Anti-CD303 Monoclonal Antibodies

Abstract

The invention relates to chimeric or humanised anti-CD303 antibodies to nucleic acids coding for the heavy and light chains of these antibodies, expression vectors, host cells, transgenic non-human animals or transgenic plants expressing said antibodies, as well as to the uses thereof in the treatment or prevention of blastic plasmacytoid dendritic cell neoplasms (BPDCN) or inflammatory diseases, in particular autoimmune diseases, involving plasmacytoid dendritic cells.

Description

FIELD OF THE INVENTION

[0001] The present invention is in the field of therapeutic antibodies for treating or preventing hematopoietic tumors of the CD4+CD56+ phenotype or inflammatory diseases, notably autoimmune diseases, involving plasmacytoid dendritic cells (pDCs). It relates to five monoclonal antibodies directed against the CD303 antigen, and to functional fragments and derivatives thereof, to the nucleic acids encoding the heavy and/or light chain of the antibody, to expression vectors, host cells, transgenic non-human animals or transgenic plants expressing said antibodies, and to therapeutic uses of said antibodies.

PRIOR ART

[0002] Dendritic cells (called "DCs" throughout the present description) are antigen-presenting cells (APCs) of the immune system. Under certain conditions, DCs have cytoplasmic projections similar to the dendrites of neurons.

[0003] Dendritic cells have two main functions:

[0004] they trigger the adaptive immune response directed against "non-self" (foreign) antigens, by presenting these foreign antigens to T lymphocytes; and

[0005] they maintain central tolerance to "self", by educating T cells in the thymus, by the so-called "negative selection" process.

[0006] DCs are capable of differentiating into various subpopulations, according to the stimuli they receive. There are three major types of DCs: conventional DCs, plasmacytoid DCs (called "pDCs") and inflammatory DCs.

[0007] Conventional DCs present self or non-self-antigens in lymphoid organs or in the periphery. Inflammatory DCs, probably derived from blood monocytes, appear only in the event of stimulation following inflammation or infection.

[0008] Plasmacytoid DCs (pDCs) are circulating, round and without dendrites in the basal state, but acquire dendrites after activation, generally by a viral antigen. After stimulation, they produce a large amount of type I interferons (IFNs), and are chiefly involved in the antiviral response or in autoimmune diseases. Phenotypically, they are notably characterized by the following markers: CD4+, CD11c-, Lin-, CD303+, CD304+.

[0009] pDCs can be the cause of hematopoietic tumors in which they acquire an additional marker (CD56). This is referred to as blastic plasmacytoid dendritic cell neoplasm (BPDCN). These tumors are also referred to as CD4+CD56+ hematopoietic tumors. These hematopoietic tumors are rare (1% of acute leukemias) and appear as cutaneous nodules associated with lymphadenopathy or swelling of the spleen and with frequent cytopenia.

[0010] The cutaneous manifestations are very quickly followed by infiltration of the bone marrow. It is now accepted that the hematopoietic cells at the origin of these tumors are pDCs.

[0011] The current treatments for these blastic plasmacytoid dendritic cell neoplasms are based on chemotherapy. Although relatively effective at first, this treatment is characterized by frequent and early relapses (about 9 months), median overall survival being only about 13 months. Another treatment is based on allografting of hematopoietic cells, but it does not enable long-term survival either.

[0012] It has been proposed in WO2012/080642 to use anti-BDCA-2 (i.e., anti-CD303) antibodies to treat these neoplasms by tumor cell depletion.

[0013] pDCs are also involved in certain inflammatory diseases, and notably in certain autoimmune diseases, in particular via their secretion of type I IFN.

[0014] One treatment is based on the use of anti-IFN.alpha. antibody. However, this treatment leads to systemic neutralization of IFN.alpha., thus potentially increasing the risk of opportunistic infections. It has thus also been proposed in WO01/365487 and WO2012/080642 to use anti-BDCA-2 (anti-CD303) antibodies (in particular antibody AC144) to treat autoimmune diseases, by removing the pDCs responsible for local inflammation.

[0015] However, in order for these treatments to be effective, it is necessary to have suitable monoclonal antibodies that allow, in humans, the most efficient as possible removal of pDCs. To that end, chimeric or humanized antibodies with high affinity for the CD303 antigen and effector capabilities (ADCC, CDC, phagocytosis, signaling via cross-linking of CD303 by Fc receptors, in particular Fc.gamma. receptor III (Fc.gamma.RIII, also called CD16) and/or apoptosis) enabling them to remove pDCs in physiological conditions are necessary. The anti-CD303 antibodies available to date being inadequate, there thus exists a need for new anti-CD303 antibodies having the desired properties.

[0016] WO2014/09339 describes humanized anti-CD303 antibodies, defined by the sequences of their heavy and light chains, and notably antibody BIIB059, which is the one having the best affinity for the CD303 antigen. Antibody BIIB059 was produced in CHO cells and characterized in terms of certain properties.

SUMMARY OF THE INVENTION

[0017] In the context of the present invention, the inventors generated five chimeric monoclonal antibodies having such properties. At least two of these chimeric antibodies (122A2 and 102E9) have a capacity to bind to the ectodomain of the human CD303 antigen that is greater than that of the antibody (BIIB059) described in WO2014/09339 (in particular 122A2). Moreover, humanized antibodies derived from these two chimeric antibodies were generated and characterized. These humanized antibodies can be produced with higher productivity than the original chimeric antibodies and, among those derived from chimeric antibody 122A2, certain have a capacity to bind to the ectodomain of the human CD303 antigen that is even higher than that of the original chimeric antibody and thus higher than that of the antibody (BIIB059) described in WO2014/09339. The chimeric and humanized antibodies produced in YB2/0 cells also have high affinity for Fc.gamma.RIIIa (CD16a), and are capable of inducing strong ADCC responses, even at low antigen density. The antibodies also have CDC activity and are capable of inhibiting the secretion of IFN-.alpha. and of TNF-.alpha..

[0018] In a first aspect, the present invention thus relates to a monoclonal antibody directed against the ectodomain of the human CD303 antigen (SEQ ID NO: 130), or a functional fragment or a derivative thereof, characterized in that:

[0019] a) it competes for binding to the human CD303 antigen with at least one antibody selected from:

[0020] i) An antibody which heavy chain variable region comprises SEQ ID NO: 43 and which light chain variable region comprises SEQ ID NO: 48;

[0021] ii) An antibody which heavy chain variable region comprises SEQ ID NO: 44 and which light chain variable region comprises SEQ ID NO: 49;

[0022] iii) An antibody which heavy chain variable region comprises SEQ ID NO: 45 and which light chain variable region comprises SEQ ID NO: 50;

[0023] iv) An antibody which heavy chain variable region comprises SEQ ID NO: 46 and which light chain variable region comprises SEQ ID NO: 51;

[0024] v) An antibody which heavy chain variable region comprises SEQ ID NO: 47 and which light chain variable region comprises SEQ ID NO: 52; and the light and heavy chain constant regions are constant regions from a non-murine species.

[0025] The present invention also relates to a monoclonal antibody directed against the ectodomain of the human CD303 antigen (SEQ ID NO: 130), or a functional fragment or a derivative thereof, characterized in that:

[0026] a) it has improved affinity for Fc.gamma.RIIIa (CD16a) compared to antibodies directed against the ectodomain of the human CD303 antigen, produced in CHO cells; and

[0027] b) the light and heavy chain constant regions are constant regions from a non-murine species.

[0028] The present invention also relates to a nucleic acid encoding the heavy and/or light chain of an antibody, functional fragment or derivative thereof according to the invention.

[0029] The present invention also relates to a vector comprising a nucleic acid according to the invention.

[0030] The present invention also relates to a host cell, a transgenic non-human animal or a transgenic plant comprising at least one nucleic acid according to the invention or a vector according to the invention.

[0031] The present invention also relates to an antibody, functional fragment or derivative thereof according to the invention, for use as a medicinal product.

[0032] The antibody, functional fragment or derivative thereof according to the invention is advantageously used in the treatment or prevention of hematopoietic tumors expressing the CD303 antigen or in the treatment or prevention of inflammatory diseases, notably autoimmune diseases.

DESCRIPTION OF THE FIGURES

[0033] FIGS. 1A-1F: Maps of the expression vectors for chimeric antibodies 122A2 (FIG. 1A), 102E9 (FIG. 1B), 104C12 (FIG. 1C), 114D11 (FIG. 1D), and 104E10 (FIG. 1E), and of the antibody BIIB059 expression vector (FIG. 1F).

[0034] FIGS. 2A-2D. Antigen-binding of the antibodies according to the invention. (FIG. 2A) Mean fluorescence intensity (MFI) of Fc.gamma. chain-CD303 Jurkat cells (expressing about 25,000-35,000 CD303 molecules/cell) labeled with the antibodies according to the invention, at different antibody concentrations (represented in logarithmic units). (FIG. 2B) Mean fluorescence intensity (MFI) of CAL-1 cells (cell line established from a BPDCN patient) labeled with the chimeric antibodies according to the invention, at different antibody concentrations (represented in logarithmic units). (FIG. 2C) Mean fluorescence intensity (MFI) of CAL-1 cells (cell line established from a BPDCN patient, expressing about 3,000-6,000 CD303 molecules/cell) labeled with one of chimeric antibodies 122A2 and 102E9, with humanized antibody BIIB059 or with an irrelevant antibody. (FIG. 2D) Mean fluorescence intensity (MFI) of CAL-1 cells transfected with a CD303 expression vector and selected for their high expression of CD303, about 40,000-50,000 CD303 molecules/cell, labeled with one of chimeric antibodies 122A2 and 102E9, with humanized antibody BIIB059 or with an irrelevant antibody.

[0035] FIGS. 3A-3B: Fc.gamma.RIIIa (CD16a)-binding. (FIG. 3A) The CD16-binding of the antibodies according to the invention was studied in a competition experiment using a phycoerythrin-coupled murine anti-CD16 antibody, 3G8. The binding of anti-CD16 3G8 to CD16 (mean fluorescence intensity values) is measured as a function of the increasing concentration of antibodies according to the invention added (.mu.g/mL). (FIG. 3B) The CD16-binding of chimeric antibodies ch.122A2 and ch.102E9 according to the invention, of the chimeric antibody Rituxan and of the humanized antibody (BIIB059) described in the application WO2014/09339 was studied in a competition experiment using a phycoerythrin-coupled murine anti-CD16 antibody, 3G8. The binding of anti-CD16 3G8 to CD16 (mean fluorescence intensity values) is measured as a function of the increasing concentration of antibodies according to the invention added (.mu.g/mL).

[0036] FIGS. 4A-4B: ADCC activities induced by the chimeric antibodies of the invention and humanized antibody BIIB059 with respect to Fc.gamma. chain-CD303 Jurkat cells (FIG. 4A) or CAL-1 cells (FIG. 4B). (A) The percentage of lysis by ADCC (% lysis, as defined in Example 2) of Fc.gamma. chain-CD303 Jurkat target cells induced by the chimeric antibodies according to the invention is represented as a function of antibody concentration (ng/mL, logarithmic scale). (B) The percentage of lysis by ADCC (% lysis, as defined in Example 2) of CAL-1 target cells induced by the chimeric antibodies according to the invention, 122A2 and 102E9, and by humanized antibody BIIB059 is represented as a function of antibody concentration (ng/mL, logarithmic scale).

[0037] FIG. 5: Inhibition induced by the antibodies of the invention of IFN-.alpha. secretion by pDCs. Amount of IFN-.alpha. (in .mu.g/mL) secreted by CpG-activated purified pDCs, in the presence of the chimeric antibodies of the invention at 10 and 0.1 .mu.g/mL, and of an irrelevant control chimeric antibody.

[0038] FIG. 6: Inhibition induced by the antibodies of the invention of TNF-.alpha. secretion by CpG-activated purified pDCs, in the presence of the chimeric antibodies (10 .mu.g/mL) of the invention and of an irrelevant control chimeric antibody.

[0039] FIG. 7: CDC activities induced by the antibodies of the invention with respect to Fc.gamma. chain-CD303 Jurkat cells. The percentage of lysis by CDC (% lysis, as defined in Example 2) of Fc.gamma. chain-CD303 Jurkat target cells induced by the chimeric antibodies according to the invention is represented as a function of antibody concentration (ng/mL, logarithmic scale).

[0040] FIGS. 8A-8N: Maps of the empty vector pCEP4 (FIG. 8A) and of the expression vectors for the heavy or light chains of humanized antibodies 122A2 (FIG. 8B to FIG. 8H) and 102E9 (FIG. 8I to FIG. 8N).

[0041] FIGS. 9a-9B: Antigen-binding of humanized antibodies derived from antibody 102E9. OD at 450 nm as a function of the concentration of humanized antibodies derived from antibody 102E9 tested at 1.25, 2.5, 5, 10 and 20 ng/mL, accompanied by the controls: supernatant alone (mock) and chimeric antibody 102E9. (FIG. 9A) Humanized antibodies 102E9H5, 102E9H6, 102E9H7, 102E9H9, 102E9H10 and 102E9H11. (FIG. 9B) Humanized antibodies 102E9H13, 102E9H14, and 102E9H15.

[0042] FIG. 10: Antigen-binding of humanized antibodies derived from antibody 102E9 at 5 ng/mL antibody. Comparison of the relative affinities of humanized antibodies derived from 102E9 for the CD303 ectodomain, the binding of the chimeric antibody being 100%. The antibodies exhibiting binding similar to that of the chimeric antibody (relative affinity of at least 70%) are indicated by *.

[0043] FIGS. 11A-11C: Antigen-binding of humanized antibodies derived from antibody 122A2. OD at 450 nm as a function of the concentration of humanized antibodies derived from antibody 122A2 tested at 1.75, 2.5, 5, and 10 ng/mL, accompanied by the controls: supernatant alone (mock) and chimeric antibody 102E9. (FIG. 11A) Humanized antibodies 122A2H5, 122A2H6, 122A2H9, 122A2H7, 122A2H10, 122A2H14, 122A2H17, 122A2H15, and hybrid antibodies 122A2H3 and 122A2H8. (FIG. 11B) Humanized antibodies 122A2H5, 122A2H6, 122A2H9, 122A2H7, 122A2H10, 122A2H14, 122A2H17, 122A2H13, 122A2H18, and 122A2H11. (FIG. 11C) Humanized hybrid antibodies 122A2H15 and 122A2H19, and antibodies 122A2H4, 122A2H8, 122A2H12, 122A2H16, 122A2H1, 122A2H2 and 122A2H3.

[0044] FIG. 12: Antigen-binding of humanized antibodies derived from antibody 102E9 at 5 ng/mL antibody. Comparison of the relative affinities of humanized antibodies derived from 102E9 for the CD303 ectodomain, the binding of the chimeric antibody being at 100%. The antibodies exhibiting better binding than that of the chimeric antibody (relative affinity >100%) are indicated by *.

[0045] FIG. 13: CD303-binding on CAL-1 cells of various antibodies derived from 122A2 selected at a concentration of 0.1 .mu.g/mL (in supernatant): observation of mean fluorescence intensity (MFI) by flow cytometry. Irrelevant mAb-supernatant: irrelevant mAb diluted in supernatant. hum: humanized antibody. hyb: hybrid antibody.

[0046] FIG. 14: Inhibition of IFN-.alpha. secretion by chimeric antibody 122A2 and humanized antibodies derived from 122A2.

[0047] FIGS. 15A-15D: Maps of the expression vectors for the heavy or light chains of humanized antibodies 122A2H5 (FIG. 15A), 122A2H7 (FIG. 15B), 122A2H9 (FIG. 15C) and 122A2H10 (FIG. 15D), for production in YB2/0 cells.

[0048] FIG. 16: Release of IL-2 by CD16 Jurkat cells activated by chimeric antibody 122A2, by humanized antibody 122A2H9, or by an irrelevant antibody.

DETAILED DESCRIPTION OF THE INVENTION

[0049] Antibody, Functional Fragment or Derivative

[0050] The present invention relates to a monoclonal antibody directed against the ectodomain of the human CD303 antigen (SEQ ID NO: 130), or a functional fragment or a derivative thereof, characterized in that:

[0051] a) it competes for binding to the human CD303 antigen with at least one antibody selected from:

[0052] i) An antibody which heavy chain variable region comprises SEQ ID NO: 43 and which light chain variable region comprises SEQ ID NO: 48;

[0053] ii) An antibody which heavy chain variable region comprises SEQ ID NO: 44 and which light chain variable region comprises SEQ ID NO: 49;

[0054] iii) An antibody which heavy chain variable region comprises SEQ ID NO: 45 and which light chain variable region comprises SEQ ID NO: 50;

[0055] iv) An antibody which heavy chain variable region comprises SEQ ID NO: 46 and which light chain variable region comprises SEQ ID NO: 51;

[0056] v) An antibody which heavy chain variable region comprises SEQ ID NO: 47 and which light chain variable region comprises SEQ ID NO: 52; and

[0057] b) the light and heavy chain constant regions are constant regions from a non-murine species.

[0058] Advantageously, the heavy chains comprise three CDR-H (heavy-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences, and the light chains comprise three CDR-L (light-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences:

[0059] i) CDR1-H-family 1: SEQ ID NO: 1, CDR2-H-family 1: SEQ ID NO: 2, CDR3-H-family 1: SEQ ID NO: 3, CDR1-L-family 1: SEQ ID NO: 4, CDR2-L-family 1: SEQ ID NO: 5, CDR3-L-family 1: SEQ ID NO: 6; or

[0060] ii) CDR1-H-family 2: SEQ ID NO: 7, CDR2-H-family 2: SEQ ID NO: 8, CDR3-H-family 2: SEQ ID NO: 9, CDR1-L-family 2: SEQ ID NO: 10, CDR2-L-family 2: SEQ ID NO: 11, CDR3-L-family 2: SEQ ID NO: 12.

[0061] Table 1 below summarizes the amino acid sequences of the CDR-IMGT of the two families of antibodies according to the invention:

TABLE-US-00001 TABLE 1 CDR amino acid sequences of the two families of antibodies according to the invention according to IMGT nomenclature. In each sequence, X may represent any amino acid. Family 1 Family 2 CDR1-H GYTFTDYS GYTFTDXS (SEQ ID NO: 1) (SEQ ID NO: 7) CDR2-H ISXYYGDX INTETGXP (SEQ ID NO: 2) (SEQ ID NO: 8) CDR3-H ARNXXXYXXXY XRNGYYVGYYAXDY (SEQ ID NO: 3) (SEQ ID NO: 9) CDR1-L QDIXNY SSVXY (SEQ ID NO: 4) (SEQ ID NO: 10) CDR2-L YTS STS (SEQ ID NO: 5) (SEQ ID NO: 11) CDR3-L QQGXTLPWT QQRRSYPXT (SEQ ID NO: 6) (SEQ ID NO: 12)

[0062] Advantageously, the heavy chains of an antibody, functional fragment or derivative thereof according to the invention comprise three CDR-H (heavy-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences, and the light chains comprise three CDR-L (light-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences:

[0063] i) CDR1-H-122A2: SEQ ID NO: 13, CDR2-H-122A2: SEQ ID NO: 14, CDR3-H-122A2: SEQ ID NO: 15, CDR1-L-122A2: SEQ ID NO: 16, CDR2-L-122A2: SEQ ID NO: 17, CDR3-L-122A2: SEQ ID NO: 18;

[0064] ii) CDR1-H-102E9: SEQ ID NO: 19, CDR2-H-102E9: SEQ ID NO: 20, CDR3-H-102E9: SEQ ID NO: 21, CDR1-L-102E9: SEQ ID NO: 22, CDR2-L-102E9: SEQ ID NO: 23, CDR3-L-102E9: SEQ ID NO: 24;

[0065] iii) CDR1-H-104C12: SEQ ID NO: 25, CDR2-H-104C12: SEQ ID NO: 26, CDR3-H-104C12: SEQ ID NO: 27, CDR1-L-104C12: SEQ ID NO: 28, CDR2-L-104C12: SEQ ID NO: 29, CDR3-L-104C12: SEQ ID NO: 30;

[0066] iv) CDR1-H-114D11: SEQ ID NO: 31, CDR2-H-114D11: SEQ ID NO: 32, CDR3-H-114D11: SEQ ID NO: 33, CDR1-L-114D11: SEQ ID NO: 34, CDR2-L-114D11: SEQ ID NO: 35, CDR3-L-114D11: SEQ ID NO: 36; or

[0067] v) CDR1-H-104E10: SEQ ID NO: 37, CDR2-H-104E10: SEQ ID NO: 38, CDR3-H-104E10: SEQ ID NO: 39, CDR1-L-104E10: SEQ ID NO: 40, CDR2-L-104E10: SEQ ID NO: 41, CDR3-L-104E10: SEQ ID NO: 42.

[0068] Advantageously, the heavy chains of an antibody, functional fragment or derivative thereof according to the invention comprise a variable region having a sequence selected from SEQ ID NOs: 43 to 47 or a sequence having at least 80% identity with one of SEQ ID NOs: 43 to 47.

[0069] Additionally or alternatively, the light chains of an antibody, functional fragment or derivative thereof according to the invention comprise a variable region having a sequence selected from SEQ ID NOs: 48 to 52 or a sequence having at least 80% identity with one of SEQ ID NOs: 48 to 52.

[0070] In a preferred embodiment, the antibody, functional fragment or derivative thereof according to the invention has heavy and light chains which variable regions have the following amino acid sequences or sequences having at least 80% identity with the following sequences:

[0071] i) Antibody 122A2: heavy chain: SEQ ID NO: 43, light chain: SEQ ID NO: 48,

[0072] ii) Antibody 102E9: heavy chain: SEQ ID NO: 44, light chain: SEQ ID NO: 49,

[0073] iii) Antibody 104C12: heavy chain: SEQ ID NO: 45, light chain: SEQ ID NO: 50,

[0074] iv) Antibody 114D11: heavy chain: SEQ ID NO: 46, light chain: SEQ ID NO: 51, or

[0075] v) Antibody 104E10: heavy chain: SEQ ID NO: 47, light chain: SEQ ID NO: 52.

[0076] Table 2 below summarizes the murine VH, JH and VL and JL gene segments used by the various antibodies according to the invention and the percent identity.

TABLE-US-00002 TABLE 2 Murine VH, JH and VL and JL segments used by the various antibodies according to the invention, as defined by IMGT. Antibody VH JH VL JL 122A2 IGHV1S137*01 IGHJ2*02 IGKV10-96*01 IGKJ1*01 (94.9%) (85%) (98.9%) (100%) 102E9 IGHV9-2-1*01 IGHJ4*01 IGKV4-57*01 IGKJ1*02 (93.9%) (100%) (95.7%) (100%) 104C12 IGHV1S137*01 IGHJ3*01 IGKV10-96*02 IGKJ1*02 (91.8%) (100%) (89.5%) (100%) 114D11 IGHV9-2-1*01 IGHJ4*01 IGKV4-57*01 IGKJ1*02 (94.9%) (94.1%) (97.9%) (100%) 104E10 IGHV9-2-1*01 IGHJ4*01 IGKV4-57*01 IGKJ1*02 (98%) (100%) (96.8%) (100%)

[0077] Table 3 below summarizes the amino acid sequences of the CDRs and the variable regions of the heavy and light chains of the anti-CD303 antibodies generated by the inventors:

TABLE-US-00003 TABLE 3 Amino acid sequences of the heavy- and light- chain CDR1, CDR2, and CDR3 according to IMGT nomenclature, and of the VH and VL fragments of the antibodies according to the invention. Antibody 122A2 Heavy chain CDR1-H- GYTFTDYS (SEQ ID NO: 13) IMGT-122A2 CDR2-H- ISTYYGDS (SEQ ID NO: 14) IMGT-122A2 CDR3-H- ARNGNFYVMDY (SEQ ID NO: 15) IMGT-122A2 VH-122A2 QVQLQQSGAELVRPGVSVKISCKGSGYTFT DYSMHWVKQSHAKSLEWIGVISTYYGDSNY NQKFKGKATMTVDKSSTTAYMELARLTSED SAIYYCARNGNFYVMDYWGQGTSVTVSS (SEQ ID NO: 43) Light chain CDR1-L- QDISNY (SEQ ID NO: 16) IMGT-122A2 CDR2-L- YTS (SEQ ID NO: 17) IMGT-122A2 CDR3-L- QQGNTLPWT (SEQ ID NO: 18) IMGT-122A2 VL-122A2 DIQMTQTTSSLSASLGDRVTISCRASQDIS NYLNWYQQKPDGTVKLLIYYTSRLHSGVPS RFSGSGSGTDYSLTISNLDQEDIATYFCQQ GNTLPWTFGGGTKLEIK (SEQ ID NO: 48) Antibody 102E9 Heavy chain CDR1-H- GYTFTDYS (SEQ ID NO: 19) IMGT-102E9 CDR2-H- INTETGEP (SEQ ID NO: 20) IMGT-102E9 CDR3-H- TRNGYYVGYYAMDY (SEQ ID NO: 21) IMGT-102E9 VH-102E9 QIHLVQSGPDLKKPGETVKISCKASGYTFT DYSMHWVKQAPGKGLKWMGWINTETGEPTY ADDFKGRFAFSLESSASTAFLQINNLKNED TSTYFCTRNGYYVGYYAMDYWGQGTSVTVS S (SEQ ID NO: 44) Light chain CDR1-L- SSVIY (SEQ ID NO: 22) IMGT-102E9 CDR2-L- STS (SEQ ID NO: 23) IMGT-102E9 CDR3-L- QQRRSYPFT (SEQ ID NO: 24) IMGT-102E9 VL-102E9 QIVLTQSPAIMSASPGEKVTITCSASSSVI YIHWFQQKPGTSPKLWIYSTSYLASGVPAR FSGSGSGTSYSLTISRMEAEDAATYYCQQR RSYPFTFGGGTKLEIK (SEQ ID NO: 49) Antibody 104C12 Heavy chain CDR1-H-IMGT- GYTFTDYS (SEQ ID NO: 25) 104C12 CDR2-H-IMGT- ISPYYGDT (SEQ ID NO: 26) 104C12 CDR3-H-IMGT- ARNDDYYRFAY (SEQ ID NO: 27) 104C12 VH-104C12 QVQLQQSGAELVGPGVSVKISCKGSGYTFT DYSMHWVKQSHAKSLEWIGVISPYYGDTNY NQKFKGKATMTVDKSSSTAYMELASLTSED SAIYFCARNDDYYRFAYWGQGTLVTVSA (SEQ ID NO: 45) Light chain CDR1-L-IMGT- QDINNY (SEQ ID NO: 28) 104C12 CDR2-L-IMGT- YTS (SEQ ID NO: 29) 104C12 CDR3-L-IMGT- QQGKTLPWT (SEQ ID NO: 30) 104C12 VL-104C12 DLQMTQTPSSLSASLGDRVTISCRASQDIN NYLSWYQEKPDGTFKLLIYYTSRLHSGVPS RFSGSGSGTDYSLTVRNLEQEDIGTYFCQQ GKTLPWTFGGGTKLEIR (SEQ ID NO: 50) Antibody 114D11 Heavy chain CDR1-H-IMGT- GYTFTDSS (SEQ ID NO: 31) 114D11 CDR2-H-IMGT- INTETGGP (SEQ ID NO: 32) 114D11 CDR3-H-IMGT- ARNGYYVGYYALDY (SEQ ID NO: 33) 114D11 VH-114D11 QIQLVQSGPELKKPGETVKISCKASGYTFT DSSMHWVQQAPNKGLKWMGWINTETGGPTY ADDFKGRFAFSLETSARTAYLQINNLKNED TATYFCARNGYYVGYYALDYWGQGTSVTVS S (SEQ ID NO: 46) Light chain CDR1-L-IMGT- SSVFY (SEQ ID NO: 34) 114D11 CDR2-L-IMGT- STS (SEQ ID NO: 35) 114D11 CDR3-L-IMGT- QQRRSYPYT (SEQ ID NO: 36) 114D11 VL-114D11 QIVLTQSPAIMSASPGEKVTITCSASSSVF YMHWFQQKPGTSPKLWIYSTSNLASGVPAR FSGSGSGTSYSLTISRMEAEDAATYYCQQR RSYPYTFGGGTKLEIK (SEQ ID NO: 51) Antibody 104E10 Heavy chain CDR1-H- GYTFTDYS (SEQ ID NO: 37) IMGT-104E10 CDR2-H- INTETGEP (SEQ ID NO: 38) IMGT-104E10 CDR3-H- ARNGYYVGYYAMDY (SEQ ID NO: 39) IMGT-104E10 VH-104E10 QIQLVQSGPELKKPGETVKISCKASGYTFT DYSMHWVKQAPGKGLKWMGWINTETGEPTY ADDFKGRFAFSLETSATTAYLQINNFKNED TATYFCARNGYYVGYYAMDYWGQGTSVTVS S (SEQ ID NO: 47) Light chain CDR1-L- SSVIY (SEQ ID NO: 40) IMGT-104E10 CDR2-L- STS (SEQ ID NO: 41) IMGT-104E10 CDR3-L- QQRRSYPYT (SEQ ID NO: 42) IMGT-104E10 VL-104E10 QIVLTQSPAIMSASPGEKVTMTCSASSSVI YMHWFQQKPGTSPKLWIYSTSNLASGVPAR FSGSGSGTSYSLTISRMEAEDAATYYCQQR RSYPYTFGGGTKLEIK (SEQ ID NO: 52)

[0078] The human CD303 antigen is C-type lectin domain family 4, member C (CLEC4), also called DLEC; HECL; BDCA2; CLECSF7; CLECSF11; or PRO34150 (see the Entrez Gene website for the CLEC4 gene). It is a type II transmembrane glycoprotein of 213 amino acids, comprising a short cytoplasmic domain with no evident signaling motif (amino acids 1-21), a transmembrane region (amino acids 22-41), a neck domain (amino acids 42-82), and a carbohydrate recognition domain (CRD; amino acids 83-213) (Dzionek et al.-2001). The mRNA sequence encoding this protein may be found in the 14 Feb. 2002 version of the GenBank database under accession number AF293615.1 (SEQ ID NO: 129), while the amino acid sequence is accessible in the 14 Feb. 2002 version of the GenBank database under accession number AAL37036.1 (SEQ ID NO: 130).

[0079] By "antibody" or "immunoglobulin" is meant a molecule comprising at least one binding domain for a given antigen and a constant domain comprising an Fc fragment capable of binding to Fc receptors (FcR). In most mammals, like humans and mice, an antibody consists of four polypeptide chains: two heavy chains and two light chains bound together by a variable number of disulfide bridges providing flexibility to the molecule. Each light chain consists of a constant domain (CL) and a variable domain (VL); the heavy chains consisting of a variable domain (VH) and three or four constant domains (CH1 to CH3 or CH1 to CH4) according to the isotype of the antibody. In a few rare mammals, such as camels and llamas, the antibodies consist of only two heavy chains, each heavy chain comprising a variable domain (VH) and a constant region.

[0080] The variable domains are involved in antigen recognition, while the constant domains are involved in the biological, pharmacokinetic and effector properties of the antibody.

[0081] The variable region differs from one antibody to another. Indeed, the genes encoding antibody heavy and light chains are respectively generated by recombination of three and two distinct gene segments called VH, DH and JH-CH for the heavy chain and VL and JL-CL for the light chain. The CH and CL segments do not participate in recombination and form the constant regions of the heavy and light chains, respectively. Recombinations of the VH-DH-JH and VL-JL segments form the variable regions of the heavy and light chains, respectively. The VH and VL regions each have three hypervariable zones or complementarity-determining regions (CDRs) called CDR1, CDR2 and CDR3, with CDR3 being the most variable since it is located in the recombination zone. These three CDRs, and particularly CDR3, are found in the portion of the antibody that will be in contact with the antigen and are thus very important for antigen recognition. Thus, antibodies retaining the three CDRs and each of the heavy and light chains of an antibody mostly retain the antigen specificity of the original antibody. In a certain number of cases, an antibody retaining only one of the CDRs, and notably CDR3, also retains the specificity of the original antibody. CDR1, CDR2 and CDR3 are each preceded by FR1, FR2 and FR3, respectively, corresponding to framework regions (FRs) that vary the least from one VH or VL segment to another. CDR3 is also followed by a framework region, FR4.

[0082] An antibody's CDRs are defined by the amino acid sequence of its heavy and light chains compared to criteria known to a person skilled in the art. Various methods for determining CDRs have been proposed, and the portion of the amino acid sequence of a heavy or light chain variable region of an antibody defined as a CDR varies according to the method chosen. The first determination method is that proposed by Kabat et al. (1991). In this method, CDRs are defined by looking for the amino acids responsible for antibody-antigen binding. A second method was proposed by the IMGT, based on determining hypervariable regions. In this method, a unique numbering has been defined to compare variable regions regardless of the antigen receptor, chain type or species (Lefranc et al. 2003). This numbering provides a standardized definition of framework regions ((FR1-IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and complementarity-determining regions (CDR1-IMGT: positions 27 to 38, CDR2-IMGT: positions 56 to 65 and CDR3-IMGT: positions 105 to 117). Finally, there is also a numbering called "common" in which the sequence of a particular CDR corresponds to the common sequence between the Kabat numbering and the IMGT numbering. Throughout the present description, the CDR sequences are indicated by the IMGT numbering. In particular, the CDRs have been determined by using the IMGT/V-QUEST program available at http://www.imgt.org/IMGT_vquest/share/textes/ and described in Brochet et al.-2008. Unlike the variable domains, whose sequence strongly varies from one antibody to another, the constant domains are characterized by an amino acid sequence that is very similar from one antibody to another, typical of the species and the isotype, with optionally a few somatic mutations. The Fc fragment naturally consists of the heavy chain constant region excluding the CH1 domain, i.e., the lower hinge region and the constant domains CH2 and CH3 or CH2 to CH4 (depending on the isotype). In human IgG1, the complete Fc fragment consists of the C-terminal portion of the heavy chain starting from the cysteine residue at position 226 (C226), the numbering of amino acid residues in the Fc fragment being throughout the present description that of the EU index described in Edelman et al.-1969 and Kabat et al.-1991. The corresponding Fc fragments of other types of immunoglobulins may easily be identified by a person skilled in the art by sequence alignments.

[0083] The Fc fragment is glycosylated in the CH2 domain with the presence, on each of the two heavy chains, of an N-glycan bound to the asparagine residue at position 297 (Asn297). The following binding domains, located in the Fc, are important for the biological properties of the antibody:

[0084] the neonatal Fc receptor (FcRn) binding domain, involved in the pharmacokinetic properties (in vivo half-life) of the antibody: Different data suggest that certain residues located at the interface of the CH2 and CH3 domains are involved in FcRn binding.

[0085] the complement C1q protein binding domain, involved in the complement-dependent cytotoxicity (CDC) response: located in the CH2 domain;

[0086] the Fc receptor (FcR) binding domain, involved in responses of the phagocytosis or antibody-dependent cell cytotoxicity (ADCC) type: located in the CH2 domain.

[0087] In the context of the invention, the Fc fragment of an antibody may be natural, as defined above, or else may be modified in various ways, provided that it comprises a functional FcR (Fc.gamma.R for IgGs) binding domain, and preferably a functional FcRn binding domain. The modifications may include deletion of certain portions of the Fc fragment, provided that the latter contains a functional FcR (Fc.gamma.R for IgGs) binding domain, and preferably a functional FcRn binding domain. The modifications may further include various amino acid substitutions able to affect the biological properties of the antibody, provided that the latter contains a functional FcR binding domain, and preferably a functional FcRn binding domain. In particular, when the antibody is an IgG, it may comprise mutations intended to increase Fc.gamma.RIIIa (CD16a)-binding, as described in WO00/42072, Shields et al.-2001, Lazar et al.-2006, WO2004/029207, WO2004/063351, WO2004/074455.

[0088] Mutations for increasing FcRn binding and thus in vivo half-life may also be present, as described for example in Shields et al.-2001, Dall'Acqua et al.-2002, Hinton et al.-2004, Dall'Acqua et al.-2006(a), WO00/42072, WO02/060919, WO2010/045193, or WO2010/106180. Other mutations, such as those for decreasing or increasing binding to complement proteins and thus the CDC response, may optionally be present (see WO99/51642, WO2004/074455, Idusogie et al.-2001, Dall'Acqua et al.-2006(b), and Moore et al.-2010).

[0089] In the context of the present invention, the preferred mutants comprising mutations for increasing FcRn binding and thus in vivo half-life are mutants comprising the following combinations of mutations in their Fc fragment, described in WO2010/106180:

[0090] N315D/A330V/N361D/A378V/N434Y,

[0091] P230S/N315D/M428L/N434Y,

[0092] E294del/T307P/N434Y,

[0093] T307A/N315D/A330V/E382V/N389T/N434Y,

[0094] V259I/N315D/N434Y, or

[0095] T256N/A378V/S383N/N434Y, where the numbering of the amino acids in the Fc fragment is that of the EU index described in Kabat et al., Sequences of Proteins of Immunological Interest, 5.sup.th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), which is incorporated herein by reference. "EU index" or "EU index of Kabat" refers to the numbering of the amino acids of human IgG1 antibody.

[0096] Alternatively, just as fragments or derivatives without the Fc fragment of the antibody may be useful in the context of the invention, notably for the treatment of inflammatory, notably autoimmune, diseases involving pDCs, the antibody according to the invention may also have a mutated Fc fragment free of effector functions. Examples of mutations leading to a mutated Fc fragment free of effector functions are the single amino acid deletions at position 293 (Del293) or 294 (Del294) of the Fc fragment, where the numbering of the amino acids in the Fc fragment is that of the EU index of Kabat (WO2012/175751).

[0097] By "monoclonal antibody" or "monoclonal antibody composition" is meant a composition comprising antibody molecules having an identical and unique antigen specificity. The antibody molecules present in the composition are likely to vary in terms of their post-translational modifications, and notably in terms of their glycosylation structures or their isoelectric point, but have all been encoded by the same heavy and light chain sequences and thus have, before any post-translational modification, the same protein sequence. Certain differences in protein sequences, related to post-translational modifications (such as for example cleavage of the heavy chain C-terminal lysine, deamidation of asparagine residues and/or isomerization of aspartate residues), may nevertheless exist between the various antibody molecules present in the composition.

[0098] The percent identities referred to in the context of the disclosure of the present invention are determined on the basis of a global alignment of sequences to be compared, i.e., on an alignment of the sequences taken in their entirety over their entire length using any algorithm well-known to a person skilled in the art, such as the algorithm of Needleman and Wunsch (1970). This sequence comparison may be performed using any software well-known to a person skilled in the art, for example the Needle software by using the "Gap open" parameter equal to 10.0, the "Gap extend" parameter equal to 0.5 and a "Blosum 62" matrix. The Needle software is for example available on the website ebi.ac.uk under the name "Align".

[0099] When the CDR or variable region of an antibody according to the invention has an amino acid sequence that is not 100% identical to one of those described above and in the sequence listing (reference sequences) but that has at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity with one such reference sequence, it may have insertions, deletions or substitutions with regard to the reference sequence. When it is a matter of substitutions, the substitution is preferably made with an "equivalent" amino acid, i.e., any amino acid whose structure is similar to that of the original amino acid and therefore unlikely to change the biological activity of the antibody. Examples of such substitutions are presented in Table 4 below:

TABLE-US-00004 TABLE 4 Substitutions with equivalent amino acids Original amino acid Substitution (s) Ala (A) Val, Gly, Pro Arg (R) Lys, His Asn (N) Gln Asp (D) Glu Cys (C) Ser Gln (Q) Asn Glu (G) Asp Gly (G) Ala His (H) Arg Ile (I) Leu Leu (L) Ile, Val, Met Lys (K) Arg Met (M) Leu Phe (F) Tyr Pro (P) Ala Ser (S) Thr, Cys Thr (T) Ser Trp (W) Tyr Tyr (Y) Phe, Trp Val (V) Leu, Ala

[0100] The antibodies may be of several isotypes, according to the nature of their constant region: the .gamma., .alpha., .mu., .epsilon. and .delta. constant regions correspond to immunoglobulins IgG, IgA, IgM, IgE and IgD, respectively. Advantageously, the monoclonal antibody present in a composition used as a medicinal product in the context of the invention is of isotype IgG. Indeed, this isotype shows a capacity to generate antibody-dependent cell cytotoxicity (ADCC) activity in the greatest number of individuals (humans). The .gamma. constant regions comprise several subtypes: .gamma.1, .gamma.2, .gamma.3, these three types of constant regions having the feature of binding human complement, and .gamma.4, thus creating the subtypes IgG1, IgG2, IgG3, and IgG4. Advantageously, the monoclonal antibody present in a composition used as a medicinal product in the context of the invention is of isotype IgG1 or IgG3, preferably IgG1.

[0101] The antibody, functional fragment or derivative thereof according to the invention is advantageously a chimeric or humanized antibody, in particular a chimeric antibody whose heavy and light chain constant region is of human origin.

[0102] By "chimeric" antibody is meant an antibody that contains a natural variable region (light chain and heavy chain) derived from an antibody of a given species in combination with the light and heavy chain constant regions of an antibody of a species heterologous to said given species. Advantageously, if the monoclonal antibody composition for use as a medicinal product according to the invention comprises a chimeric monoclonal antibody, the latter comprises human constant regions. From a non-human antibody, a chimeric antibody can be prepared by using the genetic recombination techniques well-known to a person skilled in the art. For example, the chimeric antibody can be prepared by cloning the heavy and light chains of a recombinant DNA comprising a promoter and a sequence encoding the variable region of the non-human antibody, and a sequence encoding the constant region of a human antibody. For methods for preparing chimeric antibodies, reference may be made, for example, to the document by Verhoeyen et al.-1988.

[0103] By "humanized" antibody is meant an antibody that contains CDRs derived from an antibody of non-human origin, the other portions of the antibody molecule being derived from one (or from several) human antibodies. Moreover, certain residues of the framework regions (FR) may be modified to retain binding affinity (Jones et al.-1986; Verhoeyen et al. 1988; Riechmann et al.-1988). The humanized antibodies according to the invention can be prepared by techniques known to a person skilled in the art such as CDR grafting, resurfacing, superhumanization, human string content, FR libraries, guided selection, FR shuffling and humaneering technologies, as summarized in the review by Almagro et al.-2008.

[0104] In addition to the five chimeric antibodies comprising the CDR or variable region sequences described above, the inventors also generated humanized antibodies derived from two of the five anti-CD303 antibodies obtained initially. To that end, for each of the two antibodies, several mutated heavy chain variable region sequences (mutations directed at making the sequence more similar to a human sequence) and several mutated light chain variable region sequences were generated and combined with each other in pairs to try to obtain humanized antibodies having the strongest possible capacity to bind to the human CD303 antigen (SEQ ID NO: 130) (advantageously at least 70% of the binding capacity of the murine or chimeric antibody, more advantageously similar to the binding capacity of the murine or chimeric antibody, even more advantageously higher than the binding capacity of the murine or chimeric antibody).

[0105] For antibody 122A2, the amino acid sequences of the heavy and light chain variable regions (humanized, i.e., mutated) that were tested are presented in Table 5 below:

TABLE-US-00005 TABLE 5 Amino acid sequences of the heavy and light chain variable regions (humanized, i.e., mutated) that were tested for the humanization of antibody 122A2. 122A2 - Mutations relative to humanized the chimeric VH heavy chain VH sequence Sequence 122A2-VHha L12V/R14K/V17A/S45A/ QVQLQQSGAEVVKPGASVKISCKGSGYTFTDYSM A76V/T85S/A92S/E97D/ HWVKQAHAKSLEWIGVISTYYGDSNYNQKFKGKV S99T/1101V/S123L TMTVDKSSSTAYMELSRLTSDDTAVYYCARNGNFY VMDYWGQGTLVTVSS (SEQ ID NO: 131) 122A2-VHhb L12V/R14K/V17A/K43R/ QVQLQQSGAEVVKPGASVKISCKGSGYTFTDYSM S45A/A76V/K82T/ HWVRQAHAKSLEWIGVISTYYGDSNYNQKFKGKV T85S/A92S/T95R/E97D/ TMTVDTSSSTAYMELSRLRSDDTAVYYCARNGNFY S99T/I101V/S123L VMDYWGQGTLVTVSS (SEQ ID NO: 132) 122A2-VHhc L12V/R14K/V17A/K43R/ QVQLQQSGAEVVKPGASVKISCKGSGYTFTDYSM S45A/H46P/A47G/K48Q/ HWVRQAPGQGLEWIGVISTYYGDSNYNQKFKGKV S49G/A76V/T85S/A92S/ TMTVDKSSSTAYMELSRLTSDDTAVYYCARNGNFY E97D/S99T/I101V/S123L VMDYWGQGTLVTVSS (SEQ ID NO: 133) 122A2 - Mutations relative to humanized the chimeric VL light chain VL sequence Sequence 122A2-VKha T7S/S22T/R24Q/S69T/ DIQMTQSTSSLSASLGDRVTITCQASQDISNYLNWY F103Y QQKPDGTVKLLIYYTSRLHTGVPSRFSGSGSGTDY SLTISNLDQEDIATYYCQQGNTLPWTFGGGTKLEI K (SEQ ID NO: 134) 122A2-VKhb T7S/T8P/L15V/S22T/ DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWY R24Q/S69T/F103Y QQKPDGTVKLLIYYTSRLHTGVPSRFSGSGSGTDY SLTISNLDQEDIATYYCQQGNTLPWTFGGGTKLEI K (SEQ ID NO: 135) 122A2-VKhc T7S/S22T/R24Q/R66N/ DIQMTQSTSSLSASLGDRVTITCQASQDISNYLNWY S69T/D95Q/F103Y QQKPDGTVKLLIYYTSNLHTGVPSRFSGSGSGTDY SLTISNLQQEDIATYYCQQGNTLPWTFGGGTKLEI K (SEQ ID NO: 136) 122A2-VKhd T7S/T8P/L15V/S22T/ DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWY R24Q/R66N/S69T/D95Q/ QQKPDGTVKLLIYYTSNLHTGVPSRFSGSGSGTDY F103Y SLTISNLQQEDIATYYCQQGNTLPWTFGGGTKLEI K (SEQ ID NO: 137)

[0106] Humanized antibodies 122A2 are thus advantageously selected from those whose heavy chains comprise a variable region having an amino acid sequence selected from SEQ ID NOs: 131 to 133, advantageously from those whose heavy chains comprise a variable region having an amino acid sequence selected from SEQ ID NO: 131 and 132.

[0107] Humanized antibodies 122A2 are also advantageously selected from those whose light chains comprise a variable region having an amino acid sequence selected from SEQ ID NOs: 134 to 137, advantageously from those whose light chains comprise a variable region having an amino acid sequence selected from SEQ ID NO: 134 and 135.

[0108] The various humanized antibodies 122A2 generated by the inventors have heavy and light chains comprising variable regions having the amino acid sequences described in Table 6 below. The preferred humanized antibodies 122A2 (because they exhibit antigen-binding equal to or higher than that of the original chimeric antibody) are those whose heavy and light chains comprise variable regions having the amino acid sequences comprising those described for antibodies 122A2H5, 122A2H9, 122A2H6, 122A2H10, 122A2H14, 122A2H7, 122A2H11 and 122A2H15 in Table 6 below (shown in bold in Table 6 below). The most-preferred humanized antibodies 122A2 are those exhibiting higher antigen-binding than that of the original chimeric antibody: 122A2H5, 122A2H9, 122A2H6, 122A2H10, 122A2H14, 122A2H7, and in particular 122A2H5, 122A2H9, 122A2H7, and 122A2H10.

TABLE-US-00006 TABLE 6 Amino acid sequences comprised in the VH and VL domains of the humanized antibodies derived from chimeric antibody 122A2. The sequences corresponding to the preferred antibodies (because they exhibit antigen-binding equal to or higher than that of the original chimeric antibody in ELISA) are shown in bold. Humanized antibody Amino acid sequence Amino acid sequence derived comprised in the VH comprised in the VL (VK) from 122A2 domain domain 122A2H5 122A2-VHha 122A2-VKha (SEQ ID NO: 131) (SEQ ID NO: 134) 122A2H9 122A2-VHha 122A2-VKhb (SEQ ID NO: 131) (SEQ ID NO: 135) 122A2H13 122A2-VHha 122A2-VKhc (SEQ ID NO: 131) (SEQ ID NO: 136) 122A2H17 122A2-VHha 122A2-VKhd (SEQ ID NO: 131) (SEQ ID NO: 137) 122A2H6 122A2-VHhb 122A2-VKha (SEQ ID NO: 132) (SEQ ID NO: 134) 122A2H10 122A2-VHhb 122A2-VKhb (SEQ ID NO: 132) (SEQ ID NO: 135) 122A2H14 122A2-VHhb 122A2-VKhc (SEQ ID NO: 132) (SEQ ID NO: 136) 122A2H18 122A2-VHhb 122A2-VKhd (SEQ ID NO: 132) (SEQ ID NO: 137) 122A2H7 122A2-VHhc 122A2-VKha (SEQ ID NO: 133) (SEQ ID NO: 134) 122A2H11 122A2-VHhc 122A2-VKhb (SEQ ID NO: 133) (SEQ ID NO: 135) 122A2H15 122A2-VHhc 122A2-VKhc (SEQ ID NO: 133) (SEQ ID NO: 136) 122A2H19 122A2-VHhc 122A2-VKhd (SEQ ID NO: 133) (SEQ ID NO: 137)

[0109] For antibody 102E9, the amino acid sequences of the heavy and light chain variable regions (humanized, i.e., mutated) that were tested are presented in Table 7 below:

TABLE-US-00007 TABLE 7 Amino acid sequences of the heavy and light chain variable regions (humanized, i.e., mutated) that were tested for the humanization of antibody 102E9. Sequence 102E9- Mutations humanized relative to heavy the chimeric chain VH VH sequence* 102E9- D11E/T18S/K48Q/ QIHLVQSGPELKKPGE VHha A77V/E81D/S82T/ SVKISCKASGYTFTDY A84V/F88Y/N93S/ SMHWVKQAPGQGLKWM F103Y GWINTETGEPTYADDF KGRFVFSLDTSVSTAY LQINSLKNEDTSTYYC TRNGYYVGYYAMDYWG QGTSVTVSS (SEQ ID NO: 138) 102E9- D11E/T18S/K43R/ QIHLVQSGPELKKPGE VHhb K48Q/D69Q/A77V/ SVKISCKASGYTFTDY E81D/S82T/A84V/ SMHWVRQAPGQGLKWM F88Y/N93s/F103Y GWINTETGEPTYAQDF KGRFVFSLDTSVSTAY LQINSLKNEDTSTYYC TRNGYYVGYYAMDYWG QGTSVTVSS (SEQ ID NO: 139) 102E9- P9S/D11E/T18S/ QIHLVQSGSELKKPGE VHhc K43R/K48Q/D69Q/ SVKISCKASGYTFTDY A77V/E81D/S82T/ SMHWVRQAPGQGLKWM A84V/F88Y/N93S/ GWINTETGEPTYAQDF F103Y KGRFVFSLDTSVSTAY LQINSLKNEDTSTYYC TRNGYYVGYYAMDYWG QGTSVTVSS (SEQ ID NO: 140) 102E9- Mutations humanized relative to light the chimeric chain VL VL sequence 102E9- V3Q/A9S/i10F/ QIQLTQSPSFLSASPG VKha M11L/K18R/T48K/ ERVTITCSASSSVIYI S49A/A74S/S86E/ HWFQQKPGKAPKLWIY S88T/R93S/A99F STSYLASGVPSRFSGS GSGTEYTLTISSMEAE DFATYYCQQRRSYPFT FGGGTKLEIK (SEQ ID NO: 141) 102E9- V3Q/A9S/I10F/ QIQLTQSPSFLSASPG VKhb M11L/K18R/S49A/ ERVTITCSASSSVIYI A74S/S88T/A99F HWFQQKPGTAPKLWIY STSYLASGVPSRFSGS GSGTSYTLTISRMEAE DFATYYCQQRRSYPFT FGGGTKLEIK (SEQ ID NO: 142) 102E9- V3Q/A9S/I10F/ QIQLTQSPSFLSASPG VKhc M11L/E17D/K18R/ DRVTITCSASSSVIYI T48K/S49A/A74S/ HWFQQKPGKAPKLWIY S86E/S88T/R93S/ STSYLASGVPSRFSGS E95Q/A99F GSGTEYTLTISSMQAE DFATYYCQQRRSYPFT FGGGTKLEIK (SEQ ID NO: 143) *The position of the amino acid residues corresponds to IMGT unique numbering.

[0110] Humanized antibodies 102E9 are thus advantageously selected from those whose heavy chains comprise a variable region having an amino acid sequence selected from SEQ ID NOs: 138 to 140, advantageously from those whose heavy chains comprise a variable region having the amino acid sequence SEQ ID NO: 139.

[0111] Humanized antibodies 102E9 are also advantageously selected from those whose light chains comprise a variable region having an amino acid sequence selected from SEQ ID NOs: 141 to 143, advantageously from those whose light chains comprise a variable region having the amino acid sequence SEQ ID NO: 142.

[0112] The various humanized antibodies 102E9 generated by the inventors have heavy and light chains comprising variable regions having the amino acid sequences described in Table 8 below. The preferred humanized antibodies 102E9 (because they exhibit binding on the level of the chimeric antibody similar to that of the original chimeric antibody: at least 70% of the binding of the chimeric antibody in ELISA) are those whose heavy and light chains comprise variable regions having the amino acid sequences comprising those described for antibodies 102E9H6, 102E9H7, 102E9H9, and 102E9H10 in Table 8 below (shown in bold in Table 8 below), more advantageously those whose heavy and light chains comprise variable regions having the amino acid sequences comprising those described for antibody 102E9H10 in Table 8 below.

TABLE-US-00008 TABLE 8 Amino acid sequences comprised in the VH and VL domains of the humanized antibodies derived from chimeric antibody 102E9. The sequences corresponding to the preferred antibodies (because they exhibit binding on the level of the chimeric antibody similar to that of the original chimeric antibody: at least 70% of the binding of the chimeric antibody in ELISA) are shown in bold. Humanized antibody Amino acid sequence Amino acid sequence derived comprised in the VH comprised in the VL (VK) from 102E9 domain domain 102E9H5 102E9-VHha 102E9-VKha (SEQ ID NO: 138) (SEQ ID NO: 141) 102E9H9 102E9-VHha 102E9-VKhb (SEQ ID NO: 138) (SEQ ID NO: 142) 102E9H13 102E9-VHha 102E9-VKhc (SEQ ID NO: 138) (SEQ ID NO: 143) 102E9H6 102E9-VHhb 102E9-VKha (SEQ ID NO: 139) (SEQ ID NO: 141) 102E9H10 102E9-VHhb 102E9-VKhb (SEQ ID NO: 139) (SEQ ID NO: 142) 102E9H14 102E9-VHhb 102E9-VKhc (SEQ ID NO: 139) (SEQ ID NO: 143) 102E9H7 102E9-VHhc 102E9-VKha (SEQ ID NO: 140) (SEQ ID NO: 141) 102E9H11 102E9-VHhc 102E9-VKhb (SEQ ID NO: 140) (SEQ ID NO: 142) 102E9H15 102E9-VHhc 102E9-VKhc (SEQ ID NO: 140) (SEQ ID NO: 143)

[0113] An antibody, functional fragment or derivative thereof according to the invention, which is chimeric with human constant regions, or else humanized, will advantageously comprise a human heavy chain constant region having the amino acid sequence SEQ ID NO: 53 or SEQ ID NO: 144 (which corresponds to the human heavy chain constant region sequence SEQ ID NO: 53 with an additional C-terminal lysine residue). Additionally or alternatively, an antibody, functional fragment or derivative thereof according to the invention, which is chimeric with human, or else humanized, constant regions will advantageously comprise a human light chain constant region having the amino acid sequence SEQ ID NO: 54. Preferred human heavy chain (SEQ ID NO: 53 or SEQ ID NO: 144) or light chain (SEQ ID NO: 54) constant region sequences, of isotype IgG1, are presented in Table 9 below.

TABLE-US-00009 TABLE 9 Preferred human heavy chain (SEQ ID NO: 53 or SEQ ID NO: 144) or light chain (SEQ ID NO: 54) constant region sequences. Human heavy chain constant region SEQ ID NO: 144 corresponds to human heavy chain constant region SEQ ID NO: 53 with an additional C-terminal lysine residue. Preferred ASTKGPSVFPLAPSSKSTSGGTAALG human heavy CLVKDYFPEPVTVSWNSGALTSGVHT chain constant FPAVLQSSGLYSLSSVVTVPSSSLGT region (IgG1) QTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPG (SEQ ID NO: 53) Preferred ASTKGPSVFPLAPSSKSTSGGTAALG human heavy CLVKDYFPEPVTVSWNSGALTSGVHT chain constant FPAVLQSSGLYSLSSVVTVPSSSLGT region (IgG1) QTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK (SEQ ID NO: 144) Preferred RTVAAPSVFIFPPSDEQLKSGTASVV human light CLLNNFYPREAKVQWKVDNALQSGNS chain constant QESVTEQDSKDSTYSLSSTLTLSKAD region (IgG1) YEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO: 54)

[0114] Thus, the heavy and light chains of the chimeric or humanized antibodies, functional fragments or derivatives thereof according to the invention advantageously comprise the sequences described in Table 10 below (or consist essentially of or consist of such sequences).

TABLE-US-00010 TABLE 10 Heavy and light chain amino acid sequences of the chimeric or humanized antibodies according to the invention. Antibody Heavy chain Light chain Chimeric antibodies 122A2 Fusion SEQ ID NO: 43- Fusion SEQ ID NO: 48- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 55) (SEQ ID NO: 60) 102E9 Fusion SEQ ID NO: 44- Fusion SEQ ID NO: 49- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 56) (SEQ ID NO: 61) 104C12 Fusion SEQ ID NO: 45- Fusion SEQ ID NO: 50- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 57) (SEQ ID NO: 62) 114D11 Fusion SEQ ID NO: 46- Fusion SEQ ID NO: 51- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 58) (SEQ ID NO: 63) 104E10 Fusion SEQ ID NO: 47- Fusion SEQ ID NO: 52- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 59) (SEQ ID NO: 64) 122A2 Fusion SEQ ID NO: 43- Fusion SEQ ID NO: 48- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 145) (SEQ ID NO: 60) 102E9 Fusion SEQ ID NO: 44- Fusion SEQ ID NO: 49- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 146) (SEQ ID NO: 61) 104C12 Fusion SEQ ID NO: 45- Fusion SEQ ID NO: 50- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 147) (SEQ ID NO: 62) 114D11 Fusion SEQ ID NO: 46- Fusion SEQ ID NO: 51- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 148) (SEQ ID NO: 63) 104E10 Fusion SEQ ID NO: 47- Fusion SEQ ID NO: 52- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 149) (SEQ ID NO: 64) Humanized antibodies 122A2H5 Fusion SEQ ID NO: 131- Fusion SEQ ID NO: 134- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 150) (SEQ ID NO: 153) 122A2H9 Fusion SEQ ID NO: 135- SEQ ID NO: 54 (SEQ ID NO: 154) 122A2H13 Fusion SEQ ID NO: 136- SEQ ID NO: 54 (SEQ ID NO: 155) 122A2H17 Fusion SEQ ID NO: 137- SEQ ID NO: 54 (SEQ ID NO: 156) 122A2H6 Fusion SEQ ID NO: 132- Fusion SEQ ID NO: 134- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 151) (SEQ ID NO: 153) 122A2H10 Fusion SEQ ID NO: 135- SEQ ID NO: 54 (SEQ ID NO: 154) 122A2H14 Fusion SEQ ID NO: 136- SEQ ID NO: 54 (SEQ ID NO: 155) 122A2H18 Fusion SEQ ID NO: 137- SEQ ID NO: 54 (SEQ ID NO: 156) 122A2H7 Fusion SEQ ID NO: 133- Fusion SEQ ID NO: 134- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 152) (SEQ ID NO: 153) 122A2H11 Fusion SEQ ID NO: 135- SEQ ID NO: 54 (SEQ ID NO: 154) 122A2H15 Fusion SEQ ID NO: 136- SEQ ID NO: 54 (SEQ ID NO: 155) 122A2H19 Fusion SEQ ID NO: 137- SEQ ID NO: 54 (SEQ ID NO: 156) 102E9H5 Fusion SEQ ID NO: 138- Fusion SEQ ID NO: 141- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 157) (SEQ ID NO: 160) 102E9H9 Fusion SEQ ID NO: 142- SEQ ID NO: 54 (SEQ ID NO: 161) 102E9H13 Fusion SEQ ID NO: 143- SEQ ID NO: 54 (SEQ ID NO: 162) 102E9H6 Fusion SEQ ID NO: 139- Fusion SEQ ID NO: 141- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 158) (SEQ ID NO: 160) 102E9H10 Fusion SEQ ID NO: 142- SEQ ID NO: 54 (SEQ ID NO: 161) 102E9H14 Fusion SEQ ID NO: 143- SEQ ID NO: 54 (SEQ ID NO: 162) 102E9H7 Fusion SEQ ID NO: 140- Fusion SEQ ID NO: 141- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 159) (SEQ ID NO: 160) 102E9H11 Fusion SEQ ID NO: 142- SEQ ID NO: 54 (SEQ ID NO: 161) 102E9H15 Fusion SEQ ID NO: 143- SEQ ID NO: 54 (SEQ ID NO: 162)

[0115] The heavy and/or light chain of the antibody, functional fragment or derivative thereof according to the invention advantageously further comprises at least one heterologous signal peptide of sequence SEQ ID NO: 65 (MRWSWIFLLLLSITSANA, signal peptide MB7). Indeed, this peptide has been shown to improve the expression and secretion of recombinant proteins in higher eukaryotic cell lines (see WO2011/114063). Thus, the heavy chains of the antibodies, functional fragments or derivatives thereof according to the invention advantageously comprise an amino acid sequence selected from SEQ ID NOs: 66 to 70, consisting of the N- to C-terminal fusion of the amino acid sequence of signal peptide MB7 (SEQ ID NO: 65) to one of the amino acid sequences of the VH region of the antibodies according to the invention (SEQ ID NOs: 43 to 47), or consist essentially of or consist of such sequences. Additionally or alternatively, the light chains of the antibodies, functional fragments or derivatives thereof according to the invention advantageously comprise an amino acid sequence selected from SEQ ID NOs: 71 to 75, consisting of the N- to C-terminal fusion of the amino acid sequence of signal peptide MB7 (SEQ ID NO: 65) to one of the amino acid sequences of the VL region of the antibodies according to the invention (SEQ ID NOs: 48 to 52), or consist essentially of or consist of such sequences.

[0116] By adding the preferred heavy and light chain constant regions, the preferred complete amino acid sequences of the antibodies according to the invention are obtained, as described in Table 11 below. For the heavy chain, the constant region may further contain an additional C-terminal lysine residue. Thus, the heavy and light chains of the chimeric or humanized antibodies, functional fragments or derivatives thereof according to the invention advantageously comprise the sequences described in Table 11 below (or consist essentially of or consist of such sequences).

TABLE-US-00011 TABLE 11 Heavy and light chain amino acid sequences of the chimeric and humanized antibodies according to the invention, with signal peptide MB7. Antibody Heavy chain Light chain Chimeric antibodies 122A2 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 43- SEQ ID NO: 48- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 76) (SEQ ID NO: 81) 102E9 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 44- SEQ ID NO: 49- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 77) (SEQ ID NO: 82) 104C12 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 45- SEQ ID NO: 50- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 78) (SEQ ID NO: 83) 114D11 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 46- SEQ ID NO: 51- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 79) (SEQ ID NO: 84) 104E10 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 47- SEQ ID NO: 52- SEQ ID NO: 53 SEQ ID NO: 54 (SEQ ID NO: 80) (SEQ ID NO: 85) 122A2 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 43- SEQ ID NO: 48- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 163) (SEQ ID NO: 81) 102E9 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 44- SEQ ID NO: 49- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 164) (SEQ ID NO: 82) 104C12 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 45- SEQ ID NO: 50- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 165) (SEQ ID NO: 83) 114D11 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 46- SEQ ID NO: 51- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 166) (SEQ ID NO: 84) 104E10 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 47- SEQ ID NO: 52- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 167) (SEQ ID NO: 85) Humanized antibodies 122A2H5 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 131- SEQ ID NO: 134- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 168) (SEQ ID NO: 171) 122A2H9 Fusion SEQ ID NO: 65- SEQ ID NO: 135- SEQ ID NO: 54 (SEQ ID NO: 172) 122A2H13 Fusion SEQ ID NO: 65- SEQ ID NO: 136- SEQ ID NO: 54 (SEQ ID NO: 173) 122A2H17 Fusion SEQ ID NO: 65- SEQ ID NO: 137- SEQ ID NO: 54 (SEQ ID NO: 174) 122A2H6 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 132- SEQ ID NO: 134- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 169) (SEQ ID NO: 171) 122A2H10 Fusion SEQ ID NO: 65- SEQ ID NO: 135- SEQ ID NO: 54 (SEQ ID NO: 172) 122A2H14 Fusion SEQ ID NO: 65- SEQ ID NO: 136- SEQ ID NO: 54 (SEQ ID NO: 173) 122A2H18 Fusion SEQ ID NO: 65- SEQ ID NO: 137- SEQ ID NO: 54 (SEQ ID NO: 174) 122A2H7 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 133- SEQ ID NO: 134- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 170) (SEQ ID NO: 171) 122A2H11 Fusion SEQ ID NO: 65- SEQ ID NO: 135- SEQ ID NO: 54 (SEQ ID NO: 172) 122A2H15 Fusion SEQ ID NO: 65- SEQ ID NO: 136- SEQ ID NO: 54 (SEQ ID NO: 173) 122A2H19 Fusion SEQ ID NO: 65- SEQ ID NO: 137- SEQ ID NO: 54 (SEQ ID NO: 174) 102E9H5 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 138- SEQ ID NO: 141- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 175) (SEQ ID NO: 178) 102E9H9 Fusion SEQ ID NO: 65- SEQ ID NO: 142- SEQ ID NO: 54 (SEQ ID NO: 179) 102E9H13 Fusion SEQ ID NO: 65- SEQ ID NO: 143- SEQ ID NO: 54 (SEQ ID NO: 180) 102E9H6 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 139- SEQ ID NO: 141- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 176) (SEQ ID NO: 178) 102E9H10 Fusion SEQ ID NO: 65- SEQ ID NO: 142- SEQ ID NO: 54 (SEQID NO: 179) 102E9H14 Fusion SEQ ID NO: 65- SEQ ID NO: 143- SEQ ID NO: 54 (SEQ ID NO: 180) 102E9H7 Fusion SEQ ID NO: 65- Fusion SEQ ID NO: 65- SEQ ID NO: 140- SEQ ID NO: 141- SEQ ID NO: 144 SEQ ID NO: 54 (SEQ ID NO: 177) (SEQ ID NO: 178) 102E9H11 Fusion SEQ ID NO: 65- SEQ ID NO: 142- SEQ ID NO: 54 (SEQ ID NO: 179) 102E9H15 Fusion SEQ ID NO: 65- SEQ ID NO: 143- SEQ ID NO: 54 (SEQ ID NO: 180)

[0117] The antibody, functional fragment or derivative thereof according to the invention may be produced from any host cell, any transgenic non-human animal or any transgenic plant described in the present description, and notably below in the section concerning the nucleic acids, vectors, host cells, transgenic non-human animals and transgenic plants according to the invention.

[0118] By "functional fragment" is meant an antibody fragment retaining the antigen-binding domain and thus having the same antigen specificity as the original antibody, such as the fragments Fv, ScFv, Fab, F(ab').sub.2, Fab', scFv-Fc or diabodies. A functional antibody fragment according to the invention is thus advantageously selected from the fragments Fv, ScFv, Fab, F(ab').sub.2, Fab', scFv-Fc or diabodies.

[0119] By "derivative" of an antibody is meant a fusion protein consisting of a carrier peptide and at least one CDR of the original antibody allowing it to retain its ability to recognize CD303.

[0120] The antibody, functional fragment or derivative thereof according to the invention advantageously has a low fucose content, of less than or equal to 65%.

[0121] By "fucose content" is meant the percentage of fucosylated forms within N-glycans attached to the Asn297 residue of the Fc fragment of each heavy chain of each antibody. By "low fucose content" is meant a fucose content of less than or equal to 65%. Indeed, it is known today that the fucose content of an antibody composition plays a crucial role in the capacity of said composition to induce a strong ADCC response via Fc.gamma.RIII. Advantageously, the fucose content is less than or equal to 65%, preferably less than or equal to 60%, 55% or 50%, even less than or equal to 45%, 40%, 35%, 30%, 25% or 20%. However, it is not necessary that the fucose content is nil, and it may for example be greater than or equal to 5%, 10%, 15% or 20%. The fucose content may for example be between 5% and 65%, between 5% and 60%, between 5% and 55%, between 5% and 50%, between 5% and 45%, between 5% and 40%, between 5% and 35%, between 5% and 30%, between 5% and 25%, between 5% and 20%, between 10% and 65%, between 10% and 60%, between 10% and 55%, between 10% and 50%, between 10% and 45%, between 10% and 40%, between 10% and 35%, between 10% and 30%, between 10% and 25%, between 10% and 20%, between 15% and 65%, between 15% and 60%, between 15% and 55%, between 15% and 50%, between 15% and 45%, between 15% and 40%, between 15% and 35%, between 15% and 30%, between 15% and 25%, between 15% and 20%, between 20% and 65%, between 20% and 60%, between 20% and 55%, between 20% and 50%, between 20% and 45%, between 20% and 40%, between 20% and 35%, between 20% and 30%, between 20% and 25%.

[0122] The antibody, functional fragment or derivative thereof according to the invention may moreover have different types of glycosylation (N-glycans of the oligomannose or biantennary complex type, with a variable proportion of bisecting N-acetylglucosamine (GlcNAc) residues, or of galactose residues in the case of N-glycans of the biantennary complex type), provided that they have a low fucose content. Thus, oligomannose-type N-glycans may be obtained by culturing in the presence of various glycosylation inhibitors, such as .alpha.1,2-mannosidase I inhibitors (such as deoxymannojirimycin (DMM)) or .alpha.-glucosidase inhibitors (such as castanospermine (Cs)); or by producing the antibody in the CHO cell line Lec1. Production in the milk of transgenic goats also leads to an antibody whose majority N-glycan is of the oligomannose type, with as minority forms fucosylated biantennary complex forms with one or two galactoses, without bisecting GlcNAc and without sialylation (G1F or G2F) (see WO2007/048077). N-glycans of the biantennary complex type may be obtained in most mammalian cells, but also in bacteria, yeasts or plants whose glycosylation machinery has been modified. To limit the fucose content, cell lines naturally having low activity of the enzyme 1,6-fucosyltransferase (FUT8) responsible for the addition of fucose on the GlcNAc bound to the Fc fragment; such as the YB2/0 cell line, duck embryonic cell line EB66.RTM., rat hepatoma cell lines H4-II-E (DSM ACC3129) and H4-II-Es (DSM ACC3130) or the lines NM-H9D8-E6 (DSM ACC 2807) and NM H9D8-E6Q12 (DSM ACC 2856) may be used. Lines mutant for other genes and whose expression or overexpression leads to a low fucose content may also be used, such as the CHO cell line Lec13, a mutant of the CHO line having decreased synthesis of GDP-fucose. It is also possible to select a line of interest and to decrease or abolish (notably by using interfering RNAs or by mutation or deletion of the gene expressing the protein of interest) the expression of a protein involved in the N-glycan fucosylation pathway (notably FUT8, see Yamane-Ohnuki et al.-2004; but also GMD, a gene involved in GDP-fucose transport, see Kanda et al.-2007). Another alternative consists in selecting a cell line of interest and in overexpressing a protein that interferes in some way with the fucosylation of N-glycans, such as the GnTIII (.beta.(1,4)-N-acetylglucosaminetransferase III) protein. In particular, antibodies having low fucosylated N-glycans were notably obtained by:

[0123] Production in YB2/0 (see EP1176195A1, WO01/77181, Shinkawa et al.-2003), CHO Lec13 (see Shields et al.-2002), EB66.RTM. (Olivier et al.-2010), the rat hepatoma cell lines H4-II-E (DSM ACC3129), H4-II-Es (DSM ACC3130) (see WO2012/041768) and the human lines NM-H9D8 (DSM ACC2806), NM-H9D8-E6 (DSM ACC 2807) and NM H9D8-E6Q12 (DSM ACC 2856) (see WO2008/028686).

[0124] Production in a wild-type CHO cell line in the presence of small interfering RNAs directed against FUT8 (Mod et al.-2004, Suzuki et al.-2007, Cardarelli et al.-2009, Cardarelli et al.-2010, Herbst et al.-2010) or GMD (gene encoding the GDP-fucose transporter in the Golgi apparatus, see Imai-Nishiya et al.-2007).

[0125] Production in a CHO cell line in which both alleles of the FUT8 gene encoding 1,6-fucosyltransferase have been deleted (Yamane-Ohnuki et al.-2004), or in which both alleles of the GMD gene encoding the GDP-fucose transporter in the Golgi apparatus have been deleted (Kanda et al.-2007).

[0126] Production in a CHO cell line in which the gene encoding the GnTIII (.beta.(1,4)-N-acetylglucosaminetransferase III) enzyme was overexpressed transgenically (Umana et al.-1999). In addition to low fucosylation, the N-glycans obtained are characterized by a high bisecting GlcNAc content.

[0127] Production in transgenic plants (N. benthamiana), with a strong reduction of the .beta.1,2-xylose and .alpha.1,3-fucose residue contents by means of the use of small interfering RNAs (Forthal et al.-2010).

[0128] Oligomannose-type N-glycans have a reduced in vivo half-life compared to biantennary complex-type N-glycans. Consequently, advantageously, the antibodies according to the invention have, on their Fc-fragment N-glycosylation sites, biantennary complex-type glycan structures with a low fucose content as defined above.

[0129] In particular, the monoclonal antibody according to the invention may have a content of G0+G1+G0F+G1F forms greater than 60% and a low fucose content as defined above. It may also have a content of G0+G1+G0F+G1F forms greater than 65% and a low fucose content as defined above. It may also have a content of G0+G1+G0F+G1F forms greater than 70% and a low fucose content as defined above. It may also have a content of G0+G1+G0F+G1F forms greater than 75% and a low fucose content as defined above. It may also have a content of G0+G1+G0F+G1F forms greater than 80% and a low fucose content as defined above. It may also have a content of G0+G1+G0F+G1F forms greater than 60%, 65%, 70%, 75% or 80% and a content of G0F+G1F forms of less than 50%. The forms G0, G1, G0F and G1F are as defined below:

##STR00001##

[0130] Such antibody compositions may notably be obtained by production in YB2/0 cells, in CHO Lec13 cells, in wild-type CHO cell lines cultured in the presence of small interfering RNAs directed against FUT8 or GMD, or in CHO cell lines in which both alleles of the FUT8 gene encoding 1,6-fucosyltransferase or both alleles of the GMD gene encoding the GDP-fucose transporter in the Golgi apparatus have been deleted.

[0131] However, in another embodiment, the antibody, functional fragment or derivative thereof according to the invention has a high oligomannose-type N-glycans content.

[0132] By "oligomannose-type N-glycans" is meant N-glycans whose pentasaccharide core, consisting of two N-acetylglucosamine (GlcNAc) residues (one of them being bound to the Asn297 residue of the Fc fragment of the antibody) and three mannose residues, is supplemented by one to six additional mannoses bound to the terminal mannose residues of the pentasaccharide core. The oligomannose-type N-glycans are not fucosylated.

[0133] By "oligomannose-type N-glycans content" is meant the percentage of oligomannose forms within N-glycans attached to the Asn297 residue of the Fc fragment of each heavy chain of each antibody. By "high oligomannose-type N-glycans content" is meant an oligomannose-type N-glycans content of greater than or equal to 30%, advantageously greater than or equal to 35%, greater than or equal to 40%, greater than or equal to 45%, greater than or equal to 50%, greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, or even greater than or equal to 95%.

[0134] In addition or alternatively to a low fucose content, the antibody, functional fragment or derivative thereof according to the invention has a high galactose content. By "galactose content" or "galactosylation level" of the antibody is meant a percentage calculated from an analytical chromatogram of the N-glycans released from the antibody, according to the following formula:

galactose content = i = 1 n ( number of Gal ) .times. ( % relative area ) i = 1 n ( number of A ) .times. ( % relative area ) .times. 100 ##EQU00001##

wherein:

[0135] "n" is the number of N-glycan peaks analyzed on a chromatogram, for example a normal-phase high-performance liquid chromatography (NP-HPLC) spectrum,

[0136] "number of Gal" is the number of galactoses on the antenna of the glycan corresponding to the peak,

[0137] "number of A" is the number of N-acetyl-glucosamine antennas of the glycan form corresponding to the peak, and

[0138] "% relative area" is the percentage of the area under the corresponding peak.

[0139] By "high galactose content" is meant a galactose content of greater than or equal to 30%, advantageously greater than or equal to 50%, advantageously greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, greater than or equal to 95%, or even equal to 100%.

[0140] The present invention also relates to a monoclonal antibody directed against the ectodomain of the human CD303 antigen (SEQ ID NO: 130), or a functional fragment or a derivative thereof, characterized in that:

[0141] a) it has improved affinity for Fc.gamma.RIIIa (CD16a) compared to antibodies directed against the ectodomain of the human CD303 antigen, produced in CHO cells; and

[0142] b) the light and heavy chain constant regions are constant regions from a non-murine species.

[0143] The affinity of the Fc fragment of an antibody for Fc.gamma.RIIIa (CD16a) may be measured by several methods, including surface plasmon resonance (SPR, notably using a BIAcore 2000 device--Pharmacia Biosensor, Upsala, Sweden) and Scatchard analysis. Eight genes encoding Fc.gamma.R have been identified in humans, but only five encode expressed receptors (Fc.gamma.RIa, Fc.gamma.RIIa, Fc.gamma.RIIb, Fc.gamma.RIIIa, Fc.gamma.RIIIb). All are effector cell-activating receptors, except for Fc.gamma.RIIb, which is an immune cell activation-inhibiting receptor. Fc.gamma.RIa is characterized by high affinity for immunoglobulins (Kd of 510.sup.-7 to 10.sup.-10 M) while Fc.gamma.RIIa, Fc.gamma.RIIb, Fc.gamma.RIIIa, Fc.gamma.RIIIb are characteristic of low-affinity receptors (Kd below 10.sup.-7 M). The antibodies according to the invention have improved affinity for Fc.gamma.RIIIa (CD16a) compared to antibodies directed against the ectodomain of the human CD303 antigen produced in CHO cells. In the context of this comparison, reference is preferably made to a wild-type CHO cell line producing in normal conditions antibodies in which the Fc fragment is highly fucosylated (at least 80%, preferably at least 90% of the oligosaccharides attached to the Fc fragment are fucosylated), such as one of the following lines: CHO-K-1 (ATCC.RTM. CCL-61.TM.), CHO Pro-5 (ATCC.RTM. CRL-1781.TM.), CHO dhfr-(ATCC.RTM. CRL-9096.TM.), CHO-DP12 (ATCC.RTM. CRL-12444.TM. or ATCC.RTM. CRL-12445.TM.), CHO DUKX-B11 (ATCC CRL-9010), and CHO DG-44 (Urlaub et al., Cell 33[2], 405-412, 1983). The antibodies according to the invention which have improved affinity for Fc.gamma.RIIIa (CD16a) compared to antibodies directed against the ectodomain of the human CD303 antigen produced in CHO cells (as defined above) have the advantage that this improved affinity enables them not to be displaced, or to be less displaced, from Fc.gamma.RIIIa (CD16a) by polyclonal IgG antibodies, notably the IgG present in serum. Such antibodies advantageously have high affinity for Fc.gamma.RIIIa (CD16a), i.e., affinity at least equal to 210.sup.6 M.sup.-1, at least equal to 210.sup.7M.sup.-1, 210.sup.8M.sup.-1 or 210.sup.9M.sup.-1, as determined by Scatchard analysis or BIAcore (label-free surface plasmon resonance-based) technology.

[0144] High affinity for Fc.gamma.RIIIa (CD16a), significantly improved compared to antibodies produced in CHO cells, may be obtained in the various ways described above for the antibody, functional fragment or derivative thereof according to the invention defined by its capacity to compete for binding to the CD303 ectodomain with the specific antibodies developed by the inventors and by the fact that the constant regions of its light and heavy chains are constant regions from a non-murine species. In particular, high affinity for Fc.gamma.RIIIa (CD16a), significantly improved compared to antibodies produced in CHO cells, may be obtained by:

[0145] The presence of mutations in the Fc fragment that increase Fc.gamma.RIIIa (CD16a)-binding, as described above (in particular mutations that increase the Fc.gamma.RIIIa (CD16a)-binding described in WO00/42072, Shields et al.-2001, Lazar et al.-2006, WO2004/029207, WO2004/063351, WO2004/074455); and/or

[0146] Controlling the glycosylation of the antibody, notably:

[0147] Low fucose content, within biantennary complex forms and/or via a high oligomannose-type N-glycans content, as described above, and/or

[0148] High galactose content, as described above.

[0149] Such an antibody according to the invention may in addition have any characteristic or combination of characteristics described above for the antibody, functional fragment or derivative thereof according to the invention defined by its capacity to compete for binding to the CD303 ectodomain with the specific antibodies developed by the inventors and by the fact that the constant regions of its light and heavy chains are constant regions from a non-murine species.

[0150] Nucleic Acids, Vectors, Host Cells, Transgenic Non-Human Animals and Transgenic Plants

[0151] The present invention also relates to a nucleic acid (also called nucleic or nucleotide sequence) encoding the heavy and/or light chain of an antibody, functional fragment or derivative thereof according to the invention as described above.

[0152] All the different nucleic sequences, because of degeneration of the genetic code, encoding a particular amino acid sequence are within the scope of the invention.

[0153] In particular, the sequence of a nucleic acid according to the invention may be optimized to promote the expression thereof in a host cell, a transgenic non-human animal or a transgenic plant of interest. Indeed, there are in general several three-nucleotide combinations encoding the same amino acid (except for methionine and tryptophan), called synonymous codons. However, some of these combinations are in general used preferentially by a cell or a given organism (this is referred to as genetic code usage bias). This preference depends notably on the producing organism from which the cell is derived. Consequently, when a protein derived from one or more organisms is produced in a heterologous organism or a cell of such a heterologous organism, it may be useful to modify the nucleic sequence encoding the protein to use mainly the preferred codons of the heterologous organism. Data are available in the literature concerning the use of codons preferred by different species and a person skilled in the art knows how to optimize the expression of a given protein in a heterologous organism or a cell of a heterologous organism.

[0154] A nucleic acid according to the invention advantageously comprises at least one of SEQ ID NOs: 86 to 95 (chimeric antibodies), as described in Table 12 below, which encode the amino acid sequences of the VH and VL regions of the antibodies according to the invention and have been optimized for expression in Rattus norvegicus cells.

TABLE-US-00012 TABLE 12 Preferred nucleotide sequences, optimized for expression in Rattus norvegicus cells, encoding the VH and VL regions of the antibodies, functional fragments or derivatives thereof according to the invention. Antibody VH VL 122A2 CAGGTCCAGCTGCAGCAGTCTGGGGCT GATATCCAGATGACACAGACTACAT GAGCTGGTGAGGCCTGGGGTCTCAGTG CCTCCCTGTCTGCCTCTCTGGGAGA AAGATTTCCTGCAAGGGTTCTGGCTACA CAGAGTCACCATCAGTTGCAGGGCA CATTCACTGATTATTCTATGCACTGGGT AGTCAGGACATTAGCAATTATTTAA GAAGCAGAGTCATGCAAAGAGTCTAGAG ACTGGTATCAGCAGAAACCAGATGG TGGATTGGAGTTATTAGTACTTACTATG AACTGTTAAACTCCTGATCTACTAC GTGATTCTAACTATAACCAGAAGTTCAA ACATCAAGATTACACTCAGGAGTCC GGGCAAGGCCACAATGACTGTAGACAAA CATCAAGGTTCAGTGGCAGTGGGT TCCTCCACCACAGCCTATATGGAACTTG CTGGAACAGATTATTCTCTCACCAT CCAGACTGACATCTGAGGATTCTGCCAT TAGCAACCTGGACCAAGAAGATATT CTATTACTGTGCAAGAAATGGTAATTTC GCCACTTACTTTTGCCAACAGGGTA TATGTTATGGACTACTGGGGTCAAGGAA ATACGCTTCCTTGGACGTTCGGTGG CCTCAGTCACCGTCTCCTCA AGGCACCAAGCTGGAAATCAAA (SEQ ID NO: 86) (SEQ ID NO: 91) 102E9 CAGATCCATTTGGTGCAGTCTGGACCTG CAAATTGTTCTCACCCAGTCTCCAG ACCTGAAGAAGCCTGGAGAGACAGTCAA CAATCATGTCTGCATCTCCAGGGGA GATCTCCTGCAAGGCTTCTGGTTATACC GAAGGTCACCATAACCTGCAGTGCC TTCACAGACTATTCAATGCACTGGGTGA AGCTCAAGTGTAATTTACATTCACT AGCAGGCTCCAGGAAAGGGTTTAAAGTG GGTTCCAGCAGAAGCCAGGCACTTC GATGGGCTGGATAAACACTGAGACTGGT TCCCAAACTCTGGATTTATAGCACA GAACCAACATATGCAGATGACTTCAAGG TCCTACCTGGCTTCTGGAGTCCCTG GACGGTTTGCCTTCTCTTTGGAAAGTTC CTCGCTTCAGTGGCAGTGGATCTG TGCCAGCACTGCCTTTTTGCAGATCAAC GGACCTCTTACTCTCTCACAATCAG AACCTCAAAAATGAGGACACGTCTACAT CCGAATGGAGGCTGAAGATGCTGC ATTTCTGTACTAGAAATGGTTACTACGT CACTTATTACTGCCAGCAGAGGAGA GGGTTACTATGCTATGGACTACTGGGGT AGTTACCCGTTCACGTTCGGAGGG CAAGGAACCTCAGTCACCGTCTCCTCA GGGACCAAGCTGGAAATAAAA (SEQ ID NO: 87) (SEQ ID NO: 92) 104C12 CAGGTCCAGCTGCAGCAGTCTGGGGCT GATCTCCAGATGACACAGACTCCAT GAGCTGGTGGGGCCTGGGGTCTCAGTG CCTCCCTGTCTGCCTCTCTGGGAGA AAGATTTCCTGCAAGGGTTCTGGCTACA CAGAGTCACCATCAGTTGCAGGGCA CATTCACTGATTATTCTATGCACTGGGT AGTCAGGACATTAACAATTATTTAA AAAGCAGAGTCATGCAAAGAGTCTAGAG GCTGGTATCAGGAGAAACCAGATG TGGATTGGAGTTATTAGTCCTTACTATG GAACTTTTAAACTCCTGATCTACTA GTGATACTAACTACAACCAGAAGTTCAA CACATCAAGATTACACTCAGGAGTC GGGCAAGGCCACAATGACTGTAGACAAA CCATCAAGGTTCAGTGGCAGTGGG TCCTCCAGCACAGCCTATATGGAACTTG TCTGGAACAGATTATTCTCTCACCG CCAGTCTGACATCTGAGGATTCTGCCAT TTCGCAACCTGGAACAGGAAGATAT CTATTTCTGTGCAAGAAATGATGATTAC TGGCACTTACTTTTGCCAACAGGGT TACAGGTTTGCTTACTGGGGCCAAGGGA AAAACGCTTCCGTGGACGTTCGGTG CTCTGGTCACTGTCTCTGC GAGGCACCAAGCTGGAAATCAG (SEQ ID NO: 88) (SEQ ID NO: 93) 114D11 CAGATCCAGTTGGTGCAGTCTGGACCTG CAAATTGTTCTCACCCAGTCTCCAG AGCTGAAGAAGCCTGGAGAGACAGTCAA CAATCATGTCTGCATCTCCAGGGGA GATCTCCTGCAAGGCTTCTGGTTATACC GAAGGTCACCATAACCTGCAGTGCC TTCACAGACTCTTCAATGCACTGGGTGC AGCTCAAGTGTATTTTACATGCACT AGCAGGCTCCAAACAAGGGTTTAAAGTG GGTTCCAGCAGAAGCCAGGCACTTC GATGGGCTGGATAAACACTGAGACTGGT TCCCAAACTCTGGATTTATAGCACA GGGCCAACGTATGCAGATGATTTCAAGG TCCAACCTGGCTTCTGGAGTCCCTG GACGGTTTGCCTTCTCTTTGGAAACCTC CTCGCTTCAGTGGCAGTGGATCTG TGCCAGAACTGCCTATTTGCAGATCAAC GGACCTCTTACTCTCTCACAATCAG AACCTCAAAAATGAGGACACGGCTACAT CCGAATGGAGGCTGAAGATGCTGC ATTTCTGTGCTAGAAATGGATACTACGT CACTTATTACTGCCAGCAAAGGAGA GGGGTACTATGCTCTGGACTACTGGGG AGTTACCCGTACACGTTCGGAGGG TCAAGGAACCTCAGTCACCGTCTCCTCA GGGACCAAGCTGGAAATAAAA (SEQ ID NO: 89) (SEQ ID NO: 94) 104E10 CAGATCCAGTTGGTGCAGTCTGGACCTG CAAATTGTTCTCACCCAGTCTCCAG AGCTGAAGAAGCCTGGAGAGACAGTCAA CAATCATGTCTGCATCTCCAGGGGA GATCTCCTGCAAGGCTTCTGGTTATACC GAAGGTCACCATGACCTGCAGTGCC TTCACAGACTATTCAATGCACTGGGTGA AGTTCAAGTGTAATTTACATGCACT AGCAGGCTCCAGGAAAGGGTTTAAAGTG GGTTCCAGCAGAAGCCAGGCACTTC GATGGGCTGGATAAACACTGAGACTGGT TCCCAAACTCTGGATTTATAGCACA GAGCCAACATATGCAGATGACTTCAAGG TCCAACCTGGCTTCTGGAGTCCCTG GACGGTTTGCCTTCTCTTTGGAAACCTC CTCGCTTCAGTGGCAGTGGATCTG TGCCACCACTGCCTATTTGCAGATCAAC GGACATCTTACTCTCTCACAATCAG AACTTCAAAAATGAGGACACGGCTACAT CCGAATGGAGGCTGAAGATGCTGC ATTTCTGTGCTAGAAATGGTTACTACGT CACTTATTACTGCCAGCAAAGGAGA GGGATATTATGCTATGGACTACTGGGGT AGTTACCCGTACACGTTCGGAGGG CAAGGAACCTCAGTCACCGTCTCCTCA GGGACCAAGCTGGAAATAAAA (SEQ ID NO: 90) (SEQ ID NO: 95)

[0155] A nucleic acid according to the invention may also advantageously comprise at least one of SEQ ID NOs: 181 to 187 (humanized antibodies derived from antibody 122A2), as described in Table 13 below, which encode the amino acid sequences of the VH and VL regions of the humanized antibodies according to the invention and have been optimized for expression in Rattus norvegicus cells.

TABLE-US-00013 TABLE 13 Preferred nucleotide sequences for humanized antibodies derived from antibody 122A2, optimized for expression in Rattus norvegicus cells, encoding the VH and VL regions of the antibodies, functional fragments or derivatives thereof according to the invention. Sequence 122A2- humanized heavy chain VH 122A2-VHha caggtccagctgcagcagtctggcgccgaagtggtcaagcctggcgcctccgtgaagatcagc- t gcaagggcagcggctacaccttcaccgactacagcatgcactgggtcaagcaggcccacgcca agagcctggaatggatcggcgtgatcagcacctactacggcgacagcaactacaaccagaagt tcaagggcaaagtcaccatgaccgtggacaagagcagctccaccgcctacatggaactgagca ggctgaccagcgacgacaccgccgtgtactactgcgccagaaacggcaacttctacgtgatgg actactggggccagggcaccctggtcaccgtgtcatct (SEQ ID NO: 181) 122A2-VHhb caggtccagctgcagcagtctggcgccgaagtggtcaagcctggcgcctccgtgaagatcagc- t gcaagggcagcggctacaccttcaccgactacagcatgcactgggtccgacaggcccacgcca agagcctggaatggatcggcgtgatcagcacctactacggcgacagcaactacaaccagaagt tcaagggcaaagtcaccatgaccgtggacaccagcagctccaccgcctacatggaactgagca ggctgagaagcgacgacaccgccgtgtactactgcgccagaaacggcaacttctacgtgatgg actactggggccagggcaccctggtcaccgtgtcatct (SEQ ID NO: 182) 122A2-VHhc caggtccagctgcagcagtctggcgccgaagtggtcaagcctggcgcctccgtgaagatcagc- t gcaagggcagcggctacaccttcaccgactacagcatgcactgggtccgacaggcccctggac agggcctggaatggatcggcgtgatcagcacctactacggcgacagcaactacaaccagaagt tcaagggcaaagtcaccatgaccgtggacaagagcagctccaccgcctacatggaactgagca ggctgaccagcgacgacaccgccgtgtactactgcgccagaaacggcaacttctacgtgatgg actactggggccagggcaccctggtcaccgtgtcatct (SEQ ID NO: 183) 122A2- humanized light chain VL 122A2-VKha gacatccagatgacccagagcaccagcagcctgagcgcctctctgggcgacagagtgaccatc acctgtcaggccagccaggacatcagcaactacctgaactggtatcagcagaaacccgacggc accgtgaagctgctgatctactacaccagcaggctgcacaccggcgtgcccagcagattctctg gctctggcagcggcaccgactacagcctgaccatctccaacctggaccaggaagatattgcca cctactactgccagcagggcaacaccctgccctggacattcggcggaggcaccaagctggaaa tcaag (SEQ ID NO: 184) 122A2-VKhb gacatccagatgacccagagccctagcagcctgagcgcctctgtgggcgacagagtgaccatc acctgtcaggccagccaggacatcagcaactacctgaactggtatcagcagaaacccgacggc accgtgaagctgctgatctactacaccagcaggctgcacaccggcgtgcccagcagattctctg gctctggcagcggcaccgactacagcctgaccatctccaacctggaccaggaagatattgcca cctactactgccagcagggcaacaccctgccctggacattcggcggaggcaccaagctggaaa tcaag (SEQ ID NO: 185) 122A2-VKhc gacatccagatgacccagagcaccagcagcctgagcgcctctctgggcgacagagtgaccatc acctgtcaggccagccaggacatcagcaactacctgaactggtatcagcagaaacccgacggc accgtgaagctgctgatctactacaccagcaacctgcacaccggcgtgcccagcagattcagc ggctctggctctggcaccgactacagcctgaccatctccaacctccagcaggaagatattgcca cctactactgccagcagggcaacaccctgccctggacattcggcggaggcaccaagctggaaa tcaag (SEQ ID NO: 186) 122A2-VKhd gacatccagatgacccagagccctagcagcctgagcgcctctgtgggcgacagagtgaccatc acctgtcaggccagccaggacatcagcaactacctgaactggtatcagcagaaacccgacggc accgtgaagctgctgatctactacaccagcaacctgcacaccggcgtgcccagcagattcagc ggctctggctctggcaccgactacagcctgaccatctccaacctccagcaggaagatattgcca cctactactgccagcagggcaacaccctgccctggacattcggcggaggcaccaagctggaaa tcaag (SEQ ID NO: 187)

[0156] A nucleic acid according to the invention may also advantageously comprise at least one of SEQ ID NOs: 188 to 193 (humanized antibodies derived from antibody 102E9), as described in Table 14 below, which encode the amino acid sequences of the VH and VL regions of the humanized antibodies according to the invention and have been optimized for expression in Rattus norvegicus cells.

TABLE-US-00014 TABLE 14 Preferred nucleotide sequences for humanized antibodies derived from antibody 102E9, optimized for expression in Rattus norvegicus cells, encoding the VH and VL regions of the antibodies, functional fragments or derivatives thereof according to the invention. Sequence 102E9- humanized heavy chain VH 102E9-VHha cagatccatctggtgcagagcggccctgagctgaagaaacccggcgagagcgtgaagatcagc tgcaaggccagcggctacaccttcaccgactacagcatgcactgggtcaagcaggccccaggc cagggcctgaagtggatgggctggatcaacaccgagacaggcgagcccacctacgccgacgac ttcaagggcagattcgtgttcagcctggacaccagcgtgtccaccgcctacctgcagatcaaca gcctgaagaacgaggacacctccacctactactgcacccggaacggctactacgtggggtact acgccatggactactggggccagggcacctccgtgaccgtgtcatct (SEQ ID NO: 188) 102E9-VHhb cagatccatctggtgcagagcggccctgagctgaagaaacccggcgagagcgtgaagatcagc tgcaaggccagcggctacaccttcaccgactacagcatgcactgggtccgacaggcccctgga cagggcctgaagtggatgggctggatcaacaccgagacaggcgagcccacctacgcccaggac ttcaagggcagattcgtgttcagcctggacaccagcgtgtccaccgcctacctgcagatcaaca gcctgaagaacgaggacacctccacctactactgcacccggaacggctactacgtggggtact acgccatggactactggggccagggcacctccgtgaccgtgtcatct (SEQ ID NO: 189) 102E9-VHhc cagatccatctggtgcagagcggcagcgagctgaagaaacccggcgagagcgtgaagatcagc tgcaaggccagcggctacaccttcaccgactacagcatgcactgggtccgacaggcccctgga cagggcctgaagtggatgggctggatcaacaccgagacaggcgagcccacctacgcccaggac ttcaagggcagattcgtgttcagcctggacaccagcgtgtccaccgcctacctgcagatcaaca gcctgaagaacgaggacacctccacctactactgcacccggaacggctactacgtggggtact acgccatggactactggggccagggcacctccgtgaccgtgtcatct (SEQ ID NO: 190) 102E9- humanized light chain VL 102E9-VKha cagatccagctgacccagagccctagcttcctgagcgcctctcctggcgagagagtgaccatc- a cctgtagcgccagcagctccgtgatctacatccactggttccagcagaagcccggcaaggcccc taagctgtggatctacagcaccagctacctggccagcggcgtgccaagcagattcagcggctct ggctctggcaccgagtacaccctgaccatcagctccatggaagccgaggacttcgccacctact actgccagcagaggcggagctaccccttcaccttcggcggaggcaccaagctggaaatcaag (SEQ ID NO: 191) 102E9-VKhb cagatccagctgacccagagccctagcttcctgagcgcctctcctggcgagagagtgaccatc- a cctgtagcgccagcagctccgtgatctacatccactggttccagcagaagcccggcaccgcccc taagctgtggatctacagcaccagctacctggccagcggcgtgccaagcagattcagcggctct ggcagcggcacctcctacaccctgaccatcagcaggatggaagccgaggacttcgccacctact actgccagcagaggcggagctaccccttcaccttcggcggaggcaccaagctggaaatcaag (SEQ ID NO: 192) 102E9-VKhc cagatccagctgacccagagccctagcttcctgagcgcctctcctggcgacagagtgaccatc- a cctgtagcgccagcagctccgtgatctacatccactggttccagcagaagcccggcaaggcccc taagctgtggatctacagcaccagctacctggccagcggcgtgccaagcagattcagcggctct ggctctggcaccgagtacaccctgaccatcagctccatgcaggccgaggacttcgccacctact actgccagcagaggcggagctaccccttcaccttcggcggaggcaccaagctggaaatcaag (SEQ ID NO: 193)

[0157] The nucleic sequences encoding the preferred heavy or light chain constant regions were also optimized for expression in Rattus norvegicus cells and are preferably those described in Table 15 below.

TABLE-US-00015 TABLE 15 Preferred nucleotide sequences encoding the preferred human heavy or light chain constant regions. Preferred GCCTCCACCAAGGGCCCATCCGTGTTCCCCCTG human heavy GCCCCATCCAGCAAGTCTACCTCCGGAGGCACA chain constant GCCGCCCTGGGCTGTCTGGTGAAGGACTACTTC region CCCGAGCCAGTGACCGTGTCCTGGAACTCCGGA GCCCTGACATCCGGCGTGCACACCTTCCCCGCC GTGCTGCAGTCCAGCGGCCTGTACTCTCTGTCT TCCGTGGTGACCGTGCCATCCAGCTCCCTGGGA ACCCAGACATACATCTGCAACGTGAACCACAAG CCTAGCAACACCAAGGTGGACAAGAAGGTGGAG CCTAAGAGCTGTGACAAGACACACACATGCCCT CCTTGTCCAGCCCCTGAGCTGCTGGGCGGCCCC TCCGTGTTCCTGTTCCCCCCCAAGCCTAAGGAT ACCCTGATGATCAGCAGAACCCCCGAGGTGACC TGCGTGGTGGTGGACGTGTCCCACGAGGATCCC GAGGTGAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCACAACGCTAAGACCAAGCCCAGAGAG GAGCAGTACAACAGCACATACAGAGTGGTGTCT GTGCTGACCGTGCTGCACCAGGACTGGCTGAAC GGGAAGGAGTACAAGTGCAAGGTGTCCAACAAG GCCCTGCCTGCCCCTATCGAGAAGACCATCTCT AAGGCTAAGGGGCAGCCCCGGGAGCCACAGGTG TACACCCTGCCACCCAGCCGCGACGAGCTGACC AAGAACCAGGTGTCCCTGACATGCCTGGTGAAG GGATTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAACGGCCAGCCCGAGAACAACTACAAG ACAACCCCTCCCGTGCTGGACAGCGATGGATCC TTCTTCCTGTACTCCAAGCTGACCGTGGACAAG AGCAGGTGGCAGCAGGGAAACGTGTTCTCTTGT TCCGTGATGCACGAGGCTCTGCACAACCACTAC ACCCAGAAGTCCCTGAGCCTGTCTCCAGGCAAG (SEQ ID NO: 96) Preferred CGAACTGTGGCTGCACCAAGTGTCTTCATCTTT human light CCTCCGAGTGATGAGCAGCTGAAGAGCGGGACA chain constant GCTTCTGTGGTGTGTCTGCTGAATAACTTCTAC region CCAAGAGAAGCAAAGGTCCAGTGGAAGGTGGAC AACGCCCTGCAGTCTGGCAACTCACAGGAGTCT GTCACTGAGCAGGATTCCAAGGACAGCACTTAC AGCCTGTCCAGCACCCTCACTCTGTCCAAAGCC GACTACGAAAAGCATAAGGTGTATGCTTGTGAG GTGACCCACCAGGGACTGAGCAGCCCTGTGACG AAGTCCTTCAACCGGGGCGAGTGC (SEQ ID NO: 97)

[0158] Thus, a nucleic acid encoding the heavy and/or light chain of an antibody according to the invention preferably comprises (or consists essentially of, or consists of) at least one nucleic sequence described in Table 16 below, consisting of the 5' to 3' fusion:

[0159] Of one of SEQ ID NOs: 86 to 90 encoding the VH region of the preferred chimeric antibodies according to the invention and of SEQ ID NO: 96 encoding the preferred human heavy chain constant region (see SEQ ID NOs: 98 to 102);

[0160] Of one of SEQ ID NOs: 91 to 95 encoding the VL region of the preferred chimeric antibodies according to the invention and of SEQ ID NO: 97 encoding the preferred human light chain constant region (see SEQ ID NOs: 103 to 107);

[0161] Of one of SEQ ID NOs: 181 to 183 encoding the VH region of the preferred humanized antibodies derived from chimeric antibody 122A2 according to the invention and of SEQ ID NO: 96 encoding the preferred human heavy chain constant region (see SEQ ID NOs: 194 to 196);

[0162] Of one of SEQ ID NOs: 184 to 187 encoding the VL region of the preferred humanized antibodies derived from chimeric antibody 122A2 according to the invention and of SEQ ID NO: 97 encoding the preferred human light chain constant region (see SEQ ID NO: 197 to 200);

[0163] Of one of SEQ ID NOs: 188 to 190 encoding the VH region of the preferred humanized antibodies derived from chimeric antibody 102E9 according to the invention and of SEQ ID NO: 96 encoding the preferred human heavy chain constant region (see SEQ ID NO: 201 to 203);

[0164] Of one of SEQ ID NOs: 191 to 193 encoding the VL region of the preferred humanized antibodies derived from chimeric antibody 102E9 according to the invention and of SEQ ID NO: 97 encoding the preferred human light chain constant region (see SEQ ID NO: 204 to 206).

TABLE-US-00016

[0164] TABLE 16 Preferred nucleotide sequences of the heavy and light chains of the antibodies according to the invention. Antibody Heavy chain Light chain Chimeric antibodies 122A2 Fusion SEQ ID NO: 86- Fusion SEQ ID NO: 91- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 98) (SEQ ID NO: 103) 102E9 Fusion SEQ ID NO: 87- Fusion SEQ ID NO: 92- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 99) (SEQ ID NO: 104) 104C12 Fusion SEQ ID NO: 88- Fusion SEQ ID NO: 93- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 100) (SEQ ID NO: 105) 114D11 Fusion SEQ ID NO: 89- Fusion SEQ ID NO: 94- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 101) (SEQ ID NO: 106) 104E10 Fusion SEQ ID NO: 90- Fusion SEQ ID NO: 95- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 102) (SEQ ID NO: 107) Humanized antibodies 122A2H5 Fusion SEQ ID NO: 181- Fusion SEQ ID NO: 184- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 194) (SEQ ID NO: 197) 122A2H9 Fusion SEQ ID NO: 185- SEQ ID NO: 97 (SEQ ID NO: 198) 122A2H13 Fusion SEQ ID NO: 186- SEQ ID NO: 97 (SEQ ID NO: 199) 122A2H17 Fusion SEQ ID NO: 187- SEQ ID NO: 97 (SEQ ID NO: 200) 122A2H6 Fusion SEQ ID NO: 182- Fusion SEQ ID NO: 184- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 195) (SEQ ID NO: 197) 122A2H10 Fusion SEQ ID NO: 185- SEQ ID NO: 97 (SEQ ID NO: 198) 122A2H14 Fusion SEQ ID NO: 186- SEQ ID NO: 97 (SEQ ID NO: 199) 122A2H18 Fusion SEQ ID NO: 187- SEQ ID NO: 97 (SEQ ID NO: 200) 122A2H7 Fusion SEQ ID NO: 183- Fusion SEQ ID NO: 184- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 196) (SEQ ID NO: 197) 122A2H11 Fusion SEQ ID NO: 185- SEQ ID NO: 97 (SEQ ID NO: 198) 122A2H15 Fusion SEQ ID NO: 186- SEQ ID NO: 97 (SEQ ID NO: 199) 122A2H19 Fusion SEQ ID NO: 187- SEQ ID NO: 97 (SEQ ID NO: 200) 102E9H5 Fusion SEQ ID NO: 188- Fusion SEQ ID NO: 191- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 201) (SEQ ID NO: 204) 102E9H9 Fusion SEQ ID NO: 192- SEQ ID NO: 97 (SEQ ID NO: 205) 102E9H13 Fusion SEQ ID NO: 193- SEQ ID NO: 97 (SEQ ID NO: 206) 102E9H6 Fusion SEQ ID NO: 189- Fusion SEQ ID NO: 191- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 202) (SEQ ID NO: 204) 102E9H10 Fusion SEQ ID NO: 192- SEQ ID NO: 97 (SEQ ID NO: 205) 102E9H14 Fusion SEQ ID NO: 193- SEQ ID NO: 97 (SEQ ID NO: 206) 102E9H7 Fusion SEQ ID NO: 190- Fusion SEQ ID NO: 191- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 203) (SEQ ID NO: 204) 102E9H11 Fusion SEQ ID NO: 192- SEQ ID NO: 97 (SEQ ID NO: 205) 102E9H15 Fusion SEQ ID NO: 193- SEQ ID NO: 97 (SEQ ID NO: 206)

[0165] A nucleic acid encoding the heavy and/or light chain of the antibody, functional fragment or derivative thereof according to the invention advantageously comprises a nucleic sequence encoding heterologous signal peptide MB7 (MRWSWIFLLLLSITSANA, SEQ ID NO: 65), and notably the nucleic sequence SEQ ID NO: 108 (ATGAGGTGGTCCTGGATCTTCCTGCTGCTGCTGAGCATCACCAGCGCCAACGCC). Indeed, this peptide has been shown to improve the expression and secretion of recombinant proteins in higher eukaryotic cell lines (see WO2011/114063).

[0166] Thus, a nucleic acid encoding the heavy chain of the antibodies, functional fragments or derivatives thereof according to the invention advantageously comprises (or consists essentially of, or consists of) a nucleic sequence selected from SEQ ID NOs: 109 to 113 (chimeric antibodies), SEQ ID NOs: 207 to 209 (humanized antibodies derived from chimeric antibody 122A2) and SEQ ID NOs: 214 to 216 (humanized antibodies derived from chimeric antibody 102E9), consisting of the 5' to 3' fusion of the nucleic sequence encoding signal peptide MB7 (SEQ ID NO: 108) to one of the nucleic sequences encoding the VH region of the antibodies according to the invention (SEQ ID NOs: 86 to 90 for the chimeric antibodies, SEQ ID NOs: 181 to 183 for the humanized antibodies derived from chimeric antibody 122A2, and SEQ ID NOs: 188 to 190 for the humanized antibodies derived from chimeric antibody 102E9).

[0167] Additionally or alternatively, a nucleic acid encoding the light chain of the antibodies, functional fragments or derivatives thereof according to the invention advantageously comprises (or consists essentially of, or consists of) a nucleic sequence selected from SEQ ID NOs: 114 to 118, (chimeric antibodies), SEQ ID NOs: 210 to 213 (humanized antibodies derived from chimeric antibody 122A2) and SEQ ID NOs: 217 to 219 (humanized antibodies derived from chimeric antibody 102E9), consisting of the 5' to 3' fusion of the nucleic sequence encoding signal peptide MB7 (SEQ ID NO: 108) to one of the amino acid sequences of the VL region of the antibodies according to the invention (SEQ ID NOs: 91 to 95 for the chimeric antibodies, SEQ ID NOs: 184 to 187 for the humanized antibodies derived from chimeric antibody 122A2, and SEQ ID NOs: 191 to 193 for the humanized antibodies derived from chimeric antibody 102E9).

[0168] By adding the preferred heavy and light chain constant regions, the preferred complete amino acid sequences of the antibodies according to the invention are obtained, as described in Table 17 below.

[0169] Thus, a nucleic acid encoding the heavy and/or light chain of a chimeric or humanized antibody, a functional fragment or a derivative thereof according to the invention advantageously comprises at least one sequence described in Table 17 below (or consists essentially of, or consists of, such sequences).

TABLE-US-00017 TABLE 17 Nucleic sequences encoding the heavy and light chains of the antibodies according to the invention, with signal peptide MB7. Antibody Heavy chain Light chain Chimeric antibodies 122A2 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 86- SEQ ID NO: 91- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 119) (SEQ ID NO: 124) 102E9 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 87- SEQ ID NO: 92- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 120) (SEQ ID NO: 125) 104C12 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 88- SEQ ID NO: 93- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 121) (SEQ ID NO: 126) 114D11 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 89- SEQ ID NO: 94- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 122) (SEQ ID NO: 127) 104E10 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 90- SEQ ID NO: 95- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 123) (SEQ ID NO: 128) Humanized antibodies 122A2H5 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 181- SEQ ID NO: 184- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 207) (SEQ ID NO: 210) 122A2H9 Fusion SEQ ID NO: 108- SEQ ID NO: 185- SEQ ID NO: 97 (SEQ ID NO: 211) 122A2H13 Fusion SEQ ID NO: 108- SEQ ID NO: 186- SEQ ID NO: 97 (SEQ ID NO: 212) 122A2H17 Fusion SEQ ID NO: 108- SEQ ID NO: 187- SEQ ID NO: 97 (SEQ ID NO: 213) 122A2H6 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 182- SEQ ID NO: 184- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 208) (SEQ ID NO: 210) 122A2H10 Fusion SEQ ID NO: 108- SEQ ID NO: 185- SEQ ID NO: 97 (SEQ ID NO: 211) 122A2H14 Fusion SEQ ID NO: 108- SEQ ID NO: 186- SEQ ID NO: 97 (SEQ ID NO: 212) 122A2H18 Fusion SEQ ID NO: 108- SEQ ID NO: 187- SEQ ID NO: 97 (SEQ ID NO: 213) 122A2H7 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 183- SEQ ID NO: 184- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 209) (SEQ ID NO: 210) 122A2H11 Fusion SEQ ID NO: 108- SEQ ID NO: 185- SEQ ID NO: 97 (SEQ ID NO: 211) 122A2H15 Fusion SEQ ID NO: 108- SEQ ID NO: 186- SEQ ID NO: 97 (SEQ ID NO: 212) 122A2H19 Fusion SEQ ID NO: 108- SEQ ID NO: 187- SEQ ID NO: 97 (SEQ ID NO: 213) 102E9H5 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 188- SEQ ID NO: 191- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 214) (SEQ ID NO: 217) 102E9H9 Fusion SEQ ID NO: 108- SEQ ID NO: 192- SEQ ID NO: 97 (SEQ ID NO: 218) 102E9H13 Fusion SEQ ID NO: 108- SEQ ID NO: 193- SEQ ID NO: 97 (SEQ ID NO: 219) 102E9H6 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 189- SEQ ID NO: 191- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 215) (SEQ ID NO: 217) 102E9H10 Fusion SEQ ID NO: 108- SEQ ID NO: 192- SEQ ID NO: 97 (SEQ ID NO: 218) 102E9H14 Fusion SEQ ID NO: 108- SEQ ID NO: 193- SEQ ID NO: 97 (SEQ ID NO: 219) Chimeric antibodies 102E9H7 Fusion SEQ ID NO: 108- Fusion SEQ ID NO: 108- SEQ ID NO: 190- SEQ ID NO: 191- SEQ ID NO: 96 SEQ ID NO: 97 (SEQ ID NO: 216) (SEQ ID NO: 217) 102E9H11 Fusion SEQ ID NO: 108- SEQ ID NO: 192- SEQ ID NO: 97 (SEQ ID NO: 218) 102E9H15 Fusion SEQ ID NO: 108- SEQ ID NO: 193- SEQ ID NO: 97 (SEQ ID NO: 219)

[0170] The present invention also relates to a vector comprising a nucleic acid according to the invention. Such a vector comprises the elements necessary for the expression of said nucleic sequence, and notably a promoter, a transcription initiation codon, termination sequences, and suitable transcription regulatory sequences. These elements vary according to the host used for the expression and are easily selected by persons skilled in the art based on their general knowledge. In particular, for a vector designed for expression in eukaryotic cells, the vector advantageously comprises a Kozak consensus sequence, i.e., a conserved sequence found at the translation start site of eukaryotic messenger RNA, around the AUG start codon (generally GCCGCC(A/G)CCATGG, the translation initiation codon being underlined). The vector can notably be a plasmid or viral vector. It is used to clone or express the nucleic acids according to the invention. Examples of preferred vectors able to be used in the context of the invention include:

[0171] A vector as described in WO2013/061010 (particularly preferred), comprising at least one transcription unit comprising the following regulatory elements: the hCMVie virus enhancer, said enhancer having the nucleotide sequence SEQ ID NO: 220, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 220 and essentially having transcription activation properties, and the cyclin-dependent kinase 9 (CDK9) promoter region, said promoter region having the nucleotide sequence SEQ ID NO: 221, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 221 and essentially having a promoter activity. Advantageously, the transcription unit comprised in the vector further comprises at least one of the following two additional components:

[0172] a 5' untranslated region (5' UTR) situated downstream of the promoter region, in particular selected from:

[0173] the HTLV-1 virus Long Terminal Repeat (LTR) regulatory (R) region having the nucleotide sequence SEQ ID NO: 222, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 222,

[0174] the NF-.kappa.B Repressing Factor (NRF) gene 5' UTR having the nucleotide sequence SEQ ID NO: 223, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 223,

[0175] the eukaryotic Initiation Factor 4G1 (eIF4G1) gene 5' UTR having the nucleotide sequence SEQ ID NO: 224, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 224, said nucleic acids having at least 70% sequence identity with said SEQ ID NOs: 222, 223, 224 essentially having mRNA stabilization and translation facilitator properties.

[0176] an intron situated downstream of the promoter region and upstream of the translation initiation site, in particular selected from:

[0177] the Elongation Factor 1.alpha. (EF1.alpha.) gene intron having the nucleotide sequence SEQ ID NO: 225, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 225,

[0178] the murine ROSA intron having the nucleotide sequence SEQ ID NO: 226, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 226,

[0179] the HTLV-1 virus 5' LTR intron having the nucleotide sequence SEQ ID NO: 227, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 227,

[0180] the pCI-neo intron having the nucleotide sequence SEQ ID NO: 228, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 228,

[0181] the ubiquitin gene intron having the nucleotide sequence SEQ ID NO: 229, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 229,

[0182] the human ROSA intron having the nucleotide sequence SEQ ID NO: 230, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 230.

[0183] Advantageously, the transcription unit comprised in the vector comprises the hCMVie virus enhancer, the CDK9 promoter region, the eIF4GI gene 5' UTR and the EF1.alpha. gene intron, and has the nucleotide sequence SEQ ID NO: 231 ("HKgenEFss" vector).

[0184] A vector as described in WO2013/117871, comprising at least one transcription unit comprising the following regulatory elements:

[0185] the hCMVie virus enhancer, said enhancer having the nucleotide sequence SEQ ID NO: 232, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 232 and essentially having transcription activation properties,

[0186] the .beta.-actin promoter region, said promoter region having the nucleotide sequence SEQ ID NO: 233, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 233 and essentially having a promoter activity, and

[0187] a nucleic acid situated downstream of said promoter region and upstream of the translation initiation site, said nucleic acid comprising at least one 5' untranslated region (5' UTR) selected from the following:

[0188] the HTLV-1 virus 5' Long Terminal Repeat (LTR) regulatory (R) region having the nucleotide sequence SEQ ID NO: 234, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 234,

[0189] the NF-.kappa.B Repressing Factor (NRF) gene 5' UTR having the nucleotide sequence SEQ ID NO: 235, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 235,

[0190] the eukaryotic Initiation Factor 4G1 (eIF4G1) gene 5' UTR having the nucleotide sequence SEQ ID NO: 236, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 236, said nucleic acids having at least 70% sequence identity with one of the sequences represented by SEQ ID NO: 234, SEQ ID NO: 235 or SEQ ID NO: 236 essentially having mRNA stabilization and translation facilitator properties.

[0191] The transcription unit comprised in the vector may further comprise an intron, in particular selected from the following:

[0192] the Elongation Factor 1.alpha. (EF1.alpha.) gene intron having the nucleotide sequence SEQ ID NO: 237, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 237,

[0193] the murine ROSA intron having the nucleotide sequence SEQ ID NO: 238, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 238,

[0194] the human ROSA intron having the nucleotide sequence SEQ ID NO: 239, or a nucleic acid having at least 70% sequence identity with SEQ ID NO: 239,

[0195] said intron being located:

[0196] (i) downstream of the 5' UTR and upstream of the translation initiation site, or

[0197] (ii) downstream of the promoter and upstream of the 5' UTR, or

[0198] (iii) after the translation initiation site and within a coding sequence, or

[0199] (iv) between the stop codon of the coding sequence and the polyadenylation signal.

[0200] Advantageously, the transcription unit comprised in the vector comprises the hCMVie virus enhancer, the .beta.-actin promoter region, the HTLV-1 virus 5' UTR (U1) and the eIF4GI gene 5' UTR (U3), and has the nucleotide sequence SEQ ID NO: 240.

[0201] The present invention also relates to a host cell, a transgenic non-human animal or a transgenic plant comprising at least one nucleic acid according to the invention or a vector according to the invention.

[0202] The host cell may be of prokaryotic or eukaryotic origin, and may in particular be selected from bacterial, insect, plant, yeast or mammalian cells. The antibody, functional fragment or derivative according to the invention may then be produced by culturing the host cell under suitable conditions. A host cell according to the invention can notably be obtained by transforming a cell line by the expression vector(s) for the heavy and light chains of an antibody, functional fragment or derivative thereof according to the invention, and separating the various cell clones obtained. The transformed cell line is preferably of eukaryotic origin, and may in particular be selected from insect, plant, yeast or mammalian cells. Suitable cell lines for antibody production notably include lines selected from: SP2/0; YB2/0; IR983F; human myeloma Namalwa; PERC6; CHO cell lines, notably CHO-K-1, CHO-Lec10, CHO-Lec1, CHO-Lec13, CHO Pro-5, CHO dhfr-, CHO-DP12, CHO DUKX-B11, CHO DG-44, or the CHO cell line deleted for both alleles encoding the FUT8 gene and/or the GMD gene; Wil-2; Jurkat; Vero; MoIt-4; COS-7; 293-HEK; BHK; K6H6; NSO; SP2/0-Ag 14, P3X63Ag8.653, duck embryonic cell line EB66.RTM. (Valneva); rat hepatoma cell lines H4-II-E (DSM ACC3129) and H4-II-Es (DSM ACC3130) (see WO2012/041768), NM-H9D8 (DSM ACC2806), NM-H9D8-E6 (DSM ACC 2807) and NM H9D8-E6Q12 (DSM ACC 2856) (see WO2008/028686).

[0203] A transgenic non-human animal according to the invention may be obtained by directly injecting the gene(s) of interest (here, the rearranged genes encoding the heavy and light chains of the antibody) into a fertilized egg (Gordon et al.-1980). A transgenic non-human animal may also be obtained by introducing the gene(s) of interest (here, the rearranged genes encoding the heavy and light chains of the antibody) into an embryonic stem cell and preparing the animal by a chimera aggregation method or a chimera injection method (see Manipulating the Mouse Embryo, A Laboratory Manual, Second edition, Cold Spring Harbor Laboratory Press (1994); Gene Targeting, A Practical Approach, IRL Press at Oxford University Press (1993)). A transgenic non-human animal may also be obtained by a cloning technique in which a nucleus, into which the gene(s) of interest (here, the rearranged genes encoding the heavy and light chains of the antibody) has/have been introduced, is transplanted into an enucleated egg (Ryan et al.-1997; Cibelli et al.-1998, WO00/26357). A transgenic non-human animal producing an antibody of interest can be prepared by the methods above. The antibody may then be accumulated in the transgenic animal and harvested, notably from the animal's milk or eggs. For producing antibodies in the milk of transgenic non-human animals, preparation methods are notably described in WO90/04036, WO95/17085, WO01/26455, WO2004/050847, WO2005/033281, WO2007/048077. Methods for purifying proteins of interest from milk are also known (see WO01/26455, WO2007/106078). The transgenic non-human animals of interest notably include mice, rabbits, rats, goats, bovines (notably cows), and poultry (notably chicken). A transgenic plant according to the invention may be selected from any plant allowing antibody production. Numerous antibodies have already been produced in transgenic plants and the technologies required for obtaining a transgenic plant expressing an antibody of interest and for recovering the antibody are well-known to a person skilled in the art (see Stoger et al.-2002, Fisher et al.-2003, My et al.-2003, Schillberg et al.-2005). It is also possible to influence the glycosylation obtained in the plants in order to obtain glycosylation similar to that of natural human antibodies (without xylose), but with, in addition, slight fucosylation, for example by means of small interfering RNAs (Forthal et al.-2010).

[0204] Therapeutic Uses of the Antibodies

[0205] The present invention also relates to an antibody, functional fragment or derivative thereof according to the invention, for use as a medicinal product.

[0206] In a first embodiment, the antibody, functional fragment or derivative thereof according to the invention is advantageously used in the treatment or prevention of hematopoietic tumors expressing the CD303 antigen. It is notably the case of blastic plasmacytoid dendritic cell neoplasms (BPDCN), of phenotype CD4+, CD11c-, Lin-, CD303+, CD304+, CD56+.

[0207] In a second embodiment, the antibody, functional fragment or derivative thereof according to the invention is advantageously used in the treatment or prevention of inflammatory diseases, notably autoimmune diseases. The antibody, functional fragment or derivative thereof according to the invention is advantageously used in the treatment or prevention of diseases involving pDCs, and more particularly diseases involving IFN-.alpha. secretion by pDCs. In particular, the antibody, functional fragment or derivative thereof according to the invention is advantageously used in the treatment or prevention of the following diseases, for which a role for pDCs has been established (see Wollenberg et al.-2002 and Cao-2014): atopic dermatitis, contact dermatitis, psoriasis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, type 1b diabetes, autoimmune thrombocytopenia (or thrombopenia) (notably idiopathic thrombocytopenic purpura, or ITP), systemic scleroderma (also called progressive systemic scleroderma or systemic sclerosis), rheumatoid arthritis.

[0208] The present invention also concerns:

[0209] the use of an antibody, functional fragment or derivative thereof according to the invention for preparing a medicinal product for treating or preventing hematopoietic tumors expressing the CD303 antigen, and notably blastic plasmacytoid dendritic cell neoplasms (BPDCN), of phenotype CD4+, CD11c-, Lin-, CD303+, CD304+, CD56+.

[0210] the use of an antibody, functional fragment or derivative thereof according to the invention for preparing a medicinal product for treating or preventing inflammatory diseases, notably autoimmune diseases, and in particular the diseases mentioned above.

[0211] The present invention also concerns:

[0212] the use of an antibody, functional fragment or derivative thereof according to the invention in the treatment or prevention of hematopoietic tumors expressing the CD303 antigen, and notably blastic plasmacytoid dendritic cell neoplasms (BPDCN), of phenotype CD4+, CD11c-, Lin-, CD303+, CD304+, CD56+.

[0213] the use of an antibody, functional fragment or derivative thereof according to the invention in the treatment or prevention of inflammatory diseases, notably autoimmune diseases, and in particular the diseases mentioned above.

[0214] The present invention also concerns:

[0215] a method for treating or preventing a hematopoietic tumor expressing the CD303 antigen in a patient, and notably a blastic plasmacytoid dendritic cell neoplasm (BPDCN), of phenotype CD4+, CD11c-, Lin-, CD303+, CD304+, CD56+, comprising administering to said patient an effective amount of an antibody, functional fragment or derivative thereof according to the invention.

[0216] a method for treating or preventing inflammatory disease in a patient, notably autoimmune disease, and in particular one of the diseases mentioned above, comprising administering to said patient an effective amount of an antibody, functional fragment or derivative thereof according to the invention.

[0217] By "treatment" is meant an improvement, observed at the clinical or biochemical level, of the patient's disease.

[0218] By "prevention" is meant the fact of preventing or delaying the onset of, or of decreasing the intensity of, the clinical or biochemical manifestations associated with the disease.

[0219] Persons skilled in the art know, on the basis of their general knowledge, how to determine which clinical or biochemical manifestations are associated with a given disease and which are likely to be improved (treatment) or prevented, delayed or decreased in intensity (prevention). In the context of hematopoietic tumors expressing the CD303 antigen, and notably blastic plasmacytoid dendritic cell neoplasms (BPDCN), a biological parameter of interest may be the number of blasts. In the context of inflammatory diseases, a biological parameter of interest may be the number of pDCs or the number of local or systemic molecules contributing to the inflammation (inflammatory cytokines and notably INF.alpha.).

[0220] The following examples aim at illustrating the present invention.

EXAMPLES

Example 1: Preparation and Structure of Five Chimeric Antibodies and a Humanized Antibody of the Prior Art

[0221] Five chimeric monoclonal antibodies with murine variable regions and human constant regions of IgG1 type were generated and their structures characterized. In addition, humanized antibody BIIB059, the sequences of which are described in the application WO2014/09339, was reproduced for comparison with the chimeric antibodies according to the invention.

[0222] Materials and Methods

[0223] Sequencing of the Heavy and Light Chains from Murine Hybridomas

[0224] Total RNA from each hybridoma was extracted using the NucleoSpin RNA II Kit (column purification) from Macherey-Nagel.

[0225] The mRNA was converted to cDNA and the heavy and light chains of the antibody were amplified using the GeneRacer Kit (Invitrogen) and cloned into an M13 vector. Bacteria were then transformed by the M13 vector and clones positive for the M13 sequences were sequenced.

[0226] Determination of the Heavy Chain VH, DH, JH Segments and the Light Chain VL and JL Segments

[0227] The variable portion, the V and J segments used by the heavy and light chains and the sequences of the heavy and light chain CDRs were determined by using IMGT's Domain Gap Align tool (see Ehrenmann et al.-2010 and Ehrenmann et al.-2011) available at the following address: http://www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi.

[0228] Construction of Expression Vectors for the Chimeric Antibodies

[0229] The sequences of the variable regions, VH and VL, of the five murine antibodies were optimized for preferential use of codons from Rattus norvegicus. A sequence encoding heterologous signal peptide MB7 was in addition introduced at the 5' end of the sequence encoding the variable region, VH or VL, of each antibody.

[0230] The sequences of the human constant portions were extracted from the expression vector CHK622-21 for a human anti-Rhesus D antibody (T125) by ApaI/AscI digestion for the H chain (IgG1m1.17) and DraIII/XbaI for the Kappa chain.

[0231] Lastly, the variable and constant portions of the same chain were introduced simultaneously into the generic HKgenEFss vector by ligation with KAPA T4 ligase, generating the vectors HKBDCA-2-122A2, HKBDCA-2-102E9, HKBDCA-2-104C12, HKBDCA-2-114D11, and HKBDCA-2-104E10 (see FIGS. 1A to 1E).

[0232] Production of Chimeric Antibodies

[0233] Vectors HKBDCA-2-122A2, HKBDCA-2-102E9, HKBDCA-2-104C12, HKBDCA-2-114D11, and HKBDCA-2-104E10 (see FIGS. 1A to 1E) were transfected into YB2/0 cells, and a clone producing each antibody was selected to produce the chimeric antibodies.

[0234] Production of an Antibody Corresponding to the Antibody (BIIB059) Described in WO2014/09339

[0235] Based on the sequences described in said patent application, the sequences of the heavy (H) chain and of the light (K) chain were synthesized by adding a Kozak sequence and restriction sites on each side of the two H and K sequences, to allow cloning by digestion/ligation.

[0236] The expression vector used to produce humanized antibody BIIB059 is a bicistronic vector, HKgenEFss, of 10,835 bp, which makes it possible to optimally produce the antibody in CHO cells (FIG. 1F). Cloning of the heavy and light chains is carried out in two sequential steps. The first step consists in inserting by digestion/ligation the H chain between the NheI/AscI cloning sites to produce an intermediate vector containing only this chain. During the second step, the K chain is inserted, by the same technique, between the SpeI/XbaI cloning sites. The ligation enzyme is KAPA T4 DNA Ligase (Kapa Biosystems). However, a dephosphorylation step before insertion of the K chain is necessary to prevent the linearized plasmid from circularizing, due to the blunt ends generated by the SpeI/XbaI restriction sites.

[0237] Humanized antibody BIIB059 is produced by transient transfection from the CHO cell line, in order to meet the conditions of the application WO2014/09339. This line is cultured in ProCHO4 medium, supplemented with 4 mM glutamine. In the laboratory, the line is maintained at 210.sup.5 to 310.sup.5 cells/mL, every 2 days. The solutions used for the transfection are buffer (OptiPRO) and transfection agent (Freestyle Max Reagent). Once produced, antibody BIIB059 was purified by affinity chromatography.

[0238] Results

[0239] The data concerning the heavy chain VH, DH, JH segments and the light chain VL and JL segments of the five antibodies are presented in Table 2 above. It is noted that:

[0240] The two antibodies of family 1 (122A2 and 104C12) share the use of the same VH segment (IGHV1S137*01), as well as the use of the VL (IGKV10-96*01/IGKV10-96*02) and JL (IGKJ1*01/IGKJ1*02) segments of the same family, as illustrated in Table 18 below. These two antibodies thus have a similar structure.

[0241] The three antibodies of family 2 (102E9, 114D11 and 104E10) share the use of the same VH, JH, VL and JL segments, as illustrated in Table 18 below. These three antibodies thus have a similar structure.

TABLE-US-00018

[0241] TABLE 18 The VH, JH, VL and JL segments used by the various antibodies. The identical segments within the same family are in bold. Antibody VH JH VL JL Family 1 122A2 IGHV1S137*01 IGHJ2*02 IGKV10-96*01 IGKJ1*01 104C12 IGHV1S137*01 IGHJ3*01 IGKV10-96*02 IGKJ1*02 Family 2 102E9 IGHV9-2-*01 IGHJ4*01 IGKV4-57*01 IGKJ1*02 114D11 IGHV9-2-*01 IGHJ4*01 IGKV4-57*01 IGKJ1*02 104E10 IGHV9-2-*01 IGHJ4*01 IGKV4-57*01 IGKJ1*02

[0242] Furthermore, the data concerning the amino acid sequences of the CDRs and of the variable regions of the five antibodies are presented in Table 3 above. It is noted that:

[0243] The two antibodies of family 1 (122A2 and 104C12) have the same CDR1-H and CDR2-L sequences, and in addition have highly similar CDR2-H, CDR1-L and CDR3-L sequences (a difference of only one or two amino acids). Even the CDR3-H sequences have high homology (5/11 amino acids in common), as illustrated in Table 19 below. That confirms that these two antibodies have a very similar structure.

[0244] The three antibodies of family 2 (102E9, 114D11 and 104E10) have the same CDR2-L sequences, and in addition have highly similar CDR1-H, CDR2-H, CDR1-L and CDR3-L sequences (only one amino acid of difference). Even the CDR3-H sequences have high homology (12/14 amino acids in common), as illustrated in Table 19 below. That confirms that these three antibodies have a structure that is truly highly similar.

TABLE-US-00019

[0244] TABLE 19 Sequence homology between the CDRs of antibodies of the same family. Antibody CDR1-H CDR2-H CDR3-H CDR1-L CDR2-L CDR3-L Family 1 122A2 GYTFTDYS ISTYYGDS ARNGNFYVMDY QDISNY YTS QQGNTLPWT 104C12 GYTFTDYS ISPYYGDT ARNDDYYRFAY QDINNY YTS QQGKTLPWT Family 2 102E9 GYTFTDYS INTETGEP TRNGYYVGYYAMDY SSVIY STS QQRRSYPFT 114D11 GYTFTDSS INTETGGP ARNGYYVGYYALDY SSVFY STS QQRRSYPYT 104E10 GYTFTDYS INTETGEP ARNGYYVGYYAMDY SSVIY STS QQRRSYPYT The identical amino acids within the same family are in bold.

[0245] The data concerning the amino acid sequences of the constant regions of the five antibodies are presented in Table 9 above.

[0246] Moreover, the nucleic acid sequences of the variable regions (VH and VL) and of the constant regions of each antibody are presented in Tables 12 and 15 above.

[0247] Lastly, the maps of the expression vectors for the five antibodies are presented in FIGS. 1A to 1E.

[0248] Conclusions

[0249] Five chimeric monoclonal antibodies, with murine variable regions and human constant regions of IgG1 type, and directed against the CD303 antigen, were generated and their structures characterized. It turns out that two antibodies (122A2 and 104C12) have similar structures and form an antibody subfamily (family 1), and that the other three antibodies (102E9, 114D11 and 104E10) are also very similar structurally and form another antibody subfamily (family 2).

[0250] A humanized antibody having the sequences of the antibody (BIIB059) described in the application WO2014/09339 was also produced in CHO cells (as in the application WO2014/09339).

[0251] These antibodies were then characterized in terms of their biological properties (see Example 2).

Example 2: Biological Properties of the Five Chimeric Antibodies and of an Antibody Corresponding to the Antibody (BIIB059) Described in the Application WO2014/09339

[0252] The five chimeric monoclonal antibodies, with murine variable regions and human constant regions of IgG1 type, and directed against the CD303 antigen, generated in Example 1 were tested for various biological properties. In certain cases, these properties were compared to those of an antibody corresponding to the antibody (BIIB059) described in the application WO2014/09339 (same sequences and same production line).

[0253] Materials and Methods

[0254] Tested Antibodies

[0255] Tested antibodies are those prepared as described in Example 1.

[0256] Antigen-Binding

[0257] Binding to CD303+ Cells (Fc.gamma. Chain-CD303 Jurkat, CAL-1, and CAL-1 Overexpressing CD303)

[0258] Various types of cells expressing CD303 at various antigen densities were used:

[0259] 1. Fc.gamma. chain-CD303 Jurkat cells, which express about 25,000-35,000 CD303 molecules/cell;

[0260] 2. CAL-1 cells, as described in Maeda T et al. (Int J Hematol. 2005 February; 81(2):148-54), which express about 3,000-6,000 CD303 molecules/cell;

[0261] 3. CAL-1 cells transfected with a CD303 expression vector, selected for their high CD303 expression, about 40,000-50,000 CD303 molecules/cell.

[0262] The CD303-expressing cells and the antibodies are prepared in diluent (PBS+1% FCS). 110.sup.5 cells are incubated at 4.degree. C. for 30 minutes with 100 .mu.L of antibody (anti-CD303 or negative control) at various concentrations (0-40 .mu.g/mL, final concentration).

[0263] After washing with the diluent, the antibodies are visualized by addition of a phycoerythrin (PE)-coupled goat anti-mouse IgG F(ab').sub.2 fragment (100 .mu.L diluted to 1:100 in the diluent) for 45 minutes at 4.degree. C. The cells are then washed and analyzed by flow cytometry (FC500, Beckman Coulter).

[0264] Fc.gamma.RIIIa (CD16a)-Binding

[0265] NK cells were isolated from peripheral blood mononuclear cells (PBMCs), then incubated with varying concentrations of the antibodies tested (0 to 100 .mu.g/mL) simultaneously incubated with the phycoerythrin-coupled murine antibody (3G8-PE, Beckman Coulter) at 10 .mu.L/test.

[0266] After washing, the binding of 3G8-PE to CD16 expressed by the NK cells was evaluated by flow cytometry. Mean fluorescence intensity (MFI) values are expressed as a percentage, 100% being the value obtained with the 3G8-PE antibody alone, and 0% the value obtained in the absence of 3G8-PE.

[0267] IC50 values (concentration of anti-CD303 antibody necessary to induce 50% inhibition of 3G8-binding) are calculated using the PRISM software.

[0268] ADCC

[0269] Fc.gamma. chain-CD303 Jurkat cells (35,000 cells/well) are incubated in a 96-well flat-bottom plate with NK cells and increasing concentrations of anti-CD303 antibody for 4 hours at 37.degree. C. After incubation, the supernatant is collected. Lysis of the target cells induced by the anti-CD303 antibodies is measured chromogenically by quantifying the intracellular lactate dehydrogenase (LDH) enzyme released into the supernatant by the lysed target cells (Cytotoxicity Detection Kit (LDH), Roche Diagnostics).

[0270] The percentage of lysis is calculated according to the following formula:

% lysis=[(ER-SR)/(100-SR)]-[(NC -SR)/(100-SR)]

[0271] Where ER and SR represent the experimental release (ER) and the spontaneous release (SR) of LDH, respectively, and NC represents the natural cytotoxicity of the NK cells. The results (% lysis) are expressed as a function of antibody dilution factor. For each antibody, the "50% activity" value corresponds to the antibody dilution factor necessary to induce 50% of the plateau value obtained for this antibody. This value was calculated with the PRISM software.

[0272] Inhibition of IFN-.alpha. Secretion

[0273] Preparation of the Cells

[0274] Peripheral blood mononuclear cells (PBMCs) are isolated from peripheral blood of healthy donors by Ficoll density gradient. The pDCs are purified by negative depletion (Miltenyi Biotec--Plasmacytoid Dendritic Cell Isolation Kit, human). The cells are counted and resuspended at 210.sup.5 cells/mL in diluent (RPMI 1640+10% fetal calf serum (FCS)).

[0275] IFN-.alpha. Secretion by Purified pDCs

[0276] This suspension (205 .mu.L/well) is then transferred to a 24-well flat-bottom culture plate. CpG ODN (10 .mu.M, 50 .mu.L), IL-3 (100 ng/mL, 50 .mu.L), antibody (100 .mu.g/mL, 50 .mu.L) and diluent (100 .mu.L) are added. The plate is then incubated overnight at 37.degree. C., 7% CO.sub.2.

[0277] IFN-.alpha. Assay

[0278] The culture supernatants of each well are collected and assayed by flow cytometry by using the FlowCytomix Human IFN-.alpha. Kit (Bender MedSystems BMS216FF+Basic kit BMS842OFF).

[0279] The percentage of inhibition of each sample is evaluated in relation to the negative control (CPG-activated pDCs without anti-CD303 monoclonal antibody).

[0280] The samples leading to less than 20% inhibition are considered non-inhibitors, those leading to between 20% and 75% inhibition are considered weak inhibitors, those leading to greater than 75% inhibition are considered strong inhibitors.

[0281] Inhibition of TNF-.alpha. Secretion

[0282] Preparation of the Cells

[0283] Peripheral blood mononuclear cells (PBMCs) are isolated from peripheral blood of healthy donors by Ficoll density gradient. The pDCs are purified by negative depletion (Miltenyi Biotec--Plasmacytoid Dendritic Cell Isolation Kit, human). The cells are counted and resuspended at 210.sup.5 cells/mL in diluent (RPMI 1640+10% fetal calf serum (FCS)).

[0284] TNF-.alpha. Secretion by Purified pDCs

[0285] This suspension (205 .mu.L/well) is then transferred to a 24-well flat-bottom culture plate. CpG ODN (10 .mu.M, 50 .mu.L), IL-3 (100 ng/mL, 50 .mu.L), antibody (100 .mu.g/mL, 50 .mu.L) and diluent (100 .mu.L) are added. The plate is then incubated overnight at 37.degree. C., 7% CO.sub.2.

[0286] TNF-.alpha. Assay

[0287] The culture supernatants of each well are collected and assayed by flow cytometry by using the FlowCytomix Human IFN-.alpha. Kit (Bender MedSystems BMS216FF+Basic kit BMS842OFF).

[0288] The percentage of inhibition of each sample is evaluated in relation to the negative control (CPG-activated pDCs without anti-CD303 monoclonal antibody).

[0289] The samples leading to less than 20% inhibition are considered non-inhibitors, those leading to between 20% and 75% inhibition are considered weak inhibitors, those leading to greater than 75% inhibition are considered strong inhibitors.

[0290] Measurement of Complement-Dependent Cytotoxicity (CDC) Activity

[0291] Fc.gamma. chain-CD303 Jurkat cells are incubated with increasing concentrations of anti-CD303 antibody (0 to 5,000 ng/mL) and in the presence of baby rabbit serum as source of (1:10 dilution).

[0292] After 2 hours of incubation at 37.degree. C., the amount of intracellular lactate dehydrogenase (LDH) enzyme released into the supernatant by the lysed target cells is measured with the Cytotoxicity Detection Kit (LDH) (Roche Diagnostics, product no. 11644793001).

[0293] Results

[0294] Antigen-Binding

[0295] Binding to Fc.gamma. Chain-CD303 Jurkat Cells

[0296] The results of the tests for binding of the antibodies according to the invention to their CD303 antigen on Fc.gamma. chain-CD303 Jurkat cells are presented in FIG. 2A and in Table 20 below.

TABLE-US-00020 TABLE 20 Binding of the antibodies according to the invention to their CD303 antigen on Fc.gamma. chain-CD303 Jurkat cells. 104C12 122A2 114D11 102C9 104E10 Bmax (MFI) 27.74 26.21 24.69 24.95 23.73 EC50 0.1781 0.1284 3.980 3.870 6.064 (.mu.g/mL) Bmax: maximum binding expressed as mean fluorescence intensity (MFI). EC50 (.mu.g/mL): antibody concentration in .mu.g/mL to obtain 50% of the maximum binding obtained for this antibody.

[0297] These relative Kd results and the Bmax values calculated after dose-response modeling make it possible to classify the antibodies into two groups: A first group that contains the antibodies 104C12 (Bmax: MFI=27.7; Kd=0.17 .mu.g/mL) and 122A2 (Bmax: MFI=26.2 Kd=0.13 .mu.g/mL) which are comparable and exhibit higher relative affinity than the antibodies of the second group: 114D11 (Bmax: MFI=24.7; Kd=3.9 .mu.g/mL), 104E10 (Bmax: MFI=23.7; Kd=6 .mu.g/mL) and 102E9 (Bmax: MFI=24.9; Kd=3.8 .mu.g/mL).

[0298] These results show that all the chimeric antibodies generated efficiently bind the CD303 antigen expressed on the surface of Jurkat cells, for which they are specific.

[0299] Binding to CAL-1 Cells

[0300] The results of the tests for binding of the chimeric antibodies according to the invention to their CD303 antigen on CAL-1 cells are presented in FIG. 2B and in Table 21 below.

TABLE-US-00021 TABLE 21 Binding of the chimeric antibodies according to the invention to their CD303 antigen on CAL-1 cells. 104C12 122A2 114D11 102E9 104E10 Bmax (MFI) 29.02 25.22 30.14 30.47 29.2 EC50 0.3447 0.2075 1.704 1.813 1.932 (.mu.g/mL) Bmax: maximum binding expressed as mean fluorescence intensity (MFI). EC50 (.mu.g/mL): antibody concentration in .mu.g/mL to obtain 50% of the maximum binding obtained for this antibody.

[0301] These relative Kd results and the Bmax values calculated after dose-response modeling make it possible to classify the antibodies into two groups: A first group that contains the antibodies 104C12 (Bmax: MFI=29.02 Kd=0.34 .mu.g/mL) and 122A2 (Bmax: MFI=25.2 Kd=0.20 .mu.g/mL) which are comparable and exhibit higher relative affinity than the antibodies of the second group: 114D11 (Bmax: MFI=30.1; Kd=1.7 .mu.g/mL), 104E10 (Bmax: MFI=29.2; Kd=1.93 .mu.g/mL) and 102E9 (Bmax: MFI=30.47; Kd=1.81 .mu.g/mL).

[0302] These results notably correlate with the results for binding to Jurkat-CD303 cells.

[0303] In another experiment, the CAL-1 cell-binding of chimeric antibodies 122A2 and 102E9 and of humanized antibody BIIB059 was tested. The results are presented in FIG. 2C and in Table 22 below.

TABLE-US-00022 TABLE 22 Binding of the chimeric antibodies according to the invention, 122A2 and 102E9, and of humanized antibody BIIB059 to their CD303 antigen on CAL-1 cells. 122A2 102E9 BIIB059 Bmax 13.2 14.7 11.8 EC50 (.mu.g/mL) 0.06 0.44 0.6 Relative EC50 1 6.9 9.3 (122A2 = 1) Bmax: maximum binding expressed as mean fluorescence intensity (MFI). EC50 (.mu.g/mL): antibody concentration in .mu.g/mL to obtain 50% of the maximum binding obtained for this antibody.

[0304] These data show that the two chimeric antibodies according to the invention, 122A2 and 102E9 (and in particular chimeric antibody 122A2), bind more strongly than humanized antibody 6116059 to the CD303 antigen on the surface of CAL-1 cells.

[0305] Binding to CAL-1 Cells Overexpressing the CD303 Antigen

[0306] The results of the tests for binding of the chimeric antibodies 122A2 and 102E9 according to the invention and of humanized antibody 6116059 to their CD303 antigen on CAL-1 cells transfected with a CD303 expression vector and expressing about 40,000-50,000 CD303 molecules/cell (or about 10 times more than wild-type CAL-1 cells) are presented in FIG. 2D and in Table 23 below.

TABLE-US-00023 TABLE 23 Binding of the chimeric antibodies according to the invention, 122A2 and 102E9, and of humanized antibody BIIB059 to their CD303 antigen on CAL-1 cells transfected with a CD303 expression vector and expressing about 40,000-50,000 CD303 molecules/cell (or about 10 times more than wild-type CAL-1 cells). 122A2 102E9 BIIB059 Bmax 458.1 366.2 382.2 EC50 (.mu.g/mL) 0.142 0.3629 0.7841 Relative EC50 1 2.56 5.52 (122A2 = 1) Bmax: maximum binding expressed as mean fluorescence intensity (MFI). EC50 (.mu.g/mL): antibody concentration in .mu.g/mL to obtain 50% of the maximum binding obtained for this antibody.

[0307] These data again show that the two chimeric antibodies according to the invention, 122A2 and 102E9 (and in particular chimeric antibody 122A2), bind more strongly than humanized antibody 6116059 to the CD303 antigen on the surface of CAL-1 cells transfected with a CD303 expression vector and expressing about 40,000-50,000 CD303 molecules/cell.

[0308] Fc.gamma.RIIIa (CD16a)-Binding

[0309] The results of the tests for binding to Fc.gamma.RIIIa (CD16a) of the five chimeric antibodies according to the invention are presented in FIG. 3A, and show that the chimeric antibodies according to the invention are all capable of efficiently binding CD16a, with an optimized binding affinity. They have an IC50 value below that of the antibody produced in CHO cells (Rituxan), in a range of 18.08 to 45.02 .mu.g/mL, even below 18 .mu.g/mL, as illustrated in Table 24 below.

TABLE-US-00024 TABLE 24 IC50 values (concentration of anti-CD303 antibody necessary to induce 50% inhibition of 3G8-binding) of the control (Rituxan) and of the chimeric antibodies of the invention. RITUXAN 104C12 122A2 114D11 102E9 104E10 IC50 >80 26.75 40.44 45.02 36.99 18.08 (.mu.g/mL)

[0310] The results of the tests for Fc.gamma.RIIIa (CD16a)-binding of the two chimeric antibodies according to the invention, 122A2 and 102E9, and of humanized antibody BIIB059 are presented in FIG. 3B and in Table 25 below, and show that the two chimeric antibodies according to the invention, 122A2 and 102E9, bind to Fc.gamma.RIIIa (CD16a) much more strongly than the antibodies Rituxan and BIIB059.

TABLE-US-00025 TABLE 25 IC50 values (concentration of anti-CD303 antibody necessary to induce 50% inhibition of 3G8-binding) of the control (Rituxan), of the chimeric antibodies of the invention 122A2 and 102E9, and of humanized antibody BIIB059. Antibody IC50 .mu.g/mL (50%) Rituxan >83 122A2 13 102E9 13 BIIB059 >83

[0311] ADCC

[0312] The results of the tests for ADCC of the five chimeric antibodies according to the invention on Fc.gamma. chain-CD303 Jurkat target cells are presented in FIG. 4A and in Table 26 below.

TABLE-US-00026 TABLE 26 ADCC induced by the antibodies according to the invention on Fc.gamma. chain-CD303 Jurkat target cells. 104C12 122A2 114D11 102E9 104E10 Emax 41.81 42.35 37.44 38.92 40.54 (% lysis) EC50 0.2143 0.1592 3.612 3.424 8.280 (ng/mL) Emax: maximum lysis obtained with this antibody, expressed as a percentage of lysis. EC50 (ng/mL): concentration of antibody in ng/mL to obtain 50% of the maximum lysis obtained for this antibody.

[0313] These results show that the five anti-CD303 chimeric antibodies induce lysis of Jurkat-CD303 cells (Emax about 40%). The EC50 values for 104C12 (EC50: 0.21 ng/mL), 122A2 (EC50: 0.16 ng/mL), 114D11 (EC50: 3.6 ng/mL), 102E9 (EC50: 3.4 ng/mL) and 104E10 (EC50: 8.3 ng/mL) suggest that the antibodies having high affinity are more effective with regard to ADCC than the antibodies having lower affinity.

[0314] The results of the tests for ADCC of an irrelevant antibody (anti-factor VIII inhibitor antibodies, Anti Id FVIII), of the two chimeric antibodies according to the invention, 122A2 and 102E9, and of humanized antibody B1113059 on CAL-1 target cells are presented in FIG. 4B and in Table 27 below.

TABLE-US-00027 TABLE 27 ADCC induced by the antibodies according to the invention on Fc.gamma. chain-CD303 Jurkat target cells. Anti Id FVIII 122A2 102E9 BIIB059 Emax nd 7.04 8.38 1.12 (% lysis) EC50 nd 0.93 3.80 nd (ng/mL) Emax: maximum lysis obtained with this antibody, expressed as a percentage of lysis. EC50 (ng/mL): concentration of antibody in ng/mL to obtain 50% of the maximum lysis obtained for this antibody. nd: not detectable.

[0315] These results show that, unlike humanized antibody 6116059, the two chimeric antibodies according to the invention, 122A2 and 102E9, are capable of inducing lysis of CAL-1 cells very weakly expressing the CD303 antigen. Moreover, the stronger ADCC response of the chimeric antibody according to the invention 122A2 compared to the chimeric antibody according to the invention 102E9 also suggests than the antibodies having high affinity are more effective with regard to ADCC than the antibodies having lower affinity.

[0316] Inhibition of IFN-.alpha. Secretion

[0317] The results of the tests for inhibition of IFN-.alpha. secretion by activated pDCs are presented in FIG. 5.

[0318] These results show that the five anti-CD303 chimeric antibodies induce inhibition of IFN-.alpha. secreted by CpG-activated pDCs and this at both concentrations tested (10 and 0.1 .mu.g/mL). At the concentration of 0.1 .mu.g/mL, the IFN-.alpha. assays show an advantage for antibodies 104C12 and 122A2 compared to the other three antibodies (114D11, 102E9, 104E10).

[0319] Inhibition of TNF-.alpha. Secretion

[0320] The results of the tests for inhibition of TNF-.alpha. secretion by activated pDCs are presented in FIG. 6.

[0321] These results show that the five anti-CD303 chimeric antibodies at 10 .mu.g/mL induce inhibition of TNF-.alpha. secreted by CpG-activated pDCs.

[0322] Complement-Dependent Cytotoxicity (CDC) Activity

[0323] The results of the CDC tests are presented in FIG. 7, and show that the five chimeric antibodies indeed have CDC activity.

Example 3. Preparation and Characterization of Humanized Antibodies Derived from Chimeric Antibodies 122A2 and 102E9

[0324] Materials and Methods

[0325] Definition of Humanized Sequences

[0326] A work of humanization in silico, making use of the IMGT.org database and modeling, was undertaken to define various sequences of the variable portions of the heavy and light chains containing "human amino acids" instead of their murine homologues.

[0327] For each VH or VL domain, the human gene encoding a VH or VL domain having the amino acid sequence closest to that of the murine sequence of the original chimeric antibody was determined. The closest human VH and VL genes determined for chimeric antibodies 122A2 and 102E9 are mentioned in Table 28 below:

TABLE-US-00028 TABLE 28 The human VH and VL genes closest to the murine sequences of the original chimeric antibody (IMGT nomenclature). VH VL 122A2 IGHV1-2*02 IGKV1-33*01 102E9 IGHV7-4-1*02 IGKV1-9*01

[0328] For each VH and VL domain, based on an alignment between the murine amino acid sequence of the original chimeric antibody and the amino acid sequence of the closest human gene, the different mutation positions between the two amino acid sequences (murine/human) were determined, and several murine sequences incorporating a variable number of mutations replacing a murine amino acid with a human amino acid were generated.

[0329] Thus, for each of antibodies 122A2 and 102E9, three versions of each heavy chain variable portion (Hha, Hhb and Hhc) and light chain variable portion (Kha, Khb and Khc) were determined. A fourth version of the light chain variable portion (Khd) is added, concerning antibody 122A2. These various sequences comprise variable numbers of mutations relative to the VH and VL regions of the original chimeric antibody, as described in Table 29 below:

TABLE-US-00029 TABLE 29 Mutations of the amino acid sequences of the VH and VL regions of the humanized antibodies derived from chimeric antibodies 122A2 and 102E9, compared to the VH and VL regions of the original chimeric antibody. For each VH or VL domain, the sequence with the minimum number of mutations relative to the VH and VL regions of the original chimeric antibody is indicated by **. The additional mutations of the other sequences relative to the sequence indicated by ** are underlined. Number of mutations relative to the chimeric Mutations* antibody Humanized antibodies derived from chimeric antibody 122A2 122A2 Hha** L12V/R14K/V17A/S45A/A76V/T85S/A92S/E97D/ 11 VH S99T/I101V/S123L humanized Hhb L12V/R14K/V17A/K43R/S45A/A76V/K82T/T85S/ 14 A92S/T95R/E97D/S99T/I101V/S123L Hhc L12V/R14K/V17A/K43R/S45A/ 16 H46P/A47G/K48Q/S49G/A76V/T85S/ A92S/E97D/S99T/I101V/S123L 122A2 Kha** T7S/S22T/R24Q/S69T/F103Y 5 VL Khb T7S/T8P/L15V/S22T/R24Q/S69T/F103Y 7 humanized Khc T7S/S22T/R24Q/R66N/S69T/D95Q/F103Y 7 Khd T7S/T8P/L15V/S22T/R24Q/R66N/S69T/D95Q/ 9 F103Y Humanized antibodies derived from chimeric antibody 102E9 102E9 Hha** D11E/T18S/K48Q/A77V/E81D/S82T/A84V/F88Y/ 10 VH N93S/F103Y humanized Hhb D11E/T18S/K43R/K48Q/D69Q/A77V/E81D/S82T/ 12 A84V/F88Y/N93S/F103Y Hhc P9S/D11E/T18S/K43R/K48Q/D69Q/A77V/E81D/ 13 S82T/A84V/F88Y/N93S/F103Y 102E9 Kha V3Q/A9S/I10F/M11L/K18R/T48K/S49A/A74S/ 12 VL S86E/S88T/R93S/A99F humanized Khb** V3Q/A9S/I10F/M11L/K18R/S49A/A74S/S88T/A99F 9 Khc V3Q/A9S/I10F/M11L/E17D/K18R/T48K/S49A/ 14 A74S/S86E/S88T/R93S/E95Q/A99F **The position of the amino acid residues corresponds to IMGT unique numbering.

[0330] Preparation of the Expression Vectors

[0331] The various sequences were synthesized as linear double-stranded DNA, called "String", with codon optimization for Rattus norvegicus.

[0332] The construction of the expression vectors encoding the humanized anti-CD303 antibodies is carried out by homologous recombination, by means of the In-Fusion.RTM. HD Cloning Kit (Clontech.RTM. Laboratories). The expression vector selected for each Ig heavy and light chain is the commercial vector pCEP4 (Invitrogen). It has the advantage of being highly productive when used in combination with the human cell line FreeStyle HEK-293, a line used to produce sufficient amounts of antibody quickly in order to carry out certain tests. pCEP4 is monocistronic, 10,186 bp in size and has all the elements necessary for expressing the genes of interest, i.e., an ampicillin-resistance gene, an origin of replication (pUC origin), a CMV promoter and an SV40 poly A (see FIG. 8A). The sequences of interest are cloned between the NheI and XhoI restriction sites, and downstream of the promoter (see FIGS. 8B-8N). First, digestion by these enzymes is carried out in order to open the vector where desired. Purification using the NucleoSpin Plasmid Kit (Macherey-Nagel) is then necessary to purify the linearized vector, reduced to 10,163 bp. In parallel with the synthesis of the variable portions, the constant portions of the heavy and light chains were prepared by PCR amplification, using vector CHK622-21 as matrix, and containing the constant portions of the H and K chains optimized for Rattus norvegicus. This PCR was carried out using a high-fidelity DNA polymerase, Herculase II Fusion (Agilent Technologies) and primers defined so as to add, to the constant portions, restriction sites for cloning at their 3' ends, as well as 15 bp complementary to the vector to allow recombinational cloning. Once the PCR is carried out, a purification gel (1.25% low agarose) is run to confirm that the fragments of interest were indeed amplified and as a means to recover said fragments. The samples are caused to migrate through the purification gel under low voltage to provide good separation of the DNA fragments.

[0333] Once all the gene elements are prepared, they can be assembled by means of the In-Fusion.RTM. kit. Thus, the mixture, i.e., the linearized vector (0.5 .mu.L), the "string" (1 .mu.L) at an initial concentration of 50 ng/.mu.L, and the heavy or light chain constant portion (1 .mu.L) brought up to 10 .mu.L with sterile water, is added into the kit's tube containing the lyophilized product notably consisting of the high-fidelity PCR enzyme CloneAmp.TM. HiFi. The mixture is then incubated for 15 minutes at 37.degree. C., then 15 minutes at 50.degree. C. In parallel, ligation with only the linearized vector, without the variable and constant portions, is carried out and will be used as the negative control for the experiment.

[0334] The vectors were then cloned into highly competent E. coli NEB 5-alpha bacteria, and the sequences of the various clones of each vector were confirmed by sequencing. When the clone is declared to match in sequence, a bacterial culture (300 mL) of the selected clone is prepared in order to purify the vector of interest contained therein, using the NucleoBond Xtra EF kit (Macherey-Nagel). The plasmids obtained are sterile and in sufficient amounts to carry out cotransfections in the production line.

[0335] Production of the Antibodies in FreeStyle HEK-293 Cells

[0336] The antibodies are produced by transient cotransfection from the FreeStyle human embryonic kidney (HEK)-293 cell line. This last is an immortalized cell line that has the capacity to proliferate in suspension and in the absence of serum. This HEK line, cultured in Freestyle F17 Expression Medium (Life Technologies), supplemented with 8 mM glutamine, also allows greater and faster productivity of recombinant proteins.

[0337] During the cotransfections, the controls used to validate the experiments are the growth control, which corresponds to an HEK cell culture not having undergone transfection, and a line that has been transfected with a vector, pMAX, encoding a fluorescent protein, GFP, which is used after 24 hours to determine the transfection rate. The buffer used to dilute the DNA, the transfection agent and the cells is OptiMEM.RTM. (Life Technologies). Polyethylenimine (PEI) is the transfection agent (TA), which will make it possible to introduce the vectors into the cells. A 1:2 ratio of DNA to TA and a 1:3 ratio of vector comprising the H chain to vector comprising the K chain are observed. After contacting the DNA/TA complex with the cells, the latter are then cultured with shaking at 37.degree. C., with 8% CO.sub.2.

[0338] At the conclusion of 7 days of production post-cotransfection, the cell cultures are centrifuged for 15 minutes at 3,000 g. The clarified supernatant, containing the antibodies produced, is collected and assayed using a commercial kit, FastELISA (RD-Biotech), in order to precisely estimate the amount of antibody of each supernatant for carrying out thereafter affinity studies of the humanized antibodies with respect to the CD303 protein.

[0339] Production of Certain Humanized Derivatives of Chimeric Antibody 122A2 by YB2/0 Clones Stably Transfected with an Expression Vector

[0340] YB2/0 clones were stably transfected with an expression vector comprising nucleic sequences encoding humanized antibodies 122A2H5, 122A2H7, 122A2H9 and 122A2H10 derived from chimeric antibody 122A2. The antibodies were then produced and their amount in the supernatant was assayed.

[0341] From the monocistronic vectors used for transient transfection in the HEK line, the light chains (122A2H5: pCEP4_Kha_122 A2; 122A2H9: pCEP4_Khb_122 A2; 122A2H10: pCEP4_Khb_122 A2; 122A2H7: pCEP4_Kha_122 A2) were introduced by SpeI-XbaI digestion into the HKgenEFss vector to obtain an intermediate vector. Then, on these intermediate vectors, NheI-AscI digestion was carried out to introduce the heavy chain (122A2H5: pCEP4_Hha_122 A2; 122A2H9: pCEP4_Hha_122 A2; 122A2H10: pCEP4_Hhb_122 A2; 122A2H7: pCEP4_Hhc_122 A2).

[0342] Characterization of the Antigen-Binding of the Antibodies Produced, by ELISA

[0343] The study of the binding capacity of the various antibodies produced in FreeStyle HEK-293 cells is carried out by enzyme-linked immunosorbent assay (ELISA).

[0344] This technique, which uses a colorimetric approach, makes it possible to detect and visualize antigen-antibody interactions. The principle of ELISA is, first, to coat each well of a MaxiSorp plate with 10 ng of the antigen, in this case the CD303 ectodomain. The latter was purchased from the supplier Mybiosource. Second, the various antibodies produced, contained in the supernatant, are all diluted to the same concentration, and contacted with the antigen to allow them to bind. A third step consists in adding the secondary antibodies, HRP-conjugated anti-human antibody, necessary for amplified detection of the antigen-binding of the anti-CD303 antibodies. Lastly, detection is carried out using a solution containing the substrate for the enzyme (3,3',5,5'-tetramethylbenzidine, or TMB). The appearance of coloring of the substrate indicates the formation of the antigen-antibody complex. The intensity of this coloring is proportional to the amount of enzyme present and thus to the amount of antibody tested bound to the antigen. The reaction is stopped by adding H.sub.2SO.sub.4 (acid). These colors are read using a spectrophotometer at a wavelength of 450 nm.

[0345] Characterization of the Antigen-Binding of the Antibodies Produced, by Flow Cytometry

[0346] With the aim of confirming the results obtained by ELISA, the various antibodies produced in FreeStyle HEK-293 cells are evaluated by flow cytometry. Flow cytometry makes it possible to confirm that, in a cellular context, the recombinant antibody is capable of binding to its antigen, and thus to confirm the results obtained by ELISA.

[0347] The line used to carry out this technique, CAL-1, is a leukemic cell line of plasmacytoid dendritic cells obtained from a BPDCN patient. The antibodies produced were tested in supernatant, but also in forms purified by affinity chromatography with protein A-sepharose (not elaborated upon herein).

[0348] For cell staining, the cells and the antibodies are prediluted with PBS/1% FCS. In a 100 .mu.L reaction volume, 110.sup.5 cells are incubated at 4.degree. C. for 30 minutes with the anti-CD303 antibodies to be tested, at two concentrations: 0.1 .mu.g/mL or 1 .mu.g/mL. This incubation is followed with several washings. The cell/antibody complexes thus formed are then contacted for 30 minutes at 4.degree. C. with the secondary antibody diluted 1:50, an anti-human IgG Fc F(ab').sub.2 coupled to a fluorochrome, phycoerythrin. The cells are finally washed and studied by flow cytometry (FC500, Beckman Coulter), by measuring notably the mean fluorescence intensity (MFI). Various negative controls are used to eliminate possible nonspecific binding, such as: the cells alone or directly in contact with the secondary antibody, or replacing the antibody tested with an irrelevant chimeric antibody (factor VIII anti-idiotype). Finally, other controls, such as the use of the supernatant (mock), make it possible to show that the latter does not influence the affinity of the antibodies to the membrane antigen.

[0349] Inhibition of IFN-.alpha. Secretion

[0350] Preparation of the Cells

[0351] Peripheral blood mononuclear cells (PBMCs) are isolated from peripheral blood of healthy donors by Ficoll density gradient. 10.sup.7 cells/well (200 .mu.L) are transferred to a 24-well flat-bottom culture plate, in the presence of 1 .mu.M CpG ODN 2216-1 (Invivogen) and 10 ng/mL IL-3 (product no.: 130-093-909, Miltenyi Biotec). The anti-CD303 or irrelevant antibodies were added at various concentrations (0 to 1 .mu.g/mL) in RPMI 10% FCS medium. The plate was then incubated overnight at 37'C with 7% CO.sub.2.

[0352] IFN-.alpha. Assay

[0353] The culture supernatants of each well are collected and assayed by ELISA by using the Human IFN-u Module Set kit (product no.: BMS216MST, eBioscience).

[0354] Induction of IL-2 Secretion by Jurkat-CD16 Cells

[0355] This test evaluates the capacity of the anti-CD303 antibodies to bind to CD16 (Fc.gamma. receptor III) expressed on CD16 Jurkat cells and to induce IL-2 secretion.

[0356] This test consists in contacting, in a 96-well plate: anti-CD303 antibodies, target cells expressing CD303, CD16 Jurkat cells and phorbol myristate acetate (PMA).

[0357] After incubating at 37.degree. C. overnight, the plates are centrifuged and the amount of IL-2 secreted is assayed in the supernatant.

[0358] Results

[0359] Cotransfection of the Vectors Produced in HEK-293F Cells

[0360] From vectors expressing the humanized heavy and light chain sequences, various heavy (H) chain/light (L or K) chain combinations were produced by transient cotransfection in HEK-293F cells, in order to produce various representative versions of the two candidate antibodies. In this manner, the following were produced (see Table 30 below):

[0361] 1. hybrid antibodies (one of the two Ig chains is humanized, the other is chimeric), and

[0362] 2. humanized antibodies.

TABLE-US-00030

[0362] TABLE 30 Names of the hybrid or humanized antibodies derived from chimeric antibodies 122A2 and 102E9, as a function of the humanized heavy and light chains used. Derivatives of chimeric antibody 122A2 122A2-H 122A2-Hha 122A2-Hhb 122A2-Hhc 122A2-K 122A2 122A2H1 122A2H2 122A2H3 (chimeric) (hybrid) (hybrid) (hybrid) 122A2-Kha 122A2H4 122A2H5 122A2H6 122A2H7 (hybrid) (humanized) (humanized) (humanized) 122A2-Khb 122A2H8 122A2H9 122A2H10 122A2H11 (hybrid) (humanized) (humanized) (humanized) 122A2-Khc 122A2H12 122A2H13 122A2H14 122A2H15 (hybrid) (humanized) (humanized) (humanized) 122A2-Khd 122A2H16 122A2H17 122A2H18 122A2H19 (hybrid) (humanized) (humanized) (humanized) Derivatives of chimeric antibody 102E9 102E9-H 102E9-Hha 102E9-Hhb 102E9-Hhc 102E9-K 102E9 102E9H1 102E9H2 102E9H3 (chimeric) (hybrid) (hybrid) (hybrid) 102E9-Kha 102E9H4 102E9H5 102E9H6 102E9H7 (hybrid) (humanized) (humanized) (humanized) 102E9-Khb 102E9H8 102E9H9 102E9H10 102E9H11 (hybrid) (humanized) (humanized) (humanized) 102E9-Khc 102E9H12 102E9H13 102E9H14 102E9H15 (hybrid) (humanized) (humanized) (humanized)

[0363] During the various transient cotransfections carried out to produce the set of 36 molecules, transfection efficiency was determined on day 1 using the vector pMAX.

[0364] At the conclusion of production on day 7, the supernatants, containing the proteins produced, are collected, centrifuged, filtered and finally assayed to measure the titer in IgG produced (see Tables 31 and 32 below). The concentrations thus obtained vary as a function of the type of H chain and K chain, i.e., chimeric or humanized, possessed by the various versions of the antibodies produced.

TABLE-US-00031 TABLE 31 Concentrations in .mu.g/mL on day 7 of the various supernatants containing the antibodies produced (chimeric antibody 122A2 and hybrid or humanized derivatives thereof), determined using the FastELISA kit. Concentration Heavy Light on day 7 Antibody chain chain (.mu.g/mL) Original chimeric antibody 122A2 H K 0.75 Hybrid antibodies 122A2H1 Hha K 0.13 122A2H2 Hhb K 0.42 122A2H3 Hhc K 0.67 122A2H4 H Kha 1.18 122A2H8 H Khb 1.17 122A2H12 H Khc 1.41 122A2H16 H Khd 1.33 Humanized antibodies 122A2H5 Hha Kha 5.37 122A2H9 Hha Khb 4.41 122A2H13 Hha Khc 6.40 122A2H17 Hha Khd 7.75 122A2H6 Hhb Kha 43.57 122A2H10 Hhb Khb 69.28 122A2H14 Hhb Khc 55.20 122A2H18 Hhb Khd 69.40 122A2H7 Hhc Kha 50.80 122A2H11 Hhc Khb 44.76 122A2H15 Hhc Khc 31.96 122A2H19 Hhc Khd 19.15

TABLE-US-00032 TABLE 32 Concentrations in .mu.g/mL on day 7 of the various supernatants containing the antibodies produced (chimeric antibody 102E9 and hybrid or humanized derivatives thereof), determined using the FastELISA kit. Concentration Heavy on day 7 Antibody chain Light chain (.mu.g/mL) Original chimeric antibody 102E9 H K 3.4 Hybrid antibodies 102E9H1 Hha K 6.8 102E9H2 Hhb K 5.3 102E9H3 Hhc K 2.2 102E9H4 H Kha 1.8 102E9H8 H Khb 1.4 102E9H12 H Khc 1.5 Humanized antibodies 102E9H5 Hha Kha 22.9 102E9H9 Hha Khb 11.6 102E9H13 Hha Khc 18.3 102E9H6 Hhb Kha 15.3 102E9H10 Hhb Khb 9.9 102E9H14 Hhb Khc 17.2 102E9H7 Hhc Kha 7.7 102E9H11 Hhc Khb 4.9 102E9H15 Hhc Khc 9.9

[0365] It can be noted that the antibody concentration is dependent on the combinations produced but also on the type of H and/or K chain (humanized or chimeric). In this context, the productivity of chimeric antibodies 122A2 and 102E9, as well as that of most of the hybrids (combination of a chimeric H or K chain and a humanized H or K chain, as indicated above), is much lower than the rest of the molecules. This observation is related to expression of the chimeric H and K chains, which is unfavorable to satisfactory cellular expression.

[0366] What differentiates the chimeric antibodies from the humanized antibodies are the amino acids that have been mutated; the variations in productivity are uniquely dependent on a few amino acids.

[0367] Thus, for the antibodies derived from 102E9, the hybrid antibodies having the chimeric heavy or light chain and the humanized antibodies with the Hhc heavy chain (102E9H7, 102E9H11 and 102E9H15) all have lower productivity.

[0368] In the case of the antibodies derived from 122A2, it is the chimeric K and humanized H Hha chains that lead to lower productivity. Chimeric antibody 122A2 is found to have the lowest productivity compared to certain of its hybrid and humanized derivatives. Fortuitously, humanization made it possible to increase the volume titer by up to a factor of 100, in the case of 122A2H10 (Hhb, Khb).

[0369] Lastly, it is noted that humanized antibodies 122A2 are produced better overall than humanized antibodies 102E9. That confirms that expression of antibodies of the same isotype is highly dependent on their primary sequence and chiefly on their variable portions.

[0370] Characterization of the Antigen-Binding of the Antibodies Produced, by ELISA

[0371] ELISAs were carried out from the culture supernatants collected after production. First, they are all diluted to the same concentration, so that all the samples are under the same conditions. Furthermore, the initial dilutions are made using centrifuged, filtered supernatant from the cell cultures used as growth controls during the transfections. These cultures do not express an antibody, and are thus referred to as "mock" cultures. The samples are then diluted to half, on MaxiSorp 96-well plates, using buffer containing PBS, 4% BSA and 0.05% Tween.

[0372] All the antibodies produced, whether derived from 122A2 or 102E9, give a color signal whose intensity is quantifiable when read by spectrophotometry. This may be interpreted as being the capacity of the various antibodies to bind specifically to the CD303 ectodomain. There are however differences in affinity for the antigen, which are expressed as differences in OD.sub.450.

[0373] Thus, it was possible, for each antibody produced, to graphically represent OD.sub.450 as a function of antibody concentration. The result is a biphasic curve with an exponential phase leading to a plateau. This graphical representation made it possible to classify the antibodies tested and the chimeric antibody from which they are derived as a function of their affinity for the CD303 antigen.

[0374] In the case of the antibodies derived from 102E9, the antibodies deposited in each well range from 1.25 ng/mL to 20 ng/mL. Saturation of the OD.sub.450 signal appears as of a concentration of about 10 ng/mL antibody. FIG. 9 shows the results obtained for the various humanized antibodies. A concentration of 5 ng/mL is used to classify the humanized antibodies (FIG. 10).

[0375] None of the humanized antibodies binds to the CD303 antigen as well as the chimeric antibody. Nevertheless, all the humanized antibodies preserve a reasonable capacity to bind to the CD303 antigen. Humanized antibody 102E9H10 has the best CD303 antigen-binding capacity among all the humanized antibodies. It represents a loss of binding of only about 20% compared to the original chimeric antibody, 102E9 (FIG. 10). Three other humanized antibodies, 102E9H6, 102E9H7 and 102E9H9, also have a binding capacity similar to the reference chimeric antibody. They have a CD303 ectodomain-binding capacity of 73% (102E9H6), 76% (102E9H7) and 71% (102E9H9), respectively.

[0376] In the case of the antibodies derived from 122A2, the antibody concentrations tested range from 1.75 to 10 ng/mL. The controls used are the same ones as before: the supernatant alone (mock) and the chimeric antibody, here 122A2. FIG. 11 shows the results obtained for the various humanized antibodies. A concentration of 5 ng/mL is used to classify the humanized antibodies (FIG. 12).

[0377] All the antibodies tested are capable of binding to the CD303 ectodomain. The "supernatant" negative control sample has an OD.sub.450 near zero. There is thus no nonspecific binding due to the supernatant. Moreover, a dose-response effect is also observed for all the samples tested. Most of the curves representing the various humanized antibodies are similar in appearance to that of chimeric antibody 122A2.

[0378] Lastly, several humanized antibodies of 122A2 (122A2H5, 122A2H6, 122A2H7, 122A2H9, 122A2H10, 122A2H11, 122A2H14 and 122A2H15) appear to have a CD303 ectodomain-binding capacity at least equal to (122A2H11 and 122A2H15), and sometimes significantly higher than (122A2H5, 122A2H6, 122A2H7, 122A2H9, 122A2H10, and 122A2H14), that of the chimeric antibody.

[0379] Characterization by Flow Cytometry of the Antigen-Binding of the Antibodies Produced

[0380] Antibody-binding was also studied by flow cytometry to confirm the results obtained by ELISA.

[0381] For antibody 102E9, humanized antibodies 102E9H10, 102E9H6, 102E9H7, 102E9H9 and chimeric antibody 102E9 were selected to be characterized by this technique.

[0382] For antibody 122A2, humanized antibodies 122A2H5, 122A2H6, 122A2H9, 122A2H7, 122A2H10, 122A2H14, 122A2H17, 122A2H15, hybrid antibodies 122A2H8, 122A2H3 and chimeric antibody 122A2 in supernatant were selected for the characterization. 122A2H8 represents the best hybrid antibody with affinity higher than that of the chimeric antibody, while 122A2H3 has much lower affinity than that of the parent antibody. The humanized antibodies selected count among those that have better affinity for the target protein compared to the original chimeric antibody.

[0383] In the case of antibody 102E9, there are few differences between the humanized and the chimeric antibodies (not illustrated here).

[0384] In the case of antibody 122A2, the results are presented in FIG. 13 (which represents the mean fluorescence for each antibody tested, at a concentration of 0.1 .mu.g/mL), and show that certain humanized antibodies (tested in supernatant) show better affinity compared to chimeric antibody 122A2. That is the case notably of humanized antibodies 122A2H5, 122A2H9, 102E9H7, and 122A2H10. The other humanized antibodies previously identified by ELISA as having a binding capacity at least equal to that of the chimeric antibody and tested by flow cytometry (122A2H14 and 122A2H15) have in the cytometry test binding (MFI) that is slightly lower than that of the chimeric antibody, but that remains close to that of the chimeric antibody. Consequently, the results obtained by flow cytometry back up those previously obtained by ELISA.

[0385] The same antibodies were evaluated in purified form and they show the same results.

[0386] Inhibition of IFN-.alpha. Secretion

[0387] CpG motifs induce IFN-.alpha. secretion from pDCs contained in PBMCs. In this experiment (FIG. 14), inhibition of IFN-.alpha. secretion mediated by various anti-CD303 antibodies (chimeric 122A2 and four humanized antibodies 122A2) were compared.

[0388] The IC50 values (Table 33 below) were:

[0389] 0.95 ng/mL for chimeric antibody ch.122A2,

[0390] 0.81 ng/mL for humanized antibody h122A2H5,

[0391] 0.86 ng/mL for humanized antibody h122A2H7,

[0392] 0.91 ng/mL for humanized antibody h122A2H9, and

[0393] 0.94 ng/mL for humanized antibody h122A2H10.

TABLE-US-00033

[0393] TABLE 33 50% inhibitory concentrations (IC50) for IFN- .alpha. secretion from pDCs contained in PBMCs. IC50 (ng/mL) Irrelevant control mAb n/a ch.122A2 0.9589 M22A2H5 0.8186 M22A2H7 0.8647 M22A2H9 0.9108 M22A2H10 0.9472 n/a: not applicable.

[0394] These results show that the four humanized monoclonal antibodies 122A2 tested are capable of inhibiting IFN-.alpha. secretion, with an IC50 lower than or equal to that of the chimeric antibody.

[0395] Production by YB2/0 Clones Stably Transfected with an Expression Vector for Humanized Antibodies Derived from Chimeric Antibody 122A2

[0396] Humanized antibodies 122A2H5, 122A2H7, 122A2H9 and 122A2H10, derived from chimeric antibody 122A2, appeared particularly advantageous in terms of productivity and antigen-binding. They were thus selected to produce YB2/0 clones stably transfected with an expression vector for these antibodies.

[0397] The maps of the HKgenEFss vectors expressing humanized antibodies 122A2H5, 122A2H7, 122A2H9 and 122A2H10 are presented in FIGS. 15A to 15D.

[0398] The supernatant assay data for the four clones thus obtained are presented in Table 34 below, and show that these four humanized antibodies can be produced with satisfactory productivity, with antibody 122A2H9 having the best productivity.

TABLE-US-00034 TABLE 34 Assay of the humanized antibody produced in the supernatant of stable YB2/0 clones expressing humanized antibodies 122A2H5, 122A2H7, 122A2H9 and 122A2H10, derived from chimeric antibody 122A2. Antibody Supernatant assay (.mu.g/mL) 122A2H5 17.96 122A2H7 19.8 122A2H9 20.47 122A2H10 19.32

[0399] Induction of IL-2 Secretion by Jurkat-CD16 Cells

[0400] The capacity of humanized antibody 122A2H9, derived from chimeric antibody 122A2 and produced by stable YB2/0 clones, to bind CD16 and to induce IL-2 secretion by Jurkat-CD16 cells was tested and compared to that of chimeric antibody 122A2.

[0401] An exemplary result obtained is presented in FIG. 16. In addition, the results of several experiments are presented in Table 35, expressed below in ng/mL (50%) in Table 1, this value representing the amount of antibody necessary to reach 50% of the plateau of the chimeric antibody. A lower value indicates better activity.

TABLE-US-00035 TABLE 35 Amount of antibody necessary to reach 50% of the plateau of the chimeric antibody, expressed either in ng/mL (upper portion of the table) or as a ratio between the two antibodies, the values for chimeric antibody ch122A2 being arbitrarily set to 1 so as to even out the variations between experiments. 2126 16 2126 16 2126 16 057 059 066 Mean SD 50% (ng/mL) ch122A2 60.57 124 60 92 45 122A2H9 40 97 44 60 31 50%, with ch122A2 = 1 ch122A2 1 1 1 1 0.00 122A2H9 0.66 0.78 0.74 0.73 0.06

[0402] These results show that, despite an Fc fragment sequence identical to that of the chimeric antibody, humanized antibody 122A2H9 induces slightly higher IL-2 secretion by Jurkat-CD16 cells than that of the chimeric antibody.

[0403] Conclusions

[0404] In order to optimize the immunogenic tolerance of the antibodies, humanization was carried out on two of the five chimeric antibodies generated by the inventors, with the objective of preserving similar or not significantly different affinity for the CD303 antigen. To that end, several humanized heavy and light chains were tested in combination for each of the original antibodies, and transfected into HEK-293F cells.

[0405] Following the assay of the samples, it was noted that the antibody concentration is dependent on the original amino acid sequence (humanized antibodies derived from 122A2 are produced better than humanized antibodies derived from 102E9), on the combinations produced, and also on the type of H and/or K chain (humanized or chimeric). These data confirm that, overall, expression of antibodies of the same isotype is highly dependent on their primary sequence and chiefly on their variable portions. Moreover, numerous humanized antibodies, derived from one or the other of the original two chimeric antibodies, are produced better than the original chimeric antibodies.

[0406] The antibodies thus produced were characterized by ELISA. Insofar as the antibodies tested were similar to one another, it was difficult to identify the humanized antibodies having the same antigen-binding characteristics as the original chimeric antibodies. Where the antibodies were tested at several concentrations, the analyses were focused on the concentrations where a real difference in OD.sub.450 between the various antibodies is observed. Thus, a concentration of 5 ng/mL made it possible to show that the best humanized antibody from 102E9, 102E9H10, has a CD303 ectodomain-binding capacity that is 80% of that of the chimeric antibody. In this manner, four humanized antibodies (102E9H10, 102E9H6, 102E9H7 and 102E9H9) were identified and selected to be confirmed by flow cytometry, as humanized antibodies of interest.

[0407] In the case of the humanized antibodies derived from 122A2, several antibodies are clearly identified as of the first ELISA as having a CD303 ectodomain-binding capacity at least equal to (122A2H11 and 122A2H15), indeed higher than (122A2H5, 122A2H6, 122A2H7, 122A2H9, 122A2H10, and 122A2H14), that of the chimeric antibody. These results obtained from the supernatants were supplemented by an orthogonal method using flow cytometry.

[0408] On the whole, the results presented above show that, for each chimeric antibody 122A2 and 102E9, it was possible to generate humanized antibodies (thus with reduced immunogenicity in humans), which can be produced with better productivity than the original chimeric antibody, and which have a CD303 antigen-binding capacity that is:

[0409] At least close to that of the chimeric antibody for the derivatives of chimeric antibody 102E9 (at least 80% for antibody 102E9H10, at least 70% for antibodies 102E9H6, 102E9H7 and 102E9H9).

[0410] At least equal to (122A2H11 and 122A2H15), indeed higher than (122A2H5, 122A2H6, 122A2H7, 122A2H9, 122A2H10, and 122A2H14), that of the chimeric antibody for the derivatives of chimeric antibody 122A2.

[0411] Moreover, humanized antibodies derived from 122A2 are capable of inhibiting IFN-.alpha. secretion as well as chimeric antibody 122A2.

[0412] For certain humanized antibodies derived from 122A2, stably transfected YB2/0 clones were able to be obtained, which produce the antibody with satisfactory productivity. These antibodies have a strong capacity to bind to CD16 and to induce IL-2 secretion by Jurkat-CD16 cells.

BIBLIOGRAPHIC REFERENCES

[0413] Almagro et al. Frontiers in Bioscience 13, 1619-1633, Jan. 1, 2008.

[0414] Brochet, X. et al. Nucl. Acids Res. 36, W503-508 (2008).

[0415] Cao W. J Clin Cell Immunol. 2014 Apr. 22; 5(2):212.

[0416] Cardarelli et al. Clin Cancer Res 2009 Apr. 28; 15:3376-3383.

[0417] Cardarelli et al. Cancer Immunol Immunother. 2010. 59. 257-265,

[0418] Cibelli et al., 1998 Science, 280:1256-1258.

[0419] Dall'Acqua et al. 2002, J Immunol.; 169:5171-80.

[0420] Dall'Acqua et al. 2006, J. Biol. Chem.; 281:23514-24. (a).

[0421] Dall'Acqua et al. J Immunol 2006; 177:1129-1138. (b).

[0422] Dzionek A., et al. (2001) J. Exp. Med. 194, 1823-1834.

[0423] Edelman, G. M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969).

[0424] Ehrenmann F., Kaas Q. and Lefranc M.-P. Nucleic Acids Res., 38, D301-307 (2010).

[0425] Ehrenmann, F., Lefranc, M.-P. Cold Spring Harbor Protoc., 6, 737-749 (2011).

[0426] EP1176195A1.

[0427] Fisher R, et al. Vaccine 21 (2003) 820-825.

[0428] Forthal et al, J Immunol 2010; 185;6876-6882.

[0429] Gordon et al., 1980 Proc Natl Acad Sci USA.; 77:7380-4.

[0430] Herbst R. et al. J Pharmacol Exp Ther. 2010 October; 335(1):213-22.

[0431] Hinton et al. 2004, J Biol Chem.; 279:6213-6.

[0432] Idusogie E E et al. J Immunol. 2001; 166:2571-5.

[0433] Imai-Nishiya et al, BMC Biotechnology 2007, 7:84.

[0434] Jones et al. Nature, 321:522-525, 1986.

[0435] Kabat et al., Sequences of Proteins of Immunological Interest, 5.sup.th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991).

[0436] Kanda Y et al, Journal of Biotechnology 130 (2007) 300-310.

[0437] Lazar, G. A., et al. Proc Natl Acad Sci USA. 103(11): 4005-10.

[0438] Lefranc, M.-P. et al. Dev. Comp. Immunol., 27, 55-77 (2003).

[0439] Ma J K, et al. Nat Rev Genet. 2003 October; 4(10):794-805.

[0440] Maeda T et al., Int J Hematol. 2005 February; 81(2):148-54.

[0441] Manipulating the Mouse Embryo, A Laboratory Manual, Second edition, Cold Spring Harbor Laboratory Press (1994).

[0442] Moore G L. Et al. mAbs 2:2, 181-189; March/April, 2010.

[0443] Mod K, et al. Biotechnol Bioeng. 2004 Dec. 30; 88(7):901-8.

[0444] Needleman et Wunsch. J. Mol. Biol. 48,443-453, 1970.

[0445] Olivier S. et al. MAbs. 2010 July-August; 2(4): 405-415.

[0446] Riechmann et al. Nature, 332: 323-327, 1988.

[0447] Ryan et aL, 1997 Science; 278: 873-876.

[0448] Schillberg S, et al. Vaccine 23 (2005) 1764-1769.

[0449] Shields R L, et al. J Biol Chem. 2001 Mar. 2; 276(9):6591-604.

[0450] Shields R L, et al. J Biol Chem. 2002 Jul. 26; 277(30):26733-40.

[0451] Shinkawa T, et al. J Biol Chem. 2003 Jan. 31; 278(5):3466-73.

[0452] Stoger E, et al. Molecular Breeding 9:149-158, 2002.

[0453] Suzuki et al. Clin Cancer Res 2007 Mar. 15; 13:1875-1882.

[0454] Umana et al. Nat Biotechnol. 1999 February; 17(2):176-80.

[0455] Urlaub et al., Cell 33[2], 405-412, 1983.

[0456] Verhoeyen et al. BioEssays, 8:74, 1988.

[0457] Verhoeyen et al. Science, 239:1534-1536, 1988.

[0458] WO00/42072.

[0459] WO00/26357.

[0460] WO01/365487.

[0461] WO01/77181.

[0462] WO01/26455.

[0463] WO02/060919.

[0464] WO2004/029207.

[0465] WO2004/063351.

[0466] WO2004/074455.

[0467] WO2004/050847.

[0468] WO2005/033281.

[0469] WO2007/048077.

[0470] WO2007/106078.

[0471] WO2008/028686.

[0472] WO2010/045193.

[0473] WO2010/106180.

[0474] WO2011/114063.

[0475] WO2012/041768.

[0476] WO2012/080642.

[0477] WO2012/175751.

[0478] WO2013/061010.

[0479] WO2013/117871.

[0480] WO2014/09339.

[0481] WO90/04036.

[0482] WO95/17085.

[0483] WO99/51642.

[0484] Wollenberg A. et al. J Invest Dermatol. 2002 November; 119(5):1096-102.

[0485] Yamane-Ohnuki N. et al. Biotechnol Bioeng. 2004 Sep. 5; 87(5):614-22.

Sequence CWU 1

1

24018PRTartificialCDR1-H-family 1 1Gly Tyr Thr Phe Thr Asp Tyr Ser1 528PRTartificialCDR2-H-family 1misc_feature(3)..(3)Xaa can be any naturally occurring amino acidmisc_feature(8)..(8)Xaa can be any naturally occurring amino acid 2Ile Ser Xaa Tyr Tyr Gly Asp Xaa1 5311PRTartificialCDR3-H-family 1misc_feature(4)..(6)Xaa can be any naturally occurring amino acidmisc_feature(8)..(10)Xaa can be any naturally occurring amino acid 3Ala Arg Asn Xaa Xaa Xaa Tyr Xaa Xaa Xaa Tyr1 5 1046PRTartificialCDR1-L-family 1misc_feature(4)..(4)Xaa can be any naturally occurring amino acid 4Gln Asp Ile Xaa Asn Tyr1 553PRTartificialCDR2-L-family 1 5Tyr Thr Ser169PRTartificialCDR3-L-family 1misc_feature(4)..(4)Xaa can be any naturally occurring amino acid 6Gln Gln Gly Xaa Thr Leu Pro Trp Thr1 578PRTartificialCDR1-H-family 2misc_feature(7)..(7)Xaa can be any naturally occurring amino acid 7Gly Tyr Thr Phe Thr Asp Xaa Ser1 588PRTartificialCDR2-H-family 2misc_feature(7)..(7)Xaa can be any naturally occurring amino acid 8Ile Asn Thr Glu Thr Gly Xaa Pro1 5914PRTartificialCDR3-H-family 2misc_feature(1)..(1)Xaa can be any naturally occurring amino acidmisc_feature(12)..(12)Xaa can be any naturally occurring amino acid 9Xaa Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Xaa Asp Tyr1 5 10105PRTartificialCDR1-L-family 2misc_feature(4)..(4)Xaa can be any naturally occurring amino acid 10Ser Ser Val Xaa Tyr1 5113PRTartificialCDR2-L-family 2 11Ser Thr Ser1129PRTartificialCDR3-L-family 2misc_feature(8)..(8)Xaa can be any naturally occurring amino acid 12Gln Gln Arg Arg Ser Tyr Pro Xaa Thr1 5138PRTartificialCDR1-H-122A2 13Gly Tyr Thr Phe Thr Asp Tyr Ser1 5148PRTartificialCDR2-H-122A2 14Ile Ser Thr Tyr Tyr Gly Asp Ser1 51511PRTartificialCDR3-H-122A2 15Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr1 5 10166PRTartificialCDR1-L-122A2 16Gln Asp Ile Ser Asn Tyr1 5173PRTartificialCDR2-L-122A2 17Tyr Thr Ser1189PRTartificialCDR3-L-122A2 18Gln Gln Gly Asn Thr Leu Pro Trp Thr1 5198PRTartificialCDR1-H-102E9 19Gly Tyr Thr Phe Thr Asp Tyr Ser1 5208PRTartificialCDR2-H-102E9 20Ile Asn Thr Glu Thr Gly Glu Pro1 52114PRTartificialCDR3-H-102E9 21Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr1 5 10225PRTartificialCDR1-L-102E9 22Ser Ser Val Ile Tyr1 5233PRTartificialCDR2-L-102E9 23Ser Thr Ser1249PRTartificialCDR3-L-102E9 24Gln Gln Arg Arg Ser Tyr Pro Phe Thr1 5258PRTartificialCDR1-H-104C12 25Gly Tyr Thr Phe Thr Asp Tyr Ser1 5268PRTartificialCDR2-H-104C12 26Ile Ser Pro Tyr Tyr Gly Asp Thr1 52711PRTartificialCDR3-H-104C12 27Ala Arg Asn Asp Asp Tyr Tyr Arg Phe Ala Tyr1 5 10286PRTartificialCDR1-L-104C12 28Gln Asp Ile Asn Asn Tyr1 5293PRTartificialCDR2-L-104C12 29Tyr Thr Ser1309PRTartificialCDR3-L-104C12 30Gln Gln Gly Lys Thr Leu Pro Trp Thr1 5318PRTartificialCDR1-H-114D11 31Gly Tyr Thr Phe Thr Asp Ser Ser1 5328PRTartificialCDR2-H-114D11 32Ile Asn Thr Glu Thr Gly Gly Pro1 53314PRTartificialCDR3-H-114D11 33Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Leu Asp Tyr1 5 10345PRTartificialCDR1-L-114D11 34Ser Ser Val Phe Tyr1 5353PRTartificialCDR2-L-114D11 35Ser Thr Ser1369PRTartificialCDR3-L-114D11 36Gln Gln Arg Arg Ser Tyr Pro Tyr Thr1 5378PRTartificialCDR1-H-104E10 37Gly Tyr Thr Phe Thr Asp Tyr Ser1 5388PRTartificialCDR2-H-104E10 38Ile Asn Thr Glu Thr Gly Glu Pro1 53914PRTartificialCDR3-H-104E10 39Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr1 5 10405PRTartificialCDR1-L-104E10 40Ser Ser Val Ile Tyr1 5413PRTartificialCDR2-L-104E10 41Ser Thr Ser1429PRTartificialCDR3-L-104E10 42Gln Gln Arg Arg Ser Tyr Pro Tyr Thr1 543118PRTartificialVH-122A2 43Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Ser Val Thr Val Ser Ser 11544121PRTartificialVH-102E9 44Gln Ile His Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr Ala Phe65 70 75 80Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ser Thr Tyr Phe Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser 115 12045118PRTartificialVH-104C12 45Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Gly Pro Gly Val1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ala Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys 85 90 95Ala Arg Asn Asp Asp Tyr Tyr Arg Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ala 11546121PRTartificialVH-114D11 46Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Ser 20 25 30Ser Met His Trp Val Gln Gln Ala Pro Asn Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Gly Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Leu Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser 115 12047121PRTartificialVH-104E10 47Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Asn Phe Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser 115 12048107PRTartificialVL-122A2 48Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Asp Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 10549106PRTartificialVL-102E9 49Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly1 5 10 15Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 10550107PRTartificialVL-104C12 50Asp Leu Gln Met Thr Gln Thr Pro Ser Ser Leu Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn Asn Tyr 20 25 30Leu Ser Trp Tyr Gln Glu Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Val Arg Asn Leu Glu Gln65 70 75 80Glu Asp Ile Gly Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg 100 10551106PRTartificialVL-114D11 51Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly1 5 10 15Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Phe Tyr Met 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Tyr Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 10552106PRTartificialVL-104E10 52Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly1 5 10 15Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Met 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Tyr Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 10553329PRTartificialCH 53Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly 32554107PRTartificialCL 54Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu1 5 10 15Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu65 70 75 80Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 10555447PRTartificialVH-CH-122A2 55Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155 160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265

270Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 44556450PRTartificialVH-CH-102E9 56Gln Ile His Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr Ala Phe65 70 75 80Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ser Thr Tyr Phe Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly 45057447PRTartificialVH-CH-104C12 57Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Gly Pro Gly Val1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ala Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys 85 90 95Ala Arg Asn Asp Asp Tyr Tyr Arg Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155 160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 44558450PRTartificialVH-CH-114D11 58Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Ser 20 25 30Ser Met His Trp Val Gln Gln Ala Pro Asn Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Gly Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Leu Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly 45059450PRTartificialVH-CH-104E10 59Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Asn Phe Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly 45060214PRTartificialVL-CL-122A2 60Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Asp Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly 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 21061213PRTartificialVL-CL-102E9 61Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly1 5 10 15Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu 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 21062214PRTartificialVL-CL-104C12 62Asp Leu Gln Met Thr Gln Thr Pro Ser Ser Leu Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn Asn Tyr 20 25 30Leu Ser Trp Tyr Gln Glu Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile 35

40 45Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Val Arg Asn Leu Glu Gln65 70 75 80Glu Asp Ile Gly Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu 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 21063213PRTartificialVL-CL-114D11 63Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly1 5 10 15Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Phe Tyr Met 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Tyr Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu 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 21064213PRTartificialVL-CL-104E10 64Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly1 5 10 15Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Met 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Tyr Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu 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 2106518PRTartificialMB7 signal peptide 65Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala66136PRTartificialMB7-VH-122A2 66Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro 20 25 30Gly Val Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr 85 90 95Ala Tyr Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr 100 105 110Tyr Cys Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln 115 120 125Gly Thr Ser Val Thr Val Ser Ser 130 13567139PRTartificialMB7-VH-102E9 67Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile His Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr 85 90 95Ala Phe Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ser Thr Tyr 100 105 110Phe Cys Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 130 13568136PRTartificialMB7-VH-104C12 68Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Gly Pro 20 25 30Gly Val Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr 85 90 95Ala Tyr Met Glu Leu Ala Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr 100 105 110Phe Cys Ala Arg Asn Asp Asp Tyr Tyr Arg Phe Ala Tyr Trp Gly Gln 115 120 125Gly Thr Leu Val Thr Val Ser Ala 130 13569139PRTartificialMB7-VH-114D11 69Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Ser Ser Met His Trp Val Gln Gln Ala Pro Asn Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Gly Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr 85 90 95Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr 100 105 110Phe Cys Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Leu Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 130 13570139PRTartificialMB7-VH-104E10 70Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr 85 90 95Ala Tyr Leu Gln Ile Asn Asn Phe Lys Asn Glu Asp Thr Ala Thr Tyr 100 105 110Phe Cys Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 130 13571125PRTartificialMB7-VL-122A2 71Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser 20 25 30Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser 35 40 45Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 85 90 95Asp Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 115 120 12572124PRTartificialMB7-VL-102E9 72Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 20 25 30Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile 35 40 45Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ala Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu 85 90 95Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 115 12073125PRTartificialMB7-VL-104C12 73Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Leu Gln Met Thr Gln Thr Pro Ser Ser Leu Ser Ala Ser 20 25 30Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn 35 40 45Asn Tyr Leu Ser Trp Tyr Gln Glu Lys Pro Asp Gly Thr Phe Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Val Arg Asn Leu 85 90 95Glu Gln Glu Asp Ile Gly Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg 115 120 12574124PRTartificialMB7-VL-114D11 74Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 20 25 30Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Phe 35 40 45Tyr Met His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu 85 90 95Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 115 12075124PRTartificialMB7-VL-104E10 75Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 20 25 30Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ile 35 40 45Tyr Met His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu 85 90 95Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 115 12076465PRTartificialMB7-VH-CH-122A2 76Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro 20 25 30Gly Val Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr 85 90 95Ala Tyr Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr 100 105 110Tyr Cys Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln 115 120 125Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185 190Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 195 200 205Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 340 345 350Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp385 390 395 400Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420 425 430Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460Gly46577468PRTartificialMB7-VH-CH-102E9 77Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile His Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro 20 25

30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr 85 90 95Ala Phe Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ser Thr Tyr 100 105 110Phe Cys Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly46578465PRTartificialMB7-VH-CH-104C12 78Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Gly Pro 20 25 30Gly Val Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr 85 90 95Ala Tyr Met Glu Leu Ala Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr 100 105 110Phe Cys Ala Arg Asn Asp Asp Tyr Tyr Arg Phe Ala Tyr Trp Gly Gln 115 120 125Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185 190Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 195 200 205Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 340 345 350Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp385 390 395 400Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420 425 430Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460Gly46579468PRTartificialMB7-VH-CH-114D11 79Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Ser Ser Met His Trp Val Gln Gln Ala Pro Asn Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Gly Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr 85 90 95Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr 100 105 110Phe Cys Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Leu Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly46580468PRTartificialMB7-VH-CH-104E10 80Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr 85 90 95Ala Tyr Leu Gln Ile Asn Asn Phe Lys Asn Glu Asp Thr Ala Thr Tyr 100 105 110Phe Cys Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly46581232PRTartificialMB7-VL-CL-122A2 81Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser 20 25 30Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser 35 40 45Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 85 90 95Asp Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 115 120 125Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 130 135 140Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg145 150 155 160Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 165 170 175Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 180 185 190Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 195 200 205Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 210 215 220Lys Ser Phe Asn Arg Gly Glu Cys225 23082231PRTartificialMB7-VL-CL-102E9 82Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 20 25 30Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile 35 40 45Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ala Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu 85 90 95Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 115 120 125Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 130 135 140Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu145 150 155 160Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 165 170 175Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 210 215 220Ser Phe Asn Arg Gly Glu Cys225 23083232PRTartificialMB7-VL-CL-104C12 83Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Leu Gln Met Thr Gln Thr Pro Ser Ser Leu Ser Ala Ser 20 25 30Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn 35 40 45Asn Tyr Leu Ser Trp Tyr Gln Glu Lys Pro Asp Gly Thr Phe Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Val Arg Asn Leu 85 90 95Glu Gln Glu Asp Ile Gly Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg Thr Val 115 120 125Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 130 135 140Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg145

150 155 160Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 165 170 175Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 180 185 190Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 195 200 205Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 210 215 220Lys Ser Phe Asn Arg Gly Glu Cys225 23084231PRTartificialMB7-VL-CL-114D11 84Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 20 25 30Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Phe 35 40 45Tyr Met His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu 85 90 95Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 115 120 125Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 130 135 140Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu145 150 155 160Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 165 170 175Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 210 215 220Ser Phe Asn Arg Gly Glu Cys225 23085231PRTartificialMB7-VL-CL-104E10 85Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser 20 25 30Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ile 35 40 45Tyr Met His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu 85 90 95Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 115 120 125Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 130 135 140Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu145 150 155 160Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 165 170 175Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 210 215 220Ser Phe Asn Arg Gly Glu Cys225 23086354DNAartificialVH-122A2 86caggtccagc tgcagcagtc tggggctgag ctggtgaggc ctggggtctc agtgaagatt 60tcctgcaagg gttctggcta cacattcact gattattcta tgcactgggt gaagcagagt 120catgcaaaga gtctagagtg gattggagtt attagtactt actatggtga ttctaactat 180aaccagaagt tcaagggcaa ggccacaatg actgtagaca aatcctccac cacagcctat 240atggaacttg ccagactgac atctgaggat tctgccatct attactgtgc aagaaatggt 300aatttctatg ttatggacta ctggggtcaa ggaacctcag tcaccgtctc ctca 35487363DNAartificialVH-102E9 87cagatccatt tggtgcagtc tggacctgac ctgaagaagc ctggagagac agtcaagatc 60tcctgcaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga accaacatat 180gcagatgact tcaagggacg gtttgccttc tctttggaaa gttctgccag cactgccttt 240ttgcagatca acaacctcaa aaatgaggac acgtctacat atttctgtac tagaaatggt 300tactacgtgg gttactatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360tca 36388353DNAartificialVH-104C12 88caggtccagc tgcagcagtc tggggctgag ctggtggggc ctggggtctc agtgaagatt 60tcctgcaagg gttctggcta cacattcact gattattcta tgcactgggt aaagcagagt 120catgcaaaga gtctagagtg gattggagtt attagtcctt actatggtga tactaactac 180aaccagaagt tcaagggcaa ggccacaatg actgtagaca aatcctccag cacagcctat 240atggaacttg ccagtctgac atctgaggat tctgccatct atttctgtgc aagaaatgat 300gattactaca ggtttgctta ctggggccaa gggactctgg tcactgtctc tgc 35389363DNAartificialVH-114D11 89cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60tcctgcaagg cttctggtta taccttcaca gactcttcaa tgcactgggt gcagcaggct 120ccaaacaagg gtttaaagtg gatgggctgg ataaacactg agactggtgg gccaacgtat 180gcagatgatt tcaagggacg gtttgccttc tctttggaaa cctctgccag aactgcctat 240ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc tagaaatgga 300tactacgtgg ggtactatgc tctggactac tggggtcaag gaacctcagt caccgtctcc 360tca 36390363DNAartificialVH-104E10 90cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60tcctgcaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga gccaacatat 180gcagatgact tcaagggacg gtttgccttc tctttggaaa cctctgccac cactgcctat 240ttgcagatca acaacttcaa aaatgaggac acggctacat atttctgtgc tagaaatggt 300tactacgtgg gatattatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360tca 36391321DNAartificialVL-122A2 91gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60atcagttgca gggcaagtca ggacattagc aattatttaa actggtatca gcagaaacca 120gatggaactg ttaaactcct gatctactac acatcaagat tacactcagg agtcccatca 180aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggaccaa 240gaagatattg ccacttactt ttgccaacag ggtaatacgc ttccttggac gttcggtgga 300ggcaccaagc tggaaatcaa a 32192318DNAartificialVL-102E9 92caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60ataacctgca gtgccagctc aagtgtaatt tacattcact ggttccagca gaagccaggc 120acttctccca aactctggat ttatagcaca tcctacctgg cttctggagt ccctgctcgc 180ttcagtggca gtggatctgg gacctcttac tctctcacaa tcagccgaat ggaggctgaa 240gatgctgcca cttattactg ccagcagagg agaagttacc cgttcacgtt cggagggggg 300accaagctgg aaataaaa 31893320DNAartificialVL-104C12 93gatctccaga tgacacagac tccatcctcc ctgtctgcct ctctgggaga cagagtcacc 60atcagttgca gggcaagtca ggacattaac aattatttaa gctggtatca ggagaaacca 120gatggaactt ttaaactcct gatctactac acatcaagat tacactcagg agtcccatca 180aggttcagtg gcagtgggtc tggaacagat tattctctca ccgttcgcaa cctggaacag 240gaagatattg gcacttactt ttgccaacag ggtaaaacgc ttccgtggac gttcggtgga 300ggcaccaagc tggaaatcag 32094318DNAartificialVL-114D11 94caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60ataacctgca gtgccagctc aagtgtattt tacatgcact ggttccagca gaagccaggc 120acttctccca aactctggat ttatagcaca tccaacctgg cttctggagt ccctgctcgc 180ttcagtggca gtggatctgg gacctcttac tctctcacaa tcagccgaat ggaggctgaa 240gatgctgcca cttattactg ccagcaaagg agaagttacc cgtacacgtt cggagggggg 300accaagctgg aaataaaa 31895318DNAartificialVL-104E10 95caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60atgacctgca gtgccagttc aagtgtaatt tacatgcact ggttccagca gaagccaggc 120acttctccca aactctggat ttatagcaca tccaacctgg cttctggagt ccctgctcgc 180ttcagtggca gtggatctgg gacatcttac tctctcacaa tcagccgaat ggaggctgaa 240gatgctgcca cttattactg ccagcaaagg agaagttacc cgtacacgtt cggagggggg 300accaagctgg aaataaaa 31896990DNAartificialCH 96gcctccacca agggcccatc cgtgttcccc ctggccccat ccagcaagtc tacctccgga 60ggcacagccg ccctgggctg tctggtgaag gactacttcc ccgagccagt gaccgtgtcc 120tggaactccg gagccctgac atccggcgtg cacaccttcc ccgccgtgct gcagtccagc 180ggcctgtact ctctgtcttc cgtggtgacc gtgccatcca gctccctggg aacccagaca 240tacatctgca acgtgaacca caagcctagc aacaccaagg tggacaagaa ggtggagcct 300aagagctgtg acaagacaca cacatgccct ccttgtccag cccctgagct gctgggcggc 360ccctccgtgt tcctgttccc ccccaagcct aaggataccc tgatgatcag cagaaccccc 420gaggtgacct gcgtggtggt ggacgtgtcc cacgaggatc ccgaggtgaa gttcaactgg 480tacgtggacg gcgtggaggt gcacaacgct aagaccaagc ccagagagga gcagtacaac 540agcacataca gagtggtgtc tgtgctgacc gtgctgcacc aggactggct gaacgggaag 600gagtacaagt gcaaggtgtc caacaaggcc ctgcctgccc ctatcgagaa gaccatctct 660aaggctaagg ggcagccccg ggagccacag gtgtacaccc tgccacccag ccgcgacgag 720ctgaccaaga accaggtgtc cctgacatgc ctggtgaagg gattctaccc cagcgacatc 780gccgtggagt gggagagcaa cggccagccc gagaacaact acaagacaac ccctcccgtg 840ctggacagcg atggatcctt cttcctgtac tccaagctga ccgtggacaa gagcaggtgg 900cagcagggaa acgtgttctc ttgttccgtg atgcacgagg ctctgcacaa ccactacacc 960cagaagtccc tgagcctgtc tccaggcaag 99097321DNAartificialCL 97cgaactgtgg ctgcaccaag tgtcttcatc tttcctccga gtgatgagca gctgaagagc 60gggacagctt ctgtggtgtg tctgctgaat aacttctacc caagagaagc aaaggtccag 120tggaaggtgg acaacgccct gcagtctggc aactcacagg agtctgtcac tgagcaggat 180tccaaggaca gcacttacag cctgtccagc accctcactc tgtccaaagc cgactacgaa 240aagcataagg tgtatgcttg tgaggtgacc caccagggac tgagcagccc tgtgacgaag 300tccttcaacc ggggcgagtg c 321981344DNAartificialVH-CH-122A2 98caggtccagc tgcagcagtc tggggctgag ctggtgaggc ctggggtctc agtgaagatt 60tcctgcaagg gttctggcta cacattcact gattattcta tgcactgggt gaagcagagt 120catgcaaaga gtctagagtg gattggagtt attagtactt actatggtga ttctaactat 180aaccagaagt tcaagggcaa ggccacaatg actgtagaca aatcctccac cacagcctat 240atggaacttg ccagactgac atctgaggat tctgccatct attactgtgc aagaaatggt 300aatttctatg ttatggacta ctggggtcaa ggaacctcag tcaccgtctc ctcagcctcc 360accaagggcc catccgtgtt ccccctggcc ccatccagca agtctacctc cggaggcaca 420gccgccctgg gctgtctggt gaaggactac ttccccgagc cagtgaccgt gtcctggaac 480tccggagccc tgacatccgg cgtgcacacc ttccccgccg tgctgcagtc cagcggcctg 540tactctctgt cttccgtggt gaccgtgcca tccagctccc tgggaaccca gacatacatc 600tgcaacgtga accacaagcc tagcaacacc aaggtggaca agaaggtgga gcctaagagc 660tgtgacaaga cacacacatg ccctccttgt ccagcccctg agctgctggg cggcccctcc 720gtgttcctgt tcccccccaa gcctaaggat accctgatga tcagcagaac ccccgaggtg 780acctgcgtgg tggtggacgt gtcccacgag gatcccgagg tgaagttcaa ctggtacgtg 840gacggcgtgg aggtgcacaa cgctaagacc aagcccagag aggagcagta caacagcaca 900tacagagtgg tgtctgtgct gaccgtgctg caccaggact ggctgaacgg gaaggagtac 960aagtgcaagg tgtccaacaa ggccctgcct gcccctatcg agaagaccat ctctaaggct 1020aaggggcagc cccgggagcc acaggtgtac accctgccac ccagccgcga cgagctgacc 1080aagaaccagg tgtccctgac atgcctggtg aagggattct accccagcga catcgccgtg 1140gagtgggaga gcaacggcca gcccgagaac aactacaaga caacccctcc cgtgctggac 1200agcgatggat ccttcttcct gtactccaag ctgaccgtgg acaagagcag gtggcagcag 1260ggaaacgtgt tctcttgttc cgtgatgcac gaggctctgc acaaccacta cacccagaag 1320tccctgagcc tgtctccagg caag 1344991353DNAartificialVH-CH-102E9 99cagatccatt tggtgcagtc tggacctgac ctgaagaagc ctggagagac agtcaagatc 60tcctgcaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga accaacatat 180gcagatgact tcaagggacg gtttgccttc tctttggaaa gttctgccag cactgccttt 240ttgcagatca acaacctcaa aaatgaggac acgtctacat atttctgtac tagaaatggt 300tactacgtgg gttactatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360tcagcctcca ccaagggccc atccgtgttc cccctggccc catccagcaa gtctacctcc 420ggaggcacag ccgccctggg ctgtctggtg aaggactact tccccgagcc agtgaccgtg 480tcctggaact ccggagccct gacatccggc gtgcacacct tccccgccgt gctgcagtcc 540agcggcctgt actctctgtc ttccgtggtg accgtgccat ccagctccct gggaacccag 600acatacatct gcaacgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggag 660cctaagagct gtgacaagac acacacatgc cctccttgtc cagcccctga gctgctgggc 720ggcccctccg tgttcctgtt cccccccaag cctaaggata ccctgatgat cagcagaacc 780cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg atcccgaggt gaagttcaac 840tggtacgtgg acggcgtgga ggtgcacaac gctaagacca agcccagaga ggagcagtac 900aacagcacat acagagtggt gtctgtgctg accgtgctgc accaggactg gctgaacggg 960aaggagtaca agtgcaaggt gtccaacaag gccctgcctg cccctatcga gaagaccatc 1020tctaaggcta aggggcagcc ccgggagcca caggtgtaca ccctgccacc cagccgcgac 1080gagctgacca agaaccaggt gtccctgaca tgcctggtga agggattcta ccccagcgac 1140atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac aacccctccc 1200gtgctggaca gcgatggatc cttcttcctg tactccaagc tgaccgtgga caagagcagg 1260tggcagcagg gaaacgtgtt ctcttgttcc gtgatgcacg aggctctgca caaccactac 1320acccagaagt ccctgagcct gtctccaggc aag 13531001343DNAartificialVH-CH-104C12 100caggtccagc tgcagcagtc tggggctgag ctggtggggc ctggggtctc agtgaagatt 60tcctgcaagg gttctggcta cacattcact gattattcta tgcactgggt aaagcagagt 120catgcaaaga gtctagagtg gattggagtt attagtcctt actatggtga tactaactac 180aaccagaagt tcaagggcaa ggccacaatg actgtagaca aatcctccag cacagcctat 240atggaacttg ccagtctgac atctgaggat tctgccatct atttctgtgc aagaaatgat 300gattactaca ggtttgctta ctggggccaa gggactctgg tcactgtctc tgcgcctcca 360ccaagggccc atccgtgttc cccctggccc catccagcaa gtctacctcc ggaggcacag 420ccgccctggg ctgtctggtg aaggactact tccccgagcc agtgaccgtg tcctggaact 480ccggagccct gacatccggc gtgcacacct tccccgccgt gctgcagtcc agcggcctgt 540actctctgtc ttccgtggtg accgtgccat ccagctccct gggaacccag acatacatct 600gcaacgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggag cctaagagct 660gtgacaagac acacacatgc cctccttgtc cagcccctga gctgctgggc ggcccctccg 720tgttcctgtt cccccccaag cctaaggata ccctgatgat cagcagaacc cccgaggtga 780cctgcgtggt ggtggacgtg tcccacgagg atcccgaggt gaagttcaac tggtacgtgg 840acggcgtgga ggtgcacaac gctaagacca agcccagaga ggagcagtac aacagcacat 900acagagtggt gtctgtgctg accgtgctgc accaggactg gctgaacggg aaggagtaca 960agtgcaaggt gtccaacaag gccctgcctg cccctatcga gaagaccatc tctaaggcta 1020aggggcagcc ccgggagcca caggtgtaca ccctgccacc cagccgcgac gagctgacca 1080agaaccaggt gtccctgaca tgcctggtga agggattcta ccccagcgac atcgccgtgg 1140agtgggagag caacggccag cccgagaaca actacaagac aacccctccc gtgctggaca 1200gcgatggatc cttcttcctg tactccaagc tgaccgtgga caagagcagg tggcagcagg 1260gaaacgtgtt ctcttgttcc gtgatgcacg aggctctgca caaccactac acccagaagt 1320ccctgagcct gtctccaggc aag 13431011353DNAartificialVH-CH-114D11 101cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60tcctgcaagg cttctggtta taccttcaca gactcttcaa tgcactgggt gcagcaggct 120ccaaacaagg gtttaaagtg gatgggctgg ataaacactg agactggtgg gccaacgtat 180gcagatgatt tcaagggacg gtttgccttc tctttggaaa cctctgccag aactgcctat 240ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc tagaaatgga 300tactacgtgg ggtactatgc tctggactac tggggtcaag gaacctcagt caccgtctcc 360tcagcctcca ccaagggccc atccgtgttc cccctggccc catccagcaa gtctacctcc 420ggaggcacag ccgccctggg ctgtctggtg aaggactact tccccgagcc agtgaccgtg 480tcctggaact ccggagccct gacatccggc gtgcacacct tccccgccgt gctgcagtcc 540agcggcctgt actctctgtc ttccgtggtg accgtgccat ccagctccct gggaacccag 600acatacatct gcaacgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggag 660cctaagagct gtgacaagac acacacatgc cctccttgtc cagcccctga gctgctgggc 720ggcccctccg tgttcctgtt cccccccaag cctaaggata ccctgatgat cagcagaacc 780cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg atcccgaggt gaagttcaac 840tggtacgtgg acggcgtgga ggtgcacaac gctaagacca agcccagaga ggagcagtac 900aacagcacat acagagtggt gtctgtgctg accgtgctgc accaggactg gctgaacggg 960aaggagtaca agtgcaaggt gtccaacaag gccctgcctg cccctatcga gaagaccatc 1020tctaaggcta aggggcagcc ccgggagcca caggtgtaca ccctgccacc cagccgcgac 1080gagctgacca agaaccaggt gtccctgaca tgcctggtga agggattcta ccccagcgac 1140atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac aacccctccc 1200gtgctggaca gcgatggatc cttcttcctg tactccaagc tgaccgtgga caagagcagg 1260tggcagcagg gaaacgtgtt ctcttgttcc gtgatgcacg aggctctgca caaccactac 1320acccagaagt ccctgagcct gtctccaggc aag 13531021353DNAartificialVH-CH-104E10 102cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60tcctgcaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga gccaacatat 180gcagatgact tcaagggacg gtttgccttc tctttggaaa cctctgccac cactgcctat 240ttgcagatca acaacttcaa aaatgaggac acggctacat atttctgtgc tagaaatggt 300tactacgtgg gatattatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360tcagcctcca ccaagggccc atccgtgttc cccctggccc catccagcaa gtctacctcc 420ggaggcacag ccgccctggg ctgtctggtg aaggactact tccccgagcc agtgaccgtg 480tcctggaact ccggagccct gacatccggc

gtgcacacct tccccgccgt gctgcagtcc 540agcggcctgt actctctgtc ttccgtggtg accgtgccat ccagctccct gggaacccag 600acatacatct gcaacgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggag 660cctaagagct gtgacaagac acacacatgc cctccttgtc cagcccctga gctgctgggc 720ggcccctccg tgttcctgtt cccccccaag cctaaggata ccctgatgat cagcagaacc 780cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg atcccgaggt gaagttcaac 840tggtacgtgg acggcgtgga ggtgcacaac gctaagacca agcccagaga ggagcagtac 900aacagcacat acagagtggt gtctgtgctg accgtgctgc accaggactg gctgaacggg 960aaggagtaca agtgcaaggt gtccaacaag gccctgcctg cccctatcga gaagaccatc 1020tctaaggcta aggggcagcc ccgggagcca caggtgtaca ccctgccacc cagccgcgac 1080gagctgacca agaaccaggt gtccctgaca tgcctggtga agggattcta ccccagcgac 1140atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac aacccctccc 1200gtgctggaca gcgatggatc cttcttcctg tactccaagc tgaccgtgga caagagcagg 1260tggcagcagg gaaacgtgtt ctcttgttcc gtgatgcacg aggctctgca caaccactac 1320acccagaagt ccctgagcct gtctccaggc aag 1353103642DNAartificialVL-CL-122A2 103gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60atcagttgca gggcaagtca ggacattagc aattatttaa actggtatca gcagaaacca 120gatggaactg ttaaactcct gatctactac acatcaagat tacactcagg agtcccatca 180aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggaccaa 240gaagatattg ccacttactt ttgccaacag ggtaatacgc ttccttggac gttcggtgga 300ggcaccaagc tggaaatcaa acgaactgtg gctgcaccaa gtgtcttcat ctttcctccg 360agtgatgagc agctgaagag cgggacagct tctgtggtgt gtctgctgaa taacttctac 420ccaagagaag caaaggtcca gtggaaggtg gacaacgccc tgcagtctgg caactcacag 480gagtctgtca ctgagcagga ttccaaggac agcacttaca gcctgtccag caccctcact 540ctgtccaaag ccgactacga aaagcataag gtgtatgctt gtgaggtgac ccaccaggga 600ctgagcagcc ctgtgacgaa gtccttcaac cggggcgagt gc 642104639DNAartificialVL-CL-102E9 104caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60ataacctgca gtgccagctc aagtgtaatt tacattcact ggttccagca gaagccaggc 120acttctccca aactctggat ttatagcaca tcctacctgg cttctggagt ccctgctcgc 180ttcagtggca gtggatctgg gacctcttac tctctcacaa tcagccgaat ggaggctgaa 240gatgctgcca cttattactg ccagcagagg agaagttacc cgttcacgtt cggagggggg 300accaagctgg aaataaaacg aactgtggct gcaccaagtg tcttcatctt tcctccgagt 360gatgagcagc tgaagagcgg gacagcttct gtggtgtgtc tgctgaataa cttctaccca 420agagaagcaa aggtccagtg gaaggtggac aacgccctgc agtctggcaa ctcacaggag 480tctgtcactg agcaggattc caaggacagc acttacagcc tgtccagcac cctcactctg 540tccaaagccg actacgaaaa gcataaggtg tatgcttgtg aggtgaccca ccagggactg 600agcagccctg tgacgaagtc cttcaaccgg ggcgagtgc 639105641DNAartificialVL-CL-104C12 105gatctccaga tgacacagac tccatcctcc ctgtctgcct ctctgggaga cagagtcacc 60atcagttgca gggcaagtca ggacattaac aattatttaa gctggtatca ggagaaacca 120gatggaactt ttaaactcct gatctactac acatcaagat tacactcagg agtcccatca 180aggttcagtg gcagtgggtc tggaacagat tattctctca ccgttcgcaa cctggaacag 240gaagatattg gcacttactt ttgccaacag ggtaaaacgc ttccgtggac gttcggtgga 300ggcaccaagc tggaaatcag cgaactgtgg ctgcaccaag tgtcttcatc tttcctccga 360gtgatgagca gctgaagagc gggacagctt ctgtggtgtg tctgctgaat aacttctacc 420caagagaagc aaaggtccag tggaaggtgg acaacgccct gcagtctggc aactcacagg 480agtctgtcac tgagcaggat tccaaggaca gcacttacag cctgtccagc accctcactc 540tgtccaaagc cgactacgaa aagcataagg tgtatgcttg tgaggtgacc caccagggac 600tgagcagccc tgtgacgaag tccttcaacc ggggcgagtg c 641106639DNAartificialVL-CL-114D11 106caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60ataacctgca gtgccagctc aagtgtattt tacatgcact ggttccagca gaagccaggc 120acttctccca aactctggat ttatagcaca tccaacctgg cttctggagt ccctgctcgc 180ttcagtggca gtggatctgg gacctcttac tctctcacaa tcagccgaat ggaggctgaa 240gatgctgcca cttattactg ccagcaaagg agaagttacc cgtacacgtt cggagggggg 300accaagctgg aaataaaacg aactgtggct gcaccaagtg tcttcatctt tcctccgagt 360gatgagcagc tgaagagcgg gacagcttct gtggtgtgtc tgctgaataa cttctaccca 420agagaagcaa aggtccagtg gaaggtggac aacgccctgc agtctggcaa ctcacaggag 480tctgtcactg agcaggattc caaggacagc acttacagcc tgtccagcac cctcactctg 540tccaaagccg actacgaaaa gcataaggtg tatgcttgtg aggtgaccca ccagggactg 600agcagccctg tgacgaagtc cttcaaccgg ggcgagtgc 639107639DNAartificialVL-CL-104E10 107caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60atgacctgca gtgccagttc aagtgtaatt tacatgcact ggttccagca gaagccaggc 120acttctccca aactctggat ttatagcaca tccaacctgg cttctggagt ccctgctcgc 180ttcagtggca gtggatctgg gacatcttac tctctcacaa tcagccgaat ggaggctgaa 240gatgctgcca cttattactg ccagcaaagg agaagttacc cgtacacgtt cggagggggg 300accaagctgg aaataaaacg aactgtggct gcaccaagtg tcttcatctt tcctccgagt 360gatgagcagc tgaagagcgg gacagcttct gtggtgtgtc tgctgaataa cttctaccca 420agagaagcaa aggtccagtg gaaggtggac aacgccctgc agtctggcaa ctcacaggag 480tctgtcactg agcaggattc caaggacagc acttacagcc tgtccagcac cctcactctg 540tccaaagccg actacgaaaa gcataaggtg tatgcttgtg aggtgaccca ccagggactg 600agcagccctg tgacgaagtc cttcaaccgg ggcgagtgc 63910854DNAartificialMB7 signal peptide 108atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcc 54109408DNAartificialMB7-VH-122A2 109atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaggtc 60cagctgcagc agtctggggc tgagctggtg aggcctgggg tctcagtgaa gatttcctgc 120aagggttctg gctacacatt cactgattat tctatgcact gggtgaagca gagtcatgca 180aagagtctag agtggattgg agttattagt acttactatg gtgattctaa ctataaccag 240aagttcaagg gcaaggccac aatgactgta gacaaatcct ccaccacagc ctatatggaa 300cttgccagac tgacatctga ggattctgcc atctattact gtgcaagaaa tggtaatttc 360tatgttatgg actactgggg tcaaggaacc tcagtcaccg tctcctca 408110417DNAartificialMB7-VH-102E9 110atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60catttggtgc agtctggacc tgacctgaag aagcctggag agacagtcaa gatctcctgc 120aaggcttctg gttatacctt cacagactat tcaatgcact gggtgaagca ggctccagga 180aagggtttaa agtggatggg ctggataaac actgagactg gtgaaccaac atatgcagat 240gacttcaagg gacggtttgc cttctctttg gaaagttctg ccagcactgc ctttttgcag 300atcaacaacc tcaaaaatga ggacacgtct acatatttct gtactagaaa tggttactac 360gtgggttact atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 417111407DNAartificialMB7-VH-104C12 111atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaggtc 60cagctgcagc agtctggggc tgagctggtg gggcctgggg tctcagtgaa gatttcctgc 120aagggttctg gctacacatt cactgattat tctatgcact gggtaaagca gagtcatgca 180aagagtctag agtggattgg agttattagt ccttactatg gtgatactaa ctacaaccag 240aagttcaagg gcaaggccac aatgactgta gacaaatcct ccagcacagc ctatatggaa 300cttgccagtc tgacatctga ggattctgcc atctatttct gtgcaagaaa tgatgattac 360tacaggtttg cttactgggg ccaagggact ctggtcactg tctctgc 407112417DNAartificialMB7-VH-114D11 112atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60cagttggtgc agtctggacc tgagctgaag aagcctggag agacagtcaa gatctcctgc 120aaggcttctg gttatacctt cacagactct tcaatgcact gggtgcagca ggctccaaac 180aagggtttaa agtggatggg ctggataaac actgagactg gtgggccaac gtatgcagat 240gatttcaagg gacggtttgc cttctctttg gaaacctctg ccagaactgc ctatttgcag 300atcaacaacc tcaaaaatga ggacacggct acatatttct gtgctagaaa tggatactac 360gtggggtact atgctctgga ctactggggt caaggaacct cagtcaccgt ctcctca 417113417DNAartificialMB7-VH-104E10 113atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60cagttggtgc agtctggacc tgagctgaag aagcctggag agacagtcaa gatctcctgc 120aaggcttctg gttatacctt cacagactat tcaatgcact gggtgaagca ggctccagga 180aagggtttaa agtggatggg ctggataaac actgagactg gtgagccaac atatgcagat 240gacttcaagg gacggtttgc cttctctttg gaaacctctg ccaccactgc ctatttgcag 300atcaacaact tcaaaaatga ggacacggct acatatttct gtgctagaaa tggttactac 360gtgggatatt atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 417114375DNAartificialMB7-VL-122A2 114atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgatatc 60cagatgacac agactacatc ctccctgtct gcctctctgg gagacagagt caccatcagt 120tgcagggcaa gtcaggacat tagcaattat ttaaactggt atcagcagaa accagatgga 180actgttaaac tcctgatcta ctacacatca agattacact caggagtccc atcaaggttc 240agtggcagtg ggtctggaac agattattct ctcaccatta gcaacctgga ccaagaagat 300attgccactt acttttgcca acagggtaat acgcttcctt ggacgttcgg tggaggcacc 360aagctggaaa tcaaa 375115372DNAartificialMB7-VL-102E9 115atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaaatt 60gttctcaccc agtctccagc aatcatgtct gcatctccag gggagaaggt caccataacc 120tgcagtgcca gctcaagtgt aatttacatt cactggttcc agcagaagcc aggcacttct 180cccaaactct ggatttatag cacatcctac ctggcttctg gagtccctgc tcgcttcagt 240ggcagtggat ctgggacctc ttactctctc acaatcagcc gaatggaggc tgaagatgct 300gccacttatt actgccagca gaggagaagt tacccgttca cgttcggagg ggggaccaag 360ctggaaataa aa 372116374DNAartificialMB7-VL-104C12 116atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgatctc 60cagatgacac agactccatc ctccctgtct gcctctctgg gagacagagt caccatcagt 120tgcagggcaa gtcaggacat taacaattat ttaagctggt atcaggagaa accagatgga 180acttttaaac tcctgatcta ctacacatca agattacact caggagtccc atcaaggttc 240agtggcagtg ggtctggaac agattattct ctcaccgttc gcaacctgga acaggaagat 300attggcactt acttttgcca acagggtaaa acgcttccgt ggacgttcgg tggaggcacc 360aagctggaaa tcag 374117372DNAartificialMB7-VL-114D11 117atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaaatt 60gttctcaccc agtctccagc aatcatgtct gcatctccag gggagaaggt caccataacc 120tgcagtgcca gctcaagtgt attttacatg cactggttcc agcagaagcc aggcacttct 180cccaaactct ggatttatag cacatccaac ctggcttctg gagtccctgc tcgcttcagt 240ggcagtggat ctgggacctc ttactctctc acaatcagcc gaatggaggc tgaagatgct 300gccacttatt actgccagca aaggagaagt tacccgtaca cgttcggagg ggggaccaag 360ctggaaataa aa 372118372DNAartificialMB7-VL-104E10 118atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaaatt 60gttctcaccc agtctccagc aatcatgtct gcatctccag gggagaaggt caccatgacc 120tgcagtgcca gttcaagtgt aatttacatg cactggttcc agcagaagcc aggcacttct 180cccaaactct ggatttatag cacatccaac ctggcttctg gagtccctgc tcgcttcagt 240ggcagtggat ctgggacatc ttactctctc acaatcagcc gaatggaggc tgaagatgct 300gccacttatt actgccagca aaggagaagt tacccgtaca cgttcggagg ggggaccaag 360ctggaaataa aa 3721191398DNAartificialMB7-VH-CH-122A2 119atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaggtc 60cagctgcagc agtctggggc tgagctggtg aggcctgggg tctcagtgaa gatttcctgc 120aagggttctg gctacacatt cactgattat tctatgcact gggtgaagca gagtcatgca 180aagagtctag agtggattgg agttattagt acttactatg gtgattctaa ctataaccag 240aagttcaagg gcaaggccac aatgactgta gacaaatcct ccaccacagc ctatatggaa 300cttgccagac tgacatctga ggattctgcc atctattact gtgcaagaaa tggtaatttc 360tatgttatgg actactgggg tcaaggaacc tcagtcaccg tctcctcagc ctccaccaag 420ggcccatccg tgttccccct ggccccatcc agcaagtcta cctccggagg cacagccgcc 480ctgggctgtc tggtgaagga ctacttcccc gagccagtga ccgtgtcctg gaactccgga 540gccctgacat ccggcgtgca caccttcccc gccgtgctgc agtccagcgg cctgtactct 600ctgtcttccg tggtgaccgt gccatccagc tccctgggaa cccagacata catctgcaac 660gtgaaccaca agcctagcaa caccaaggtg gacaagaagg tggagcctaa gagctgtgac 720aagacacaca catgccctcc ttgtccagcc cctgagctgc tgggcggccc ctccgtgttc 780ctgttccccc ccaagcctaa ggataccctg atgatcagca gaacccccga ggtgacctgc 840gtggtggtgg acgtgtccca cgaggatccc gaggtgaagt tcaactggta cgtggacggc 900gtggaggtgc acaacgctaa gaccaagccc agagaggagc agtacaacag cacatacaga 960gtggtgtctg tgctgaccgt gctgcaccag gactggctga acgggaagga gtacaagtgc 1020aaggtgtcca acaaggccct gcctgcccct atcgagaaga ccatctctaa ggctaagggg 1080cagccccggg agccacaggt gtacaccctg ccacccagcc gcgacgagct gaccaagaac 1140caggtgtccc tgacatgcct ggtgaaggga ttctacccca gcgacatcgc cgtggagtgg 1200gagagcaacg gccagcccga gaacaactac aagacaaccc ctcccgtgct ggacagcgat 1260ggatccttct tcctgtactc caagctgacc gtggacaaga gcaggtggca gcagggaaac 1320gtgttctctt gttccgtgat gcacgaggct ctgcacaacc actacaccca gaagtccctg 1380agcctgtctc caggcaag 13981201407DNAartificialMB7-VH-CH-102E9 120atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60catttggtgc agtctggacc tgacctgaag aagcctggag agacagtcaa gatctcctgc 120aaggcttctg gttatacctt cacagactat tcaatgcact gggtgaagca ggctccagga 180aagggtttaa agtggatggg ctggataaac actgagactg gtgaaccaac atatgcagat 240gacttcaagg gacggtttgc cttctctttg gaaagttctg ccagcactgc ctttttgcag 300atcaacaacc tcaaaaatga ggacacgtct acatatttct gtactagaaa tggttactac 360gtgggttact atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctcagcc 420tccaccaagg gcccatccgt gttccccctg gccccatcca gcaagtctac ctccggaggc 480acagccgccc tgggctgtct ggtgaaggac tacttccccg agccagtgac cgtgtcctgg 540aactccggag ccctgacatc cggcgtgcac accttccccg ccgtgctgca gtccagcggc 600ctgtactctc tgtcttccgt ggtgaccgtg ccatccagct ccctgggaac ccagacatac 660atctgcaacg tgaaccacaa gcctagcaac accaaggtgg acaagaaggt ggagcctaag 720agctgtgaca agacacacac atgccctcct tgtccagccc ctgagctgct gggcggcccc 780tccgtgttcc tgttcccccc caagcctaag gataccctga tgatcagcag aacccccgag 840gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aggtgaagtt caactggtac 900gtggacggcg tggaggtgca caacgctaag accaagccca gagaggagca gtacaacagc 960acatacagag tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cgggaaggag 1020tacaagtgca aggtgtccaa caaggccctg cctgccccta tcgagaagac catctctaag 1080gctaaggggc agccccggga gccacaggtg tacaccctgc cacccagccg cgacgagctg 1140accaagaacc aggtgtccct gacatgcctg gtgaagggat tctaccccag cgacatcgcc 1200gtggagtggg agagcaacgg ccagcccgag aacaactaca agacaacccc tcccgtgctg 1260gacagcgatg gatccttctt cctgtactcc aagctgaccg tggacaagag caggtggcag 1320cagggaaacg tgttctcttg ttccgtgatg cacgaggctc tgcacaacca ctacacccag 1380aagtccctga gcctgtctcc aggcaag 14071211397DNAartificialMB7-VH-CH-104C12 121atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaggtc 60cagctgcagc agtctggggc tgagctggtg gggcctgggg tctcagtgaa gatttcctgc 120aagggttctg gctacacatt cactgattat tctatgcact gggtaaagca gagtcatgca 180aagagtctag agtggattgg agttattagt ccttactatg gtgatactaa ctacaaccag 240aagttcaagg gcaaggccac aatgactgta gacaaatcct ccagcacagc ctatatggaa 300cttgccagtc tgacatctga ggattctgcc atctatttct gtgcaagaaa tgatgattac 360tacaggtttg cttactgggg ccaagggact ctggtcactg tctctgcgcc tccaccaagg 420gcccatccgt gttccccctg gccccatcca gcaagtctac ctccggaggc acagccgccc 480tgggctgtct ggtgaaggac tacttccccg agccagtgac cgtgtcctgg aactccggag 540ccctgacatc cggcgtgcac accttccccg ccgtgctgca gtccagcggc ctgtactctc 600tgtcttccgt ggtgaccgtg ccatccagct ccctgggaac ccagacatac atctgcaacg 660tgaaccacaa gcctagcaac accaaggtgg acaagaaggt ggagcctaag agctgtgaca 720agacacacac atgccctcct tgtccagccc ctgagctgct gggcggcccc tccgtgttcc 780tgttcccccc caagcctaag gataccctga tgatcagcag aacccccgag gtgacctgcg 840tggtggtgga cgtgtcccac gaggatcccg aggtgaagtt caactggtac gtggacggcg 900tggaggtgca caacgctaag accaagccca gagaggagca gtacaacagc acatacagag 960tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cgggaaggag tacaagtgca 1020aggtgtccaa caaggccctg cctgccccta tcgagaagac catctctaag gctaaggggc 1080agccccggga gccacaggtg tacaccctgc cacccagccg cgacgagctg accaagaacc 1140aggtgtccct gacatgcctg gtgaagggat tctaccccag cgacatcgcc gtggagtggg 1200agagcaacgg ccagcccgag aacaactaca agacaacccc tcccgtgctg gacagcgatg 1260gatccttctt cctgtactcc aagctgaccg tggacaagag caggtggcag cagggaaacg 1320tgttctcttg ttccgtgatg cacgaggctc tgcacaacca ctacacccag aagtccctga 1380gcctgtctcc aggcaag 13971221407DNAartificialMB7-VH-CH-114D11 122atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60cagttggtgc agtctggacc tgagctgaag aagcctggag agacagtcaa gatctcctgc 120aaggcttctg gttatacctt cacagactct tcaatgcact gggtgcagca ggctccaaac 180aagggtttaa agtggatggg ctggataaac actgagactg gtgggccaac gtatgcagat 240gatttcaagg gacggtttgc cttctctttg gaaacctctg ccagaactgc ctatttgcag 300atcaacaacc tcaaaaatga ggacacggct acatatttct gtgctagaaa tggatactac 360gtggggtact atgctctgga ctactggggt caaggaacct cagtcaccgt ctcctcagcc 420tccaccaagg gcccatccgt gttccccctg gccccatcca gcaagtctac ctccggaggc 480acagccgccc tgggctgtct ggtgaaggac tacttccccg agccagtgac cgtgtcctgg 540aactccggag ccctgacatc cggcgtgcac accttccccg ccgtgctgca gtccagcggc 600ctgtactctc tgtcttccgt ggtgaccgtg ccatccagct ccctgggaac ccagacatac 660atctgcaacg tgaaccacaa gcctagcaac accaaggtgg acaagaaggt ggagcctaag 720agctgtgaca agacacacac atgccctcct tgtccagccc ctgagctgct gggcggcccc 780tccgtgttcc tgttcccccc caagcctaag gataccctga tgatcagcag aacccccgag 840gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aggtgaagtt caactggtac 900gtggacggcg tggaggtgca caacgctaag accaagccca gagaggagca gtacaacagc 960acatacagag tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cgggaaggag 1020tacaagtgca aggtgtccaa caaggccctg cctgccccta tcgagaagac catctctaag 1080gctaaggggc agccccggga gccacaggtg tacaccctgc cacccagccg cgacgagctg 1140accaagaacc aggtgtccct gacatgcctg gtgaagggat tctaccccag cgacatcgcc 1200gtggagtggg agagcaacgg ccagcccgag aacaactaca agacaacccc tcccgtgctg 1260gacagcgatg gatccttctt cctgtactcc aagctgaccg tggacaagag caggtggcag 1320cagggaaacg tgttctcttg ttccgtgatg cacgaggctc tgcacaacca ctacacccag 1380aagtccctga gcctgtctcc aggcaag 14071231407DNAartificialMB7-VH-CH-104E10 123atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60cagttggtgc agtctggacc

tgagctgaag aagcctggag agacagtcaa gatctcctgc 120aaggcttctg gttatacctt cacagactat tcaatgcact gggtgaagca ggctccagga 180aagggtttaa agtggatggg ctggataaac actgagactg gtgagccaac atatgcagat 240gacttcaagg gacggtttgc cttctctttg gaaacctctg ccaccactgc ctatttgcag 300atcaacaact tcaaaaatga ggacacggct acatatttct gtgctagaaa tggttactac 360gtgggatatt atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctcagcc 420tccaccaagg gcccatccgt gttccccctg gccccatcca gcaagtctac ctccggaggc 480acagccgccc tgggctgtct ggtgaaggac tacttccccg agccagtgac cgtgtcctgg 540aactccggag ccctgacatc cggcgtgcac accttccccg ccgtgctgca gtccagcggc 600ctgtactctc tgtcttccgt ggtgaccgtg ccatccagct ccctgggaac ccagacatac 660atctgcaacg tgaaccacaa gcctagcaac accaaggtgg acaagaaggt ggagcctaag 720agctgtgaca agacacacac atgccctcct tgtccagccc ctgagctgct gggcggcccc 780tccgtgttcc tgttcccccc caagcctaag gataccctga tgatcagcag aacccccgag 840gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aggtgaagtt caactggtac 900gtggacggcg tggaggtgca caacgctaag accaagccca gagaggagca gtacaacagc 960acatacagag tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cgggaaggag 1020tacaagtgca aggtgtccaa caaggccctg cctgccccta tcgagaagac catctctaag 1080gctaaggggc agccccggga gccacaggtg tacaccctgc cacccagccg cgacgagctg 1140accaagaacc aggtgtccct gacatgcctg gtgaagggat tctaccccag cgacatcgcc 1200gtggagtggg agagcaacgg ccagcccgag aacaactaca agacaacccc tcccgtgctg 1260gacagcgatg gatccttctt cctgtactcc aagctgaccg tggacaagag caggtggcag 1320cagggaaacg tgttctcttg ttccgtgatg cacgaggctc tgcacaacca ctacacccag 1380aagtccctga gcctgtctcc aggcaag 1407124696DNAartificialMB7-VL-CL-122A2 124atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgatatc 60cagatgacac agactacatc ctccctgtct gcctctctgg gagacagagt caccatcagt 120tgcagggcaa gtcaggacat tagcaattat ttaaactggt atcagcagaa accagatgga 180actgttaaac tcctgatcta ctacacatca agattacact caggagtccc atcaaggttc 240agtggcagtg ggtctggaac agattattct ctcaccatta gcaacctgga ccaagaagat 300attgccactt acttttgcca acagggtaat acgcttcctt ggacgttcgg tggaggcacc 360aagctggaaa tcaaacgaac tgtggctgca ccaagtgtct tcatctttcc tccgagtgat 420gagcagctga agagcgggac agcttctgtg gtgtgtctgc tgaataactt ctacccaaga 480gaagcaaagg tccagtggaa ggtggacaac gccctgcagt ctggcaactc acaggagtct 540gtcactgagc aggattccaa ggacagcact tacagcctgt ccagcaccct cactctgtcc 600aaagccgact acgaaaagca taaggtgtat gcttgtgagg tgacccacca gggactgagc 660agccctgtga cgaagtcctt caaccggggc gagtgc 696125693DNAartificialMB7-VL-CL-102E9 125atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaaatt 60gttctcaccc agtctccagc aatcatgtct gcatctccag gggagaaggt caccataacc 120tgcagtgcca gctcaagtgt aatttacatt cactggttcc agcagaagcc aggcacttct 180cccaaactct ggatttatag cacatcctac ctggcttctg gagtccctgc tcgcttcagt 240ggcagtggat ctgggacctc ttactctctc acaatcagcc gaatggaggc tgaagatgct 300gccacttatt actgccagca gaggagaagt tacccgttca cgttcggagg ggggaccaag 360ctggaaataa aacgaactgt ggctgcacca agtgtcttca tctttcctcc gagtgatgag 420cagctgaaga gcgggacagc ttctgtggtg tgtctgctga ataacttcta cccaagagaa 480gcaaaggtcc agtggaaggt ggacaacgcc ctgcagtctg gcaactcaca ggagtctgtc 540actgagcagg attccaagga cagcacttac agcctgtcca gcaccctcac tctgtccaaa 600gccgactacg aaaagcataa ggtgtatgct tgtgaggtga cccaccaggg actgagcagc 660cctgtgacga agtccttcaa ccggggcgag tgc 693126695DNAartificialMB7-VL-CL-104C12 126atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgatctc 60cagatgacac agactccatc ctccctgtct gcctctctgg gagacagagt caccatcagt 120tgcagggcaa gtcaggacat taacaattat ttaagctggt atcaggagaa accagatgga 180acttttaaac tcctgatcta ctacacatca agattacact caggagtccc atcaaggttc 240agtggcagtg ggtctggaac agattattct ctcaccgttc gcaacctgga acaggaagat 300attggcactt acttttgcca acagggtaaa acgcttccgt ggacgttcgg tggaggcacc 360aagctggaaa tcagcgaact gtggctgcac caagtgtctt catctttcct ccgagtgatg 420agcagctgaa gagcgggaca gcttctgtgg tgtgtctgct gaataacttc tacccaagag 480aagcaaaggt ccagtggaag gtggacaacg ccctgcagtc tggcaactca caggagtctg 540tcactgagca ggattccaag gacagcactt acagcctgtc cagcaccctc actctgtcca 600aagccgacta cgaaaagcat aaggtgtatg cttgtgaggt gacccaccag ggactgagca 660gccctgtgac gaagtccttc aaccggggcg agtgc 695127693DNAartificialMB7-VL-CL-114D11 127atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaaatt 60gttctcaccc agtctccagc aatcatgtct gcatctccag gggagaaggt caccataacc 120tgcagtgcca gctcaagtgt attttacatg cactggttcc agcagaagcc aggcacttct 180cccaaactct ggatttatag cacatccaac ctggcttctg gagtccctgc tcgcttcagt 240ggcagtggat ctgggacctc ttactctctc acaatcagcc gaatggaggc tgaagatgct 300gccacttatt actgccagca aaggagaagt tacccgtaca cgttcggagg ggggaccaag 360ctggaaataa aacgaactgt ggctgcacca agtgtcttca tctttcctcc gagtgatgag 420cagctgaaga gcgggacagc ttctgtggtg tgtctgctga ataacttcta cccaagagaa 480gcaaaggtcc agtggaaggt ggacaacgcc ctgcagtctg gcaactcaca ggagtctgtc 540actgagcagg attccaagga cagcacttac agcctgtcca gcaccctcac tctgtccaaa 600gccgactacg aaaagcataa ggtgtatgct tgtgaggtga cccaccaggg actgagcagc 660cctgtgacga agtccttcaa ccggggcgag tgc 693128693DNAartificialMB7-VL-CL-104E10 128atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaaatt 60gttctcaccc agtctccagc aatcatgtct gcatctccag gggagaaggt caccatgacc 120tgcagtgcca gttcaagtgt aatttacatg cactggttcc agcagaagcc aggcacttct 180cccaaactct ggatttatag cacatccaac ctggcttctg gagtccctgc tcgcttcagt 240ggcagtggat ctgggacatc ttactctctc acaatcagcc gaatggaggc tgaagatgct 300gccacttatt actgccagca aaggagaagt tacccgtaca cgttcggagg ggggaccaag 360ctggaaataa aacgaactgt ggctgcacca agtgtcttca tctttcctcc gagtgatgag 420cagctgaaga gcgggacagc ttctgtggtg tgtctgctga ataacttcta cccaagagaa 480gcaaaggtcc agtggaaggt ggacaacgcc ctgcagtctg gcaactcaca ggagtctgtc 540actgagcagg attccaagga cagcacttac agcctgtcca gcaccctcac tctgtccaaa 600gccgactacg aaaagcataa ggtgtatgct tgtgaggtga cccaccaggg actgagcagc 660cctgtgacga agtccttcaa ccggggcgag tgc 6931291313DNAHomo sapiensmisc_featureCD303 humain (AF293615.1) 129cagtgattct cgtgcctcag cctcctgagt agccgaaatt acagacgtgt gccaccatgc 60ttggctaatt ttttggattt ttagtagaga tggggtttca ctatgttggc caggctagtc 120ttgaactcct ggcctgaagc aatccgccca cctcagcctc ccaaagtgct gagattatag 180gcacgagcca ctacacctgg ccacaaaatt ctttaaagaa gccaatccca tcctccctca 240agagccaagg ggccacctca ccctcttgtt acagcagatc ctgcctccca cagtcaccct 300gctcccaagt gcaacctctg tctgaccctg catggtgtgc ggtgccctcc tgcctcaggc 360cgcgaagaag gatctaaggg cttggcttgt ttgaaagaac cacaccccga aagtaacatc 420tttggagaaa gtgatacaag agcttctgca cccacctgat agaggaagtc caaagggtgt 480gcgcacacac aatggtgcct gaagaagagc ctcaagaccg agagaaagga ctctggtggt 540tccagttgaa ggtctggtcc atggcagtcg tatccatctt gctcctcagt gtctgtttca 600ctgtgagttc tgtggtgcct cacaatttta tgtatagcaa aactgtcaag aggctgtcca 660agttacgaga gtatcaacag tatcatccaa gcctgacctg cgtcatggaa ggaaaggaca 720tagaagattg gagctgctgc ccaacccctt ggacttcatt tcagtctagt tgctacttta 780tttctactgg gatgcaatct tggactaaga gtcaaaagaa ctgttctgtg atgggggctg 840atctggtggt gatcaacacc agggaagaac aggatttcat cattcagaat ctgaaaagaa 900attcttctta ttttctgggg ctgtcagatc cagggggtcg gcgacattgg caatgggttg 960accagacacc atacaatgaa aatgtcacat tctggcactc aggtgaaccc aataaccttg 1020atgagcgttg tgcgataata aatttccgtt cttcagaaga atggggctgg aatgacattc 1080actgtcatgt acctcagaag tcaatttgca agatgaagaa gatctacata taaatgaaat 1140attctccctg gaaatgtgtt tgggttggca tccaccgttg tagaaagcta aattgatttt 1200ttaatttatg tgtaagtttt gtacaaggaa tgcccctaaa atgtttcagc aggctgtcac 1260ctattacact tatgatataa tccaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 1313130213PRTHomo sapiensmisc_featureCD303 humain (AAL37036.1) 130Met Val Pro Glu Glu Glu Pro Gln Asp Arg Glu Lys Gly Leu Trp Trp1 5 10 15Phe Gln Leu Lys Val Trp Ser Met Ala Val Val Ser Ile Leu Leu Leu 20 25 30Ser Val Cys Phe Thr Val Ser Ser Val Val Pro His Asn Phe Met Tyr 35 40 45Ser Lys Thr Val Lys Arg Leu Ser Lys Leu Arg Glu Tyr Gln Gln Tyr 50 55 60His Pro Ser Leu Thr Cys Val Met Glu Gly Lys Asp Ile Glu Asp Trp65 70 75 80Ser Cys Cys Pro Thr Pro Trp Thr Ser Phe Gln Ser Ser Cys Tyr Phe 85 90 95Ile Ser Thr Gly Met Gln Ser Trp Thr Lys Ser Gln Lys Asn Cys Ser 100 105 110Val Met Gly Ala Asp Leu Val Val Ile Asn Thr Arg Glu Glu Gln Asp 115 120 125Phe Ile Ile Gln Asn Leu Lys Arg Asn Ser Ser Tyr Phe Leu Gly Leu 130 135 140Ser Asp Pro Gly Gly Arg Arg His Trp Gln Trp Val Asp Gln Thr Pro145 150 155 160Tyr Asn Glu Asn Val Thr Phe Trp His Ser Gly Glu Pro Asn Asn Leu 165 170 175Asp Glu Arg Cys Ala Ile Ile Asn Phe Arg Ser Ser Glu Glu Trp Gly 180 185 190Trp Asn Asp Ile His Cys His Val Pro Gln Lys Ser Ile Cys Lys Met 195 200 205Lys Lys Ile Tyr Ile 210131118PRTartificial122A2-VHha 131Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115132118PRTartificial122A2-VHhb 132Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Val Thr Met Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115133118PRTartificial122A2-VHhc 133Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser 115134107PRTartificial122A2-VKha 134Asp Ile Gln Met Thr Gln Ser Thr Ser Ser Leu Ser Ala Ser Leu 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 Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Asp Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105135107PRTartificial122A2-VKhb 135Asp 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 Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Asp Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105136107PRTartificial122A2-VKhc 136Asp Ile Gln Met Thr Gln Ser Thr Ser Ser Leu Ser Ala Ser Leu 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 Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Gln Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105137107PRTartificial122A2-VKhd 137Asp 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 Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Gln Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105138121PRTartificial102E9-VHha 138Gln Ile His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr Tyr Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser 115 120139121PRTartificial102E9-VHhb 139Gln Ile His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Gln Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr Tyr Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser 115 120140121PRTartificial102E9-VHhc 140Gln Ile His Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Gln Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr Tyr Cys 85 90

95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser 115 120141106PRTartificial102E9-VKha 141Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Pro Gly1 5 10 15Glu Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Met Glu Ala Glu65 70 75 80Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105142106PRTartificial102E9-VKhb 142Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Pro Gly1 5 10 15Glu Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ala Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105143106PRTartificial102E9-VKhc 143Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Pro Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Met Gln Ala Glu65 70 75 80Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105144330PRTartificialCH 144Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330145448PRTartificialVH-CH-122A2 145Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155 160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445146451PRTartificialVH-CH-102E9 146Gln Ile His Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr Ala Phe65 70 75 80Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ser Thr Tyr Phe Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450147448PRTartificialVH-CH-104C12 147Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Gly Pro Gly Val1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ala Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys 85 90 95Ala Arg Asn Asp Asp Tyr Tyr Arg Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155 160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445148451PRTartificialVH-CH-114D11 148Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Ser 20 25 30Ser Met His Trp Val Gln Gln Ala Pro Asn Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Gly Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Leu Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450149451PRTartificialVH-CH-104E10 149Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Asn Phe Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450150448PRTartificial122A2-VHha-CH 150Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155 160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445151448PRTartificial122A2-VHhb-CH 151Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala His Ala Lys Ser Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Val Thr Met Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155 160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445152448PRTartificial122A2-VHhc-CH 152Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln Lys Phe 50 55 60Lys Gly Lys Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155 160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395 400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445153214PRTartificial122A2-VKha-CL 153Asp Ile Gln Met Thr Gln Ser Thr Ser Ser Leu Ser Ala Ser Leu 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 Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Asp Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly 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 210154214PRTartificial122A2-VKhb-CL 154Asp 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 Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Asp Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly 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 210155214PRTartificial122A2-VKhc-CL 155Asp Ile Gln Met Thr Gln Ser Thr Ser Ser Leu Ser Ala Ser Leu 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 Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Gln Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly 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 210156214PRTartificial122A2-VKhd-CL 156Asp 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 Asp Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Gln Gln65 70 75 80Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95Thr Phe Gly Gly 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 210157451PRTartificial102E9-VHha-CH 157Gln Ile His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr Tyr Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450158451PRTartificial102E9-VHhb-CH 158Gln Ile His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Gln Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr Tyr Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450159451PRTartificial102E9-VHhc-CH 159Gln Ile His Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Glu1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met 35 40 45Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Gln Asp Phe 50 55 60Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr65 70 75 80Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr Tyr Cys 85 90 95Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr Trp Gly 100 105 110Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly225 230 235 240Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly305 310 315 320Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro385 390 395 400Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445Pro Gly Lys 450160213PRTartificial102E9-VKha-CL 160Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Pro Gly1 5 10 15Glu Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Met Glu Ala Glu65 70 75 80Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu 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 210161213PRTartificial102E9-VKhb-CL 161Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Pro Gly1 5 10 15Glu Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Thr Ala Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Arg Met Glu Ala Glu65 70 75 80Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu 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 210162213PRTartificial102E9-VKhc-CL 162Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Pro Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile Tyr Ile 20 25 30His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr 35 40 45Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Met Gln Ala Glu65 70 75 80Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro Phe Thr 85 90 95Phe Gly Gly Gly Thr Lys Leu 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 210163466PRTartificialMB7-VH-CH-122A2 163Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro 20 25 30Gly Val Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Thr Thr 85 90 95Ala Tyr Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr 100 105 110Tyr Cys Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln 115 120 125Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185 190Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 195 200 205Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 210 215

220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 340 345 350Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp385 390 395 400Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420 425 430Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460Gly Lys465164469PRTartificialMB7-VH-CH-102E9 164Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile His Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr 85 90 95Ala Phe Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ser Thr Tyr 100 105 110Phe Cys Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly Lys465165466PRTartificialMB7-VH-CH-104C12 165Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Gly Pro 20 25 30Gly Val Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr 85 90 95Ala Tyr Met Glu Leu Ala Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr 100 105 110Phe Cys Ala Arg Asn Asp Asp Tyr Tyr Arg Phe Ala Tyr Trp Gly Gln 115 120 125Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185 190Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 195 200 205Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 340 345 350Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp385 390 395 400Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420 425 430Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460Gly Lys465166469PRTartificialMB7-VH-CH-114D11 166Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Ser Ser Met His Trp Val Gln Gln Ala Pro Asn Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Gly Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Arg Thr 85 90 95Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr 100 105 110Phe Cys Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Leu Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly Lys465167469PRTartificialMB7-VH-CH-104E10 167Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr 85 90 95Ala Tyr Leu Gln Ile Asn Asn Phe Lys Asn Glu Asp Thr Ala Thr Tyr 100 105 110Phe Cys Ala Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly Lys465168466PRTartificial122A2-MB7-VHha-CH 168Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro 20 25 30Gly Ala Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr 85 90 95Ala Tyr Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr 100 105 110Tyr Cys Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln 115 120 125Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185 190Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 195 200 205Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335Glu Tyr Lys Cys Lys

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 340 345 350Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp385 390 395 400Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420 425 430Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460Gly Lys465169466PRTartificial122A2-MB7-VHhb-CH 169Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro 20 25 30Gly Ala Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Arg Gln Ala His Ala Lys Ser Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Val Thr Met Thr Val Asp Thr Ser Ser Ser Thr 85 90 95Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr 100 105 110Tyr Cys Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln 115 120 125Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185 190Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 195 200 205Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 340 345 350Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp385 390 395 400Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420 425 430Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460Gly Lys465170466PRTartificial122A2-MB7-VHhc-CH 170Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro 20 25 30Gly Ala Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu 50 55 60Trp Ile Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ser Asn Tyr Asn Gln65 70 75 80Lys Phe Lys Gly Lys Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr 85 90 95Ala Tyr Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr 100 105 110Tyr Cys Ala Arg Asn Gly Asn Phe Tyr Val Met Asp Tyr Trp Gly Gln 115 120 125Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 130 135 140Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala145 150 155 160Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185 190Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 195 200 205Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 210 215 220Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp225 230 235 240Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 245 250 255Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295 300Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg305 310 315 320Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 325 330 335Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 340 345 350Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 370 375 380Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp385 390 395 400Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 405 410 415Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420 425 430Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 435 440 445Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 450 455 460Gly Lys465171232PRTartificial122A2-MB7-VKha-CL 171Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Ile Gln Met Thr Gln Ser Thr Ser Ser Leu Ser Ala Ser 20 25 30Leu Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser 35 40 45Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 85 90 95Asp Gln Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 115 120 125Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 130 135 140Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg145 150 155 160Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 165 170 175Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 180 185 190Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 195 200 205Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 210 215 220Lys Ser Phe Asn Arg Gly Glu Cys225 230172232PRTartificial122A2-MB7-VKhb-CL 172Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 20 25 30Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser 35 40 45Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 85 90 95Asp Gln Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 115 120 125Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 130 135 140Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg145 150 155 160Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 165 170 175Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 180 185 190Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 195 200 205Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 210 215 220Lys Ser Phe Asn Arg Gly Glu Cys225 230173232PRTartificial122A2-MB7-VKhc-CL 173Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Ile Gln Met Thr Gln Ser Thr Ser Ser Leu Ser Ala Ser 20 25 30Leu Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser 35 40 45Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 85 90 95Gln Gln Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 115 120 125Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 130 135 140Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg145 150 155 160Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 165 170 175Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 180 185 190Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 195 200 205Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 210 215 220Lys Ser Phe Asn Arg Gly Glu Cys225 230174232PRTartificial122A2-MB7-VKhd-CL 174Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 20 25 30Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser 35 40 45Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu 50 55 60Leu Ile Tyr Tyr Thr Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu 85 90 95Gln Gln Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu 100 105 110Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val 115 120 125Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 130 135 140Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg145 150 155 160Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 165 170 175Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 180 185 190Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 195 200 205Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 210 215 220Lys Ser Phe Asn Arg Gly Glu Cys225 230175469PRTartificial102E9-MB7-VHha-CH 175Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp65 70 75 80Asp Phe Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr 85 90 95Ala Tyr Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr 100 105 110Tyr Cys Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly Lys465176469PRTartificial102E9-MB7-VHhb-CH 176Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile His Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro 20 25 30Gly Glu Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Gln65 70 75 80Asp Phe Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr 85 90 95Ala Tyr Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr 100 105 110Tyr Cys Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly Lys465177469PRTartificial102E9-MB7-VHhc-CH 177Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile His Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro 20 25 30Gly Glu Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 35 40 45Asp Tyr Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys 50 55 60Trp Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Gln65 70 75 80Asp Phe Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr 85 90 95Ala Tyr Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ser Thr Tyr 100 105 110Tyr Cys Thr Arg Asn Gly Tyr Tyr Val Gly Tyr Tyr Ala Met Asp Tyr 115 120 125Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly 130 135 140Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly145 150 155 160Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 165 170 175Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 180 185 190Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 195 200 205Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 210 215 220Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys225 230 235 240Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 245 250 255Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 290 295 300Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser305 310 315 320Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 340 345 350Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln 370 375 380Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala385 390 395 400Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 435 440 445Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460Leu Ser Pro Gly Lys465178231PRTartificial102E9-MB7-VKha-CL 178Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser 20 25 30Pro Gly Glu Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile 35 40 45Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Met Glu 85 90 95Ala Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 115 120 125Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 130 135 140Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu145 150 155 160Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 165 170 175Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 210 215 220Ser Phe Asn Arg Gly Glu Cys225 230179231PRTartificial102E9-MB7-VKhb-CL 179Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser 20 25 30Pro Gly Glu Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile 35 40 45Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Thr Ala Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Arg Met Glu 85 90 95Ala Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 115 120 125Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 130 135 140Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu145 150 155 160Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 165 170 175Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 210 215 220Ser Phe Asn Arg Gly Glu Cys225 230180231PRTartificial102E9-MB7-VKhc-CL 180Met Arg Trp Ser Trp Ile Phe Leu Leu Leu Leu Ser Ile Thr Ser Ala1 5 10 15Asn Ala Gln Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser 20 25 30Pro Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ile 35 40 45Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp 50 55 60Ile Tyr Ser Thr Ser Tyr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser65 70 75 80Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Met Gln 85 90 95Ala Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Arg Ser Tyr Pro 100 105 110Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 115 120 125Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 130 135 140Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu145 150 155 160Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 165 170 175Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 210 215 220Ser Phe Asn Arg Gly Glu Cys225 230181354DNAartificial122A2-VHha 181caggtccagc tgcagcagtc tggcgccgaa gtggtcaagc ctggcgcctc cgtgaagatc 60agctgcaagg gcagcggcta caccttcacc gactacagca tgcactgggt caagcaggcc 120cacgccaaga gcctggaatg gatcggcgtg atcagcacct actacggcga cagcaactac 180aaccagaagt tcaagggcaa agtcaccatg accgtggaca agagcagctc caccgcctac 240atggaactga gcaggctgac cagcgacgac accgccgtgt actactgcgc cagaaacggc 300aacttctacg tgatggacta ctggggccag ggcaccctgg tcaccgtgtc atct 354182354DNAartificial122A2-VHhb 182caggtccagc tgcagcagtc tggcgccgaa gtggtcaagc ctggcgcctc cgtgaagatc 60agctgcaagg gcagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cacgccaaga gcctggaatg gatcggcgtg atcagcacct actacggcga cagcaactac 180aaccagaagt tcaagggcaa agtcaccatg accgtggaca ccagcagctc caccgcctac 240atggaactga gcaggctgag aagcgacgac accgccgtgt actactgcgc cagaaacggc 300aacttctacg tgatggacta ctggggccag ggcaccctgg tcaccgtgtc atct 354183354DNAartificial122A2-VHhc 183caggtccagc tgcagcagtc tggcgccgaa gtggtcaagc ctggcgcctc cgtgaagatc 60agctgcaagg gcagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cctggacagg gcctggaatg gatcggcgtg atcagcacct actacggcga cagcaactac 180aaccagaagt tcaagggcaa agtcaccatg accgtggaca agagcagctc caccgcctac 240atggaactga gcaggctgac cagcgacgac accgccgtgt actactgcgc cagaaacggc 300aacttctacg tgatggacta ctggggccag ggcaccctgg tcaccgtgtc atct 354184321DNAartificial122A2-VKha 184gacatccaga tgacccagag caccagcagc ctgagcgcct ctctgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaggc tgcacaccgg cgtgcccagc 180agattctctg gctctggcag cggcaccgac tacagcctga ccatctccaa cctggaccag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa g 321185321DNAartificial122A2-VKhb 185gacatccaga tgacccagag ccctagcagc ctgagcgcct ctgtgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaggc tgcacaccgg cgtgcccagc 180agattctctg gctctggcag cggcaccgac tacagcctga ccatctccaa cctggaccag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa g 321186321DNAartificial122A2-VKhc 186gacatccaga tgacccagag caccagcagc ctgagcgcct ctctgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaacc tgcacaccgg cgtgcccagc 180agattcagcg gctctggctc tggcaccgac tacagcctga ccatctccaa cctccagcag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa g 321187321DNAartificial122A2-VKhd 187gacatccaga tgacccagag ccctagcagc ctgagcgcct ctgtgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaacc tgcacaccgg cgtgcccagc 180agattcagcg gctctggctc tggcaccgac tacagcctga ccatctccaa cctccagcag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa g 321188363DNAartificial102E9-VHha 188cagatccatc tggtgcagag cggccctgag ctgaagaaac ccggcgagag cgtgaagatc 60agctgcaagg ccagcggcta caccttcacc gactacagca tgcactgggt caagcaggcc 120ccaggccagg gcctgaagtg gatgggctgg atcaacaccg agacaggcga gcccacctac 180gccgacgact tcaagggcag attcgtgttc agcctggaca ccagcgtgtc caccgcctac 240ctgcagatca acagcctgaa gaacgaggac acctccacct actactgcac ccggaacggc 300tactacgtgg ggtactacgc catggactac tggggccagg gcacctccgt gaccgtgtca 360tct 363189363DNAartificial102E9-VHhb 189cagatccatc tggtgcagag cggccctgag ctgaagaaac ccggcgagag cgtgaagatc 60agctgcaagg ccagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cctggacagg gcctgaagtg gatgggctgg atcaacaccg agacaggcga gcccacctac 180gcccaggact tcaagggcag attcgtgttc agcctggaca ccagcgtgtc caccgcctac 240ctgcagatca acagcctgaa gaacgaggac acctccacct actactgcac ccggaacggc 300tactacgtgg ggtactacgc catggactac tggggccagg gcacctccgt gaccgtgtca 360tct 363190363DNAartificial102E9-VHhc 190cagatccatc tggtgcagag cggcagcgag ctgaagaaac ccggcgagag cgtgaagatc 60agctgcaagg ccagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cctggacagg gcctgaagtg gatgggctgg atcaacaccg agacaggcga gcccacctac 180gcccaggact tcaagggcag attcgtgttc agcctggaca ccagcgtgtc caccgcctac 240ctgcagatca acagcctgaa gaacgaggac acctccacct actactgcac ccggaacggc 300tactacgtgg ggtactacgc catggactac tggggccagg gcacctccgt gaccgtgtca 360tct 363191318DNAartificial102E9-VKha 191cagatccagc tgacccagag ccctagcttc ctgagcgcct ctcctggcga gagagtgacc 60atcacctgta gcgccagcag ctccgtgatc tacatccact ggttccagca gaagcccggc 120aaggccccta agctgtggat ctacagcacc agctacctgg ccagcggcgt gccaagcaga 180ttcagcggct ctggctctgg caccgagtac accctgacca tcagctccat ggaagccgag 240gacttcgcca cctactactg ccagcagagg cggagctacc ccttcacctt cggcggaggc 300accaagctgg aaatcaag 318192318DNAartificial102E9-VKhb 192cagatccagc tgacccagag ccctagcttc ctgagcgcct ctcctggcga gagagtgacc 60atcacctgta gcgccagcag ctccgtgatc tacatccact ggttccagca gaagcccggc 120accgccccta agctgtggat ctacagcacc agctacctgg ccagcggcgt gccaagcaga 180ttcagcggct ctggcagcgg cacctcctac accctgacca tcagcaggat ggaagccgag 240gacttcgcca cctactactg ccagcagagg cggagctacc ccttcacctt cggcggaggc 300accaagctgg aaatcaag

318193318DNAartificial102E9-VKhc 193cagatccagc tgacccagag ccctagcttc ctgagcgcct ctcctggcga cagagtgacc 60atcacctgta gcgccagcag ctccgtgatc tacatccact ggttccagca gaagcccggc 120aaggccccta agctgtggat ctacagcacc agctacctgg ccagcggcgt gccaagcaga 180ttcagcggct ctggctctgg caccgagtac accctgacca tcagctccat gcaggccgag 240gacttcgcca cctactactg ccagcagagg cggagctacc ccttcacctt cggcggaggc 300accaagctgg aaatcaag 3181941344DNAartificial122A2-VHha-CH 194caggtccagc tgcagcagtc tggcgccgaa gtggtcaagc ctggcgcctc cgtgaagatc 60agctgcaagg gcagcggcta caccttcacc gactacagca tgcactgggt caagcaggcc 120cacgccaaga gcctggaatg gatcggcgtg atcagcacct actacggcga cagcaactac 180aaccagaagt tcaagggcaa agtcaccatg accgtggaca agagcagctc caccgcctac 240atggaactga gcaggctgac cagcgacgac accgccgtgt actactgcgc cagaaacggc 300aacttctacg tgatggacta ctggggccag ggcaccctgg tcaccgtgtc atctgcctcc 360accaagggcc catccgtgtt ccccctggcc ccatccagca agtctacctc cggaggcaca 420gccgccctgg gctgtctggt gaaggactac ttccccgagc cagtgaccgt gtcctggaac 480tccggagccc tgacatccgg cgtgcacacc ttccccgccg tgctgcagtc cagcggcctg 540tactctctgt cttccgtggt gaccgtgcca tccagctccc tgggaaccca gacatacatc 600tgcaacgtga accacaagcc tagcaacacc aaggtggaca agaaggtgga gcctaagagc 660tgtgacaaga cacacacatg ccctccttgt ccagcccctg agctgctggg cggcccctcc 720gtgttcctgt tcccccccaa gcctaaggat accctgatga tcagcagaac ccccgaggtg 780acctgcgtgg tggtggacgt gtcccacgag gatcccgagg tgaagttcaa ctggtacgtg 840gacggcgtgg aggtgcacaa cgctaagacc aagcccagag aggagcagta caacagcaca 900tacagagtgg tgtctgtgct gaccgtgctg caccaggact ggctgaacgg gaaggagtac 960aagtgcaagg tgtccaacaa ggccctgcct gcccctatcg agaagaccat ctctaaggct 1020aaggggcagc cccgggagcc acaggtgtac accctgccac ccagccgcga cgagctgacc 1080aagaaccagg tgtccctgac atgcctggtg aagggattct accccagcga catcgccgtg 1140gagtgggaga gcaacggcca gcccgagaac aactacaaga caacccctcc cgtgctggac 1200agcgatggat ccttcttcct gtactccaag ctgaccgtgg acaagagcag gtggcagcag 1260ggaaacgtgt tctcttgttc cgtgatgcac gaggctctgc acaaccacta cacccagaag 1320tccctgagcc tgtctccagg caag 13441951344DNAartificial122A2-VHhb-CH 195caggtccagc tgcagcagtc tggcgccgaa gtggtcaagc ctggcgcctc cgtgaagatc 60agctgcaagg gcagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cacgccaaga gcctggaatg gatcggcgtg atcagcacct actacggcga cagcaactac 180aaccagaagt tcaagggcaa agtcaccatg accgtggaca ccagcagctc caccgcctac 240atggaactga gcaggctgag aagcgacgac accgccgtgt actactgcgc cagaaacggc 300aacttctacg tgatggacta ctggggccag ggcaccctgg tcaccgtgtc atctgcctcc 360accaagggcc catccgtgtt ccccctggcc ccatccagca agtctacctc cggaggcaca 420gccgccctgg gctgtctggt gaaggactac ttccccgagc cagtgaccgt gtcctggaac 480tccggagccc tgacatccgg cgtgcacacc ttccccgccg tgctgcagtc cagcggcctg 540tactctctgt cttccgtggt gaccgtgcca tccagctccc tgggaaccca gacatacatc 600tgcaacgtga accacaagcc tagcaacacc aaggtggaca agaaggtgga gcctaagagc 660tgtgacaaga cacacacatg ccctccttgt ccagcccctg agctgctggg cggcccctcc 720gtgttcctgt tcccccccaa gcctaaggat accctgatga tcagcagaac ccccgaggtg 780acctgcgtgg tggtggacgt gtcccacgag gatcccgagg tgaagttcaa ctggtacgtg 840gacggcgtgg aggtgcacaa cgctaagacc aagcccagag aggagcagta caacagcaca 900tacagagtgg tgtctgtgct gaccgtgctg caccaggact ggctgaacgg gaaggagtac 960aagtgcaagg tgtccaacaa ggccctgcct gcccctatcg agaagaccat ctctaaggct 1020aaggggcagc cccgggagcc acaggtgtac accctgccac ccagccgcga cgagctgacc 1080aagaaccagg tgtccctgac atgcctggtg aagggattct accccagcga catcgccgtg 1140gagtgggaga gcaacggcca gcccgagaac aactacaaga caacccctcc cgtgctggac 1200agcgatggat ccttcttcct gtactccaag ctgaccgtgg acaagagcag gtggcagcag 1260ggaaacgtgt tctcttgttc cgtgatgcac gaggctctgc acaaccacta cacccagaag 1320tccctgagcc tgtctccagg caag 13441961344DNAartificial122A2-VHhc-CH 196caggtccagc tgcagcagtc tggcgccgaa gtggtcaagc ctggcgcctc cgtgaagatc 60agctgcaagg gcagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cctggacagg gcctggaatg gatcggcgtg atcagcacct actacggcga cagcaactac 180aaccagaagt tcaagggcaa agtcaccatg accgtggaca agagcagctc caccgcctac 240atggaactga gcaggctgac cagcgacgac accgccgtgt actactgcgc cagaaacggc 300aacttctacg tgatggacta ctggggccag ggcaccctgg tcaccgtgtc atctgcctcc 360accaagggcc catccgtgtt ccccctggcc ccatccagca agtctacctc cggaggcaca 420gccgccctgg gctgtctggt gaaggactac ttccccgagc cagtgaccgt gtcctggaac 480tccggagccc tgacatccgg cgtgcacacc ttccccgccg tgctgcagtc cagcggcctg 540tactctctgt cttccgtggt gaccgtgcca tccagctccc tgggaaccca gacatacatc 600tgcaacgtga accacaagcc tagcaacacc aaggtggaca agaaggtgga gcctaagagc 660tgtgacaaga cacacacatg ccctccttgt ccagcccctg agctgctggg cggcccctcc 720gtgttcctgt tcccccccaa gcctaaggat accctgatga tcagcagaac ccccgaggtg 780acctgcgtgg tggtggacgt gtcccacgag gatcccgagg tgaagttcaa ctggtacgtg 840gacggcgtgg aggtgcacaa cgctaagacc aagcccagag aggagcagta caacagcaca 900tacagagtgg tgtctgtgct gaccgtgctg caccaggact ggctgaacgg gaaggagtac 960aagtgcaagg tgtccaacaa ggccctgcct gcccctatcg agaagaccat ctctaaggct 1020aaggggcagc cccgggagcc acaggtgtac accctgccac ccagccgcga cgagctgacc 1080aagaaccagg tgtccctgac atgcctggtg aagggattct accccagcga catcgccgtg 1140gagtgggaga gcaacggcca gcccgagaac aactacaaga caacccctcc cgtgctggac 1200agcgatggat ccttcttcct gtactccaag ctgaccgtgg acaagagcag gtggcagcag 1260ggaaacgtgt tctcttgttc cgtgatgcac gaggctctgc acaaccacta cacccagaag 1320tccctgagcc tgtctccagg caag 1344197642DNAartificial122A2-VKha-CL 197gacatccaga tgacccagag caccagcagc ctgagcgcct ctctgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaggc tgcacaccgg cgtgcccagc 180agattctctg gctctggcag cggcaccgac tacagcctga ccatctccaa cctggaccag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa gcgaactgtg gctgcaccaa gtgtcttcat ctttcctccg 360agtgatgagc agctgaagag cgggacagct tctgtggtgt gtctgctgaa taacttctac 420ccaagagaag caaaggtcca gtggaaggtg gacaacgccc tgcagtctgg caactcacag 480gagtctgtca ctgagcagga ttccaaggac agcacttaca gcctgtccag caccctcact 540ctgtccaaag ccgactacga aaagcataag gtgtatgctt gtgaggtgac ccaccaggga 600ctgagcagcc ctgtgacgaa gtccttcaac cggggcgagt gc 642198642DNAartificial122A2-VKhb-CL 198gacatccaga tgacccagag ccctagcagc ctgagcgcct ctgtgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaggc tgcacaccgg cgtgcccagc 180agattctctg gctctggcag cggcaccgac tacagcctga ccatctccaa cctggaccag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa gcgaactgtg gctgcaccaa gtgtcttcat ctttcctccg 360agtgatgagc agctgaagag cgggacagct tctgtggtgt gtctgctgaa taacttctac 420ccaagagaag caaaggtcca gtggaaggtg gacaacgccc tgcagtctgg caactcacag 480gagtctgtca ctgagcagga ttccaaggac agcacttaca gcctgtccag caccctcact 540ctgtccaaag ccgactacga aaagcataag gtgtatgctt gtgaggtgac ccaccaggga 600ctgagcagcc ctgtgacgaa gtccttcaac cggggcgagt gc 642199642DNAartificial122A2-VKhc-CL 199gacatccaga tgacccagag caccagcagc ctgagcgcct ctctgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaacc tgcacaccgg cgtgcccagc 180agattcagcg gctctggctc tggcaccgac tacagcctga ccatctccaa cctccagcag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa gcgaactgtg gctgcaccaa gtgtcttcat ctttcctccg 360agtgatgagc agctgaagag cgggacagct tctgtggtgt gtctgctgaa taacttctac 420ccaagagaag caaaggtcca gtggaaggtg gacaacgccc tgcagtctgg caactcacag 480gagtctgtca ctgagcagga ttccaaggac agcacttaca gcctgtccag caccctcact 540ctgtccaaag ccgactacga aaagcataag gtgtatgctt gtgaggtgac ccaccaggga 600ctgagcagcc ctgtgacgaa gtccttcaac cggggcgagt gc 642200642DNAartificial122A2-VKhd-CL 200gacatccaga tgacccagag ccctagcagc ctgagcgcct ctgtgggcga cagagtgacc 60atcacctgtc aggccagcca ggacatcagc aactacctga actggtatca gcagaaaccc 120gacggcaccg tgaagctgct gatctactac accagcaacc tgcacaccgg cgtgcccagc 180agattcagcg gctctggctc tggcaccgac tacagcctga ccatctccaa cctccagcag 240gaagatattg ccacctacta ctgccagcag ggcaacaccc tgccctggac attcggcgga 300ggcaccaagc tggaaatcaa gcgaactgtg gctgcaccaa gtgtcttcat ctttcctccg 360agtgatgagc agctgaagag cgggacagct tctgtggtgt gtctgctgaa taacttctac 420ccaagagaag caaaggtcca gtggaaggtg gacaacgccc tgcagtctgg caactcacag 480gagtctgtca ctgagcagga ttccaaggac agcacttaca gcctgtccag caccctcact 540ctgtccaaag ccgactacga aaagcataag gtgtatgctt gtgaggtgac ccaccaggga 600ctgagcagcc ctgtgacgaa gtccttcaac cggggcgagt gc 6422011353DNAartificial102E9-VHha-CH 201cagatccatc tggtgcagag cggccctgag ctgaagaaac ccggcgagag cgtgaagatc 60agctgcaagg ccagcggcta caccttcacc gactacagca tgcactgggt caagcaggcc 120ccaggccagg gcctgaagtg gatgggctgg atcaacaccg agacaggcga gcccacctac 180gccgacgact tcaagggcag attcgtgttc agcctggaca ccagcgtgtc caccgcctac 240ctgcagatca acagcctgaa gaacgaggac acctccacct actactgcac ccggaacggc 300tactacgtgg ggtactacgc catggactac tggggccagg gcacctccgt gaccgtgtca 360tctgcctcca ccaagggccc atccgtgttc cccctggccc catccagcaa gtctacctcc 420ggaggcacag ccgccctggg ctgtctggtg aaggactact tccccgagcc agtgaccgtg 480tcctggaact ccggagccct gacatccggc gtgcacacct tccccgccgt gctgcagtcc 540agcggcctgt actctctgtc ttccgtggtg accgtgccat ccagctccct gggaacccag 600acatacatct gcaacgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggag 660cctaagagct gtgacaagac acacacatgc cctccttgtc cagcccctga gctgctgggc 720ggcccctccg tgttcctgtt cccccccaag cctaaggata ccctgatgat cagcagaacc 780cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg atcccgaggt gaagttcaac 840tggtacgtgg acggcgtgga ggtgcacaac gctaagacca agcccagaga ggagcagtac 900aacagcacat acagagtggt gtctgtgctg accgtgctgc accaggactg gctgaacggg 960aaggagtaca agtgcaaggt gtccaacaag gccctgcctg cccctatcga gaagaccatc 1020tctaaggcta aggggcagcc ccgggagcca caggtgtaca ccctgccacc cagccgcgac 1080gagctgacca agaaccaggt gtccctgaca tgcctggtga agggattcta ccccagcgac 1140atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac aacccctccc 1200gtgctggaca gcgatggatc cttcttcctg tactccaagc tgaccgtgga caagagcagg 1260tggcagcagg gaaacgtgtt ctcttgttcc gtgatgcacg aggctctgca caaccactac 1320acccagaagt ccctgagcct gtctccaggc aag 13532021353DNAartificial102E9-VHhb-CH 202cagatccatc tggtgcagag cggccctgag ctgaagaaac ccggcgagag cgtgaagatc 60agctgcaagg ccagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cctggacagg gcctgaagtg gatgggctgg atcaacaccg agacaggcga gcccacctac 180gcccaggact tcaagggcag attcgtgttc agcctggaca ccagcgtgtc caccgcctac 240ctgcagatca acagcctgaa gaacgaggac acctccacct actactgcac ccggaacggc 300tactacgtgg ggtactacgc catggactac tggggccagg gcacctccgt gaccgtgtca 360tctgcctcca ccaagggccc atccgtgttc cccctggccc catccagcaa gtctacctcc 420ggaggcacag ccgccctggg ctgtctggtg aaggactact tccccgagcc agtgaccgtg 480tcctggaact ccggagccct gacatccggc gtgcacacct tccccgccgt gctgcagtcc 540agcggcctgt actctctgtc ttccgtggtg accgtgccat ccagctccct gggaacccag 600acatacatct gcaacgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggag 660cctaagagct gtgacaagac acacacatgc cctccttgtc cagcccctga gctgctgggc 720ggcccctccg tgttcctgtt cccccccaag cctaaggata ccctgatgat cagcagaacc 780cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg atcccgaggt gaagttcaac 840tggtacgtgg acggcgtgga ggtgcacaac gctaagacca agcccagaga ggagcagtac 900aacagcacat acagagtggt gtctgtgctg accgtgctgc accaggactg gctgaacggg 960aaggagtaca agtgcaaggt gtccaacaag gccctgcctg cccctatcga gaagaccatc 1020tctaaggcta aggggcagcc ccgggagcca caggtgtaca ccctgccacc cagccgcgac 1080gagctgacca agaaccaggt gtccctgaca tgcctggtga agggattcta ccccagcgac 1140atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac aacccctccc 1200gtgctggaca gcgatggatc cttcttcctg tactccaagc tgaccgtgga caagagcagg 1260tggcagcagg gaaacgtgtt ctcttgttcc gtgatgcacg aggctctgca caaccactac 1320acccagaagt ccctgagcct gtctccaggc aag 13532031353DNAartificial102E9-VHhc-CH 203cagatccatc tggtgcagag cggcagcgag ctgaagaaac ccggcgagag cgtgaagatc 60agctgcaagg ccagcggcta caccttcacc gactacagca tgcactgggt ccgacaggcc 120cctggacagg gcctgaagtg gatgggctgg atcaacaccg agacaggcga gcccacctac 180gcccaggact tcaagggcag attcgtgttc agcctggaca ccagcgtgtc caccgcctac 240ctgcagatca acagcctgaa gaacgaggac acctccacct actactgcac ccggaacggc 300tactacgtgg ggtactacgc catggactac tggggccagg gcacctccgt gaccgtgtca 360tctgcctcca ccaagggccc atccgtgttc cccctggccc catccagcaa gtctacctcc 420ggaggcacag ccgccctggg ctgtctggtg aaggactact tccccgagcc agtgaccgtg 480tcctggaact ccggagccct gacatccggc gtgcacacct tccccgccgt gctgcagtcc 540agcggcctgt actctctgtc ttccgtggtg accgtgccat ccagctccct gggaacccag 600acatacatct gcaacgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggag 660cctaagagct gtgacaagac acacacatgc cctccttgtc cagcccctga gctgctgggc 720ggcccctccg tgttcctgtt cccccccaag cctaaggata ccctgatgat cagcagaacc 780cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg atcccgaggt gaagttcaac 840tggtacgtgg acggcgtgga ggtgcacaac gctaagacca agcccagaga ggagcagtac 900aacagcacat acagagtggt gtctgtgctg accgtgctgc accaggactg gctgaacggg 960aaggagtaca agtgcaaggt gtccaacaag gccctgcctg cccctatcga gaagaccatc 1020tctaaggcta aggggcagcc ccgggagcca caggtgtaca ccctgccacc cagccgcgac 1080gagctgacca agaaccaggt gtccctgaca tgcctggtga agggattcta ccccagcgac 1140atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac aacccctccc 1200gtgctggaca gcgatggatc cttcttcctg tactccaagc tgaccgtgga caagagcagg 1260tggcagcagg gaaacgtgtt ctcttgttcc gtgatgcacg aggctctgca caaccactac 1320acccagaagt ccctgagcct gtctccaggc aag 1353204639DNAartificial102E9-VKha-CL 204cagatccagc tgacccagag ccctagcttc ctgagcgcct ctcctggcga gagagtgacc 60atcacctgta gcgccagcag ctccgtgatc tacatccact ggttccagca gaagcccggc 120aaggccccta agctgtggat ctacagcacc agctacctgg ccagcggcgt gccaagcaga 180ttcagcggct ctggctctgg caccgagtac accctgacca tcagctccat ggaagccgag 240gacttcgcca cctactactg ccagcagagg cggagctacc ccttcacctt cggcggaggc 300accaagctgg aaatcaagcg aactgtggct gcaccaagtg tcttcatctt tcctccgagt 360gatgagcagc tgaagagcgg gacagcttct gtggtgtgtc tgctgaataa cttctaccca 420agagaagcaa aggtccagtg gaaggtggac aacgccctgc agtctggcaa ctcacaggag 480tctgtcactg agcaggattc caaggacagc acttacagcc tgtccagcac cctcactctg 540tccaaagccg actacgaaaa gcataaggtg tatgcttgtg aggtgaccca ccagggactg 600agcagccctg tgacgaagtc cttcaaccgg ggcgagtgc 639205639DNAartificial102E9-VKhb-CL 205cagatccagc tgacccagag ccctagcttc ctgagcgcct ctcctggcga gagagtgacc 60atcacctgta gcgccagcag ctccgtgatc tacatccact ggttccagca gaagcccggc 120accgccccta agctgtggat ctacagcacc agctacctgg ccagcggcgt gccaagcaga 180ttcagcggct ctggcagcgg cacctcctac accctgacca tcagcaggat ggaagccgag 240gacttcgcca cctactactg ccagcagagg cggagctacc ccttcacctt cggcggaggc 300accaagctgg aaatcaagcg aactgtggct gcaccaagtg tcttcatctt tcctccgagt 360gatgagcagc tgaagagcgg gacagcttct gtggtgtgtc tgctgaataa cttctaccca 420agagaagcaa aggtccagtg gaaggtggac aacgccctgc agtctggcaa ctcacaggag 480tctgtcactg agcaggattc caaggacagc acttacagcc tgtccagcac cctcactctg 540tccaaagccg actacgaaaa gcataaggtg tatgcttgtg aggtgaccca ccagggactg 600agcagccctg tgacgaagtc cttcaaccgg ggcgagtgc 639206639DNAartificial102E9-VKhc-CL 206cagatccagc tgacccagag ccctagcttc ctgagcgcct ctcctggcga cagagtgacc 60atcacctgta gcgccagcag ctccgtgatc tacatccact ggttccagca gaagcccggc 120aaggccccta agctgtggat ctacagcacc agctacctgg ccagcggcgt gccaagcaga 180ttcagcggct ctggctctgg caccgagtac accctgacca tcagctccat gcaggccgag 240gacttcgcca cctactactg ccagcagagg cggagctacc ccttcacctt cggcggaggc 300accaagctgg aaatcaagcg aactgtggct gcaccaagtg tcttcatctt tcctccgagt 360gatgagcagc tgaagagcgg gacagcttct gtggtgtgtc tgctgaataa cttctaccca 420agagaagcaa aggtccagtg gaaggtggac aacgccctgc agtctggcaa ctcacaggag 480tctgtcactg agcaggattc caaggacagc acttacagcc tgtccagcac cctcactctg 540tccaaagccg actacgaaaa gcataaggtg tatgcttgtg aggtgaccca ccagggactg 600agcagccctg tgacgaagtc cttcaaccgg ggcgagtgc 6392071398DNAartificial122A2-MB7-VHha-CH 207atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaggtc 60cagctgcagc agtctggcgc cgaagtggtc aagcctggcg cctccgtgaa gatcagctgc 120aagggcagcg gctacacctt caccgactac agcatgcact gggtcaagca ggcccacgcc 180aagagcctgg aatggatcgg cgtgatcagc acctactacg gcgacagcaa ctacaaccag 240aagttcaagg gcaaagtcac catgaccgtg gacaagagca gctccaccgc ctacatggaa 300ctgagcaggc tgaccagcga cgacaccgcc gtgtactact gcgccagaaa cggcaacttc 360tacgtgatgg actactgggg ccagggcacc ctggtcaccg tgtcatctgc ctccaccaag 420ggcccatccg tgttccccct ggccccatcc agcaagtcta cctccggagg cacagccgcc 480ctgggctgtc tggtgaagga ctacttcccc gagccagtga ccgtgtcctg gaactccgga 540gccctgacat ccggcgtgca caccttcccc gccgtgctgc agtccagcgg cctgtactct 600ctgtcttccg tggtgaccgt gccatccagc tccctgggaa cccagacata catctgcaac 660gtgaaccaca agcctagcaa caccaaggtg gacaagaagg tggagcctaa gagctgtgac 720aagacacaca catgccctcc ttgtccagcc cctgagctgc tgggcggccc ctccgtgttc 780ctgttccccc ccaagcctaa ggataccctg atgatcagca gaacccccga ggtgacctgc 840gtggtggtgg acgtgtccca cgaggatccc gaggtgaagt tcaactggta cgtggacggc 900gtggaggtgc acaacgctaa gaccaagccc agagaggagc agtacaacag cacatacaga 960gtggtgtctg tgctgaccgt gctgcaccag gactggctga acgggaagga gtacaagtgc 1020aaggtgtcca acaaggccct gcctgcccct atcgagaaga ccatctctaa ggctaagggg 1080cagccccggg agccacaggt gtacaccctg ccacccagcc gcgacgagct gaccaagaac 1140caggtgtccc tgacatgcct ggtgaaggga ttctacccca gcgacatcgc cgtggagtgg 1200gagagcaacg gccagcccga gaacaactac aagacaaccc ctcccgtgct ggacagcgat 1260ggatccttct tcctgtactc caagctgacc gtggacaaga gcaggtggca gcagggaaac 1320gtgttctctt gttccgtgat

gcacgaggct ctgcacaacc actacaccca gaagtccctg 1380agcctgtctc caggcaag 13982081398DNAartificial122A2-MB7-VHhb-CH 208atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaggtc 60cagctgcagc agtctggcgc cgaagtggtc aagcctggcg cctccgtgaa gatcagctgc 120aagggcagcg gctacacctt caccgactac agcatgcact gggtccgaca ggcccacgcc 180aagagcctgg aatggatcgg cgtgatcagc acctactacg gcgacagcaa ctacaaccag 240aagttcaagg gcaaagtcac catgaccgtg gacaccagca gctccaccgc ctacatggaa 300ctgagcaggc tgagaagcga cgacaccgcc gtgtactact gcgccagaaa cggcaacttc 360tacgtgatgg actactgggg ccagggcacc ctggtcaccg tgtcatctgc ctccaccaag 420ggcccatccg tgttccccct ggccccatcc agcaagtcta cctccggagg cacagccgcc 480ctgggctgtc tggtgaagga ctacttcccc gagccagtga ccgtgtcctg gaactccgga 540gccctgacat ccggcgtgca caccttcccc gccgtgctgc agtccagcgg cctgtactct 600ctgtcttccg tggtgaccgt gccatccagc tccctgggaa cccagacata catctgcaac 660gtgaaccaca agcctagcaa caccaaggtg gacaagaagg tggagcctaa gagctgtgac 720aagacacaca catgccctcc ttgtccagcc cctgagctgc tgggcggccc ctccgtgttc 780ctgttccccc ccaagcctaa ggataccctg atgatcagca gaacccccga ggtgacctgc 840gtggtggtgg acgtgtccca cgaggatccc gaggtgaagt tcaactggta cgtggacggc 900gtggaggtgc acaacgctaa gaccaagccc agagaggagc agtacaacag cacatacaga 960gtggtgtctg tgctgaccgt gctgcaccag gactggctga acgggaagga gtacaagtgc 1020aaggtgtcca acaaggccct gcctgcccct atcgagaaga ccatctctaa ggctaagggg 1080cagccccggg agccacaggt gtacaccctg ccacccagcc gcgacgagct gaccaagaac 1140caggtgtccc tgacatgcct ggtgaaggga ttctacccca gcgacatcgc cgtggagtgg 1200gagagcaacg gccagcccga gaacaactac aagacaaccc ctcccgtgct ggacagcgat 1260ggatccttct tcctgtactc caagctgacc gtggacaaga gcaggtggca gcagggaaac 1320gtgttctctt gttccgtgat gcacgaggct ctgcacaacc actacaccca gaagtccctg 1380agcctgtctc caggcaag 13982091398DNAartificial122A2-MB7-VHhc-CH 209atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccaggtc 60cagctgcagc agtctggcgc cgaagtggtc aagcctggcg cctccgtgaa gatcagctgc 120aagggcagcg gctacacctt caccgactac agcatgcact gggtccgaca ggcccctgga 180cagggcctgg aatggatcgg cgtgatcagc acctactacg gcgacagcaa ctacaaccag 240aagttcaagg gcaaagtcac catgaccgtg gacaagagca gctccaccgc ctacatggaa 300ctgagcaggc tgaccagcga cgacaccgcc gtgtactact gcgccagaaa cggcaacttc 360tacgtgatgg actactgggg ccagggcacc ctggtcaccg tgtcatctgc ctccaccaag 420ggcccatccg tgttccccct ggccccatcc agcaagtcta cctccggagg cacagccgcc 480ctgggctgtc tggtgaagga ctacttcccc gagccagtga ccgtgtcctg gaactccgga 540gccctgacat ccggcgtgca caccttcccc gccgtgctgc agtccagcgg cctgtactct 600ctgtcttccg tggtgaccgt gccatccagc tccctgggaa cccagacata catctgcaac 660gtgaaccaca agcctagcaa caccaaggtg gacaagaagg tggagcctaa gagctgtgac 720aagacacaca catgccctcc ttgtccagcc cctgagctgc tgggcggccc ctccgtgttc 780ctgttccccc ccaagcctaa ggataccctg atgatcagca gaacccccga ggtgacctgc 840gtggtggtgg acgtgtccca cgaggatccc gaggtgaagt tcaactggta cgtggacggc 900gtggaggtgc acaacgctaa gaccaagccc agagaggagc agtacaacag cacatacaga 960gtggtgtctg tgctgaccgt gctgcaccag gactggctga acgggaagga gtacaagtgc 1020aaggtgtcca acaaggccct gcctgcccct atcgagaaga ccatctctaa ggctaagggg 1080cagccccggg agccacaggt gtacaccctg ccacccagcc gcgacgagct gaccaagaac 1140caggtgtccc tgacatgcct ggtgaaggga ttctacccca gcgacatcgc cgtggagtgg 1200gagagcaacg gccagcccga gaacaactac aagacaaccc ctcccgtgct ggacagcgat 1260ggatccttct tcctgtactc caagctgacc gtggacaaga gcaggtggca gcagggaaac 1320gtgttctctt gttccgtgat gcacgaggct ctgcacaacc actacaccca gaagtccctg 1380agcctgtctc caggcaag 1398210696DNAartificial122A2-MB7-VKha-CL 210atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgacatc 60cagatgaccc agagcaccag cagcctgagc gcctctctgg gcgacagagt gaccatcacc 120tgtcaggcca gccaggacat cagcaactac ctgaactggt atcagcagaa acccgacggc 180accgtgaagc tgctgatcta ctacaccagc aggctgcaca ccggcgtgcc cagcagattc 240tctggctctg gcagcggcac cgactacagc ctgaccatct ccaacctgga ccaggaagat 300attgccacct actactgcca gcagggcaac accctgccct ggacattcgg cggaggcacc 360aagctggaaa tcaagcgaac tgtggctgca ccaagtgtct tcatctttcc tccgagtgat 420gagcagctga agagcgggac agcttctgtg gtgtgtctgc tgaataactt ctacccaaga 480gaagcaaagg tccagtggaa ggtggacaac gccctgcagt ctggcaactc acaggagtct 540gtcactgagc aggattccaa ggacagcact tacagcctgt ccagcaccct cactctgtcc 600aaagccgact acgaaaagca taaggtgtat gcttgtgagg tgacccacca gggactgagc 660agccctgtga cgaagtcctt caaccggggc gagtgc 696211696DNAartificial122A2-MB7-VKhb-CL 211atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgacatc 60cagatgaccc agagccctag cagcctgagc gcctctgtgg gcgacagagt gaccatcacc 120tgtcaggcca gccaggacat cagcaactac ctgaactggt atcagcagaa acccgacggc 180accgtgaagc tgctgatcta ctacaccagc aggctgcaca ccggcgtgcc cagcagattc 240tctggctctg gcagcggcac cgactacagc ctgaccatct ccaacctgga ccaggaagat 300attgccacct actactgcca gcagggcaac accctgccct ggacattcgg cggaggcacc 360aagctggaaa tcaagcgaac tgtggctgca ccaagtgtct tcatctttcc tccgagtgat 420gagcagctga agagcgggac agcttctgtg gtgtgtctgc tgaataactt ctacccaaga 480gaagcaaagg tccagtggaa ggtggacaac gccctgcagt ctggcaactc acaggagtct 540gtcactgagc aggattccaa ggacagcact tacagcctgt ccagcaccct cactctgtcc 600aaagccgact acgaaaagca taaggtgtat gcttgtgagg tgacccacca gggactgagc 660agccctgtga cgaagtcctt caaccggggc gagtgc 696212696DNAartificial122A2-MB7-VKhc-CL 212atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgacatc 60cagatgaccc agagcaccag cagcctgagc gcctctctgg gcgacagagt gaccatcacc 120tgtcaggcca gccaggacat cagcaactac ctgaactggt atcagcagaa acccgacggc 180accgtgaagc tgctgatcta ctacaccagc aacctgcaca ccggcgtgcc cagcagattc 240agcggctctg gctctggcac cgactacagc ctgaccatct ccaacctcca gcaggaagat 300attgccacct actactgcca gcagggcaac accctgccct ggacattcgg cggaggcacc 360aagctggaaa tcaagcgaac tgtggctgca ccaagtgtct tcatctttcc tccgagtgat 420gagcagctga agagcgggac agcttctgtg gtgtgtctgc tgaataactt ctacccaaga 480gaagcaaagg tccagtggaa ggtggacaac gccctgcagt ctggcaactc acaggagtct 540gtcactgagc aggattccaa ggacagcact tacagcctgt ccagcaccct cactctgtcc 600aaagccgact acgaaaagca taaggtgtat gcttgtgagg tgacccacca gggactgagc 660agccctgtga cgaagtcctt caaccggggc gagtgc 696213696DNAartificial122A2-MB7-VKhd-CL 213atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgccgacatc 60cagatgaccc agagccctag cagcctgagc gcctctgtgg gcgacagagt gaccatcacc 120tgtcaggcca gccaggacat cagcaactac ctgaactggt atcagcagaa acccgacggc 180accgtgaagc tgctgatcta ctacaccagc aacctgcaca ccggcgtgcc cagcagattc 240agcggctctg gctctggcac cgactacagc ctgaccatct ccaacctcca gcaggaagat 300attgccacct actactgcca gcagggcaac accctgccct ggacattcgg cggaggcacc 360aagctggaaa tcaagcgaac tgtggctgca ccaagtgtct tcatctttcc tccgagtgat 420gagcagctga agagcgggac agcttctgtg gtgtgtctgc tgaataactt ctacccaaga 480gaagcaaagg tccagtggaa ggtggacaac gccctgcagt ctggcaactc acaggagtct 540gtcactgagc aggattccaa ggacagcact tacagcctgt ccagcaccct cactctgtcc 600aaagccgact acgaaaagca taaggtgtat gcttgtgagg tgacccacca gggactgagc 660agccctgtga cgaagtcctt caaccggggc gagtgc 6962141407DNAartificial102E9-MB7-VHha-CH 214atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60catctggtgc agagcggccc tgagctgaag aaacccggcg agagcgtgaa gatcagctgc 120aaggccagcg gctacacctt caccgactac agcatgcact gggtcaagca ggccccaggc 180cagggcctga agtggatggg ctggatcaac accgagacag gcgagcccac ctacgccgac 240gacttcaagg gcagattcgt gttcagcctg gacaccagcg tgtccaccgc ctacctgcag 300atcaacagcc tgaagaacga ggacacctcc acctactact gcacccggaa cggctactac 360gtggggtact acgccatgga ctactggggc cagggcacct ccgtgaccgt gtcatctgcc 420tccaccaagg gcccatccgt gttccccctg gccccatcca gcaagtctac ctccggaggc 480acagccgccc tgggctgtct ggtgaaggac tacttccccg agccagtgac cgtgtcctgg 540aactccggag ccctgacatc cggcgtgcac accttccccg ccgtgctgca gtccagcggc 600ctgtactctc tgtcttccgt ggtgaccgtg ccatccagct ccctgggaac ccagacatac 660atctgcaacg tgaaccacaa gcctagcaac accaaggtgg acaagaaggt ggagcctaag 720agctgtgaca agacacacac atgccctcct tgtccagccc ctgagctgct gggcggcccc 780tccgtgttcc tgttcccccc caagcctaag gataccctga tgatcagcag aacccccgag 840gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aggtgaagtt caactggtac 900gtggacggcg tggaggtgca caacgctaag accaagccca gagaggagca gtacaacagc 960acatacagag tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cgggaaggag 1020tacaagtgca aggtgtccaa caaggccctg cctgccccta tcgagaagac catctctaag 1080gctaaggggc agccccggga gccacaggtg tacaccctgc cacccagccg cgacgagctg 1140accaagaacc aggtgtccct gacatgcctg gtgaagggat tctaccccag cgacatcgcc 1200gtggagtggg agagcaacgg ccagcccgag aacaactaca agacaacccc tcccgtgctg 1260gacagcgatg gatccttctt cctgtactcc aagctgaccg tggacaagag caggtggcag 1320cagggaaacg tgttctcttg ttccgtgatg cacgaggctc tgcacaacca ctacacccag 1380aagtccctga gcctgtctcc aggcaag 14072151407DNAartificial102E9-MB7-VHhb-CH 215atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60catctggtgc agagcggccc tgagctgaag aaacccggcg agagcgtgaa gatcagctgc 120aaggccagcg gctacacctt caccgactac agcatgcact gggtccgaca ggcccctgga 180cagggcctga agtggatggg ctggatcaac accgagacag gcgagcccac ctacgcccag 240gacttcaagg gcagattcgt gttcagcctg gacaccagcg tgtccaccgc ctacctgcag 300atcaacagcc tgaagaacga ggacacctcc acctactact gcacccggaa cggctactac 360gtggggtact acgccatgga ctactggggc cagggcacct ccgtgaccgt gtcatctgcc 420tccaccaagg gcccatccgt gttccccctg gccccatcca gcaagtctac ctccggaggc 480acagccgccc tgggctgtct ggtgaaggac tacttccccg agccagtgac cgtgtcctgg 540aactccggag ccctgacatc cggcgtgcac accttccccg ccgtgctgca gtccagcggc 600ctgtactctc tgtcttccgt ggtgaccgtg ccatccagct ccctgggaac ccagacatac 660atctgcaacg tgaaccacaa gcctagcaac accaaggtgg acaagaaggt ggagcctaag 720agctgtgaca agacacacac atgccctcct tgtccagccc ctgagctgct gggcggcccc 780tccgtgttcc tgttcccccc caagcctaag gataccctga tgatcagcag aacccccgag 840gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aggtgaagtt caactggtac 900gtggacggcg tggaggtgca caacgctaag accaagccca gagaggagca gtacaacagc 960acatacagag tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cgggaaggag 1020tacaagtgca aggtgtccaa caaggccctg cctgccccta tcgagaagac catctctaag 1080gctaaggggc agccccggga gccacaggtg tacaccctgc cacccagccg cgacgagctg 1140accaagaacc aggtgtccct gacatgcctg gtgaagggat tctaccccag cgacatcgcc 1200gtggagtggg agagcaacgg ccagcccgag aacaactaca agacaacccc tcccgtgctg 1260gacagcgatg gatccttctt cctgtactcc aagctgaccg tggacaagag caggtggcag 1320cagggaaacg tgttctcttg ttccgtgatg cacgaggctc tgcacaacca ctacacccag 1380aagtccctga gcctgtctcc aggcaag 14072161407DNAartificial102E9-MB7-VHhc-CH 216atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60catctggtgc agagcggcag cgagctgaag aaacccggcg agagcgtgaa gatcagctgc 120aaggccagcg gctacacctt caccgactac agcatgcact gggtccgaca ggcccctgga 180cagggcctga agtggatggg ctggatcaac accgagacag gcgagcccac ctacgcccag 240gacttcaagg gcagattcgt gttcagcctg gacaccagcg tgtccaccgc ctacctgcag 300atcaacagcc tgaagaacga ggacacctcc acctactact gcacccggaa cggctactac 360gtggggtact acgccatgga ctactggggc cagggcacct ccgtgaccgt gtcatctgcc 420tccaccaagg gcccatccgt gttccccctg gccccatcca gcaagtctac ctccggaggc 480acagccgccc tgggctgtct ggtgaaggac tacttccccg agccagtgac cgtgtcctgg 540aactccggag ccctgacatc cggcgtgcac accttccccg ccgtgctgca gtccagcggc 600ctgtactctc tgtcttccgt ggtgaccgtg ccatccagct ccctgggaac ccagacatac 660atctgcaacg tgaaccacaa gcctagcaac accaaggtgg acaagaaggt ggagcctaag 720agctgtgaca agacacacac atgccctcct tgtccagccc ctgagctgct gggcggcccc 780tccgtgttcc tgttcccccc caagcctaag gataccctga tgatcagcag aacccccgag 840gtgacctgcg tggtggtgga cgtgtcccac gaggatcccg aggtgaagtt caactggtac 900gtggacggcg tggaggtgca caacgctaag accaagccca gagaggagca gtacaacagc 960acatacagag tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cgggaaggag 1020tacaagtgca aggtgtccaa caaggccctg cctgccccta tcgagaagac catctctaag 1080gctaaggggc agccccggga gccacaggtg tacaccctgc cacccagccg cgacgagctg 1140accaagaacc aggtgtccct gacatgcctg gtgaagggat tctaccccag cgacatcgcc 1200gtggagtggg agagcaacgg ccagcccgag aacaactaca agacaacccc tcccgtgctg 1260gacagcgatg gatccttctt cctgtactcc aagctgaccg tggacaagag caggtggcag 1320cagggaaacg tgttctcttg ttccgtgatg cacgaggctc tgcacaacca ctacacccag 1380aagtccctga gcctgtctcc aggcaag 1407217693DNAartificial102E9-MB7-VKha-CL 217atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60cagctgaccc agagccctag cttcctgagc gcctctcctg gcgagagagt gaccatcacc 120tgtagcgcca gcagctccgt gatctacatc cactggttcc agcagaagcc cggcaaggcc 180cctaagctgt ggatctacag caccagctac ctggccagcg gcgtgccaag cagattcagc 240ggctctggct ctggcaccga gtacaccctg accatcagct ccatggaagc cgaggacttc 300gccacctact actgccagca gaggcggagc taccccttca ccttcggcgg aggcaccaag 360ctggaaatca agcgaactgt ggctgcacca agtgtcttca tctttcctcc gagtgatgag 420cagctgaaga gcgggacagc ttctgtggtg tgtctgctga ataacttcta cccaagagaa 480gcaaaggtcc agtggaaggt ggacaacgcc ctgcagtctg gcaactcaca ggagtctgtc 540actgagcagg attccaagga cagcacttac agcctgtcca gcaccctcac tctgtccaaa 600gccgactacg aaaagcataa ggtgtatgct tgtgaggtga cccaccaggg actgagcagc 660cctgtgacga agtccttcaa ccggggcgag tgc 693218693DNAartificial102E9-MB7-VKhb-CL 218atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60cagctgaccc agagccctag cttcctgagc gcctctcctg gcgagagagt gaccatcacc 120tgtagcgcca gcagctccgt gatctacatc cactggttcc agcagaagcc cggcaccgcc 180cctaagctgt ggatctacag caccagctac ctggccagcg gcgtgccaag cagattcagc 240ggctctggca gcggcacctc ctacaccctg accatcagca ggatggaagc cgaggacttc 300gccacctact actgccagca gaggcggagc taccccttca ccttcggcgg aggcaccaag 360ctggaaatca agcgaactgt ggctgcacca agtgtcttca tctttcctcc gagtgatgag 420cagctgaaga gcgggacagc ttctgtggtg tgtctgctga ataacttcta cccaagagaa 480gcaaaggtcc agtggaaggt ggacaacgcc ctgcagtctg gcaactcaca ggagtctgtc 540actgagcagg attccaagga cagcacttac agcctgtcca gcaccctcac tctgtccaaa 600gccgactacg aaaagcataa ggtgtatgct tgtgaggtga cccaccaggg actgagcagc 660cctgtgacga agtccttcaa ccggggcgag tgc 693219693DNAartificial102E9-MB7-VKhc-CL 219atgaggtggt cctggatctt cctgctgctg ctgagcatca ccagcgccaa cgcccagatc 60cagctgaccc agagccctag cttcctgagc gcctctcctg gcgacagagt gaccatcacc 120tgtagcgcca gcagctccgt gatctacatc cactggttcc agcagaagcc cggcaaggcc 180cctaagctgt ggatctacag caccagctac ctggccagcg gcgtgccaag cagattcagc 240ggctctggct ctggcaccga gtacaccctg accatcagct ccatgcaggc cgaggacttc 300gccacctact actgccagca gaggcggagc taccccttca ccttcggcgg aggcaccaag 360ctggaaatca agcgaactgt ggctgcacca agtgtcttca tctttcctcc gagtgatgag 420cagctgaaga gcgggacagc ttctgtggtg tgtctgctga ataacttcta cccaagagaa 480gcaaaggtcc agtggaaggt ggacaacgcc ctgcagtctg gcaactcaca ggagtctgtc 540actgagcagg attccaagga cagcacttac agcctgtcca gcaccctcac tctgtccaaa 600gccgactacg aaaagcataa ggtgtatgct tgtgaggtga cccaccaggg actgagcagc 660cctgtgacga agtccttcaa ccggggcgag tgc 693220306DNAartificialenhancer du virus hCMVe 220gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat 60tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc 120aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc 180caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt 240acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta 300ccatgg 306221352DNAartificialregion promotrice de la cycline dependante des kinases 9 (CDK9) 221catgcagcgg gacgcgccac cccgagcccc agctccggcg ccccggctcc ccgcgccccc 60gatcggggcc gccgctagta gtggcggcgg cggaggcggg ggcagcggcg gcggcggcgg 120aggcgcctct gcagctccgg ctccccctgg cctctcggga actacaagtc ccagggggcc 180tggcggtggg cggcgggcgg aagaggcggg gtcggcgccg cgaggccgga agtggccgtg 240gaggcggaag tggcgcggcc gcggaggggc ctggagtgcg gcggcggcgg gacccggagc 300aggagcggcg gcagcagcga ctgggggcgg cggcggcgcg ttggaggcgg cc 352222267DNAartificialregion LTR du virus HTLV-1 222ggctcgcatc tctccttcac gcgcccgccg ccctacctga ggccgccatc cacgccggtt 60gagtcgcgtt ctgccgcctc ccgcctgtgg tgcctcctga actgcgtccg ccgtctaggt 120aagtttaaag ctcaggtcga gaccgggcct ttgtccggcg ctcccttgga gcctacctag 180actcagccgg ctctccacgc tttgcctgac cctgcttgct caactctacg tctttgtttc 240gttttctgtt ctgcgccgtt acagatc 267223653DNAartificialregion 5' UTR du gene NRF 223cagagtaatg acatggttcc ttccatcctc caaaggtgac caataatagt ttgtaagtat 60cattatgaac taatgaattt tcaacatatt tgatatattt caatccattg ccatcattgt 120tcttatcgat atttgagttg gctcactttg ccagtaagag tctattcaaa ttggcttctg 180agtccatttg acacaacacc tttgatcttt gacagtttcc ttggttttag gtgctagatg 240atttctcagg ctcaccttag acatttcctg ccacagactt agaatcagcc atttctctaa 300ggaccctgat tccatttcat gagaaatgat agagaccaca atcaaaacaa gtcatgaatt 360tatactgata ttttcaattc aaattaaaga tgaggttttt gctaaatttt tttgagttta 420tatttgtatg tcttatgctg aaaaatcttg tttcctaatt agtaacataa ttattcattt 480gatgggtaaa tattttaggg ccgattcttt ggttttatag ccaagatacc ctgttgataa 540agtcttgtgg gagcaattat aagactggct tattttgaag ctttttaaaa aagacatcct 600tacctgtttt aactgtagat tatattaact taaataggta cagcccacgc ttg 653224314DNAartificialregion 5' UTR du gene eIF4GI 224gctggtgggt

agggatgagg gagggagggg cattgtgatg tacagggctg ctctgtgaga 60tcaagggtct cttaagggtg ggagctgggg cagggactac gagagcagcc agatgggctg 120aaagtggaac tcaaggggtt tctggcacct acctacctgc ttcccgctgg ggggtgggga 180gttggcccag agtcttaaga ttggggcagg gtggagaggt gggctcttcc tgcttcccac 240tcatcttata gctttctttc cccagatccg aattcgagat ccaaaccaag gaggaaagga 300tatcacagag gaga 314225939DNAartificialintron du gene EFla 225gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta cgggttatgg cccttgcgtg 60ccttgaatta cttccacctg gctgcagtac gtgattcttg atcccgagct tcgggttgga 120agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg tgcttgagtt 180gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct tcgcgcctgt 240ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc tgcgacgctt 300tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg tatttcggtt 360tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc ggcgaggcgg 420ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg ccggcctgct 480ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag gctggcccgg 540tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc agggagctca 600aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca aaggaaaagg 660gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc gccgtccagg 720cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg ggaggggttt 780tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc agcttggcac 840ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt cattctcaag 900cctcagacag tggttcaaag tttttttctt ccatttcag 939226351DNAartificialintron murin ROSA 226gtaggggatc gggactctgg cgggagggcg gcttggtgcg tttgcgggga tgggcggccg 60cggcaggccc tccgagcgtg gtggagccgt tctgtgagac agccgggtac gagtcgtgac 120gctggaaggg gcaagcgggt ggtgggcagg aatgcggtcc gccctgcagc aaccggaggg 180ggagggagaa gggagcggaa aagtctccac cggacgcggc catggctcgg gggggggggg 240gcagcggagg agcgcttccg gccgacgtct cgtcgctgat tggcttcttt tcctcccgcc 300gtgtgtgaaa acacaattgt actaaccttc ttctctttcc tctcctgaca g 351227288DNAartificialintron 5'LTR du virus HTLV-1 227ggctcgcatc tctccttcac gcgcccgccg ccctacctga ggccgccatc cacgccggtt 60gagtcgcgtt ctgccgcctc ccgcctgtgg tgcctcctga actgcgtccg ccgtctaggt 120aagtttaaag ctcaggtcga gaccgggcct ttgtccggcg ctcccttgga gcctacctag 180actcagccgg ctctccacgc tttgcctgac cctgcttgct caactctacg tctttgtttc 240gttttctgtt ctgcgccgtt acagatccaa gctgtgaccg gcgcctac 288228133DNAartificialintron pcineo 228gtaagtatca aggttacaag acaggtttaa ggagaccaat agaaactggg cttgtcgaga 60cagagaagac tcttgcgttt ctgataggca cctattggtc ttactgacat ccactttgcc 120tttctctcca cag 133229812DNAartificialintron du gene ubiquitine 229gtgagtagcg ggctgctggg ctggccgggg ctttcgtggc cgccgggccg ctcggtggga 60cggaagcgtg tggagagacc gccaagggct gtagtctggg tccgcgagca aggttgccct 120gaactggggg ttggggggag cgcagcaaaa tggcggctgt tcccgagtct tgaatggaag 180acgcttgtga ggcgggctgt gaggtcgttg aaacaaggtg gggggcatgg tgggcggcaa 240gaacccaagg tcttgaggcc ttcgctaatg cgggaaagct cttattcggg tgagatgggc 300tggggcacca tctggggacc ctgacgtgaa gtttgtcact gactggagaa ctcggtttgt 360cgtctgttgc gggggcggca gttatggcgg tgccgttggg cagtgcaccc gtacctttgg 420gagcgcgcgc cctcgtcgtg tcgtgacgtc acccgttctg ttggcttata atgcagggtg 480gggccacctg ccggtaggtg tgcggtaggc ttttctccgt cgcaggacgc agggttcggg 540cctagggtag gctctcctga atcgacaggc gccggacctc tggtgagggg agggataagt 600gaggcgtcag tttctttggt cggttttatg tacctatctt cttaagtagc tgaagctccg 660gttttgaact atgcgctcgg ggttggcgag tgtgttttgt gaagtttttt aggcaccttt 720tgaaatgtaa tcatttgggt caatatgtaa ttttcagtgt tagactagta aattgtccgc 780taaattctgg ccgtttttgg cttttttgtt ag 8122301217DNAartificialintron humain ROSA 230gtaggggagc ggaactctgg tgggagggga ggtgcggtgc actgggggga tgggtggcta 60ggggggccgt ctggtggctt gcgggggttg cctttcccgt gggaagtcgg gaacataatg 120tttgttacgt tgggagggaa aggggtggct ggatgcaggc gggagggagg cccgccctgc 180ggcaaccgga gggggaggga gaagggagcg gaaaatgctc gaaaccggac ggagccattg 240ctctcgcaga gggaggagcg cttccggcta gcctcttgtc gccgattggc cgtttctcct 300cccgccgtgt gtgaaaacac aaatggcgta ttctggttgg agtaaagctc ctgtcagtta 360caccgtcggg agtacgcagc cgcttagcga ctctcgcgtt gccccctggg tggggcgggt 420aggtaggtgg ggtgtagaga tgctgggtgt gcgggcgcgg ccggcctcct gcggcgggag 480gggagggtca gtgaaattgg ctctggcgcg ggcgtcctcc caccctcccc ttccttcggg 540ggagtcggtt tacccgccgc ctgcttgtct tcgacacctg attggctgtc gaagctgtgg 600gaccgggccc ttgctactgg ctcgagtctc acatgagcga aaccactgcg cggggcgcgg 660gggtggcggg gaggcgggcg ttggtacggt cctccccgag gccgagcgcc gcagtgtctg 720gccccgcgcc cctgcgcaac gtggcaggaa gcgcgcgctg gaggcggggg cgggctgccg 780gccgagactt ctggatggcg gcggccgcgg ctccgccccg ggttcccacc gcctgaaggg 840cgagacaagc ccgacctgct acaggcactc gtgggggtgg gggaggagcg ggggtcggtc 900cggctggttt gtgggtggga ggcgcttgtt ctccaaaaac cggcgcgagc tgcaatcctg 960agggagctgc ggtggaggag gtggagagaa ggccgcaccc ttctgggcag ggggagggga 1020gtgccgcaat acctttatgg gagttctttg ctgcctcccg tcttgtaagg accgccctgg 1080gcctggaaga agccctccct cctttcctcc tcgcgtgatc tcgtcatcgc ctccatgtcg 1140agtcgcttct cgattatggg cgggattctt ttgcctagac aattgtacta accttcttct 1200ctttcctctc ctgacag 12172311964DNAartificialsequence unite transcription 231gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat 60tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc 120aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc 180caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt 240acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta 300ccatggcccg ggtcgcgaca tgcagcggga cgcgccaccc cgagccccag ctccggcgcc 360ccggctcccc gcgcccccga tcggggccgc cgctagtagt ggcggcggcg gaggcggggg 420cagcggcggc ggcggcggag gcgcctctgc agctccggct ccccctggcc tctcgggaac 480tacaagtccc agggggcctg gcggtgggcg gcgggcggaa gaggcggggt cggcgccgcg 540aggccggaag tggccgtgga ggcggaagtg gcgcggccgc ggaggggcct ggagtgcggc 600ggcggcggga cccggagcag gagcggcggc agcagcgact gggggcggcg gcggcgcgtt 660ggaggcggcc ggatccgttt aacgctggtg ggtagggatg agggagggag gggcattgtg 720atgtacaggg ctgctctgtg agatcaaggg tctcttaagg gtgggagctg gggcagggac 780tacgagagca gccagatggg ctgaaagtgg aactcaaggg gtttctggca cctacctacc 840tgcttcccgc tggggggtgg ggagttggcc cagagtctta agattggggc agggtggaga 900ggtgggctct tcctgcttcc cactcatctt atagctttct ttccccagat ccgaattcga 960gatccaaacc aaggaggaaa ggatatcaca gaggagagct agtcgggttt gccgccagaa 1020cacaggtaag tgccgtgtgt ggttcccgcg ggcctggcct ctttacgggt tatggccctt 1080gcgtgccttg aattacttcc acctggctgc agtacgtgat tcttgatccc gagcttcggg 1140ttggaagtgg gtgggagagt tcgaggcctt gcgcttaagg agccccttcg cctcgtgctt 1200gagttgaggc ctggcctggg cgctggggcc gccgcgtgcg aatctggtgg caccttcgcg 1260cctgtctcgc tgctttcgat aagtctctag ccatttaaaa tttttgatga cctgctgcga 1320cgcttttttt ctggcaagat agtcttgtaa atgcgggcca agatctgcac actggtattt 1380cggtttttgg ggccgcgggc ggcgacgggg cccgtgcgtc ccagcgcaca tgttcggcga 1440ggcggggcct gcgagcgcgg ccaccgagaa tcggacgggg gtagtctcaa gctggccggc 1500ctgctctggt gcctggcctc gcgccgccgt gtatcgcccc gccctgggcg gcaaggctgg 1560cccggtcggc accagttgcg tgagcggaaa gatggccgct tcccggccct gctgcaggga 1620gctcaaaatg gaggacgcgg cgctcgggag agcgggcggg tgagtcaccc acacaaagga 1680aaagggcctt tccgtcctca gccgtcgctt catgtgactc cacggagtac cgggcgccgt 1740ccaggcacct cgattagttc tcgagctttt ggagtacgtc gtctttaggt tggggggagg 1800ggttttatgc gatggagttt ccccacactg agtgggtgga gactgaagtt aggccagctt 1860ggcacttgat gtaattctcc ttggaatttg ccctttttga gtttggatct tggttcattc 1920tcaagcctca gacagtggtt caaagttttt ttcttccatt tcag 1964232306DNAartificialenhancer du virus hCMVie 232gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat 60tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc 120aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc 180caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt 240acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta 300ccatgg 306233283DNAartificialregion promotrice de la beta-actine 233catggtcgag gtgagcccca cgttctgctt cactctcccc atctcccccc cctccccacc 60cccaattttg tatttattta ttttttaatt attttgtgca gcgatggggg cggggggggg 120gggggggcgc gcgccaggcg gggcggggcg gggcgagggg cggggcgggg cgaggcggag 180aggtgcggcg gcagccaatc agagcggcgc gctccgaaag tttcctttta tggcgaggcg 240gcggcggcgg cggccctata aaaagcgaag cgcgcggcgg gcg 283234267DNAartificialregion regulatrice R du 5' Long Terminal Repeat (LTR) du virus HTLV-1 234ggctcgcatc tctccttcac gcgcccgccg ccctacctga ggccgccatc cacgccggtt 60gagtcgcgtt ctgccgcctc ccgcctgtgg tgcctcctga actgcgtccg ccgtctaggt 120aagtttaaag ctcaggtcga gaccgggcct ttgtccggcg ctcccttgga gcctacctag 180actcagccgg ctctccacgc tttgcctgac cctgcttgct caactctacg tctttgtttc 240gttttctgtt ctgcgccgtt acagatc 267235653DNAartificialregion 5' UTR du gene NRF 235cagagtaatg acatggttcc ttccatcctc caaaggtgac caataatagt ttgtaagtat 60cattatgaac taatgaattt tcaacatatt tgatatattt caatccattg ccatcattgt 120tcttatcgat atttgagttg gctcactttg ccagtaagag tctattcaaa ttggcttctg 180agtccatttg acacaacacc tttgatcttt gacagtttcc ttggttttag gtgctagatg 240atttctcagg ctcaccttag acatttcctg ccacagactt agaatcagcc atttctctaa 300ggaccctgat tccatttcat gagaaatgat agagaccaca atcaaaacaa gtcatgaatt 360tatactgata ttttcaattc aaattaaaga tgaggttttt gctaaatttt tttgagttta 420tatttgtatg tcttatgctg aaaaatcttg tttcctaatt agtaacataa ttattcattt 480gatgggtaaa tattttaggg ccgattcttt ggttttatag ccaagatacc ctgttgataa 540agtcttgtgg gagcaattat aagactggct tattttgaag ctttttaaaa aagacatcct 600tacctgtttt aactgtagat tatattaact taaataggta cagcccacgc ttg 653236314DNAartificialregion 5' UTR du gene eIF4GI 236gctggtgggt agggatgagg gagggagggg cattgtgatg tacagggctg ctctgtgaga 60tcaagggtct cttaagggtg ggagctgggg cagggactac gagagcagcc agatgggctg 120aaagtggaac tcaaggggtt tctggcacct acctacctgc ttcccgctgg ggggtgggga 180gttggcccag agtcttaaga ttggggcagg gtggagaggt gggctcttcc tgcttcccac 240tcatcttata gctttctttc cccagatccg aattcgagat ccaaaccaag gaggaaagga 300tatcacagag gaga 314237939DNAartificialintron du gene Elongation Factor la (EFla) 237gtaagtgccg tgtgtggttc ccgcgggcct ggcctcttta cgggttatgg cccttgcgtg 60ccttgaatta cttccacctg gctgcagtac gtgattcttg atcccgagct tcgggttgga 120agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg tgcttgagtt 180gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct tcgcgcctgt 240ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc tgcgacgctt 300tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg tatttcggtt 360tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc ggcgaggcgg 420ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg ccggcctgct 480ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag gctggcccgg 540tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc agggagctca 600aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca aaggaaaagg 660gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc gccgtccagg 720cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg ggaggggttt 780tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc agcttggcac 840ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt cattctcaag 900cctcagacag tggttcaaag tttttttctt ccatttcag 939238351DNAartificialintron murin ROSA 238gtaggggatc gggactctgg cgggagggcg gcttggtgcg tttgcgggga tgggcggccg 60cggcaggccc tccgagcgtg gtggagccgt tctgtgagac agccgggtac gagtcgtgac 120gctggaaggg gcaagcgggt ggtgggcagg aatgcggtcc gccctgcagc aaccggaggg 180ggagggagaa gggagcggaa aagtctccac cggacgcggc catggctcgg gggggggggg 240gcagcggagg agcgcttccg gccgacgtct cgtcgctgat tggcttcttt tcctcccgcc 300gtgtgtgaaa acacaattgt actaaccttc ttctctttcc tctcctgaca g 3512391217DNAartificialintron humain ROSA 239gtaggggagc ggaactctgg tgggagggga ggtgcggtgc actgggggga tgggtggcta 60ggggggccgt ctggtggctt gcgggggttg cctttcccgt gggaagtcgg gaacataatg 120tttgttacgt tgggagggaa aggggtggct ggatgcaggc gggagggagg cccgccctgc 180ggcaaccgga gggggaggga gaagggagcg gaaaatgctc gaaaccggac ggagccattg 240ctctcgcaga gggaggagcg cttccggcta gcctcttgtc gccgattggc cgtttctcct 300cccgccgtgt gtgaaaacac aaatggcgta ttctggttgg agtaaagctc ctgtcagtta 360caccgtcggg agtacgcagc cgcttagcga ctctcgcgtt gccccctggg tggggcgggt 420aggtaggtgg ggtgtagaga tgctgggtgt gcgggcgcgg ccggcctcct gcggcgggag 480gggagggtca gtgaaattgg ctctggcgcg ggcgtcctcc caccctcccc ttccttcggg 540ggagtcggtt tacccgccgc ctgcttgtct tcgacacctg attggctgtc gaagctgtgg 600gaccgggccc ttgctactgg ctcgagtctc acatgagcga aaccactgcg cggggcgcgg 660gggtggcggg gaggcgggcg ttggtacggt cctccccgag gccgagcgcc gcagtgtctg 720gccccgcgcc cctgcgcaac gtggcaggaa gcgcgcgctg gaggcggggg cgggctgccg 780gccgagactt ctggatggcg gcggccgcgg ctccgccccg ggttcccacc gcctgaaggg 840cgagacaagc ccgacctgct acaggcactc gtgggggtgg gggaggagcg ggggtcggtc 900cggctggttt gtgggtggga ggcgcttgtt ctccaaaaac cggcgcgagc tgcaatcctg 960agggagctgc ggtggaggag gtggagagaa ggccgcaccc ttctgggcag ggggagggga 1020gtgccgcaat acctttatgg gagttctttg ctgcctcccg tcttgtaagg accgccctgg 1080gcctggaaga agccctccct cctttcctcc tcgcgtgatc tcgtcatcgc ctccatgtcg 1140agtcgcttct cgattatggg cgggattctt ttgcctagac aattgtacta accttcttct 1200ctttcctctc ctgacag 12172401205DNAartificialsequence unite transcription 240gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat 60tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc 120aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc 180caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt 240acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta 300ccatggcccg ggtcgcgaca tggtcgaggt gagccccacg ttctgcttca ctctccccat 360ctcccccccc tccccacccc caattttgta tttatttatt ttttaattat tttgtgcagc 420gatgggggcg gggggggggg gggggcgcgc gccaggcggg gcggggcggg gcgaggggcg 480gggcggggcg aggcggagag gtgcggcggc agccaatcag agcggcgcgc tccgaaagtt 540tccttttatg gcgaggcggc ggcggcggcg gccctataaa aagcgaagcg cgcggcgggc 600ggatccgttt aaacggctcg catctctcct tcacgcgccc gccgccctac ctgaggccgc 660catccacgcc ggttgagtcg cgttctgccg cctcccgcct gtggtgcctc ctgaactgcg 720tccgccgtct aggtaagttt aaagctcagg tcgagaccgg gcctttgtcc ggcgctccct 780tggagcctac ctagactcag ccggctctcc acgctttgcc tgaccctgct tgctcaactc 840tacgtctttg tttcgttttc tgttctgcgc cgttacagat cactagttaa cgctggtggg 900tagggatgag ggagggaggg gcattgtgat gtacagggct gctctgtgag atcaagggtc 960tcttaagggt gggagctggg gcagggacta cgagagcagc cagatgggct gaaagtggaa 1020ctcaaggggt ttctggcacc tacctacctg cttcccgctg gggggtgggg agttggccca 1080gagtcttaag attggggcag ggtggagagg tgggctcttc ctgcttccca ctcatcttat 1140agctttcttt ccccagatcc gaattcgaga tccaaaccaa ggaggaaagg atatcacaga 1200ggaga 1205

Claims

1.-30. (canceled)

31. A monoclonal antibody directed against the ectodomain of human CD303 antigen (SEQ ID NO: 130), or a functional fragment or a derivative thereof, wherein: a) the monoclonal antibody competes for binding to the human CD303 antigen with at least one antibody selected from: i) an antibody whose heavy chain variable region comprises SEQ ID NO: 43 and whose light chain variable region comprises SEQ ID NO: 48; ii) an antibody whose heavy chain variable region comprises SEQ ID NO: 44 and whose light chain variable region comprises SEQ ID NO: 49; iii) an antibody whose heavy chain variable region comprises SEQ ID NO: 45 and whose light chain variable region comprises SEQ ID NO: 50; iv) an antibody whose heavy chain variable region comprises SEQ ID NO: 46 and whose light chain variable region comprises SEQ ID NO: 51; v) an antibody whose heavy chain variable region comprises SEQ ID NO: 47 and whose light chain variable region comprises SEQ ID NO: 52; and b) the light and heavy chain constant regions of the monoclonal antibody are constant regions from a non-murine species.

32. The antibody, functional fragment or derivative thereof according to claim 31, wherein its heavy chains comprise three CDR-H (heavy-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences, and its light chains comprise three CDR-L (light-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences: i) CDR1-H-family 1: SEQ ID NO: 1, CDR2-H-family 1: SEQ ID NO: 2, CDR3-H-family 1: SEQ ID NO: 3, CDR1-L-family 1: SEQ ID NO: 4, CDR2-L-family 1: SEQ ID NO: 5, CDR3-L-family 1: SEQ ID NO: 6; or ii) CDR1-H-family 2: SEQ ID NO: 7, CDR2-H-family 2: SEQ ID NO: 8, CDR3-H-family 2: SEQ ID NO: 9, CDR1-L-family 2: SEQ ID NO: 10, CDR2-L-family 2: SEQ ID NO: 11, CDR3-L-family 2: SEQ ID NO: 12.

33. The antibody, functional fragment or derivative thereof according to claim 32, wherein the heavy chains comprise three CDR-H (heavy-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences, and the light chains comprise three CDR-L (light-chain CDR according to IMGT nomenclature) having the following amino acid sequences, or sequences having at least 80% identity with the following sequences: i) CDR1-H-122A2: SEQ ID NO: 13, CDR2-H-122A2: SEQ ID NO: 14, CDR3-H-122A2: SEQ ID NO: 15, CDR1-L-122A2: SEQ ID NO: 16, CDR2-L-122A2: SEQ ID NO: 17, CDR3-L-122A2: SEQ ID NO: 18; ii) CDR1-H-102E9: SEQ ID NO: 19, CDR2-H-102E9: SEQ ID NO: 20, CDR3-H-102E9: SEQ ID NO: 21, CDR1-L-102E9: SEQ ID NO: 22, CDR2-L-102E9: SEQ ID NO: 23, CDR3-L-102E9: SEQ ID NO: 24; iii) CDR1-H-104C12: SEQ ID NO: 25, CDR2-H-104C12: SEQ ID NO: 26, CDR3-H-104C12: SEQ ID NO: 27, CDR1-L-104C12: SEQ ID NO: 28, CDR2-L-104C12: SEQ ID NO: 29, CDR3-L-104C12: SEQ ID NO: 30; iv) CDR1-H-114D11: SEQ ID NO: 31, CDR2-H-114D11: SEQ ID NO: 32, CDR3-H-114D11: SEQ ID NO: 33, CDR1-L-114D11: SEQ ID NO: 34, CDR2-L-114D11: SEQ ID NO: 35, CDR3-L-114D11: SEQ ID NO: 36; or v) CDR1-H-104E10: SEQ ID NO: 37, CDR2-H-104E10: SEQ ID NO: 38, CDR3-H-104E10: SEQ ID NO: 39, CDR1-L-104E10: SEQ ID NO: 40, CDR2-L-104E10: SEQ ID NO: 41, CDR3-L-104E10: SEQ ID NO: 42.

34. The antibody, functional fragment or derivative thereof according to claim 31, wherein its heavy chains comprise a variable region having a sequence selected from SEQ ID NOs: 43 to 47, 131 to 133, and 138 to 140, or having a sequence with at least 80% identity with one of SEQ ID NOs: 43 to 47, 131 to 133, and 138 to 140.

35. The antibody, functional fragment or derivative thereof according to claim 34, wherein its light chains comprise a variable region having a sequence selected from SEQ ID NOs: 48 to 52, 134 to 137, and 141 to 143, or having a sequence with at least 80% identity with one of SEQ ID NOs: 48 to 52, 134 to 137, and 141 to 143.

36. The antibody, functional fragment or derivative thereof according to claim 31, wherein it is a chimeric antibody.

37. The antibody, functional fragment or derivative thereof according to claim 36, wherein it is a chimeric antibody whose heavy and light chains constant region is of human origin.

38. The antibody, functional fragment or derivative thereof according to claim 37, wherein it has heavy and light chains comprising the following amino acid sequences or sequences having at least 80% identity with the following sequences: i) antibody 122A2: heavy chain: SEQ ID NO: 55, light chain: SEQ ID NO: 60, ii) antibody 102E9: heavy chain: SEQ ID NO: 56, light chain: SEQ ID NO: 61, iii) antibody 104C12: heavy chain: SEQ ID NO: 57, light chain: SEQ ID NO: 62, iv) antibody 114D11: heavy chain: SEQ ID NO: 58, light chain: SEQ ID NO: 63, or v) antibody 104E10: heavy chain: SEQ ID NO: 59, light chain: SEQ ID NO: 64.

39. The antibody, functional fragment or derivative thereof according to claim 31, wherein it is a humanized antibody.

40. The antibody, functional fragment or derivative thereof according to claim 39, wherein its heavy chains comprise a variable region having a sequence selected from SEQ ID NOs: 131 to 133 and 138 to 140 or having a sequence with at least 80% identity with one of SEQ ID NOs: 131 to 133.

41. The antibody, functional fragment or derivative thereof according to claim 40, wherein its light chains comprise a variable region having a sequence selected from SEQ ID NOs: 134 to 137 and 141 to 143 or having a sequence with at least 80% identity with one of SEQ ID NOs: 134 to 137 and 141 to 143.

42. The antibody, functional fragment or derivative thereof according to claim 39, wherein it has heavy and light chains with variable regions having the following amino acid sequences or having sequences with at least 80% identity with the following sequences: i) antibody 122A2H5: heavy chain: SEQ ID NO: 131, light chain: SEQ ID NO: 134, ii) antibody 122A2H6: heavy chain: SEQ ID NO: 132, light chain: SEQ ID NO: 134, iii) antibody 122A2H7: heavy chain: SEQ ID NO: 133, light chain: SEQ ID NO: 134, iv) antibody 122A2H9: heavy chain: SEQ ID NO: 131, light chain: SEQ ID NO: 135, v) antibody 122A2H10: heavy chain: SEQ ID NO: 132, light chain: SEQ ID NO: 135, vi) antibody 122A2H14: heavy chain: SEQ ID NO: 132, light chain: SEQ ID NO: 136, vii) antibody 102E9H6: heavy chain: SEQ ID NO: 139, light chain: SEQ ID NO: 141, viii) antibody 102E9H7: heavy chain: SEQ ID NO: 140, light chain: SEQ ID NO: 141, ix) antibody 102E9H9: heavy chain: SEQ ID NO: 138, light chain: SEQ ID NO: 142, x) antibody 102E9H10: heavy chain: SEQ ID NO: 139, light chain: SEQ ID NO: 142.

43. The antibody, functional fragment or derivative thereof according to claim 42, wherein it has heavy and light chains comprising the following amino acid sequences or sequences having at least 80% identity with the following sequences: i) antibody 122A2H5: heavy chain: SEQ ID NO: 150, light chain: SEQ ID NO: 153, ii) antibody 122A2H6: heavy chain: SEQ ID NO: 151, light chain: SEQ ID NO: 153, iii) antibody 122A2H7: heavy chain: SEQ ID NO: 152, light chain: SEQ ID NO: 153, iv) antibody 122A2H9: heavy chain: SEQ ID NO: 150, light chain: SEQ ID NO: 154, v) antibody 122A2H10: heavy chain: SEQ ID NO: 151, light chain: SEQ ID NO: 154, vi) antibody 122A2H14: heavy chain: SEQ ID NO: 151, light chain: SEQ ID NO: 155, vii) antibody 102E9H6: heavy chain: SEQ ID NO: 158, light chain: SEQ ID NO: 160, viii) antibody 102E9H7: heavy chain: SEQ ID NO: 159, light chain: SEQ ID NO: 160, ix) antibody 102E9H9: heavy chain: SEQ ID NO: 157, light chain: SEQ ID NO: 161, x) antibody 102E9H10: heavy chain: SEQ ID NO: 158, light chain: SEQ ID NO: 161.

44. The antibody, functional fragment or derivative thereof according to claim 31, wherein it is of IgG isotype.

45. The antibody, functional fragment or derivative thereof according to claim 31, wherein its heavy chain and/or its light chain further comprise(s) a heterologous signal peptide of SEQ ID NO: 65.

46. The antibody, functional fragment or derivative thereof according to claim 31, wherein it is produced in a cell line selected from: SP2/0; YB2/0; IR983F; human myeloma Namalwa; PERC6; CHO cell lines, notably CHO-K-1, CHO-Lec10, CHO-Lec1, CHO-Lec13, CHO Pro-5, CHO dhfr-, or the CHO cell line deleted for both alleles encoding the FUT8 gene and/or the GMD gene; Wil-2; Jurkat; Vero; MoIt-4; COS-7; 293-HEK; BHK; K6H6; NSO; SP2/0-Ag 14, P3X63Ag8.653, duck embryonic cell line EB66.RTM. (Valneva); rat hepatoma cell lines H4-II-E (DSM ACC3129) and H4-II-Es (DSM ACC3130), NM-H9D8 (DSM ACC2806), NM-H9D8-E6 (DSM ACC 2807) and NM H9D8-E6Q12 (DSM ACC 2856).

47. The antibody, functional fragment or derivative thereof according to claim 31, having: a) fucose content less than or equal to 65%; b) oligomannose-type N-glycans content greater than or equal to 30%; or c) galactose content greater than or equal to 50%.

48. The antibody, functional fragment or derivative thereof according to claim 31, wherein: a) the Fc fragment has the following mutations or combinations of mutations in their Fc fragment: N315D/A330V/N361D/A378V/N434Y, P230S/N315D/M428L/N434Y, E294del/T307P/N434Y, T307A/N315D/A330V/E382V/N389T/N434Y, V259I/N315D/N434Y, or T256N/A378V/S383N/N434Y, wherein the numbering of Fc fragment amino acids is that of the EU index of Kabat; or b) it has a deletion of the amino acid at position 293 (Del293) or 294 (Del294) of the Fc fragment, where the numbering of Fc fragment amino acids is that of the EU index of Kabat.

49. The functional fragment according to claim 31, wherein it is selected from the fragments Fv, ScFv, Fab, F(ab')2, Fab', scFv-Fc and diabodies.

50. A nucleic acid encoding the heavy and/or light chain of an antibody, functional fragment or derivative thereof according to claim 31.

51. The nucleic acid according to claim 50, comprising at least one of SEQ ID NOs: 86 to 95, and 181 to 193.

52. A vector comprising a nucleic acid according to claim 50.

53. A host cell, transgenic non-human animal or transgenic plant comprising at least one nucleic acid according to claim 50 or a vector comprising the nucleic acid.

54. The host cell according to claim 53, selected from the following lines: SP2/0; YB2/0; IR983F; human myeloma Namalwa; PERC6; CHO cell lines, notably CHO-K-1, CHO-Lec10, CHO-Lec1, CHO-Lec13, CHO Pro-5, CHO dhfr-, or the CHO cell line deleted for both alleles encoding the FUT8 gene and/or the GMD gene; Wil-2; Jurkat; Vero; MoIt-4; COS-7; 293-HEK; BHK; K6H6; NSO; SP2/0-Ag 14, P3X63Ag8.653, duck embryonic cell line EB66.RTM. (Valneva); rat hepatoma cell lines H4-II-E (DSM ACC3129) and H4-II-Es (DSM ACC3130), NM-H9D8 (DSM ACC2806), NM-H9D8-E6 (DSM ACC 2807) and NM H9D8-E6Q12 (DSM ACC 2856).

55. A method for treating or preventing a hematopoietic tumor expressing the CD303 antigen in a patient, comprising administering to said patient an effective amount of an antibody, functional fragment or derivative thereof according to claim 31.

56. A method for treating or preventing inflammatory disease in a patient, comprising administering to said patient an effective amount of an antibody, functional fragment or derivative thereof according to claim 31.

57. A monoclonal antibody directed against the ectodomain of human CD303 antigen (SEQ ID NO: 130), or a functional fragment or a derivative thereof, wherein: the monoclonal antibody has improved affinity for Fey receptor Ma (Fc.gamma.RIIIa, CD16a) compared to antibodies directed against the ectodomain of the human CD303 antigen, produced in CHO cells; and the light and heavy chain constant regions of the monoclonal antibody are constant regions from a non-murine species.