodium acetate, 150 mM NaCl, pH 5 and stored at -20° C.

j. In Vitro Neutralization Assays

j-1 Preparation of Live RSV for In Vitro Use

[0237] Human laryngeal epithelial HEp-2 cells (ATCC CLL-23) were seeded in 175 cm² flasks at 1×10⁷ cells/flask. The cells were infected with either the RSV Long (ATCC number VR-26), the RSV A2 (Advanced Biotechnologies Inc., ATCC number VR-1540) the RSV B1 (ATCC number VR-1400) or the RSV B Wash/18537 (Advanced Biotechnologies Inc., ATCC number VR-1580) strain in 3 ml serum-free medium at a ratio of 0.1 pfu/cell. Cells were infected for 2 h at 37° C.; 5% CO₂ followed by addition of 37 ml of complete MEM medium. Cells were incubated until cytopathic effects were visible. The cells were detached by scraping and the media and cells were sonicated for 20 sec and aliquoted, snap frozen in liquid nitrogen and stored at -80° C.

j-2 Plaque Reduction Neutralization Test (PRNT)

[0238] HEp-2 cells were seeded in 96-well culture plates at 2×10⁴ cells/well, and incubated overnight at 37° C.; 5% CO₂. The test substances were diluted in serum-free MEM and allowed to pre-incubate with RSV in the absence or presence of complement (Complement sera from rabbit, Sigma) for 30 min at 37° C. This mixture was applied to the monolayer of HEp-2 cells and incubated for 24-72 h at 37° C.; 5% CO₂. The cells were fixed with 80% acetone; 20% PBS for 20 min. After washing, biotinylated goat anti-RSV antibody (AbD Serotec) was added (1:200) in PBS with 1% BSA and incubated for 1 h at room temperature. After washing, HRP-avidin was added and allowed to incubate for 30 min. Plaques were developed by incubation with 3-amino-9-ethylcarbazole (AEC) substrate until plaques were visible by microscopy, e.g., for 25 min (RSV Long) or 45 min (RSV B1). Plaques were counted in a Bioreader (Bio-Sys GmbH). EC₅₀ values (effective concentrations required to induce a 50% reduction in the number of plaques) were calculated where applicable to allow for a comparison of the potencies.

j-3 Fusion Inhibition Assay

[0239] The fusion inhibition assay was essentially performed as the plaque reduction neutralization assay except that RSV was allowed to infect before addition of test substances. In practice, virus was added in serum-free medium to the mono-layer of HEp-2 cells for 1.5 h. Supernatants were removed and test substances were added in complete MEM medium with or without complement (Complement sera from rabbit, Sigma). The plates were incubated overnight and processed as described above for the plaque reduction neutralization assay.

j-4 Microneutralization Assay

[0240] In addition to the PRNT and fusion inhibition assay described in Sections j-2 and j-3, a microneutralization assay based on the detection of RSV proteins was employed for the determination of RSV neutralization and fusion inhibition.

[0241] For the neutralization test, the test substances were diluted in serum-free MEM and allowed to pre-incubate with RSV in the absence or presence of complement (Complement sera from rabbit, Sigma) in 96-well culture plates for 30 min at room temperature. Trypsinated HEp-2 cells were added at 1.5×10⁴ cells/well, and incubated for 2-3 days at 37° C.; 5% CO₂. The cells were washed and fixed with 80% acetone; 20% PBS for 15 minutes at 4° C. and dried. The plates were then blocked with PBS with 0.5% gelatin for 30 min at room temperature and stained with a pool of murine monoclonal antibodies against RSV proteins (NCL-RSV3, Novocastra), diluted 1:200 in PBS with 0.5% gelatin and 0.5% Tween-20, for 2 h at room temperature. After washing, Polyclonal Rabbit anti-mouse Immunoglobulin HRP-conjugate (P0260; DakoCytomation), diluted 1:1000 in PBS with 0.5% gelatin and 0.5% Tween-20 was added and allowed to incubate for 2 h at room temperature. The plates were washed and developed by addition of ortho-phenylendiamine. The reaction was stopped by addition of H₂SO₄ and the plates were read in an ELISA plate reader at 490 nm.

[0242] The fusion inhibition assay was essentially performed as the microneutralization test with the exception that virus was added to cells and incubated for 1.5 h at 37° C.; 5% CO₂ before the test substances, diluted in complete MEM, were added. The plates were incubated for 2-3 days at 37° C.; 5% CO₂ and developed as described above.

k. In Vivo Protection Assays

k-1 Mouse Challenge Model

[0243] 7-8-weeks old female BALB/c mice were inoculated intraperitoneally with 0.2 ml antibody preparation on day-1 of study. Placebo treated mice were similarly inoculated i.p. with 0.1 ml PBS buffer. On day 0 of study, the mice were anesthetized using inhaled isofluorane and inoculated intranasally with 10^-6-10^-7 pfu of RSV strain A2 in 50 μl or with cell lysate (mock inoculum). Animals were allowed 30 seconds to aspirate the inoculum whilst held upright until fully recovered from the anaesthesia.

[0244] Five days after challenge, the mice were killed with an overdose of sodium pentobarbitone. At post-mortem, blood was obtained by exsanguination from the axillary vessels for preparation of sera. Lungs were removed and homogenized in 2.5 ml buffer with sterile sand. Lung homogenates were centrifuged to sediment sand and cell debris and supernatants were aliquoted and stored at -70° C.

[0245] In a long-term version of the challenge model, groups of animals were killed at different time points, i.e., 5, 27 and 69 days after challenge and lung homogenates and serum samples were prepared as described above. In addition, separate groups of animals that were killed at the same time points were used for bronchoalveolar lavage (BAL) and histopathology samples. Briefly, the airways were cannulated and lavaged with 1 ml of saline. The total number of cells present in the BAL was determined by light microscopy. Cytospin preparations of BAL cells were stained with hematoxylin and eosin and differential cell counts made using oil immersion microscopy. Following lavage, the lungs were fixated for histopathology. The fixed tissue samples were prepared by inflating the lungs with buffered formalin, and the fixed tissue was embedded in paraffin blocks for processing and hematoxylin and eosin staining by standard methods. The tissue samples were examined by light microscopy for signs of inflammation. Lung pathology scores were determined as the sum of the severity score multiplied by the prevalence score for each of 3 lung lobes (Table 5a). The maximal lung pathology score for one mouse is thus 36.

TABLE-US-00005 TABLE 5a Lung histopathology scoring system used for the mouse challenge studies. Severity Prevalence 0 Normal 0 Normal 1 perivascular & peribronchial cell 1 <25% of sample infiltration <3 cells thick 2 perivascular & peribronchial cell 2 25 to 50% of infiltration 4 to 10 cells thick sample 3 perivascular & peribronchial cell 3 51-75% of sample infiltration >10 cells thick 4 >75% of sample

[0246] The virus load was initially determined by quantification of the number of RSV RNA copies in the lung samples using reverse transcriptase (RT-) PCR. RNA was extracted from the lung homogenate samples using the MagNA Pure LC Total Nucleic Acid kit (Roche Diagnostics) automated extraction system according to the manufacturer's instructions. Detection of RSV RNA was performed by single-tube real-time RT-PCR using the LightCycler instrument and reagents (Roche Diagnostics) with primers and fluorophore-labeled probes specific for the N gene of RSV subtype A as described by Whiley et al. (J. Clinical Microbiol. 2002, 40: 4418-22). Samples with known RSV RNA copy numbers were similarly analyzed to derive a standard curve.

[0247] Subsequently, the number of RSV RNA copies in the lung samples was determined using quantitative reverse transcriptase (RT-) PCR. RNA was extracted from the lung homogenate samples using the RNeasy mini kit (Qiagen) according to the manufacturer's instructions. Detection of RSV RNA was performed by using the SuperScript III Platinum One-Step Quantitative RT-PCR System (Invitrogen) with primers and fluorophore-labeled probes specific for the N gene of RSV subtype A as described in Table 5b below. Samples with known RSV RNA copy numbers were similarly analyzed to derive a standard curve.

TABLE-US-00006 TABLE 5b RSV subtype A specific primers and probe for quantitative RT-PCR. Name Sequence 5'-3' RSV-A forward CAA CAA AGA TCA ACT TCT GTC ATC RSV-A reverse GCA CAT CAT AAT TAG GAG TAT CAA T RSA Probe 6-FAM-CA CCA TCC AAC GGA GCA CAG GAG AT-TAMRA

[0248] The levels of different cytokines and chemokines in lung tissue samples were determined by a commercial multiplexed immunoassay at Rules-Based Medicine (Austin, Tex.) using their rodent multi-analyte profile (MAP).

k-2 Cotton Rat Challenge Model

[0249] 6-8-weeks old female cotton rats (Sigmodon hispidus) are inoculated intraperitoneally with 0.5 ml antibody preparation or placebo (PBS) on day-1 of study. 24 hours later, the animals are lightly anaesthetised with isofluorane and given an intranasal challenge of 10^-6-10^-7 pfu RSV strain A2 or control medium (mock inoculum). A total volume of 100 μl inoculum is administered and distributed evenly to both nares. After completion of the intranasal challenge each animal is held in the upright position for a minimum of 30 seconds to allow full inspiration of the inoculum. Five days after challenge, the animals are killed by lethal intraperitoneal injection of pentobarbitone and exsanguinated by cardiac puncture. Serum samples are obtained and frozen at -80° C. and each animal is dissected under aseptic conditions for removal of lungs and nasal tissue. The tissue samples are homogenized and the supernatants stored in aliquots at -80° C.

[0250] The virus load in the tissue samples is determined by quantification of the number of RSV RNA copies by a Taq-Man real-time assay based on the method of Van Elden et al. (J Clin Microbiol. 2003, 41(9):4378-4381). Briefly, RNA is extracted from the lung homogenate samples using the RNeasy (Qiagen) method according to the manufacturer's instructions. The extracted RNA is reverse transcribed into cDNA and subsequently amplified by PCR using the Superscript III Platinum One Step Quantitative RT-PCR System (Invitrogen) with primers and labelled probes specific for the N gene of RSV subtype A. Samples with known RSV concentrations are similarly analyzed to derive a standard curve.

k-3 Pharmacokinetics Study in Mice

[0251] 7-8-weeks old female BALB/c mice were inoculated intraperitoneally with 0.2 ml antibody preparation on day 0. Serum samples were taken from the orbital plexus at multiple time points (0 hours, 4 hours, 25 hours, days 3, 6, 9, 13, 16, 21, 24, and 29) after antibody treatment. Mice were sacrificed by cervical dislocation at days 1 (25 hours), 6 and 29 and lung tissues were removed and homogenized in 1.5 ml buffer using a tissuelyzer (Qiagen). The lung homogenates were afterwards centrifuged to sediment cell debris and supernatants were stored at -70° C. The levels of human antibody present in serum samples and lung homogenates were measured using a human IgG1 kappa ELISA.

Example 2

[0252] In the present Example the isolation, screening, selection and banking of clones containing cognate V_H and V_L pairs expressed as full-length antibodies with anti-RSV specificity was illustrated.

Donors

[0253] A total of 89 donors were recruited among the employees and parents of the children who were hospitalized at the Department of Paediatrics at Hvidovre Hospital (Denmark) during the RSV season. A initial blood sample of 18 ml was drawn, CD19.sup.+ B cells were purified (Example 1, Section a) and screened for the presence of anti-RSV antibodies using ELISpot (Example 1, Section b) and the frequency of plasma cells was determined by FACS analysis.

[0254] Eleven donors were found positive in the screening of the initial blood samples and a second blood sample of 450 ml was collected from ten of these. The plasma blasts were single-cell sorted according to Example 1, Section a. ELISpot was performed on a fraction of the CD19 positive B cells.

[0255] Four donors with ELISpot frequencies in the second blood donation between 0.2 and 0.6% RSV specific plasma cells (IgG.sup.+ and IgA.sup.+) of the total plasma cell population were identified. These frequencies were considered high enough to proceed to linkage of repertoires of cognate Y_R and V_L pairs.

Isolation of Cognate V_H and V_L Coding Pairs

[0256] The nucleic acids encoding the antibody repertoires were isolated from the single cell-sorted plasma cells from the five donors, by multiplex overlap-extension RT-PCR (Example 1, section c). The multiplex overlap-extension RT-PCR creates a physical link between the heavy chain variable region gene fragment (V_H) and the full-length light chain (LC). The protocol was designed to amplify antibody genes of all V_H-gene families and the kappa light chain, by using two primer sets, one for V_H amplification and one for the LC amplification. Following the reverse transcription and multiplex overlap-extension PCR, the linked sequences were subjected to a second PCR amplification with a nested primer set.

[0257] Each donor was processed individually, and 1480 to 2450 overlap products were generated by the multiplex overlap-extension RT-PCR. The generated collection of cognate linked V_H and V_L coding pairs from each donor were pooled and inserted into a mammalian IgG expression vector (FIG. 3) as described in Example 1 section d). The generated repertoires were transformed into E. coli, and consolidated into twenty 384-well master plates and stored. The repertoires constituted between 1×10⁶ and 3.6×10⁶ clones per donor.

Screening

[0258] IgG antibody-containing supernatants were obtained from CHO cells transiently transfected with DNA prepared from bacterial clones from the master plates. The supernatants were screened as described in Example 1, section e. Approximately 600 primary hits were sequenced and aligned. The majority fell in clusters of two or more members, but there were also clones that only were isolated once, so-called singletons. Representative clones from each cluster and the singletons were subjected to validation studies as described in Example 1, section e). A number of the primary hits were excluded from further characterization due to unwanted sequence features such as unpaired cysteines, non-conservative mutations, which are potential PCR errors, insertions and/or deletion of multiple codons, and truncations.

[0259] A total of 85 unique clones passed the validation. These are summarized in Table 6. Each clone number specifies a particular V_H and V_L pair. The IGHV and IGKV gene family is indicated for each clone and specifies the frame work regions (FR) of the selected clones. The amino acid sequence of the complementarity determining regions (CDR) of an antibody expressed from each clone are shown, where CDRH1, CDRH2, CDRH3 indicate the CDR regions 1, 2 and 3 of the heavy chain and CDRL1, CDRL2 and CDRL3 indicate the CDR regions 1, 2 and 3 of the light chain.

[0260] The complete variable heavy and light chain sequence can be established from the information in Table 6.

[0261] Further details to the individual columns of Table 6 are given below.

[0262] The IGHV and IGKV gene family names, were assigned according to the official HUGO/IMGT nomenclature (IMGT; Lefranc & Lefranc, 2001, The Immunoglobulin FactsBook, Academic Press). Numbering and alignments are according to Chothia (Al-Lazikani et al. 1997 J. Mol. Biol. 273:927-48). Clone 809 has a 2 codon insertion 5' to CDRH1, which likely translates into an extended CDR loop. Clone 831 has a 1 codon deletion at position 31 in CDRH1.

[0263] The column "Ag" indicates the RSV associated antigen recognized by the antibody produced from the named clone, as determined by ELISA, FLISA and/or Biacore. "+" indicates that the clone binds to RSV particles and/or RSV-infected cells, but that the antigen has not been identified.

[0264] The column "Epitope" indicates the antigenic site or epitope recognized by the antibody produced from the named clone (see Table 4 and below). "U" indicates that the epitope is unknown. UCI and UCII refer to unknown cluster I and II. Antibodies belonging to these clusters have similar reactivity profiles but have currently not been assigned to a particular epitope. Some antibodies recognize complex epitopes, such as A&C. Epitopes indicated in ( ) have only been identified in ELISA.

TABLE-US-00007 TABLE 6 Summary of sequence and specificity of each unique validated clone. CDRH1 CDRH2 CDRH3 CDRL1 CDRL2 CDRL3 3 3 5 6 9 0 0 2 3 3 5 8 9 9 Clone IGHV gene lab2345 012abc3456789012345 234567890abcdefghijklmn123 IGKV gene 45678901abcdef234 0123456 89012345ab678 Ag Epitope 735 4-59 D--YDWS NIN---YRGNTNYNPSLKS CARDVGYGGGQYFAM--------DVW 3-11 RASQSVNS------HLA NTFNRVT CQQRSNWPPALTF F UCI 736 3-30 T--YGMH FIRY--DGSTQDYVDSVKG CAKDMDYYGSRSYSVTYYYGM--DVW 1-39 RASQRISN------HLN GASTLQS CQQSYRTPP-INF F A/II 743 1-69 T--YALT RITP--MFDITNYAQKFQG CARRGAVALVPAAEDPYYYGM--DVW 2-28 RSSQSLLHS-NGNNYLD LASNRAS CMQSLQT---PTF G Centr. dom 744 1-2 G--YYMH WINT--SSGGTNYAQKFQG CAREDGTMGTNSWYGWF------DPW 3-20 RASQSVSSS-----YLA GASSRAT CQQYDSSLSTWTF F A/II 793 3-11 D--YYMS YINR--GGTTIYYADSVKG CARGLILALPTATVELGAF----DIW 1-39 RASQSITG------YLN ATSTLQS CQQSYNT---LTF G Conserved 794 1-18 N--YGLN WINA--YNDNTYYSPSLQG CARSYRSQTDILTGRYKGPGDVFDNW 1-12 RASEGISS------WLA AASTLQS CQQTNSFP--YTF G GCRRA 795 4-30-4 SGDYYWS YIF---HSGTTYYNPSLKS CARDVDDFPVWGMNRYL------ALW 3-20 RASQSVSSS-----YLA GASTGAT CQQYGRTP--YTF F UCI 796 3-30 H--FGMH IISY--DGNNVHYADSVKG CAKDDVATDLAAYYYF-------DVW 2-29 RSSQSLLRS-DGKTFLY EVSSRFS CMQGLKIR--RTF G Conserved 797 1-18 R--FGIS WISA--DNGNTYYAQNFQD CVRGGVVTNRVYYYYGM------DVW 1-9 RASQGISS------YLA AASTLQS CQQVDTYP--LTF G GCRRA 798 7-4-1 S--YVMN WINT--NTGDPAYAQDFTG CAWFGEFGLF-------------DYW 1-16 RASQDINN------YLA AASSLQS CQQYKSLP--FTF G GCRRA 799 3-30 N--YGMH VISY--DGRNKYFADSVKG CARGSVQVWLHLGLF--------DNW 1-5 RASQSVSS------WVA EASNLES CQQYHSYSG-YTF F U 800 3-33 D--YGMN VIWH--DGSNKNYLDSVKG CARTPYEFWSGYYF---------DFW 1D-13 RASQGITD------SLA AASRLES CQQYSKSP--ATF F F1 801 3-33 S--YAMH VIYY--EGSNEYYADSVKG CARKWLGM---------------DFW 2-28 RSSQSLLNS-NGFNYVD LGSNRAS CMQALETP--LTF F F1 802 3-48 S--YEMN YIGT--GGSDIYYGDSVKG CARARPGYKV-------------DFW 1-9 RASQGISS------YLA VASILES CQQSKSFP--PTF F U 803 4-30-4 SGDYFWS YIY---SSGSTFYNASLKS CARGGTLYTTGGEM---------HIW 3-20 RASQTVSSS-----YLV GASTRAT CQQYGGSG--LTF F U 804 3-64 N--YAMH ATST--DGGSTYYADSLKG CARRFWGFGNFF-----------DYW 3-20 RASQSVSSG-----YLA GASGRAT CQQYFGSP--YTF F F1 805 4-59 G--DFWS YIY---YRGSTYYNPSLKS CAREGHHSGSGDYYSFF------DYW 1-39 RASQGINT------YLN AASSLQS CQQSANSP--HTF F (F1) 806 5-51 S--YWIG IVYP--GDSDTTYSPSFQG CVRRGGFCTATGCYAGHWF----DPW 3-20 RASQSISSG-----YLA GASHRAT CQQYGSSL--WTF + U 808 2-70 TTRMSVS RID---WDDDKYYSTSLKT CARIVFHTSGGYYNPYM------DVW 1-39 RASQTIAS------YLS TASSLQS CQHSYNTP--YTF F (F1) 809 5-51 FVSTWIG IINP--ADSDTRYSPSFQG CARRAYDSGWHF-----------EHW 3D-15 RASQSVGS------KLA GASTRAT CQQYNNWPP-YTF F (F1) 810 1-69 N--YAIN RIIP--VFDTTNYAQKFQG CLRGSTRGWDTDGF---------DIW 1D-17 RASQGISN------YLV AASSLQS CLQHNISP--YTF F A/II 811 1-46 N--YYIH VINP--NGGSTTSAQKFQD CARQRSVTGGFDAWLLIPDAS--NTW 4-1 RSSETVLYTSKNQSYLA WASTRES CQQFFRSP--FTF G Conserved 812 1-69 S--YSIS MILP--ISGTTNYAQTFQG CARVFREFSTSTLDPYYF-----DYW 3-20 RASQSVSSS-----YIA AASRRAT CQHYGNSL--FTF F F1 813 5-51 S--YWIG IIYP--GDSDTRNSPSFQG CVRQGGYYDRNGYHEKYAF----DIW 1-5 RASQSISS------WLA KSSILES CQHYNSYS--GTF F (F1) 814 3-30-3 D--YAMH VISY--DGANEYYAESVKG CARAGRSSMNEEVIMYF------DNW 1-5 RASQSIGS------RLA DASSLES CQQYNRDSP-WTF G Conserved 816 3-23 T--YAMT VIRA--SGDSEIYADSVRG CANIGQRRYCSGDHCYGHF----DYW 2-28 RSSQSLLHS-DGRYYVD LASNRAS CMQGLHTP--WTF G Conserved 817 3-30 T--HGMH IISL--DGIKTHYADSVKG CAKDHIGGTNAYFEWTVPF----DGW 3-15 WASQTIGG------NLA GASTRAT CQQYKNW---YTF F A/II 818 2-70 AGRVGVS RID---WDDDKAFRTSLKT CARTQVFASGGYYLYYL------DHW 1-39 RASQTIAS------YVN AASNLQS CQQSYSYRA-LTF F B/I/F1 819 4-30-4 GADYYWS FIY---DSGSTYYNPSLRS CARDLGYGGNSYSHSYYYGL---DVW 3-11 RASQSVSS------SLA DASYRVT CQQRSNWPPGLTF F A/II 822 5-51 N--SWIG IIYP--GDSTTTYTPSFQG CARQGRGF---------------GLW 1D-33 QASQDITY------YLS DVSNLER CQQYDFLP--YTF F U 823 4-b SG-HFWG SIF---HSGTTFHNPSLKS CARVHGGGF--------------DHW 1D-33 QASQDIGD------SLN DASNLET CQHYVNLPPSFTF + U 824 4-59 N--YYWG HIY---FGGNTNYNPSLQS CARDSSNWPAGY-----------EDW 1D-13 RPSQDISS------ALA GASTLDY CQQFNTYP--FTF F A/II* (F1&C) 825 1-18 S--NGLS WISA--SSGNKKYAPKFQG CAKDGGTYVPYSDAF--------DFW 4-1 KSSQSVLYNSNNKNYLA LASTREY CQQYYQTP--LTF F A/II* (UCI) 827 1-24 A--LSKH FFDP--EDGDTGYAQKFQG CATVAAAGNF-------------DNW 1-39 RASQFISS------YLH AASTLQS CQQSYTNP--YTF F (A&C/)IV* 828 1-3 T--NGLH LINA--GNGDTRFSQKFQG CARIAITMVRNPF----------DIW 1-5 RASQSIGS------WLA KESNLES CQQYKND---WTF + A&C 829 2-70 RNRMSVS RID---WDDDKFYNTSLQT CARTGIYDSSGYYLYYF------DYW 1-39 RASQSIAS------YLN AASSLHS CQHSYSTR--FTF F U (F1) 830 1-13 T--YGVS WISA--YNGNTYYLQKLQG CARDRVGGSSSEVLSRAKNYGL-DVW 1-5 RASQSVTS------ELA KASSLES CQQYNSFP--YTF G GCRRA 831 1-3 ---YAMH WINV--GNGQTKYSQRFQG CARRASQYGEVYGNYF-------DYW 1-5 RASQNIYN------WLA DASTLES CQQYNSLS--PTF F A/II 833 3-30 Y--IGMH AISY--DGSNKQYADSVKG CAKDDFGNSNGVFFMSRV-----AFW 1-12 RANQDIDN------YLA GASKLQT CQQAKSFP--FTF G Centr. dom 834 1-18 T--YGLN WVSA--HNGNTYYAEKFHD CVRGFNEQQLVPGLSFWF-----DYW 1-12 RASQGISK------RLA GASSLQH CQQADSFP--FTF G GCRRA 835 1-18 S--YGFS WSSV--YNGDTNYAQKFHG CARDRNVVLLPAAPFGGM-----DVW 1-9 RASQGISS------YLA AASTLQS CQQLNSYP--RTF G GCRR 836 4-b SG-HYWG SIY---DSGNTYYTPSLKS CARGSPGDAF-------------DIW 1-12 RASQGIGT------WLA AASRLQS CQQAYSFP--RTF F (A/II) 838 3-30 T--FGMH VISY--DGNKKYYADSVKG CAAQTPYFNESSGLV--------PDW 1-27 RASQGISN------YLA AASTLQS CQKYNSAP--QTF G Conserved 839 3-30 S--YGLH EISY--DGGSKFYTDSVKG CARDLGDGYTAWGWF--------DPW 3-20 RASQSVGGR-----SLA DASNRAT CQQYGSPP--WTF G GCRRA 841 1-18 S--FGIS WISA--YNGNTDYAQRLQD CTRDESMLRGVTEGFGPI-----DYW 4-1 RSSQSVLYSSNNKNYLA WASTRAS CQQFHSTP--RTF G GCRRA 842 1-18 R--YGIS WISA--YNGNTYYAQNLQG CVISFDSTIAAAEYF--------DYW 1-5 RASQTISN------SLA KASTLES CQQYNSFS--FTF G GCRRA 843 1-18 N--SGVS WISA--YNGNTYYRQSLQD CAREGHYSGSSSYQRDDAF----DIW 1-16 RASQGISN------YLA TTSTLRS CQQYHSFP--YTF G GCRRA 845 1-18 S--YGIS WIGT--DNGNTYYAQKFQG CARGGTIEATPEREYYYYGM---DVW 1-9 RASQGISS------YLA AASTLQS CQQLNTYP--LTF G GCRRA 846 4-30-2 SGGYSWS YIY---HSGSTYYNPSLKS CASRSFYGDY-------------VYW 3-20 RASQSVSSS-----YLA GASSRAT CQQYGSSP--FTF F U 848 4-61 SDKNYWS RLY---PSGNTDYHPSLKS CAKEGSGWYF-------------ESW 1-5 RASQGISA------WLA DASTLAS CQQYRSYS--YTF F U 849 3-73 G--STMH RIRSKANSYATEYAASVKG CTRHVGEMSTIWWYF--------DLW 1-39 RASQSISS------YLN AASSLQS CQQSYSTP--YTF F U 850 1-3 T--YTLH LINA--ANGHTKYSQRFQG CAKSGSHYGEVYGAYF-------DYW 1-5 RASQNIYN------WLA DASSLES CQQYNIYS--PTF F (A/II) 851 1-18 S--LGFS WTSA--HNGNTYYAEEFQD CARDRGPGYSDSSFYVF------DYW 2-24 RSSQSLVNS-DGNTYLS QISKRFS CMQATQFP--FTF G GCRRA 852 1-69 G--YTIH RLVP--SLNIPNYAQKFQG CTRAPRGSTASHLLF--------DYW 1D-33 QASQDVSY------YLN DTSNLVT CLQYHYLP--YTF F U 853 5-51 N--YWIG VIFP--ADSDARYSPSFQG CARPKYYFDSSGQFSEMYYF---DFW 3-20 RASQSVSSN-----YLA GASSRAA CQQYGNSP--LTF G Centr. dom 855 1-18 N--YAFS WISG--SNGNTYYAEKFQG CARDLLRSTYF------------DYW 1D-12 RASQAISN------WLA AASSLQS CQQADTFP--FTF G GCRRA 856 1-18 N--YGFS WISA--YNGNTYYAQNLQG CARDGNTAGVDMWSRDGF-----DIW 2-40 RSSQSLLDSNDGNTYLD TFSYRAS CMQRIEFP--YTF G GCRRA 857 3-23 S--YAMN GISG--SGGSTYYGDSVKG CAKEPWIDIVVASVISPYYYDGMDVW 2-28 RSSQSLLHR-NEYNYLD WGSNRAS CMQTLQTP--RTF F F1 858 1-69 G--YTIS RVVP--TLGFPNYAQKFQG CARMNLGSHSGRPGF--------DMW 1D-33 QASQDISN------YLN DATKLET CQHFANLP--YTF F B/I/F1 859 3-33 K--YGIH VISY--DGSKKYFTDSVKG CATGGGVNVTSWSDVEHSSSL--GYW 1-27 RASQGIRN------YLA AASTLQS CQRYNSAP--LTF G Conserved 861 3-30 S--YGMH FIWN--DGSNKYYADSVKG CVKDEVYDSSGYYLYYF------DSW 1-39 RASQIIAS------YLN AASSLQS CQQSYSTPI-FTF F F1 863 3-23 S--YTMS SISA--STVLTYYADSVKG CAKDYDFWSGYPGGQYWFF----DLW 3-11 RTSQSVSS------YLA DASNRAT CQQRSDW---LTF F A/II 866 1-18 T--YGIS WISA--DNGNTYYAQKFQG CVRGGTYSSDVEYYYYGM-----DVW 1-9 RASQGISI------YLA AASTLQT CQQLNIYP--LTF G GCRRA 867 1-69 R--YTIH RVVP--SLGIPNYAPKFQG CARLTLGSYTGRPGF--------DSW 1D-33 QASQDINN------YLN DATDLET CQHFANLP--YTF F (F1) 868 4-b NA-YYWG SIH---HSGSAYYNSSLKS CARDTILTFGEPHWF--------DPW 3-15 RASQSIKN------NLA GASARAT CQEYNNWPL-LTF G Conserved 869 3-30 Y--YAMH VISY--GETNKLYADSVKG CARDLRYLTYYSGSGD-------DSW 3-20 RASQSLSDN-----YLA GASSRPT CQQYGTTP--ITF G Conserved 870 4-59 N--YYWS EIS---NTWSTNYNPSLKS CARGLFYDSGGYYLFYF------QHW 1-39 RASQRIAS------YLN AASSLQS CQQSYSTPI-YTF F (F1) 871 3-33 N--YGMH VIWY--DDSNKQYGDSVKG CARASEYSISWRHRGVL------DYW 1D-33 QASQGISN------YLN DASNLES CQQYDNFP--YTF F UCI 874 3-30 H--YGMH VISH--DGNIKYSADSVKG CHGEGYSTSWLGTAAL-------DYW 1-27 RASQGIRN------FLA AASTLQS CQKYNSAP--WTF G Conserved 879 3-23 A--YAMS AISG--GGGTTYYADSVKG CAKTRGYSYTWGDAF--------DLW 3-15 RASQSVTS------NLA GASTRAT CQQYNNWP--QTF F U 880 2-5 TSKLGVG LVD---WDDDRRYRPSLKS CAHSAYYTSSGYYLQYF------HHW 1-39 RASQTIAS------YVN AASSLQS CQQSYSFP--YTF F UCII 881 3-48 S--YEMT HIGN--SGSMIYYADSVKG CARSDYYDSSGYYLLYL------DSW 1-39 RASQTIAS------YVN AASNLQS CQQSYSVPR-LTF F UCII 884 1-3 N--FAMH YINA--VNGNTQYSQKFQG CARNNGGSAIIF-----------YYW 1-39 RSSQTISV------FLN AASSLHS CQESFSS---STF F U 885 4-b SN-YYWG SMH---HSGSSYYKPSLKS CARDLVVVTDISIKNYF------DPW 3-11 RASQSVTK------YLA DASNRAT CQHRRSW---PTF + U 886 3-30 S--YGMH VISN--DGSNKYYADSVKG CAKTTDQRLLVDWF---------DPW 3-15 RASQSVSS------NLA SASTRAT CQQYNMWPP-WTF F A/II 887 2-70 TSRMSVS RID---WDDDKYYSTSLKT CARTLVYAPDSYYLYYF------DYW 1-39 RASQTIAS------YVN AASRLQS CQQSYSIP--WTF F U (F1) 888 4-39 SSNFYWG SIF---YSGTTYYNPSLKS CARHGFRYCNNGVCSINLDAF--DIW 2-28 RSSQSLLRT-NGYNYLD LGSIRAS CMQSLQTS--ITF G GCRR 889 1-18 T--YGIS WISA--YNGNTFYAQRLQG CARDLRMLPGGLPTRRGM-----DVW 1-5 RASQSISS------WLA KASSLES CQQYNSYP--YTF G GCRRA 890 1-46 K--FYIH IINP--SGGSTTYAQTFQD CARGIREGGVSVEDWMLVYSWF-DPW 1-39 RASQNIRT------FIN AASKLES CQQGHSTP--YTF G Conserved 891 3-30 S--YTMH VVSY--DGNHNDYADSVKG CVRAPGSMGL-------------DVW 2-28 RSSQSLLHR-NGYNHLD LGSNRAS CMQALQTP--RTF G Centr. dom 892 3-15 N--AWMS LIKSHFEGGATDYAAPVKG CAPLGGPTPF-------------DYW 1-17

RAGQGIRN------DLG GASTLQS CLQHNSYP--WTF + U 893 3-30 I--YGMH VISY--DGAKKFYANSVKG CATASTYFYDSR-----------DYW 2-24 RSSRSLVHS-DGNTYLS KISNRFS CLQATQF---LTF G Conserved 894 3-33 D--YGMH VIWH--DGSNIRYADSVRG CARVPFQIWSGLYF---------DHW 3-15 RASQSVGN------NLA GASTRAT CQQYDKWP--ETF F C* (UCI) 924 4-b SE-YYWG SVH---HSGSTYYNPSLKS CARDRVALGVHYWYF--------DIW 3-15 RASQSVSS------HLA GASTRAT CQQYDNWL--PTF G Centr. dom 955 1-46 D--YCMH ILNP--DGGTTFYAEKFQD CAILIARAYCGLADGQEGDF---DTW 1-5 RASRSITS------WLA KASSLQS CQQYNSYP--LTF SH A2 aa42-64 *new binding experiments have confirmed binding to the epitope with asterisk

[0265] The amino acid sequences from top to bottom in the column termed CDRH1 are set forth in the same order in SEQ ID NOs: 201-285.

[0266] The amino acid sequences from top to bottom in the column termed CDRH2 are set forth in the same order in SEQ ID NOs. 286-370.

[0267] The amino acid sequences from top to bottom in the column termed CDRH3 are set forth in the same order in SEQ ID NOs: 371-455.

[0268] The amino acid sequences from top to bottom in the column termed CDRL1 are set forth in the same order in SEQ ID NOs. 456-540.

[0269] The amino acid sequences from top to bottom in the column termed CDRL2 are set forth in the same order in SEQ ID NOs: 541-625.

[0270] The amino acid sequences from top to bottom in the column termed CDRL3 are set forth in the same order in SEQ ID NOs. 626-710.

Characterization of Antigen Specificity

[0271] During validation the antigen specificity of the clones was determined to some degree by the binding to viral particles, soluble G and F protein as well as fragments of the G protein.

[0272] For clones with anti-F reactivity the specificity of the individual antibodies expressed from the clones was assessed further in order to determine the antigenic site and, if possible, the epitope bound by the individual clones (see Example 1, Section g-4). FIG. 4, illustrates characterization of the epitope specificity of antibody obtained from clone 801 using Biacore analysis. The analysis show that when protein F is blocked by 133-1h or Palivizumab (antigenic site C and II, respectively) prior to injection of antibody 801 into the Biacore cell, a high degree of antibody 801 binding can be detected. The binding of competed 801 antibody is reduced a little when compared to binding of uncompeted 801 antibody. The reduction is however so low that it is more likely to be due to steric hindrance than direct competition for the binding site. Blockage of protein F with the 9c5 antibody (antigenic site F1) prior to injection of antibody 801 into the Biacore cell shows an almost complete inhibition of antibody 801 binding to the F protein. It is therefore concluded that antibody 801 binds protein F at the F1 site, or very close to it.

[0273] For clones with anti-G reactivity the specificity of the individual antibodies expressed from the clones was assessed further to determine whether the individual antibody binds to the central domain of the G protein, to the conserved region, or to the GCRR, and also whether the epitope is conserved or subtype specific. This was done by ELISA and/or FLISA using the following G protein fragments:

G(B):residue 66-292 from RSV strain 18537 (expressed in DG44 CHO cells) G(B) Fragment: Residue 127-203 from RSV strain 18537 (expressed in E. coli) GCRR A: Residues 171-187 from RSV strain Long (synthesized with selectively formed cysteine bridges) GCRR B: Residues 171-187 from RSV strain 18537 (synthesized with selectively formed cysteine bridges) G conserved: Residues 164-176

[0274] Additional epitope analyses were also performed on the anti-G reactive clones by competition assays as described in Example 1, Section g-4.

[0275] Further, one of the clones identified in a screening procedure as described in Example 1, Section e, produces an SH specific antibody. Additionally, a number of clones bind one or more of the tested RSV strains, but the antigen has not been determined.

[0276] Data relating to antigen specificity for all the validated clones are summarized in Table 6. None of the validated clones bind to human laryngeal epithelial cells, nor does any of the tested G-specific clones (793, 816, 835, 841, 853, 855, 856, and 888) bind to human fractalkine (CX3CL1).

Characterization of Binding Kinetics

[0277] The binding affinity for recombinant RSV antigens was determined by surface plasmon resonance for a number antibody clones. The analysis was performed with Fab fragments prepared by enzymatic cleavage of the full-length antibodies. Data for a number of high-affinity antibody clones with K_D values in the picomolar to nanomolar range is presented in Table 7. Fab fragments derived from commercially available Palivizumab (Synagis) were similarly analyzed for reference.

TABLE-US-00008 TABLE 7 Kinetic binding constants and affinities of selected clones. Fab clone k_on k_off t₁/2 K_D (antigen) (10⁵M^-1s^-1) (10^-5 l/s) (min) (pM) 735 (F) 4.07 9.18 130 226 810 (F) 17.40 34.80 33 200 818 (F) 1.92 2.20 530 115 817 (F) 0.92 7.54 150 820 819 (F) 3.56 4.99 230 140 825 (F) 7.72 15.00 77 195 858 (F) 4.97 0.34 3400 7 831 (F) 3.72 42 28 1130 796 (G) 8.33 40.3 28.67 480 811 (G) 4.98 17.1 68 340 816 (G) 20.20 17.80 65 90 838 (G) 2.64 5.06 230 190 853 (G) 17.7 140 8.25 790 859 (G) 3.8 4.63 250 120 Synagis (F) 2.00 75.70 15 3780

Generation of a Cell Bank of Clones Expressing an Individual Antibody

[0278] A subset of 47 unique cognate V_H and V_L coding pairs corresponding to clone nr 735, 736, 744, 793, 795, 796, 799, 800, 801, 804, 810, 811, 812, 814, 816, 817, 818, 819, 824, 825, 827, 828, 829, 830, 831, 835, 838, 841, 853, 855, 856, 857, 858, 859, 861, 863, 868, 870, 871, 880, 881, 884, 885, 886, 888, 894 and 955 in Table 6 were selected for the generation of stable individual expression cell lines which each express a unique antibody from a single V_H and V_L gene sequence. The full sequences (DNA and deduced amino acid) of 44 selected clones (the above-identified except 828, 885, and 955) are shown in SEQ ID NOs 1-176.

[0279] The 44 clones are characterized by producing the following V_H sequences, which are set forth in SEQ ID NOs. 1-44:

TABLE-US-00009 Clone No. 735: QVQLQESGPGLVKPSETLSLTCTVSNGAIGDYDWSWIRQSPGKGLEWIGNIN YRGNTNYNPSLKSRVTMSLRTSTMQFSLKLSSATAADTAVYYCARDVGYGG GQYFAMDVWSPGTTVTVSS Clone No. 736: QVQLVESGGGVVQPGGSLRLSCTASGFTFSTYGMHWVRQAPGKGLEWVAFI RYDGSTQDYVDSVKGRFTISRDNSKNMVYVQMNSLRVEDTAVYYCAKDMD YYGSRSYSVTYYYGMDVWGQGTTVTVSS Clone No. 744: QVQLVQSGAEVKKPGASVKVSCKASGYTFSGYYMHWVRQAPGQGLEWMG WINTSSGGTNYAQKFQGRVTMTRDTSISTAHMELRRLRSDDTAVYYCARED GTMGTNSWYGWFDPWGQGTLVTVSS Clone No. 793: QVQLVESGGGLVKPGGSLRLSCAASGFPFGDYYMSWIRQAPGKGLEWVAYI NRGGTTIYYADSVKGRFTISRDNAKNSLFLQMNSLRAGDTALYYCARGLILA LPTATVELGAFDIWGQGTMVTVSS Clone No. 795: QVQLQESGPGLVKPSQTLSLTCTVSGASISSGDYYWSWIRQSPRKGLEWIGYI FHSGTTYYNPSLKSRAVISLDTSKNQFSLRLTSVTAADTAVYYCARDVDDFP VWGMNRYLALWGRGTLVTVSS Clone No. 796: QVQLVESGGGVVQPGRSLRLSCAASGFSFSHFGMHWVRQVPGKGLEWVAIIS YDGNNVHYADSVKGRFTISRDNSKNTLFLQMNSLRDDDTGVYYCAKDDVA TDLAAYYYFDVWGRGTLVTVSS Clone No. 799: QVQLVESGGGVVQPGRSLKLSCEASGFNFNNYGMHWVRQAPGKGLEWVAV ISYDGRNKYFADSVKGRFIISRDDSRNTVFLQMNSLRVEDTAVYYCARGSVQ VWLHLGLFDNWGQGTLVTVSS Clone No. 800: QVQLVESGGAVVQPGRSLRLSCEVSGFSFSDYGMNWVRQGPGKGLEWVAVI WHDGSNKNYLDSVKGRFTVSRDNSKNTLFLQMNSLRAEDTAVYYCARTPYE FWSGYYFDFWGQGTLVTVSS Clone No. 801: QVQLVESGGGVVQPGRSLRLSCAASGFPFNSYAMHWVRQAPGKGLEWVAVI YYEGSNEYYADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARKWLG MDFWGQGTLVTVSS Clone No. 804: EVQLVESGGGLVRPGGSLRLSCSASGFTFSNYAMHWVRQAPGKRLEYVSAT STDGGSTYYADSLKGTFTISRDNSKNTLYLQMSSLSTEDTAIYYCARRFWGFG NFFDYWGRGTLVTVSS Clone No. 810: QVQLVQSGAEVKKSGSSVKVSCRASGGTFGNYAINWVRQAPGQGLEWVGRI IPVFDTTNYAQKFQGRVTITADRSTNTAIMQLSSLRPQDTAMYYCLRGSTRG WDTDGFDIWGQGTMVTVSS Clone No. 811: QVQLVQSGAVVETPGASVKVSCKASGYIFGNYYIHWVRQAPGQGLEWMAVI NPNGGSTTSAQKFQDRITVTRDTSTTTVYLEVDNLRSEDTATYYCARQRSVT GGFDAWLLIPDASNTWGQGTMVTVSS Clone No. 812: QVQLVQSGAEMKKPGSSVKVSCKASGGSFSSYSISWVRQAPGRGLEWVGMI LPISGTTNYAQTFQGRVIISADTSTSTAYMELTSLTSEDTAVYFCARVFREFST STLDPYYFDYWGQGTLVTVSS Clone No. 814: QVQLVESGGGVVQPGKSVRLSCVGSGFRLMDYAMHWVRQAPGKGLDWVA VISYDGANEYYAESVKGRFTVSRDNSDNTLYLQMKSLRAEDTAVYFCARAG RSSMNEEVIMYFDNWGLGTLVTVSS Clone No. 816: EVQLLESGGGLVQPGGSLRLSCVASGFTFSTYAMTWVRQAPGKGLEWVSVI RASGDSEIYADSVRGRFTISRDNSKNTVFLQMDSLRVEDTAVYFCANIGQRR YCSGDHCYGHFDYWGQGTLVTVSS Clone No. 817: QVQLVESGGGVVQPGRSLRLSCAASGFGFNTHGMHWVRQAPGKGLEWLSII SLDGIKTHYADSVKGRFTISRDNSKNTVFLQLSGLRPEDTAVYYCAKDHIGGT NAYFEWTVPFDGWGQGTLVTVSS Clone No. 818: QVTLRESGPAVVKPTETLTLTCAFSGFSLNAGRVGVSWIRQPPGQAPEWLARI DWDDDKAFRTSLKTRLSISKDSSKNQVVLTLSNMDPADTATYYCARTQVFA SGGYYLYYLDHWGQGTLVTVSS Clone No. 819: QVQLQESGPGLVKPSQTLSLTCTVSSGAISGADYYWSWIRQPPGKGLEWVGF IYDSGSTYYNPSLRSRVTISIDTSKKQFSLKLTSVTAADTAVYYCARDLGYGG NSYSHSYYYGLDVWGRGTTVTVSS Clone No. 824: QVQLQESGPGLVKPSETLSLTCTVSGGSIGNYYWGWIRQPPGKGLEWIGHIYF GGNTNYNPSLQSRVTISVDTSRNQFSLKLNSVTAADTAVYYCARDSSNWPAG YEDWGQGTLVTVSS Clone No. 825: QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSNGLSWVRQAPGQGFEWLGW ISASSGNKKYAPKFQGRVTLTTDISTSTAYMELRSLRSDDTAVYYCAKDGGT YVPYSDAFDFWGQGTMVTVSS Clone No. 827: QVQLVQSGAEVKKPGASVKVSCRVSGHTFTALSKHWMRQGPGGGLEWMGF FDPEDGDTGYAQKFQGRVTMTEDTATGTAYMELSSLTSDDTAVYYCATVAA AGNFDNWGQGTLVTVSS Clone No. 829: QVTLKESGPALVKATQTLTLTCTFSGFSLSRNRMSVSWIRQPPGKALEWLARI DWDDDKFYNTSLQTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTGIYD SSGYYLYYFDYWGQGTLVTVSS Clone No. 830: QVQLVQSGAEVKVPGASVKVSCKASGYTFTTYGVSWVRQAPGQGLEWMG WISAYNGNTYYLQKLQGRVTMTTDTSTSTAYMELRGLRSDDTAMYYCARD RVGGSSSEVLSRAKNYGLDVWGQGTTVTVSS Clone No. 831: QVQLVQSGAEVKKPGASVKVSCKASANIFTYAMHWVRQAPGQRLEWMGWI NVGNGQTKYSQRFQGRVTITRDTSATTAYMELSTLRSEDTAVYYCARRASQ YGEVYGNYFDYWGQGTLVTVSS Clone No. 835: QVQLVQSGAEVKRPGASVKVSCKASGYTFISYGFSWVRQAPGQGLEWMGW SSVYNGDTNYAQKFHGRVNMTTDTSTNTAYMELRGLRSDDTAVYFCARDR NVVLLPAAPFGGMDVWGQGTMVTVSS Clone No. 838: QVQLVESGGGVVQPGTSLRLSCAASGFTFSTFGMHWVRQAPGKGLEWVAVI SYDGNKKYYADSVKGRFTISRDNSKNTLYLQVNSLRVEDTAVYYCAAQTPY FNESSGLVPDWGQGTLVTVSS Clone No. 841: QVQLVQSGAEVKKPGASVKVSCKASGYTFISFGISWVRQAPGQGLEWMGWI SAYNGNTDYAQRLQDRVTMTRDTATSTAYLELRSLKSDDTAVYYCTRDESM LRGVTEGFGPIDYWGQGTLVTVSS Clone No. 853: EVQLVQSGAEVKKPGQSLKISCKTSGYIFTNYWIGWVRQRPGKGLEWMGVIF PADSDARYSPSFQGQVTISADKSIGTAYLQWSSLKASDTAIYYCARPKYYFDS SGQFSEMYYFDFWGQGTLVTVSS Clone No. 855: QVQLVQSGPEVKKPGASVKVSCKASGYVLTNYAFSWVRQAPGQGLEWLGW ISGSNGNTYYAEKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYFCARDLLR STYFDYWGQGTLVTVSS Clone No. 856: QVQLVQSGAEVKKPGASVKVSCKASGYTFSNYGFSWVRQAPGRGLEWMG WISAYNGNTYYAQNLQGRVTMTTDTSTTTAYMVLRSLRSDDTAMYYCARD GNTAGVDMWSRDGFDIWGQGTMVTVSS Clone No. 857: EVQLLESGGGLVQPGGPLRLSCVASGFSFSSYAMNWIRLAPGKGLEWVSGIS GSGGSTYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKEPWIDI VVASVISPYYYDGMDVWGQGTTVTVSS Clone No. 858: QVQLVQSGAEVKKPGSSVKVSCKASGGSFDGYTISWLRQAPGQGLEWMGR VVPTLGFPNYAQKFQGRVTVTADRSTNTAYLELSRLTSEDTAVYYCARMNL GSHSGRPGFDMWGQGTLVTVSS Clone No. 859: QVQLVESGGGVVQPGRSLRLSCAVSGSSFSKYGIHWVRQAPGKGLEWVAVIS YDGSKKYFTDSVKGRFTIARDNSQNTVFLQMNSLRAEDTAVYYCATGGGVN VTSWSDVEHSSSLGYWGLGTLVTVSS Clone No. 861: QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFI WNDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVKDEV YDSSGYYLYYFDSWGQGTLVTVSS Clone No. 863: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVSSIS ASTVLTYYADSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYCAKDYDFW SGYPGGQYWFFDLWGRGTLVTVSS Clone No. 868: QVQLQESGPGLVTPSETLSVTCTVSNYSIDNAYYWGWIRQPPGKGLEWIGSIH HSGSAYYNSSLKSRATISIDTSKNQFSLNLRSVTAADTAVYYCARDT$$TFGEP

HWFDPWGQGTLVTVSS Clone No. 870: QVQLQESGPGLVKPSETLSLTCTVSGDSISNYYWSWIRQPPGKGLEWIGEISN TWSTNYNPSLKSRVTISLDMPKNQLSLKLSSVTAADTAVYYCARGLFYDSGG YYLFYFQHWGQGTLVTVSS Clone No. 871: QVQLVESGGGVVQPGRSLRVSCAASGFTFSNYGMHWVRQAPGKGLEWVAV IWYDDSNKQYGDSVKGRFTISRDNSKSTLYLQMDRLRVEDTAVYYCARASE YSISWRHRGVLDYWGQGTLVTVSS Clone No. 880: QITLKESGPTLVRPTQTLTLTCTFSGFSLSTSKLGVGWIRQPPGKALEWLALV DWDDDRRYRPSLKSRLTVTKDTSKNQVVLTMTNMDPVDTATYYCAHSAYY TSSGYYLQYFHHWGPGTLVTVSS Clone No. 881: EVQLVESGGGVVQPGGSLRLSCEVSGFTFNSYEMTWVRQAPGKGLEWVSHI GNSGSMIYYADSVKGRFTISRDNAKNSLYLQMNSLRVEDTAVYYCARSDYY DSSGYYLLYLDSWGHGTLVTVSS Clone No. 884: QVQLVQSGAEVRKPGASVKVSCKASGHTFINFAMHWVRQAPGQGLEWMGY INAVNGNTQYSQKFQGRVTFTRDTSANTAYMELSSLRSEDTAVYYCARNNG GSAIIFYYWGQGTLVTVSS Clone No. 886: QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYGMHWVRQAPGKGLEWVAVI SNDGSNKYYADSVKGRFTISRDNSKKTMYLQMNSLRAEDTAVYFCAKTTDQ RLLVDWFDPWGQGTLVTVSS Clone No. 888: QLQLQESGPGLVKPSETLSLTCTASGGSINSSNFYWGWIRQPPGKGLEWIGSIF YSGTTYYNPSLKSRVTISVDTSKNQFSLKLSPVTAADTAVYHCARHGFRYCN NGVCSINLDAFDIWGQGTMVTVSS Clone No. 894: QVQLVESGGGVVQPGKSLRLSCAASGFRFSDYGMHWVRQAPSKGLEWVAVI WHDGSNIRYADSVRGRFSISRDNSKNTLYLQMNSMRADDTAFYYCARVPFQI WSGLYFDHWGQGTLVTVSS These V_H amino acid sequences are in the clones encoded by the following nucleic acid sequences, which are also set forth as SEQ ID NOs. 45-88: Clone No. 735: caggtgcagctgcaggagtcgggcccaggactggtgaagccttcggagaccctgtccctcacgtgcactgtgtc- taatgg cgccatcggcgactacgactggagctggattcgtcagtccccagggaagggactggagtggattgggaacataa- attaca gagggaacaccaactacaacccctccctcaagagtcgagtcaccatgtccctacgcacgtccacgatgcagttc- tccctga agctgagctctgcgaccgctgcggacacggccgtctattactgtgcgagagatgtaggctacggtggcgggcag- tatttc gcgatggacgtctggagcccagggaccacggtcaccgtctcgagt Clone No. 736: caggtgcagctggtggagtctgggggaggcgtggtccagcctggggggtccctgagactctcctgtacagcgtc- tggatt caccttcagtacctatggcatgcactgggtccgccaggctcccggcaaggggctggaatgggtggcatttatac- ggtatga tggaagtactcaagactatgtagactccgtgaagggccgattcaccatctccagagacaattccaagaatatgg- tgtatgtg cagatgaacagcctgagagttgaggacacggctgtctattactgtgcgaaagacatggattactatggttcgcg- gagttattc tgtcacctactactacggaatggacgtctggggccaagggaccacggtcaccgtctcgagt Clone No. 744: caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttc- tggata caccttcagcggctattatatgcactgggtgcgacaggcccctggacaagggcttgagtggatgggatggatca- acacta gcagtggtggcacaaactatgcgcagaagtttcagggcagggtcaccatgaccagggacacgtccatcagcaca- gccca catggaactgaggaggctgagatctgacgacacggccgtgtattattgtgcgagagaggacggcaccatgggta- ctaata gttggtatggctggttcgacccctggggccagggaaccctggtcaccgtctcgagt Clone No. 793: caggtgcagctggtggagtctgggggaggcttggtcaagcctggggggtccctgagactctcctgtgcggcctc- tggatt ccccttcggtgactactacatgagctggatccgccaggctccagggaagggactggagtgggttgcatacatta- atagag gtggcactaccatatactacgcagactctgtgaagggccgattcaccatctccagggacaacgccaagaactcc- ctgtttct gcaaatgaacagcctgagagccggggacacggccctctattactgtgcgagagggctaattctagcactaccga- ctgcta cggttgagttaggagcttttgatatctggggccaagggacaatggtcaccgtctcgagt Clone No. 795: caggtgcagctgcaggagtcgggcccaggactggtgaagccttcacagaccctgtccctcacctgcactgtctc- tggtgc ctccatcagcagtggtgattattactggagttggatccgtcagtctccaaggaagggcctggagtggattgggt- acatcttcc acagtgggaccacgtactacaacccgtccctcaagagtcgagctgtcatctcactggacacgtccaagaaccaa- ttctccc tgaggctgacgtctgtgactgccgcagacacggccgtctattattgtgccagagatgtcgacgattttcccgtt- tggggtatg aatcgatatcttgccctctggggccggggaaccctggtcaccgtctcgagt Clone No. 796: caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctc- tggatt cagcttcagtcactttggcatgcactgggtccgccaggttccaggcaaggggctggagtgggtggcaattatat- catatgat gggaataatgtacactatgccgactccgtaaagggccgattcaccatctccagagacaattccaagaacacgct- gtttctgc aaatgaacagcctgagagatgacgacacgggtgtgtattactgtgcgaaggacgacgtggcgacagatttggct- gcctac tactacttcgatgtctggggccgtggcaccctggtcaccgtctcgagt Clone No. 799: caggtgcagctggtggagtctgggggcggcgtggtccagcctgggaggtccctgaaactctcttgtgaagcctc- tggattc aacttcaataattatggcatgcactgggtccgccaggcaccaggcaaggggctggagtgggtggcagttatttc- atatgac ggaagaaataagtattttgctgactccgtgaagggccgattcatcatctccagagacgattccaggaacacagt- gtttctgca aatgaacagcctgcgagttgaagatacggccgtctattactgtgcgagaggcagcgtacaagtctggctacatt- tgggactt tttgacaactggggccagggaaccctggtcaccgtctcgagt Clone No. 800: caggtgcagctggtggagtctgggggagccgtggtccagcctgggaggtccctgagactctcctgtgaagtgtc- tggatt cagtttcagtgactatggcatgaactgggtccgccagggtccaggcaaggggctggagtgggtggcagttatat- ggcatg acggaagtaataaaaattatctagactccgtgaagggccgattcaccgtctccagagacaattccaagaacaca- ttgtttctg caaatgaacagcctgagagccgaagacacggctgtatattactgtgcgaggacgccttacgagttttggagtgg- ctattact ttgacttctggggccagggaaccctggtcaccgtctcgagt Clone No. 801: caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcgtc- tggatt ccccttcaatagctatgccatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagtgatat- attatga agggagtaatgaatattatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacactc- tgtatttgc aaatggatagcctgagagccgaggacacggctgtctattactgtgcgaggaagtggctggggatggacttctgg- ggcca gggaaccctggtcaccgtctcgagt Clone No. 804: gaggtgcagctggtggagtctgggggaggcttggtccggcctggggggtccctgagactctcctgttcagcctc- tggattc accttcagtaactatgctatgcactgggtccgccaggctccagggaagagactggaatatgtttcagctactag- tactgatg gggggagcacatactacgcagactccctaaagggcacattcaccatctccagagacaattccaagaacacactg- tatcttc aaatgagcagtctcagtactgaggacacggctatttattactgcgcccgccgattctggggatttggaaacttt- tttgactact ggggccggggaaccctggtcaccgtctcgagt Clone No. 810: caggtgcagctggtgcagtctggggctgaggtgaagaagtccgggtcctcggtgaaggtctcctgcagggcttc- tggag gcaccttcggcaattatgctatcaactgggtgcgacaggcccctggacaagggcttgagtgggtgggaaggatc- atccct gtctttgatacaacaaactacgcacagaagttccagggcagagtcacgattaccgcggacagatccacaaacac- agccat catgcaactgagcagtctgcgacctcaggacacggccatgtattattgtttgagaggttccacccgtggctggg- atactgat ggttttgatatctggggccaagggacaatggtcaccgtctcgagt Clone No. 811: caggttcagctggtgcagtctggggctgtcgtggagacgcctggggcctcagtgaaggtctcctgcaaggcatc- tggata catcttcggcaactactatatccactgggtgcggcaggcccctggacaagggcttgagtggatggcagttatca- atcccaat ggtggtagcacaacttccgcacagaagttccaagacagaatcaccgtgaccagggacacgtccacgaccactgt- ctatttg gaggttgacaacctgagatctgaggacacggccacatattattgtgcgagacagagatctgtaacagggggctt- tgacgc gtggcttttaatcccagatgcttctaatacctggggccaggggacaatggtcaccgtctcgagt Clone No. 812: caggtgcagctggtgcagtctggggctgagatgaagaagcctgggtcctcggtgaaggtctcctgcaaggcttc- tggagg ctccttcagcagctattctatcagctgggtgcgacaggcccctggacgagggcttgagtgggtgggaatgatcc- tgcctatc tctggtacaacaaactacgcacagacatttcagggcagagtcatcattagcgcggacacatccacgagcacagc- ctacat

ggagctgaccagcctcacatctgaagacacggccgtgtatttctgtgcgagagtctttagagaatttagcacct- cgacccttg acccctactactttgactactggggccagggaaccctggtcaccgtctcgagt Clone No. 814: caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaagtccgtgagactctcctgtgtaggctc- tggctt caggctcatggactatgctatgcactgggtccgccaggctccaggcaagggactggattgggtggcagttattt- catatgat ggagccaatgaatactacgcagagtccgtgaagggccgattcaccgtctccagagacaattcagacaacactct- gtatcta caaatgaagagcctgagagctgaggacacggctgtgtatttctgtgcgagagcgggccgttcctctatgaatga- agaagtt attatgtactttgacaactggggcctgggaaccctggtcaccgtctcgagt Clone No. 816: gaggtgcagctgttggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgtagcctc- cggattc acctttagtacctacgccatgacctgggtccgccaggctccagggaaggggctggagtgggtctcagtcattcg- tgctagt ggtgatagtgaaatctacgcagactccgtgaggggccggttcaccatctccagagacaattccaagaacacggt- gtttctg caaatggacagcctgagagtcgaggacacggccgtatatttctgtgcgaatataggccagcgtcggtattgtag- tggtgatc actgctacggacactttgactactggggccagggaaccctggtcaccgtctcgagt Clone No. 817: caggtgcagctggtggagtctgggggaggcgtggtccaacctgggaggtccctgagactctcctgtgcagcctc- tggatt cggcttcaacacccatggcatgcactgggtccgccaggctccaggcaaggggctggagtggctgtcaattatct- cacttga tgggattaagacccactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgg- tgtttcta caattgagtggcctgagacctgaagacacggctgtatattactgtgcgaaagatcatattggggggacgaacgc- atattttg aatggacagtcccgtttgacggctggggccagggaaccctggtcaccgtctcgagt Clone No. 818: caggtcaccttgagggagtctggtccagcggtggtgaagcccacagaaacgctcactctgacctgcgccttctc- tgggttc tcactcaacgccggtagagtgggtgtgagttggatccgtcagcccccagggcaggccccggaatggcttgcacg- cattga ttgggatgatgataaagcgttccgcacatctctgaagaccagactcagcatctccaaggactcctccaaaaacc- aggtggt ccttacactgagcaacatggaccctgcggacacagccacatattactgtgcccggacacaggtcttcgcaagtg- gaggct actacttgtactaccttgaccactggggccagggaaccctggtcaccgtctcgagt Clone No. 819: caggtgcagctgcaggagtcgggcccaggactggtgaagccttcacagaccctgtccctcacctgcactgtctc- tagtgg cgccatcagtggtgctgattactactggagttggatccgccagcccccagggaagggcctggagtgggttgggt- tcatcta tgacagtgggagcacctactacaacccgtccctcaggagtcgagtgaccatatcaatagacacgtccaagaagc- agttctc cctgaagctgacctctgtgactgccgcagacacggccgtgtattactgtgccagagatctaggctacggtggta- actcttac tcccactcctactactacggtttggacgtctggggccgagggaccacggtcaccgtctcgagt Clone No. 824: caggtgcagctgcaggagtcgggcccaggactggtgaagccttcggagaccctgtccctcacctgcactgtctc- tggtgg ctccatcggaaattactactggggctggatccggcagcccccagggaagggacttgagtggattgggcatatct- acttcgg tggcaacaccaactacaacccttccctccagagtcgagtcaccatttcagtcgacacgtccaggaaccagttct- ccctgaag ttgaactctgtgaccgccgcggacacggccgtgtattactgtgcgagggatagcagcaactggcccgcaggcta- tgagga ctggggccagggaaccctggtcaccgtctcgagt Clone No. 825: caggttcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggtttc- tggttac acctttaccagtaatggtctcagctgggtgcgacaggcccctggacaagggtttgagtggctgggatggatcag- cgctagt agtggaaacaaaaagtatgccccgaaattccagggaagagtcaccttgaccacagacatttccacgagcacagc- ctacat ggaactgaggagtctgagatctgacgatacggccgtatattactgtgcgaaagatgggggcacctacgtgccct- attctgat gcctttgatttctggggccaggggacaatggtcaccgtctcgagt Clone No. 827: caggtccagctggtacagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctgcagggtttc- cggaca cactttcactgcattatccaaacactggatgcgacagggtcctggaggagggcttgagtggatgggattttttg- atcctgaag atggtgacacaggctacgcacagaagttccagggcagagtcaccatgaccgaggacacagccacaggcacagcc- taca tggagctgagcagcctgacatctgacgacacggccgtatattattgtgcaacagtagcggcagctggaaacttt- gacaact ggggccagggaaccctggtcaccgtctcgagt Clone No. 829: caggtcaccttgaaggagtctggtcctgcgctggtgaaagccacacagaccctgacactgacctgcaccttctc- tgggtttt cactcagtaggaatagaatgagtgtgagctggatccgtcagcccccagggaaggccctggagtggcttgcacgc- attgat tgggatgatgataaattctacaacacatctctgcagaccaggctcaccatctccaaggacacctccaaaaacca- ggtggtc cttacaatgaccaacatggaccctgtggacacagccacctattactgcgcacggactgggatatatgatagtag- tggttatta cctctactactttgactactggggccagggaaccctggtcaccgtctcgagt Clone No. 830: caggtgcagctggtgcagtctggagctgaggtgaaggtgcctggggcctcagtgaaggtctcctgcaaggcttc- tggttac acctttaccacttacggtgtcagctgggtgcggcaggcccctggacaagggcttgagtggatgggttggatcag- cgcttac aatggtaacacatactatctacagaagctccagggcagagtcaccatgaccacagacacatccacgagcacagc- ctacat ggagctgcggggcctgaggtctgacgacacggccatgtattactgtgcgagagatcgtgttgggggcagctcgt- ccgag gttctatcgcgggccaaaaactacggtttggacgtctggggccaagggaccacggtcaccgtctcgagt Clone No. 831: caggttcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagttaaggtttcctgcaaggcttc- tgcaaac atcttcacttatgcaatgcattgggtgcgccaggcccccggacaaaggcttgagtggatgggatggatcaacgt- tggcaat ggtcagacaaaatattcacagaggttccagggcagagtcaccattaccagggacacgtccgcgactacagccta- catgga gctgagcaccctgagatctgaggacacggctgtgtattactgtgcgaggcgtgcgagccaatatggggaggtct- atggca actactttgactactggggccagggaaccctggtcaccgtctcgagt Clone No. 835: caggtgcagctggtgcagtctggagctgaggtgaagaggcctggggcctcagtgaaggtctcctgcaaggcttc- aggtta cacctttatcagctatggtttcagagggtgcgacaggcccctggacaagggcttgagtggatgggatggagcag- cgttta caatggtgacacaaactatgcacagaagttccacggcagagtcaacatgacgactgacacatcgacgaacacgg- cctac atggaactcaggggcctgagatctgacgacacggccgtgtatttctgtgcgagggatcgcaatgttgttctact- tccagctg ctccttttggaggtatggacgtctggggccaagggacaatggtcaccgtctcgagt Clone No. 838: caggtgcagctggtggagtctgggggaggcgtggtccagccggggacttccctgagactctcctgtgcagcctc- tggatt caccttcagtacgtttggcatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagttatat- catatga tggaaataagaaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgc- tgtatctg caagtgaacagcctgagagtcgaggacacggctgtgtattactgtgcggcccaaactccatatttcaatgagag- cagtggg ttagtgccggactggggccagggcaccctggtcaccgtctcgagt Clone No. 841: caggtgcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttc- tggtta cacctttatcagttttggcatcagctgggtgcgacaggcccctggacaaggacttgagtggatgggatggatca- ggcttac aatggtaacacagactatgcacagaggctccaggacagagtcaccatgactagagacacagccacgagcacagc- ctact tggagctgaggagcctgaaatctgacgacacggccgtgtactattgcactagagacgagtcgatgcttcgggga- gttactg aaggattcggacccattgactactggggccagggaaccctggtcaccgtctcgagt Clone No. 853: gaagtgcagctggtgcagtaggagcagaggtgaaaaagccggggcagtctctgaagatctcctgtaagacttct- ggata catctttaccaactactggatcggctgggtgcgccagaggcccgggaaaggcctggagtggatgggggtcatct- ttcctgc tgactctgatgccagatacagcccgtcgttccaaggccaggtcaccatctcagccgacaagtccatcggtactg- cctacct gcagtggagtagcctgaaggcctcggacaccgccatatattactgtgcgagaccgaaatattactttgatagta- gtgggcaa ttctccgagatgtactactttgacttctggggccagggaaccctggtcaccgtctcgagt Clone No. 855: caggttcagaggtgcagtaggacctgaggtgaagaagcctggggcctcagtgaaggtacctgcaaggcttctgg- ttat gtgttgaccaactatgccttcagctgggtgcggcaggcccctggacaagggcttgagtggctgggatggatcag- cggctc caatggtaacacatactatgcagagaagttccagggccgagtcaccatgaccacagacacatccacgagcacag- cctac atggagctgaggagtctgagatctgacgacacggccgtttatttctgtgcgagagatcttctgcggtccactta- ctttgactac tggggccagggaaccctggtcaccgtctcgagt Clone No. 856: caggtgcagctggtgcagtctggagctgaggtgaagaagcctggggcctcagtgaaggtctcctgcaaggcttc- tggtta caccttttccaactacggtttcagctgggtgcgacaggcccctggacgagggcttgagtggatgggatggatca- gcgctta

caatggtaacacatactatgcacagaacctccagggcagagtcaccatgaccacagacacatccacgaccacag- cctac atggtactgaggagcctgagatctgacgacacggccatgtattactgtgcgagagatggaaatacagcaggggt- tgatatg tggtcgcgtgatggttttgatatctggggccaggggacaatggtcaccgtctcgagt Clone No. 857: gaggtgcagctgaggagtagggggaggcttggtacagcctggggggcccctgaggctctcctgtgtagcctctg- gattc agctttagcagctatgccatgaactggatccgcctggctccagggaaggggctggagtgggtctcaggtattag- tggtagc ggtggtagcacttactacggagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgct- gtatctg caaatgaacagcctgagagccgaggacacggccgtatattactgtgcgaaagagccgtggatcgatatagtagt- ggcatc tgttatatccccctactactacgacggaatggacgtaggggccaagggaccacggtcaccgtctcgagt Clone No. 858: caggttcagctggtgcagtctggggctgaggtgaagaagcctgggtcctcggtgaaggtctcctgcaaggcctc- tggagg atccttcgacggctacactatcagctggctgcgacaggcccctggacaggggcttgagtggatgggaagggtcg- tcccta cacttggttttccaaactacgcacagaagttccaaggcagagtcaccgttaccgcggacagatccaccaacaca- gcctact tggaattgagcagactgacatctgaagacacggccgtatattactgtgcgaggatgaatctcggatcgcatagc- gggcgcc ccgggttcgacatgtggggccaaggaaccctggtcaccgtctcgagt Clone No. 859: caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccttgagactctcctgtgcagtgtc- tggatc cagcttcagtaaatatggcatacactgggtccgccaggctccaggcaaggggctggagtgggtggcagttatat- cgtatga tggaagtaaaaagtatttcacagactccgtgaagggccgattcaccatcgccagagacaattcccagaacacgg- tttttctg caaatgaacagcctgagagccgaggacacggctgtctattactgtgcgacaggagggggtgttaatgtcacctc- gtggtc cgacgtagagcactcgtcgtccttaggctactggggcctgggaaccctggtcaccgtctcgagt Clone No. 861: caggtgcagctggtggagtctgggggaggcgtggtccagcctggggggtccctgagactctcctgtgcagcgtc- tggatt caccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcatttatat- ggaatga tggaagtaataaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgc- tgtatctg caaatgaacagcctgagagctgaggacacggctgtgtattactgtgtgaaagatgaggtctatgatagtagtgg- ttattacct gtactactttgactcttggggccagggaaccctggtcaccgtctcgagt Clone No. 863: gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctc- tggattc acgtttagctcctataccatgagctgggtccgccaggctccagggaaggggctggagtgggtctcaagtattag- tgctagt actgttacacatactacgcagactccgtgaagggccgcttcaccatctccagagacaattccaagaacacgctg- tatctgc aaatgagtagcctgagagccgaggacacggccgtatattactgtgcgaaagattacgatttttggagtggctat- cccgggg gacagtactggttcttcgatctctggggccgtggcaccctggtcaccgtctcgagt Clone No. 868: caggtgcagctgcaggagtcgggcccaggactggtgacgccttcggagaccctgtccgtcacttgcactgtctc- taattatt ccatcgacaatgcttactactggggctggatccggcagcccccagggaagggtctggagtggataggcagtatc- catcat agtgggagcgcctactacaattcgtccctcaagagtcgagccaccatatctatagacacgtccaagaaccaatt- ctcgttga acctgaggtctgtgaccgccgcagacacggccgtatattactgtgcgcgcgataccatcctcacgttcggggag- ccccact ggttcgacccctggggccagggaaccctggtcaccgtctcgagt Clone No. 870: caggtgcagctgcaggagtcgggcccaggactggtgaagccttcggagaccttgtccctcacctgcactgtctc- aggtga ctccatcagtaattactactggagttggatccggcagcccccagggaagggactggagtggattggagaaatat- ctaacac ttggagcaccaattacaacccctccctcaagagtcgagtcaccatatctctagacatgcccaagaaccagttgt- ccctgaag ctgagctctgtgaccgctgcggacacggccgtatattactgtgcgagagggcttttctatgacagtggtggtta- ctacttgtttt acttccaacactggggccagggcaccctggtcaccgtctcgagt Clone No. 871: caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagagtctcctgtgcagcgtc- tggatt caccttcagtaactatggcatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagttatat- ggtatga tgacagtaataaacagtatggagactccgtgaagggccgattcaccatctccagagacaattccaagagtacgc- tgtatctg caaatggacagactgagagtcgaggacacggctgtgtattattgtgcgagagcctccgagtatagtatcagctg- gcgacac aggggggtccttgactactggggccagggaaccctggtcaccgtctcgagt Clone No. 880: cagatcaccttgaaggagtctggtcctacgctggtgagacccacacagaccctcacactgacctgcaccttctc- tgggttct cactcagcactagtaaactgggtgtgggctggatccgtcagcccccaggaaaggccctggagtggcttgcactc- gttgatt gggatgatgataggcgctacaggccatctttgaagagcaggctcaccgtcaccaaggacacctccaaaaaccag- gtggt ccttacaatgaccaacatggaccctgtggacacagccacatattactgtgcacacagtgcctactatactagta- gtggttatta cctcaatacttccatcactggggcccgggcaccctggtcaccgtctcgagt Clone No. 881: gaggtgcagctggtggagtctgggggaggcgtggtacagcctggaggctccctgagactctcctgtgaagtctc- cggatt caccttcaatagttatgaaatgacctgggtccgccaggccccagggaaggggctggagtgggtttcacacattg- gtaatag tggttctatgatatactacgctgactctgtgaagggccgattcaccatctccagagacaacgccaagaactcac- tatatctgc aaatgaacagcctgagagtcgaggacacggctgtttattactgtgcgaggtcagattactatgatagtagtggt- tattatctcc tctacttagactcctggggccatggaaccctggtcaccgtctcgagt Clone No. 884: caggtgcagaggtgcagtctggggctgaggtgaggaagcctggggcctcagtgaaggtttcctgcaaggcttct- ggaca tactttcattaactttgctatgcattgggtgcgccaggcccccggacaggggcttgagtggatgggatacatca- acgctgtca atggtaacacacagtattcacagaagttccagggcagagtcacctttacgagggacacatccgcgaacacagcc- tacatg gagctgagcagcctgagatctgaagacacggctgtgtattactgtgcgagaaacaatgggggctctgctatcat- tttttacta ctggggccagggaaccctggtcaccgtctcgagt Clone No. 886: caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctc- tggatt cagcttcagtagctatggcatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagttatat- caaatg atggaagtaataaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaaaacg- atgtatct gcaaatgaacagcctgagagctgaggacacggctgtgtatttctgtgcgaagacaacagaccagcggctattag- tggact ggttcgacccctggggccagggaaccctggtcaccgtctcgagt Clone No. 888: cagctgcagctgcaggagtcgggcccaggactggtgaagccatcggagaccctgtccctcacctgcactgcctc- tggtg gctccatcaacagtagtaatttctactggggctggatccgccagcccccagggaaggggctggagtggattggg- agtatct tttatagtgggaccacctactacaacccgtccctcaagagtcgagtcaccatatccgtagacacgtccaagaac- cagttctc cctgaagctgagccctgtgaccgccgcagacacggctgtctatcactgtgcgagacatggcttccggtattgta- ataatggt gtatgctctataaatctcgatgcttttgatatctggggccaagggacaatggtcaccgtctcgagt Clone No. 894: caggtgcagctggtggagtctgggggaggcgtcgtccagcctggaaagtccctgagactctcctgtgcagcgtc- tggatt cagattcagtgactacggcatgcactgggtccggcaggctccaagcaaggggctggagtgggtggcagttatct- ggcatg acggaagtaatataaggtatgcagactccgtgaggggccgattttccatctccagagacaattccaagaacacg- ctgtattt gcaaatgaacagcatgagagccgacgacacggctttttattattgtgcgagagtcccgttccagatttggagtg- gtctttatttt gaccactggggccagggaaccctggtcaccgtctcgagt

[0280] In the same clones, the complete amino acid sequences of the light chains (i.e. light chains including constant and variable regions) have the following amino acid sequences, which are also set forth as SEQ ID NOs: 89-132:

TABLE-US-00010 Clone No. 735: EIVLTQSPATLSLSPGERATLSCRASQSVNSHLAWYQQKPGQAPRLLIYNTFN RVTGIPARFSGSGSGTDFTLTISSLATEDFGVYYCQQRSNWPPALTFGGGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 736: DIQMTQSPSSLSASVGDRVTFTCRASQRISNHLNWYQQKPGKAPKLLIFGAST LQSGAPSRFSGSGSGTDFTLTITNVQPDDFATYYCQQSYRTPPINFGQGTRLDI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 744: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASS RATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDSSLSTWTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 793: DIQMTQSPSSLSASVGDRVTITCRASQSITGYLNWYQQKPGKAPKLLIYATST LQSEVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYNTLTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 795: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIHGAST GATGTPDRFSGSGSGTDFTLTISTLEPEDFAVYYCQQYGRTPYTFGQGTKLEN KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 796: DIVMTQTPLSLSVTPGQPASISCRSSQSLLRSDGKTFLYWYLQKPGQSPQPLM YEVSSRFSGVPDRFSGSGSGADFTLNISRVETEDVGIYYCMQGLKIRRTFGPGT KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 799: DIQMTQSPSTLSASVGDRVTFSCRASQSVSSWVAWYQQKPGKAPKLLISEAS NLESGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYHSYSGYTFGQGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 800: AIQLTQSPSSLSASVGDRVTLTCRASQGITDSLAWYQQKPGKAPKVLLYAAS RLESGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYSKSPATFGPGTKVEI RRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 801: DIVMTQSPLSLPVTPGEPASISCRSSQSLLNSNGFNYVDWYLQKPGQSPQLLIY LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALETPLTFGGG TKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 804: EIVLTQSPGTLSLSPGGRATLSCRASQSVSSGYLAWYQQKPGQAPRLLIYGAS GRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYFGSPYTFGQGTKLEL KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 810: NIQMTQSPSAMSASVGDRVTITCRASQGISNYLVWFQQKPGKVPKRLIYAASS LQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNISPYTFGQGTKLETK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 811: DIVMTQSPDSLAVSLGERATINCRSSETVLYTSKNQSYLAWYQQKARQPPKL LLYWASTRESGVPARFSGSGSGTDFTLAISSLQAEDVAVYYCQQFFRSPFTFG PGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC Clone No. 812: EIVLTQSPGTLSLSPGERVTLSCRASQSVSSSYIAWYQQKPGQAPRLVIYAASR RATGVPDRFSGSGSATDFTLTISRLEPEDLAVYYCQHYGNSLFTFGPGTKVDV KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 814: DIQMTQSPSTLSASVGDRVTITCRASQSIGSRLAWYQQQPGKAPKFLIYDASS LESGVPSRFSGSGSGTEFTLTISSLQPEDLATYYCQQYNRDSPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 816: DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSDGRYYVDWYLQKPGQSPHLLIY LASNRASGVPDRFTGSGSGTDFTLKISRVEAEDVGVYYCMQGLHTPWTFGQ GTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC Clone No. 817: EIVMTQSPATLSASPGERATLSCWASQTIGGNLAWYQQKPGQAPRLLIYGAS TRATGVPARFSGSGSGTEFTLAISSLQSEDFAVYYCQQYKNWYTFGQGTKLE LKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC Clone No. 818: DIQMTQSPSSLSASVGDRVTITCRASQTIASYVNWYQQKPGRAPSLLIYAASN LQSGVPPRFSGSGSGTDFTLTISGLQPDDFATYYCQQSYSYRALTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 819: EIVLTQSPATLSLSPGERATLSCRASQSVSSSLAWYQQTPGQAPRLLIYDASYR VTGIPARFSGSGSGIDFTLTISSLEPEDFAVYYCQQRSNWPPGLTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 824: AIQLTQSPSSLSASVGDTVTVTCRPSQDISSALAWYQQKPGKPPKLLIYGASTL DYGVPLRFSGTASGTHFTLTISSLQPEDFATYYCQQFNTYPFTFGPGTKVDIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 825: DIVMTQSPDSLAVSLGERATINCKSSQSVLYNSNNKNYLAWYQQKPGQPPKL LIHLASTREYGVPDRFSGSGSGTDFALIISSLQAEDVAVYYCQQYYQTPLTFG QGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC Clone No. 827: DIQMTQSPSSLAASVGDRVTITCRASQFISSYLHWYQQRPGKAPKLLMYAAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTNPYTFGQGTKLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 829: DIQMTQSPSSLSASVGDRVTITCRASQSIASYLNWYQQKPGKAPKLLIYAASS LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHSYSTRFTFGPGTKVDVK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 830: DIQMTQSPSTLSASVGDRVTITCRASQSVTSELAWYQQKPGKAPNFLIYKASS LESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 831: DIQMTQSPSTLSASVGDRLTITCRASQNIYNWLAWYQQKPGKAPKLLIYDAS TLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSLSPTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 835: DIQLTQSPSFLSASLEDRVTITCRASQGISSYLAWYQQKPGKAPKLLLDAASTL

QSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPRTFGQGTKVDIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 838: DIQMTQSPSSLSASVGDRVSITCRASQGISNYLAWYQQKPGKVPKLLIYAAST LQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPQTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 841: DIVMTQSPDSLAVSLGERATINCRSSQSVLYSSNNKNYLAWYQQKPGQPPKL LVYWASTRASGVPDRFSGSGSGTDFTLTLSSLQAEDVAVYYCQQFHSTPRTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC Clone No. 853: EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYGAS SRAAGMPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGNSPLTFGGGTEVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC Clone No. 855: DIQMTQSPSSVSASVGDRVTITCRASQAISNWLAWYQQKPGKAPKLLIYAASS LQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQADTFPFTFGPGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 856: DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSNDGNTYLDWYLQKPGQSPQLLI YTFSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEFPYTFGQG TKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC Clone No. 857: DIVMTQSPLSLPVTPGEPASISCRSSQSLLHRNEYNYLDWYLQKPGQSPQLLIY WGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQTLQTPRTFGQG TKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC Clone No. 858: DIQMTQSPSSVSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIFDATK LETGVPTRFIGSGSGTDFTVTITSLQPEDVATYYCQHFANLPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 859: DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKVPKLLVFAAS TLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQRYNSAPLTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 861: DIQMTQSPSSLSASVGDRVTITCRASQIIASYLNWYQQKPGRAPKLLIYAASSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPIFTFGPGTKVNIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 863: EIVLTQSPATLSLSPGERATLSCRTSQSVSSYLAWYQQKPGQAPRLLIYDASN RATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSDWLTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 868: EIVMTQSPATLSVSPGERATLSCRASQSIKNNLAWYQVKPGQAPRLLTSGASA RATGIPGRFSGSGSGTDFTLTISSLQSEDIAVYYCQEYNNWPLLTFGGGTKVEI QRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 870: DIQMTQSPPSLSASVGDRVTITCRASQRIASYLNWYQQKPGRAPKLLIFAASSL QSGVPSRFSGSGSGTDFTLTISSLQPEDYATYYCQQSYSTPIYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 871: DIQMTQSPSSLSASVGDRVTITCQASQGISNYLNWYQQKPGKAPKLLIFDASN LESEVPSRFSGRGSGTDFTFSISSLQPEDIATYFCQQYDNFPYTFGQGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 880: DIQMTQSPSSLAASVGDRVTITCRASQTIASYVNWYQQKPGKAPNLLIYAASS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFASYFCQQSYSFPYTFGQGTKLDIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 881: DIQMTQSPSSLSASVGDRVTITCRASQTIASYVNWYQQKPGKAPKLLIYAASN LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSVPRLTFGGGTKVDI TRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Clone No. 884: DIQMTQSPSSLSASVGDRVTITCRSSQTISVFLNWYQQKPGKAPKLLIYAASSL HSAVPSRFSGSGSGTDFTLTISSLQPEDSATYYCQESFSSSTFGGGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Clone No. 886: EIVMTQSPATLSVSPGETATLSCRASQSVSSNLAWYQHKPGQAPRLLIHSAST RATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNMWPPWTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC Clone No. 888: DIVMTQSPLSLPVTPGAPASISCRSSQSLLRTNGYNYLDWYLQKPGQSPQLLIY LGSIRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQSLQTSITFGQGT RLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC Clone No. 894: EIVMTQSPATLSVSPGERATLSCRASQSVGNNLAWYQQRPGQAPRLLIYGAS TRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYDKWPETFGQGTKVD IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC

[0281] The light chain encoding nucleic acid fragments in these clones have the following nucleic acid sequences, which are also provided as SEQ ID NOs: 133-176:

TABLE-US-00011 Clone No 735: gaaattgtgttgacacagtctccagccaccctgtccttgtctccaggagaaagagccaccctctcctgcagggc- cagtcag agtgttaacagccacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctataatacatt- caataggg tcactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagccttgcg- actgaag attttggcgtttattactgtcagcagcgtagcaactggcctcccgccctcactttcggcggagggaccaaagtg- gagatcaa acgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctg- ttgtgtgcctg ctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactccca- ggagag tgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacg- aga aacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggga- gagtgt Clone No 736: gacatccagatgacccagtctccatcctccctgtctgcatctgtgggagacagagtcaccttcacttgccgggc- cagtcaga ggattagcaaccatttaaattggtatcaacaaaagccagggaaagcccctaaactcctgatctttggtgcatcc- actcttcaa agtggggccccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcactaatgtacaacc- tgacgattt tgcaacttactactgtcaacagagttacagaactcccccgatcaacttcggccaagggacacgcctggacatta- agcgaac tgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgt- gcctgctgaat aacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagag- tgtcac agagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaac- aca aagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 744: gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagccaccctctcctgcagggc- cagtcag agtgttagcagcagctacttagcctggtatcagcagaaacctggccaggctcccaggctcctcatctatggtgc- atccagca gggccactggcatcccagacaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagactg- gagcct gaagattttgcagtgtattactgtcagcagtatgatagctcactttctacgtggacgttcggccaagggaccaa- ggtggaaat caaacgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcct- ctgttgtgtg cctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaact- cccagg agagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagac- tac gagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacag- ggga gagtgt Clone No 793: gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggc- aagtcag agcattaccggctatttaaattggtatcagcagaaaccagggaaagcccctaaactcctgatctatgctacatc- cactttgca aagtgaggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtcttcaac- ctgaagatt ttgcaacttactactgtcaacagagttataataccctcactttcggcggagggaccaaggtggagatcaaacga- actgtggc tgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgc- tgaataacttct atcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcaca- gagca ggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaag- tcta cgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 795: gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagccaccctctcctgcagggc- cagtcag agtgttagcagcagctacttagcctggtatcagcagaaacctggccaggctcccaggctcctcatacatggcgc- atccacc ggggccactggcaccccagacaggttcagtggcagtgggtctgggacagacttcactctcaccatcagtacact- ggagcc tgaagattttgcagtgtattactgtcagcaatatggtaggacaccgtacacttttggccaggggaccaagctgg- agaacaaa cgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgt- tgtgtgcctgc tgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccag- gagagt gtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacga- gaa acacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggag- agtgt Clone No 796: gatattgtgatgacccagactccactctctctgtccgtcacccctggacagccggcctccatctcctgcaggtc- tagtcagag cctcctgcgaagtgatggaaagacgtttttgtattggtatctgcagaagccaggccagtctccccaacccctaa- tgtatgagg tgtccagccggttctctggagtgccagataggttcagtggcagcgggtcaggggcagatttcacactgaacatc- agccgg gtggagactgaggatgttgggatctattactgcatgcaaggtttgaaaattcgtcggacgtttggcccagggac- caaggtcg aaatcaagcgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact- gcctctgttg tgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggt- aactccc aggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagca- gac tacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaa- caggg gagagtgt Clone No 799: gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccttctcttgccgggc- cagtcaga gtgttagtagttgggtggcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctctgaggcctcc- aatttgga aagtggggtcccatcccggttcagcggcagtggatccgggacagaattcactctcaccatcagcagcctgcagc- ctgaag attttgcaacttattactgccaacagtatcatagttactctgggtacacttttggccaggggaccaagttggaa- atcaagcgaa ctgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtg- tgcctgctgaa taacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggaga- gtgtca cagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaa- cac aaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg- t Clone No 800: gccatccagttgacccagtctccatcgtccctgtctgcatctgtaggcgacagagtcaccctcacttgccgggc- gagtcag ggcattaccgattctttagcctggtatcagcagaaaccagggaaagcccctaaggtcctgctctatgctgcttc- cagattgga aagtggggtcccatccaggttcagtggccgtggatctgggacggatttcactctcaccatcagcagcctgcagc- ctgaaga ctttgcaacttattactgtcaacagtattctaagtcccctgcgacgttcggcccagggaccaaggtggaaatca- gacgaact gtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtg- cctgctgaata acttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagt- gtcaca gagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaaca- caa agtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 801: gatattgtgatgacccagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtc- tagtcaga gcctcctaaatagtaatggattcaactatgtggattggtacctgcagaagccagggcagtctccacaactcctg- atctatttgg gttctaatcgggcctccggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaatc- agcagag tggaggctgaggatgttggggtttattactgcatgcaagctctagaaactccgctcactttcggcggagggacc- aaggtgg agatcaaacgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact- gcctctgttg tgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggt- aactccc aggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagca- gac tacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaa- caggg gagagtgt Clone No 804: gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccagggggaagagccaccctctcctgcagggc- cagtcag agtgttagcagcggctacttagcctggtaccagcagaaacctggccaggctcccaggctcctcatctatggtgc- atccggc agggccactggcatcccagacaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagact- ggagcc tgaagattttgcagtgtattactgtcagcagtattttggctcaccgtacacttttggccaggggaccaagctgg- agctcaaacg aactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttg- tgtgcctgctg aataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccagga- gagtgt cacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgaga- aac

acaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagag- tgt Clone No 810: aacatccagatgacccagtctccatctgccatgtctgcatctgtaggagacagagtcaccatcacttgtcgggc- gagtcagg gcattagtaattatttagtctggtttcagcagaaaccagggaaagtccctaagcgcctgatctatgctgcatcc- agtttgcaaa gtggggtcccatcaaggttcagcggcagtggatctgggacagaattcactctcacaatcagcagcctgcagcct- gaagatt ttgcaacttattactgtctacagcataatatttccccttacacttttggccaggggaccaagctggagaccaaa- cgaactgtgg ctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctg- ctgaataacttc tatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcac- agagc aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaa- gtct acgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 811: gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaactgcaggtc- cagtga gactgttttatacacctctaaaaatcagagctacttagcttggtaccagcagaaagcacgacagcctcctaaac- tactccttta ctgggcatctacccgggaatccggggtccctgcccgattcagtggcagcggatctgggacagatttcactctcg- ccatcag cagcctgcaggctgaagatgtggcagtttattactgtcagcaattttttaggagtcctttcactttcggccccg- ggaccagact ggagattaaacgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaa- ctgcctctgt tgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgg- gtaactc ccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaag- cag actacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttc- aacag gggagagtgt Clone No 812: gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagttaccctctcttgcagggc- cagtcaga gtgttagcagcagttacatagcctggtaccagcagaagcctggccaggctcccaggctcgtcatctatgctgca- tcccgca gggccactggcgtcccagacaggttcagtggcagtgggtctgcgacagacttcactctcaccatcagtagactg- gagcct gaagatcttgcagtgtattactgtcagcactatggtaactcactattcactttcggccctgggaccaaggtgga- tgtcaaacg aactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttg- tgtgcctgctg aataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccagga- gagtgt cacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgaga- aac acaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagag- tgt Clone No 814: gacatccagatgacccagtctccctccaccctgtctgcatctgtcggagacagagtcaccatcacttgccgggc- cagtcag agtattggtagccggttggcctggtatcagcagcaaccagggaaagcccctaaattcctgatctatgatgcctc- cagtttgg aaagtggggtcccatcaaggttcagcggcagtggatcagggacagaattcactctcaccatcagcagcctgcag- ccgga ggatcttgcaacttattactgccaacagtacaatagagattctccgtggacgttcggccaagggaccaaggtgg- aaatcaa gcgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctg- ttgtgtgcct gctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactccc- aggaga gtgtcacagagcaggacagcaaggacagcacctacagcctcagcacgcacctgacgctgagcaaagcagactac- gag aaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggg- agagt gt Clone No 816: gatattgtgatgacccagtctccactctccctgcccgtcaccccaggagagccggcctccatctcctgcaggtc- tagtcaga gcctcctgcatagtgatggacgctactatgtggattggtacctgcagaagccagggcagtctccacacctcctg- atctatttg gcttctaatcgggcctccggggtccctgacaggttcactggcagtggatcaggcacagattttacactgaaaat- cagcaga gtggaggctgaggatgttggcgtttattactgcatgcaaggtctacacactccttggacgttcggccaggggac- caaggtg gacatcaagcgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaac- tgcctctgtt gtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcggg- taactcc caggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagc- aga ctacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttca- acagg ggagagtgt Clone No 817: gaaattgtaatgacacagtctccagccaccctgtctgcgtccccaggggaaagagccaccctctcctgttgggc- cagtcag actattggaggcaacttagcctggtaccagcagaaacctggccaggctcccaggctcctcatctatggtgcatc- caccagg gccactggtgtcccagccaggttcagtggcagtgggtctgggacagagttcactctcgccatcagcagcctgca- gtagaa gattttgcagtttattactgtcagcagtataaaaactggtacacttttggccaggggaccaagctggagctcaa- acgaactgt ggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcc- tgctgaataac ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt- cacaga gcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacaca- aag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 818: gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggc- aagtcag accattgccagttacgtaaattggtaccaacaaaaaccagggagagcccctagtctcctgatctatgctgcatc- taacttgca gagtggggtcccaccaaggttcagtggcagtggatctgggacagacttcactctcaccatcagcggtctgcaac- ctgacg attttgcaacttattactgtcaacagagttacagttatcgagcgctcactttcggcggagggaccaaggtggag- atcaaacga actgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgt- gtgcctgctga ataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggag- agtgtc acagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaa- aca caaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagt- gt Clone No 819: gaaattgtgttgacacagtctccagccaccctgtcgttgtccccaggggaaagagccaccctctcctgcagggc- cagtcag agtgttagcagctccttagcctggtaccaacagacacctggccaggctcccaggcttctcatctatgatgcgtc- ctacaggg tcactggcatcccagccaggttcagtggcagtgggtctgggatagacttcactctcaccatcagcagcctagag- cctgaag attttgcagtttactattgtcagcagcgtagcaactggcctccggggctcactttcggcggggggaccaaggtg- gagatcaa acgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctg- ttgtgtgcctg ctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactccca- ggagag tgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacg- aga aacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggga- gagtgt Clone No 824: gccatccagttgacccagtctccatcctccctgtctgcatctgttggagacacagtcaccgtcacttgccggcc- aagtcagg acattagcagtgctttagcctggtatcagcagaaaccagggaaacctcctaagctcctgatctatggtgcctcc- actttggatt atggggtcccattaaggttcagcggcactgcatctgggacacatttcactctcaccatcagcagcctgcaacct- gaagatttt gcaacttattactgtcaacagtttaatacttacccattcactttcggccctgggaccaaagtggatatcaaacg- aactgtggct gcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgct- gaataacttcta tcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacag- agca ggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaag- tcta cgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 825: gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaactgcaagtc- cagcca gagtgttttatacaactccaacaataagaactacttagcctggtatcagcagaaacaggacagcctcctaagct- cctcattc acttggcatctacccgggaatacggggtccctgaccgattcagtggcagcgggtctgggacagatttcgctctc- atcatca gcagcctgcaggctgaagatgtggcagtttattactgtcaacaatattatcaaactcctctaacttttggccag- gggaccaag gtggagatcaaacgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgg- aactgcctct gttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatc- gggtaact

cccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaa- gca gactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagctt- caaca ggggagagtgt Clone No 827: gacatccagatgacccagtctccatcctccctggctgcatctgtaggagacagagtcaccatcacttgccgggc- aagtcag ttcattagcagctatttacattggtatcagcaaagaccaggcaaggcccctaaactcctgatgtatgctgcctc- cactttgcaa agtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacc- tgaagatt ttgcaacttactactgtcaacagagttacactaacccatacacttttggccaggggaccaagctggagatcaaa- cgaactgt ggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcc- tgctgaataac ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt- cacaga gcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacaca- aag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 829: gacatccagatgacccagtctccatcctccctatctgcatctgtaggagacagagtcaccatcacttgccgggc- aagtcaga gcattgccagctatttaaattggtatcagcagaaaccagggaaagcccccaaactcctgatctatgctgcatcc- agtttgcat agtggggtcccatcaagattcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacc- tgaagattt tgcaacttactactgtcaacacagttacagtactcgattcactttcggccctgggaccaaagtggatgtcaaac- gaactgtgg ctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctg- ctgaataacttc tatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcac- agagc aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaa- gtct acgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 830: gacatccagatgacccagtctccttcgaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggc- cagtcag agtgttactagtgagttggcctggtatcagcagaaaccagggaaagcccctaacttcctgatctataaggcgtc- tagtttaga aagtggggtcccatcaaggttcagcggcagtggatctgggacagaattcactctcaccatcagcagcctgcagc- ctgatg attttgcaacttattactgccaacagtataatagttttccgtacacttttggccaggggaccaagctggagatc- aaacgaactgt ggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcc- tgctgaataac ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt- cacaga gcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacaca- aag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 831: gacatccagatgacccagtctccttccaccctgtctgcatctgtaggcgacagactcaccatcacttgccgggc- cagtcaga atatttataactggttggcctggtatcagcagaaaccagggaaagcccctaaactcctgatctatgacgcctcc- actttggaa agtggggtcccatcaaggttcagcggcagtggatctgggacagagttcactctcaccatcagcagcctgcagcc- tgatgat tttgcgacttattactgccaacaatataatagtttgtctccgacgttcggccaagggaccaaggtggaaatcaa- gcgaactgt ggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcc- tgctgaataac ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt- cacaga gcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacaca- aag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 835: gacatccagttgacccagtctccatccttcctgtctgcatctttagaagacagagtcactatcacttgccgggc- cagtcaggg cattagcagttatttagcctggtatcagcaaaaaccagggaaagcccctaagctcctgctcgatgctgcatcca- ctttgcaaa gtggggtcccatcaaggttcagcggcagtggatctgggacagagttcactctcacaatcagcagcctgcagcct- gaagatt ttgcaacttattactgtcaacagcttaatagttaccctcggacgttcggccaagggaccaaggtggacatcaaa- cgaactgt ggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcc- tgctgaataac ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt- cacaga gcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacaca- aag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 838: gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcagcatcacttgccgggc- gagtcag ggcattagcaattatttagcctggtatcagcagaaaccagggaaggttcctaagctcctgatctatgctgcatc- cactttgcaa tcaggggtcccatctcggttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcc- tgaggat gttgcaacttattactgtcaaaagtataacagtgcccctcaaacgttcggccaagggaccaaggtggaaatcaa- acgaact gtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtg- cctgctgaata acttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagt- gtcaca gagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaaca- caa agtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 841: gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaactgcaggtc- cagcca gagtgttttatacagctccaacaataagaactacttagcttggtaccagcagaaaccaggacagcctcctaagc- tgctcgttt actgggcatcaacccgggcatccggggtccctgaccgattcagtggcagcgggtctgggacagatttcactctc- accctc agcagcctgcaggctgaagatgtggcagtttattactgtcagcagtttcatagtactcctcggacgttcggcca- agggacca aggtggagatcaaacgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatct- ggaactgcc tctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctcca- atcgggta actcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagc- aaa gcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagag- cttca acaggggagagtgt Clone No 853: gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagccaccctctcctgcagggc- cagtcag agtgttagcagcaactacttagcctggtaccagcagaaacctggccaggctcccaggctcctcatctatggtgc- atccagc agggccgctggcatgccagacaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagact- ggagc ctgaagattttgcagtgtattactgtcagcagtatggtaactcaccgctcactttcggcggagggaccgaggtg- gagatcaa acgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctg- ttgtgtgcctg ctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactccca- ggagag tgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacg- aga aacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggga- gagtgt Clone No 855: gacatccagatgacccagtctccatcttctgtgtctgcatctgtaggagacagagtcaccatcacttgtcgggc- gagtcagg ctattagtaactggttagcctggtatcagcagaaaccaggaaaagcccctaagctcctgatctatgctgcatcc- agtttgcaa agtggggtcccatcaagattcagcggcagtggatctgggacagatttcactctcactatcagcggcctgcagcc- tgaggat tttgcaacttactattgtcaacaggctgacactttccctttcactttcggccctgggaccaaagtggatatcaa- acgaactgtgg ctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctg- ctgaataacttc tatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcac- agagc aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaa- gtct acgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 856: gatattgtgatgacccagactccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtc- tagtcaga gcctcttggatagtaatgatggaaacacctatttggactggtacctgcagaagccagggcagtctccacagctc- ctgatttat acattttcctatcgggcctctggagtcccagacaggttcagtggcagtgggtctggcactgatttcacactgaa- aatcagca gggtggaggccgaggatgttggagtttattactgcatgcaacgtatcgagtttccgtacacttttggccagggg- accaagct ggagatcaaacgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaa- ctgcctctgt tgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgg- gtaactc ccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaag- cag actacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttc-

aacag gggagagtgt Clone No 857: gatattgtgatgacccagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtc- tagtcaga gcctcctgcatagaaatgagtacaactatttggattggtacttgcagaagccagggcagtctccacagctcctg- atctattgg ggttctaatcgggcctccggggtccctgacaggttcagtggcagtggatcaggcacagattttacactgaaaat- cagcaga gtggaggctgaggatgttggggtttattactgcatgcaaactctacaaactcctcggacgttcggccaagggac- caaggtg gaaatcaaacgaactgtggctgcaccatctgtatcatcttcccgccatctgatgagcagttgaaatctggaact- gcctctgtt gtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcggg- taactcc caggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagc- aga ctacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttca- acagg ggagagtgt Clone No 858: gacatccagatgacccagtctccatcctccgtgtctgcatctgtgggagacagagtcaccatcacttgccaggc- gagtcaa gacattagcaactatttaaattggtatcagcagaaaccagggaaagcccctaagctcctgatcttcgatgcaac- caaattgg agacaggggtcccaacaaggttcattggaagtggatctgggacagattttactgtcaccatcaccagcctgcag- cctgaag atgttgcaacatattactgtcaacactttgctaatctcccatacacttttggccaggggaccaagctggagatc- aagcgaact gtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtg- cctgctgaata acttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagt- gtcaca gagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaaca- caa agtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 859: gacatccagatgacccagtctccatcttccctgtctgcatctgtaggagacagagtcaccatcacttgccgggc- gagtcagg gcattaggaattatttagcctggtatcagcagaaaccagggaaagttcctaagctcctggtctttgctgcatcc- actttgcaat caggggtcccatctcggttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcct- gaggatg ttgcaacttattactgtcaaaggtataacagtgccccgctcactttcggcggagggacgaaggtggagatcaaa- cgaactgt ggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcc- tgctgaataac ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt- cacaga gcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacaca- aag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 861: gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggc- aagtcag atcattgccagctatttaaatggtatcagcagaaaccaggcagagcccctaagctcctgatctatgctgcatcc- agtttgcaa agtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacc- tgaagatt ttgcaacttactactgtcaacagagttacagtacccccatattcactttcggccctgggaccaaggtgaatatc- aaacgaact gtggctgcaccatctgtatcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgc- ctgctgaata acttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagt- gtcaca gagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaaca- caa agtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 863: gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggaaagagccaccctctcctgcaggac- cagtcaga gtgttagcagctacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctatgatgcttcc- aatagggc cactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagc- ctgaag attttgcagtttattactgtcagcagcgtagtgactggctcactttcggcggagggaccaaggtggagatcaaa- cgaactgt ggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcc- tgctgaataac ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgt- cacaga gcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacaca- aag tctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 868: gaaattgtaatgacacagtctccagccaccctgtctgtgtctccaggggaaagagccaccctctcctgcagggc- cagtcag agtattaaaaacaacttggcctggtaccaggtgaaacctggccaggctcccaggctcctcacctctggtgcatc- cgccagg gccactggaattccaggcaggttcagtggcagtgggtctgggactgacttcactctcaccatcagcagcctcca- gtctgaa gatattgcagtttattactgtcaggagtataataattggcccctgctcactttcggcggagggaccaaggtgga- gatccaacg aactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttg- tgtgcctgctg aataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccagga- gagtgt cacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgaga- aac acaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagag- tgt Clone No 870: gacatccagatgacccagtctcctccctccctgtctgcatctgtgggagacagagtcaccatcacttgccgggc- aagtcag aggattgccagctatttaaattggtatcagcagaaaccagggagagcccctaagctcctgatctttgctgcatc- cagtttaca aagtggggtcccatcaaggttcagtggcagtggatctgggacagacttcactctcaccatcagtagtctgcaac- ctgaagat tatgcgacttactactgtcaacagagttacagtactcccatctacacttttggccaggggaccaagctggagat- caaacgaa ctgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtg- tgcctgctgaa taacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggaga- gtgtca cagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaa- cac aaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg- t Clone No 871: gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggc- gagtcag ggcattagcaactatttaaattggtatcaacagaaaccagggaaagcccctaagctcctgatcttcgatgcatc- caatttgga atcagaggtcccatcaaggttcagtggacgtggatctgggacagattttactttctccatcagcagcctgcagc- ctgaagata ttgcaacatatttctgtcaacagtatgataatttcccgtacacttttggccaggggaccaagctggagatcaaa- cgaactgtgg ctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctg- ctgaataacttc tatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcac- agagc aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaa- gtct acgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 880: gacatccagatgacccagtctccatcctccctggctgcatctgtaggagacagagtcaccatcacctgccgggc- aagtcag acgattgccagttatgtaaattggtatcaacagaaaccagggaaagcccctaatctcctgatctatgctgcatc- cagtttgcaa agtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacc- tgaagatt ttgcatcttacttctgtcaacagagttacagtttcccgtacacttttggccaggggaccaagctggatatcaaa- cgaactgtgg ctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctg- ctgaataacttc tatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcac- agagc aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaa- gtct acgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 881: gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggc- aagtcag accattgccagctatgtaaattggtatcagcagaaaccagggaaagcccctaagctcctgatctatgctgcatc- caatttgca aagtggggtccctcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacc- tgaagat tttgcaacttactactgtcaacagagttacagtgtccctcggctcactttcggcggagggaccaaggtggacat- cacacgaa ctgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtg- tgcctgctgaa taacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggaga- gtgtca cagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaa- cac aaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg- t Clone No 884:

gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccggtc- aagtcaga ccattagcgtctttttaaattggtatcagcagaaaccagggaaagcccctaagctcctgatctatgccgcatcc- agtttgcaca gtgcggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct- gaagattct gcaacttactactgtcaagagagtttcagtagctcaactttcggcggagggaccaaggtggagatcaaacgaac- tgtggct gcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgct- gaataacttcta tcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacag- agca ggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaag- tcta cgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Clone No 886: gaaattgtaatgacacagtctccagccaccctgtctgtgtctccaggggaaacagccaccctctcctgcagggc- cagtcag agtgttagcagcaacttagcctggtaccaacataaacctggccaggctcccaggctcctcatccatagtgcatc- caccagg gccactgggatcccagccaggttcagtggcagtgggtctgggacagagttcactctcaccataagcagcctgca- gtctga agattttgcagtttattactgtcagcagtataatatgtggcctccctggacgttcggccaagggaccaaggtgg- aaatcaaac gaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgtt- gtgtgcctgct gaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccagg- agagtg tcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgag- aaa cacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggaga- gtgt Clone No 888: gatattgtgatgacccagtctccactctccctgcccgtcacccctggagcgccggcctccatctcctgcaggtc- tagtcaga gcctcctgcgtactaatggatacaactatttggattggtacctgcagaagccagggcagtctccacagctcctg- atctatttg ggttctattcgggcctccggggtccctgacaggttcagtggcagtggctcaggcacagattttacactgaaaat- cagcaga gtggaggctgaggatgttggggtttattactgcatgcaatctctacaaacttcgatcaccttcggccaagggac- acgactgg agattaaacgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaact- gcctctgttgt gtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggta- actccca ggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcag- act acgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaac- agggg agagtgt Clone No 894: gaaattgtaatgacacagtctccagccaccctgtctgtgtctccgggggaaagagccaccctctcctgcagggc- tagtcag agtgttggcaacaacttagcctggtaccagcagagacctggccaggctcccagactcctcatctatggtgcgtc- caccagg gccactggtatcccagccaggttcagtggcagtgggtctgggacagagttcactctcaccatcagcagcctgca- gtctgag gattttgcagtttattactgtcagcagtatgataagtggcctgagacgttcggccaggggaccaaggtggacat- caagcgaa ctgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtg- tgcctgctgaa taacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggaga- gtgtca cagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaa- cac aaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtg- t

[0282] In all of the above-discussed 44 clones, the encoded antibodies include the same constant IgG heavy chain, which has the following amino acid sequence (SEQ ID NO: 178):

TABLE-US-00012 SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0283] The genomic sequence encoding this heavy chain has the following nucleic acid sequence (SEQ ID NO: 177):

TABLE-US-00013 agtgcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcgg- ccctgg gctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtg- cacac cttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgg- gcaccca gacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagagagttggtgagaggccagcac- aggg agggagggtgtctgctggaagccaggctcagcgctcctgcctggacgcatcccggctatgcagtcccagtccag- ggcag caaggcaggccccgtctgcctcttcacccggaggcctctgcccgccccactcatgctcagggagagggtcttct- ggcttttt ccccaggctctgggcaggcacaggctaggtgcccctaacccaggccctgcacacaaaggggcaggtgctgggct- cag acctgccaagagccatatccgggaggaccctgcccctgacctaagcccaccccaaaggccaaactctccactcc- ctcag ctcggacaccttctctcctcccagattccagtaactcccaatcttctctctgcagagcccaaatcttgtgacaa- aactcacaca tgcccaccgtgcccaggtaagccagcccaggcctcgccctccagctcaaggcgggacaggtgccctagagtagc- ctgc atccagggacaggccccagccgggtgctgacacgtccacctccatctcttcctcagcacctgaactcctggggg- gaccgt cagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtg- gtggacg tgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag- ccgcg ggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggca- aggag tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaaggtgggac- ccgtg gggtgcgagggccacatggacagaggccggctcggcccaccctctgccctgagagtgaccgctgtaccaacctc- tgtcc ctacagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtc- agc ctgacctgcctggtcaaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggaga- acaact acaagaccacgcctcccgtgctggactccgacggctccttcttcctctatagcaagctcaccgtggacaagagc- aggtgg cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctc- cctgtcc ccgggtaaatga

[0284] In this sequence exons are indicated by double underlining. Further, the initial Ser-encoding nucleotides agt (bold underline) are created as a consequence of the introduction into the XhoI digested expression vector of an XhoI digested PCR product encoding the variable heavy chain site in the IgG expression vector.

[0285] The above-discussed V_H and V_L coding pairs were selected according to the binding specificity to various antigens and peptides in ELISA and/or FLISA, epitope mapping, antigen diversity, and sequence diversity. The selected cognate V-gene pairs were subjected to clone repair (Example 1, Section f) if errors were identified. The individual expression constructs were co-transfected with a Flp-recombinase expressing plasmid into the CHO-FlpIn recipient cell line (Invitrogen), followed by antibiotic selection of integrants. The transfections, selection, and adaptation to serum free culture was performed as described in Example 1, section g-1 and g-2.

[0286] The stably transfected, serum free suspension culture adapted individual expression cell lines were cryopreserved in multiple ampoules, to generate a cell bank of individual antibody producing cell lines.

Example 3

[0287] In vitro neutralization experiments have been performed both with single antibody clones and with combinations of purified antibodies. All the antibody mixtures described below are constituted of a number of individual anti-RSV antibodies of the present invention, which were combined into a mixture using equal amounts of the different antibodies.

Testing of Single Antibodies

[0288] Initially, the neutralizing activity of each antibody was determined in the PRNT in the presence of complement against RSV subtype A and B strains as described above in Example 1, section j-2. The EC₅₀ values of a number of the purified antibodies are shown in Table 8. Interestingly, while most anti-F antibodies individually exhibited virus neutralizing activity, no EC₅₀ values could be determined for the majority of the anti-RSV protein G antibodies. This could be interpreted as indicating that these antibodies are not capable of neutralizing the vireo individually. However, subsequent refinement of the assay yielded EC₅₀ values for clones with G-reactivity as well. Blank fields indicate that the analysis has not been performed yet. ND indicates that an EC₅₀ value could not be determined in the PRNT due to a very low or lacking neutralizing activity.

TABLE-US-00014 TABLE 8 EC₅₀ values of purified anti-RSV protein F and protein G antibodies against RSV subtype A and B. EC₅₀ value (μg/ml) Clone Antigen-specificity Long A2 18537 B1 793 G 2.52 0.09 800 F 0.15 0.16 810 F 0.04-0.06 0.02 0.02-0.14 0.29 816 G ND ND 818 F (1.86) 0.21 0.15* 819 F 0.18 0.09 824 F 0.03 0.007 0.02 0.07 825 F 0.12 0.04 827 F 0.16 0.10 831 F 0.08 0.72 1.66 853 G (1.49) 0.14 0.13* 855 G 6.35 ND 856 G ND ND 858 F ND 0.13 868 G ND 880 F 0.38 0.95 0.40 888 G 0.14 894 F 0.08 0.07 Synagis F 0.14 0.15 0.20 *value from new determination

Mixtures of Anti-F Antibodies

[0289] The ability of mixtures of anti-RSV protein F antibodies to neutralize RSV strains of subtype A and B was compared with the neutralizing effect obtained using Palivizumab (also an anti-F antibody). The neutralization capability was assessed using the microneutralization test or the PRNT as described in Example 1, Section j. In an initial experiment two antibody mixtures, anti-F(I) and anti-F(II), containing five and eleven distinct anti-F antibodies, respectively were compared against Palivizumab using the microneutralizating test. Anti-F(I) is composed of antibodies obtained from clones 810, 818, 819, 825 and 827. Antibodies 810 and 819 bind to antigenic site A/II, antibody 818 to site B/I or F1, antibody 825 binds to a complex epitope overlapping with sites A and C and antibody 827 binds to another complex epitope overlapping with site IV (see Table 6). Anti-F(II) is composed of antibodies obtained from clones 735, 800, 810, 818, 819, 825, 827, 863, 880, 884 and 894. Anti-F(II) contains multiple binders to some of the defined antigenic sites: antibodies 810, 819 and 863 binds A/II, antibodies 800 and 818 binds F1 (or B/I), antibodies 827 and 825 to the complex epitopes described above, antibodies 735 and 894 belong to unknown cluster (UC)I, antibody 880 to UCII, and 884 binds to another currently unknown epitope (see Table 6). As shown in FIG. 5, both composition Anti-F(I) and F(II) were more potent than Palivizumab with respect to neutralization of RSV strains of both subtypes.

[0290] FIG. 5 also shows that the combination of five antibodies (anti-F(I)) appeared to be more potent than the combination of eleven antibodies (Anti-F(II)). The anti-F(I) mixture contains some of the most potent individually neutralizing antibodies of the different epitope specificities that have been defined so far. The anti-F(II) mixture contains the same five highly potent antibodies, but it also contains additional binders to some of the defined epitopes and the included antibodies also display a wider range of neutralizing activity on their own. It is thus possible that the activity of the highly potent antibodies becomes diluted in the anti-F(II) combination due to competition for binding to the neutralizing epitopes on the F protein. However, since there potentially are other effects than the neutralizing effect associated with each individual antibody, e.g. increased phagocytosis, increased antibody-dependent cellular cytotoxicity (ADCC), anti-inflammatory effects, complement activation, and a decreased likelihood of generating escape mutants, when considered in vivo, this result should not be taken as an indication that a mixture of five is better than a mixture of eleven antibodies when used in vivo.

[0291] Both the in vitro assays and the combinations of clones have been refined since this initial experiment and a number of combinations of F-specific antibody clones that are highly potent in the presence of complement have been identified. The neutralizing potencies, expressed as EC₅₀ values (effective concentrations required to induce a 50% reduction in the number of plaques), of additional anti-F antibody compositions are listed in Table 9. Irrespective of the exact number of clones in the compositions, the majority of the tested combinations of F-specific antibodies are more potent than Palivizumab with respect to neutralization of RSV strain subtype A.

Mixtures of Anti-G Antibodies

[0292] The ability of mixtures of anti-G antibodies to neutralize RSV strains of subtype A was tested using the PRNT as described in Example 1, section j-2. The EC₅₀ values from the tested anti-G antibody compositions are listed in Table 9. Most of the compositions of two anti-G antibodies did not exhibit a markedly increased ability to neutralize virus compared to the individual anti-G antibodies. Some combinations of two or three anti-G antibodies never reached 100% neutralization of the virus, irrespective of the concentration. However, when additional anti-G antibodies were added to the composition the potency increased, possibly indicating a synergistic neutralizing effect between the anti-G antibodies. FIG. 7 shows an example of the increase in potency when combining multiple G-specific clones.

Mixtures of Anti-F and Anti-G Antibodies

[0293] The ability of mixtures of anti-RSV protein F and protein G antibodies to neutralize RSV subtype B strain was compared with the neutralizing effect obtained using Palivizumab. The neutralization capability was assessed using either the microneutralization fusion inhibition assay as described in Example 1, Section j-4 or the plaque reduction neutralization assay (Example 1, section j-2).

[0294] Initially, the neutralizing activity of two antibody mixtures, anti-F(I) G and anti-F(II) G, was measured in the microneutralization fusion inhibition assay. Each of these mixtures contains the anti-F antibodies of composition anti-F(I) and anti-F(II) described above as well as anti-G antibodies obtained from clones 793, 796, 838, 841, 856 and 888, where antibodies 793, 796, 838 bind to the conserved region of the G protein, 841, 856 binds to the GCRR of RSV subtype A and 888 binds to the GCRR of both subtypes (see Table 6). As shown in FIG. 6, both composition Anti-F(I) G and F(II)G were more potent than Palivizumab with respect to neutralization of the RSV B1 strain. Further, the neutralizing activity of the two mixtures was more or less equal. Thus, it seems that when the anti-F antibodies are combined with a number of protein G-specific clones, the potency difference previously observed between the two anti-F antibody mixtures is diminished. This may indicate a general increase in the neutralizing activity when antibodies that recognize a wide range of antigens and epitopes on RSV are combined.

[0295] A large number of different combinations of both anti-F and anti-G antibodies have since then been tested in the PRNT in the presence or absence of complement. EC₅₀ values obtained by this assay in the presence of active complement are presented in Table 9. All of the tested compositions including both anti-F and anti-G antibodies do neutralize RSV subtype A and the majority of these are more potent than Palivizumab.

[0296] The results and results shown in Tables 7 and 8 also show that antibodies with naturally high affinities could repeatedly be obtained from human donors using the antibody cloning technique of the present invention.

TABLE-US-00015 TABLE 9 EC₅₀ values of combinations of anti-RSV antibodies against RSV subtype A and B. Composition EC50 value (μg/ml) Number Antibodies in composition Long A2 18537 B1 1 810, 818, 819, 825, 827 0.19 0.38 2 810, 818, 819, 825, 827, 831, 858, 0.34 863, 884, 894, 793, 796, 816, 838, 853, 856, 859, 888 3 810, 818, 825, 827, 884, 886, 793, 0.30 853, 868, 888 4 810, 818, 825, 827, 831, 858, 884, 0.19 886, 793, 796, 816, 853, 856, 868, 888 5 810, 818, 825, 827, 831, 858, 884, 0.21 886, 793, 853, 868, 888 6 810, 819, 825, 827, 831, 793, 853, 0.20 856, 858, 868 7 810, 811, 817, 819, 825, 827, 831, 0.18 838, 853, 856, 858, 859, 863, 868 8 800, 801, 811, 838, 853, 855, 859, (ND) 861, 880, 894, 736, 795, 796, 799 0.92* 9 810, 818, 825 0.14 0.03 0.29 10 810, 818, 819, 825, 827, 884 0.21 0.42 11 810, 818, 819, 825, 827, 884, 886 0.15 0.29 12 793, 816, 853, 856 0.06 13 793, 816, 853, 855, 856 0.03 0.03 0.86 14 793, 868, 888, 853, 856 0.34 15 793, 796, 818, 816, 838, 853, 855, 0.11 856, 859, 868, 888 16 810, 818, 827 0.11 0.21 17 810, 818, 825, 827, 858, 886 0.10 0.05 0.16 18 810, 818, 825, 827, 858, 886, 793, 0.04 0.06 0.15 816, 853, 855, 856 19 818, 825, 827, 858, 886, 793, 816, 0.06 853, 855, 856 20 810, 818, 819, 825, 827, 858, 793, 0.10 0.06 816, 853, 855, 856 21 810, 793, 816, 853, 855, 856 0.04 22 818, 825, 827, 831, 858, 886, 793, 0.06 816, 853, 855, 856 23 818, 825, 827, 831, 858, 819, 793, 0.06 0.03 816, 853, 855, 856 24 818, 827, 831, 858, 819, 793, 816, 0.06 0.04 853, 855, 856 25 810, 818, 819, 824, 825, 827, 858, 0.07 793, 816, 853, 855, 856 26 831, 818, 819, 824, 825, 827, 858, 0.08 793, 816, 853, 855, 856 27 831, 818, 819, 824, 827, 858, 793, 0.05 816, 853, 855, 856 28 810, 818, 824 0.03-0.06 0.04 0.04 0.04 29 810, 824 0.05 30 818, 824 0.04 31 810, 818 0.08-0.11 32 824, 793, 816, 853, 855, 856 0.05 33 810, 818, 819, 824, 825, 827, 858, 0.03-0.07 0.06 0.03 0.06 894, 793, 816, 853, 855, 856 34 810, 818, 819, 824, 825, 827, 894, 0.07 793, 816, 853, 855, 856 35 793, 816 5.94 36 855, 856 ND 37 793, 856 ND 38 793, 853 2.35 39 853, 856 0.21 40 793, 853, 856 2.84 41 793, 816, 853 1.97 42 853, 855, 856 0.25 43 793, 816, 853, 856 0.45 44 793, 853, 855 0.26 45 793, 853, 855, 856 0.16 46 816, 853, 855, 856 0.07 47 816, 856 0.06 48 816, 853 0.75 49 816, 853, 856 0.07 50 810, 818, 824, 816 0.09 51 810, 818, 824, 853 0.11 52 810, 818, 824, 856 0.10 53 810, 818, 824, 816, 853 0.09 54 810, 818, 824, 816, 856 0.05 55 810, 818, 824, 853, 856 0.08 56 810, 818, 824, 816, 853, 856 0.05 0.03-0.05 0.03 0.06 Palivizumab (Synagis) 0.14 0.15 0.20 Blank fields indicate that the analysis has not been performed yet. ND indicates that an EC₅₀ value could not be determined in the PRNT due to a very low or lacking neutralizing activity. *value from new determination

Example 4

Reduction of Viral Loads in the Lungs of RSV-Infected Mice

[0297] The in vivo protective capacity of combinations of purified antibodies of the invention against RSV infection has been demonstrated in the BALB/c mouse model (Taylor et al. 1984. Immunology 52, 137-142; Mejias, et al. 2005. Antimicrob. Agents Chemother. 49: 4700-4707) as described in Example 1, Section k-1. In Table 10, data from an experiment with three different anti-RSV rpAb consisting of equal amounts of different antibody clones of the invention (described in table 9) are presented in comparison with data from uninfected control animals and placebo (PBS) treated animals of the same experiment. Each treatment group contained 5 mice and the samples were obtained on day five post-infection, which is approximately at the peak of virus replication in this model. As shown in Table 10, the rpAb combinations effectively reduce the virus load by at least an order of magnitude when given prophylactically. Copy numbers are presented as means standard deviations. The copy number was at or below the limit of detection of this assay, i.e., 3.8 log 10 RNA copies/ml, for two of the treatment groups.

TABLE-US-00016 TABLE 10 Virus loads in the lungs of mice following prophylaxis and RSV challenge. Virus load by RT-PCR (log10 Treatment group RNA copies/ml) New data Uninfected Negative PBS 5.14 ± 0.09 4.25 Anti-RSV rpAb 18 (50 mg/kg) ND Anti-RSV rpAb 18 (5 mg/kg) 4.61 ± 0.22 3.64 Anti-RSV rpAb 9 (50 mg/kg) Small F Hi ND Anti-RSV rpAb 9 (5 mg/kg) Small F Lo 4.74 ± 0.38 3.82 Anti-RSV rpAb 17 (50 mg/kg) Large F Hi 4.41 ± 0.14 3.04 Anti-RSV rpAb 17 (5 mg/kg) Large F Lo 4.69 ± 0.05 3.90

[0298] Samples have subsequently been analyzed using a different quantitative RT-PCR set-up (described in Section k-1). In table 11a, data from an experiment with four different anti-RSV rpAb consisting of equal amounts of different antibody clones of the invention (described in table 9) and clone 810 alone are presented in comparison with data from uninfected control animals and placebo (PBS) treated animals of the same experiment. Each treatment group contained 5 mice and the samples were obtained on day five post-infection, which is approximately at the peak of virus replication in this model. As shown in Table 11a, the rpAb combinations effectively reduce the virus load by at least an order of magnitude when given prophylactically at 25 mg/kg of body weight. Copy numbers are presented as means±standard deviations.

TABLE-US-00017 TABLE 11a Virus loads in the lungs of mice following prophylaxis and RSV challenge. Virus load by RT-PCR Treatment group (dose) (log10 RSV RNA copies/ng total RNA) Uninfected Negative PBS 4.11 ± 0.12 Anti-RSV rpAb 18 (25 mg/kg) 2.74 ± 0.16 Anti-RSV rpAb 18 (5 mg/kg) 3.40 ± 0.09 Anti-RSV rpAb 9 (25 mg/kg) 2.95 ± 0.19 Anti-RSV rpAb 9 (5 mg/kg) 3.56 ± 0.31 Anti-RSV rpAb 17 (25 mg/kg) 2.81 ± 0.29 Anti-RSV rpAb 17 (5 mg/kg) 3.39 ± 0.12 Anti-RSV rpAb 13 (25 mg/kg) 3.02 ± 0.33 Anti-RSV rpAb 13 (5 mg/kg) 3.34 ± 0.26 Clone 810 (25 mg/kg) 3.03 ± 0.16 Clone 810 (5 mg/kg) 3.37 ± 0.22

[0299] In table 11b, data from a second study with three different anti-RSV rpAb consisting of equal, amounts of different antibody clones of the invention (described in table 9) and clone 824 alone are presented in comparison with data from uninfected control animals, placebo (PBS) treated animals and Palivizumab (Synagis) treated animals of the same experiment. Each treatment group contained 5 mice and the samples were obtained on day five post-infection. Copy numbers are presented as means±standard deviations.

[0300] In table 11c, data from a third study with anti-RSV rpAb 33 consisting of equal amounts of different antibody clones of the invention (described in table 9) are presented in comparison with data from uninfected control animals, placebo (PBS) treated animals and Palivizumab (Synagis) treated animals of the same experiment. Each treatment group except the last three contained 5' mice and the samples were obtained on day five post-infection. One mouse was removed from each of the groups treated with anti-RSV rpAb 33 at 15, 5 and 1.5 mg/kg body weight since it was discovered that they were never injected with antibody. Copy numbers are presented as means±standard deviations.

[0301] In all three studies, there is a statistically significant reduction of the RSV

[0302] RNA copy number in the antibody-treated groups as compared to the Placebo-treated control (p<0.05; homoscedastic t-test). In the second study, the virus load in the groups treated with the antibodies of the invention are significantly lower than in the Synagis-treated groups at the corresponding doses (Table 11b). In the third study, the virus load is significantly lower in the groups treated with the anti-RSV rpAb 33 than in the Synagis-treated groups at all tested doses (Table 11c).

TABLE-US-00018 TABLE 11b Virus loads in the lungs of mice following prophylaxis and RSV challenge. Virus load by RT-PCR Treatment group (dose) (log10 RSV RNA copies/ng total RNA) Uninfected Negative PBS 4.22 ± 0.20 Synagis (15 mg/kg) 3.68 ± 0.25 Synagis (3 mg/kg) 3.83 ± 0.12 Anti-RSV rpAb 28 (15 mg/kg) 2.96 ± 0.19 Anti-RSV rpAb 28 (3 mg/kg) 3.32 ± 0.23 Anti-RSV rpAb 33 (15 mg/kg) 2.95 ± 0.30 Anti-RSV rpAb 33 (3 mg/kg) 3.66 ± 0.07 Anti-RSV rpAb 56 (15 mg/kg) 2.66 ± 0.18 Anti-RSV rpAb 56 (3 mg/kg) 3.25 ± 0.38 Clone 824 (15 mg/kg) 2.51 ± 0.28 Clone 824 (3 mg/kg) 3.09 ± 0.18

TABLE-US-00019 TABLE 11c Virus loads in the lungs of mice following prophylaxis and RSV challenge. Virus load by RT-PCR Treatment group (dose) (log10 RSV RNA copies/ng total RNA) Uninfected Negative PBS 4.13 ± 0.17 Synagis (45 mg/kg) 3.56 ± 0.22 Synagis (15 mg/kg) 3.60 ± 0.27 Synagis (5 mg/kg) 3.77 ± 0.14 Synagis (1.5 mg/kg) 3.86 ± 0.12 Anti-RSV rpAb 33 (45 mg/kg) 2.38 ± 0.18 Anti-RSV rpAb 33 (15 mg/kg)* 2.70 ± 0.18 Anti-RSV rpAb 33 (5 mg/kg)* 3.15 ± 0.24 Anti-RSV rpAb 33 (1.5 mg/kg)* 3.53 ± 0.12 The asterisk indicates that the group only contained four animals.

[0303] Finally, in Table 11d, data from a long-term study with anti-RSV rpAb 33 consisting of equal amounts of different antibody clones constituting rpAB 33 (described in table 9) are presented in comparison with data from uninfected control animals and placebo (PBS) treated animals of the same experiment. Each treatment group contained 5 mice and the samples were obtained on day 5, 27 and 69 post-infection. Copy numbers are presented as means f standard deviations. Due to the very low copy numbers on day 69 post-infection, copy numbers were calculated per ml of lung tissue. The limit of detection of this assay is approximately 2 log 10 RNA copies/ml lung tissue homogenate.

[0304] At all three time points, there is a statistically significant reduction of the RSV RNA copy number in the antibody-treated group as compared to the Placebo-treated control (p<0.01; homoscedastic t-test) (Table 11d).

TABLE-US-00020 TABLE 11d Virus loads in the lungs of mice following prophylaxis and RSV challenge. Virus load by RT-PCR (log10 RSV RNA copies/ml lung homogenate) Treatment group (dose) Day 5 Day 27 Day 69 Uninfected Negative Negative Negative PBS 9.36 ± 0.15 4.52 ± 0.22 4.05 ± 0.18 Anti-RSV rpAb 33 7.51 ± 0.22 3.22 ± 0.22 2.68 ± 0.41 (45 mg/kg) Each treatment group contained 5 animals per time point.

Cytokine and Chemokine Levels in Lung Samples from RSV Infected Mice

[0305] Lung samples from a pilot mouse prophylaxis study were analyzed by a commercial multiplexed immunoassay to determine the levels of different cytokines and chemokines following RSV infection and antibody prophylaxis with rpAb 18 (Table 9) as described in Example 1, Section k-1. Samples from uninfected and untreated animals were also analyzed to obtain normative data for the BALB/c mouse. All samples were obtained on day five post-infection. Data are presented as means±standard deviations.

[0306] The analysis showed (Table 12) that the levels of a number of cytokines and chemokines that have been indicated as important markers of RSV infection and the subsequent inflammatory response, both in humans and mice, including interferon (IFN)-γ, interleukin (IL)-1β, IL-4, IL-6, IL-8 (KC/GROα), IL-10, macrophage inflammatory protein (MIP)-1α, Regulated upon activation of normal T cell expressed and secreted (RANTES, CCL5) and tumor necrosis factor (TNF)-α were increased in the lungs of the placebo-treated animals, whereas the lungs of the animals treated with approx. 50 mg/kg of rpAb had levels more or less on par with the uninfected control animals. Similar results were also obtained with other anti-RSV rpAb combinations. It should be noted that mice do not have a clear-cut homologue for IL-8, but they have a functional homologue for human GROα (similar function to IL-8) named KC.

[0307] The kinetics of the inflammatory response and the dose-response effects of antibody prophylaxis remain to be investigated.

TABLE-US-00021 TABLE 12 Levels of cytokines and chemokines in lung tissue from RSV infected mice Level in tissue anti-RSV sample Uninfected Placebo rpAb treated (pg/ml) control mice treated mice mice IL-1β 270 ± 71 570 ± 100 310 ± 140 IL-4 7.7 ± 4.7 26 ± 4.6 14 ± 8.5 IL-6 6.4 ± 2.6 22 ± 12 8.2 ± 3.8 IL-10 120 ± 17 320 ± 58 170 ± 41 IFN-γ 20 ± 7.6 420 ± 88 81 ± 72 KC/GROα (IL-8) 51 ± 38 290 ± 83 94 ± 99 MIP-1α (CCL3) 39 ± 16 940 ± 170 160 ± 110 RANTES (CCL5) 60 ± 28 380 ± 32 140 ± 66 TNF-α 18 ± 6.1 95 ± 10 38 ± 25

Effect of Antibody Prophylaxis on Pulmonary Pathology and Infiltrating Cells in RSV Infected Mice

[0308] The lung tissue histopathology samples from the long-term study were examined for signs of inflammation and scored according to the system described in Example 1, Section k-1. Each treatment group contained 5 mice and the samples were obtained on day 5, 27 and 69 post-infection. One mouse was removed from the group treated with anti-RSV rpAb 33 and killed on day 5 post-infection since it was discovered that it had not been injected with antibody. Data are presented as means±standard deviations. Five days after RSV infection, there was a significant increase in pulmonary pathology in the placebo-treated mice when compared with the uninfected control mice (p<0.005; heteroscedastic t-test; Table 13). The signs of inflammation decreased over time, but were still significant compared to the uninfected control mice at day 69 post-infection (p<0.0001). The pulmonary pathology was characterized by peribronchiolar and perivascular accumulations of lymphocytes and alveolitis at day 5 post-infection and by small perivascular and peribronchiolar accumulations of lymphocytes at days 27 and 69 post-infection. In contrast, there was little or no lymphoid accumulation in the lungs of antibody-treated mice and the lungs were similar to those of uninfected control mice. Pulmonary pathology in the placebo-treated mice was also significantly greater than in the antibody-treated mice (p<0.02 at day 5, <0.03 at day 27 and <0.0001 at day 69).

TABLE-US-00022 TABLE 13 Mouse lung pathology scores following prophylaxis and RSV challenge. Lung pathology score (Severity × Prevalence) Treatment group (dose) Day 5 Day 27 Day 69 Uninfected 0 0.4 ± 0.5 0 PBS 10.8 ± 4.3 2.8 ± 1.1 2.6 ± 0.5 Anti-RSV rpAb 33 (45 mg/kg) 3 ± 0.8* 0.6 ± 0.9 0.2 ± 0.4 The asterisk indicates that the group only contained four animals.

[0309] The perivascular and peribronchiolar lymphoid accumulations in the lungs of RSV-infected mice, 28 and 70 days after infection correlated with increased numbers of lymphocytes in the BAL. As shown in Table 14, there was a significant increase in the number of inflammatory cells in BAL from placebo-treated mice compared with control uninfected mice at days 5, 27 and 69 post-infection (p<0.002; p<0.03; p<0.03 respectively). The pulmonary inflammatory response in mice treated with anti-RSV rpAb 33 was significantly less than that in placebo-treated mice at all time points and (p<0.003 at day 5; p<0.03 at day 27; p<0.02 at day 69 respectively). The groups are the same as for the lung pathology described above and data are presented as means standard deviations.

TABLE-US-00023 TABLE 14 Leukocyte counts in BAL following prophylaxis and RSV challenge. BAL cell counts (×10⁵) Treatment group (dose) Day 5 Day 27 Day 69 Uninfected 1.1 ± 0.2 1.4 ± 0.3 1.0 ± 0.1 PBS 7.2 ± 2.0 3.0 ± 1.0 1.8 ± 0.5 Anti-RSV rpAb 33 (45 mg/kg) 1.8 ± 0.5* 1.5 ± 0.3 0.9 ± 0.1 The asterisk indicates that the group only contained four animals.

Pharmacokinetics of Human rpAb in Mice

[0310] The pharmacokinetic profile of combinations of purified antibodies of the invention was determined in BALB/c mice as described in Example 1, section 1. Two different anti-RSV rpAb 33 and anti-RSV rpAb 56 (see Table 9), consisting of equal amounts of different antibody clones of the invention were investigated. Each treatment group consisted of 15 mice. The measured human IgG levels in serum samples and lung homogenates corresponds to the level of anti-RSV rpAb present at the specific time points.

[0311] FIG. 8 shows the serum pharmacokinetic profiles of anti-RSV rpAb 33 and anti-RSV rpAb 56 at an antibody dose of 15 mg/kg. Using these data, a number of parameters were determined, which are summarized in Table 15. The two different Anti-RSV rpAb compositions have similar pharmacokinetic profiles with a half-life (T₁/2) of 11 days. These findings have been verified using a dose of 37.5 mg/kg.

TABLE-US-00024 TABLE 15 Serum pharmacokinetic data obtained in mice C_max T_max AUC T₁/2 (mg/ml) (hours) (0-694)* (days) Anti-RSV rpAb 33 15.4 25 51 11.1 Anti-RSV rpAb 56 17.2 25 52 11.0 *Area Under Curve between time = 0 hours and time = 694 hours.

[0312] Since the primary target of RSV during infection is the lung tissue, the presence of anti-RSV rpAb in this tissue is vital for efficacy. To determine the distribution of anti-RSV rpAb 33 and anti-RSV rpAb 56 (according to Table 9) to lung tissue, the IgG1 levels was measured in lung homogenates at days 1 (25 hours), 6, and 29 after antibody treatment. At all measured time points, the levels of anti-RSV rpAb 33 and anti-RSV rpAb 56 in lung tissue was found to be almost identical with a maximal average IgG1 concentration around 0.006 mg/ml at day 1 after antibody treatment. At days 6 and 29 the levels had decreased. However, IgG1 could still be measured in lung tissue at day 29 after antibody treatment. These findings show that not only is anti-RSV rpAb composition 33 and anti-RSV rpAb composition 56 present in lung tissue shortly after treatment but antibodies can be found in detectable levels up to at least 29 days after treatment.

Sequence CWU 1

7141122PRThomo sapiens 1Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Asn Gly Ala Ile Gly Asp Tyr 20 25 30Asp Trp Ser Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Asn Ile Asn Tyr Arg Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Met Ser Leu Arg Thr Ser Thr Met Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Ala Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Val Gly Tyr Gly Gly Gly Gln Tyr Phe Ala Met Asp Val Trp 100 105 110Ser Pro Gly Thr Thr Val Thr Val Ser Ser 115 1202129PRThomo sapiens 2Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Phe Ile Arg Tyr Asp Gly Ser Thr Gln Asp Tyr Val Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Val Tyr65 70 75 80Val Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Met Asp Tyr Tyr Gly Ser Arg Ser Tyr Ser Val Thr Tyr 100 105 110Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125Ser3125PRThomo sapiens 3Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Gly Tyr 20 25 30Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Thr Ser Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala His65 70 75 80Met Glu Leu Arg Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Asp Gly Thr Met Gly Thr Asn Ser Trp Tyr Gly Trp Phe 100 105 110Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 1254127PRThomo sapiens 4Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Gly Asp Tyr 20 25 30Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Tyr Ile Asn Arg Gly Gly Thr Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Arg Gly Leu Ile Leu Ala Leu Pro Thr Ala Thr Val Glu Leu Gly 100 105 110Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 1255126PRThomo sapiens 5Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Ala Ser Ile Ser Ser Gly 20 25 30Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Ser Pro Arg Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Ile Phe His Ser Gly Thr Thr Tyr Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Ala Val Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Asp Val Asp Asp Phe Pro Val Trp Gly Met Asn Arg Tyr 100 105 110Leu Ala Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 1256124PRThomo sapiens 6Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser His Phe 20 25 30Gly Met His Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ile Ile Ser Tyr Asp Gly Asn Asn Val His Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe65 70 75 80Leu Gln Met Asn Ser Leu Arg Asp Asp Asp Thr Gly Val Tyr Tyr Cys 85 90 95Ala Lys Asp Asp Val Ala Thr Asp Leu Ala Ala Tyr Tyr Tyr Phe Asp 100 105 110Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 1207123PRThomo sapiens 7Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Asn Phe Asn Asn Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Arg Asn Lys Tyr Phe Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Ile Ile Ser Arg Asp Asp Ser Arg Asn Thr Val Phe65 70 75 80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ser Val Gln Val Trp Leu His Leu Gly Leu Phe Asp Asn 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1208122PRThomo sapiens 8Gln Val Gln Leu Val Glu Ser Gly Gly Ala Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Glu Val Ser Gly Phe Ser Phe Ser Asp Tyr 20 25 30Gly Met Asn Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp His Asp Gly Ser Asn Lys Asn Tyr Leu Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Thr Pro Tyr Glu Phe Trp Ser Gly Tyr Tyr Phe Asp Phe Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 1209116PRThomo sapiens 9Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Asn Ser Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Tyr Tyr Glu Gly Ser Asn Glu Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asp Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Lys Trp Leu Gly Met Asp Phe Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser 11510120PRThomo sapiens 10Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Tyr Val 35 40 45Ser Ala Thr Ser Thr Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Leu 50 55 60Lys Gly Thr Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Ser Ser Leu Ser Thr Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95Ala Arg Arg Phe Trp Gly Phe Gly Asn Phe Phe Asp Tyr Trp Gly Arg 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 12011122PRThomo sapiens 11Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Ser Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Arg Ala Ser Gly Gly Thr Phe Gly Asn Tyr 20 25 30Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Ile Pro Val Phe Asp Thr Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Arg Ser Thr Asn Thr Ala Ile65 70 75 80Met Gln Leu Ser Ser Leu Arg Pro Gln Asp Thr Ala Met Tyr Tyr Cys 85 90 95Leu Arg Gly Ser Thr Arg Gly Trp Asp Thr Asp Gly Phe Asp Ile Trp 100 105 110Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 12012129PRThomo sapiens 12Gln Val Gln Leu Val Gln Ser Gly Ala Val Val Glu Thr Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Gly Asn Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Ala Val Ile Asn Pro Asn Gly Gly Ser Thr Thr Ser Ala Gln Lys Phe 50 55 60Gln Asp Arg Ile Thr Val Thr Arg Asp Thr Ser Thr Thr Thr Val Tyr65 70 75 80Leu Glu Val Asp Asn Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95Ala Arg Gln Arg Ser Val Thr Gly Gly Phe Asp Ala Trp Leu Leu Ile 100 105 110Pro Asp Ala Ser Asn Thr Trp Gly Gln Gly Thr Met Val Thr Val Ser 115 120 125Ser13126PRThomo sapiens 13Gln Val Gln Leu Val Gln Ser Gly Ala Glu Met Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ser Phe Ser Ser Tyr 20 25 30Ser Ile Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45Gly Met Ile Leu Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Thr Phe 50 55 60Gln Gly Arg Val Ile Ile Ser Ala Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Thr Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Arg Val Phe Arg Glu Phe Ser Thr Ser Thr Leu Asp Pro Tyr Tyr 100 105 110Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12514125PRThomo sapiens 14Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Lys1 5 10 15Ser Val Arg Leu Ser Cys Val Gly Ser Gly Phe Arg Leu Met Asp Tyr 20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ala Asn Glu Tyr Tyr Ala Glu Ser Val 50 55 60Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Asp Asn Thr Leu Tyr65 70 75 80Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Arg Ala Gly Arg Ser Ser Met Asn Glu Glu Val Ile Met Tyr Phe 100 105 110Asp Asn Trp Gly Leu Gly Thr Leu Val Thr Val Ser Ser 115 120 12515127PRThomo sapiens 15Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Arg Ala Ser Gly Asp Ser Glu Ile Tyr Ala Asp Ser Val 50 55 60Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Phe65 70 75 80Leu Gln Met Asp Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Asn Ile Gly Gln Arg Arg Tyr Cys Ser Gly Asp His Cys Tyr Gly 100 105 110His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12516127PRThomo sapiens 16Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Gly Phe Asn Thr His 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45Ser Ile Ile Ser Leu Asp Gly Ile Lys Thr His Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Phe65 70 75 80Leu Gln Leu Ser Gly Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp His Ile Gly Gly Thr Asn Ala Tyr Phe Glu Trp Thr Val 100 105 110Pro Phe Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12517126PRThomo sapiens 17Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Val Val Lys Pro Thr Glu1 5 10 15Thr Leu Thr Leu Thr Cys Ala Phe Ser Gly Phe Ser Leu Asn Ala Gly 20 25 30Arg Val Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Gln Ala Pro Glu 35 40 45Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Ala Phe Arg Thr Ser 50 55 60Leu Lys Thr Arg Leu Ser Ile Ser Lys Asp Ser Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Leu Ser Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala Arg Thr Gln Val Phe Ala Ser Gly Gly Tyr Tyr Leu Tyr Tyr 100 105 110Leu Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12518129PRThomo sapiens 18Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Ser Gly Ala Ile Ser Gly Ala 20 25 30Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Val Gly Phe Ile Tyr Asp Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60Leu Arg Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Lys Lys Gln Phe65 70 75 80Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg Asp Leu Gly Tyr Gly Gly Asn Ser Tyr Ser His Ser Tyr 100 105 110Tyr Tyr Gly Leu Asp Val Trp Gly Arg Gly Thr Thr Val Thr Val Ser 115 120 125Ser19119PRThomo sapiens 19Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Gly Asn Tyr 20 25 30Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly His Ile Tyr Phe Gly Gly Asn Thr Asn Tyr Asn Pro Ser Leu Gln 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Arg Asn Gln Phe Ser Leu65 70 75 80Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asp Ser Ser Asn Trp Pro Ala Gly Tyr Glu Asp Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11520123PRThomo sapiens 20Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Ser Asn 20 25 30Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Phe Glu Trp Leu 35 40 45Gly Trp Ile Ser Ala Ser Ser Gly Asn Lys Lys Tyr Ala Pro Lys Phe 50 55 60Gln Gly Arg

Val Thr Leu Thr Thr Asp Ile Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Gly Gly Thr Tyr Val Pro Tyr Ser Asp Ala Phe Asp Phe 100 105 110Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 12021118PRThomo sapiens 21Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Arg Val Ser Gly His Thr Phe Thr Ala Leu 20 25 30Ser Lys His Trp Met Arg Gln Gly Pro Gly Gly Gly Leu Glu Trp Met 35 40 45Gly Phe Phe Asp Pro Glu Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ala Thr Gly Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Thr Val Ala Ala Ala Gly Asn Phe Asp Asn Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser 11522126PRThomo sapiens 22Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Ala Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Arg Asn 20 25 30Arg Met Ser Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Phe Tyr Asn Thr Ser 50 55 60Leu Gln Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala Arg Thr Gly Ile Tyr Asp Ser Ser Gly Tyr Tyr Leu Tyr Tyr 100 105 110Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12523130PRThomo sapiens 23Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Val Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30Gly Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Tyr Tyr Leu Gln Lys Leu 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Gly Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Val Gly Gly Ser Ser Ser Glu Val Leu Ser Arg Ala 100 105 110Lys Asn Tyr Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125Ser Ser 13024123PRThomo sapiens 24Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Ala Asn Ile Phe Thr Tyr Ala 20 25 30Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met Gly 35 40 45Trp Ile Asn Val Gly Asn Gly Gln Thr Lys Tyr Ser Gln Arg Phe Gln 50 55 60Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Thr Thr Ala Tyr Met65 70 75 80Glu Leu Ser Thr Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Arg Ala Ser Gln Tyr Gly Glu Val Tyr Gly Asn Tyr Phe Asp Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12025126PRThomo sapiens 25Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Arg Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Ser Tyr 20 25 30Gly Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ser Ser Val Tyr Asn Gly Asp Thr Asn Tyr Ala Gln Lys Phe 50 55 60His Gly Arg Val Asn Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr65 70 75 80Met Glu Leu Arg Gly Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Arg Asp Arg Asn Val Val Leu Leu Pro Ala Ala Pro Phe Gly Gly 100 105 110Met Asp Val Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 12526123PRThomo sapiens 26Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Thr1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Phe 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Asn Lys Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Val Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ala Gln Thr Pro Tyr Phe Asn Glu Ser Ser Gly Leu Val Pro Asp 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12027126PRThomo sapiens 27Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Ser Phe 20 25 30Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asp Tyr Ala Gln Arg Leu 50 55 60Gln Asp Arg Val Thr Met Thr Arg Asp Thr Ala Thr Ser Thr Ala Tyr65 70 75 80Leu Glu Leu Arg Ser Leu Lys Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Asp Glu Ser Met Leu Arg Gly Val Thr Glu Gly Phe Gly Pro 100 105 110Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12528128PRThomo sapiens 28Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Gln1 5 10 15Ser Leu Lys Ile Ser Cys Lys Thr Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30Trp Ile Gly Trp Val Arg Gln Arg Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Val Ile Phe Pro Ala Asp Ser Asp Ala Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Gly Thr Ala Tyr65 70 75 80Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Ile Tyr Tyr Cys 85 90 95Ala Arg Pro Lys Tyr Tyr Phe Asp Ser Ser Gly Gln Phe Ser Glu Met 100 105 110Tyr Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12529119PRThomo sapiens 29Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Val Leu Thr Asn Tyr 20 25 30Ala Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Leu 35 40 45Gly Trp Ile Ser Gly Ser Asn Gly Asn Thr Tyr Tyr Ala Glu Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Arg Asp Leu Leu Arg Ser Thr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11530126PRThomo sapiens 30Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asn Tyr 20 25 30Gly Phe Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Tyr Tyr Ala Gln Asn Leu 50 55 60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr65 70 75 80Met Val Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Asn Thr Ala Gly Val Asp Met Trp Ser Arg Asp Gly 100 105 110Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 12531131PRThomo sapiens 31Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Pro Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30Ala Met Asn Trp Ile Arg Leu Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Gly Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Glu Pro Trp Ile Asp Ile Val Val Ala Ser Val Ile Ser Pro 100 105 110Tyr Tyr Tyr Asp Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125Val Ser Ser 13032123PRThomo sapiens 32Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ser Phe Asp Gly Tyr 20 25 30Thr Ile Ser Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Arg Val Val Pro Thr Leu Gly Phe Pro Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Val Thr Ala Asp Arg Ser Thr Asn Thr Ala Tyr65 70 75 80Leu Glu Leu Ser Arg Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Met Asn Leu Gly Ser His Ser Gly Arg Pro Gly Phe Asp Met 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12033129PRThomo sapiens 33Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ser Ser Phe Ser Lys Tyr 20 25 30Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Tyr Asp Gly Ser Lys Lys Tyr Phe Thr Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ala Arg Asp Asn Ser Gln Asn Thr Val Phe65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Thr Gly Gly Gly Val Asn Val Thr Ser Trp Ser Asp Val Glu His 100 105 110Ser Ser Ser Leu Gly Tyr Trp Gly Leu Gly Thr Leu Val Thr Val Ser 115 120 125Ser34125PRThomo sapiens 34Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Phe Ile Trp Asn Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Lys Asp Glu Val Tyr Asp Ser Ser Gly Tyr Tyr Leu Tyr Tyr Phe 100 105 110Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12535127PRThomo sapiens 35Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Ala Ser Thr Val Leu Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Tyr Asp Phe Trp Ser Gly Tyr Pro Gly Gly Gln Tyr Trp 100 105 110Phe Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 12536123PRThomo sapiens 36Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Thr Pro Ser Glu1 5 10 15Thr Leu Ser Val Thr Cys Thr Val Ser Asn Tyr Ser Ile Asp Asn Ala 20 25 30Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45Ile Gly Ser Ile His His Ser Gly Ser Ala Tyr Tyr Asn Ser Ser Leu 50 55 60Lys Ser Arg Ala Thr Ile Ser Ile Asp Thr Ser Lys Asn Gln Phe Ser65 70 75 80Leu Asn Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Thr Ile Leu Thr Phe Gly Glu Pro His Trp Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12037124PRThomo sapiens 37Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Ser Asn Thr Trp Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Leu Asp Met Pro Lys Asn Gln Leu Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gly Leu Phe Tyr Asp Ser Gly Gly Tyr Tyr Leu Phe Tyr Phe Gln 100 105 110His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12038125PRThomo sapiens 38Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Tyr Asp Asp Ser Asn Lys Gln Tyr Gly Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr65 70 75 80Leu Gln Met Asp Arg Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ala Ser Glu Tyr Ser Ile Ser Trp Arg His Arg Gly Val Leu 100 105 110Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 12539126PRThomo sapiens 39Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Arg Pro Thr Gln1 5 10 15Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30Lys Leu Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45Trp Leu Ala Leu Val Asp Trp Asp Asp Asp Arg Arg Tyr Arg Pro Ser 50 55 60Leu Lys Ser Arg Leu Thr Val Thr Lys Asp Thr Ser Lys Asn Gln Val65 70 75 80Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95Cys Ala His Ser Ala Tyr Tyr Thr Ser Ser Gly Tyr Tyr Leu Gln Tyr 100 105 110Phe His His Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 115

120 12540125PRThomo sapiens 40Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Glu Val Ser Gly Phe Thr Phe Asn Ser Tyr 20 25 30Glu Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser His Ile Gly Asn Ser Gly Ser Met Ile Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Ser Asp Tyr Tyr Asp Ser Ser Gly Tyr Tyr Leu Leu Tyr Leu 100 105 110Asp Ser Trp Gly His Gly Thr Leu Val Thr Val Ser Ser 115 120 12541120PRThomo sapiens 41Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly His Thr Phe Ile Asn Phe 20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Tyr Ile Asn Ala Val Asn Gly Asn Thr Gln Tyr Ser Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Phe Thr Arg Asp Thr Ser Ala Asn Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Asn Gly Gly Ser Ala Ile Ile Phe Tyr Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 12042122PRThomo sapiens 42Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Ser Asn Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Lys Thr Met Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Lys Thr Thr Asp Gln Arg Leu Leu Val Asp Trp Phe Asp Pro Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12043130PRThomo sapiens 43Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Gly Ser Ile Asn Ser Ser 20 25 30Asn Phe Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Ser Ile Phe Tyr Ser Gly Thr Thr Tyr Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Pro Val Thr Ala Ala Asp Thr Ala Val Tyr His 85 90 95Cys Ala Arg His Gly Phe Arg Tyr Cys Asn Asn Gly Val Cys Ser Ile 100 105 110Asn Leu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val 115 120 125Ser Ser 13044122PRThomo sapiens 44Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Lys1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Arg Phe Ser Asp Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Ser Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp His Asp Gly Ser Asn Ile Arg Tyr Ala Asp Ser Val 50 55 60Arg Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Met Arg Ala Asp Asp Thr Ala Phe Tyr Tyr Cys 85 90 95Ala Arg Val Pro Phe Gln Ile Trp Ser Gly Leu Tyr Phe Asp His Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12045366DNAhomo sapiens 45caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acgtgcactg tgtctaatgg cgccatcggc gactacgact ggagctggat tcgtcagtcc 120ccagggaagg gactggagtg gattgggaac ataaattaca gagggaacac caactacaac 180ccctccctca agagtcgagt caccatgtcc ctacgcacgt ccacgatgca gttctccctg 240aagctgagct ctgcgaccgc tgcggacacg gccgtctatt actgtgcgag agatgtaggc 300tacggtggcg ggcagtattt cgcgatggac gtctggagcc cagggaccac ggtcaccgtc 360tcgagt 36646387DNAhomo sapiens 46caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctggggggtc cctgagactc 60tcctgtacag cgtctggatt caccttcagt acctatggca tgcactgggt ccgccaggct 120cccggcaagg ggctggaatg ggtggcattt atacggtatg atggaagtac tcaagactat 180gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa tatggtgtat 240gtgcagatga acagcctgag agttgaggac acggctgtct attactgtgc gaaagacatg 300gattactatg gttcgcggag ttattctgtc acctactact acggaatgga cgtctggggc 360caagggacca cggtcaccgt ctcgagt 38747375DNAhomo sapiens 47caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcagc ggctattata tgcactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaacacta gcagtggtgg cacaaactat 180gcgcagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcccac 240atggaactga ggaggctgag atctgacgac acggccgtgt attattgtgc gagagaggac 300ggcaccatgg gtactaatag ttggtatggc tggttcgacc cctggggcca gggaaccctg 360gtcaccgtct cgagt 37548381DNAhomo sapiens 48caggtgcagc tggtggagtc tgggggaggc ttggtcaagc ctggggggtc cctgagactc 60tcctgtgcgg cctctggatt ccccttcggt gactactaca tgagctggat ccgccaggct 120ccagggaagg gactggagtg ggttgcatac attaatagag gtggcactac catatactac 180gcagactctg tgaagggccg attcaccatc tccagggaca acgccaagaa ctccctgttt 240ctgcaaatga acagcctgag agccggggac acggccctct attactgtgc gagagggcta 300attctagcac taccgactgc tacggttgag ttaggagctt ttgatatctg gggccaaggg 360acaatggtca ccgtctcgag t 38149378DNAhomo sapiens 49caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgc ctccatcagc agtggtgatt attactggag ttggatccgt 120cagtctccaa ggaagggcct ggagtggatt gggtacatct tccacagtgg gaccacgtac 180tacaacccgt ccctcaagag tcgagctgtc atctcactgg acacgtccaa gaaccaattc 240tccctgaggc tgacgtctgt gactgccgca gacacggccg tctattattg tgccagagat 300gtcgacgatt ttcccgtttg gggtatgaat cgatatcttg ccctctgggg ccggggaacc 360ctggtcaccg tctcgagt 37850372DNAhomo sapiens 50caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt cagcttcagt cactttggca tgcactgggt ccgccaggtt 120ccaggcaagg ggctggagtg ggtggcaatt atatcatatg atgggaataa tgtacactat 180gccgactccg taaagggccg attcaccatc tccagagaca attccaagaa cacgctgttt 240ctgcaaatga acagcctgag agatgacgac acgggtgtgt attactgtgc gaaggacgac 300gtggcgacag atttggctgc ctactactac ttcgatgtct ggggccgtgg caccctggtc 360accgtctcga gt 37251369DNAhomo sapiens 51caggtgcagc tggtggagtc tgggggcggc gtggtccagc ctgggaggtc cctgaaactc 60tcttgtgaag cctctggatt caacttcaat aattatggca tgcactgggt ccgccaggca 120ccaggcaagg ggctggagtg ggtggcagtt atttcatatg acggaagaaa taagtatttt 180gctgactccg tgaagggccg attcatcatc tccagagacg attccaggaa cacagtgttt 240ctgcaaatga acagcctgcg agttgaagat acggccgtct attactgtgc gagaggcagc 300gtacaagtct ggctacattt gggacttttt gacaactggg gccagggaac cctggtcacc 360gtctcgagt 36952366DNAhomo sapiens 52caggtgcagc tggtggagtc tgggggagcc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgaag tgtctggatt cagtttcagt gactatggca tgaactgggt ccgccagggt 120ccaggcaagg ggctggagtg ggtggcagtt atatggcatg acggaagtaa taaaaattat 180ctagactccg tgaagggccg attcaccgtc tccagagaca attccaagaa cacattgttt 240ctgcaaatga acagcctgag agccgaagac acggctgtat attactgtgc gaggacgcct 300tacgagtttt ggagtggcta ttactttgac ttctggggcc agggaaccct ggtcaccgtc 360tcgagt 36653348DNAhomo sapiens 53caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt ccccttcaat agctatgcca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtg atatattatg aagggagtaa tgaatattat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cactctgtat 240ttgcaaatgg atagcctgag agccgaggac acggctgtct attactgtgc gaggaagtgg 300ctggggatgg acttctgggg ccagggaacc ctggtcaccg tctcgagt 34854360DNAhomo sapiens 54gaggtgcagc tggtggagtc tgggggaggc ttggtccggc ctggggggtc cctgagactc 60tcctgttcag cctctggatt caccttcagt aactatgcta tgcactgggt ccgccaggct 120ccagggaaga gactggaata tgtttcagct actagtactg atggggggag cacatactac 180gcagactccc taaagggcac attcaccatc tccagagaca attccaagaa cacactgtat 240cttcaaatga gcagtctcag tactgaggac acggctattt attactgcgc ccgccgattc 300tggggatttg gaaacttttt tgactactgg ggccggggaa ccctggtcac cgtctcgagt 36055366DNAhomo sapiens 55caggtgcagc tggtgcagtc tggggctgag gtgaagaagt ccgggtcctc ggtgaaggtc 60tcctgcaggg cttctggagg caccttcggc aattatgcta tcaactgggt gcgacaggcc 120cctggacaag ggcttgagtg ggtgggaagg atcatccctg tctttgatac aacaaactac 180gcacagaagt tccagggcag agtcacgatt accgcggaca gatccacaaa cacagccatc 240atgcaactga gcagtctgcg acctcaggac acggccatgt attattgttt gagaggttcc 300acccgtggct gggatactga tggttttgat atctggggcc aagggacaat ggtcaccgtc 360tcgagt 36656387DNAhomo sapiens 56caggttcagc tggtgcagtc tggggctgtc gtggagacgc ctggggcctc agtgaaggtc 60tcctgcaagg catctggata catcttcggc aactactata tccactgggt gcggcaggcc 120cctggacaag ggcttgagtg gatggcagtt atcaatccca atggtggtag cacaacttcc 180gcacagaagt tccaagacag aatcaccgtg accagggaca cgtccacgac cactgtctat 240ttggaggttg acaacctgag atctgaggac acggccacat attattgtgc gagacagaga 300tctgtaacag ggggctttga cgcgtggctt ttaatcccag atgcttctaa tacctggggc 360caggggacaa tggtcaccgt ctcgagt 38757378DNAhomo sapiens 57caggtgcagc tggtgcagtc tggggctgag atgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggagg ctccttcagc agctattcta tcagctgggt gcgacaggcc 120cctggacgag ggcttgagtg ggtgggaatg atcctgccta tctctggtac aacaaactac 180gcacagacat ttcagggcag agtcatcatt agcgcggaca catccacgag cacagcctac 240atggagctga ccagcctcac atctgaagac acggccgtgt atttctgtgc gagagtcttt 300agagaattta gcacctcgac ccttgacccc tactactttg actactgggg ccagggaacc 360ctggtcaccg tctcgagt 37858375DNAhomo sapiens 58caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaagtc cgtgagactc 60tcctgtgtag gctctggctt caggctcatg gactatgcta tgcactgggt ccgccaggct 120ccaggcaagg gactggattg ggtggcagtt atttcatatg atggagccaa tgaatactac 180gcagagtccg tgaagggccg attcaccgtc tccagagaca attcagacaa cactctgtat 240ctacaaatga agagcctgag agctgaggac acggctgtgt atttctgtgc gagagcgggc 300cgttcctcta tgaatgaaga agttattatg tactttgaca actggggcct gggaaccctg 360gtcaccgtct cgagt 37559381DNAhomo sapiens 59gaggtgcagc tgttggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgtag cctccggatt cacctttagt acctacgcca tgacctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcagtc attcgtgcta gtggtgatag tgaaatctac 180gcagactccg tgaggggccg gttcaccatc tccagagaca attccaagaa cacggtgttt 240ctgcaaatgg acagcctgag agtcgaggac acggccgtat atttctgtgc gaatataggc 300cagcgtcggt attgtagtgg tgatcactgc tacggacact ttgactactg gggccaggga 360accctggtca ccgtctcgag t 38160381DNAhomo sapiens 60caggtgcagc tggtggagtc tgggggaggc gtggtccaac ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt cggcttcaac acccatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg gctgtcaatt atctcacttg atgggattaa gacccactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacggtgttt 240ctacaattga gtggcctgag acctgaagac acggctgtat attactgtgc gaaagatcat 300attgggggga cgaacgcata ttttgaatgg acagtcccgt ttgacggctg gggccaggga 360accctggtca ccgtctcgag t 38161378DNAhomo sapiens 61caggtcacct tgagggagtc tggtccagcg gtggtgaagc ccacagaaac gctcactctg 60acctgcgcct tctctgggtt ctcactcaac gccggtagag tgggtgtgag ttggatccgt 120cagcccccag ggcaggcccc ggaatggctt gcacgcattg attgggatga tgataaagcg 180ttccgcacat ctctgaagac cagactcagc atctccaagg actcctccaa aaaccaggtg 240gtccttacac tgagcaacat ggaccctgcg gacacagcca catattactg tgcccggaca 300caggtcttcg caagtggagg ctactacttg tactaccttg accactgggg ccagggaacc 360ctggtcaccg tctcgagt 37862387DNAhomo sapiens 62caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctagtgg cgccatcagt ggtgctgatt actactggag ttggatccgc 120cagcccccag ggaagggcct ggagtgggtt gggttcatct atgacagtgg gagcacctac 180tacaacccgt ccctcaggag tcgagtgacc atatcaatag acacgtccaa gaagcagttc 240tccctgaagc tgacctctgt gactgccgca gacacggccg tgtattactg tgccagagat 300ctaggctacg gtggtaactc ttactcccac tcctactact acggtttgga cgtctggggc 360cgagggacca cggtcaccgt ctcgagt 38763357DNAhomo sapiens 63caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcgga aattactact ggggctggat ccggcagccc 120ccagggaagg gacttgagtg gattgggcat atctacttcg gtggcaacac caactacaac 180ccttccctcc agagtcgagt caccatttca gtcgacacgt ccaggaacca gttctccctg 240aagttgaact ctgtgaccgc cgcggacacg gccgtgtatt actgtgcgag ggatagcagc 300aactggcccg caggctatga ggactggggc cagggaaccc tggtcaccgt ctcgagt 35764369DNAhomo sapiens 64caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg tttctggtta cacctttacc agtaatggtc tcagctgggt gcgacaggcc 120cctggacaag ggtttgagtg gctgggatgg atcagcgcta gtagtggaaa caaaaagtat 180gccccgaaat tccagggaag agtcaccttg accacagaca tttccacgag cacagcctac 240atggaactga ggagtctgag atctgacgat acggccgtat attactgtgc gaaagatggg 300ggcacctacg tgccctattc tgatgccttt gatttctggg gccaggggac aatggtcacc 360gtctcgagt 36965354DNAhomo sapiens 65caggtccagc tggtacagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaggg tttccggaca cactttcact gcattatcca aacactggat gcgacagggt 120cctggaggag ggcttgagtg gatgggattt tttgatcctg aagatggtga cacaggctac 180gcacagaagt tccagggcag agtcaccatg accgaggaca cagccacagg cacagcctac 240atggagctga gcagcctgac atctgacgac acggccgtat attattgtgc aacagtagcg 300gcagctggaa actttgacaa ctggggccag ggaaccctgg tcaccgtctc gagt 35466378DNAhomo sapiens 66caggtcacct tgaaggagtc tggtcctgcg ctggtgaaag ccacacagac cctgacactg 60acctgcacct tctctgggtt ttcactcagt aggaatagaa tgagtgtgag ctggatccgt 120cagcccccag ggaaggccct ggagtggctt gcacgcattg attgggatga tgataaattc 180tacaacacat ctctgcagac caggctcacc atctccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca cctattactg cgcacggact 300gggatatatg atagtagtgg ttattacctc tactactttg actactgggg ccagggaacc 360ctggtcaccg tctcgagt 37867390DNAhomo sapiens 67caggtgcagc tggtgcagtc tggagctgag gtgaaggtgc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttacc acttacggtg tcagctgggt gcggcaggcc 120cctggacaag ggcttgagtg gatgggttgg atcagcgctt acaatggtaa cacatactat 180ctacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240atggagctgc ggggcctgag gtctgacgac acggccatgt attactgtgc gagagatcgt 300gttgggggca gctcgtccga ggttctatcg cgggccaaaa actacggttt ggacgtctgg 360ggccaaggga ccacggtcac cgtctcgagt 39068369DNAhomo sapiens 68caggttcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agttaaggtt 60tcctgcaagg cttctgcaaa catcttcact tatgcaatgc attgggtgcg ccaggccccc 120ggacaaaggc ttgagtggat gggatggatc aacgttggca atggtcagac aaaatattca 180cagaggttcc agggcagagt caccattacc agggacacgt ccgcgactac agcctacatg 240gagctgagca ccctgagatc tgaggacacg gctgtgtatt actgtgcgag gcgtgcgagc 300caatatgggg aggtctatgg caactacttt gactactggg gccagggaac cctggtcacc 360gtctcgagt 36969378DNAhomo sapiens 69caggtgcagc tggtgcagtc tggagctgag gtgaagaggc ctggggcctc agtgaaggtc 60tcctgcaagg cttcaggtta cacctttatc agctatggtt tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg agcagcgttt acaatggtga cacaaactat 180gcacagaagt tccacggcag agtcaacatg acgactgaca catcgacgaa cacggcctac 240atggaactca ggggcctgag atctgacgac acggccgtgt atttctgtgc gagggatcgc 300aatgttgttc tacttccagc tgctcctttt ggaggtatgg acgtctgggg ccaagggaca 360atggtcaccg tctcgagt 37870369DNAhomo sapiens 70caggtgcagc tggtggagtc tgggggaggc gtggtccagc cggggacttc cctgagactc 60tcctgtgcag cctctggatt caccttcagt acgtttggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaaataa gaaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaagtga acagcctgag agtcgaggac acggctgtgt attactgtgc ggcccaaact 300ccatatttca atgagagcag tgggttagtg ccggactggg gccagggcac cctggtcacc 360gtctcgagt

36971378DNAhomo sapiens 71caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttatc agttttggca tcagctgggt gcgacaggcc 120cctggacaag gacttgagtg gatgggatgg atcagcgctt acaatggtaa cacagactat 180gcacagaggc tccaggacag agtcaccatg actagagaca cagccacgag cacagcctac 240ttggagctga ggagcctgaa atctgacgac acggccgtgt actattgcac tagagacgag 300tcgatgcttc ggggagttac tgaaggattc ggacccattg actactgggg ccagggaacc 360ctggtcaccg tctcgagt 37872384DNAhomo sapiens 72gaagtgcagc tggtgcagtc tggagcagag gtgaaaaagc cggggcagtc tctgaagatc 60tcctgtaaga cttctggata catctttacc aactactgga tcggctgggt gcgccagagg 120cccgggaaag gcctggagtg gatgggggtc atctttcctg ctgactctga tgccagatac 180agcccgtcgt tccaaggcca ggtcaccatc tcagccgaca agtccatcgg tactgcctac 240ctgcagtgga gtagcctgaa ggcctcggac accgccatat attactgtgc gagaccgaaa 300tattactttg atagtagtgg gcaattctcc gagatgtact actttgactt ctggggccag 360ggaaccctgg tcaccgtctc gagt 38473357DNAhomo sapiens 73caggttcagc tggtgcagtc tggacctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta tgtgttgacc aactatgcct tcagctgggt gcggcaggcc 120cctggacaag ggcttgagtg gctgggatgg atcagcggct ccaatggtaa cacatactat 180gcagagaagt tccagggccg agtcaccatg accacagaca catccacgag cacagcctac 240atggagctga ggagtctgag atctgacgac acggccgttt atttctgtgc gagagatctt 300ctgcggtcca cttactttga ctactggggc cagggaaccc tggtcaccgt ctcgagt 35774378DNAhomo sapiens 74caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta caccttttcc aactacggtt tcagctgggt gcgacaggcc 120cctggacgag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacatactat 180gcacagaacc tccagggcag agtcaccatg accacagaca catccacgac cacagcctac 240atggtactga ggagcctgag atctgacgac acggccatgt attactgtgc gagagatgga 300aatacagcag gggttgatat gtggtcgcgt gatggttttg atatctgggg ccaggggaca 360atggtcaccg tctcgagt 37875393DNAhomo sapiens 75gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggcc cctgaggctc 60tcctgtgtag cctctggatt cagctttagc agctatgcca tgaactggat ccgcctggct 120ccagggaagg ggctggagtg ggtctcaggt attagtggta gcggtggtag cacttactac 180ggagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagagccg 300tggatcgata tagtagtggc atctgttata tccccctact actacgacgg aatggacgtc 360tggggccaag ggaccacggt caccgtctcg agt 39376369DNAhomo sapiens 76caggttcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cctctggagg atccttcgac ggctacacta tcagctggct gcgacaggcc 120cctggacagg ggcttgagtg gatgggaagg gtcgtcccta cacttggttt tccaaactac 180gcacagaagt tccaaggcag agtcaccgtt accgcggaca gatccaccaa cacagcctac 240ttggaattga gcagactgac atctgaagac acggccgtat attactgtgc gaggatgaat 300ctcggatcgc atagcgggcg ccccgggttc gacatgtggg gccaaggaac cctggtcacc 360gtctcgagt 36977387DNAhomo sapiens 77caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cttgagactc 60tcctgtgcag tgtctggatc cagcttcagt aaatatggca tacactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcgtatg atggaagtaa aaagtatttc 180acagactccg tgaagggccg attcaccatc gccagagaca attcccagaa cacggttttt 240ctgcaaatga acagcctgag agccgaggac acggctgtct attactgtgc gacaggaggg 300ggtgttaatg tcacctcgtg gtccgacgta gagcactcgt cgtccttagg ctactggggc 360ctgggaaccc tggtcaccgt ctcgagt 38778375DNAhomo sapiens 78caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctggggggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcattt atatggaatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgt gaaagatgag 300gtctatgata gtagtggtta ttacctgtac tactttgact cttggggcca gggaaccctg 360gtcaccgtct cgagt 37579381DNAhomo sapiens 79gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacgtttagc tcctatacca tgagctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtctcaagt attagtgcta gtactgttct cacatactac 180gcagactccg tgaagggccg cttcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga gtagcctgag agccgaggac acggccgtat attactgtgc gaaagattac 300gatttttgga gtggctatcc cgggggacag tactggttct tcgatctctg gggccgtggc 360accctggtca ccgtctcgag t 38180369DNAhomo sapiens 80caggtgcagc tgcaggagtc gggcccagga ctggtgacgc cttcggagac cctgtccgtc 60acttgcactg tctctaatta ttccatcgac aatgcttact actggggctg gatccggcag 120cccccaggga agggtctgga gtggataggc agtatccatc atagtgggag cgcctactac 180aattcgtccc tcaagagtcg agccaccata tctatagaca cgtccaagaa ccaattctcg 240ttgaacctga ggtctgtgac cgccgcagac acggccgtat attactgtgc gcgcgatacc 300atcctcacgt tcggggagcc ccactggttc gacccctggg gccagggaac cctggtcacc 360gtctcgagt 36981372DNAhomo sapiens 81caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cttgtccctc 60acctgcactg tctcaggtga ctccatcagt aattactact ggagttggat ccggcagccc 120ccagggaagg gactggagtg gattggagaa atatctaaca cttggagcac caattacaac 180ccctccctca agagtcgagt caccatatct ctagacatgc ccaagaacca gttgtccctg 240aagctgagct ctgtgaccgc tgcggacacg gccgtatatt actgtgcgag agggcttttc 300tatgacagtg gtggttacta cttgttttac ttccaacact ggggccaggg caccctggtc 360accgtctcga gt 37282375DNAhomo sapiens 82caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagagtc 60tcctgtgcag cgtctggatt caccttcagt aactatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atgacagtaa taaacagtat 180ggagactccg tgaagggccg attcaccatc tccagagaca attccaagag tacgctgtat 240ctgcaaatgg acagactgag agtcgaggac acggctgtgt attattgtgc gagagcctcc 300gagtatagta tcagctggcg acacaggggg gtccttgact actggggcca gggaaccctg 360gtcaccgtct cgagt 37583378DNAhomo sapiens 83cagatcacct tgaaggagtc tggtcctacg ctggtgagac ccacacagac cctcacactg 60acctgcacct tctctgggtt ctcactcagc actagtaaac tgggtgtggg ctggatccgt 120cagcccccag gaaaggccct ggagtggctt gcactcgttg attgggatga tgataggcgc 180tacaggccat ctttgaagag caggctcacc gtcaccaagg acacctccaa aaaccaggtg 240gtccttacaa tgaccaacat ggaccctgtg gacacagcca catattactg tgcacacagt 300gcctactata ctagtagtgg ttattacctt caatacttcc atcactgggg cccgggcacc 360ctggtcaccg tctcgagt 37884375DNAhomo sapiens 84gaggtgcagc tggtggagtc tgggggaggc gtggtacagc ctggaggctc cctgagactc 60tcctgtgaag tctccggatt caccttcaat agttatgaaa tgacctgggt ccgccaggcc 120ccagggaagg ggctggagtg ggtttcacac attggtaata gtggttctat gatatactac 180gctgactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactatat 240ctgcaaatga acagcctgag agtcgaggac acggctgttt attactgtgc gaggtcagat 300tactatgata gtagtggtta ttatctcctc tacttagact cctggggcca tggaaccctg 360gtcaccgtct cgagt 37585360DNAhomo sapiens 85caggtgcagc tggtgcagtc tggggctgag gtgaggaagc ctggggcctc agtgaaggtt 60tcctgcaagg cttctggaca tactttcatt aactttgcta tgcattgggt gcgccaggcc 120cccggacagg ggcttgagtg gatgggatac atcaacgctg tcaatggtaa cacacagtat 180tcacagaagt tccagggcag agtcaccttt acgagggaca catccgcgaa cacagcctac 240atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagaaacaat 300gggggctctg ctatcatttt ttactactgg ggccagggaa ccctggtcac cgtctcgagt 36086366DNAhomo sapiens 86caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctggatt cagcttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatcaaatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa aacgatgtat 240ctgcaaatga acagcctgag agctgaggac acggctgtgt atttctgtgc gaagacaaca 300gaccagcggc tattagtgga ctggttcgac ccctggggcc agggaaccct ggtcaccgtc 360tcgagt 36687390DNAhomo sapiens 87cagctgcagc tgcaggagtc gggcccagga ctggtgaagc catcggagac cctgtccctc 60acctgcactg cctctggtgg ctccatcaac agtagtaatt tctactgggg ctggatccgc 120cagcccccag ggaaggggct ggagtggatt gggagtatct tttatagtgg gaccacctac 180tacaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240tccctgaagc tgagccctgt gaccgccgca gacacggctg tctatcactg tgcgagacat 300ggcttccggt attgtaataa tggtgtatgc tctataaatc tcgatgcttt tgatatctgg 360ggccaaggga caatggtcac cgtctcgagt 39088366DNAhomo sapiens 88caggtgcagc tggtggagtc tgggggaggc gtcgtccagc ctggaaagtc cctgagactc 60tcctgtgcag cgtctggatt cagattcagt gactacggca tgcactgggt ccggcaggct 120ccaagcaagg ggctggagtg ggtggcagtt atctggcatg acggaagtaa tataaggtat 180gcagactccg tgaggggccg attttccatc tccagagaca attccaagaa cacgctgtat 240ttgcaaatga acagcatgag agccgacgac acggcttttt attattgtgc gagagtcccg 300ttccagattt ggagtggtct ttattttgac cactggggcc agggaaccct ggtcaccgtc 360tcgagt 36689216PRThomo sapiens 89Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Asn Ser His 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asn Thr Phe Asn Arg Val Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Ala Thr65 70 75 80Glu Asp Phe Gly Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95Ala Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val 100 105 110Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn145 150 155 160Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205Lys Ser Phe Asn Arg Gly Glu Cys 210 21590215PRThomo sapiens 90Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Phe Thr Cys Arg Ala Ser Gln Arg Ile Ser Asn His 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Phe Gly Ala Ser Thr Leu Gln Ser Gly Ala Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Arg Thr Pro Pro 85 90 95Ile Asn Phe Gly Gln Gly Thr Arg Leu Asp Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys210 21591217PRThomo sapiens 91Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Ser Ser Leu 85 90 95Ser Thr Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr 100 105 110Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 115 120 125Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly145 150 155 160Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 165 170 175Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 195 200 205Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21592213PRThomo sapiens 92Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Thr Gly Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Thr Ser Thr Leu Gln Ser Glu Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Asn Thr Leu Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 21093215PRThomo sapiens 93Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile His Gly Ala Ser Thr Gly Ala Thr Gly Thr Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Thr Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Arg Thr Pro 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Asn Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 21594219PRThomo sapiens 94Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Arg Ser 20 25 30Asp Gly Lys Thr Phe Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Pro Leu Met Tyr Glu Val Ser Ser Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Asn Ile65 70 75 80Ser Arg Val Glu Thr Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Gly 85 90 95Leu Lys Ile Arg Arg Thr Phe Gly Pro Gly Thr

Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21595215PRThomo sapiens 95Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Phe Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Trp 20 25 30Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Ser Glu Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Tyr Ser Gly 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 21596214PRThomo sapiens 96Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Leu Thr Cys Arg Ala Ser Gln Gly Ile Thr Asp Ser 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Leu 35 40 45Tyr Ala Ala Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Lys Ser Pro Ala 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Arg Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 21097219PRThomo sapiens 97Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30Asn Gly Phe Asn Tyr Val Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95Leu Glu Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21598215PRThomo sapiens 98Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Gly Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Gly 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Gly Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Gly Ser Pro 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 21599214PRThomo sapiens 99Asn Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Val Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ile Ser Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Thr Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210100220PRThomo sapiens 100Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Glu Thr Val Leu Tyr Thr 20 25 30Ser Lys Asn Gln Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Ala Arg Gln 35 40 45Pro Pro Lys Leu Leu Leu Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Phe Phe Arg Ser Pro Phe Thr Phe Gly Pro Gly Thr Arg Leu Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220101215PRThomo sapiens 101Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Ile Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Val 35 40 45Ile Tyr Ala Ala Ser Arg Arg Ala Thr Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln His Tyr Gly Asn Ser Leu 85 90 95Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Val Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215102215PRThomo sapiens 102Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Arg 20 25 30Leu Ala Trp Tyr Gln Gln Gln Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Arg Asp Ser Pro 85 90 95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215103219PRThomo sapiens 103Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asp Gly Arg Tyr Tyr Val Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro His Leu Leu Ile Tyr Leu Ala Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly 85 90 95Leu His Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215104213PRThomo sapiens 104Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Trp Ala Ser Gln Thr Ile Gly Gly Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Ala Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Asn Trp Tyr Thr 85 90 95Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210105215PRThomo sapiens 105Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ala Ser Tyr 20 25 30Val Asn Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Ser Leu Leu Ile 35 40 45Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Pro Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Tyr Arg Ala 85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu

Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215106216PRThomo sapiens 106Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Leu Ala Trp Tyr Gln Gln Thr Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Tyr Arg Val Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Ile Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95Gly Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val 100 105 110Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 115 120 125Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn145 150 155 160Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205Lys Ser Phe Asn Arg Gly Glu Cys 210 215107214PRThomo sapiens 107Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Thr Val Thr Val Thr Cys Arg Pro Ser Gln Asp Ile Ser Ser Ala 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Leu Asp Tyr Gly Val Pro Leu Arg Phe Ser Gly 50 55 60Thr Ala Ser Gly Thr His Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Thr Tyr Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210108220PRThomo sapiens 108Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Asn 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Ile His Leu Ala Ser Thr Arg Glu Tyr Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Ile65 70 75 80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Tyr Tyr Gln Thr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220109214PRThomo sapiens 109Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ala Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Phe Ile Ser Ser Tyr 20 25 30Leu His Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Lys Leu Leu Met 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Asn Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210110214PRThomo sapiens 110Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ala Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Tyr Ser Thr Arg Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Val Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210111214PRThomo sapiens 111Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Thr Ser Glu 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Phe Leu Ile 35 40 45Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210112214PRThomo sapiens 112Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Leu Thr Ile Thr Cys Arg Ala Ser Gln Asn Ile Tyr Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Ser Pro 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210113214PRThomo sapiens 113Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Leu Glu1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu 35 40 45Asp Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Arg 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210114214PRThomo sapiens 114Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Ser Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Gln 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210115220PRThomo sapiens 115Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Pro Pro Lys Leu Leu Val Tyr Trp Ala Ser Thr Arg Ala Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Leu Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95Phe His Ser Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220116215PRThomo sapiens 116Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Ala Gly Met Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Pro 85 90 95Leu Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215117214PRThomo sapiens 117Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Ser Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala

Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asp Thr Phe Pro Phe 85 90 95Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210118220PRThomo sapiens 118Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser 20 25 30Asn Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln 35 40 45Ser Pro Gln Leu Leu Ile Tyr Thr Phe Ser Tyr Arg Ala Ser Gly Val 50 55 60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys65 70 75 80Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln 85 90 95Arg Ile Glu Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220119219PRThomo sapiens 119Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Arg 20 25 30Asn Glu Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Trp Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Thr 85 90 95Leu Gln Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215120214PRThomo sapiens 120Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Phe Asp Ala Thr Lys Leu Glu Thr Gly Val Pro Thr Arg Phe Ile Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Val Thr Ile Thr Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln His Phe Ala Asn Leu Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210121214PRThomo sapiens 121Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Val 35 40 45Phe Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Ser Ala Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210122215PRThomo sapiens 122Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ile Ile Ala Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Ile 85 90 95Phe Thr Phe Gly Pro Gly Thr Lys Val Asn Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215123213PRThomo sapiens 123Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asp Trp Leu Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210124215PRThomo sapiens 124Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Lys Asn Asn 20 25 30Leu Ala Trp Tyr Gln Val Lys Pro Gly Gln Ala Pro Arg Leu Leu Thr 35 40 45Ser Gly Ala Ser Ala Arg Ala Thr Gly Ile Pro Gly Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Ile Ala Val Tyr Tyr Cys Gln Glu Tyr Asn Asn Trp Pro Leu 85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Gln Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215125215PRThomo sapiens 125Asp Ile Gln Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ala Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Leu Leu Ile 35 40 45Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Tyr Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Ile 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215126214PRThomo sapiens 126Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Phe Asp Ala Ser Asn Leu Glu Ser Glu Val Pro Ser Arg Phe Ser Gly 50 55 60Arg Gly Ser Gly Thr Asp Phe Thr Phe Ser Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Tyr Asp Asn Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210127214PRThomo sapiens 127Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ala Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ala Ser Tyr 20 25 30Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Ser Tyr Phe Cys Gln Gln Ser Tyr Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Asp Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210128215PRThomo sapiens 128Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ala Ser Tyr 20 25 30Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Val Pro Arg 85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Thr Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215129213PRThomo sapiens 129Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Thr Ile Ser Val Phe 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu His Ser Ala Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Glu Ser Phe Ser Ser Ser Thr 85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu145 150 155 160Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205Asn Arg Gly Glu Cys 210130215PRThomo sapiens 130Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Thr Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30Leu Ala Trp Tyr Gln His Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45His Ser Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Met Trp Pro Pro 85 90 95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215131219PRThomo sapiens 131Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Ala Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Arg Thr 20 25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu Gly Ser Ile Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser 85 90 95Leu Gln Thr Ser Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215132214PRThomo sapiens 132Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Asn Asn 20 25 30Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Lys Trp Pro Glu 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210133648DNAhomo sapiens 133gaaattgtgt tgacacagtc tccagccacc ctgtccttgt ctccaggaga aagagccacc 60ctctcctgca gggccagtca gagtgttaac agccacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctataat acattcaata gggtcactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag ccttgcgact 240gaagattttg gcgtttatta ctgtcagcag cgtagcaact ggcctcccgc cctcactttc 300ggcggaggga ccaaagtgga gatcaaacga actgtggctg caccatctgt cttcatcttc 360ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 420ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 480tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 540ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 600cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 648134645DNAhomo sapiens 134gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtgggaga cagagtcacc 60ttcacttgcc gggccagtca gaggattagc aaccatttaa attggtatca acaaaagcca 120gggaaagccc ctaaactcct gatctttggt gcatccactc ttcaaagtgg ggccccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcactaa tgtacaacct 240gacgattttg caacttacta ctgtcaacag agttacagaa ctcccccgat caacttcggc 300caagggacac gcctggacat taagcgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645135651DNAhomo sapiens 135gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta tcagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatgata gctcactttc tacgtggacg 300ttcggccaag ggaccaaggt ggaaatcaaa cgaactgtgg ctgcaccatc tgtcttcatc 360ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651136639DNAhomo sapiens 136gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattacc ggctatttaa attggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgct acatccactt tgcaaagtga ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tcttcaacct 240gaagattttg caacttacta ctgtcaacag agttataata ccctcacttt cggcggaggg 300accaaggtgg agatcaaacg aactgtggct gcaccatctg tcttcatctt cccgccatct 360gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639137645DNAhomo sapiens 137gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta tcagcagaaa 120cctggccagg ctcccaggct cctcatacat ggcgcatcca ccggggccac tggcacccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag tacactggag 240cctgaagatt ttgcagtgta ttactgtcag caatatggta ggacaccgta cacttttggc 300caggggacca agctggagaa caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645138657DNAhomo sapiens 138gatattgtga tgacccagac tccactctct ctgtccgtca cccctggaca gccggcctcc 60atctcctgca ggtctagtca gagcctcctg cgaagtgatg gaaagacgtt tttgtattgg 120tatctgcaga agccaggcca gtctccccaa cccctaatgt atgaggtgtc cagccggttc 180tctggagtgc cagataggtt cagtggcagc gggtcagggg cagatttcac actgaacatc 240agccgggtgg agactgagga tgttgggatc tattactgca tgcaaggttt gaaaattcgt 300cggacgtttg gcccagggac caaggtcgaa atcaagcgaa ctgtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657139645DNAhomo sapiens 139gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60ttctcttgcc gggccagtca gagtgttagt agttgggtgg cctggtatca gcagaaacca 120ggaaaagccc ctaagctcct gatctctgag gcctccaatt tggaaagtgg ggtcccatcc 180cggttcagcg gcagtggatc cgggacagaa ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgccaacag tatcatagtt actctgggta cacttttggc 300caggggacca agttggaaat caagcgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645140642DNAhomo sapiens 140gccatccagt tgacccagtc tccatcgtcc ctgtctgcat ctgtaggcga cagagtcacc 60ctcacttgcc gggcgagtca gggcattacc gattctttag cctggtatca gcagaaacca 120gggaaagccc ctaaggtcct gctctatgct gcttccagat tggaaagtgg ggtcccatcc 180aggttcagtg gccgtggatc tgggacggat ttcactctca ccatcagcag cctgcagcct 240gaagactttg caacttatta ctgtcaacag tattctaagt cccctgcgac gttcggccca 300gggaccaagg tggaaatcag acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642141657DNAhomo sapiens 141gatattgtga tgacccagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctccta aatagtaatg gattcaacta tgtggattgg 120tacctgcaga agccagggca gtctccacaa ctcctgatct atttgggttc taatcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct agaaactccg 300ctcactttcg gcggagggac caaggtggag atcaaacgaa ctgtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657142645DNAhomo sapiens 142gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccaggggg aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcggctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatccg gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtattttg gctcaccgta cacttttggc 300caggggacca agctggagct caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645143642DNAhomo sapiens 143aacatccaga tgacccagtc tccatctgcc atgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca gggcattagt aattatttag tctggtttca gcagaaacca 120gggaaagtcc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacag cataatattt ccccttacac ttttggccag 300gggaccaagc tggagaccaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642144660DNAhomo sapiens 144gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca ggtccagtga gactgtttta tacacctcta aaaatcagag ctacttagct 120tggtaccagc agaaagcacg acagcctcct aaactactcc tttactgggc atctacccgg 180gaatccgggg tccctgcccg attcagtggc agcggatctg ggacagattt cactctcgcc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaatt ttttaggagt 300cctttcactt tcggccccgg gaccagactg gagattaaac gaactgtggc tgcaccatct 360gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660145645DNAhomo sapiens 145gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagttacc 60ctctcttgca gggccagtca gagtgttagc agcagttaca tagcctggta ccagcagaag 120cctggccagg ctcccaggct cgtcatctat gctgcatccc gcagggccac tggcgtccca 180gacaggttca gtggcagtgg gtctgcgaca gacttcactc tcaccatcag tagactggag 240cctgaagatc ttgcagtgta ttactgtcag cactatggta actcactatt cactttcggc 300cctgggacca aggtggatgt caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645146645DNAhomo sapiens 146gacatccaga tgacccagtc tccctccacc ctgtctgcat ctgtcggaga cagagtcacc 60atcacttgcc gggccagtca gagtattggt agccggttgg cctggtatca gcagcaacca 120gggaaagccc ctaaattcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc agggacagaa ttcactctca ccatcagcag cctgcagccg 240gaggatcttg caacttatta ctgccaacag tacaatagag attctccgtg gacgttcggc 300caagggacca aggtggaaat caagcgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg

agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645147657DNAhomo sapiens 147gatattgtga tgacccagtc tccactctcc ctgcccgtca ccccaggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg catagtgatg gacgctacta tgtggattgg 120tacctgcaga agccagggca gtctccacac ctcctgatct atttggcttc taatcgggcc 180tccggggtcc ctgacaggtt cactggcagt ggatcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggcgtt tattactgca tgcaaggtct acacactcct 300tggacgttcg gccaggggac caaggtggac atcaagcgaa ctgtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657148639DNAhomo sapiens 148gaaattgtaa tgacacagtc tccagccacc ctgtctgcgt ccccagggga aagagccacc 60ctctcctgtt gggccagtca gactattgga ggcaacttag cctggtacca gcagaaacct 120ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tgtcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctcg ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataaaaact ggtacacttt tggccagggg 300accaagctgg agctcaaacg aactgtggct gcaccatctg tcttcatctt cccgccatct 360gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639149645DNAhomo sapiens 149gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gaccattgcc agttacgtaa attggtacca acaaaaacca 120gggagagccc ctagtctcct gatctatgct gcatctaact tgcagagtgg ggtcccacca 180aggttcagtg gcagtggatc tgggacagac ttcactctca ccatcagcgg tctgcaacct 240gacgattttg caacttatta ctgtcaacag agttacagtt atcgagcgct cactttcggc 300ggagggacca aggtggagat caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645150648DNAhomo sapiens 150gaaattgtgt tgacacagtc tccagccacc ctgtcgttgt ccccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctccttag cctggtacca acagacacct 120ggccaggctc ccaggcttct catctatgat gcgtcctaca gggtcactgg catcccagcc 180aggttcagtg gcagtgggtc tgggatagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttacta ttgtcagcag cgtagcaact ggcctccggg gctcactttc 300ggcgggggga ccaaggtgga gatcaaacga actgtggctg caccatctgt cttcatcttc 360ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 420ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 480tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 540ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 600cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 648151642DNAhomo sapiens 151gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgttggaga cacagtcacc 60gtcacttgcc ggccaagtca ggacattagc agtgctttag cctggtatca gcagaaacca 120gggaaacctc ctaagctcct gatctatggt gcctccactt tggattatgg ggtcccatta 180aggttcagcg gcactgcatc tgggacacat ttcactctca ccatcagcag cctgcaacct 240gaagattttg caacttatta ctgtcaacag tttaatactt acccattcac tttcggccct 300gggaccaaag tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642152660DNAhomo sapiens 152gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacaactcca acaataagaa ctacttagcc 120tggtatcagc agaaaccagg acagcctcct aagctcctca ttcacttggc atctacccgg 180gaatacgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cgctctcatc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcaacaata ttatcaaact 300cctctaactt ttggccaggg gaccaaggtg gagatcaaac gaactgtggc tgcaccatct 360gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660153642DNAhomo sapiens 153gacatccaga tgacccagtc tccatcctcc ctggctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gttcattagc agctatttac attggtatca gcaaagacca 120ggcaaggccc ctaaactcct gatgtatgct gcctccactt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacacta acccatacac ttttggccag 300gggaccaagc tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642154642DNAhomo sapiens 154gacatccaga tgacccagtc tccatcctcc ctatctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gagcattgcc agctatttaa attggtatca gcagaaacca 120gggaaagccc ccaaactcct gatctatgct gcatccagtt tgcatagtgg ggtcccatca 180agattcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacac agttacagta ctcgattcac tttcggccct 300gggaccaaag tggatgtcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642155642DNAhomo sapiens 155gacatccaga tgacccagtc tccttcgacc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggccagtca gagtgttact agtgagttgg cctggtatca gcagaaacca 120gggaaagccc ctaacttcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaacag tataatagtt ttccgtacac ttttggccag 300gggaccaagc tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642156642DNAhomo sapiens 156gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggcga cagactcacc 60atcacttgcc gggccagtca gaatatttat aactggttgg cctggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgac gcctccactt tggaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240gatgattttg cgacttatta ctgccaacaa tataatagtt tgtctccgac gttcggccaa 300gggaccaagg tggaaatcaa gcgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642157642DNAhomo sapiens 157gacatccagt tgacccagtc tccatccttc ctgtctgcat ctttagaaga cagagtcact 60atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120gggaaagccc ctaagctcct gctcgatgct gcatccactt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagag ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt accctcggac gttcggccaa 300gggaccaagg tggacatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642158642DNAhomo sapiens 158gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcagc 60atcacttgcc gggcgagtca gggcattagc aattatttag cctggtatca gcagaaacca 120gggaaggttc ctaagctcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaggatgttg caacttatta ctgtcaaaag tataacagtg cccctcaaac gttcggccaa 300gggaccaagg tggaaatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642159660DNAhomo sapiens 159gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca ggtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctcg tttactgggc atcaacccgg 180gcatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240ctcagcagcc tgcaggctga agatgtggca gtttattact gtcagcagtt tcatagtact 300cctcggacgt tcggccaagg gaccaaggtg gagatcaaac gaactgtggc tgcaccatct 360gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660160645DNAhomo sapiens 160gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaactact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccgc tggcatgcca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta actcaccgct cactttcggc 300ggagggaccg aggtggagat caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645161642DNAhomo sapiens 161gacatccaga tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60atcacttgtc gggcgagtca ggctattagt aactggttag cctggtatca gcagaaacca 120ggaaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180agattcagcg gcagtggatc tgggacagat ttcactctca ctatcagcgg cctgcagcct 240gaggattttg caacttacta ttgtcaacag gctgacactt tccctttcac tttcggccct 300gggaccaaag tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642162660DNAhomo sapiens 162gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcttg gatagtaatg atggaaacac ctatttggac 120tggtacctgc agaagccagg gcagtctcca cagctcctga tttatacatt ttcctatcgg 180gcctctggag tcccagacag gttcagtggc agtgggtctg gcactgattt cacactgaaa 240atcagcaggg tggaggccga ggatgttgga gtttattact gcatgcaacg tatcgagttt 300ccgtacactt ttggccaggg gaccaagctg gagatcaaac gaactgtggc tgcaccatct 360gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660163657DNAhomo sapiens 163gatattgtga tgacccagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg catagaaatg agtacaacta tttggattgg 120tacttgcaga agccagggca gtctccacag ctcctgatct attggggttc taatcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaaactct acaaactcct 300cggacgttcg gccaagggac caaggtggaa atcaaacgaa ctgtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657164642DNAhomo sapiens 164gacatccaga tgacccagtc tccatcctcc gtgtctgcat ctgtgggaga cagagtcacc 60atcacttgcc aggcgagtca agacattagc aactatttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatcttcgat gcaaccaaat tggagacagg ggtcccaaca 180aggttcattg gaagtggatc tgggacagat tttactgtca ccatcaccag cctgcagcct 240gaagatgttg caacatatta ctgtcaacac tttgctaatc tcccatacac ttttggccag 300gggaccaagc tggagatcaa gcgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642165642DNAhomo sapiens 165gacatccaga tgacccagtc tccatcttcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcgagtca gggcattagg aattatttag cctggtatca gcagaaacca 120gggaaagttc ctaagctcct ggtctttgct gcatccactt tgcaatcagg ggtcccatct 180cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaggatgttg caacttatta ctgtcaaagg tataacagtg ccccgctcac tttcggcgga 300gggacgaagg tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642166645DNAhomo sapiens 166gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gatcattgcc agctatttaa attggtatca gcagaaacca 120ggcagagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagta cccccatatt cactttcggc 300cctgggacca aggtgaatat caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645167639DNAhomo sapiens 167gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca ggaccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcttccaata gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagtgact ggctcacttt cggcggaggg 300accaaggtgg agatcaaacg aactgtggct gcaccatctg tcttcatctt cccgccatct 360gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639168645DNAhomo sapiens 168gaaattgtaa tgacacagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtattaaa aacaacttgg cctggtacca ggtgaaacct 120ggccaggctc ccaggctcct cacctctggt gcatccgcca gggccactgg aattccaggc 180aggttcagtg gcagtgggtc tgggactgac ttcactctca ccatcagcag cctccagtct 240gaagatattg cagtttatta

ctgtcaggag tataataatt ggcccctgct cactttcggc 300ggagggacca aggtggagat ccaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645169645DNAhomo sapiens 169gacatccaga tgacccagtc tcctccctcc ctgtctgcat ctgtgggaga cagagtcacc 60atcacttgcc gggcaagtca gaggattgcc agctatttaa attggtatca gcagaaacca 120gggagagccc ctaagctcct gatctttgct gcatccagtt tacaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagac ttcactctca ccatcagtag tctgcaacct 240gaagattatg cgacttacta ctgtcaacag agttacagta ctcccatcta cacttttggc 300caggggacca agctggagat caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645170642DNAhomo sapiens 170gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc aggcgagtca gggcattagc aactatttaa attggtatca acagaaacca 120gggaaagccc ctaagctcct gatcttcgat gcatccaatt tggaatcaga ggtcccatca 180aggttcagtg gacgtggatc tgggacagat tttactttct ccatcagcag cctgcagcct 240gaagatattg caacatattt ctgtcaacag tatgataatt tcccgtacac ttttggccag 300gggaccaagc tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642171642DNAhomo sapiens 171gacatccaga tgacccagtc tccatcctcc ctggctgcat ctgtaggaga cagagtcacc 60atcacctgcc gggcaagtca gacgattgcc agttatgtaa attggtatca acagaaacca 120gggaaagccc ctaatctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg catcttactt ctgtcaacag agttacagtt tcccgtacac ttttggccag 300gggaccaagc tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642172645DNAhomo sapiens 172gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gaccattgcc agctatgtaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccaatt tgcaaagtgg ggtcccttca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattttg caacttacta ctgtcaacag agttacagtg tccctcggct cactttcggc 300ggagggacca aggtggacat cacacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645173639DNAhomo sapiens 173gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc ggtcaagtca gaccattagc gtctttttaa attggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctatgcc gcatccagtt tgcacagtgc ggtcccatca 180aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240gaagattctg caacttacta ctgtcaagag agtttcagta gctcaacttt cggcggaggg 300accaaggtgg agatcaaacg aactgtggct gcaccatctg tcttcatctt cccgccatct 360gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639174645DNAhomo sapiens 174gaaattgtaa tgacacagtc tccagccacc ctgtctgtgt ctccagggga aacagccacc 60ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca acataaacct 120ggccaggctc ccaggctcct catccatagt gcatccacca gggccactgg gatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccataagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataatatgt ggcctccctg gacgttcggc 300caagggacca aggtggaaat caaacgaact gtggctgcac catctgtctt catcttcccg 360ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645175657DNAhomo sapiens 175gatattgtga tgacccagtc tccactctcc ctgcccgtca cccctggagc gccggcctcc 60atctcctgca ggtctagtca gagcctcctg cgtactaatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc tattcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggctcaggca cagattttac actgaaaatc 240agcagagtgg aggctgagga tgttggggtt tattactgca tgcaatctct acaaacttcg 300atcaccttcg gccaagggac acgactggag attaaacgaa ctgtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657176642DNAhomo sapiens 176gaaattgtaa tgacacagtc tccagccacc ctgtctgtgt ctccggggga aagagccacc 60ctctcctgca gggctagtca gagtgttggc aacaacttag cctggtacca gcagagacct 120ggccaggctc ccagactcct catctatggt gcgtccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240gaggattttg cagtttatta ctgtcagcag tatgataagt ggcctgagac gttcggccag 300gggaccaagg tggacatcaa gcgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 6421771602DNAHomo sapiensCDS(1)..(298)CDS(690)..(734)CDS(853)..(1182)CDS(1280)..(1599) 177agt gcc tcc acc aag ggc cca tcg gtc ttc ccc ctg gca ccc tcc tcc 48Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser1 5 10 15aag agc acc tct ggg ggc aca gcg gcc ctg ggc tgc ctg gtc aag gac 96Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 20 25 30tac ttc ccc gaa ccg gtg acg gtg tcg tgg aac tca ggc gcc ctg acc 144Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 35 40 45agc ggc gtg cac acc ttc ccg gct gtc cta cag tcc tca gga ctc tac 192Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 50 55 60tcc ctc agc agc gtg gtg acc gtg ccc tcc agc agc ttg ggc acc cag 240Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln65 70 75 80acc tac atc tgc aac gtg aat cac aag ccc agc aac acc aag gtg gac 288Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp 85 90 95aag aga gtt g gtgagaggcc agcacaggga gggagggtgt ctgctggaag 338Lys Arg Valccaggctcag cgctcctgcc tggacgcatc ccggctatgc agtcccagtc cagggcagca 398aggcaggccc cgtctgcctc ttcacccgga ggcctctgcc cgccccactc atgctcaggg 458agagggtctt ctggcttttt ccccaggctc tgggcaggca caggctaggt gcccctaacc 518caggccctgc acacaaaggg gcaggtgctg ggctcagacc tgccaagagc catatccggg 578aggaccctgc ccctgaccta agcccacccc aaaggccaaa ctctccactc cctcagctcg 638gacaccttct ctcctcccag attccagtaa ctcccaatct tctctctgca g ag ccc 694Glu Proaaa tct tgt gac aaa act cac aca tgc cca ccg tgc cca g gtaagccagc 744 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 105 110ccaggcctcg ccctccagct caaggcggga caggtgccct agagtagcct gcatccaggg 804acaggcccca gccgggtgct gacacgtcca cctccatctc ttcctcag ca cct gaa 860Ala Pro Gluctc ctg ggg gga ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac 908Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp115 120 125 130acc ctc atg atc tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac 956Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 135 140 145gtg agc cac gaa gac cct gag gtc aag ttc aac tgg tac gtg gac ggc 1004Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 150 155 160 gtg gag gtg cat aat gcc aag aca aag ccg cgg gag gag cag tac aac 1052Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 165 170 175 agc acg tac cgt gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg 1100Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 180 185 190 ctg aat ggc aag gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca 1148Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro195 200 205 210gcc ccc atc gag aaa acc atc tcc aaa gcc aaa g gtgggacccg 1192Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys215 220 225tggggtgcga gggccacatg gacagaggcc ggctcggccc accctctgcc ctgagagtga 1252ccgctgtacc aacctctgtc cctacag gg cag ccc cga gaa cca cag gtg tac 1305Gly Gln Pro Arg Glu Pro Gln Val Tyr 230acc ctg ccc cca tcc cgg gag gag atg acc aag aac cag gtc agc ctg 1353Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu235 240 245 250acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg 1401Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 255 260 265gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct ccc gtg 1449Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 270 275 280ctg gac tcc gac ggc tcc ttc ttc ctc tat agc aag ctc acc gtg gac 1497Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 285 290 295aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat 1545Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 300 305 310gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg tcc ccg 1593Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro315 320 325 330ggt aaa tga 1602Gly Lys178331PRTHomo sapiens 178Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser1 5 10 15Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp20 25 30Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr35 40 45Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr50 55 60Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln65 70 75 80Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp85 90 95Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro100 105 110Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro115 120 125Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr130 135 140Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn145 150 155 160Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg165 170 175Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val180 185 190Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser195 200 205Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys210 215 220Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu225 230 235 240Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe245 250 255Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu260 265 270Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe275 280 285Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly290 295 300Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr305 310 315 320Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys325 33017920DNAartificial sequenceSynthetic DNA primer 179gacngatggg cccttggtgg 2018020DNAartificial sequenceSynthetic DNA primer 180gagtggctcc tgggggaaga 2018136DNAartificial sequenceSynthetic DNA primer 181tattcccatg gcgcgcccag ntgcagctgg tgcant 3618236DNAartificial sequenceSynthetic DNA primer 182tattcccatg gcgcgccnag gtccagctgg tncagt 3618336DNAartificial sequenceSynthetic DNA primer 183tattcccatg gcgcgcccag ntcaccttga aggagt 3618435DNAartificial sequenceSynthetic DNA primer 184tattcccatg gcgcgccnag gtgcagctgg tggag 3518536DNAartificial sequenceSynthetic DNA primer 185tattcccatg gcgcgcccag gtgcagctac agcagt 3618636DNAartificial sequenceSynthetic DNA primer 186tattcccatg gcgcgcccag ntgcagctgc aggagt 3618736DNAartificial sequenceSynthetic DNA primer 187tattcccatg gcgcgccgan gtgcagctgg tgcagt 3618837DNAartificial sequenceSynthetic DNA primer 188tattcccatg gcgcgcccag gtacagctgc agcagtc 3718938DNAartificial sequenceSynthetic DNA primer 189atatatatgc ggccgcttat taacactctc ccctgttg 3819045DNAartificial sequenceSynthetic DNA primer 190ggcgcgccat gggaatagct agccgacatc cagntgaccc agtct 4519145DNAartificial sequenceSynthetic DNA primer 191ggcgcgccat gggaatagct agccgatgtt gtgatgactc agtct 4519245DNAartificial sequenceSynthetic DNA primer 192ggcgcgccat gggaatagct agccgaaatt gtgntgacnc agtct 4519345DNAartificial sequenceSynthetic DNA primer 193ggcgcgccat gggaatagct agccgatatt gtgatgaccc acact 4519443DNAartificial sequenceSynthetic DNA primer 194ggcgcgccat gggaatagct agccgaaacg acactcacgc agt 4319545DNAartificial sequenceSynthetic DNA primer 195ggcgcgccat gggaatagct agccgaaatt gtgctgactc agtct 4519651DNAartificial sequenceSynthetic DNA primer 196accgcctcca ccggcggccg cttattaaca ctctcccctg ttgaagctct t 5119730DNAartificial sequenceSynthetic DNA primer 197ggaggcgctc gagacggtga ccagggtgcc 3019830DNAartificial sequenceSynthetic DNA primer 198ggaggcgctc gagacggtga ccattgtccc 3019930DNAartificial sequenceSynthetic DNA primer 199ggaggcgctc gagacggtga ccagggttcc 3020030DNAartificial sequenceSynthetic DNA primer 200ggaggcgctc gagacggtga ccgtggtccc 302015PRTHomo sapiens 201Asp Tyr Asp Trp Ser1 52025PRTHomo sapiens 202Thr Tyr Gly Met His1 52035PRTHomo sapiens 203Thr Tyr Ala Leu Thr1 52045PRTHomo sapiens 204Gly Tyr Tyr Met His1 52055PRTHomo sapiens 205Asp Tyr Tyr Met Ser1 52065PRTHomo sapiens 206Asn Tyr Gly Leu Asn1 52077PRTHomo sapiens 207Ser Gly Asp Tyr Tyr Trp Ser1 52085PRTHomo sapiens 208His Phe Gly Met His1 52095PRTHomo sapiens 209Arg Phe Gly Ile Ser1 52105PRTHomo sapiens 210Ser Tyr Val Met Asn1 52115PRTHomo sapiens 211Asn Tyr Gly Met His1

52125PRTHomo sapiens 212Asp Tyr Gly Met Asn1 52135PRTHomo sapiens 213Ser Tyr Ala Met His1 52145PRTHomo sapiens 214Ser Tyr Glu Met Asn1 52157PRTHomo sapiens 215Ser Gly Asp Tyr Phe Trp Ser1 52165PRTHomo sapiens 216Asn Tyr Ala Met His1 52175PRTHomo sapiens 217Gly Asp Phe Trp Ser1 52185PRTHomo sapiens 218Ser Tyr Trp Ile Gly1 52197PRTHomo sapiens 219Thr Thr Arg Met Ser Val Ser1 52207PRTHomo sapiens 220Phe Val Ser Thr Trp Ile Gly1 52215PRTHomo sapiens 221Asn Tyr Ala Ile Asn1 52225PRTHomo sapiens 222Asn Tyr Tyr Ile His1 52235PRTHomo sapiens 223Ser Tyr Ser Ile Ser1 52245PRTHomo sapiens 224Ser Tyr Trp Ile Gly1 52255PRTHomo sapiens 225Asp Tyr Ala Met His1 52265PRTHomo sapiens 226Thr Tyr Ala Met Thr1 52275PRTHomo sapiens 227Thr His Gly Met His1 52287PRTHomo sapiens 228Ala Gly Arg Val Gly Val Ser1 52297PRTHomo sapiens 229Gly Ala Asp Tyr Tyr Trp Ser1 52305PRTHomo sapiens 230Asn Ser Trp Ile Gly1 52316PRTHomo sapiens 231Ser Gly His Phe Trp Gly1 52325PRTHomo sapiens 232Asn Tyr Tyr Trp Gly1 52335PRTHomo sapiens 233Ser Asn Gly Leu Ser1 52345PRTHomo sapiens 234Ala Leu Ser Lys His1 52355PRTHomo sapiens 235Thr Asn Gly Leu His1 52367PRTHomo sapiens 236Arg Asn Arg Met Ser Val Ser1 52375PRTHomo sapiens 237Thr Tyr Gly Val Ser1 52384PRTHomo sapiens 238Tyr Ala Met His12395PRTHomo sapiens 239Tyr Ile Gly Met His1 52405PRTHomo sapiens 240Thr Tyr Gly Leu Asn1 52415PRTHomo sapiens 241Ser Tyr Gly Phe Ser1 52426PRTHomo sapiens 242Ser Gly His Tyr Trp Gly1 52435PRTHomo sapiens 243Thr Phe Gly Met His1 52445PRTHomo sapiens 244Ser Tyr Gly Leu His1 52455PRTHomo sapiens 245Ser Phe Gly Ile Ser1 52465PRTHomo sapiens 246Arg Tyr Gly Ile Ser1 52475PRTHomo sapiens 247Asn Ser Gly Val Ser1 52485PRTHomo sapiens 248Ser Tyr Gly Ile Ser1 52497PRTHomo sapiens 249Ser Gly Gly Tyr Ser Trp Ser1 52507PRTHomo sapiens 250Ser Asp Lys Asn Tyr Trp Ser1 52515PRTHomo sapiens 251Gly Ser Thr Met His1 52525PRTHomo sapiens 252Thr Tyr Thr Leu His1 52535PRTHomo sapiens 253Ser Leu Gly Phe Ser1 52545PRTHomo sapiens 254Gly Tyr Thr Ile His1 52555PRTHomo sapiens 255Asn Tyr Trp Ile Gly1 52565PRTHomo sapiens 256Asn Tyr Ala Phe Ser1 52575PRTHomo sapiens 257Asn Tyr Gly Phe Ser1 52585PRTHomo sapiens 258Ser Tyr Ala Met Asn1 52595PRTHomo sapiens 259Gly Tyr Thr Ile Ser1 52605PRTHomo sapiens 260Lys Tyr Gly Ile His1 52615PRTHomo sapiens 261Ser Tyr Gly Met His1 52625PRTHomo sapiens 262Ser Tyr Thr Met Ser1 52635PRTHomo sapiens 263Thr Tyr Gly Ile Ser1 52645PRTHomo sapiens 264Arg Tyr Thr Ile His1 52656PRTHomo sapiens 265Asn Ala Tyr Tyr Trp Gly1 52665PRTHomo sapiens 266Tyr Tyr Ala Met His1 52675PRTHomo sapiens 267Asn Tyr Tyr Trp Ser1 52685PRTHomo sapiens 268Asn Tyr Gly Met His1 52695PRTHomo sapiens 269His Tyr Gly Met His1 52705PRTHomo sapiens 270Ala Tyr Ala Met Ser1 52717PRTHomo sapiens 271Thr Ser Lys Leu Gly Val Gly1 52725PRTHomo sapiens 272Ser Tyr Glu Met Thr1 52735PRTHomo sapiens 273Asn Phe Ala Met His1 52746PRTHomo sapiens 274Ser Asn Tyr Tyr Trp Gly1 52755PRTHomo sapiens 275Ser Tyr Gly Met His1 52767PRTHomo sapiens 276Thr Ser Arg Met Ser Val Ser1 52777PRTHomo sapiens 277Ser Ser Asn Phe Tyr Trp Gly1 52785PRTHomo sapiens 278Thr Tyr Gly Ile Ser1 52795PRTHomo sapiens 279Lys Phe Tyr Ile His1 52805PRTHomo sapiens 280Ser Tyr Thr Met His1 52815PRTHomo sapiens 281Asn Ala Trp Met Ser1 52825PRTHomo sapiens 282Ile Tyr Gly Met His1 52835PRTHomo sapiens 283Asp Tyr Gly Met His1 52846PRTHomo sapiens 284Ser Glu Tyr Tyr Trp Gly1 52855PRTHomo sapiens 285Asp Tyr Cys Met His1 528616PRTHomo sapiens 286Asn Ile Asn Tyr Arg Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser1 5 10 1528717PRTHomo sapiens 287Phe Ile Arg Tyr Asp Gly Ser Thr Gln Asp Tyr Val Asp Ser Val Lys1 5 10 15Gly28817PRTHomo sapiens 288Arg Ile Thr Pro Met Phe Asp Ile Thr Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly28917PRTHomo sapiens 289Trp Ile Asn Thr Ser Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly29017PRTHomo sapiens 290Tyr Ile Asn Arg Gly Gly Thr Thr Ile Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly29117PRTHomo sapiens 291Trp Ile Asn Ala Tyr Asn Asp Asn Thr Tyr Tyr Ser Pro Ser Leu Gln1 5 10 15Gly29216PRTHomo sapiens 292Tyr Ile Phe His Ser Gly Thr Thr Tyr Tyr Asn Pro Ser Leu Lys Ser1 5 10 1529317PRTHomo sapiens 293Ile Ile Ser Tyr Asp Gly Asn Asn Val His Tyr Ala Asp Ser Val Lys1 5 10 15Gly29417PRTHomo sapiens 294Trp Ile Ser Ala Asp Asn Gly Asn Thr Tyr Tyr Ala Gln Asn Phe Gln1 5 10 15Asp29517PRTHomo sapiens 295Trp Ile Asn Thr Asn Thr Gly Asp Pro Ala Tyr Ala Gln Asp Phe Thr1 5 10 15Gly29617PRTHomo sapiens 296Val Ile Ser Tyr Asp Gly Arg Asn Lys Tyr Phe Ala Asp Ser Val Lys1 5 10 15Gly29717PRTHomo sapiens 297Val Ile Trp His Asp Gly Ser Asn Lys Asn Tyr Leu Asp Ser Val Lys1 5 10 15Gly29817PRTHomo sapiens 298Val Ile Tyr Tyr Glu Gly Ser Asn Glu Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly29917PRTHomo sapiens 299Tyr Ile Gly Thr Gly Gly Ser Asp Ile Tyr Tyr Gly Asp Ser Val Lys1 5 10 15Gly30016PRTHomo sapiens 300Tyr Ile Tyr Ser Ser Gly Ser Thr Phe Tyr Asn Ala Ser Leu Lys Ser1 5 10 1530117PRTHomo sapiens 301Ala Thr Ser Thr Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Leu Lys1 5 10 15Gly30216PRTHomo sapiens 302Tyr Ile Tyr Tyr Arg Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser1 5 10 1530317PRTHomo sapiens 303Ile Val Tyr Pro Gly Asp Ser Asp Thr Thr Tyr Ser Pro Ser Phe Gln1 5 10 15Gly30416PRTHomo sapiens 304Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr Ser Thr Ser Leu Lys Thr1 5 10 1530517PRTHomo sapiens 305Ile Ile Asn Pro Ala Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln1 5 10 15Gly30617PRTHomo sapiens 306Arg Ile Ile Pro Val Phe Asp Thr Thr Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly30717PRTHomo sapiens 307Val Ile Asn Pro Asn Gly Gly Ser Thr Thr Ser Ala Gln Lys Phe Gln1 5 10 15Asp30817PRTHomo sapiens 308Met Ile Leu Pro Ile Ser Gly Thr Thr Asn Tyr Ala Gln Thr Phe Gln1 5 10 15Gly30917PRTHomo sapiens 309Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Asn Ser Pro Ser Phe Gln1 5 10 15Gly31017PRTHomo sapiens 310Val Ile Ser Tyr Asp Gly Ala Asn Glu Tyr Tyr Ala Glu Ser Val Lys1 5 10 15Gly31117PRTHomo sapiens 311Val Ile Arg Ala Ser Gly Asp Ser Glu Ile Tyr Ala Asp Ser Val Arg1 5 10 15Gly31217PRTHomo sapiens 312Ile Ile Ser Leu Asp Gly Ile Lys Thr His Tyr Ala Asp Ser Val Lys1 5 10 15Gly31316PRTHomo sapiens 313Arg Ile Asp Trp Asp Asp Asp Lys Ala Phe Arg Thr Ser Leu Lys Thr1 5 10 1531416PRTHomo sapiens 314Phe Ile Tyr Asp Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Ser1 5 10 1531517PRTHomo sapiens 315Ile Ile Tyr Pro Gly Asp Ser Thr Thr Thr Tyr Thr Pro Ser Phe Gln1 5 10 15Gly31616PRTHomo sapiens 316Ser Ile Phe His Ser Gly Thr Thr Phe His Asn Pro Ser Leu Lys Ser1 5 10 1531716PRTHomo sapiens 317His Ile Tyr Phe Gly Gly Asn Thr Asn Tyr Asn Pro Ser Leu Gln Ser1 5 10 1531817PRTHomo sapiens 318Trp Ile Ser Ala Ser Ser Gly Asn Lys Lys Tyr Ala Pro Lys Phe Gln1 5 10 15Gly31917PRTHomo sapiens 319Phe Phe Asp Pro Glu Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe Gln1 5 10 15Gly32017PRTHomo sapiens 320Leu Ile Asn Ala Gly Asn Gly Asp Thr Arg Phe Ser Gln Lys Phe Gln1 5 10 15Gly32116PRTHomo sapiens 321Arg Ile Asp Trp Asp Asp Asp Lys Phe Tyr Asn Thr Ser Leu Gln Thr1 5 10 1532217PRTHomo sapiens 322Trp Ile Ser Ala Tyr Asn Gly Asn Thr Tyr Tyr Leu Gln Lys Leu Gln1 5 10 15Gly32317PRTHomo sapiens 323Trp Ile Asn Val Gly Asn Gly Gln Thr Lys Tyr Ser Gln Arg Phe Gln1 5 10 15Gly32417PRTHomo sapiens 324Ala Ile Ser Tyr Asp Gly Ser Asn Lys Gln Tyr Ala Asp Ser Val Lys1 5 10 15Gly32517PRTHomo sapiens 325Trp Val Ser Ala His Asn Gly Asn Thr Tyr Tyr Ala Glu Lys Phe His1 5 10 15Asp32617PRTHomo sapiens 326Trp Ser Ser Val Tyr Asn Gly Asp Thr Asn Tyr Ala Gln Lys Phe His1 5 10 15Gly32716PRTHomo sapiens 327Ser Ile Tyr Asp Ser Gly Asn Thr Tyr Tyr Thr Pro Ser Leu Lys Ser1 5 10 1532817PRTHomo sapiens 328Val Ile Ser Tyr Asp Gly Asn Lys Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly32917PRTHomo sapiens 329Glu Ile Ser Tyr Asp Gly Gly Ser Lys Phe Tyr Thr Asp Ser Val Lys1 5 10 15Gly33017PRTHomo sapiens 330Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asp Tyr Ala Gln Arg Leu Gln1 5 10 15Asp33117PRTHomo sapiens 331Trp Ile Ser Ala Tyr Asn Gly Asn Thr Tyr Tyr Ala Gln Asn Leu Gln1 5 10 15Gly33217PRTHomo sapiens 332Trp Ile Ser Ala Tyr Asn Gly Asn Thr Tyr Tyr Arg Gln Ser Leu Gln1 5 10 15Asp33317PRTHomo sapiens 333Trp Ile Gly Thr Asp Asn Gly Asn Thr Tyr Tyr Ala Gln Lys Phe Gln1 5 10 15Gly33416PRTHomo sapiens 334Tyr Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser1 5 10 1533516PRTHomo sapiens 335Arg Leu Tyr Pro Ser Gly Asn Thr Asp Tyr His Pro Ser Leu Lys Ser1 5 10 1533619PRTHomo sapiens 336Arg Ile Arg Ser Lys Ala Asn Ser Tyr Ala Thr Glu Tyr Ala Ala Ser1 5 10 15Val Lys Gly33717PRTHomo sapiens 337Leu Ile Asn Ala Ala Asn Gly His Thr Lys Tyr Ser Gln Arg Phe Gln1 5 10 15Gly33817PRTHomo sapiens 338Trp Thr Ser Ala His Asn Gly Asn Thr Tyr Tyr Ala Glu Glu Phe Gln1 5 10 15Asp33917PRTHomo sapiens 339Arg Leu Val Pro Ser Leu Asn Ile Pro Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly34017PRTHomo sapiens 340Val Ile Phe Pro Ala Asp Ser Asp Ala Arg Tyr Ser Pro Ser Phe Gln1 5 10 15Gly34117PRTHomo sapiens 341Trp Ile Ser Gly Ser Asn Gly Asn Thr Tyr Tyr Ala Glu Lys Phe Gln1 5 10 15Gly34217PRTHomo sapiens 342Trp Ile Ser Ala Tyr Asn Gly Asn Thr Tyr Tyr Ala Gln Asn Leu Gln1 5 10 15Gly34317PRTHomo sapiens 343Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Gly Asp Ser Val Lys1 5 10 15Gly34417PRTHomo sapiens 344Arg Val Val Pro Thr Leu Gly Phe Pro Asn Tyr Ala Gln Lys Phe Gln1 5 10 15Gly34517PRTHomo sapiens 345Val Ile Ser Tyr Asp Gly Ser Lys Lys Tyr Phe Thr Asp Ser Val Lys1 5 10 15Gly34617PRTHomo sapiens 346Phe Ile Trp Asn Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly34717PRTHomo sapiens 347Ser Ile Ser Ala Ser Thr Val Leu Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly34817PRTHomo sapiens 348Trp Ile Ser Ala Asp Asn Gly Asn Thr Tyr Tyr Ala Gln Lys Phe Gln1 5 10 15Gly34917PRTHomo sapiens 349Arg Val Val Pro Ser Leu Gly Ile Pro Asn Tyr Ala Pro Lys Phe Gln1 5 10 15Gly35016PRTHomo sapiens 350Ser Ile His His Ser Gly Ser Ala Tyr Tyr Asn Ser Ser Leu Lys Ser1 5 10 1535117PRTHomo sapiens 351Val Ile Ser Tyr Gly Glu Thr Asn Lys Leu Tyr Ala Asp Ser Val Lys1 5 10 15Gly35216PRTHomo sapiens 352Glu Ile Ser Asn Thr Trp Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser1 5 10 1535317PRTHomo sapiens 353Val Ile Trp Tyr Asp Asp Ser Asn Lys Gln Tyr Gly Asp Ser Val Lys1 5 10 15Gly35417PRTHomo sapiens 354Val Ile Ser His Asp Gly Asn Ile Lys Tyr Ser Ala Asp Ser Val Lys1 5 10 15Gly35517PRTHomo sapiens 355Ala Ile Ser Gly Gly Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly35616PRTHomo sapiens 356Leu Val Asp Trp Asp Asp Asp Arg Arg Tyr Arg Pro Ser Leu Lys Ser1 5 10 1535717PRTHomo sapiens 357His Ile Gly Asn Ser Gly Ser Met Ile Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly35817PRTHomo sapiens 358Tyr Ile Asn Ala Val Asn Gly Asn Thr Gln Tyr Ser Gln Lys Phe Gln1 5 10 15Gly35916PRTHomo sapiens 359Ser Met His His Ser Gly Ser Ser Tyr Tyr Lys Pro Ser Leu Lys Ser1 5 10 1536017PRTHomo sapiens 360Val Ile Ser Asn Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys1 5 10 15Gly36116PRTHomo sapiens 361Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr Ser Thr Ser Leu Lys Thr1 5 10 1536216PRTHomo sapiens 362Ser Ile Phe Tyr Ser Gly Thr Thr Tyr Tyr Asn Pro Ser Leu Lys Ser1 5 10 1536317PRTHomo sapiens 363Trp Ile Ser Ala Tyr Asn Gly Asn Thr Phe Tyr Ala Gln Arg Leu Gln1 5 10 15Gly36417PRTHomo sapiens 364Ile Ile Asn Pro Ser Gly Gly Ser Thr Thr Tyr Ala Gln Thr Phe Gln1 5 10 15Asp36517PRTHomo sapiens 365Val Val Ser Tyr Asp Gly Asn His Asn Asp Tyr Ala Asp Ser Val Lys1 5 10 15Gly36619PRTHomo sapiens 366Leu Ile Lys Ser His Phe Glu Gly Gly Ala Thr Asp Tyr Ala Ala Pro1 5 10 15Val Lys Gly36717PRTHomo sapiens 367Val Ile Ser Tyr Asp Gly Ala Lys Lys Phe Tyr Ala Asn Ser Val Lys1 5 10 15Gly36817PRTHomo sapiens 368Val Ile Trp His Asp Gly Ser Asn Ile Arg Tyr Ala Asp Ser Val Arg1 5 10 15Gly36916PRTHomo sapiens 369Ser Val His His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser1 5 10 1537017PRTHomo sapiens 370Ile Leu Asn Pro Asp Gly Gly Thr Thr Phe Tyr Ala Glu Lys Phe Gln1 5 10 15Asp37118PRTHomo sapiens 371Cys Ala Arg Asp Val Gly Tyr Gly Gly Gly Gln Tyr Phe Ala Met Asp1 5 10 15Val Trp37224PRTHomo sapiens 372Cys Ala Lys Asp Met Asp Tyr Tyr Gly Ser Arg Ser Tyr Ser Val Thr1 5 10 15Tyr Tyr Tyr Gly Met Asp Val Trp 2037324PRTHomo sapiens 373Cys Ala Arg Arg Gly Ala Val Ala Leu Val Pro Ala Ala Glu Asp Pro1 5 10 15Tyr Tyr Tyr Gly Met Asp Val Trp 2037420PRTHomo sapiens 374Cys Ala Arg Glu Asp Gly Thr Met Gly Thr Asn Ser Trp Tyr Gly Trp1 5 10 15Phe Asp Pro Trp 2037522PRTHomo sapiens 375Cys Ala Arg Gly Leu Ile Leu Ala Leu Pro Thr Ala Thr Val Glu Leu1 5 10 15Gly Ala Phe Asp Ile Trp 2037626PRTHomo sapiens 376Cys Ala Arg Ser Tyr Arg Ser Gln Thr Asp Ile Leu Thr Gly Arg Tyr1 5 10 15Lys Gly Pro Gly Asp Val Phe Asp Asn Trp 20 2537720PRTHomo sapiens 377Cys Ala Arg Asp Val Asp Asp Phe Pro Val Trp Gly Met Asn Arg Tyr1 5 10 15Leu Ala Leu Trp

2037819PRTHomo sapiens 378Cys Ala Lys Asp Asp Val Ala Thr Asp Leu Ala Ala Tyr Tyr Tyr Phe1 5 10 15Asp Val Trp37920PRTHomo sapiens 379Cys Val Arg Gly Gly Val Val Thr Asn Arg Val Tyr Tyr Tyr Tyr Gly1 5 10 15Met Asp Val Trp 2038013PRTHomo sapiens 380Cys Ala Trp Phe Gly Glu Phe Gly Leu Phe Asp Tyr Trp1 5 1038118PRTHomo sapiens 381Cys Ala Arg Gly Ser Val Gln Val Trp Leu His Leu Gly Leu Phe Asp1 5 10 15Asn Trp38217PRTHomo sapiens 382Cys Ala Arg Thr Pro Tyr Glu Phe Trp Ser Gly Tyr Tyr Phe Asp Phe1 5 10 15Trp38311PRTHomo sapiens 383Cys Ala Arg Lys Trp Leu Gly Met Asp Phe Trp1 5 1038413PRTHomo sapiens 384Cys Ala Arg Ala Arg Pro Gly Tyr Lys Val Asp Phe Trp1 5 1038517PRTHomo sapiens 385Cys Ala Arg Gly Gly Thr Leu Tyr Thr Thr Gly Gly Glu Met His Ile1 5 10 15Trp38615PRTHomo sapiens 386Cys Ala Arg Arg Phe Trp Gly Phe Gly Asn Phe Phe Asp Tyr Trp1 5 10 1538720PRTHomo sapiens 387Cys Ala Arg Glu Gly His His Ser Gly Ser Gly Asp Tyr Tyr Ser Phe1 5 10 15Phe Asp Tyr Trp 2038822PRTHomo sapiens 388Cys Val Arg Arg Gly Gly Phe Cys Thr Ala Thr Gly Cys Tyr Ala Gly1 5 10 15His Trp Phe Asp Pro Trp 2038920PRTHomo sapiens 389Cys Ala Arg Ile Val Phe His Thr Ser Gly Gly Tyr Tyr Asn Pro Tyr1 5 10 15Met Asp Val Trp 2039015PRTHomo sapiens 390Cys Ala Arg Arg Ala Tyr Asp Ser Gly Trp His Phe Glu His Trp1 5 10 1539117PRTHomo sapiens 391Cys Leu Arg Gly Ser Thr Arg Gly Trp Asp Thr Asp Gly Phe Asp Ile1 5 10 15Trp39224PRTHomo sapiens 392Cys Ala Arg Gln Arg Ser Val Thr Gly Gly Phe Asp Ala Trp Leu Leu1 5 10 15Ile Pro Asp Ala Ser Asn Thr Trp 20 39321PRTHomo sapiens 393Cys Ala Arg Val Phe Arg Glu Phe Ser Thr Ser Thr Leu Asp Pro Tyr1 5 10 15Tyr Phe Asp Tyr Trp 2039422PRTHomo sapiens 394Cys Val Arg Gln Gly Gly Tyr Tyr Asp Arg Asn Gly Tyr His Glu Lys1 5 10 15Tyr Ala Phe Asp Ile Trp 2039520PRTHomo sapiens 395Cys Ala Arg Ala Gly Arg Ser Ser Met Asn Glu Glu Val Ile Met Tyr1 5 10 15Phe Asp Asn Trp 2039622PRTHomo sapiens 396Cys Ala Asn Ile Gly Gln Arg Arg Tyr Cys Ser Gly Asp His Cys Tyr1 5 10 15Gly His Phe Asp Tyr Trp 2039722PRTHomo sapiens 397Cys Ala Lys Asp His Ile Gly Gly Thr Asn Ala Tyr Phe Glu Trp Thr1 5 10 15Val Pro Phe Asp Gly Trp 2039820PRTHomo sapiens 398Cys Ala Arg Thr Gln Val Phe Ala Ser Gly Gly Tyr Tyr Leu Tyr Tyr1 5 10 15Leu Asp His Trp 2039923PRTHomo sapiens 399Cys Ala Arg Asp Leu Gly Tyr Gly Gly Asn Ser Tyr Ser His Ser Tyr1 5 10 15Tyr Tyr Gly Leu Asp Val Trp 2040011PRTHomo sapiens 400Cys Ala Arg Gln Gly Arg Gly Phe Gly Leu Trp1 5 1040112PRTHomo sapiens 401Cys Ala Arg Val His Gly Gly Gly Phe Asp His Trp1 5 1040215PRTHomo sapiens 402Cys Ala Arg Asp Ser Ser Asn Trp Pro Ala Gly Tyr Glu Asp Trp1 5 10 1540318PRTHomo sapiens 403Cys Ala Lys Asp Gly Gly Thr Tyr Val Pro Tyr Ser Asp Ala Phe Asp1 5 10 15Phe Trp40413PRTHomo sapiens 404Cys Ala Thr Val Ala Ala Ala Gly Asn Phe Asp Asn Trp1 5 1040516PRTHomo sapiens 405Cys Ala Arg Ile Ala Ile Thr Met Val Arg Asn Pro Phe Asp Ile Trp1 5 10 1540620PRTHomo sapiens 406Cys Ala Arg Thr Gly Ile Tyr Asp Ser Ser Gly Tyr Tyr Leu Tyr Tyr1 5 10 15Phe Asp Tyr Trp 2040725PRTHomo sapiens 407Cys Ala Arg Asp Arg Val Gly Gly Ser Ser Ser Glu Val Leu Ser Arg1 5 10 15Ala Lys Asn Tyr Gly Leu Asp Val Trp 20 2540819PRTHomo sapiens 408Cys Ala Arg Arg Ala Ser Gln Tyr Gly Glu Val Tyr Gly Asn Tyr Phe1 5 10 15Asp Tyr Trp40921PRTHomo sapiens 409Cys Ala Lys Asp Asp Phe Gly Asn Ser Asn Gly Val Phe Phe Met Ser1 5 10 15Arg Val Ala Phe Trp 2041021PRTHomo sapiens 410Cys Val Arg Gly Phe Asn Glu Gln Gln Leu Val Pro Gly Leu Ser Phe1 5 10 15Trp Phe Asp Tyr Trp 2041121PRTHomo sapiens 411Cys Ala Arg Asp Arg Asn Val Val Leu Leu Pro Ala Ala Pro Phe Gly1 5 10 15Gly Met Asp Val Trp 2041213PRTHomo sapiens 412Cys Ala Arg Gly Ser Pro Gly Asp Ala Phe Asp Ile Trp1 5 1041318PRTHomo sapiens 413Cys Ala Ala Gln Thr Pro Tyr Phe Asn Glu Ser Ser Gly Leu Val Pro1 5 10 15Asp Trp41418PRTHomo sapiens 414Cys Ala Arg Asp Leu Gly Asp Gly Tyr Thr Ala Trp Gly Trp Phe Asp1 5 10 15Pro Trp41521PRTHomo sapiens 415Cys Thr Arg Asp Glu Ser Met Leu Arg Gly Val Thr Glu Gly Phe Gly1 5 10 15Pro Ile Asp Tyr Trp 2041618PRTHomo sapiens 416Cys Val Ile Ser Phe Asp Ser Thr Ile Ala Ala Ala Glu Tyr Phe Asp1 5 10 15Tyr Trp41722PRTHomo sapiens 417Cys Ala Arg Glu Gly His Tyr Ser Gly Ser Ser Ser Tyr Gln Arg Asp1 5 10 15Asp Ala Phe Asp Ile Trp 2041823PRTHomo sapiens 418Cys Ala Arg Gly Gly Thr Ile Glu Ala Thr Pro Glu Arg Glu Tyr Tyr1 5 10 15Tyr Tyr Gly Met Asp Val Trp 2041913PRTHomo sapiens 419Cys Ala Ser Arg Ser Phe Tyr Gly Asp Tyr Val Tyr Trp1 5 1042013PRTHomo sapiens 420Cys Ala Lys Glu Gly Ser Gly Trp Tyr Phe Glu Ser Trp1 5 1042118PRTHomo sapiens 421Cys Thr Arg His Val Gly Glu Met Ser Thr Ile Trp Trp Tyr Phe Asp1 5 10 15Leu Trp42219PRTHomo sapiens 422Cys Ala Lys Ser Gly Ser His Tyr Gly Glu Val Tyr Gly Ala Tyr Phe1 5 10 15Asp Tyr Trp42320PRTHomo sapiens 423Cys Ala Arg Asp Arg Gly Pro Gly Tyr Ser Asp Ser Ser Phe Tyr Val1 5 10 15Phe Asp Tyr Trp 2042418PRTHomo sapiens 424Cys Thr Arg Ala Pro Arg Gly Ser Thr Ala Ser His Leu Leu Phe Asp1 5 10 15Tyr Trp42523PRTHomo sapiens 425Cys Ala Arg Pro Lys Tyr Tyr Phe Asp Ser Ser Gly Gln Phe Ser Glu1 5 10 15Met Tyr Tyr Phe Asp Phe Trp 2042614PRTHomo sapiens 426Cys Ala Arg Asp Leu Leu Arg Ser Thr Tyr Phe Asp Tyr Trp1 5 1042721PRTHomo sapiens 427Cys Ala Arg Asp Gly Asn Thr Ala Gly Val Asp Met Trp Ser Arg Asp1 5 10 15Gly Phe Asp Ile Trp 2042826PRTHomo sapiens 428Cys Ala Lys Glu Pro Trp Ile Asp Ile Val Val Ala Ser Val Ile Ser1 5 10 15Pro Tyr Tyr Tyr Asp Gly Met Asp Val Trp 20 2542918PRTHomo sapiens 429Cys Ala Arg Met Asn Leu Gly Ser His Ser Gly Arg Pro Gly Phe Asp1 5 10 15Met Trp43024PRTHomo sapiens 430Cys Ala Thr Gly Gly Gly Val Asn Val Thr Ser Trp Ser Asp Val Glu1 5 10 15His Ser Ser Ser Leu Gly Tyr Trp 2043120PRTHomo sapiens 431Cys Val Lys Asp Glu Val Tyr Asp Ser Ser Gly Tyr Tyr Leu Tyr Tyr1 5 10 15Phe Asp Ser Trp 2043222PRTHomo sapiens 432Cys Ala Lys Asp Tyr Asp Phe Trp Ser Gly Tyr Pro Gly Gly Gln Tyr1 5 10 15Trp Phe Phe Asp Leu Trp 2043321PRTHomo sapiens 433Cys Val Arg Gly Gly Thr Tyr Ser Ser Asp Val Glu Tyr Tyr Tyr Tyr1 5 10 15Gly Met Asp Val Trp 2043418PRTHomo sapiens 434Cys Ala Arg Leu Thr Leu Gly Ser Tyr Thr Gly Arg Pro Gly Phe Asp1 5 10 15Ser Trp43518PRTHomo sapiens 435Cys Ala Arg Asp Thr Ile Leu Thr Phe Gly Glu Pro His Trp Phe Asp1 5 10 15Pro Trp43619PRTHomo sapiens 436Cys Ala Arg Asp Leu Arg Tyr Leu Thr Tyr Tyr Ser Gly Ser Gly Asp1 5 10 15Asp Ser Trp43720PRTHomo sapiens 437Cys Ala Arg Gly Leu Phe Tyr Asp Ser Gly Gly Tyr Tyr Leu Phe Tyr1 5 10 15Phe Gln His Trp 2043820PRTHomo sapiens 438Cys Ala Arg Ala Ser Glu Tyr Ser Ile Ser Trp Arg His Arg Gly Val1 5 10 15Leu Asp Tyr Trp 2043919PRTHomo sapiens 439Cys His Gly Glu Gly Tyr Ser Thr Ser Trp Leu Gly Thr Ala Ala Leu1 5 10 15Asp Tyr Trp44018PRTHomo sapiens 440Cys Ala Lys Thr Arg Gly Tyr Ser Tyr Thr Trp Gly Asp Ala Phe Asp1 5 10 15Leu Trp44120PRTHomo sapiens 441Cys Ala His Ser Ala Tyr Tyr Thr Ser Ser Gly Tyr Tyr Leu Gln Tyr1 5 10 15Phe His His Trp 2044220PRTHomo sapiens 442Cys Ala Arg Ser Asp Tyr Tyr Asp Ser Ser Gly Tyr Tyr Leu Leu Tyr1 5 10 15Leu Asp Ser Trp 2044315PRTHomo sapiens 443Cys Ala Arg Asn Asn Gly Gly Ser Ala Ile Ile Phe Tyr Tyr Trp1 5 10 1544420PRTHomo sapiens 444Cys Ala Arg Asp Leu Val Val Val Thr Asp Ile Ser Ile Lys Asn Tyr1 5 10 15Phe Asp Pro Trp 2044517PRTHomo sapiens 445Cys Ala Lys Thr Thr Asp Gln Arg Leu Leu Val Asp Trp Phe Asp Pro1 5 10 15Trp44620PRTHomo sapiens 446Cys Ala Arg Thr Leu Val Tyr Ala Pro Asp Ser Tyr Tyr Leu Tyr Tyr1 5 10 15Phe Asp Tyr Trp 2044724PRTHomo sapiens 447Cys Ala Arg His Gly Phe Arg Tyr Cys Asn Asn Gly Val Cys Ser Ile1 5 10 15Asn Leu Asp Ala Phe Asp Ile Trp 2044821PRTHomo sapiens 448Cys Ala Arg Asp Leu Arg Met Leu Pro Gly Gly Leu Pro Thr Arg Arg1 5 10 15Gly Met Asp Val Trp 2044925PRTHomo sapiens 449Cys Ala Arg Gly Ile Arg Glu Gly Gly Val Ser Val Glu Asp Trp Met1 5 10 15Leu Val Tyr Ser Trp Phe Asp Pro Trp 20 2545013PRTHomo sapiens 450Cys Val Arg Ala Pro Gly Ser Met Gly Leu Asp Val Trp1 5 1045113PRTHomo sapiens 451Cys Ala Pro Leu Gly Gly Pro Thr Pro Phe Asp Tyr Trp1 5 1045215PRTHomo sapiens 452Cys Ala Thr Ala Ser Thr Tyr Phe Tyr Asp Ser Arg Asp Tyr Trp1 5 10 1545317PRTHomo sapiens 453Cys Ala Arg Val Pro Phe Gln Ile Trp Ser Gly Leu Tyr Phe Asp His1 5 10 15Trp45418PRTHomo sapiens 454Cys Ala Arg Asp Arg Val Ala Leu Gly Val His Tyr Trp Tyr Phe Asp1 5 10 15Ile Trp45523PRTHomo sapiens 455Cys Ala Ile Leu Ile Ala Arg Ala Tyr Cys Gly Leu Ala Asp Gly Gln1 5 10 15Glu Gly Asp Phe Asp Thr Trp 2045611PRTHomo sapiens 456Arg Ala Ser Gln Ser Val Asn Ser His Leu Ala1 5 1045711PRTHomo sapiens 457Arg Ala Ser Gln Arg Ile Ser Asn His Leu Asn1 5 1045816PRTHomo sapiens 458Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Asn Asn Tyr Leu Asp1 5 10 1545912PRTHomo sapiens 459Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala1 5 1046011PRTHomo sapiens 460Arg Ala Ser Gln Ser Ile Thr Gly Tyr Leu Asn1 5 1046111PRTHomo sapiens 461Arg Ala Ser Glu Gly Ile Ser Ser Trp Leu Ala1 5 1046212PRTHomo sapiens 462Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala1 5 1046316PRTHomo sapiens 463Arg Ser Ser Gln Ser Leu Leu Arg Ser Asp Gly Lys Thr Phe Leu Tyr1 5 10 1546411PRTHomo sapiens 464Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala1 5 1046511PRTHomo sapiens 465Arg Ala Ser Gln Asp Ile Asn Asn Tyr Leu Ala1 5 1046611PRTHomo sapiens 466Arg Ala Ser Gln Ser Val Ser Ser Trp Val Ala1 5 1046711PRTHomo sapiens 467Arg Ala Ser Gln Gly Ile Thr Asp Ser Leu Ala1 5 1046816PRTHomo sapiens 468Arg Ser Ser Gln Ser Leu Leu Asn Ser Asn Gly Phe Asn Tyr Val Asp1 5 10 1546911PRTHomo sapiens 469Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala1 5 1047012PRTHomo sapiens 470Arg Ala Ser Gln Thr Val Ser Ser Ser Tyr Leu Val1 5 1047112PRTHomo sapiens 471Arg Ala Ser Gln Ser Val Ser Ser Gly Tyr Leu Ala1 5 1047211PRTHomo sapiens 472Arg Ala Ser Gln Gly Ile Asn Thr Tyr Leu Asn1 5 1047312PRTHomo sapiens 473Arg Ala Ser Gln Ser Ile Ser Ser Gly Tyr Leu Ala1 5 1047411PRTHomo sapiens 474Arg Ala Ser Gln Thr Ile Ala Ser Tyr Leu Ser1 5 1047511PRTHomo sapiens 475Arg Ala Ser Gln Ser Val Gly Ser Lys Leu Ala1 5 1047611PRTHomo sapiens 476Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Val1 5 1047717PRTHomo sapiens 477Arg Ser Ser Glu Thr Val Leu Tyr Thr Ser Lys Asn Gln Ser Tyr Leu1 5 10 15Ala47812PRTHomo sapiens 478Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Ile Ala1 5 1047911PRTHomo sapiens 479Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala1 5 1048011PRTHomo sapiens 480Arg Ala Ser Gln Ser Ile Gly Ser Arg Leu Ala1 5 1048116PRTHomo sapiens 481Arg Ser Ser Gln Ser Leu Leu His Ser Asp Gly Arg Tyr Tyr Val Asp1 5 10 1548211PRTHomo sapiens 482Trp Ala Ser Gln Thr Ile Gly Gly Asn Leu Ala1 5 1048311PRTHomo sapiens 483Arg Ala Ser Gln Thr Ile Ala Ser Tyr Val Asn1 5 1048411PRTHomo sapiens 484Arg Ala Ser Gln Ser Val Ser Ser Ser Leu Ala1 5 1048511PRTHomo sapiens 485Gln Ala Ser Gln Asp Ile Thr Tyr Tyr Leu Ser1 5 1048611PRTHomo sapiens 486Gln Ala Ser Gln Asp Ile Gly Asp Ser Leu Asn1 5 1048711PRTHomo sapiens 487Arg Pro Ser Gln Asp Ile Ser Ser Ala Leu Ala1 5 1048817PRTHomo sapiens 488Lys Ser Ser Gln Ser Val Leu Tyr Asn Ser Asn Asn Lys Asn Tyr Leu1 5 10 15Ala48911PRTHomo sapiens 489Arg Ala Ser Gln Phe Ile Ser Ser Tyr Leu His1 5 1049011PRTHomo sapiens 490Arg Ala Ser Gln Ser Ile Gly Ser Trp Leu Ala1 5 1049111PRTHomo sapiens 491Arg Ala Ser Gln Ser Ile Ala Ser Tyr Leu Asn1 5 1049211PRTHomo sapiens 492Arg Ala Ser Gln Ser Val Thr Ser Glu Leu Ala1 5 1049311PRTHomo sapiens 493Arg Ala Ser Gln Asn Ile Tyr Asn Trp Leu Ala1 5 1049411PRTHomo sapiens 494Arg Ala Asn Gln Asp Ile Asp Asn Tyr Leu Ala1 5 1049511PRTHomo sapiens 495Arg Ala Ser Gln Gly Ile Ser Lys Arg Leu Ala1 5 1049611PRTHomo sapiens 496Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala1 5 1049711PRTHomo sapiens 497Arg Ala Ser Gln Gly Ile Gly Thr Trp Leu Ala1 5 1049811PRTHomo sapiens 498Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala1 5 1049912PRTHomo sapiens 499Arg Ala Ser Gln Ser Val Gly Gly Arg Ser Leu Ala1 5 1050017PRTHomo sapiens 500Arg Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu1 5 10 15Ala50111PRTHomo sapiens 501Arg Ala Ser Gln Thr Ile Ser Asn Ser Leu Ala1 5 1050211PRTHomo sapiens 502Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala1 5 1050311PRTHomo sapiens 503Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala1 5 1050412PRTHomo sapiens 504Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala1 5 1050511PRTHomo sapiens 505Arg Ala Ser Gln Gly Ile Ser Ala Trp Leu Ala1 5 1050611PRTHomo sapiens 506Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn1

5 1050711PRTHomo sapiens 507Arg Ala Ser Gln Asn Ile Tyr Asn Trp Leu Ala1 5 1050816PRTHomo sapiens 508Arg Ser Ser Gln Ser Leu Val Asn Ser Asp Gly Asn Thr Tyr Leu Ser1 5 10 1550911PRTHomo sapiens 509Gln Ala Ser Gln Asp Val Ser Tyr Tyr Leu Asn1 5 1051012PRTHomo sapiens 510Arg Ala Ser Gln Ser Val Ser Ser Asn Tyr Leu Ala1 5 1051111PRTHomo sapiens 511Arg Ala Ser Gln Ala Ile Ser Asn Trp Leu Ala1 5 1051217PRTHomo sapiens 512Arg Ser Ser Gln Ser Leu Leu Asp Ser Asn Asp Gly Asn Thr Tyr Leu1 5 10 15Asp51316PRTHomo sapiens 513Arg Ser Ser Gln Ser Leu Leu His Arg Asn Glu Tyr Asn Tyr Leu Asp1 5 10 1551411PRTHomo sapiens 514Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn1 5 1051511PRTHomo sapiens 515Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala1 5 1051611PRTHomo sapiens 516Arg Ala Ser Gln Ile Ile Ala Ser Tyr Leu Asn1 5 1051711PRTHomo sapiens 517Arg Thr Ser Gln Ser Val Ser Ser Tyr Leu Ala1 5 1051811PRTHomo sapiens 518Arg Ala Ser Gln Gly Ile Ser Ile Tyr Leu Ala1 5 1051911PRTHomo sapiens 519Gln Ala Ser Gln Asp Ile Asn Asn Tyr Leu Asn1 5 1052011PRTHomo sapiens 520Arg Ala Ser Gln Ser Ile Lys Asn Asn Leu Ala1 5 1052112PRTHomo sapiens 521Arg Ala Ser Gln Ser Leu Ser Asp Asn Tyr Leu Ala1 5 1052211PRTHomo sapiens 522Arg Ala Ser Gln Arg Ile Ala Ser Tyr Leu Asn1 5 1052311PRTHomo sapiens 523Gln Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn1 5 1052411PRTHomo sapiens 524Arg Ala Ser Gln Gly Ile Arg Asn Phe Leu Ala1 5 1052511PRTHomo sapiens 525Arg Ala Ser Gln Ser Val Thr Ser Asn Leu Ala1 5 1052611PRTHomo sapiens 526Arg Ala Ser Gln Thr Ile Ala Ser Tyr Val Asn1 5 1052711PRTHomo sapiens 527Arg Ala Ser Gln Thr Ile Ala Ser Tyr Val Asn1 5 1052811PRTHomo sapiens 528Arg Ser Ser Gln Thr Ile Ser Val Phe Leu Asn1 5 1052911PRTHomo sapiens 529Arg Ala Ser Gln Ser Val Thr Lys Tyr Leu Ala1 5 1053011PRTHomo sapiens 530Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala1 5 1053111PRTHomo sapiens 531Arg Ala Ser Gln Thr Ile Ala Ser Tyr Val Asn1 5 1053216PRTHomo sapiens 532Arg Ser Ser Gln Ser Leu Leu Arg Thr Asn Gly Tyr Asn Tyr Leu Asp1 5 10 1553311PRTHomo sapiens 533Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala1 5 1053411PRTHomo sapiens 534Arg Ala Ser Gln Asn Ile Arg Thr Phe Ile Asn1 5 1053516PRTHomo sapiens 535Arg Ser Ser Gln Ser Leu Leu His Arg Asn Gly Tyr Asn His Leu Asp1 5 10 1553611PRTHomo sapiens 536Arg Ala Gly Gln Gly Ile Arg Asn Asp Leu Gly1 5 1053716PRTHomo sapiens 537Arg Ser Ser Arg Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser1 5 10 1553811PRTHomo sapiens 538Arg Ala Ser Gln Ser Val Gly Asn Asn Leu Ala1 5 1053911PRTHomo sapiens 539Arg Ala Ser Gln Ser Val Ser Ser His Leu Ala1 5 1054011PRTHomo sapiens 540Arg Ala Ser Arg Ser Ile Thr Ser Trp Leu Ala1 5 105417PRTHomo sapiens 541Asn Thr Phe Asn Arg Val Thr1 55427PRTHomo sapiens 542Gly Ala Ser Thr Leu Gln Ser1 55437PRTHomo sapiens 543Leu Ala Ser Asn Arg Ala Ser1 55447PRTHomo sapiens 544Gly Ala Ser Ser Arg Ala Thr1 55457PRTHomo sapiens 545Ala Thr Ser Thr Leu Gln Ser1 55467PRTHomo sapiens 546Ala Ala Ser Thr Leu Gln Ser1 55477PRTHomo sapiens 547Gly Ala Ser Thr Gly Ala Thr1 55487PRTHomo sapiens 548Glu Val Ser Ser Arg Phe Ser1 55497PRTHomo sapiens 549Ala Ala Ser Thr Leu Gln Ser1 55507PRTHomo sapiens 550Ala Ala Ser Ser Leu Gln Ser1 55517PRTHomo sapiens 551Glu Ala Ser Asn Leu Glu Ser1 55527PRTHomo sapiens 552Ala Ala Ser Arg Leu Glu Ser1 55537PRTHomo sapiens 553Leu Gly Ser Asn Arg Ala Ser1 55547PRTHomo sapiens 554Val Ala Ser Ile Leu Glu Ser1 55557PRTHomo sapiens 555Gly Ala Ser Thr Arg Ala Thr1 55567PRTHomo sapiens 556Gly Ala Ser Gly Arg Ala Thr1 55577PRTHomo sapiens 557Ala Ala Ser Ser Leu Gln Ser1 55587PRTHomo sapiens 558Gly Ala Ser His Arg Ala Thr1 55597PRTHomo sapiens 559Thr Ala Ser Ser Leu Gln Ser1 55607PRTHomo sapiens 560Gly Ala Ser Thr Arg Ala Thr1 55617PRTHomo sapiens 561Ala Ala Ser Ser Leu Gln Ser1 55627PRTHomo sapiens 562Trp Ala Ser Thr Arg Glu Ser1 55637PRTHomo sapiens 563Ala Ala Ser Arg Arg Ala Thr1 55647PRTHomo sapiens 564Lys Ser Ser Ile Leu Glu Ser1 55657PRTHomo sapiens 565Asp Ala Ser Ser Leu Glu Ser1 55667PRTHomo sapiens 566Leu Ala Ser Asn Arg Ala Ser1 55677PRTHomo sapiens 567Gly Ala Ser Thr Arg Ala Thr1 55687PRTHomo sapiens 568Ala Ala Ser Asn Leu Gln Ser1 55697PRTHomo sapiens 569Asp Ala Ser Tyr Arg Val Thr1 55707PRTHomo sapiens 570Asp Val Ser Asn Leu Glu Arg1 55717PRTHomo sapiens 571Asp Ala Ser Asn Leu Glu Thr1 55727PRTHomo sapiens 572Gly Ala Ser Thr Leu Asp Tyr1 55737PRTHomo sapiens 573Leu Ala Ser Thr Arg Glu Tyr1 55747PRTHomo sapiens 574Ala Ala Ser Thr Leu Gln Ser1 55757PRTHomo sapiens 575Lys Glu Ser Asn Leu Glu Ser1 55767PRTHomo sapiens 576Ala Ala Ser Ser Leu His Ser1 55777PRTHomo sapiens 577Lys Ala Ser Ser Leu Glu Ser1 55787PRTHomo sapiens 578Asp Ala Ser Thr Leu Glu Ser1 55797PRTHomo sapiens 579Gly Ala Ser Lys Leu Gln Thr1 55807PRTHomo sapiens 580Gly Ala Ser Ser Leu Gln His1 55817PRTHomo sapiens 581Ala Ala Ser Thr Leu Gln Ser1 55827PRTHomo sapiens 582Ala Ala Ser Arg Leu Gln Ser1 55837PRTHomo sapiens 583Ala Ala Ser Thr Leu Gln Ser1 55847PRTHomo sapiens 584Asp Ala Ser Asn Arg Ala Thr1 55857PRTHomo sapiens 585Trp Ala Ser Thr Arg Ala Ser1 55867PRTHomo sapiens 586Lys Ala Ser Thr Leu Glu Ser1 55877PRTHomo sapiens 587Thr Thr Ser Thr Leu Arg Ser1 55887PRTHomo sapiens 588Ala Ala Ser Thr Leu Gln Ser1 55897PRTHomo sapiens 589Gly Ala Ser Ser Arg Ala Thr1 55907PRTHomo sapiens 590Asp Ala Ser Thr Leu Ala Ser1 55917PRTHomo sapiens 591Ala Ala Ser Ser Leu Gln Ser1 55927PRTHomo sapiens 592Asp Ala Ser Ser Leu Glu Ser1 55937PRTHomo sapiens 593Gln Ile Ser Lys Arg Phe Ser1 55947PRTHomo sapiens 594Asp Thr Ser Asn Leu Val Thr1 55957PRTHomo sapiens 595Gly Ala Ser Ser Arg Ala Ala1 55967PRTHomo sapiens 596Ala Ala Ser Ser Leu Gln Ser1 55977PRTHomo sapiens 597Thr Phe Ser Tyr Arg Ala Ser1 55987PRTHomo sapiens 598Trp Gly Ser Asn Arg Ala Ser1 55997PRTHomo sapiens 599Asp Ala Thr Lys Leu Glu Thr1 56007PRTHomo sapiens 600Ala Ala Ser Thr Leu Gln Ser1 56017PRTHomo sapiens 601Ala Ala Ser Ser Leu Gln Ser1 56027PRTHomo sapiens 602Asp Ala Ser Asn Arg Ala Thr1 56037PRTHomo sapiens 603Ala Ala Ser Thr Leu Gln Thr1 56047PRTHomo sapiens 604Asp Ala Thr Asp Leu Glu Thr1 56057PRTHomo sapiens 605Gly Ala Ser Ala Arg Ala Thr1 56067PRTHomo sapiens 606Gly Ala Ser Ser Arg Pro Thr1 56077PRTHomo sapiens 607Ala Ala Ser Ser Leu Gln Ser1 56087PRTHomo sapiens 608Asp Ala Ser Asn Leu Glu Ser1 56097PRTHomo sapiens 609Ala Ala Ser Thr Leu Gln Ser1 56107PRTHomo sapiens 610Gly Ala Ser Thr Arg Ala Thr1 56117PRTHomo sapiens 611Ala Ala Ser Ser Leu Gln Ser1 56127PRTHomo sapiens 612Ala Ala Ser Asn Leu Gln Ser1 56137PRTHomo sapiens 613Ala Ala Ser Ser Leu His Ser1 56147PRTHomo sapiens 614Asp Ala Ser Asn Arg Ala Thr1 56157PRTHomo sapiens 615Ser Ala Ser Thr Arg Ala Thr1 56167PRTHomo sapiens 616Ala Ala Ser Arg Leu Gln Ser1 56177PRTHomo sapiens 617Leu Gly Ser Ile Arg Ala Ser1 56187PRTHomo sapiens 618Lys Ala Ser Ser Leu Glu Ser1 56197PRTHomo sapiens 619Ala Ala Ser Lys Leu Glu Ser1 56207PRTHomo sapiens 620Leu Gly Ser Asn Arg Ala Ser1 56217PRTHomo sapiens 621Gly Ala Ser Thr Leu Gln Ser1 56227PRTHomo sapiens 622Lys Ile Ser Asn Arg Phe Ser1 56237PRTHomo sapiens 623Gly Ala Ser Thr Arg Ala Thr1 56247PRTHomo sapiens 624Gly Ala Ser Thr Arg Ala Thr1 56257PRTHomo sapiens 625Lys Ala Ser Ser Leu Gln Ser1 562613PRTHomo sapiens 626Cys Gln Gln Arg Ser Asn Trp Pro Pro Ala Leu Thr Phe1 5 1062712PRTHomo sapiens 627Cys Gln Gln Ser Tyr Arg Thr Pro Pro Ile Asn Phe1 5 1062810PRTHomo sapiens 628Cys Met Gln Ser Leu Gln Thr Pro Thr Phe1 5 1062913PRTHomo sapiens 629Cys Gln Gln Tyr Asp Ser Ser Leu Ser Thr Trp Thr Phe1 5 1063010PRTHomo sapiens 630Cys Gln Gln Ser Tyr Asn Thr Leu Thr Phe1 5 1063111PRTHomo sapiens 631Cys Gln Gln Thr Asn Ser Phe Pro Tyr Thr Phe1 5 1063211PRTHomo sapiens 632Cys Gln Gln Tyr Gly Arg Thr Pro Tyr Thr Phe1 5 1063311PRTHomo sapiens 633Cys Met Gln Gly Leu Lys Ile Arg Arg Thr Phe1 5 1063411PRTHomo sapiens 634Cys Gln Gln Val Asp Thr Tyr Pro Leu Thr Phe1 5 1063511PRTHomo sapiens 635Cys Gln Gln Tyr Lys Ser Leu Pro Phe Thr Phe1 5 1063612PRTHomo sapiens 636Cys Gln Gln Tyr His Ser Tyr Ser Gly Tyr Thr Phe1 5 1063711PRTHomo sapiens 637Cys Gln Gln Tyr Ser Lys Ser Pro Ala Thr Phe1 5 1063811PRTHomo sapiens 638Cys Met Gln Ala Leu Glu Thr Pro Leu Thr Phe1 5 1063911PRTHomo sapiens 639Cys Gln Gln Ser Lys Ser Phe Pro Pro Thr Phe1 5 1064011PRTHomo sapiens 640Cys Gln Gln Tyr Gly Gly Ser Gly Leu Thr Phe1 5 1064111PRTHomo sapiens 641Cys Gln Gln Tyr Phe Gly Ser Pro Tyr Thr Phe1 5 1064211PRTHomo sapiens 642Cys Gln Gln Ser Ala Asn Ser Pro His Thr Phe1 5 1064311PRTHomo sapiens 643Cys Gln Gln Tyr Gly Ser Ser Leu Trp Thr Phe1 5 1064411PRTHomo sapiens 644Cys Gln His Ser Tyr Asn Thr Pro Tyr Thr Phe1 5 1064512PRTHomo sapiens 645Cys Gln Gln Tyr Asn Asn Trp Pro Pro Tyr Thr Phe1 5 1064611PRTHomo sapiens 646Cys Leu Gln His Asn Ile Ser Pro Tyr Thr Phe1 5 1064711PRTHomo sapiens 647Cys Gln Gln Phe Phe Arg Ser Pro Phe Thr Phe1 5 1064811PRTHomo sapiens 648Cys Gln His Tyr Gly Asn Ser Leu Phe Thr Phe1 5 1064911PRTHomo sapiens 649Cys Gln His Tyr Asn Ser Tyr Ser Gly Thr Phe1 5 1065012PRTHomo sapiens 650Cys Gln Gln Tyr Asn Arg Asp Ser Pro Trp Thr Phe1 5 1065111PRTHomo sapiens 651Cys Met Gln Gly Leu His Thr Pro Trp Thr Phe1 5 1065210PRTHomo sapiens 652Cys Gln Gln Tyr Lys Asn Trp Tyr Thr Phe1 5 1065312PRTHomo sapiens 653Cys Gln Gln Ser Tyr Ser Tyr Arg Ala Leu Thr Phe1 5 1065413PRTHomo sapiens 654Cys Gln Gln Arg Ser Asn Trp Pro Pro Gly Leu Thr Phe1 5 1065511PRTHomo sapiens 655Cys Gln Gln Tyr Asp Phe Leu Pro Tyr Thr Phe1 5 1065613PRTHomo sapiens 656Cys Gln His Tyr Val Asn Leu Pro Pro Ser Phe Thr Phe1 5 1065711PRTHomo sapiens 657Cys Gln Gln Phe Asn Thr Tyr Pro Phe Thr Phe1 5 1065811PRTHomo sapiens 658Cys Gln Gln Tyr Tyr Gln Thr Pro Leu Thr Phe1 5 1065911PRTHomo sapiens 659Cys Gln Gln Ser Tyr Thr Asn Pro Tyr Thr Phe1 5 1066010PRTHomo sapiens 660Cys Gln Gln Tyr Lys Asn Asp Trp Thr Phe1 5 1066111PRTHomo sapiens 661Cys Gln His Ser Tyr Ser Thr Arg Phe Thr Phe1 5 1066211PRTHomo sapiens 662Cys Gln Gln Tyr Asn Ser Phe Pro Tyr Thr Phe1 5 1066311PRTHomo sapiens 663Cys Gln Gln Tyr Asn Ser Leu Ser Pro Thr Phe1 5 1066411PRTHomo sapiens 664Cys Gln Gln Ala Lys Ser Phe Pro Phe Thr Phe1 5 1066511PRTHomo sapiens 665Cys Gln Gln Ala Asp Ser Phe Pro Phe Thr Phe1 5 1066611PRTHomo sapiens 666Cys Gln Gln Leu Asn Ser Tyr Pro Arg Thr Phe1 5 1066711PRTHomo sapiens 667Cys Gln Gln Ala Tyr Ser Phe Pro Arg Thr Phe1 5 1066811PRTHomo sapiens 668Cys Gln Lys Tyr Asn Ser Ala Pro Gln Thr Phe1 5 1066911PRTHomo sapiens 669Cys Gln Gln Tyr Gly Ser Pro Pro Trp Thr Phe1 5 1067011PRTHomo sapiens 670Cys Gln Gln Phe His Ser Thr Pro Arg Thr Phe1 5 1067111PRTHomo sapiens 671Cys Gln Gln Tyr Asn Ser Phe Ser Phe Thr Phe1 5 1067211PRTHomo sapiens 672Cys Gln Gln Tyr His Ser Phe Pro Tyr Thr Phe1 5 1067311PRTHomo sapiens 673Cys Gln Gln Leu Asn Thr Tyr Pro Leu Thr Phe1 5 1067411PRTHomo sapiens 674Cys Gln Gln Tyr Gly Ser Ser Pro Phe Thr Phe1 5 1067511PRTHomo sapiens 675Cys Gln Gln Tyr Arg Ser Tyr Ser Tyr Thr Phe1 5 1067611PRTHomo sapiens 676Cys Gln Gln Ser Tyr Ser Thr Pro Tyr Thr Phe1 5 1067711PRTHomo sapiens 677Cys Gln Gln Tyr Asn Ile Tyr Ser Pro Thr Phe1 5 1067811PRTHomo sapiens 678Cys Met Gln Ala Thr Gln Phe Pro Phe Thr Phe1 5 1067911PRTHomo sapiens 679Cys Leu Gln Tyr His Tyr Leu Pro Tyr Thr Phe1 5 1068011PRTHomo sapiens 680Cys Gln Gln Tyr Gly Asn Ser Pro Leu Thr Phe1 5 1068111PRTHomo sapiens 681Cys Gln Gln Ala Asp Thr Phe Pro Phe Thr Phe1 5 1068211PRTHomo sapiens 682Cys Met Gln Arg Ile Glu Phe Pro Tyr Thr Phe1 5 1068311PRTHomo sapiens 683Cys Met Gln Thr Leu Gln Thr Pro Arg Thr Phe1 5 1068411PRTHomo sapiens 684Cys Gln His Phe Ala Asn Leu Pro Tyr Thr Phe1 5 1068511PRTHomo sapiens 685Cys Gln Arg Tyr Asn Ser Ala Pro Leu Thr Phe1 5 1068612PRTHomo sapiens 686Cys Gln Gln Ser Tyr Ser Thr Pro Ile Phe Thr Phe1 5 1068710PRTHomo sapiens 687Cys Gln Gln Arg Ser Asp Trp Leu Thr Phe1 5 1068811PRTHomo sapiens 688Cys Gln Gln Leu Asn Ile Tyr Pro Leu Thr Phe1 5 1068911PRTHomo sapiens 689Cys Gln His Phe Ala Asn Leu Pro Tyr Thr Phe1 5 1069012PRTHomo sapiens 690Cys Gln Glu Tyr Asn Asn Trp Pro Leu Leu Thr Phe1 5 1069111PRTHomo sapiens 691Cys Gln Gln Tyr Gly Thr Thr Pro Ile Thr Phe1 5 1069212PRTHomo sapiens 692Cys Gln Gln Ser Tyr Ser Thr Pro Ile Tyr Thr Phe1 5 1069311PRTHomo sapiens 693Cys Gln Gln Tyr Asp Asn Phe Pro Tyr Thr Phe1 5 1069411PRTHomo sapiens 694Cys Gln Lys Tyr Asn Ser Ala Pro Trp Thr Phe1 5 1069511PRTHomo sapiens 695Cys Gln Gln Tyr Asn Asn Trp Pro Gln Thr Phe1 5 1069611PRTHomo sapiens 696Cys Gln Gln Ser Tyr Ser Phe Pro Tyr Thr Phe1 5 1069712PRTHomo sapiens 697Cys Gln Gln Ser Tyr Ser Val Pro Arg Leu Thr Phe1 5 1069810PRTHomo sapiens 698Cys Gln Glu Ser Phe Ser Ser Ser Thr Phe1 5 1069910PRTHomo sapiens 699Cys Gln His Arg Arg Ser Trp Pro Thr Phe1 5 1070012PRTHomo sapiens 700Cys Gln Gln Tyr Asn Met Trp Pro Pro Trp Thr Phe1 5 1070111PRTHomo sapiens 701Cys Gln Gln Ser Tyr Ser Ile

Pro Trp Thr Phe1 5 1070211PRTHomo sapiens 702Cys Met Gln Ser Leu Gln Thr Ser Ile Thr Phe1 5 1070311PRTHomo sapiens 703Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr Phe1 5 1070411PRTHomo sapiens 704Cys Gln Gln Gly His Ser Thr Pro Tyr Thr Phe1 5 1070511PRTHomo sapiens 705Cys Met Gln Ala Leu Gln Thr Pro Arg Thr Phe1 5 1070611PRTHomo sapiens 706Cys Leu Gln His Asn Ser Tyr Pro Trp Thr Phe1 5 1070710PRTHomo sapiens 707Cys Leu Gln Ala Thr Gln Phe Leu Thr Phe1 5 1070811PRTHomo sapiens 708Cys Gln Gln Tyr Asp Lys Trp Pro Glu Thr Phe1 5 1070911PRTHomo sapiens 709Cys Gln Gln Tyr Asp Asn Trp Leu Pro Thr Phe1 5 1071011PRTHomo sapiens 710Cys Gln Gln Tyr Asn Ser Tyr Pro Leu Thr Phe1 5 10711298PRTrespiratory syncytial virus 711Met Ser Lys Asn Lys Asp Gln Arg Thr Ala Lys Thr Leu Glu Lys Thr1 5 10 15Trp Asp Thr Leu Asn His Leu Leu Phe Ile Ser Ser Gly Leu Tyr Lys 20 25 30Leu Asn Leu Lys Ser Ile Ala Gln Ile Thr Leu Ser Ile Leu Ala Met 35 40 45Ile Ile Ser Thr Ser Leu Ile Ile Thr Ala Ile Ile Phe Ile Ala Ser 50 55 60Ala Asn His Lys Val Thr Leu Thr Thr Ala Ile Ile Gln Asp Ala Thr65 70 75 80Ser Gln Ile Lys Asn Thr Thr Pro Thr Tyr Leu Thr Gln Asp Pro Gln 85 90 95 Leu Gly Ile Ser Phe Ser Asn Leu Ser Glu Ile Thr Ser Gln Thr Thr 100 105 110Thr Ile Leu Ala Ser Thr Thr Pro Gly Val Lys Ser Asn Leu Gln Pro 115 120 125Thr Thr Val Lys Thr Lys Asn Thr Thr Thr Thr Gln Thr Gln Pro Ser 130 135 140Lys Pro Thr Thr Lys Gln Arg Gln Asn Lys Pro Pro Asn Lys Pro Asn145 150 155 160Asn Asp Phe His Phe Glu Val Phe Asn Phe Val Pro Cys Ser Ile Cys 165 170 175Ser Asn Asn Pro Thr Cys Trp Ala Ile Cys Lys Arg Ile Pro Asn Lys 180 185 190 Lys Pro Gly Lys Lys Thr Thr Thr Lys Pro Thr Lys Lys Pro Thr Phe 195 200 205Lys Thr Thr Lys Lys Asp His Lys Pro Gln Thr Thr Lys Pro Lys Glu 210 215 220Val Pro Thr Thr Lys Pro Thr Glu Glu Pro Thr Ile Asn Thr Thr Lys225 230 235 240Thr Asn Ile Ile Thr Thr Leu Leu Thr Asn Asn Thr Thr Gly Asn Pro 245 250 255Lys Leu Thr Ser Gln Met Glu Thr Phe His Ser Thr Ser Ser Glu Gly 260 265 270Asn Leu Ser Pro Ser Gln Val Ser Thr Thr Ser Glu His Pro Ser Gln 275 280 285Pro Ser Ser Pro Pro Asn Thr Thr Arg Gln 290 295712292PRTrespiratory syncytial virus 712Met Ser Lys His Lys Asn Gln Arg Thr Ala Arg Thr Leu Glu Lys Thr1 5 10 15Trp Asp Thr Leu Asn His Leu Ile Val Ile Ser Ser Cys Leu Tyr Arg 20 25 30Leu Asn Leu Lys Ser Ile Ala Gln Ile Ala Leu Ser Val Leu Ala Met 35 40 45Ile Ile Ser Thr Ser Leu Ile Ile Ala Ala Ile Ile Phe Ile Ile Ser 50 55 60Ala Asn His Lys Val Thr Leu Thr Thr Val Thr Val Gln Thr Ile Lys65 70 75 80Asn His Thr Glu Lys Asn Ile Ser Thr Tyr Leu Thr Gln Val Pro Pro 85 90 95Glu Arg Val Asn Ser Ser Lys Gln Pro Thr Thr Thr Ser Pro Ile His 100 105 110Thr Asn Ser Ala Thr Ile Ser Pro Asn Thr Lys Ser Glu Thr His His 115 120 125Thr Thr Ala Gln Thr Lys Gly Arg Ile Thr Thr Ser Thr Gln Thr Asn 130 135 140Lys Pro Ser Thr Lys Ser Arg Ser Lys Asn Pro Pro Lys Lys Pro Lys145 150 155 160Asp Asp Tyr His Phe Glu Val Phe Asn Phe Val Pro Cys Ser Ile Cys 165 170 175Gly Asn Asn Gln Leu Cys Lys Ser Ile Cys Lys Thr Ile Pro Ser Asn 180 185 190Lys Pro Lys Lys Lys Pro Thr Ile Lys Pro Thr Asn Lys Pro Thr Thr 195 200 205Lys Thr Thr Asn Lys Arg Asp Pro Lys Thr Pro Ala Lys Met Pro Lys 210 215 220Lys Glu Ile Ile Thr Asn Pro Ala Lys Lys Pro Thr Leu Lys Thr Thr225 230 235 240Glu Arg Asp Thr Ser Ile Ser Gln Ser Thr Val Leu Asp Thr Ile Thr 245 250 255Pro Lys Tyr Thr Ile Gln Gln Gln Ser Leu His Ser Thr Thr Ser Glu 260 265 270Asn Thr Pro Ser Ser Thr Gln Ile Pro Thr Ala Ser Glu Pro Ser Thr 275 280 285Leu Asn Pro Asn 29071377PRTrespiratory syncytial virus 713Gln Pro Thr Thr Val Lys Thr Lys Asn Thr Thr Thr Thr Gln Thr Gln1 5 10 15Pro Ser Lys Pro Thr Thr Lys Gln Arg Gln Asn Lys Pro Pro Asn Lys 20 25 30Pro Asn Asn Asp Phe His Phe Glu Val Phe Asn Phe Val Pro Cys Ser 35 40 45Ile Cys Ser Asn Asn Pro Thr Cys Trp Ala Ile Cys Lys Arg Ile Pro 50 55 60Asn Lys Lys Pro Gly Lys Lys Thr Thr Thr Lys Pro Thr65 70 7571477PRTrespiratory syncytial virus 714His His Thr Thr Ala Gln Thr Lys Gly Arg Ile Thr Thr Ser Thr Gln1 5 10 15Thr Asn Lys Pro Ser Thr Lys Ser Arg Ser Lys Asn Pro Pro Lys Lys 20 25 30Pro Lys Asp Asp Tyr His Phe Glu Val Phe Asn Phe Val Pro Cys Ser 35 40 45Ile Cys Gly Asn Asn Gln Leu Cys Lys Ser Ile Cys Lys Thr Ile Pro 50 55 60Ser Asn Lys Pro Lys Lys Lys Pro Thr Ile Lys Pro Thr65 70 75

Claims

1. (canceled)

2. An anti-RSV antibody comprising a CDRH3 having the general formula: CAX₁X₂X₃X₄X₅X₆PX₇X₈X₉X₁- 0X₁₁W where X₁ to X₁₁ are selected individually from the groups of amino acids listed below X.sub.1.dbd.R or K; X₂=D, E, N or Q; X.sub.3.dbd.S, T, G or A; X.sub.4.dbd.S, T, G or A; X.sub.5.dbd.N, Q, D or E; X.sub.6.dbd.W, Y, F or H; X₇=A, G, V, or S; X₈=G, A, V, or S; X.sub.9.dbd.Y, F, W or H; X₁₀=E or D; and X₁₁=D, E, N or Q; and a CDRL3 described by the following formula: CX₁X₂X₃X₄X₅X₆PX₇TF where X₁ to X₇ are selected individually from the groups of amino acids listed below: X₁=Q or H; X₂=Q, E or H; X.sub.3.dbd.F, Y, W or H; X.sub.4.dbd.N, Q or H; X₅=T, S, G or A; X.sub.6.dbd.Y, F, W or H; and X.sub.7.dbd.F, Y, W or H.

3. The antibody of claim 2, comprising SEQ ID NOs: 232, 317, 487, and 572, wherein up to 2 amino acids have been changed compared to said SEQ ID Nos.

4. The antibody of claim 2, comprising a CDRH3 region having the formula CARDSSNWPAGYEDW (SEQ ID NO 402), and a CDRL3 region having the formula CQQFNTYPFTF (SEQ ID NO 657).

5. The antibody of claim 2, comprising a V_H region encoded by SEQ ID NO: 19.

6. The antibody of claim 2, comprising a V_L region encoded by amino acids 1 to 107 of SEQ ID NO: 107.

7. The antibody of claim 2, comprising a light chain encoded by SEQ ID NO: 107.

8. The antibody of claim 2, comprising a C_H as defined in SEQ ID NO: 178.

9. The antibody of claim 2, having a binding specificity of an antibody comprising CDR1, CDR2 and CDR3 regions of SEQ ID NOs: 232, 317, 402, 487, 572 and 657.

10. The antibody of claim 1, being capable of neutralizing subtypes A and B of RSV in a virus neutralization assay.

11. The antibody of claim 2, being capable of providing a significant reduction of RSV virus load in the lungs of a mammal infected with RSV.

12. An antibody composition comprising the anti-RSV antibody of claim 2, and one or more additional anti-RSV antibodies.

13. The antibody composition of claim 12, wherein the one or more additional anti-RSV antibodies are selected from the group consisting of human antibodies, humanized antibodies, and chimeric human-mouse antibodies.

14. The antibody composition of claim 12, wherein the one or more additional anti-RSV antibodies comprises: (i) a CDRH1 selected from the group consisting of SEQ ID NOs: 201-285; (ii) a CDRH2 selected from the group consisting of SEQ ID NOs: 286-370; (iii) a CDRH3 selected from the group consisting of SEQ ID NOs: 371-455; (iv) a CDRL1 selected from the group consisting of SEQ ID NOs: 456-540; (v) CDRL2 selected from the group consisting of SEQ ID NOs: 541-625; and (vi) a CDRL3 selected from the group consisting of SEQ ID NOs: 626-710.

15. A composition comprising an anti-RSV antibody comprising: (i) a CDRH1 selected from the group consisting of SEQ ID NOs: 201-285; (ii) a CDRH2 selected from the group consisting of SEQ ID NOs: 286-370; (iii) a CDRH3 selected from the group consisting of SEQ ID NOs: 371-455; (iv) a CDRL1 selected from the group consisting of SEQ ID NOs: 456-540; (v) a CDRL2 selected from the group consisting of SEQ ID NOs: 541-625; and (vi) a CDRL3 selected from the group consisting of SEQ ID NOs: 626-710.

16. The composition of claim 15, being capable of neutralizing RSV subtype A in a virus neutralization assay.

17. The composition of claim 15, being capable of neutralizing RSV subtype B in a virus neutralization assay.

18. The composition of claim 15, further comprising one or more additional anti-RSV antibodies.

19. A method of preventing, treating or ameliorating one or more symptoms associated with a RSV infection in a mammal, comprising administering an effective amount of the anti-RSV antibody according to claim 2.

20. The method according to claim 19, wherein the effective amount is between 0.1-50 mg antibody per kg of body weight.

21. The method according to claim 19, wherein the anti-RSV antibody is administered at least 1 time per year.

22. The method according to claim 21, wherein the anti-RSV antibody is administered at regular intervals during a period of the year where there is an increased risk of attracting an RSV infection.

23. The method according to claim 22, wherein the regular intervals are weekly, bi-weekly, monthly, or bi-monthly.

24. An isolated nucleic acid fragment which encodes the anti-RSV antibody of claim 2.

25-35. (canceled)

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