EA040295B1 - ANTIBODY MOLECULES AGAINST LAG-3 AND THEIR APPLICATIONS - Google Patents

Description

Cross-reference to related applications

This application claims priority of U.S. Provisional Application No. 61/953536 filed March 14, 2014, U.S. Provisional Application No. 62/059690 filed October 3, 2014, and U.S. Provisional Application No. 62/094889 filed December 19, 2014, thus , the contents of the above applications are incorporated by reference in their entirety.

Sequence list

The invention contains a sequence listing which has been provided electronically in ASCII format and which is thus incorporated by reference in its entirety. The specified ASCII copy, created on March 10, 2015, is named C2160-7001WO_SL.txt and is 258890 bytes in size.

Prior Art

The lymphocyte activation gene 3 or LAG-3 (also known as CD223) is a member of the immunoglobulin supergene family and is expressed in activated T cells (Huard et al., (1994) Immunogenetics 39:213), NK cells (Triebel et al., ( 1990) J. Exp. Med., 171:1393-1405), regulatory T cells (Huang et al., (2004) Immunity, 21:SOS-SIS; Camisaschi et al., (2010) J. Immunol. 184 :65456551; Gagliani et al., (2013) Nat. Med., 19:739-746) and plasmacytoid dendritic cells (DC) (Workman et al., (2009) J. Immunol., 182:1885-1891) . LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically similar to CD4.

Like CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al., (1992) J. Exp. Med., 176:327-337; Huard et al., (1996) Eur. J. Immunol., 26:11801186). It has been suggested that direct binding of LAG-3 to MHC class II plays a role in the suppression of antigen-dependent stimulation of CD4 ⁺ T-lymphocytes (Huard et al., (1994) Eur. J. Immunol., 24:3216-3221), and also demonstrated that blockade of LAG-3 restores CD8+ lymphocytes in tumor or self-antigen models (Gross et al., (2007) J. Clin. Invest., 117:3383-3392) and virus models (Blackburn et al., (2009) Nat. Immunol ., 10:29-37). In addition, the intracytoplasmic region of LAG-3 can interact with LAP (LAG-3-associated protein), which is a signal transducer molecule involved in the inhibition of the CD3/TCR activation pathway (Iouzalen et al., (2001) Eur. J. Immunol., 31:28852891). Furthermore, regulatory T cells (T _reg ) CD4+CD25+ have been shown to express LAG-3 when activated, which contributes to suppressive activity of Treg cells (Huang C. et al., (2004) Immunity, 21:503-513) . LAG-3 can also negatively regulate T cell homeostasis via Treg cells in both T cell dependent and T cell independent mechanisms (Workman CJ and Vignali DA, (2005) J. Immunol., 174:688-695).

Given the important role of LAG-3 in suppressing the immune response, there is a need to develop new agents that modulate its activity by activating the immune system. Such agents can be used, for example, in the immunotherapy of cancers and in the treatment of other conditions such as chronic infection.

The essence of the invention

Disclosed herein are antibody molecules (eg, humanized antibody molecules) that bind to the lymphocyte activation gene 3 (LAG-3) with high affinity and specificity. In one embodiment, the anti-LAG-3 antibody molecules comprise a novel combination of framework regions (eg, FW1, FW2, FW3, and/or FW4), eg, novel combinations of heavy chain frameworks and/or light chain frameworks. Also disclosed are nucleic acid molecules encoding antibody molecules, expression vectors, host cells, and methods for producing antibody molecules. Also provided are immunoconjugates, poly- or bispecific antibody molecules, and pharmaceutical compositions containing antibody molecules. As described herein, anti-LAG-3 antibody molecules can be used (alone or in combination with other agents or therapies) for the treatment, prevention, and/or diagnosis of malignant disorders (e.g., solid tumors and soft tissue tumors) as well as infectious diseases. Thus, the present description describes compositions and methods for detecting LAG-3, as well as methods for treating various disorders, including cancer and/or infectious diseases, using anti-LAG-3 antibody molecules.

Thus, in one aspect, the invention provides an antibody molecule (e.g., an isolated or recombinant antibody molecule) having one or more of the following properties:

(i) binds to LAG-3, such as human LAG-3, with high affinity, such as an affinity constant of at least about 10 ⁷ M' ¹ , typically about 10 ⁸ M' ¹ , and more specifically from about 10 ⁹ M ^-1 to 10 ¹⁰ M ^-1 or stronger;

(ii) binds to LAG-3, e.g., a LAG-3-CHO transfectant, with a K _D of less than: 5, 4, 3, 2, 1 nM, e.g., 1 to 3 nM (e.g., about 1.92 nM or about 2.3 nM);

(iii) does not substantially bind to CD4;

(iv) inhibits LAG-3 binding to a class II major histocompatibility complex (MHC) molecule, eg, has an IC ₅₀ of about 1 to 20 nM, 5 to 15 nM, eg, 5.5 nM;

(v) binds to the D1 domain of LAG-3 (e.g., human LAG-3), e.g., binds to a domain

- 1 040295 nom D1, but does not associate with the additional loop region of the D1 domain;

(vi) modulates (eg, stimulates, enhances, or restores) an immune response, such as an antigen-specific T cell response or an antitumor response;

(vii) binds specifically to an epitope on LAG-3, eg the same or a similar epitope as the epitope recognized by the mouse monoclonal antibody BAP050 or the chimeric BAP050-chi antibody;

(viii) binds to an epitope on LAG-3 other than the epitope recognized by the BMS986016 antibody;

(ix) has the same or similar binding affinity or specificity, or both, as any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050 -hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,

BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) -Ser BAP050hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050hum12-Ser BAP050-hum13-Ser BAP050-hum14-Ser -Ser, BAP050-hum18-Ser, BAP050hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-CloneI or BAP050-Clone-J.

(x) has the same or similar binding affinity or specificity, or both, as the antibody molecule (eg, heavy chain variable region and light chain variable region) described in Table. 1;

(xi) has the same or similar binding affinity or specificity, or both, as an antibody molecule (eg, heavy chain variable region and light chain variable region) with the amino acid sequence shown in table. 1;

(xii) has the same or similar binding affinity or specificity, or both, as the antibody molecule (eg, heavy chain variable region and light chain variable region) encoded by the nucleotide sequence shown in Table. 1;

(xiii) inhibits, e.g. competitively inhibits, the binding of a second antibody molecule to LAG-3, wherein the second antibody molecule is an antibody molecule as described herein, e.g. an antibody molecule selected, for example, from any of BAP050-hum01, BAP050hum02, BAP050-hum03 BAP050-hum04 BAP050-hum05 BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050 hum20, huBAP050(Ser) hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050 hum09-Ser BAP050-huml0-Ser BAP050-hum11-Ser , BAP050 hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J;

(xiv) binds the same or overlapping epitope to a second anti-LAG-3 antibody molecule, wherein the second antibody molecule is an antibody molecule as described herein, e.g. an antibody molecule selected, for example, from any of BAP050-hum01, BAP050hum02, BAP050-hum03 BAP050-hum04 BAP050-hum05 BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050 hum20, huBAP050(Ser) hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050 hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050-hum12-Ser BAP050-hum13-Ser , BAP050 hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J;

(xv) competes for inhibition and/or binds to the same epitope as the second anti-LAG-3 antibody molecule, e.g., as measured by the Biacore method, the FACS method, or both, where the second antibody molecule is the antibody molecule described by as used herein, for example, an antibody molecule selected, for example, from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,

BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14,

BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-huml8, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050 -hum04Ser BAP050-hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050-hum12-Ser , BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G , BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J;

(xvi) has one or more of the biological properties of an antibody molecule described in

- 2 040295 the present description, for example, an antibody molecule selected, for example, from any of BAP050-hum01,

BAP050-hum02,

BAP050-hum08,

BAP050-hum14,

BAP050-hum03,

BAP050-hum09,

BAP050-hum15,

BAP050-hum04,

BAP050-hum10,

BAP050-hum16,

BAP050-hum05,

BAP050-hum11,

BAP050-hum17,

BAP050-hum06,

BAP050-hum12,

BAP050-hum18,

BAP050-hum07,

BAP050-hum13,

BAP050-hum19,

BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser,

BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,

BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,

BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050- Clone-I or BAP050-Clone-J;

(xvii) has one or more of the pharmacokinetic properties of an antibody molecule as described herein, e.g. an antibody molecule selected, for example, from any of BAP050hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050hum13 BAP050-hum14 BAP050-hum15 BAP050-hum16 BAP050-hum17 BAP050-hum18 hum20, huBAP050(Ser) (ex. -Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050-hum12-Ser BAP050 hum13-Ser BAP050-hum14-Ser BAP050-hum15-Ser BAP050-hum18-Ser BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050Clone-J, or (xviii) inhibits one or more activities of LAG-3, for example leading to one or more of: elevated ia antigen-dependent stimulation of CD4+ T-lymphocytes; increasing T cell proliferation; increased expression of an activation antigen, eg CD25; increased expression of a cytokine, such as interferon-γ (IFN-γ), interleukin 2 (IL-2), or interleukin 4 (IL-4); increased expression of a chemokine, eg CCL3, CCL4 or CCL5; reducing the suppressor activity of Treg cells; increase in T-cell homeostasis; increase in tumor infiltrating lymphocytes or decrease the likelihood of malignant cells slipping from immunological surveillance.

As used herein, huBAP050(Ser) refers to a humanized BAP050 antibody molecule, eg, any of the humanized BAP050 antibody molecule described herein, eg, as described in Table 1. 1 which contains a Cys to Ser substitution at position 84 of heavy chain framework 3 (VHFW3). In some embodiments, the huBAP050(Ser) antibody molecule is selected from BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07- Ser BAP050-hum08-Ser BAP050hum09-Ser BAP050-huml0-Ser BAP050-hum11-Ser BAP050-hum12-Ser BAP050-hum13-Ser BAP050hum14-Ser Ser, BAP050-hum19-Ser or BAP050-hum20-Ser.

In some embodiments, an anti-LAG-3 antibody molecule binds to LAG-3 with high affinity, e.g., an equilibrium dissociation constant (KD) that is about the same or at least about 10, 20, 30, 40, 50, 60%, 70%, 80%, or 90% higher or lower than the KD of an anti-LAG-3 mouse antibody molecule or a chimeric anti-LAG-3 antibody molecule, such as an anti-LAG-3 mouse antibody molecule or a chimeric anti-LAG-3 antibody molecule described herein . In one embodiment, an anti-LAG-3 antibody molecule binds to a LAG-3, e.g., a LAG-3-CHO transfectant, with a KD of less than 5, 4, 3, 2 nM, e.g., 1 to 3 nM (e.g., about 1. 92 nM or approximately 2.3 nM).

In some embodiments, the level of expression of an anti-LAG-3 antibody molecule is about the same, higher, or lower, such as at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher or lower than the level of expression of a mouse antibody molecule or a chimeric antibody molecule, for example, a mouse anti-LAG-3 antibody molecule or a chimeric anti-LAG-3 antibody molecule described herein. In some embodiments, the antibody molecule is expressed in CHO cells.

In some embodiments, an anti-LAG-3 antibody molecule reduces one or more LAG-3-associated activities with an IC ₅₀ (concentration at 50% inhibition) that is about the same, higher, or lower, such as at least about 10 , 20, 30, 40, 50, 60, 70, 80, or 90% higher or lower than the IC ₅₀ of an anti-LAG-3 mouse antibody molecule or a chimeric anti-LAG-3 antibody molecule, e.g. an anti-LAG-3 mouse antibody or chimeric anti-LAG-3 antibody molecule described herein. In some embodiments, the LAG-3-related activity is the binding of an MHC class II molecule to LAG-3. In some embodiments, the LAG-3 associated activity is the binding of LSECtin to LAG-3. In one embodiment, the IC ₅₀ of an anti-LAG-3 antibody is about 1 to 20 nM, 5 to 15 nM, 5.5 nM (eg, detectable by inhibition of MHC class II binding or L-SECtin).

In some embodiments, an anti-LAG-3 antibody molecule has about the same or improved stability, e.g., is at least about 0.5, 1,

- 3 040295

2, 3, 4, 5, 6, 7, 8, 9, or 10 times more stable in vivo or in vitro than a mouse anti-LAG-3 antibody molecule or a chimeric anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule 3 mice or a chimeric anti-LAG-3 antibody molecule as described herein.

In one embodiment, the anti-LAG-3 antibody molecule is a humanized antibody molecule and is characterized by a risk score based on T cell epitope analysis of 800 to 1200, 850 to 1150, 900 to 1100, 950 to 1050, or risk score, as described in the present description.

In another embodiment, an anti-LAG-3 antibody molecule comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050 -hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,

BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-huml0 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050-hum15 BAP050-hum16 BAP050-hum17 hum19, BAP050-hum20, huBAP050(Ser) (ex. -hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,

BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050 -Clone-H, BAP050-Clone-I or BAP050Clone-J, or as described in Table. 1, or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In yet another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, three, or four variable regions from an antibody described herein, eg an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050- hum03 BAP050hum04 BAP050-hum05 BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) ,

BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,

BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser,

BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,

BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or as described in Table 1, or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences. In one embodiment, the antibody molecule contains a substitution (eg, a Cys to Ser substitution at position 84) in heavy chain framework region 3 (VHFW3) (eg, as shown in Tables 1 and 2).

In yet another embodiment, an anti-LAG-3 antibody molecule comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050hum04 BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050hum10 -hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser)

BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,

BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser,

BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,

BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or as described in Table 1 or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In yet another embodiment, an anti-LAG-3 antibody molecule comprises at least one or two light chain variable regions from an antibody described herein, eg an antibody selected from BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050- hum04 BAP050-hum05 BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050-hum15 BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) BAP050hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050hum11-Ser BAP050-hum12-Ser BAP050-hum13-Ser , BAP050-hum15-Ser, BAP050hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050Clone-H, BAP050-Clone-I or BAP050-Clone- J, or as described in table. 1, or the encoded nucleotide

- 4 040295 sequence in the table. 1, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In yet another embodiment, the anti-LAG-3 antibody molecule contains a heavy chain constant region for IgG4, eg, human IgG4. In one embodiment, human IgG4 contains a substitution at position 228 according to EU numbering (eg, substitution Ser for Pro). In yet another embodiment, the anti-LAG-3 antibody molecule contains a heavy chain constant region for IgG1, eg, human IgG1. In one embodiment, human IgG1 contains a substitution at position 297 according to EU numbering (eg, Asn to Ala substitution). In one embodiment, human IgG1 comprises a substitution at position 265 according to EU numbering, a substitution at position 329 according to EU numbering, or both (e.g., substitution of Asp to Al at position 265 according to EU numbering and/or substitution of Pro to Al at position 329 according to EU numbering). In one embodiment, human IgG1 comprises a substitution at position 234 according to EU numbering, a substitution at position 235 according to EU numbering, or both (e.g., substitution of Leu to Al at position 234 according to EU numbering and/or substitution of Leu to Al at position 235 according to EU numbering). In one embodiment, the heavy chain constant region contains the amino acid sequence shown in Table 1. 3, or a sequence substantially identical to it (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical).

In yet another embodiment, the anti-LAG-3 antibody molecule comprises a κ light chain constant region, such as a human κ light chain constant region. In one embodiment, the implementation of the constant region of the light chain contains the amino acid sequence shown in table. 3, or a sequence substantially identical to it (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical).

In another embodiment, an anti-LAG-3 antibody molecule comprises a heavy chain constant region for IgG4, such as human IgG4, and a κ light chain constant region, such as a human κ light chain constant region, such as a heavy and light chain constant region, comprising an amino acid the sequence indicated in the table. 3, or a sequence substantially identical to it (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical). In one embodiment, the constant region is a mutant IgG4, e.g., a mutant human IgG4 (e.g., contains a mutation at position 228 according to EU numbering (e.g., an S228P mutation). In another embodiment, the anti-LAG-3 antibody molecule contains a constant a heavy chain region for IgG1, e.g., human IgG1, and a κ light chain constant region, e.g., a human κ light chain constant region, e.g. identical (e.g. at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) In one embodiment, human IgG1 contains a substitution at position 297 according to EU numbering (e.g., substitution Asn to Ala) In one embodiment, human IgG1 contains a substitution at position 265 according to EU numbering, a substitution at position 329 according to EU numbering EU numbering or both (e.g. replacing Asp with Al at position 265 according to EU numbering and/or replacing Pro with Al at position 329 according to EU numbering). In one embodiment, the human IgGl comprises a substitution at position 234 according to EU numbering, a substitution at position 235 according to EU numbering, or both (e.g., substitution of Leu to Al at position 234 according to EU numbering and/or substitution of Leu to Al at position 235 according to EU numbering).

In another embodiment, an anti-LAG-3 antibody molecule comprises a heavy chain variable domain and constant region, a light chain variable domain and constant region, or both, comprising the amino acid sequence BAP050-hum01, BAP050-hum02, BAP050hum03, BAP050-hum04, BAP050 -hum05 BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050hum15 BAP050-hum16 , BAP050-hum19, BAP050-hum20, huBAP050(Ser) BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J, or as described in table. 1, or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences. An anti-LAG-3 antibody molecule optionally contains a leader sequence from the heavy chain, the light chain, or both, as shown in Table 1. 4, or a sequence substantially identical to it.

- 5 040295

In yet another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from the heavy chain variable region of an antibody described herein, e.g., an antibody selected from any of

BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,

BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,

BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,

BAP050-hum19, BAP050-hum20, huBAP050(Ser) , BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,

BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or

BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050Clone-J, or as described in Table 1, or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contains at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, such as conservative substitutions) relative to one, two, or three CDRs shown in Table. 1.

In one embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs (or all CDRs in total) from a heavy chain variable region comprising the amino acid sequence shown in Table 1. 1, or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or collectively all CDRs) contain one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions relative to the amino acid sequence shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1.

In yet another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from the light chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP050-hum01, BAP050 -hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,

BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,

BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,

BAP050-hum19, BAP050-hum20, huBAP050(Ser) , BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,

BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050 -Clone-H, BAP050-Clone-I or BAP050Clone-J, or as described in Table. 1, or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contains at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, such as conservative substitutions) relative to one, two, or three CDRs permuted in Table. 1.

In another embodiment, an anti-LAG-3 antibody molecule contains at least one, two, or three CDRs (or all CDRs in total) from a light chain variable region containing the amino acid sequence shown in Table 1. 1 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or collectively all CDRs) contain one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions relative to the amino acid shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1.

In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six CDRs (or all of the CDRs in total) from the heavy and light chain variable regions containing the amino acid shown in Table 1. 1 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or collectively all CDRs) contain one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contains at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, such as conservative substitutions) relative to one, two, three, four, five, or six CDRs shown in Table 1. 1.

In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six CDRs (or all CDRs in total) from the heavy and light chain variable regions, comprising the amino acid sequence represented by in table. 1 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or collectively all CDRs) contain one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1. 1 or encoded by the nucleotide sequence shown in table. 1.

In one embodiment, an anti-LAG-3 antibody molecule contains all six CDRs from an antibody described herein, such as an antibody selected from any of BAP050hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050- hum06 BAP050hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050hum13 BAP050-hum14 BAP050-hum15 BAP050-hum16 hum20, huBAP050(Ser) (ex. -Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050-hum12-Ser BAP050 hum13-Ser BAP050-hum14-Ser BAP050-hum15-Ser BAP050-hum18-Ser BAP050-hum19-Ser or BAP050hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J, or as described in Table 1 or encoded by the nucleotide sequence in the table. 1, or closely related CDRs, e.g., CDRs that are identical or that contain at least one amino acid change, but no more than two, three, or four changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two , three, four, five or six CDRs shown in Table. 1. In one embodiment, an anti-LAG-3 antibody molecule may comprise any of the CDRs described herein.

In one embodiment, the anti-LAG-3 antibody molecule contains at least one, two, or three no Rabat CDRs (e.g., at least one, two, or three CDRs as defined by Rabat as listed in Table 1) of heavy chain variable region of an antibody described by hum02, hum08, hum14, herein, e.g. hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050 hum20, huBAP050(Ser) hum01-Ser BAP050-hum02-Ser BAP050-hum03-Ser BAP050hum04-Ser BAP050-hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050hum09-Ser BAP050- hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser) , BAP050-Clone-F , BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or as described in Table 1, or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contain at least one amino acid change, but no more than two, three or four changes (eg, substitutions, deletions or insertions, such as conservative substitutions) relative to one, two or three Rabat CDRs shown in Table. 1.

In one embodiment, the anti-LAG-3 antibody molecule contains at least one, two, or three no Rabat CDRs (e.g., at least one, two, or three CDRs as defined by Rabat as listed in Table 1) of the light chain variable region of an antibody as described herein, for example an antibody selected from any of BAP050-hum01, BAP050hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050 hum20, huBAP050(Ser) hum0l-Ser BAP050-hum02-Ser BAP050-hum03-Ser BAP050hum04-Ser BAP050-hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050hum09-Ser hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser) , BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or as described in Table 1, or encoded by the nucleotide sequence in the table. 1 or sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contain at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, such as conservative substitutions) relative to one, two, or three Rabat CDRs shown in Table 1. 1.

In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six Rabat CDRs (e.g., at least one, two, three, four, five, or six CDRs according to as defined by Rabat as indicated in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g.

- 7 040295 selected from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum11 , BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,

BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser,

BAP050-huml2-Ser, BAP050-huml3-Ser, BAP050-huml4-Ser, BAP050-huml5-Ser, BAP050-huml8-Ser,

BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,

BAP050-Clone-I or BAP050-Clone-J, or as described in Table 1, or encoded by the nucleotide sequence in Table 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contain at least one amino acid change, but no more than two, three, or four changes (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to at least one, two, three, four, five, or six CDRs of Rabat et al., presented in table. 1. In one embodiment, an anti-LAG-3 antibody molecule may comprise any of the CDRs described herein.

In yet another embodiment, an anti-LAG-3 antibody molecule contains all six Rabat CDRs (e.g., all six Rabat CDRs as defined in Table 1) of the heavy and light chain variable regions of an antibody described herein. e.g. an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04,

BAP050-hum05 BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050-hum15 hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) -Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050hum11-Ser BAP050-hum12-Ser BAP050-hum13-Ser BAP050-hum14-Ser BAP050 -hum15-Ser, BAP050hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050Clone-H, BAP050-Clone-I or BAP050-Clone-J, or as described in Table. 1, or encoded by the nucleotide sequence in the table. 1, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contain at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, eg, conservative substitutions) relative to all six Rabat et al. CDRs shown in Table 1. 1. In one embodiment, an anti-LAG-3 antibody molecule may comprise any of the CDRs described herein.

In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, or three hypervariable loops (e.g., at least one, two, or three hypervariable loops as defined by Chothia as listed in Table 1) from the variable the heavy chain region of an antibody described herein, for example an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,

BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,

BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,

BAP050-hum19, BAP050-hum20, huBAP050(Ser) , BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,

BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or

BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050Clone-J according to Chothia (e.g., at least one, two, or three hypervariable loops in according to the definition according to Chothia, as indicated in Table 1) or encoded by the nucleotide sequence in Table 1. 1 or sequence substantially identical (e.g., at least 80, 85,

90, 92, 95, 97, 98, 99% or more identical) to any of the above sequences, or which contain at least one amino acid change, but no more than two, three, or four changes (e.g., substitutions, deletions, or insertions , for example, conservative substitutions) relative to one, two or three hypervariable loops according to Chothia, presented in table. 1.

In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, or three Chothia hypervariable loops (e.g., at least one, two, or three CDRs as defined by Chothia as listed in Table 1) of the light chain variable region of an antibody as described herein, e.g. an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,

BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,

BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,

- 8 040295

BAP050-hum19, BAP050-hum20, huBAP050(Ser) , BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050 -hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050Clone- J, or encoded by the nucleotide sequence in the table. 1 or sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contain at least one amino acid change, but no more than two, three or four changes (for example, substitutions, deletions or insertions, for example, conservative substitutions) relative to one, two or three hypervariable loops according to Chothia, presented in table. 1.

In yet another embodiment, an anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six hypervariable loops (e.g., at least one, two, three, four, five, or six hypervariable loops according to as defined by Chothia as indicated in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g. BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050hum15 BAP050-hum16 hum19, BAP050-hum20, huBAP050(Ser) (for example, BAP050-hum01-Ser, hum05-Ser, BAP050-hum06-Ser, hum10-Ser, BAP050-hum11-Ser, hum15-Ser, BAP050-hum18-Ser,

BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,

BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,

BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,

BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F,

BAP050BAP050BAP050BAP050Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or as described in Table 1, or encoded by the nucleotide sequence in the table. 1, or at least amino acids from such hypervariable loops that contact LAG-3. In one embodiment, an anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six Chothia hypervariable loops from Table 1. 1.

In one embodiment, an anti-LAG-3 antibody molecule contains all six hypervariable loops (e.g., all six hypervariable loops as defined by Chothia as listed in Table 1) of an antibody described herein, e.g., an antibody selected from any from BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11,

BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,

BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) -Ser BAP050hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050hum12-Ser BAP050-hum13-Ser BAP050-hum14-Ser -Ser, BAP050-hum18-Ser, BAP050hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-CloneI or BAP050-Clone-J, or closely related hypervariable loops, for example, hypervariable loops that are identical or that contain at least one amino acid change, but no more than two, three or four changes (for example, substitutions, deletions or insertions, for example, conservative substitutions) relative to all six hypervariable loops, presented in table. 1. In one embodiment, an anti-LAG-3 antibody molecule may comprise any of the hypervariable loops described herein.

In yet another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody selected from any of BAP050- hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10,

BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16,

BAP050-hum17, BAP050-hum18, hum01-Ser, hum06-Ser, hum11-Ser, hum18-Ser,

BAP050-hum02-Ser, BAP050-hum07-Ser,

BAP050-hum12-Ser, BAP050-hum19-Ser

BAP050-hum19, BAP050-hum20, huBAP050(Ser) , BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,

BAP050BAP050BAP050BAP050Clone-H, BAP050-Clone-I, or BAP050-Clone-J, for example, the same canonical structures as at least loop 1 and/or loop 2 of the heavy and/or light chain variable domains of an antibody described herein. For descriptions of the canonical structures of hypervariable loops, see, for example, Chothia et al., (1992) J. Mol. Biol., 227:799-817; Tomlinson et al., (1992) J. Mol. Biol., 227:776798. These structures can be determined directly from the tables described in these references.

In certain embodiments, the anti-LAG-3 antibody molecule comprises the combination

- 9 040295

CDR or hypervariable loops as defined by Rabat et al. and Chothia et al.

In one embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs or hypervariable loops from the heavy chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP050-hum01, BAP050-hum02 , BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,

BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,

BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19,

BAP050-hum20, huBAP050(Ser) (ex. -Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050-hum12-Ser BAP050-hum13-Ser BAP050-hum14-Ser BAP050-hum15-Ser , BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J, as defined by the Rabat and Chothia (eg, at least one, two, or three CDRs or hypervariable loops as defined by Rabat and Chothia, as indicated in Table 1), or encoded by the nucleotide sequence in Table 1. 1 or sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences, or which contain at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, eg, conservative substitutions) relative to one, two, or three CDRs or Rabat and/or Chothia hypervariable loops shown in Table 1. 1.

For example, an anti-LAG-3 antibody molecule may contain the VH CDR1 of Rabat et al. or hypervariable loop 1 VH by Chothia et al., or a combination thereof, for example, as shown in table. 1. In one embodiment, the combination of the Rabat CDR and the Chothia CDR1 VH contains the amino acid sequence GFTLTNYGMN (SEQ ID NO: 286) or an amino acid sequence substantially identical to it (e.g., containing at least one amino acid change, but no more than two, three or four changes (eg substitutions, deletions or insertions, eg conservative substitutions)). The anti-LAG-3 antibody molecule may further comprise, for example, the VH CDR 2-3 of Rabat et al. and CDR 1-3 VL according to Rabat et al., for example, as shown in table. 1. Thus, in some embodiments, framework regions are determined based on a combination of CDRs as determined by Rabat et al. and hypervariable loops as determined by Chothia et al. based on VH hypervariable loop 1 according to Chothia et al., and VH FR2 determined based on VH CDR 1-2 according to Rabat et al., for example, as shown in Table. 1. An anti-LAG-3 antibody molecule may further comprise, for example, FR 3-4 VH as determined from CDR 2-3 VH by Rabat et al. Rabat et al.

An anti-LAG-3 antibody molecule may contain any combination of CDRs or hypervariable loops as defined by Rabat and Chothia. In one embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs from the light chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050- hum03 BAP050-hum04 BAP050-hum05 BAP050hum06 BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050hum12 BAP050-hum13 BAP050-hum14 BAP050-hum17, BAP050hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) -hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14 -Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone- I or BAP050Clone-J, as defined by the Rabat and Chothia (for example, at least one, two or three CDRs as defined by the Rabat and Chothia, as indicated in Table 1).

In one of the embodiments, for example, an embodiment containing a variable region, CDR (for example, CDR or Rabat CDR) or other sequence specified in the present description, for example, in table. 1, an antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, or is an antibody molecule that contains an antigen-binding fragment of an antibody, such as a semi-antibody or an antigen-binding fragment of a semi-antibody. In certain embodiments, the antibody molecule is a bispecific antibody molecule having a first binding specificity for LAG-3 and a second binding specificity for PD-1, TIM-3, CEACAM (e.g., CEACAM-1 and/or CEACAM-5), PD- L1 or PD-L2.

In one embodiment, the anti-LAG-3 antibody comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 286; the amino acid sequence of VHCDR2 SEQ ID NO: 2 and the amino acid sequence of VHCDR3 SEQ ID NO: 3, and

- 10 040295 (ii) a light chain variable region (VL) containing the amino acid sequence

VLCDR1 SEQ ID NO: 10, VLCDR2 amino acid sequence SEQ ID NO: 11, and VLCDR3 amino acid sequence SEQ ID NO: 12.

In another embodiment, the anti-LAG-3 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 286; the amino acid sequence of VHCDR2 SEQ ID NO: 5 and the amino acid sequence of VHCDR3 SEQ ID NO: 3, and (ii) a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 13, the amino acid sequence of VLCDR2 SEQ ID NO: 14 and the amino acid sequence VLCDR3 SEQ ID NO: 15.

In one embodiment, the anti-LAG-3 antibody molecule comprises the amino acid sequence of VHCDR1 SEQ ID NO: 1. In another embodiment, the anti-LAG-3 antibody molecule comprises the amino acid sequence of VHCDR1 SEQ ID NO: 4. In yet another embodiment, the anti-LAG antibody molecule -3 contains the amino acid sequence of VHCDR1 SEQ ID NO: 286.

In one embodiment, the light or heavy chain variable framework (e.g., a region comprising at least FR1, FR2, FR3, and optionally FR4) of an anti-LAG-3 antibody molecule can be selected from: (a) a light or heavy chain variable framework containing at least 80%, 85%, 87%, 90%, 92%, 93%, 95%, 97%, 98%, or preferably 100% of amino acid residues from a human light or heavy chain variable framework region, e.g., a light or heavy chain variable framework region residue from a mature human antibodies, human germline sequences, or human consensus sequences; (b) a light or heavy chain variable framework region comprising 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of amino acid residues from a human light or heavy chain variable framework, e.g. a light or heavy chain variable framework region from a mature human antibody, human germline sequence, or human consensus sequence; (c) a non-human framework (eg, a rodent framework); or (d) a non-human framework that has been modified, eg, to remove antigenic or cytotoxic determinants, eg, deimmunized or partially humanized. In one embodiment, the light or heavy chain variable framework (specifically FR1, FR2, and/or FR3) contains the light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the human germline VL or VH segment framework regions.

In certain embodiments, an anti-LAG-3 antibody molecule comprises a heavy chain variable domain comprising at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions, of the amino acid sequence of BAP050-chi-HC, such as the amino acid sequence of the FR region in the entire variable region, such as shown in FIG. 9A-9B or SEQ ID NO: 20 or 22. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable domain comprising one or more of: E at position 1, V at position 2, A at position 9, V at position 11, A at position 16, S at position 17, L at position 18, R at position 19, V at position 20, V or G at position 24, I at position 37, A or S at position 40, R or T at position 41, S at position 42, Q or R at position 43, R at position 44, E at position 46, I or L at position 48, V at position 68, V or T at position 69, I at position 70, A at position 72, D at position 73, K at position 74, V or I at position 76, Y at position 80, W at position 83, C or S at position 84, S or T at position 85, A at position 88, E or S at position 89, V or M at position 93 or Y at position 95 of the BAP050-chi-HC amino acid sequence, e.g., the FR amino acid sequence in the entire variable region, e.g. 9B or SEQ ID NO: 20 or 22. In one embodiment, the antibody molecule contains a substitution (e.g., a Cys to Ser substitution at position 84) in heavy chain framework region 3 (VHFW3) (e.g., as shown in Table 9B). 2).

Alternatively, or in combination with the BAP050-chi-HC heavy chain substitutions described herein, an anti-LAG-3 antibody molecule contains a light chain variable domain comprising at least one, two, three, four, five, six, seven, ten , fifteen, twenty or more amino acid substitutions, eg amino acid substitutions or deletions from the BAP050-chi-LC amino acid sequence, eg the amino acid sequence shown in FIG. 10A-10B or SEQ ID NO: 24 or 26. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable domain comprising one or more of: E or A at position 1, V at position 3, L at position 4, S in position 7, P in position 8, A or L or D in position 9, T or F in position 10, Q in position 11, P in position 12, V or L in position 13, T in position 14, V or P at position 15, K at position 16, Q or E at position 17, T or P or K at position 18, A at position 19, S at position 20, L at position 21, T at position 22, L at position 37,

- 11 040295

G at 41, K or Q at 42, A or S at 43, P at 44, R or Q at 45, L at 46, I at 58, P or D at 60, Y at position 67, E at position 70, F at position 71, T at position 72, F at position 73, N at position 76, S or R at position 77, I at position 78, Q at position 79, A or S or P at position 80, D at position 81, A or F at position 83, Y or V at position 8 5 or F at position 87 of the BAP050-chi-LC amino acid sequence, for example the amino acid sequence shown in FIG. 10A10B or SEQ ID NO: 2 4 or 26.

In other embodiments, an anti-LAG-3 antibody molecule contains one, two, three, or four heavy chain framework regions (e.g., the VHFW amino acid sequence or nucleotide sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2) or the sequence substantially identical to them (eg, sequence at least about 85%, 90%, 95%, 99% or more identical to them and/or containing one, two, three or more substitutions, insertions or deletions, eg conservative substitutions). In one embodiment, the antibody molecule contains a substitution (eg, a Cys to Ser substitution at position 84) in heavy chain framework region 3 (VHFW3) (eg, as shown in Table 2).

In other embodiments, an anti-LAG-3 antibody molecule comprises one, two, three, or four light chain framework regions (e.g., the VLFW amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2) or a sequence substantially equal to identical (for example, the sequence is at least about 85%, 90%, 95%, 99% or more identical to it and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In other embodiments, an anti-LAG-3 antibody molecule contains one, two, three, or four heavy chain framework regions (e.g., the VHFW amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2) or a sequence substantially named after identical and one, two, three or four light chain framework regions (eg, the VLFW amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2) or a sequence substantially identical to them.

In some embodiments, the anti-LAG-3 antibody molecule comprises heavy chain framework 1 (VHFW1) BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08 BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser , BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, BAP050-Clone-F, or BAP050Clone-G (for example, SEQ ID NO : 187). In some embodiments, the antibody molecule comprises framework region 1 (VHFW1) BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, or BAP050-hum20, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050 -hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J (e.g. SEQ ID NO: 190). In some embodiments, the antibody molecule comprises BAP050-hum16 heavy chain framework region 1 (VHFW1) (eg, SEQ ID NO: 194). In some embodiments, the antibody molecule comprises heavy chain framework 1 (VHFW1) BAP050hum17 (eg, SEQ ID NO: 196). In other embodiments, the antibody molecule comprises a heavy chain framework region 1 (VHFW1) containing or encoded by a sequence substantially identical (e.g., sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises heavy chain framework region 2 (VHFW2) BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08 BAP050-hum03-Ser, BAP050-hum03-Ser, BAP050hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser , BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050hum13-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, BAP050-Clone-F, BAP050-Clone-G, or BAP050Clone-J (for example, SEQ ID NO :

198) . In some embodiments, the antibody molecule comprises a heavy chain framework region 2 (VHFW2) of BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050hum20, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11- Ser, BAP050-hum12-Ser, BAP050-hum20Ser or BAP050-Clone-I (e.g. SEQ ID NO: 202). In some embodiments, the antibody molecule comprises the BAP050-hum14, BAP050-hum15, BAP050-hum14-Ser, or BAP050-hum15-Ser heavy chain framework region 2 (VHFW2) (eg, SEQ ID NO: 206). In some embodiments, the antibody molecule comprises the BAP050-hum16 heavy chain framework region 2 (VHFW2) (eg, SEQ ID NO: 208). In other embodiments, the antibody molecule contains a backbone

- 12 040295 heavy chain region 2 (VHFW2) containing or encoded by a sequence that is substantially identical (e.g., a sequence of at least about 85

90%, 95%, 99% or more identical) to any of the above sequences and/or containing one, two, three or more substitutions, insertions or deletions, eg conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises heavy chain framework 3 (VHFW3) BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08 . In some embodiments, the antibody molecule comprises heavy chain framework 3 (VHFW3) BAP050-hum01-Ser, BAP050hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050hum07 -Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050hum12-Ser BAP050-hum13-Ser BAP050-hum14-Ser BAP050-hum15-Ser BAP050 -hum18-Ser, BAP050 hum19-Ser, BAP050-hum20-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J (e.g. SEQ ID NO: 212). In some embodiments, the antibody molecule comprises the BAP050-hum16 heavy chain framework 3 (VHFW3) (eg, SEQ ID NO: 217). In some embodiments, the antibody molecule comprises the BAP050-hum17 heavy chain framework 3 (VHFW3) (eg, SEQ ID NO: 219). In other embodiments, the antibody molecule comprises a heavy chain framework 3 (VHFW3) containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises heavy chain framework 4 (VHFW4) BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04,

BAP050-hum05 BAP050-hum06 BAP050-hum07 BAP050-hum08 BAP050-hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050-hum15 hum17, BAP050-hum18, BAP050-hum19 or BAP050-hum20, BAP050-hum01-Ser, BAP050hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050hum07- Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050hum12-Ser BAP050-hum13-Ser BAP050-hum14-Ser hum18-Ser, BAP050 hum19-Ser, BAP050-hum20-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J (for example, SEQ ID NO : 221). In other embodiments, the antibody molecule comprises a heavy chain framework 4 (VHFW4) containing or encoded by a sequence substantially identical (e.g., sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, an anti-LAG-3 antibody molecule comprises light chain framework 1 (VLFW1) BAP050-hum01, BAP050-hum02, BAP050-hum04, BAP050-hum07, BAP050hum09, BAP050-hum11, BAP050-hum13, BAP050-hum17, BAP050 -hum01-Ser, BAP050-hum02-Ser, BAP050-hum04-Ser, BAP050-hum07-Ser, BAP050-hum09-Ser, BAP050-hum11-Ser, BAP050-hum13-Ser, BAP050-Clone-F, BAP050-Clone -G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J (e.g. SEQ ID NO: 226). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) of BAP050-hum03, BAP050-hum10, BAP050-hum14, BAP050-hum03-Ser, BAP050-hum10-Ser, or BAP050-hum14-Ser (e.g., SEQ ID NO : 230). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) of BAP050-hum05 or BAP050-hum05-Ser (eg, SEQ ID NO: 232). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) of BAP050-hum06, BAP050-hum20, BAP050hum06-Ser, or BAP050-hum20-Ser (eg, SEQ ID NO: 234). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) BAP050-hum08, BAP050-hum12, BAP050-hum15, BAP050-hum16, BAP050-hum19, BAP050-hum08-Ser, BAP050-hum12-Ser, BAP050hum15-Ser or BAP050-hum19-Ser (eg SEQ ID NO: 236). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) of BAP050-hum18 or BAP050hum18-Ser (eg, SEQ ID NO: 238). In other embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, an anti-LAG-3 antibody molecule comprises light chain framework 2 (VLFW2) BAP050-hum01, BAP050-hum02, BAP050-hum05, BAP050-hum09, BAP050hum13, BAP050-hum17, BAP050-hum01-Ser, BAP050-hum02 -Ser, BAP050-hum05-Ser, BAP050-hum09-Ser, BAP050-hum13-Ser, BAP050-hum17-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050

- 13 040295

Clone-I or BAP050-Clone-J (e.g. SEQ ID NO: 240). In some embodiments, the antibody molecule comprises light chain framework 2 (VLFW2) BAP050-hum03, BAP050-hum06,

BAP050-hum08, BAP050-hum10, BAP050-hum12, BAP050-hum14, BAP050-hum15, BAP050-hum16,

BAP050-hum18 BAP050-hum19 BAP050-hum20 BAP050-hum03-Ser BAP050-hum06-Ser BAP050hum08-Ser BAP050-hum10-Ser BAP050-hum12-Ser BAP050-hum14-Ser Ser, BAP050hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser (e.g. SEQ ID NO: 244). In some embodiments, the antibody molecule comprises light chain framework 2 (VLFW2) BAP050hum04 or BAP050-hum04-Ser (eg, SEQ ID NO: 246). In some embodiments, the antibody molecule comprises light chain framework 2 (VLFW2) of BAP050-hum07, BAP050-hum11, BAP050-hum07-Ser, or BAP050-hum11-Ser (eg, SEQ ID NO: 248). In other embodiments, the antibody molecule comprises a light chain framework 2 (VLFW2) containing or encoded by a sequence substantially identical (e.g., sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, an anti-LAG-3 antibody molecule comprises a light chain framework region 3 (VLFW3) BAP050-hum01, BAP050-hum03, BAP050-hum05, BAP050-hum10, BAP050hum14, BAP050-hum19, BAP050-hum01-Ser, BAP050-hum03 -Ser, BAP050-hum05-Ser, BAP050-hum10-Ser, BAP050-hum14-Ser, BAP050-hum19-Ser or BAP050-Clone-F (e.g. SEQ ID NO: 252). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) BAP050-hum02, BAP050-hum09, BAP050-hum13, BAP050-hum02-Ser, BAP050-hum09-Ser, BAP050hum13-Ser, BAP050-Clone-G, BAP050 -Clone-H or BAP050-Clone-J (eg SEQ ID NO: 255). In some embodiments, the antibody molecule comprises a BAP050-hum04 or BAP050-hum04-Ser light chain framework 3 (VLFW3) (eg, SEQ ID NO: 259). In some embodiments, the antibody molecule comprises a BAP050-hum06, BAP050hum07, BAP050-hum11, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum11-Ser, or BAP050-Clone-I light chain framework 3 (VLFW3) (e.g. , SEQ ID NO: 261). In some embodiments, the antibody molecule comprises a light chain framework region 3 (VLFW3) BAP050-hum08, BAP050-hum12, BAP050-hum15, BAP050-hum16, BAP050-hum18, BAP050-hum08-Ser, BAP050-hum12-Ser, BAP050-hum15 -Ser or BAP050-hum18-Ser (eg SEQ ID NO: 265). In some embodiments, the antibody molecule comprises a BAP050-hum17 light chain framework 3 (VLFW3) (eg, SEQ ID NO: 267). In some embodiments, the antibody molecule comprises a BAP050hum20 or BAP050-hum20-Ser light chain framework 3 (VLFW3) (eg, SEQ ID NO: 269). In other embodiments, the antibody molecule comprises a light chain 3 (VHLW3) framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises light chain framework 4 (VLFW4) BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050 -hum09 BAP050-hum10 BAP050hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050-hum15 BAP050-hum16 BAP050hum17 BAP050-hum18 BAP050-hum19 BAP050-hum20

BAP050-hum03-Ser,

BAP050-hum08-Ser,

BAP050-hum13-Ser,

BAP050-hum04-Ser,

BAP050-hum09-Ser,

BAP050-hum14-Ser,

BAP050-hum05-Ser

BAP050-hum10-Ser

BAP050-hum15-Ser

BAP050-hum01-Ser,

BAP050-hum06-Ser,

BAP050-hum11-Ser,

BAP050-hum18-Ser,

BAP050-hum02-Ser,

BAP050-hum07-Ser,

BAP050-hum12-Ser,

BAP050-hum19-Ser,

BAP050-hum20-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050Clone-J (e.g. SEQ ID NO: 271). In other embodiments, the antibody molecule comprises a light chain framework 4 (VLFW4) containing or encoded by a sequence substantially identical (e.g., sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, an anti-LAG-3 antibody molecule comprises heavy chain framework regions 1-3 BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum18, BAP050-hum19 (for example, SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)). In some embodiments, the antibody molecule comprises BAP050-hum09, BAP050hum10, BAP050-hum11, BAP050-hum12, BAP050-hum20 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2 ) and SEQ ID NO: 210 (VHFW3)). In some embodiments, the antibody molecule comprises BAP050-hum13 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)). In some embodiments, the antibody molecule comprises BAP050-hum14 or BAP050-14 040295 hum15 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2) and SEQ ID NO: 210 ( VHFW3)). In some embodiments, the antibody molecule comprises BAP050-hum16 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 194 (VHFW1), SEQ ID NO: 208 (VHFW2), and SEQ ID NO: 217 (VHFW3)). In some embodiments, the antibody molecule comprises BAP050-hum17 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 196 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 219 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,

BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum18-Ser,

BAP050-hum19-Ser, BAP050-Clone-F or BAP050-Clone-G (e.g. SEQ ID NO: 187 (VHFW1), SEQ ID

NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050hum11-Ser, BAP050-hum12-Ser, BAP050-hum20-Ser, BAP050-Clone-H, or BAP050- Clone I (for example, SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2) and SEQ ID NO: 212 (VHFW3)). In some embodiments, the antibody molecule comprises BAP050-hum13-Ser or BAP050-Clone-J heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)). In some embodiments, the antibody molecule comprises BAP050-hum14-Ser or BAP050-hum15-Ser heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 212 (VHFW3)). In some embodiments, the antibody molecule further comprises a framework region

BAP050-hum03,

BAP050-hum09,

BAP050-hum15,

BAP050-hum04,

BAP050-hum10,

BAP050-hum16,

BAP050-hum05,

BAP050-hum11,

BAP050-hum17, heavy chain BAP050-hum01, BAP050-hum06, BAP050-hum07, BAP050-hum12, BAP050-hum13, BAP050-hum18, BAP050-hum19,

BAP050-hum02,

BAP050-hum08,

BAP050-hum14,

BAP050-hum20,

BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09-Ser, BAP050-hum11-Ser, BAP050-hum13-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050- Clone-H, BAP050-Clone-I or BAP050Clone-J (e.g. SEQ ID NO: 221). In other embodiments, the antibody molecule comprises a heavy chain framework region containing or encoded by a sequence substantially identical (e.g., sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, an anti-LAG-3 antibody molecule comprises BAP050-hum01, BAP050-hum01-Ser, or BAP050-Clone-F light chain framework regions 1-3 (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 252 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 BAP050-hum02, BAP050-hum09, BAP050-hum13, BAP050-hum02-Ser, BAP050-hum09-Ser, BAP050-hum13-Ser, BAP050-Clone-G, BAP050Clone-H or BAP050-Clone-J (for example, SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 255 (VLFW3)). In some embodiments, the antibody molecule comprises BAP050-hum03, BAP050-hum10, BAP050-hum14, BAP050-hum03-Ser, BAP050hum10-Ser, or BAP050-hum14-Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 230 ( VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 252 (VLFW3)). In some embodiments, the antibody molecule comprises BAP050-hum04 or BAP050-hum04-Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 246 (VLFW2), and SEQ ID NO: 259 ( VLFW3)). In some embodiments, the antibody molecule comprises BAP050-hum05 or BAP050-hum05Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 232 (VLFW1), SEQ ID NO: 240 (VLFW2), and SEQ ID NO: 252 (VLFW3) ). In some embodiments, the antibody molecule comprises BAP050-hum0 6 or BAP050-hum0 6-Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 234 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 261 (VLFW3)). In some embodiments, the antibody molecule comprises BAP050-hum07, BAP050-hum11, BAP050-hum07-Ser, BAP050hum11-Ser, or BAP050-Clone-I light chain framework regions 1-3 (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 248 (VLFW2) and SEQ ID NO: 261 (VLFW3)). In some embodiments, the antibody molecule comprises BAP050-hum08, BAP050-hum12, BAP050-hum15, BAP050-hum16, BAP050hum08-Ser, BAP050-hum12-Ser, or BAP050-hum15-Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 265 (VLFW3)). In some embodiments, the antibody molecule comprises BAP050-hum17 light chain framework regions 1-3 (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 267 (VLFW3)). In some embodiments, the antibody molecule comprises BAP050-hum18 or BAP050-hum18-Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 238 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 265 ( VLFW3)). In some embodiments, the antibody molecule comprises BAP050hum19 or BAP050-hum19-Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 252 (VLFW3) ). In some embodiments, the antibody molecule comprises BAP050-hum20 or BAP050-hum20-Ser light chain framework regions 1-3 (e.g., SEQ ID NO: 234 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 269 ( VLFW3)). In some embodiments, the antibody molecule further comprises heavy chain framework region 4 BAP050-hum01, BAP050-hum02,

- 15 040295

BAP050-hum03,

BAP050-hum09,

BAP050-hum15,

BAP050-hum04,

BAP050-hum10,

BAP050-hum16,

BAP050-hum05,

BAP050-hum11,

BAP050-hum17,

BAP050-hum06,

BAP050-hum12,

BAP050-hum18,

BAP050-hum07,

BAP050-hum13,

BAP050-hum19,

BAP050-hum08,

BAP050-hum14,

BAP050-hum20,

BAP050-hum01-Ser,

BAP050-hum06-Ser,

BAP050-hum11-Ser,

BAP050-hum02-Ser,

BAP050-hum07-Ser,

BAP050-hum12-Ser,

BAP050-hum03-Ser,

BAP050-hum08-Ser,

BAP050-hum13-Ser,

BAP050-hum04-Ser,

BAP050-hum09-Ser,

BAP050-hum14-Ser,

BAP050-hum05-Ser

BAP050-hum10-Ser

BAP050-hum15-Ser

BAP050-hum18-Ser, BAP050-hum19-Ser, BAP050-hum20-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050Clone-H, BAP050-Clone-I or BAP050-Clone-J (e.g. SEQ ID NO: 271). In other embodiments, the antibody molecule comprises a light chain framework region containing or encoded by a sequence substantially identical (e.g., sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum01 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum01-Ser or BAP050Clone-F heavy chain framework regions 1-3 (e.g. SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)) and framework BAP050-hum01, BAP050-hum01-Ser or BAP050-Clone-F light chain regions 1-3 (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 252 (VLFW3) ). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences, and /or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum02 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum02-Ser or BAP050Clone-G heavy chain framework regions 1-3 (e.g. SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and BAP050-hum02, BAP050-hum02-Ser or BAP050-Clone-G light chain framework regions 1-3 (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 255 (VLFW3 )). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences, and /or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum03 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum03-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)) and framework regions 1-3 light chain BAP050-hum03 (for example, SEQ ID NO: 230 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 252 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences, and /or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum04 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum04-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)) and framework regions 1-3 light chain BAP050-hum04 (for example, SEQ ID NO: 226 (VLFW1), SEQ ID NO: 246 (VLFW2) and SEQ ID NO: 259 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences, and /or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum05 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum05-Ser (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and light chain frameworks 1-3 of BAP050-hum05 or BAP050-hum05-Ser (for example, SEQ ID NO: 232 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 252 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum06 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum06-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and framework regions 1- 3 light chain BAP050-hum06 (for example, SEQ ID NO: 234 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 261 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum07 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum07-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and framework regions 1- 3 light chain BAP050-hum07 (for example, SEQ ID NO: 226 (VLFW1), SEQ ID NO: 248 (VLFW2) and SEQ ID NO: 261 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences, and /or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum08 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum08-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and framework regions 1- 3 light chain BAP050-hum08 (for example, SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 265 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences, and /or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum09 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum09-Ser or BAP050-Clone-H (e.g. SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and framework regions 1-3 light chain BAP050-hum09, BAP050-hum09-Ser or BAP050-C1one-H (e.g. SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 255 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences and/ or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum10 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum10-Ser heavy chain (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and framework regions 1- 3 light chain BAP050-hum10 (for example, SEQ ID NO: 230 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 252 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences, and /or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum11 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum11-Ser or BAP050-Clone-I (for example, SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VhFW2) and SEQ ID NO: 212 (VHFW3)), and framework regions 1-3 light chain BAP050-hum11, BAP050-hum11-Ser or BAP050-Clone-I (for example, SEQ ID NO: 226 (VLFW1), SEQ ID NO: 248 (VLFW2) and SEQ ID NO: 261 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence that is substantially identical (e.g., at least about 85%, 90%, 95, 99% or more sequence identical) to any of the above sequences. - 17 040295 and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum12 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum12-Ser (e.g. SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and BAP050-hum12 light chain framework regions 1-3 or BAP050-hum12-Ser (for example, SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 265 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum13 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum13-Ser or BAP050Clone-J heavy chain framework regions 1-3 (e.g. SEQ ID NO: 190 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and BAP050-hum13, BAP050-hum13-Ser or BAP050-Clone-J light chain framework regions 1-3 (e.g. SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2) and SEQ ID NO: 255 (VLFW3 )). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum14 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum14-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2) and SEQ ID NO: 210 (VHFW3)), and framework regions 1- 3 light chain BAP050-hum14 (eg, SEQ ID NO: 230 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 252 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum15 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum15-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2) and SEQ ID NO: 210 (VHFW3)), and framework regions 1- 3 light chain BAP050-hum15 (for example, SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 265 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum16 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 194 (VHFW1), SEQ ID NO: 208 (VHFW2), and SEQ ID NO: 217 (VHFW3) ), and BAP050-hum16 light chain framework regions 1-3 (eg, SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 265 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum17 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 196 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 219 (VHFW3) ), and BAP050-hum17 light chain framework regions 1-3 (eg, SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2), and SEQ ID NO: 267 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum18 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)) or BAP050-hum18-Ser heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and BAP050-hum18 light chain frameworks 1-3 (eg, SEQ ID NO: 238 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 265 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum19 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or framework regions 1-3 of the BAP050-hum18-Ser heavy chain (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and framework regions 1- 3 light chain BAP050-hum19 (for example, SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 252 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises BAP050-hum20 heavy chain framework regions 1-3 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3) ) or BAP050-hum20-Ser (e.g. SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2) and SEQ ID NO: 212 (VHFW3)), and BAP050-hum20 light chain frameworks 1-3 ( for example, SEQ ID NO: 234 (VLFW1), SEQ ID NO: 244 (VLFW2) and SEQ ID NO: 269 (VLFW3)). In other embodiments, the antibody molecule comprises a heavy chain and light chain framework region containing or encoded by a sequence substantially identical (e.g., at least about 85%, 90%, 95%, 99% or more sequence identical) to any of the above sequences. and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In some embodiments, an anti-LAG-3 antibody molecule comprises a heavy chain framework region comprising a combination of FW1, FW2, and FW3 framework regions, as shown in FIG. 4 or 6. In another embodiment, the antibody molecule comprises a light chain framework region comprising a combination of FW1, FW2, and FW3 framework regions as shown in FIG. 4 or 6. In other embodiments, the antibody molecule comprises a heavy chain framework region comprising a combination of FW1, FW2, and FW3 framework regions as shown in FIG. 4 or 6 and a light chain framework comprising a combination of FW1, FW2 and FW3 frameworks as shown in FIG. 4 or 6.

In one embodiment, the heavy or light chain variable domain or both of an anti-LAG-3 antibody contains an amino acid sequence that is substantially identical to the amino acid described herein, e.g., at least 70, 75, 80, 85, 90 , 92, 95, 97, 98, 99% or more identical to the variable region of the antibody described in the present description, for example, an antibody selected from any of BAP050-hum01, BAP050-hum02,

BAP050-hum03,

BAP050-hum09,

BAP050-hum15,

BAP050-hum04,

BAP050-hum10,

BAP050-hum16,

BAP050-hum05,

BAP050-hum11,

BAP050-hum17,

BAP050-hum06,

BAP050-hum12,

BAP050-hum18,

BAP050-hum07,

BAP050-hum13,

BAP050-hum19,

BAP050-hum08,

BAP050-hum14,

BAP050-hum20, huBAP050(Ser) (ex. ), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or as described in Table 1, or encoded by the nucleotide sequence in the table. 1, or which differs by at least 1 or 5 residues, but less than 40, 30, 20, or 10 residues, from the variable region of an antibody described herein.

In one embodiment, the heavy or light chain variable region or both of an anti-LAG-3 antibody molecule contains an amino acid sequence encoded by a nucleic acid sequence described herein or a nucleic acid that hybridizes to a nucleic acid sequence described herein (e.g. , a specific nucleic acid sequence, or a nucleic acid sequence encoding the amino acid sequence described herein, for example, as shown in Tables 1 and 2) or its complement, for example, under low stringency, medium stringency, or high stringency hybridization conditions, or other hybridization conditions described in the present description.

In another embodiment, an anti-LAG-3 antibody molecule contains at least one, two, three, or four antigen-binding regions, e.g., variable regions containing

- 19 040295 amino acid sequence, as indicated in the table. 1, or a sequence substantially identical to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it, or that differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the sequences presented in Table 1). In another embodiment, the anti-LAG-3 antibody molecule contains a VH and/or VL domain encoded by a nucleic acid containing the nucleotide sequence as shown in Table 1. 1, or a sequence substantially identical to it (e.g., a sequence that is at least about 70%, 75%, 85%, 90%, 95%, 99% or more identical to it, or which differs by no more than 3%, 6%, 15%, 30% or 45 nucleotides from the sequences shown in Table 1).

In yet another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, or three CDRs from the heavy chain variable region containing the amino acid sequence as listed in Table 1. 1, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and / or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions) . In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, or three CDRs from a light chain variable region containing the amino acid sequence as listed in Table 1. 1, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions) . In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions containing the amino acid sequence as shown in Table 1. 1, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions) . In one embodiment, at least one, two, three, four, five, or six CDRs are determined by Rabat, for example, as shown in Table 1. 1. In another embodiment, at least one, two, three, four, five or six CDRs are determined by Chothia, for example, as shown in table. 1.

In one embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs and/or hypervariable loops from a heavy chain variable region comprising the amino acid sequence of an antibody described herein, e.g., an antibody selected from any of BAP050 -hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10,

BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16,

BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) , BAP050hum12-Ser, BAP050-hum13-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, as summarized in Table 1, or a sequence substantially identical to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and / or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions) . In another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs from a light chain variable region comprising the amino acid sequence of an antibody described herein, e.g., an antibody selected from any of

BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,

BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,

BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,

BAP050-hum19, BAP050-hum20, huBAP050(Ser) , BAP050-hum13-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, as summarized in Table 1, or a sequence substantially identical to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and / or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions) . In one embodiment, an anti-LAG-3 antibody molecule contains all six CDRs and/or hypervariable loops described herein, such as those described in Table 1. 1.

In one embodiment, an anti-LAG-3 antibody molecule contains a variable region that is sequence identical or that differs by 1, 2, 3, or 4 amino acids from the variable region described herein (e.g., the FR region described herein).

In one embodiment, the anti-LAG-3 antibody molecule is a complete antibody or a fragment thereof (eg, Fab, F(ab') ₂ , Fv, or single chain Fv fragment (scFv)). In certain embodiments, the anti-LAG-3 antibody molecule is a monoclonal antibody or an antibody with a single specificity. An anti-LAG-3 antibody molecule can also

- 20 040295 are humanized, chimeric, camel, shark or in vitro derived antibody molecules. In one embodiment, the anti-LAG-3 antibody molecule is thus a humanized antibody molecule. The heavy and light chains of an anti-LAG-3 antibody molecule may be full length (e.g., the antibody may contain at least one and preferably two complete heavy chains and at least one and preferably two complete light chains) or may contain an antigen binding fragment (e.g., Fab , F(ab') ₂ , Fv, single chain Fv fragment, single domain antibody, diabody (dAb), bivalent or bispecific antibody or fragment thereof, single domain variant or camelid antibody).

In certain embodiments, the anti-LAG-3 antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity for LAG-3 and a second binding specificity for PD-1, TIM-3, CEACAM (e.g., CEACAM-1 and/or CEACAM-5), PD-L1, or PD- L2. In one embodiment, the bispecific antibody molecule binds to LAG-3 and PD-1. In another embodiment, the bispecific antibody molecule binds to LAG-3 and TIM-3. In another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM (eg, CEACAM-1 and/or CEACAM-5). In another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM-1. In yet another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM-5. In another embodiment, the bispecific antibody molecule binds to LAG-3 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to LAG-3 and PD-L2. Any combination of the above molecules can be produced in a polyspecific antibody molecule, e.g. a trispecific antibody, which has a first binding specificity for LAG-3 and a second and third binding specificity for one or more of: PD-1, TIM-3, CEACAM (e.g., SEACAM-1 or SEACAM-5), PD-L1 or PD-L2.

In other embodiments, an anti-LAG-3 antibody molecule is used in combination with a bispecific molecule comprising one or more of: PD-1, TIM-3, CEACAM (e.g., CEACAM-1 or CEACAM-5), PD-L1, or PD- L2. In one embodiment, the bispecific antibody molecule used in combination binds to CEACAM (eg, CEACAM-1 and/or CEACAM-5) and PD-1. In another embodiment, the bispecific antibody molecule used in combination binds to CEACAM (eg, CEACAM-1 and/or CEACAM-5) and TIM-3. In another embodiment, the bispecific antibody molecule used in combination binds to PD-1 and TIM-3.

In other embodiments, the anti-LAG-3 antibody molecule comprises a heavy chain constant region (Fc) selected from, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE heavy chain constant regions; in particular selected, for example, from IgG1, IgG2, IgG3 and IgG4 heavy chain constant regions, more specifically IgG1, IgG2 or IgG4 heavy chain constant region (eg human IgG1, IgG2 or IgG4). In one embodiment, the heavy chain constant region is human IgG1 or human IgG4. In another embodiment, the anti-LAG-3 antibody molecule comprises a light chain constant region selected, for example, from κ light chain or λ chain constant regions, preferably a κ chain (eg, human κ chain). In one embodiment, the constant region is altered, e.g., mutated to modify properties of the anti-LAG-3 antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, number of cysteine residues, cell effector function, or function complement). For example, a constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K), and 478 (N to F) to change Fc receptor binding (e.g., mutant positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K), and 314 (N to F) of SEQ ID NO: 212 or 214, or positions 135 ( M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) SEQ ID NOs: 215, 216, 217 or 218). In another embodiment, the IgG4 heavy chain constant region, eg human IgG4, is mutated at position 228 according to EU numbering (eg S to P), eg as shown in Table 1. 3. In certain embodiments, the anti-LAG-3 antibody molecule contains human IgG4 mutated at position 228 according to EU numbering (eg, S to P), for example, as shown in Table. 3 and the light chain constant region, for example, as shown in Table 3. 3. In yet another embodiment, the IgG1 heavy chain constant region, e.g. human IgG1, is mutated at one or more of position 297 according to EU numbering (e.g. N to A), position 265 according to EU numbering (e.g. , D to A), EU regulation 329 (e.g. P to A), EU regulation 234 (e.g. L to A) or EU regulation 235 (e.g. L to A) , for example, as shown in Table. 3. In certain embodiments, the anti-LAG-3 antibody molecule contains a human IgGl mutated at one or more of the above positions, for example, as shown in Table 1. 3, and a κ light chain constant region, for example, as shown in Table 3. 3.

In one embodiment, the anti-LAG-3 antibody molecule is isolated or recombinant.

In one embodiment, the anti-LAG-3 antibody molecule is a humanized antibody molecule.

In one embodiment, the risk score of the anti-LAG-3 antibody molecule based on T cell epitope analysis is less than 1200, 1150, 1100, 1050, 1000, 950, 900, 850, or 800.

In one embodiment, the anti-LAG-3 antibody molecule is a humanized antibody molecule and has a risk score based on T cell epitope analysis of 800 to 1200, 850 to 1150, 900 to 1100, 950 to 1050, or risk score, as described in the present description.

The invention also relates to a nucleic acid molecule that contains one or more nucleotide sequences that encode heavy and light chain variable regions, CDRs, hypervariable loops and/or framework regions of anti-LAG-3 antibody molecules as described herein. In certain embodiments, the nucleotide sequence encoding the anti-LAG-3 antibody molecule is codon-optimized. For example, the invention relates to first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an anti-LAG-3 antibody molecule selected from one or more of, for example, any of BAP050-hum01, BAP050-hum02, BAP050-hum03 BAP050-hum04, BAP050-hum05, BAP050hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09 -hum17, BAP050hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050-hum12-Ser BAP050-hum13-Ser BAP050-hum14- Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050Clone-J, as summarized in Table. 1, or a sequence substantially identical to it. For example, the nucleic acid may contain a nucleotide sequence, as indicated in table. 1 and 2, or a sequence substantially identical to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences presented in Tables 1 and 2.

In other embodiments, the nucleic acid molecule comprises a nucleotide sequence encoding a heavy chain variable domain and a heavy chain constant region comprising the amino acid sequence BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050 -Clone-J, or as described in Table. 1, or encoded by the nucleotide sequence in table. 1 or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In other embodiments, the nucleic acid comprises a nucleotide sequence encoding a light chain variable domain and/or a light chain constant region comprising the amino acid sequence BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or as described in Table. 1, or encoded by the nucleotide sequence in table. 1 or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

The above nucleotide sequences encoding the heavy and light chain variable domain and the constant regions of an anti-LAG-3 antibody may be contained in separate nucleic acid molecules or in the same nucleic acid molecule. In certain embodiments, the implementation of the nucleic acid molecules contain a nucleotide sequence encoding a leader sequence, for example, the leader sequence, as shown in table. 4, or a sequence substantially identical to it.

In certain embodiments, the nucleic acid molecule comprises a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a heavy chain variable region containing an amino acid sequence as listed in Table 1. 1, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and / or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions) .

In another embodiment, the nucleic acid molecule comprises a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a light chain variable region containing an amino acid sequence as set forth in Table 1, or a sequence substantially homologous to it (e.g., the sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or containing one, two, three or more substitutions, insertions or deletions, such as conservative substitutions).

In yet another embodiment, the nucleic acid molecule may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops from the heavy and light chain variable regions containing the amino acid sequence as indicated in Table 1, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and / or containing one, two, three or more substitutions, insertions or deletions, for example conservative substitutions).

In one embodiment, the nucleic acid molecule comprises a nucleotide sequence encoding an anti-LAG-3 antibody molecule that contains a substitution (e.g., a Cys to Ser substitution at position 84) in heavy chain framework region 3 (VHFW3) (e.g., as shown in Table .1 and 2).

In another embodiment, the nucleic acid molecule contains one or more heavy chain framework regions (e.g., any of VHFW1 (a type), VHFW1 (b type), VHFW1 (c type),

VHFW1 (d type), VHFW2 (a type), VHFW2 (b type), VHFW2 (c type), VHFW2 (d type), VHFW3 (a type),

VHFW3 (a' type), VHFW3 (b type), VHFW3 (c type), or VHFW4, or any combination thereof, such as a combination of framework regions as described herein) for any of BAP050-hum01, BAP050-hum02, BAP050 -hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,

BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,

BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19,

BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser,

BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,

BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,

BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP049-Clone-F, BAP049-Clone-G, BAP049-Clone-H, BAP049 -Clone-I or BAP049-Clone-J, as summarized in Table. 1 and 2, or a sequence substantially identical to it. For example, a nucleic acid molecule may contain a nucleotide sequence, as indicated in table. 1 and 2, or a sequence substantially identical to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides from sequences shown in Tables 1 and 2).

In another embodiment, the nucleic acid molecule contains one or more light chain framework regions (e.g., any of VLFW1 (a type), VLFW1 (b type), VLFW1 (c type), VLFW1 (d type), VLFW1 (e type), VLFW1 (f type), VLFW2 (a type), VLFW2 (b type), VLFW2 (c type), VLFW2 (d type), VLFW3 (a type), VLFW3 (b type), VLFW3 (c type), VLFW3 ( d type), VLFW3 (e type), VLFW3 (f type), VLFW3 (g type), or VLFW4, or any combination thereof, such as a combination of framework regions as described herein) for any of the BAP050-hum01,

BAP050-hum02,

BAP050-hum03,

BAP050-hum09,

BAP050-hum15,

BAP050-hum04,

BAP050-hum10,

BAP050-hum16,

BAP050-hum05,

BAP050-hum11,

BAP050-hum17,

BAP050-hum06,

BAP050-hum12,

BAP050-hum18,

BAP050-hum07,

BAP050-hum13,

BAP050-hum19,

BAP050-hum08,

BAP050-hum14,

BAP050-hum20, huBAP050(Ser) (ex. , BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050 -hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP049-Clone-F, BAP049-Clone-G, BAP049-Clone-H, BAP049-Clone-I or BAP049-Clone-J, as summarized in table. 1 and 2, or a sequence substantially identical to it. For example, a nucleic acid molecule may contain a nucleotide sequence, as indicated in table. 1 and 2, or a sequence substantially identical to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences presented in Tables 1 and 2).

In another embodiment, the nucleic acid molecule contains one or more heavy chain framework regions and one or more light chain framework regions, as described herein. The framework regions of the heavy and light chains may be contained in the same vector or in different vectors.

In another aspect, the invention relates to host cells and vectors containing the nucleic acids described in the present description. Nucleic acids can be contained in the same vector or different vectors contained in the same host cell or different host cells. The host cell may be a eukaryotic cell, such as a mammalian cell, an insect cell, a yeast cell, or a prokaryotic cell, such as E. coli. For example, a mammalian cell may be a cultured cell or cell line. Exemplary mammalian cells include lymphocyte cell lines (e.g., NSO), Chinese Hamster Ovary (CHO) cells, human Per C6 cell line (e.g., PER C6 cells from Crucell), COS cells, oocytes, and cells from a transgenic animal, e.g., an epithelial cell. mammal.

In one aspect, the invention relates to a method for providing an antibody molecule described

- 23 040295 referred to in this specification. The method includes: providing a LAG-3 antigen (eg, an antigen containing at least a portion of a LAG-3 epitope); obtaining an antibody molecule that specifically binds to the LAG-3 polypeptide, and assessing whether the antibody molecule specifically binds to the LAG-3 polypeptide, or assessing the effectiveness of the antibody molecule to modulate, for example, inhibit, LAG-3 activity. The method may further comprise administering the antibody molecule to a subject, such as a human or non-human animal.

In another aspect, the invention relates to compositions, eg, pharmaceutical compositions, that contain a pharmaceutically acceptable carrier, excipient or stabilizer and at least one anti-LAG3 antibody molecule as described herein. In one embodiment, the composition, eg, a pharmaceutical composition, comprises a combination of an anti-LAG-3 antibody molecule and one or more agents, eg, a therapeutic agent or other antibody molecule, as described herein. In one embodiment, the antibody molecule is conjugated to a label or therapeutic agent.

The antibody molecules described herein can inhibit, reduce, or neutralize one or more LAG-3 activities. In one embodiment, the anti-LAG-3 antibody molecule results in one or more of: increased antigen-dependent stimulation of CD4+ T lymphocytes or CD8+ T lymphocytes, increased T cell proliferation; increased expression of an activation antigen, such as CD25; increased expression of a cytokine, e.g., interferon-γ (IFNγ), interleukin 2 (IL-2), interleukin 4 (IL-4), chemokine ligand 3 (CCL3) (C-C motif), chemokine ligand 4 (CCL4) (motif C-C) or chemokine ligand 5 (CCL5) (C-C motif); reducing the suppressive activity of Treg cells, increasing T cell homeostasis, increasing tumor infiltrating lymphocytes, or reducing the likelihood of malignant cells escaping immunological surveillance. Thus, such antibody molecules can be used alone or in combination for the treatment or prevention of disorders where it is desirable to enhance the immune response in the individual.

Use of an anti-LAG-3 antibody molecule.

Thus, another aspect relates to a method for modulating an immune response in an individual. The method includes administering to an individual an antibody molecule as described herein (e.g., a therapeutically effective amount of an anti-LAG-3 antibody molecule), alone or in combination with one or more agents or methods, in a manner that modulates the immune response in the individual. In one embodiment, the antibody molecule restores, enhances, stimulates, or enhances an immune response in an individual.

The subject may be a mammal, such as a primate, preferably a higher primate, such as a human (eg, a patient suffering from or at risk of a disorder described herein). In one embodiment, the implementation of the individual needs to enhance the immune response. In some embodiments, the anti-LAG-3 antibody molecule restores, enhances, or stimulates an antigen-specific T cell response, such as the production of interleukin 2 (IL-2) or interferon-γ (IFN-γ) in an antigen-specific T cell response in an individual. In some embodiments, the implementation of the immune response is an antitumor response. In one of the embodiments, the implementation of the individual suffers from or is at risk of disorders described in the present description, such as cancer or infectious disorders, as described in the present description. In certain embodiments, the individual is immunocompromised or at risk of being immunocompromised. For example, the individual is receiving or has received chemotherapy treatment and/or radiation therapy. Alternatively, or in combination, the individual is immunocompromised or at risk of being immunocompromised as a result of an infection.

One aspect relates to a method of treating (eg, one or more of reducing, inhibiting, or slowing the progression) of a cancer or tumor in an individual. The method includes administering to an individual an anti-LAG-3 antibody molecule as described herein, e.g., a therapeutically effective amount of an anti-LAG-3 antibody molecule alone, e.g., as monotherapy, or in combination, e.g., with one or more agents or methods. In certain embodiments, an anti-LAG-3 antibody molecule is administered in combination with a costimulatory molecule modulator (eg, a costimulatory molecule agonist) or an inhibitory molecule modulator (eg, an immune checkpoint inhibitor inhibitor), for example, as described herein. In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with an immune checkpoint modulator inhibitor or activator (e.g., PD-1 inhibitor (e.g., anti-PD-1 antibody molecule), PD-L1 inhibitor (e.g., anti-PD-1 antibody molecule), PD-L1), a TIM-3 modulator (eg, a TIM-3 activator or inhibitor, eg, an anti-TIM-3 antibody molecule), or a CTLA-4 inhibitor (eg, an anti-CTLA4 antibody).

In certain embodiments, the cancer being treated with the anti-LAG-3 antibody molecule alone or in combination includes, but is not limited to, a solid tumor

- 24 040295 hol, hematological malignant tumor (eg leukemia, lymphoma, myeloma) and their metastatic lesion. In one embodiment, the cancer is a solid tumor. Examples of solid tumors include malignancies such as sarcomas and carcinomas (eg, adenocarcinomas) of various organ systems, such as adenocarcinomas affecting the lung, breast, lymphatic, gastrointestinal or colorectal, genital, and genitourinary tracts (eg, kidney cells, urothelium, bladder), pharynx, CNS (eg brain, neuronal or glial cells), skin (eg melanoma), head and neck (eg head and neck squamous cell carcinoma (HNCC)) and pancreas. For example, melanoma, colon cancer, gastric cancer, rectal cancer, renal cell carcinoma, breast cancer (eg, breast cancer in which one, two, or all of the estrogen receptors, the progesterone receptor, or Her2/neu are not expressed, such as triple negative breast cancer), liver cancer, lung cancer (eg, non-small cell lung cancer (NSCLC) (eg, NSCLC with histologic evidence of squamous and/or non-squamous cells) or small cell lung cancer), prostate cancer, malignant tumor of the head or neck ( for example, HPV+ squamous cell carcinoma), malignant tumor of the small intestine, and malignant tumor of the esophagus. Examples of hematologic malignancies include, but are not limited to, leukemia (eg, myeloid leukemia, lymphoid leukemia, or chronic lymphocytic leukemia (CLL)), lymphoma (eg, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma or mantle cell lymphoma (MCL)) and myeloma, such as multiple myeloma. The cancer may be at an early, intermediate, late stage, or may be a metastatic cancer.

In some embodiments, the cancer is selected from colorectal cancer (eg, CRC), melanoma, eg, advanced stage melanoma (eg, stage II-IV melanoma), or HLA-A2 positive melanoma; pancreatic cancer, eg advanced stage pancreatic cancer; breast cancer, eg metastatic breast carcinoma or triple negative breast cancer; head and neck cancer (eg, HNSCC); esophageal cancer; renal cell carcinoma (RCC), such as clear cell renal cell carcinoma (ccRCC) or metastatic renal cell carcinoma (MRCC); lung cancer (eg, NSCLC); cervical cancer; bladder cancer or hematologic malignancy, such as leukemia (eg, lymphocytic leukemia) or lymphoma (eg, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or CLL eg relapsing or resistant chronic lymphocytic leukemia).

In one embodiment, the cancer is an advanced melanoma or an inoperable melanoma that has not responded to other therapies. In other embodiments, the cancer is a melanoma with a BRAF mutation (eg, a BRAF V600 mutation). In other embodiments, the anti-LAG-3 antibody molecule is administered alone (eg, as monotherapy) or in combination with one or more second agents (eg, a BRAF inhibitor). In one embodiment, for the treatment of melanoma, an anti-LAG-3 antibody molecule is administered in combination (e.g., before or after treatment or concomitantly with) an immune checkpoint modulator inhibitor (e.g., PD-1 inhibitor, PD-L1 inhibitor, TIM- 3, a CEACAM inhibitor (eg, CEACAM1 and/or CEACAM5) or a CTLA4 inhibitor (eg, an anti-CLA4 antibody, eg, ipilimumab)) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib). In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with a PD-1 or PD-L1 inhibitor, such as an anti-PD-1 antibody or anti-PD-L1 antibody molecule for the treatment of melanoma, as described herein.

In one embodiment, the anti-LAG-3 antibody molecule is administered alone, e.g., as monotherapy or in combination with an immune checkpoint modulator inhibitor (e.g., PD-1 inhibitor (e.g., anti-PD-1 antibody molecule), PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule), a TIM-3 inhibitor (eg, an anti-TIM-3 antibody molecule), a CEACAM inhibitor (eg, CEACAM1 and/or CEACAM5) (eg, an anti-CEACAM antibody molecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody) for the treatment of head and neck cancer (e.g., HNSCC) In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with a PD-1 or PD-L1 inhibitor, for example, an anti-PD- 1 or an anti-PD-L1 antibody for the treatment of head and neck cancer as described herein.

In one embodiment, an anti-LAG-3 antibody molecule is administered alone, e.g., as monotherapy or in combination with an immune checkpoint modulator inhibitor or activator (e.g., PD-1 inhibitor (e.g., anti-PD-1 antibody molecule), PD- L1 (eg, anti-PD-L1 antibody molecule), TIM-3 modulator (eg, TIM-3 activator or inhibitor, eg, anti-TIM-3 antibody molecule), CEACAM inhibitor (eg, CEACAM1 and/or CEACAM5) (for example, an anti-CEACAM antibody molecule) or an inhibitor

CTLA-4 (eg, anti-CTLA4 antibody) for the treatment of lung cancer (eg, NSCLC). In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with a PD-1 or PD-L1 inhibitor, e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody molecule for the treatment of lung cancer (e.g., NSCLC), as described in this description.

In one embodiment, the anti-LAG-3 antibody molecule is administered alone, e.g., as monotherapy or in combination with an immune checkpoint modulator inhibitor (e.g., PD-1 inhibitor (e.g., anti-PD-1 antibody molecule), PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule), a TIM-3 inhibitor (eg, an anti-TIM-3 antibody molecule), a CEACAM inhibitor (eg, CEACAM1 and/or CEACAM5) (eg, an anti-CEACAM antibody molecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody) for the treatment of gastric cancer In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with a PD-1 or PD-L1 inhibitor, for example, an anti-PD-1 antibody or an anti-PD-L1 antibody molecule for treatment of gastric cancer, as described in the present description.

In one embodiment, an anti-LAG-3 antibody molecule is administered alone, e.g., as monotherapy or in combination with an immune checkpoint modulator inhibitor (e.g., a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule), a PD-L1 inhibitor ( e.g., an anti-PD-L1 antibody molecule), a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule), a CEACAM inhibitor (e.g., CEACAM1 and/or CEACAM5) (e.g., an anti-CEACAM antibody molecule), or a CTLA-4 inhibitor ( for example, an anti-CTLA4 antibody) for the treatment of lymphomas (eg, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) or CLL, for example, relapsed or resistant chronic lymphocytic In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with a PD-1 or PD-L1 inhibitor, e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody molecule for the treatment of lymph ohms, as described in the present description.

In one embodiment, the cancer microenvironment is characterized by increased levels of PD-L1 expression. Alternatively, or in combination, the cancer microenvironment may be characterized by increased expression of IFNy and/or CD8.

In some embodiments, an anti-LAG-3 antibody molecule is administered alone or in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) or a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule) to treat an individual who suffers from a tumor, or is identified as suffering from a tumor that is characterized by one or more of a high level or expression of PD-L1 or is positive for a tumor infiltrating lymphocyte (TIL)+ (e.g., characterized by an increased number of TILs) or that and others. In certain embodiments, the individual suffers from or is identified as suffering from a tumor that is characterized by high levels or expression of PD-L1 and that is TIL+. In some embodiments, the methods described herein further comprise identifying an individual based on having a tumor that is characterized by one or more of high levels or expression of PD-L1, or being TIL+, or both. In certain embodiments, the methods described herein further include identifying an individual based on the fact that he suffers from a tumor that is characterized by a high level or expression of PD-L1 and is TIL+. In some embodiments, tumors that are TIL+ are positive for CD8 and IFNy. In some embodiments, the individual has or is identified with a high percentage of cells that are positive for one, two or more of PD-L1, CD8, and/or IFNy. In certain embodiments, the individual has or is identified with a high percentage of cells that are positive for all of PD-L1, CD8, and IFNy.

In some embodiments, the methods described herein further comprise identifying an individual based on having a high percentage of cells that are positive for one, two or more of PD-L1, CD8, and/or IFNy. In certain embodiments, the methods described herein further comprise identifying an individual based on having a high percentage of cells that are positive for all of PD-L1, CD8, and IFNy. In some embodiments, the subject suffers or is identified as suffering from one, two or more of PD-L1, CD8 and/or IFNy and one or more of lung cancer, eg lung squamous cell carcinoma or lung adenocarcinoma; head and neck cancer; squamous cell carcinoma of the cervix; stomach cancer; esophageal cancer; thyroid cancer; melanoma and/or malignant tumor of the nasopharynx (NPC). In certain embodiments, the methods described herein further describe identifying an individual based on having one, two, or more of PD-L1, CD8, and/or IFNy, and one or more of lung cancer, e.g., squamous cell carcinoma. lung or lung adenocarcinoma; head and neck cancer; squamous cell carcinoma of the cervix; stomach cancer; thyroid cancer; melanoma and / or malignant tumor of the nasopharynx.

The methods and compositions described herein are useful in the treatment of metastatic lesions associated with the above cancers.

In a further aspect, the invention relates to a method of treating an infectious disease in a subject, comprising administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, alone or in combination with one or more agents or methods. Antibodies of the invention are preferred for use in the method, although other anti-LAG-3 antibodies or antigen-binding fragments thereof may be used instead of (or in combination with the anti-LAG-3 antibody molecule described herein).

In one embodiment, the infectious disease is hepatitis (eg, hepatitis B infection). In a particular embodiment, the LAG-3 antibody molecule is administered in combination with a hepatitis B antigen or hepatitis B vaccine, and optionally in combination with an aluminum-containing adjuvant.

In another embodiment, the infectious disease is influenza. In a particular embodiment, the LAG-3 antibody molecule is administered in combination with an influenza antigen or influenza vaccine.

Moreover, the invention relates to a method of enhancing an immune response to an antigen in an individual, comprising administering to the individual: (i) an antigen, and (ii) an anti-LAG-3 antibody molecule such that the immune response to the antigen in the individual is enhanced. The antigen may be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen from a pathogen.

The anti-LAG-3 antibody molecule, alone or in combination, can be administered to an individual systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary insertion), topically, or by application to mucous membranes, such as the nose, throat, and bronchioles.

One of skill in the art can determine doses and treatment regimens for an anti-LAG-3 antibody molecule. In certain embodiments, the anti-LAG-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg , about 1 to 10 mg/kg, or about 1 mg/kg, 3 mg/kg, or 10 mg/kg. The dosing schedule may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 10 to 20 mg/kg once every two weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered (eg, intravenously) at a dose of about 3 to 800 mg, eg, about 3, 20, 80, 240, or 800 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered alone at a dose of about 20 to 800 mg, such as about 3, 20, 80, 240, or 800 mg. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 3 to 240 mg, such as about 3, 20, 80, or 240 mg, when combined with a second agent or treatment, such as a second agent or treatment described in this description. In one embodiment, an anti-LAG-3 antibody molecule is administered every 2 weeks (eg, during weeks 1, 3, 5, 7) during each cycle of 8 weeks, eg up to 96 weeks.

The antibody molecules described herein are preferred for use in the methods described herein, although other anti-LAG-3 antibodies may be used instead of or in combination with the anti-LAG-3 antibody molecule of the invention.

Methods of combined treatment.

The methods and compositions described herein may be used in combination with other agents or treatments. In one embodiment, the methods described herein comprise administering to an individual an anti-LAG-3 antibody molecule as described herein in combination with an agent or therapeutic or treatment method in an amount effective to treat or prevent the disorder. The anti-LAG-3 antibody molecule and the agent or therapeutic method or method of treatment can be administered simultaneously or sequentially in any order. Any combination and sequence of anti-LAG-3 antibody molecules and other therapeutic agents, procedures, or methods may be used (eg, as described herein). The antibody molecule and/or other therapeutic agents, procedures or methods may be administered during a period of active disorder or during remission or less active disease. The antibody molecule can be administered prior to another treatment, concurrently with treatment, after treatment, or during remission of a disorder.

In certain embodiments, the methods and compositions described herein are administered in combination with one or more other antibody molecules, chemotherapy, other cancer therapies (e.g., cancer targeted therapies, gene therapy, cancer therapies, virus-based, RNA-based therapies, bone marrow transplantation, nanotherapy, or oncolytic drugs), cytotoxic agents, immunologic therapies (eg, cytokine- or cell-based immunologic therapies), surgery (eg, lumpectomy or mastectomy), and/or types of radiation therapy or combinations of any of the above. Additional therapy may be adjuvant or neoadjuvant therapy. In some embodiments, the complementary therapy is an enzymatic inhibitor (eg, a small molecule enzymatic inhibitor) or a metastasis inhibitor.

Exemplary cytotoxic agents that can be administered in combination include antimicrotubulin agents, topoisomerase inhibitors, antimetabolites, mitosis inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalators, agents capable of disrupting the signal transduction pathway, agents that promote apoptosis, proteasome inhibitors, and radiation. (e.g., local or whole body irradiation (e.g., γ-irradiation). In other embodiments, the adjunctive therapy is surgery or radiation, or a combination thereof. In other embodiments, the adjunctive therapy is therapy directed at one or more of the pathways PI3K/AKT/mTOR, HSP90 inhibitor, or tubulin inhibitor Illustrative other antibody molecules that can be administered in combination include, but are not limited to, checkpoint inhibitors (e.g., anti-PD-1 antibodies, anti-PD-L1 antibodies, etc.) ), which the stimulus immune cell (eg, GITR or CD137 agonist antibodies), cancer antibodies (eg, rituximab (Rituxan® or MabThera®), trastuzumab (Herceptin®), cetuximab (Erbitux®).

Alternatively, or in combination with the above combinations, the methods and compositions described herein may be administered in combination with one or more of: an immunomodulator (e.g., an activator of a costimulatory molecule or an inhibitor of an immunoinhibitory molecule, e.g., an immune checkpoint molecule), a vaccine, e.g. a therapeutic cancer vaccine; or other forms of cellular immunotherapy.

Illustrative, non-limiting combinations and uses of anti-LAG-3 antibody molecules include those listed below.

In certain embodiments, the anti-LAG-3 antibody molecule is administered in combination with a costimulatory molecule modulator (eg, a costimulatory molecule agonist) or an inhibitory molecule modulator (eg, an immune checkpoint inhibitor inhibitor).

In one embodiment, the anti-LAG-3 antibody molecule is administered in combination with a modulator, such as an agonist, of a costimulatory molecule. In one embodiment, the co-stimulatory molecule agonist is selected from an agonist (e.g., agonist antibody or soluble fusion) ligand OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4- 1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83.

In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with an inhibitor of an inhibitory molecule (or immune checkpoint) selected from PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, VISTA, BTLA , TIGIT, LAIR1, CD160, 2B4, CEACAM (eg, CEACAM-1 and/or CEACAM-5) and/or TGFRe. Inhibition of the inhibitory molecule can be carried out by inhibition at the level of DNA, RNA or protein. In embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA, or shRNA) can be used to inhibit the expression of an inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, such as a soluble ligand or an antibody or antibody fragment that binds to an inhibitory molecule. In one embodiment, the inhibitor is a soluble ligand (eg, CTLA-4-Ig) or an antibody or antibody fragment that binds to PD-1, PD-L1, PD-L2, or CTLA-4.

For example, an anti-LAG-3 antibody molecule can be administered in combination with an inhibitor, such as an antibody or antibody fragment that binds to PD-1, PD-L1, PD-L2, or CTLA-4, to treat cancer (e.g., cancer selected from: colorectal cancer (eg, CRC); melanoma, eg, advanced stage melanoma (eg, stage IIIV melanoma) or HLA-A2 positive melanoma; pancreatic cancer, eg, advanced pancreatic cancer; breast cancer , such as metastatic breast carcinoma or triple-negative breast cancer; head and neck cancer (eg, HNSCC); esophageal cancer; renal cell carcinoma (RCC), such as clear cell renal cell carcinoma (ccRCC) or metastatic renal cell carcinoma (MRCC); lung cancer ( eg, NSCLC); cervical cancer; bladder cancer or hematologic malignancy, eg leukemia (eg, lymphocytic leukemia) or lymphoma (eg, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or CLL, such as relapsing or resistant chronic lymphocytic leukemia).

In one embodiment, an anti-LAG-3-1 antibody molecule is administered in combination with (eg, before, concomitantly, or after) treatment with an anti-CTLA4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib).

In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody (eg, nivolumab or pembroquizumab) or an antigen-binding fragment thereof. In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with an anti-TIM-3 antibody or antigen-binding fragment thereof. In yet another embodiment, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-L1 antibody or antigen-binding fragment thereof. In other embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody and an anti-TIM-3 antibody (or antigen-binding fragments thereof). In certain embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody and an anti-PD-L1 antibody (or antigen-binding fragments thereof). In certain embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-TIM-3 antibody and an anti-PD-L1 antibody (or antigen-binding fragments thereof).

In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with a CEACAM inhibitor (eg, a CEACAM-1 and/or CEACAM-5 inhibitor), eg, an anti-CEACAM antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with a CEACAM-1 inhibitor, such as an anti-CEACAM-1 antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with a CEACAM-5 inhibitor, eg, an anti-CEACAM-5 antibody molecule.

In other embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-CEACAM antibody molecule (eg, anti-CEACAM-1 and/or anti-CEACAM-5 antibody) and an anti-PD-1 antibody molecule. In other embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-CEACAM antibody molecule (eg, anti-CEACAM-1 and/or anti-CEACAM-5 antibody) and an anti-TIM-3 antibody molecule. In other embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-CEACAM antibody molecule (eg, anti-CEACAM-1 and/or anti-CEACAM-5 antibody) and an anti-PD-L1 antibody molecule. The combination of antibodies recited herein may be administered separately, eg as single antibodies or antigen-binding fragments thereof, or linked, eg as a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody is administered that comprises an anti-LAG-3 antibody molecule and one of: an anti-TIM-3 antibody, an anti-CEACAM antibody (e.g., an anti-CEACAM-1 and/or an anti-CEACAM-5 antibody), an anti-CEACAM-5 antibody. PD-L1 or antibodies against PD-1 or an antigen-binding fragment thereof. In certain embodiments, the combination of antibodies listed herein is used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor or a hematologic malignancy). In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody or an anti-PD-L1 antibody to treat a solid tumor.

In other embodiments, the anti-LAG-3 antibody molecule is administered in combination with a cytokine. The cytokine can be administered as a molecule fused to an anti-LAG-3 antibody molecule or as separate formulations. In one embodiment, the LAG-3 antibody is administered in combination with one, two, three or more cytokines, eg, as a fusion molecule or as separate compositions. In one embodiment, the cytokine is an interleukin (IL) selected from one, two, three or more of IL-1, IL-2, IL-12, IL-12, IL-15, or IL-21. In one embodiment, the bispecific antibody molecule has a first binding specificity for a first target (e.g., LAG-3), a second binding specificity for a second target (e.g., PD-1, TIM-3, or PD-L1), and is optionally associated with an interleukin domain (eg IL-12), eg full-length IL-12 or a portion thereof. In certain embodiments, a combination of an anti-LAG-3 antibody molecule and a cytokine described herein is used to treat a cancer, eg a cancer as described herein (eg a solid tumor).

In other embodiments, the anti-LAG-3 antibody molecule is administered in combination with a vaccine, such as a therapeutic cancer vaccine or other forms of cellular immunotherapy. In one embodiment, the vaccine is peptide-based, DNA-based, RNA-based, or antigen-based, or combinations thereof. In embodiments, the vaccine contains one or more peptides, nucleic acids (eg, DNA or RNA), antigens, or a combination thereof. In certain embodiments, the cancer vaccine contains an adjuvant (eg, aluminum phosphate or aluminum hydroxide). In some embodiments, the methods described herein are carried out in combination with one or more of surgical tissue removal, chemotherapy, or other cancer therapy, and

- 29 040295 the primary or only target is metastatic lesions, for example, metastases in the bone marrow or lymph nodes.

In one embodiment, the cancer is melanoma, eg, advanced stage melanoma (eg, stage II-IV melanoma) or HLAA2 positive melanoma. In a particular embodiment, the anti-LAG-3 antibody molecule is administered in combination with a tumor antigenic peptide, eg one or more HLA-A2 peptides, and optionally in combination with an adjuvant, eg Montanide™. Exemplary tumor peptides that can be administered in combination with an anti-LAG-3 antibody molecule include one or more of tyrosinase.A2, MAGE-C2.A2, NY-ESO-1b.A2, MAGE-4.A2, MAGE-3. A2, MAGE-1.A2, NA17.A2 (GnTV) hMAGE-10.A2.

In another embodiment, the cancer is pancreatic cancer, such as advanced stage pancreatic cancer. In a certain embodiment, the antibody molecule can be administered in combination with a chemotherapeutic agent, such as gemcitabine.

In another embodiment, the cancer is breast cancer, such as metastatic breast carcinoma or triple negative breast cancer. In a certain embodiment, the antibody molecule can be administered in combination with a chemotherapeutic agent, such as paclitaxel.

In another embodiment, the cancer is a renal cell carcinoma, eg, advanced stage (eg, stage IV) clear cell carcinoma or metastatic renal cell carcinoma (MRCC).

In another embodiment, the cancer is head or neck cancer, eg HPV+ squamous cell carcinoma.

In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with an antigen. For example, an anti-LAG-3 antibody molecule can be combined with a hepatitis B antigen (eg, Engerix B). In other embodiments, an anti-LAG-3 antibody molecule is administered in combination with an influenza antigen.

The anti-LAG-3 antibody molecule may be used alone in conjugated form, or it may be linked to a substance, such as a cytotoxic agent or molecule (eg, a therapeutic drug; a radiation-emitting compound; molecules of plant, fungal, or bacterial origin, or a biological protein ( e.g., a protein toxin) or particle (e.g., a recombinant viral particle, e.g., through a virus coat protein.) For example, an antibody can be coupled to a radioactive isotope such as an α-, β- or γ-emitter or a β- and γ-emitter.

Additional methods of combined treatment.

The methods and compositions described herein (eg, anti-LAG-3 antibodies and methods of using them) can be used in combination with other agents or therapeutic methods, for example, a second therapeutic agent selected from one or more of the agents listed in Table. 7. In one embodiment, the methods described herein comprise administering to an individual an anti-LAG-3 antibody molecule as described herein (optionally in combination with one or more inhibitors of PD-1, PD-L1, TIM3, CEACAM ( for example, CEACAM-1 and/or CEACAM-5) or CTLA-4)) further include the introduction of a second therapeutic agent selected from one or more of the agents listed in table. 7 in an amount effective to treat or prevent a disorder, such as a disorder as described herein, such as cancer. When administered in combination, the anti-LAG-3 antibody molecule, the additional agent (e.g., second or third agent), or all, may be administered in an amount or dose that is higher, lower, or the same as the amount or dose of each agent used alone, e.g. as monotherapy. In certain embodiments, the amount or dose of anti-LAG-3 antibody, additional agent (e.g., second or third agent), or all administered is lower (e.g., at least 20%, at least 30%, at least 40 % or at least 50%) than the amount or dose of each agent used alone, for example as monotherapy. In other embodiments, the amount or dose of anti-LAG-3 antibody, additional agent (e.g., second or third agent), or all that results in the desired effect (e.g., treatment of cancer) is lower (e.g., at least 20%, at least 30%, at least 40% or at least 50% lower).

In other embodiments, the implementation of the second therapeutic agent is selected from one or more of the funds listed in table. 7. In one embodiment, the cancer is selected from lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC with histological features of squamous and/or non-squamous cells or NSCLC adenocarcinoma) or a cancer described in the publication shown in Table. 7. In some embodiments, the second therapeutic agent is selected from one or more of: 1) a protein kinase C inhibitor (PKC); 2) heat shock protein inhibitor 90 (HSP90); 3) a phosphoinositide 3-kinase inhibitor (PI3K) and/or a rapamycin target (mTOR); 4) a cytochrome P450 inhibitor (eg a CYP17 inhibitor or a 17a-hydroxylase/C17-20 lyase inhibitor); 5) an iron chelating agent; 6) an aromatase inhibitor; 7) a p53 inhibitor, eg an inhibitor of the p53/Mdm2 interaction; 8) apoptosis inducer; 9) an angiogenesis inhibitor; 10) an aldosterone synthase inhibitor; 11) protein receptor inhibitor smoothened (SMO); 12) a prolactin receptor (PRLR) inhibitor; 13) an inhibitor of the Wnt signaling cascade; 14) a CDK4/6 inhibitor; 15) fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) an inhibitor of macrophage colony stimulating factor (M-CSF); 17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (eg, FLK-1/KDR), PDGFRbeta, c-KIT, or Raf kinase C; 19) a somatostatin agonist and/or a growth hormone releasing inhibitor; 20) an anaplastic lymphoma kinase (ALK) inhibitor; 21) inhibitor of insulin-like growth factor receptor 1 (IGF-1R); 22) P-glycoprotein 1 inhibitor; 23) an inhibitor of vascular endothelial growth factor receptor (VEGFR); 24) BCR-ABL kinase inhibitor; 25) an FGFR inhibitor; 26) CYP11B2 inhibitor; 27) an HDM2 inhibitor, eg an HDM2-p53 interaction inhibitor; 28) a tyrosine kinase inhibitor; 29) c-MET inhibitor; 30) a JAK inhibitor; 31) DAC inhibitor; 32) 11b-hydroxylase inhibitor; 33) an IAP inhibitor; 34) a PIM kinase inhibitor; 35) porcupine inhibitor; 36) a BRAF inhibitor, eg BRAF V600E or wild-type BRAF; 37) HER3 inhibitor; 38) MEK inhibitor or 39) lipid kinase inhibitor, for example, as described in the present description and in table. 7.

In one embodiment, the second therapeutic agent is selected from one or more of: Compound A8, Compound A17, Compound A23, Compound A24, Compound A27, Compound A29, Compound A33, and Compound A13.

In other embodiments, the second therapeutic agent is selected from one or more of Compound A5, Compound A8, Compound A17, Compound A23, Compound A24, Compound A29, and Compound A40.

In other embodiments, the second therapeutic agent is selected from one or more of: Compound A9, Compound A16, Compound A17, Compound A21, Compound A22, Compound A25, Compound A28, Compound A48, and Compound 49.

In embodiments, the second therapeutic agent is administered at or below a therapeutic dose. In certain embodiments, the concentration of the second therapeutic agent that is necessary to produce inhibition, such as growth inhibition, is lower when the second therapeutic agent is administered in combination with an anti-LAG-3 antibody molecule than when the second therapeutic agent is administered alone. In certain embodiments, the concentration of the anti-LAG-3 antibody molecule that is necessary to obtain inhibition, e.g., growth inhibition, is lower when the anti-LAG-3 antibody molecule is administered in combination with a second therapeutic agent than when the anti-LAG-3 antibody molecule is administered separately. In certain embodiments, in combination treatment, the concentration of the second therapeutic agent that is necessary to obtain inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second therapeutic agent as monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% below. In certain embodiments, in the combination treatment, the concentration of the anti-LAG-3 antibody molecule that is necessary to obtain inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the anti-PD-1 antibody molecule as monotherapy, e.g., by 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 6070%, 70-80% or 80-90% below.

Detection.

In another aspect, the invention relates to methods for detecting the presence of LAG-3 in a sample, eg in vitro or in vivo (eg, a biological sample, eg, serum, semen, or urine, or a tissue biopsy, eg, from a hyperproliferative or malignant lesion). The method of the invention can be used to evaluate (eg, monitor treatment or progression, diagnose and/or staging a disorder as described herein, eg, a hyperproliferative or malignant disorder in an individual). The method includes: (i) contacting a sample (and optionally a reference sample, such as a control sample) with an anti-LAG-3 antibody molecule as described herein, or administering it to an individual under conditions that allow interaction to occur, and (ii) detecting the formation of a complex between the antibody molecule and the sample (and optionally a reference sample, such as a control sample). Complex formation is indicative of the presence of LAG-3 and may indicate the appropriateness or need for the treatment described herein. The method may include immunohistochemistry, immunocytochemistry, flow cytometry (e.g., FACS), magnetic beads complexing with an antibody molecule, ELISA assays, PCR techniques (e.g., OT-31 040295

PCR).

Typically, an anti-LAG-3 antibody molecule used in in vivo and in vitro diagnostic methods is directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound binding agent. Suitable detectable substances include various biologically active enzymes, prosthetic groups, fluorescent substances, luminescent substances, paramagnetic (eg active in nuclear magnetic resonance) substances and radioactive substances.

Additional embodiments relate to a method for treating cancer, comprising: identifying in a sample (e.g., a sample obtained from an individual containing cancer cells and optionally immune cells such as TIL) the presence of one, two, or all of PD-L1, CD8, or IFN- γ, thus providing an estimate for one, two, or all PD-L1, CD8, and IFN-γ. The method may further include comparing the PD-L1, CD8 and/or IFN-γ values with a reference value, such as a reference value. If the PD-L1, CD8, and/or IFN-γ values are greater than a reference value, such as a control value, then administering a therapeutically effective amount of an anti-LAG-3 antibody (eg, an anti-LAG-3 antibody described herein) alone or in combinations with an anti-PD-1 antibody molecule, an anti-PD-L1 antibody molecule, or both, the subject is optionally in combination with one or more other agents, thereby treating cancer. The malignant tumor may be, for example, a malignant tumor as described herein, such as lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), gastric cancer, thyroid cancer, melanoma , malignant tumor of the nasopharynx or breast cancer, such as TN breast cancer, such as IM-TN breast cancer. In some embodiments, the cancer is ER+ breast cancer or pancreatic cancer.

Also provided is a method for treating cancer, comprising: testing a sample (e.g., a sample containing cancer cells obtained from an individual) for the presence of PDL1, thereby identifying a PD-L1 value, comparing the PD-L1 value with a control value, and if the PD-L1 value is L1 are greater than the control value, then administering a therapeutically effective amount of an anti-LAG-3 antibody (e.g., an anti-LAG-3 antibody described herein) alone or in combination with an anti-PD-1 antibody molecule, an anti-PD-L1 antibody molecule, or both to the individual, optionally in combination with one or more other agents, thus treating the cancer. The cancer may be, for example, a cancer as described herein, thus the cancer is non-small cell adenocarcinoma (ASA) of the lung (NSCLC), NSCLC squamous cell carcinoma (SCC), or hepatocellular carcinoma (HCC).

In another aspect, the invention relates to diagnostic or therapeutic kits that contain the anti-LAG-3 antibody molecules described herein and instructions for use.

All publications, patent applications, patents and other references mentioned in the present description are incorporated by reference in their entirety.

Other features, objects and advantages of the invention will become apparent from the description and drawings and from the claims.

Brief description of the drawings

In FIG. 1 illustrates the amino acid sequences of the variable regions of the light (SEQ ID NO: 16) and heavy (SEQ ID NO: 6) chains of the BAP050 mouse anti-LAG-3 mAb. Light and heavy chain CDR sequences based on Rabat numbering are underlined. Light and heavy chain CDR sequences based on Chothia numbering are in bold italics;

in fig. 2 - amino acid sequences of the variable regions of the light (SEQ ID NO: 16) and heavy (SEQ ID NO: 6) chains of the anti-LAG-3 mouse BAP050 mAb captured with the germline sequences (SEQ ID NO: 290-291, respectively, in order of appearance). ). The upper and lower sequences are the germline (GL) and BAP050 (Mu mAb) sequences, respectively. Light and heavy chain CDR sequences based on Rabat numbering are underlined. Light and heavy chain CDR sequences based on Chothia numbering are in bold italics. - means an identical amino acid residue;

in fig. 3 is a bar graph showing the results of a FACS binding assay for twenty clones of humanized BAP050 (BAP050-hum01 - BAP050-hum20) and chimeric mAb (BAP050-chi). Antibody concentrations are 200, 100, 50, 25, and 12.5 ng/mL from the leftmost bar to the rightmost bar for each mAb tested;

in fig. 4 Structural analysis of humanized BAP049 clones (a, b, c, d, e, f, g are different types of framework sequences). Also presented are the mAb concentrations in the samples;

- 32 040295 in FIG. 5A-5B show the binding affinity and specificity of humanized mAbs measured in a competitive binding assay using a constant concentration of mouse FITC labeled mAb, serial dilutions of test antibodies, and LAG-3 expressing CHO cells. The experiment was carried out twice and the results are shown in FIG. 5A and 5B, respectively;

in fig. 6 - Ranking of humanized BAP050 clones based on FACS data, competitive binding analysis and structural analysis. Also presented are the mAb concentrations in the samples;

in fig. 7 - Binding affinity and specificity of huBAP050(Ser) clones as measured in a competitive binding assay using a constant concentration of mouse FITC-labeled mAb, serial dilutions of test antibodies, and LAG-3 expressing CHO cells. huBAP050(Ser) clones such as BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09Ser, BAP050-hum11-Ser, BAP050-hum12-Ser and BAP050-hum13-Ser were evaluated. Also included in the assays are the mouse mAb BAP050, the chimeric mAb BAP050-chi, and the humanized BAP050-hum01, BAP050-hum02, BAP050hum05, BAP050-hum09, BAP050-hum11, BAP050-hum12, and BAP050-hum13;

in fig. 8 - blocking the binding of LAG-3-Ig to Daudi cells clones huBAP050(Ser). huBAP050(Ser) clones such as BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, and BAP050-hum13- Ser. The assays also included mouse BAP050 mAb and chimeric BAP050-chi mAb;

in fig. 9A-9B are sequence alignments of the heavy chain variable domain for twenty clones of humanized BAP050 and BAP050 chimera (BAP050-chi). In FIG. 9A shows all sequences (SEQ ID NOS: 20, 28, 28, 28, 28, 28, 28, 28, 28, 28, 28, 64, 64, 64, 64, 64, 68, 72, 72, 76 and 80 respectively in order of appearance). In FIG. 9B shows only amino acid sequences that differ from the mouse sequence (SEQ ID NOs: 20, 28, 28, 28, 28, 28, 28, 28, 28, 28, 28, 64, 64, 64, 64, 64, 68, 72, 72, 76 and 80, respectively, in order of appearance);

in fig. 10A-10B are sequence alignments of the light chain variable domain for twenty clones of humanized BAP050 and BAP050 chimera (BAP050-chi). In FIG. 10A shows all sequences (SEQ ID NOS: 24, 32, 36, 36, 36, 292, 292, 292, 44, 48, 52, 56, 56, 60, 60, 60, 60, 84, 88, 92 and 96 respectively in order of appearance). In FIG. 10B shows only amino acid sequences that differ from the mouse sequence (SEQ ID NOs: 24, 32, 36, 36, 36, 292, 292, 292, 44, 48, 52, 56, 56, 60, 60, 60, 60, 84, 88, 92 and 96, respectively, in order of appearance);

in fig. 11 shows exemplary cancers that affect relatively high proportions of patients who are triple positive for PDL1/CD8/IFN-y;

in fig. 12 is an exemplary ER+ breast cancer and pancreatic cancer that affects relatively high proportions of patients who are triple positive for PD-L1/CD8/IFN-y;

in fig. 13 is the proportion of patients with exemplary breast cancer that are triple positive for PD-Ll/CD8/IFN-y;

in fig. 14 is the proportion of patients with exemplary colon cancers that are triple positive for PD-L1/CD8/IFN-y.

Brief description of the tables

Tab. 1 is a summary of the amino acid and nucleotide sequences for mouse anti-LAG-3 antibody molecules, chimeric anti-LAG3 antibody molecules, and humanized anti-LAG3 antibody molecules. Antibody molecules include mouse BAP050 mAbs and chimeric BAP050-chi mAbs, humanized BAP050-hum01 BAP050-hum20, BAP050-hum01-Ser - BAP050-hum15-Ser, BAP050-hum18-Ser BAP050-hum20-Ser and BAP050-Clone-F mAbs - BAP050-Clone-J. This table shows the amino acid and nucleotide sequences of the heavy and light chain CDRs, the amino acid and nucleotide sequences of the heavy and light chain variable regions, and the amino acid and nucleotide sequences of the heavy and light chains.

In table. 2 illustrates the amino acid and nucleotide sequences of heavy and light chain framework regions for the humanized mAbs BAP050-hum01 - BAP049-hum20, BAP050hum01-Ser - BAP050-hum15-Ser, BAP050-hum18-Ser - BAP050-hum20-Ser and BAP049-Clone-F - BAP049Clone-J.

In table. 3 illustrates the amino acid sequences of the constant region for human IgG heavy chains and human κ light chain.

In table. 4 shows the amino acid sequences of the heavy and light chain leader sequences for the humanized mAbs BAP050-Clone-F to BAP050-Clone-J.

Tab. 5 is a summary of yield, titer, monomer content, and endotoxin levels for exemplary humanized BAP050 mAbs expressed in CHO cells.

In table. 6 shows charged isoforms as detected by the Novex IEF assay for exemplary humanized BAP050 mAbs expressed in CHO cells.

Tab. 7 is a summary of selected therapeutic agents that can be administered in combination with anti-LAG-3 antibody molecules and other immunomodulators (eg, one or more of a costimulatory molecule activator and/or an immune checkpoint molecule inhibitor) described in the present description. In table. 7 from left to right is the following: the designation of the compound of the second therapeutic agent, the structure of the compound, and the patent publication(s) in which the compound is described.

Detailed description

The immune system has the ability to recognize and eliminate tumor cells, but tumors can use many strategies to evade the immune system. Blockade of immune checkpoints is one approach to activate or restore therapeutic antitumor immunity. The lymphocyte activation gene 3 (LAG-3) has been described as an inhibitory receptor at the immunological synapse (Chen and Flies, (2013) Nat. Rev. Immunol., 13(4):227-42). Thus, blocking LAG-3 can lead to increased antitumor immunity.

Several cell types express LAG-3. For example, LAG-3 is expressed by activated CD4+ and CD8+ T cells, Treg cells, natural killer (NK) cells, and plasmacytoid dendritic cells (DC). LAG-3 is expressed in tumor infiltrating lymphocytes, such as lymphocytes infiltrating head and neck squamous cell carcinoma (HNSCC). LAG-3 is expressed by highly suppressor induced and natural Treg cells. For example, highly suppressive FoxP3+ nTreg and FoxP3-iTreg are LAG-3 positive in melanoma and colorectal cancer (Camisaschi et al., (2010) J. Immunol., 184(11):6545-6551; Scurr et al., ( 2014) Mucosal Immunol., 7(2):428-439).

LAG-3 negatively regulates signaling and T-cell function. LAG-3 ligands include, for example, MHC class II and L-SECtin. Anti-LSECtin antibody has been shown to inhibit the growth of B16 melanoma cells (Xu et al., (2014) Cancer Res., 74(13):3418-3428). Blockade of LAG3 can restore effector cell activity, reduce Treg suppressor activity, and/or enhance the antitumor activity of an anti-PD-1 antibody.

It is believed that, as a rule, LAG-3 is not only co-expressed by PD-1+ cells, and a single blockade can restore the in vitro activities of the cells. The degree of CD8+ T cell depletion, for example, as demonstrated by percentages of IFN-y/TNF-α dual producers, correlates with the number of inhibitory receptors expressed (Blackburn et al., (2009) Nat. Immunol., 10(1): 29-37). A high level of PD-1/LAG-3 expression correlates with the penetration of T cells into melanoma. Co-blockade of LAG-3 with an anti-PD-1 or PD-L1 antibody may result in tumor suppressor activities in preclinical models. For example, in models of fibrosarcoma Sa1N and colon carcinoma MC38 demonstrate the effectiveness of blockade by anti-LAG-3 antibodies and anti-PD-1 antibodies (Woo et al., (2012) Cancer Res., 72(4):917-27).

Blockade of LAG-3 is also effective in the lymphocytic choriomeningitis virus (LCMV) model. For example, PD-L1 plus LAG-3 blockade during chronic LCMV infection enhances CD8+ T cell antiviral responses (Blackburn et al., (2009) Nat. Immunol., 10(1): 29-37).

Thus, the present invention relates at least in part to antibody molecules (eg, humanized antibody molecules) that bind to the lymphocyte activation gene 3 (LAG-3) with high affinity and specificity. In one embodiment, humanized anti-LAG-3 antibodies are described that are of low immunogenicity. For example, humanized BAP050 antibodies have been found to have a risk score of less than 1200, 1150, 1100, 1050, 1000, 950, 900, 850, or 800 according to the T cell epitope assays described herein. In other embodiments, a selected combination of framework regions, such as those shown in FIG. 4 and 6 is characterized by certain production efficiencies and binding properties.

Additional aspects of the invention include nucleic acid molecules encoding antibody molecules, expression vectors, host cells, and methods for producing antibody molecules. Also provided are immunoconjugates, poly- or bispecific molecules, and pharmaceutical compositions containing antibody molecules. The anti-LAG-3 antibody molecules described herein can be used to treat, prevent, and/or diagnose cancerous or malignant disorders (e.g., cancers such as melanoma, e.g., advanced melanoma; pancreatic cancer, e.g., cancer advanced pancreatic cancer; solid tumors; breast cancer, such as metastatic breast carcinoma; renal cell carcinoma, such as advanced renal cell carcinoma or metastatic renal cell carcinoma (MRCC), or clear cell renal cell carcinoma), and infectious diseases (eg, hepatitis e.g. hepatitis B, influenza). Thus, the present description describes methods for detecting LAG-3, as well as methods for treating various disorders, including cancer and infectious diseases, using anti-LAG-3 antibody molecules alone or in combination.

The term lymphocyte activation gene 3 or LAG-3 includes all mammalian isoforms, e.g., human LAG-3, human LAG-3 homologue species, and analogues containing at least one

- 34 040295 shared epitope with LAG-3. The amino acid and nucleotide sequences of LAG-3, eg human LAG-3, are known in the art, eg Triebel et al., (1990) J. Exp. Med. 171:1393-1405.

Additional terms are defined below and throughout the application.

As used herein, the singular refers to one or more than one (eg, at least one) grammatical entity.

The term or is used herein to refer to and is used interchangeably with the term and/or unless the context clearly dictates otherwise.

Approximately and approximately, as a rule, mean an acceptable degree of error for the quantity being measured, taking into account the nature or accuracy of the measurements. Exemplary error rates are within 20 percent (%), typically within 10%, and more particularly within 5% of a given value or range of values.

The compositions and methods of the present invention include polypeptides and nucleic acids containing predefined sequences or sequences substantially identical or similar to them, for example sequences at least 70%, 75%, 80%, 85%, 90%, 95% identical or greater than the predefined sequence. With regard to amino acid sequence, the term substantially identical is used herein to refer to the first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical or ii) conservative substitutions of aligned amino acid residues in the second amino acid sequence, such that the first and the second amino acid sequences may share a common structural domain and/or a common functional activity. For example, amino acid sequences that contain a common structural domain that shares at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, such as the sequence provided herein. description.

With respect to a nucleotide sequence, the term substantially identical is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide, having a common functional activity, or encode a common structural domain of a peptide polypeptide or a common functional activity of a polypeptide. For example, nucleotide sequences that have at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, such as the sequence provided herein.

The term functional variant refers to polypeptides that contain a substantially identical amino acid sequence with the natural sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more of the activities of the natural sequence.

Calculations of homology or sequence identity between sequences (terms used interchangeably herein) are performed as follows.

To determine the percent identity of two amino acid sequences or two nucleic acid sequences, sequences are aligned for optimal comparison (e.g., gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes ). In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70, 80, 90, 100% of the length of the reference sequence. The amino acid residues or nucleotides at the respective amino acid positions or nucleotide positions are then compared. When a position in the first sequence occupies the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical in position (as used herein, amino acid or nucleic acid identity is equivalent to amino acid or nucleic acid homology).

The percent identity of two sequences depends on the number of identical positions common to the sequences, taking into account the number of gaps and the length of each gap that must be entered to optimally align the two sequences.

Comparing sequences and determining the percent identity of two sequences can be done using a mathematical algorithm. In a preferred embodiment, the percent identity of two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J. Mol. Biol., 48:444-453), which is built into the GAP program in the GCG software package (available at http:/ /www.gcg.com), using a Blossum 62 matrix or a PAM250 matrix and a gap penalty of 16, 14, 12, 10, 8, 6, or 4 and a gap penalty of

- 35 040295 extension of gap 1, 2, 3, 4, 5 or 6. In yet another preferred embodiment, the percent identity of two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg. com) using the NWSgapdna.CMP matrix and a gap penalty of 40, 50, 60, 70, or 80 and a gap extension penalty of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the set that should be used is unless otherwise noted) is a Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

The percent identity of two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), which is built into the ALIGN program (version 2.0), using a weight table of PAM120 residue substitutions, gap extension penalty 12 and gap penalty 4.

The nucleic acid sequences and protein sequences described herein can be used as a query sequence for searching public databases, for example, to identify other members of the family or related sequences. Such searches can be carried out using the programs NBLAST and XBLAST (version 2.0) Altschul et al., (1990) J. Mol. Biol., 215:403-10. BLAST nucleotide searches can be performed using the NBLAST program, score=100, wordlength=12, to obtain nucleotide sequences homologous to the nucleic acid molecules (SEQ ID NO: 1) of the invention. BLAST protein searches can be performed using the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules of the invention. Gapped BLAST can be used to generate gapped alignments for comparison purposes as described in Altschul et al., (1997) Nucleic Acids Res., 25:3389-3402. When using the BLAST and Gapped BLAST programs, you can use the default settings of the respective programs (for example, XBLAST and NBLAST). See http://www.ncbi.nlm.nih.gov.

As used herein, the term hybridize under low stringency, medium stringency, high stringency, or very high stringency conditions describes the conditions for hybridization and washing. Guidelines for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley and Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and non-aqueous methods are described in this link and either can be used. Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6x sodium chloride/sodium citrate (SSC) at approximately 45°C followed by two washes in 0.2xSSC, 0 .1% SDS at at least 50°C (washing temperature can be increased up to 55°C for low stringency conditions); 2) medium stringency hybridization conditions in 6x SSC at approximately 45°C followed by one or more washes in 0.2xSSC, 0.1% SDS at 60°C; 3) High stringency hybridization conditions in 6xSSC at approximately 45°C followed by one or more washes in 0.2xSSC, 0.1% SDS at 65°C, and preferably 4) Very stringent hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65°C followed by one or more washes at 0.2xSSC, 1% SDS at 65°C. Very high stringency conditions (4) are the preferred conditions and conditions to be used unless otherwise indicated.

It should be understood that the molecules of the present invention may contain additional conservative or non-basic amino acid substitutions that do not significantly affect their function.

The term amino acid is intended to include all molecules, whether natural or synthetic, that contain an amino functional group and an acid functional group and are capable of being incorporated into a natural amino acid polymer. Illustrative amino acids include naturally occurring amino acids, analogs, derivatives and related compounds; amino acid analogs containing various side chains; and all stereoisomers of any of the above. As used herein, the term amino acid includes D- or L-optical isomers and peptidomimetics.

A conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue containing the same side chain. Families of amino acid residues containing similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (eg, threonine, valine, isoleucine), and aromatic side chains (eg, tyrosine, phenylalanine , tryptophan, histidine).

In the present description, the terms polypeptide, peptide and protein (if single chain) are used

- 36 040295 are used interchangeably to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids. The terms also include an amino acid polymer that has been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation such as conjugation with a labeling moiety. The polypeptide can be isolated from natural sources, can be obtained by recombinant methods from a eukaryotic or prokaryotic host, or it can be the product of synthetic methods.

The terms nucleic acid, nucleic acid sequence, nucleotide sequence or polynucleotide sequence and polynucleotide are used interchangeably. They refer to the polymeric form of nucleotides of any length, deoxyribonucleotides or ribonucleotides or their analogues. The polynucleotide may be single stranded or double stranded, and in the case of single stranded, may be a coding strand or a non-coding (antisense) strand. The polynucleotide may contain modified nucleotides, such as methylated nucleotides, and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. The polynucleotide can be further modified after polymerization, such as by conjugation with a labeling moiety. The nucleic acid may be a recombinant polynucleotide or a polynucleotide of genomic DNA, cDNA, semi-synthetic or synthetic origin, which does not occur in nature, or is linked to another polynucleotide in an unnatural arrangement.

As used herein, the term isolated refers to a substance that is removed from its original or natural environment (eg, natural environment if it is natural). For example, a natural polynucleotide or polypeptide contained in a living animal is not isolated, but a particular polynucleotide or polypeptide separated by human intervention from some or all of the coexisting substances in the natural system is isolated. Such polynucleotides may be part of a vector, and/or such polynucleotides or polypeptides may be part of compositions and at the same time be isolated, t. such a vector or composition is not part of the environment in which it occurs naturally.

Various aspects of the invention are described in more detail below. Additional definitions are indicated throughout the description.

Antibody molecules.

In one embodiment, the antibody molecule binds to LAG-3 of a mammal, such as a human. For example, an antibody molecule specifically binds to an epitope, eg a linear or conformational epitope (eg an epitope as described herein) on LAG-3. In some embodiments, the antibody molecule binds to one or more extracellular Ig-like domains of LAG-3, such as the first, second, third, or fourth extracellular Ig-like domain of LAG-3.

As used herein, the term antibody molecule refers to a protein, such as an immunoglobin chain or fragment thereof, containing at least one immunoglobulin variable domain sequence. The term antibody molecule includes, for example, a monoclonal antibody (including a full-length antibody that contains the Fc region of an immunoglobulin). In one embodiment, the antibody molecule comprises a full length antibody or a full length immunoglobin chain. In one embodiment, the antibody molecule comprises an antigen-binding or functional fragment of a full length antibody or a full length immunoglobulin chain.

In one embodiment, the antibody molecule is a monospecific antibody molecule and binds to a single epitope. For example, a monospecific antibody molecule containing a plurality of immunoglobulin variable domain sequences, each of which binds to the same epitope.

In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g., it comprises a constellation of immunoglobulin variable domain sequences, wherein the first immunoglobulin variable domain sequence of the constellation has binding specificity for a first epitope and the second immunoglobulin variable domain sequence of the population has binding specificity for a second epitope. . In one embodiment, the first and second epitopes are on the same antigen, eg, on the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, such as different proteins (or different subunits of a multimeric protein). In one embodiment, the multispecific antibody molecule contains a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule,

- 37 040295 a trispecific antibody molecule or a tetraspecific antibody molecule.

In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence that has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In one embodiment, the first and second epitopes are on the same antigen, such as the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, such as different proteins (or different subunits of a multimeric protein). In one embodiment, the bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity for a first epitope, and a heavy chain variable domain sequence and a light chain variable domain sequence that have binding specificity for a second epitope. In one embodiment, the bispecific antibody molecule comprises a semi-antibody having binding specificity for a first epitope and a semi-antibody having binding specificity for a second epitope. In one embodiment, the bispecific antibody molecule comprises a semi-antibody or fragment thereof having binding specificity for a first epitope and a semi-antibody or fragment thereof having binding specificity for a second epitope. In one embodiment, the bispecific antibody molecule comprises an scFv or fragment thereof having binding specificity for a first epitope and an scFv or fragment thereof having binding specificity for a second epitope. In one embodiment, the first epitope is localized to LAG-3 and the second epitope is localized to PD-1, TIM-3, CEACAM (eg, CEACAM-1 and/or CEACAM-5), PD-L1, or PD-L2.

In one embodiment, the antibody molecule comprises a diabody and a single chain molecule, as well as an antigen-binding antibody fragment (eg, Fab, F(ab') ₂ and Fv). For example, an antibody molecule may comprise a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light chain (L) variable domain sequence (abbreviated herein as VL). In one embodiment, the antibody molecule contains or consists of a heavy chain and a light chain (referred to herein as a semi-antibody. In another example, the antibody molecule contains the variable domain sequences of two heavy (H) chains and the variable domain sequence of two light (L) chains , thus forming two antigen-binding sites such as Fab, Fab', F(ab') ₂ , Fc, Fd, Fd', Fv, single chain antibodies (eg scFv), single variable domain antibodies, diabodies (Dab) ( bivalent and bispecific) and chimeric (e.g., humanized) antibodies, which can be obtained by modifying whole antibodies or antibodies synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind to their respective antigen or receptor. Antibodies and antibody fragments may be derived from any class of antibodies, including but not limited to IgG, IgA, I gM, IgD, and IgE, and from any subclass (eg, IgG1, IgG2, IgG3, and IgG4) of antibodies. The antibody molecule preparation may be monoclonal or polyclonal. The antibody molecule can also be a human antibody, a humanized antibody, a CDR-grafted antibody, or an in vitro-produced antibody. The antibody may comprise a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, or IgG4. The antibody may also contain a light chain selected from, for example, k- or λ-chain. In the present description, the term immunoglobulin (Ig) is used interchangeably with the term antibody.

Examples of antigen-binding fragments of an antibody molecule include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab') ₂ fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of one antibody arm, (v) a diabody fragment (dAb) which consists of a VH domain; (vi) a camelid antibody variable domain or camelized variable domain; (vii) single chain Fv (scFv), see, for example, Bird et al., (1988) Science, 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. sci. USA 85:58795883); (viii) single domain antibody. These antibody fragments are prepared by conventional methods known to those skilled in the art, and the fragments are screened for suitability in the same manner as intact antibodies.

The term antibody includes intact molecules as well as their functional fragments. The constant regions of antibodies can be altered, eg, mutated, modified properties of the antibody, (eg, increased or decreased one or more of: Fc receptor binding, antibody glycosylation, cysteine residue number, cellular effector function, or complement function).

- 38 040295

The antibodies of the present invention may also be single domain antibodies. Single domain antibodies may include antibodies whose complementarity determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies that naturally lack light chains, single domain antibodies derived from conventional 4 chain antibodies, engineered antibodies, and single domain frameworks other than those derived from antibodies. . Single domain antibodies can be any single domain antibodies of the state of the art or any single domain antibodies in the future. Single domain antibodies can be obtained from any species, including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and cattle. According to another aspect of the invention, the single domain antibody is a naturally occurring single domain antibody, known as a heavy chain antibody, containing no light chains. Such single domain antibodies are described, for example, in WO 94/04678. For clarity, such a variable domain derived from a heavy chain antibody naturally lacking a light chain is referred to herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins. Such a VHH molecule can be obtained from antibodies induced in Camelidae species such as camel, llama, dromedary, alpaca and guanaco. Other species along with the Camelidae can produce heavy chain antibodies that do not naturally contain a light chain; such VHHs are within the scope of the invention.

The VH and VL regions can be subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with regions that are more conserved called framework regions (FRs or FWs). The extent of the framework region and CDR has been accurately determined by a number of methods (see Rabat E.A. et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia C. et al., (1987) J. Mol. Biol., 196:901-917, and the AbM definition used in Oxford Molecular AbM antibody modeling software Generally see, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains, in: Antibody Engineering Lab Manual (Ed.: Duebel S. and Kontermann R., Springer-Verlag, Heidelberg).

As used herein, the terms complementarity determining region and CDR refer to amino acid sequences in the variable regions of an antibody that confer antigen specificity and binding affinity. Basically, there are three CDRs in each heavy chain variable region (HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, LCDR3).

The precise boundaries of the amino acid sequence of a given CDR can be determined using a number of well known schemes, including those described by Rabat et al., (1991), Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (Rabat numbering system), Al-Lazikani et al., (1997) JMB 273, 927-948 (Chothia numbering system). As used herein, CDRs defined by the Chothia numbering scheme are also sometimes referred to as hypervariable loops.

For example, according to Rabat, CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3), and CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Chothia, CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2) and 95-102 (HCDR3), and amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2) and 91- 96 (LCDR3). As a result of combining Rabat and Chothia CDR definitions, CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) in the human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.

Generally, unless specifically indicated, anti-LAG-3 antibody molecules may contain any combination of one or more Rabat CDRs and/or Chothia hypervariable loops, such as those described in Table 1. 1. In one embodiment, the following definitions are used for the anti-LAG-3 antibody molecule described in Table 1. 1: HCDR1 according to the combined Rabat and Chothia CDR definitions and HCCDR 2-3 and LCCDR 1-3 according to the Rabat CDR definition. By all definitions, each VH and VL typically contains three CDRs and four FRs, arranged from N-terminus to C-terminus in the following order: FR1, CDR1, FR2, CDr2, FR3, CDR3, FR4.

As used herein, an immunoglobulin variable domain sequence refers to an amino acid sequence that can form an immunoglobulin variable domain structure. For example, the sequence may contain all or part of the amino acid sequence of a naturally occurring variable domain. For example, the sequence may or may not contain one, two or more N- or C-terminal amino acids, or may contain other changes that are compatible with the formation of the protein structure.

The term antigen-binding site refers to the portion of an antibody molecule that contains determinants that form a surface that binds to a LAG-3 polypeptide or epitope thereof. For proteins (or protein mimetics), the antigen binding site typically contains one or more loops (at least four amino acids or amino acid mimetics) that form a surface that binds to the LAG-3 polypeptide. Typically, the antigen-binding site of an antibody molecule contains at least one or two CDRs and/or hypervariable loops or more, specifically at least three, four, five or six CDRs and/or hypervariable loops.

As used herein, the terms compete or cross-compete are used interchangeably to refer to the ability of an antibody molecule to prevent an anti-LAG-3 antibody molecule, such as the anti-LAG-3 antibody molecule provided herein, from binding to a target, such as human LAG-3. Interfering with binding can be direct or indirect (eg, through allosteric modulation of the antibody or target molecule). The extent to which an antibody molecule is able to prevent another antibody molecule from binding to a target, and thus whether it can be said to compete, can be determined using a competitive binding assay, such as a FACS assay, ELISA assay, or BIACORE. In some embodiments, the implementation of the analysis of competitive binding is a quantitative analysis of competitive binding. In some embodiments, the first anti-LAG-3 antibody molecule is considered to compete for target binding with the second anti-LAG-3 antibody molecule when the binding of the first anti-LAG-3 antibody molecule to the target is reduced by 10% or more, e.g., by 20% or more, 30% or more 40% or more 50% or more 55% or more 60% or more 65% or more 70% or more 75% or more 80% % or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competitive binding assay (eg, a competitive assay described herein).

As used herein, the term epitope refers to a region of an antigen (eg, human LAG-3) that specifically interacts with an antibody molecule. Such regions, referred to herein as epitope determinants, typically contain or are part of elements such as amino acid side chains or sugar side chains. The epitope determinant can be determined by methods known in the art or described herein, for example, by crystallography or by hydrogen-deuterium exchange. At least one or more regions on an antibody molecule that interact specifically with an epitope determinant are typically located in the CDR. Typically, an epitope has specific three-dimensional structural characteristics. Typically, an epitope has specific charge characteristics. Some epitopes are linear epitopes while others are conformational epitopes.

As used herein, the terms monoclonal antibody or monoclonal antibody composition refer to a preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition has a single binding specificity and affinity for a particular epitope. The monoclonal antibody can be produced by hybridoma technology or by methods that do not use hybridoma technology (eg, recombinant methods).

A substantially human protein is a protein that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMA can create difficulties in a number of circumstances, for example, if the antibody molecule is administered intermittently, such as in the treatment of a chronic or relapsing disease state. A HAMA response can make intermittent administration of the antibody potentially ineffective due to increased serum clearance of the antibody (see, for example, Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)), as well as due to possible allergic reactions (see ., for example, LoBuglio et al., Hybridoma, 5:5117-5123 (1986)).

The antibody molecule may be a polyclonal or monoclonal antibody. In other embodiments, the implementation of the antibody can be obtained recombinantly, for example, obtained through phage display or combinatorial methods.

Phage display and combinatorial methods for producing antibodies are known in the art (as described, for example, in Ladner et al. US Pat. No. 5,223,409; Kang et al. International Publication No. WO 92/18 619; Dower et al. International Publication No. WO 91/ 17271 Winter et al International Publication No WO 92/20791 Markland et al International Publication No WO 92/15679 Breitling et al International Publication No WO 93/01288 McCafferty et al International Publication No WO 92/01047 Garrard et al, International Publication No. WO 92/09690, Ladner et al, International Publication No. WO 90/02809, Fuchs et al., (1991) Bio/Technology, 9:1370-1372, Hay et al., (1992) Hum. Antibod Hybridomas 3:81-85 Huse et al. (1989) Science 246:1275-1281 Griffths et al. ) J. Mol. Biol., 226:889-896; Clackson et al., (1991) Nature, 352:624-628; Gram et al., (1992) PNAS, 89:3576-3580; Garrad et al. , (1991) Bio/Technology, 9:1373-1377 Hoogenboom et al., (1991) Nuc. Acid. Re s., 19:4133-4137 and Barbas et al., (1991) PNAS, 88:7978-7982, the contents of which are incorporated herein by reference).

In one embodiment, the antibody is a fully human antibody (e.g., an antibody derived from a mouse that has been genetically modified to produce an anti-body sequence from a human immunoglobulin) or a non-human antibody, such as a rodent (mouse or rat) antibody. , goat, primate (e.g. monkey), camel. Preferably, the non-human antibody is a rodent (mouse or rat). Methods for producing rodent antibodies are known in the art.

Human monoclonal antibodies can be generated using transgenic mice carrying human immunoglobulin genes rather than the mouse system. Splenocytes from such transgenic mice immunized with an antigen of interest are used to generate a hybridoma that secretes a human mAb with specific affinities for epitopes from a human protein (see, for example, Wood et al. WO 91/00906, Kucherlapati et al. publication PCT WO 91/10741 Lonberg et al International application WO 92/03918 Kay et al International application 92/03917 Lonberg N. et al., 1994 Nature, 368:856-859 Green L. L. et al. Nature Genet., 7:13-21; Morrison S. L. et al., 1994 Proc. Natl. Acad. Sci. USA, 81:6851-6855; Bruggeman et al., 1993 Year. Immunol., 7:33-40; Tuaillon et al., 1993 PNAS, 90:3720-3724; Bruggeman et al., 1991 Eur. J. Immunol., 21:1323-1326).

The antibody may be an antibody in which the variable region or portion thereof, such as a CDR, is derived from a non-human organism, such as a rat or mouse. The invention includes chimeric, CDR-grafted and humanized antibodies. The invention includes antibodies derived from a non-human organism, such as a rat or mouse, and then modified, such as in a variable framework region or constant region, to reduce antigenicity in humans.

Chimeric antibodies can be produced by recombinant DNA technologies known in the art (see Robinson et al. International Patent Publication PCT/US86/02269; Akira et al. European Patent Application 184187; Taniguchi M., European Patent Application 171496; Morrison et al. EP 173494 Neuberger et al WO 86/01533 Cabilly et al US Patent No. 4816567 Cabilly et al EP 125023 Better et al (1988 Science, 240:1041-1043) Liu et al. (1987) PNAS 84:3439-3443 Liu et al. 1987 J. Immunol. 139:3521-3526 Sun et al. (1987) PNAS 84:214-218 Nishimura et al., 1987, Cane Res., 47:999-1005, Wood et al., (1985) Nature, 314:446-449, and Shaw et al., 1988, J. Natl Cancer Inst., 80: 1553-1559).

A humanized or CDR-grafted antibody contains at least one or two, but typically all three, of the recipient's (Ig heavy and/or light chain) CDRs that have replaced the donor's CDR. In an antibody, at least a portion of a non-human CDR may be replaced, or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to change the number of CDRs needed to bind the humanized antibody to LAG-3. Preferably, the donor is a rodent antibody, such as a rat or mouse antibody, and the recipient is a human scaffold or a human consensus scaffold. Typically, an immunoglobulin providing a CDR is referred to as a donor, and an immunoglobulin providing a scaffold is referred to as an acceptor. In one embodiment, the donor immunoglobulin is non-human (eg, rodent). The acceptor framework is a native framework (eg, human) or a consensus framework or a sequence approximately 85% or more, preferably 90%, 95%, 99% or more identical to it.

As used herein, the term consensus sequence refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see, for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family proteins, each position in the consensus sequence is occupied by the amino acid that occurs most frequently in the position in the family.If two amino acids occur with equal frequency, either can be in the consensus sequence.The consensus framework refers to the framework region in the consensus sequence of an immunoglobulin.

The antibody can be humanized by methods known in the art (see, for example, Morrison S. L., 1985, Science, 229:1202-1207, by Oi et al., 1986, BioTechniques, 4:214, and by Queen et al. US 5585089, US 5693761 and US 5693762, the contents of which are thus incorporated by reference).

Humanized or CDR-grafted antibodies can be produced by CDR grafting or CDR replacement, where one, two or all of the CDRs of an immunoglobulin chain can be replaced. See, for example, US Pat. No. 5,225,539; Jones et al., 1986 Nature, 321:552-525; Verhoeyan et al., 1988 Science 239:1534; Beidler et al., 1988 J. Immunol., 141:4053-4060; Winter US 5225539, the contents of which are expressly incorporated into the present description by reference. Winter describes a CDR grafting method that can be used to produce humanized antibodies of the present invention (UK GB 2188638 A filed March 26, 1987; Winter US 5225539), the contents of which are expressly incorporated by reference.

Also within the scope of the invention are humanized antibodies in which specific amino acids have been substituted, removed, or added. The criteria for selecting amino acids from a donor are described in US 5585089, for example columns 12-16 of US 5585089, for example columns 12-16 of US 5585089, the content of which is thus incorporated by reference. Other methods for humanizing antibodies are described in Padlan et al. EP

- 41 040295

519596 Al, published December 23, 1992.

The antibody molecule may be a single chain antibody. Single chain antibody (scFV) can be engineered (see, for example, Colcher D. et al., (1999) Ann. NY Acad. Sci., 880:263-80; and Reiter Y. (1996) Clin. Cancer. Res. 2:245-52). Single chain antibodies can be dimerized or multimerized to produce polyvalent antibodies having specificities for different epitopes of the same target protein.

In other embodiments, the antibody molecule comprises a heavy chain constant region selected, for example, from IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE heavy chain constant regions; in particular selected, for example, from the constant regions of the heavy chain (eg human) IgG1, IgG2, IgG3 and IgG4. In another embodiment, the antibody molecule comprises a light chain constant region selected, for example, from light chain (eg, human) κ-chain or λ-chain constant regions. The constant region can be altered, eg, mutated, modified properties of the antibody (eg, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, cysteine residue count, cellular effector function, and/or complement function). In one embodiment, the antibody has an effector function and can fix complement. In other embodiments, the antibody does not recruit effector cells or fix complement. In another embodiment, the antibody has reduced or no ability to bind to the Fc receptor. For example, it is an isotype or subtype, fragment, or other mutant that does not support binding to an Fc receptor, for example, it contains a mutated Fc receptor-binding region, or such a region has been deleted.

Methods for changing the constant region of an antibody are known in the art. Antibodies with altered function, such as altered affinity for an effector ligand, such as an FcR on a cell or component C1 of complement, can be generated by substituting at least one amino acid residue in the constant region of an antibody with another residue (see, for example, EP 388151 A1, US Pat. No. 5624821 and US patent No. 5648260, the contents of which are thus incorporated by reference). A similar type of change can be described which, when applied to an immunoglobulin of a mouse or other species, reduces or abolishes these functions.

An antibody molecule can be derivatized or linked to another functional molecule (eg, another peptide or protein). As used herein, a derivatized antibody molecule is one that has been modified. Derivatization methods include, but are not limited to, the addition of a fluorescent moiety, a radionucleotide, a toxin, an enzyme, or an affinity ligand such as biotin. Thus, the antibody molecules of the invention are intended to include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule can be operably linked (via chemical linkage, genetic fusion, non-covalent linkage, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent. and/or a protein or peptide that can mediate the binding of an antibody or antibody region to another molecule (such as a streptavidin core region or a polyhistidine tag).

One type of derivatized antibody molecule is obtained by cross-linking two or more antibodies (of the same type or different types, for example, to obtain bispecific antibodies). Suitable crosslinkers include crosslinkers that are heterobifunctional, containing two distinct reactive groups separated by a suitable spacer (eg, meta-maleimidobenzoyl-N-hydroxysuccinimido ester), or homobifunctional (eg, disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, 111.

Suitable detectable agents with which an antibody molecule of the invention can be derivatized (or labeled) include fluorescent compounds, various enzymes, prosthetic groups, luminescent substances, bioluminescent substances, fluorescent emitting metal atoms such as europium (Eu) and other lanthanides, and radioactive substances (described below). Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl chloride, phycoerythrin, and the like. The antibody can also be derivatized with detectable enzymes such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, and the like. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to form a detectable reaction product. For example, when horseradish peroxidase detectable is contained, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that is detectable. The antibody molecule can also be derivatized with a prosthetic group (e.g. streptavidin/biotin and avidi

- 42 040295 nom/biotin).

For example, an antibody can be derivatized with biotin and detected by indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent substances include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin, an example of a luminescent substance includes luminol, and examples of bioluminescent substances include luciferase, luciferin and aequorin.

A labeled antibody molecule can be used, for example, diagnostically and/or experimentally in a number of situations, including (i) to isolate a specific antigen by standard methods such as affinity chromatography or immunoprecipitation; (ii) to detect a specific antigen (eg, in a cell lysate or cell supernatant) to assess the relative magnitude and pattern of protein expression; (iii) to monitor tissue protein levels as part of a clinical testing procedure, eg to determine the efficacy of a given treatment regimen.

Antibody molecules can be conjugated to another molecular entity, typically a label or therapeutic (eg, cytotoxic or cytostatic) agent or moiety. Radioactive isotopes can be used for diagnostic or therapeutic applications. Radioactive isotopes that can be bound to anti-PSMA antibodies include, but are not limited to, α-, β- or γ-emitters or β- and γ-emitters. Such radioactive isotopes include, but are not limited to, iodine ( ¹³¹ I or ¹²⁵ I), yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ As), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re) , bismuth ( ²¹² Bi or ²¹³ Bi), indium ( ^1P 1p), technetium ( ⁹⁹ mTc), phosphorus ( ³² R), rhodium ( ¹⁸⁸ Rh), sulfur ( ³⁵ S), carbon ( ¹⁴ C), tritium ( ³ H ), chromium ( ⁵¹ Cr), chlorine ( ³⁶ Cl), cobalt ( ⁵⁷ Co or ⁵⁸ Co), iron ( ⁵⁹ Fe), selenium ( ⁷⁵ Se) or gallium ( ⁶⁷ Ga). Radioactive isotopes useful as therapeutic agents include yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ As), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re), bismuth ( ²¹² Bi or ²¹³ Bi) and rhodium ( ¹⁸⁸ Rh). Radioactive isotopes useful as labels, for example for diagnostic applications, include iodine ( ¹³¹ I or ¹²⁵ I), indium ( ¹¹¹ In), technetium ( ⁹⁹ mTc), phosphorus ( ³² P), carbon ( ¹⁴ C) and tritium ( ³ H) or one or more of the therapeutic isotopes listed above.

The invention relates to radioactively labeled antibody molecules and methods for labeling them. In one embodiment, a method for labeling an antibody molecule is described. The method includes bringing the antibody molecule into contact with a chelating agent, thereby obtaining a conjugated antibody. The conjugated antibody is radioactively labeled with a radioactive isotope such as ¹¹¹ indium, ⁹⁰ yttrium, and ¹⁷⁷ lutetium, thereby producing a labeled antibody molecule.

As discussed above, an antibody molecule can be conjugated to a therapeutic agent. Therapeutically active radioactive isotopes have already been mentioned. Examples of other therapeutic agents include taxol, cytochalasin B, gramicidin D, ethidium bromistium, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracenedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine , tetracaine, lidocaine, propranolol, puromycin, maytansinoids, for example, maytansinol (see US patent No. 5208020), CC-1065 (see US patents No. 5475092, 5585499, 5846545) and their analogues or homologues. Therapeutic agents include, but are not limited to, antimetabolites (eg, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracildecarbazine), alkylating agents (eg, mechlorethamine, thioprea chlorambucil, CC-1065, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannite, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum(II) (DDP) cisplatin), anthracyclines (eg, daunorubicin (formerly known as daunomycin) and doxorubicin), antibiotics (eg, dactinomycin (formerly known as actinomycin), bleomycin, mithramycin, and anthramycin (AMC)) and antimitotic agents (eg, vincristine, vinblastine, taxol, and maytansinoids).

In one aspect, the invention relates to a method of providing a target-binding molecule that specifically binds to the LAG-3 receptor. For example, the target-binding molecule is an antibody molecule. The method includes: providing a target protein that contains at least a region of a non-human protein, where the region is homologous (at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96, 97, 98% identical) to the corresponding region of the human target protein, but differs in at least one amino acid (eg, at least one, two, three, four, five, six, seven, eight, or nine amino acids); obtaining an antibody molecule that specifically binds to the antigen; and evaluating the effectiveness of the binding agent to modulate the activity of the target protein. The method may further comprise administering a binding agent (eg, an antibody molecule) or derivative (eg, a humanized antibody molecule) to a human subject.

The present invention relates to an isolated nucleic acid molecule encoding the above antibody molecule, vectors and their host cells. A nucleic acid molecule includes, but is not limited to, RNA, genomic DNA, and cDNA.

In certain embodiments, the antibody molecule is a polyspecific (eg, bispecific or trispecific) antibody molecule. Protocols for the production of bispecific or heterodimeric antibody molecules are known in the art, including, but not limited to, for example, the ridge-in-the-trough approach described, for example, in US 5,731,168; Fc pairing mediated by electrostatic interaction as described, for example, in WO 09/089004, WO 06/106905 and WO 2010/129304; formation of heterodimers by standard exchange engineered domain (SEED) technology, as described, for example, in WO 07/110205; Fab arm replacement as described, for example, in WO 08/119353, WO 2011/131746 and WO 2013/060867; a dual antibody conjugate, eg by cross-linking an antibody to form a bispecific structure using a heterobifunctional reagent containing a reactive amino group and a reactive sulfhydryl group, as described, eg, in US 4,433,059; bispecific antibody determinants obtained by recombination of semi-antibodies (heavy-light chain pairs or Fab) from different antibodies through a cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described, for example, in US 4444878; trifunctional antibodies, eg three Fab' fragments, cross-linked via reactive sulfhydryl groups, as described, for example, in US 5273743; biosynthetic binding proteins, eg a pair of scFvs cross-linked via C-terminal tails, preferably by chemical cross-linking via reactive disulfide or amino groups, as described, for example, in US 5,534,254; bifunctional antibodies, eg Fab fragments with different binding specificities, dimerized through leucine zippers (eg c-fos and c-jun), which contain a replaced constant domain, as described, for example, in US 5582996; bispecific and oligospecific mono- and oligovalent receptors, e.g., the VH-CH1 regions of two antibodies (two Fab fragments) linked via a polypeptide spacer between the CH1 region of one antibody and the VH region of another antibody, typically with linked light chains, as described, for example, in US 5591828; bispecific DNA-antibody conjugates, eg, cross-linking of antibodies or Fab fragments through a double-stranded portion of the DNA, as described, for example, in US 5,635,602; bispecific fusion proteins, eg, an expression construct containing two scFvs with a hydrophilic helical peptide linker between it and the complete constant region, as described, for example, in US 5,637,481; polyvalent and polyspecific binding proteins, for example, a dimer of polypeptides containing a first domain with an Ig heavy chain variable region binding region and a second domain with an Ig light chain variable region binding region, generally referred to as diabodies (higher order structures also include making bispecific, trispecific, or tetraspecific molecules as described, for example, in US 5837242; mini-antibody constructs with linked VL and VH chains further connected to peptide hinge and CH3 antibody spencers that can be dimerized to give bispecific/multivalent molecules, as described, for example, in US 5,837,821; VH and VL domains linked to a short peptide linker (e.g., 5 or 10 amino acids) or no linker in any orientation, which can form dimers to form bispecific diabodies; trimers and tetramers as described, for example, in US 5,844,094; thread VH domains (or VL domains in members of the family) connected by peptide bonds with cross-linked groups at the C-terminus, additionally linked to VL domains to form a series of FV (or scFv), as described, for example, in US 5864019, and single-chain binding polypeptides with VH and VL domain linked through a peptide linker, are combined into polyvalent structures by non-covalent or chemical cross-linking to form, for example, homobivalent, heterobivalent, trivalent and tetravalent structures using scFV or diabody type format as described in, for example, US 5,869,620. Additional illustrative polyspecific and bispecific molecules and methods for their preparation can be found, for example, in US 5910573, US 5932448, US 5959083, US 5989830, US 6005079, US 6239259, US 6294353, US 6333396, US 6476198, US 6511663, US 6670453, US 67438 6833441, US 7129330, US 7183076, US 7521056, US

7527787, US 7534866, US 7612181, US

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2009263392А1, US 2009274649А1, ЕР346087А2, WO 0006605A2, WO 02072635А2, WO 04081051A1, WO 06020258A2, WO 2007044887A2, WO 2007095338A2, WO 2007137760А2, WO 2008119353A1, WO 2009021754A2, WO 2009068630А1, WO 9103493A1, WO 9323537A1, WO 9409131A1, WO 9412625A2, WO 9509917A1, WO 9637621A2, WO 9964460A1. The contents of the above referenced applications are incorporated herein by reference in their entirety.

In other embodiments, an anti-LAG-3 antibody molecule (e.g., a monospecific, bispecific, or polyspecific antibody molecule) is covalently linked, such as fused to another partner, such as a protein, such as one, two, or more cytokines,

- 44 040295 eg as a fusion molecule, eg a fusion protein. In other embodiments, the implementation of the fusion molecule contains one or more proteins, such as one, two or more cytokines. In one embodiment, the cytokine is an interleukin (IL) selected from one, two, three or more IL-1, IL-2, IL-12, IL-15, or IL-21. In one embodiment, the bispecific antibody molecule has a first binding specificity for a first target (e.g., LAG-3), a second binding specificity for a second target (e.g., PD-1, TIM-3, or PD-L1), and is optionally associated with an interleukin domain (eg, IL-12), eg, full length IL-12 or a portion thereof.

A fusion protein and a fusion polypeptide refer to a polypeptide containing at least two regions covalently linked to each other, where each of the regions is a polypeptide having a different property. The property may be a biological property such as in vitro or in vivo activity. The property can also be a simple chemical or physical property such as binding to a target molecule, catalyzing a reaction, etc. The two regions may be linked directly by a single peptide bond or via a peptide linker, but are in reading frame with each other.

The present invention relates to an isolated nucleic acid molecule encoding the above antibody molecules, vectors and their host cells. A nucleic acid molecule includes, but is not limited to, RNA, genomic DNA, and cDNA.

Illustrative anti-LAG-3 antibody molecules.

In certain embodiments, an anti-LAG-3 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 286; the amino acid sequence of VHCDR2 SEQ ID NO: 2 and the amino acid sequence of VHCDR3 SEQ ID NO: 3, and (ii) a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 10, the amino acid sequence of VLCDR2 SEQ ID NO: 11 and the amino acid sequence VLCDR3 SEQ ID NO: 12.

In other embodiments, the anti-LAG-3 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 286; the amino acid sequence of VHCDR2 SEQ ID NO: 5 and the amino acid sequence of VHCDR3 SEQ ID NO: 3, and (ii) a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 13, the amino acid sequence of VLCDR2 SEQ ID NO: 14 and the amino acid sequence VLCDR3 SEQ ID NO: 15.

In embodiments of the above antibody molecules, VHCDR1 contains the amino acid sequence of SEQ ID NO: 1. In other embodiments, VHCDR1 contains the amino acid sequence of SEQ ID NO: 4. In other embodiments, VHCDR1 contains the amino acid sequence of SEQ ID NO: 286.

In embodiments, the above antibody molecules comprise a heavy chain variable region comprising at least one framework (FW) region comprising the amino acid sequence of any of SEQ ID NOs: 187, 190, 194, 196, 198, 202, 206, 208, 210 , 212, 217, 219 or 221 or an amino acid sequence at least 90% identical to it, or containing no more than two substitutions, insertions or deletions of amino acids compared to the amino acid sequence of any of SEQ ID NOs: 187, 190, 194, 196, 198, 202, 206, 208, 210, 212, 217, 219 or 221.

In other embodiments, the above antibody molecules comprise a heavy chain variable region comprising at least one framework region comprising the amino acid sequence of any of SEQ ID NOs: 187, 190, 194, 196, 198, 202, 206, 208, 210, 212 , 217, 219 or 221.

In other embodiments, the above antibody molecules comprise a heavy chain variable region comprising at least two, three, or four framework regions comprising the amino acid sequences of any of SEQ ID NOs: 187, 190, 194, 196, 198, 202, 206, 208 , 210, 212, 217, 219 or 221.

In other embodiments, the above antibody molecules comprise the amino acid sequence of VHFW1 SEQ ID NO: 187, 190, 194, or 196, the amino acid sequence of VHFW2 SEQ ID NO: 198, 202, 206, or 208, and the amino acid sequence of VHFW3 SEQ ID NO: 210, 212, 217 or 219, and optionally additionally containing the amino acid sequence of VHFW4 SEQ ID NO: 221.

In other embodiments, the above antibody molecules comprise a light chain variable region comprising at least one framework region comprising the amino acid sequence of any of SEQ ID NOs: 226, 230, 232, 234, 236, 238, 240, 244, 246, 248 , 252, 255, 259, 261, 265, 267, 269, or 271, or an amino acid sequence at least 90% identical to it, or containing no more than two substitutions, insertions, or deletions of amino acids compared to the amino acid sequence of any of 226, 230, 232, 234, 236, 238, 240, 244, 246, 248, 252,

- 45 040295

255, 259, 261, 265, 267, 269 or 271.

In other embodiments, the above antibody molecules comprise a light chain variable region comprising at least one framework region comprising the amino acid sequence of any of SEQ ID NOs: 226, 230, 232, 234, 236, 238, 240, 244, 246, 248 , 252, 255,

259, 261, 265, 267, 269 or 271.

In other embodiments, the above antibody molecules comprise a light chain variable region comprising at least two, three, or four framework regions comprising the amino acid sequences of any of SEQ ID NOs: 226, 230, 232, 234, 236, 238, 240, 244 , 246, 248, 252, 255, 259, 261, 265, 267, 269 or 271.

In other embodiments, the above antibody molecules comprise the amino acid sequence of VLFW1 SEQ ID NO: 226, 230, 232, 234, 236, or 2385, the amino acid sequence of VLFW2 SEQ ID NO: 240, 244, 246, or 248, and the amino acid sequence of VLFW3 SEQ ID NO: 252, 255, 259, 261, 265, 267 or 269, and optionally additionally containing the amino acid sequence of VLFW4 SEQ ID NO: 271.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain containing an amino acid sequence at least 85% identical to any of ID NOs: 8, 28, 64, 68, 72, 76, 80, 100, 104, or 108.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 8, 28, 64, 68, 72, 76, 80, 100, 104, or 108.

In other embodiments, the above antibody molecules comprise a light chain variable domain containing an amino acid sequence at least 85% identical to any of ID NOs: 32, 36, 40, 44, 48, 52, 56, 60, 84, 88, 92 or 96.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32, 36, 40, 44, 48, 52, 56, 60, 84, 88, 92, or 96.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 8.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 18.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 30.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 64.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 66.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 70.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 72.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 74.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 76.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 78.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 80.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 82.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 100.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 or SEQ ID NO: 113.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 104.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 106.

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In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 122.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 108.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 110.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 134.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 34.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 36.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 42.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 46.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 48.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 50.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 52.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 54.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 84.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 86.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 88.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 90.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 92.

In other embodiments, the above antibody molecules comprise a light chain containing the amino acid sequence of SEQ ID NO: 94.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 96.

In other embodiments, the above antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 98.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 32.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2-8 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 36.

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In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 48.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 52.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 36.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 68 or SEQ ID NO: 108 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 36.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 8 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 40.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 8 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 76 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 84.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 88.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 92.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 96.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 34.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain,

- 48 040295 containing the amino acid sequence of SEQ ID NO: 42.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 46.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 50.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 54.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106 and a light chain containing the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106 and a light chain containing the amino acid sequence of SEQ ID NO: 42.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106 and a light chain containing the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106 and a light chain containing the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 70 or SEQ ID NO: 110 and a light chain containing the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 74 or SEQ ID NO: 18 and a light chain containing the amino acid sequence of SEQ ID NO: 42.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 74 or SEQ ID NO: 18 and a light chain containing the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 78 and a light chain containing the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 82 and a light chain containing the amino acid sequence of SEQ ID NO: 86.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102 and a light chain containing the amino acid sequence of SEQ ID NO: 94.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106 and a light chain containing the amino acid sequence of SEQ ID NO: 98.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 113 and a light chain containing the amino acid sequence of SEQ ID NO: 34.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 113 and a light chain containing the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 122 and a light chain containing the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 122 and a light chain containing the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the above antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 134 and a light chain containing the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the above antibody molecules are selected from a Fab fragment,

F(ab') ₂ , Fv or single chain Fv fragment (scFv).

In other embodiments, the above antibody molecules comprise a heavy chain constant region selected from IgG1, IgG2, IgG3, and IgG4.

In other embodiments, the above antibody molecules comprise a light chain constant region selected from k- or λ-chain light chain constant regions.

In other embodiments, the above antibody molecules comprise a human IgG4 heavy chain constant region with a mutation at position 228 according to EU numbering or position 108 of SEQ ID NO: 275 or 277 and a k light chain constant region.

In other embodiments, the above antibody molecules comprise a human IgG4 heavy chain constant region with a serine to proline mutation at position 228 according to EU numbering or position 108 of SEQ ID NO: 275 or 277 and a k light chain constant region.

In other embodiments, the above antibody molecules comprise a human IgG1 heavy chain constant region with an asparagine to alanine mutation at position 297 according to EU numbering or position 180 of SEQ ID NO: 279 and a k light chain constant region.

In other embodiments, the above antibody molecules comprise a human IgG1 heavy chain constant region with an aspartate to alanine mutation at position 265 according to EU numbering or position 148, and a proline to alanine mutation at position 329 according to EU numbering or position 212 SEQ ID NO: 280 and light k-chain constant region.

In other embodiments, the above antibody molecules comprise a human IgG1 heavy chain constant region with a leucine to alanine mutation at position 234 according to EU numbering or position 117 and a leucine to alanine mutation at position 235 according to EU numbering or position 118 of SEQ ID NO :281 and the light k-chain constant region.

In other embodiments, the above antibody molecules are capable of binding to human LAG-3 with a dissociation constant (KD) of less than about 0.2 nM.

In some embodiments, the above antibody molecules bind to human LAG-3 with a K _D of less than about 0.2, 0.15, 0.1, 0.05, or 0.02 nM, such as about 0.05 to 0, 15 nM, eg about 0.11 nM, eg as measured by the Biacore method.

In other embodiments, the above antibody molecules bind to cynomolgus monkey LAG-3 with a KD of less than about 0.2, 0.15, 0.1, 0.05, or 0.02 nM, e.g., from about 0.05 to 0, 15 nM, for example, as measured by the Biacore method.

In certain embodiments, the above antibody molecules bind to human LAG3 and cynomolgus monkey LAG-3 with a similar KD, eg in the nM range, eg as measured by the Biacore method. In some embodiments, the above antibody molecules bind to a human LAG-3-Ig fusion protein with a KD of less than about 0.5, 0.2, 0.1, 0.05, 0.025, or 0.01 nM, e.g., as measured ELISA.

In some embodiments, the above antibody molecules bind to CHO cells that express human LAG-3 (e.g., LAG-3 transfected CHO cells) with a KD of less than about 4, 2.5, 2, 1.5, 1, 0, 75, 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 nM, e.g., about 2.3, 1.92 nM, or about 0.2 nM, e.g., as measured by FACS analysis .

In some embodiments, the above antibody molecules bind to human T cells with a KD of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 nM, e.g., about 0.26 nM, e.g. as measured by FACS analysis.

In some embodiments, the above antibody molecules bind to cells that express LAG-3 (e.g., human LAG-3 expressing 300.19 cells) with a K _D less than about 20, 15, 10, 5, 2, or 1 nM, e.g., about 13 .6 nM, for example, as measured by FACS analysis.

In some embodiments, the above antibody molecules bind to cells that express rhesus macaque LAG-3 (e.g., cells transfected with rhesus macaque LAG-3) with a K _D of less than about 15, 10, 9, 8, 6, 5, 2 or 1 nM, eg about 8.03 nM, eg as measured by FACS analysis.

In certain embodiments, the above antibody molecules do not cross-react with mouse LAG-3. In some embodiments, the above antibodies do not cross-react with rat LAG-3. In other embodiments, the above antibodies do not cross-react with rhesus monkey LAG-3. In some embodiments, the above antibodies do not cross-react with rat LAG-3. For example, cross-reactivity can be measured by the Biacore method or by a binding assay using cells that express LAG-3 (eg, human LAG-3 expressing 300.19 cells).

In other embodiments, the above antibody molecules bind to an extracellular Ig-like domain of LAG-3 (e.g., human LAG-3), e.g., any of domain 1 (D1), domain 2 (D2), domain 3 (D3 ) or domain 4 (D4). In some embodiments, the above antibody molecules bind to one or more amino acid residues in D1. In some embodiments, the above antibody molecules do not bind to the additional D1 loop or fragment thereof (eg, as measured by the Biacore method or the FACS method). In some embodiments, the above antibodies do not bind to D2. In some embodiments, the above antibody molecules bind to D1 and D2. In some embodiments, the above antibody molecules bind to one or more amino acid residues in D1 and/or D2 that bind to an MHC class II molecule. In other embodiments, the above antibody molecules are capable of reducing the binding of LAG-3 to a class II major histocompatibility complex (MHC) molecule or a cell that expresses a class II MHC molecule. In some embodiments, the above antibody molecules reduce (e.g., block) LAG-3-Ig binding to an MHC class II molecule, e.g., on Raji cells or Daudi cells with an _IC50 of less than about 10, 8, 5, 4, 3, 2, 1 or 0.5 nM, eg from about 8 nM to about 10 nM, or from about 2 nM to about 3 nM, for example about 5.5 nM or about 2.3 nM.

In other embodiments, the above antibody molecules are capable of enhancing an antigen-specific T cell response.

In embodiments, the antibody molecule is a monospecific antibody molecule or a bispecific antibody molecule. In embodiments, the antibody molecule has a first binding specificity for LAG-3 and a second binding specificity for PD-1, TIM3, CEACAM (eg, CEACAM-1 and/or CEACAM-5), PD-L1, or PD-L2. In embodiments, the antibody molecule comprises an antigen-binding fragment of an antibody, such as a semi-antibody or an antigen-binding fragment of a semi-antibody.

In some embodiments, the above antibody molecules increase IL-2 expression by staphylococcal enterotoxin B (SEB) activated cells (e.g., at 25 μg/ml) by at least about 2, 3, 4, 5 times, e.g., from about 2 up to 3-fold compared to IL-2 expression when an isotype control (eg, IgG4) is used, eg, as measured in the SEB T cell activation assay or ex vivo human whole blood assay.

In some embodiments, the above antibody molecules increase the expression of IFN-γ by T cells stimulated with an anti-CD3 antibody (e.g., at 0.1 μg/mL) by at least about 0.5, 1, 2, 3, 4, 5 , 6, 7, or 8 times, eg, about 0.9 to 5.1 times, eg, about 3 times, compared to IFN-γ expression when an isotype control (eg, IgG4) is used, eg, as measured in an activity assay IFN-γ.

In some embodiments, the above antibody molecules increase the expression of IFN-γ by SEB-activated T cells (e.g., at 3 pg/mL) at least about 2, 3, 4, 5-fold, e.g., about 1.2 to 2 times, eg, about 1.6 times, compared to IFN-γ expression when an isotype control (eg, IgG4) is used, eg, as measured in an IFN-γ activity assay.

In some embodiments, the above antibody molecules do not increase IL-2 or IFN-γ expression without T cell receptor activation (eg, in the absence of SEB).

In some embodiments, the above antibody molecules increase the expression of IFN-γ by T cells activated with CMV peptide by at least about 2, 3, 4, 5 times, for example, from about 1.1 to 1.7 times, for example, about 1 .4 times compared to IFN-γ expression when an isotype control (eg, IgG4) is used, eg as measured in an IFN-γ activity assay. In some embodiments, the above antibody molecules increase the proliferation of CD8+ T cells activated by the CMV peptide by at least about 1, 2, 3, 4, 5 times, for example, about 1.5 times, compared to the proliferation of CD8 ⁺ T cells, when an isotype control (eg IgG4) is used, eg as measured by the percentage of CD8+ T cells that have gone through at least n (eg n=2 or 4) cell divisions.

In certain embodiments, the Cmax of the above antibody molecules is from about 50 µg/ml to about 400 µg/ml, from about 100 µg/ml to about 350 µg/ml, from about 150 µg/ml to about 300 µg/ml. ml, or from about 200 µg/ml to about 250 µg/ml, eg about 166 µg/ml, for example, as measured in an animal.

In certain embodiments, the T _1/2 of the above antibody molecules is from about 50 hours to about 400 hours, from about 100 hours to about 350 hours, from about 150 hours to about 300 hours, or from about 200 hours to about 250 hours, for example approximately 231.9 hours, for example, as measured in an animal.

In some embodiments, the above antibody molecules bind to LAG-3 with

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Kd below 5χ10 ^-4 , 1χ10 ⁴ , 5x105 or 1χ10 ⁵ s ^-1 , for example about 7x105 s ^-1 , for example, as measured by the Biacore method. In some embodiments, the above antibodies bind to LAG3 with a Ka faster than 1x10 ⁴ , 5x10 ⁴ , lx 105, 5x105 or lx10 ⁶ M ^-1 s ^-1 , e.g., approximately 6.41x105 M ^-1 s ^-1 , e.g., as measured Biacore method.

In another aspect, the invention relates to an isolated nucleic acid molecule encoding any of the above antibody molecules, to vectors and their host cells.

In one embodiment, the isolated nucleic acid encodes the heavy chain variable region or the light chain variable region of an antibody, or both, of any of the above antibody molecules.

In one embodiment, the isolated nucleic acid encodes heavy chain CDRs 1-3, wherein said nucleic acid comprises the nucleotide sequence of SEQ ID NOs: 140-144, 151-155, 162-166, 173-177, 184-186, or 287.

In another embodiment, the isolated nucleic acid encodes light chain CDRs 1-3, wherein said nucleic acid comprises the nucleotide sequence of SEQ ID NOs: 145-150, 156-161, 167-172, or 178-183.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a heavy chain variable domain, wherein said nucleotide sequence is at least 85% identical to any of ID NOs: 9, 29, 65, 69, 73, 77, 81, 101, 105, 109, 112, 121, 124, 125, 132 or 133.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a heavy chain variable domain, wherein said nucleotide sequence comprises any of SEQ ID NOs: 9, 29, 65, 69, 73, 77, 81, 101, 105, 109, 112, 121, 124, 125, 132 or 133.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a heavy chain, wherein said nucleotide sequence is at least 85% identical to any of ID NOs: 19, 31, 67, 71, 75, 79, 83, 103, 107, 111, 114, 123, 126, 127, 135 or 136.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a heavy chain, wherein said nucleotide sequence comprises any of SEQ ID nO: 19, 31, 67, 71, 75, 79, 83, 103, 107, 111, 114, 123, 126, 127, 135 or 136.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a light chain variable domain, wherein said nucleotide sequence is at least 85% identical to any of ID NOs: 33, 37, 41, 45, 49, 53, 57, 61, 85, 89, 93, 97, 115, 118, 128, 129 or 137.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a light chain variable domain, wherein said nucleotide sequence comprises any of SEQ ID NOs: 33, 37, 41, 45, 49, 53, 57, 61, 85, 89, 93, 97, 115, 118, 128, 129 or 137.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a light chain, wherein said nucleotide sequence is at least 85% identical to any of ID NOs: 35, 39, 43, 47, 51, 55, 59, 63, 87, 91, 95, 99, 117, 120, 130, 131, 138 or 139.

In other embodiments, the above nucleic acid further comprises a nucleotide sequence encoding a light chain, wherein said nucleotide sequence comprises any of SEQ ID nO: 35, 39, 43, 47, 51, 55, 59, 63, 87, 91, 95, 99, 117, 120, 130, 131, 138 or 139.

Certain embodiments relate to one or more expression vectors and host cells containing the above nucleic acids.

Also provided is a method for producing an antibody molecule or fragment thereof, comprising culturing a host cell as described herein under conditions suitable for gene expression.

Pharmaceutical compositions and kits.

In another aspect, the present invention relates to compositions, such as pharmaceutically acceptable compositions, which contain the antibody molecule described in the present description, formulated together with a pharmaceutically acceptable carrier. As used herein, a pharmaceutically acceptable carrier includes any and all diluents, dispersion media, isotonic and absorption delaying agents, and the like, which are physiologically compatible. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal, or epidermal administration (eg, by injection or infusion).

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The compositions of the present invention may be in a number of forms. They include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (eg injectable and infusion solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended route of administration and therapeutic application. Specific preferred compositions are in the form of injectable or infusion solutions. The preferred route of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody is administered by intravenous infusion or injection. In another preferred embodiment, the antibody is administered via intramuscular or subcutaneous injection.

As used herein, the phrases parenteral administration and parenterally administered means methods of administration other than enteral and topical administration, generally by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal , subcutaneous, intradermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

Therapeutic compositions generally must be sterile and stable under the conditions of preparation and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high antibody concentration. Sterile injectable solutions can be prepared by incorporating the active compound (ie, antibody or antibody fragment) in the required amount in a suitable solvent with one or a combination of the ingredients listed above, if necessary, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the necessary other ingredients from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which provides a powder of the active ingredient plus any additional desired ingredient from a previously filter-sterilized solution thereof. Suitable fluidity of the solution can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using surfactants.

Prolonged absorption of injectable compositions can be obtained by introducing into the composition an agent that delays absorption, such as monostearate salts and gelatin.

Antibody molecules can be administered by a number of methods known in the art, although for many therapeutic applications the preferred route/method of administration is intravenous injection or infusion. In one embodiment, the antibody molecule is administered by intravenous infusion at a rate of greater than 20 mg/min, such as 20-40 mg/min and preferably greater than or equal to 40 mg/min to give a dose of about 35 to 440 mg/m ² , preferably from about 70 to 310 mg/m ² and more preferably from about 110 to 130 mg/m ² . In another embodiment, the antibody molecule is administered by intravenous infusion at a rate of less than 10 mg/min; preferably less than or equal to 5 mg/min to give a dose of about 1 to 100 mg/m ² , preferably about 5 to 50 mg/m ² , about 7 to 25 mg/m ² and more preferably about 10 mg/m ² . As will be appreciated by one of skill in the art, the route and/or mode of administration varies depending on the desired results. In certain embodiments, the active compound can be formulated with a carrier that protects the compound from rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, the antibody molecule can be administered orally, for example with an inert diluent or an ingestible food carrier. The compound (and other ingredients, if desired) can also be encapsulated in a hard or soft gelatin shell, compressed into tablets, or administered directly to the individual's food. For oral therapeutic administration, the compounds can be combined with excipients and used in the form of swallowable tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, implant capsules, and the like. For administration of a compound of the invention by a route other than parenteral administration, it may be necessary to coat the compound or co-administer the compound with a substance to prevent its inactivation. Therapeutic compositions can also be administered using medical devices known in the art.

Dosing regimens are adjusted to provide the desired optimal response (for example, those

- 53 040295 rapeutic response). For example, a single bolus may be administered, multiple sub-doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the need for a therapeutic situation. It is particularly preferred to formulate parenteral compositions in unit dosage form for ease of administration and dosage uniformity. As used herein, unit dosage form refers to physically discrete units suitable as unit doses for individuals to be treated; each unit contains a certain amount of active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. The requirements for unit dosage forms of the invention are determined by and directly dependent on (a) the unique characteristics of the active compound and the competitive therapeutic effect to be obtained, and (b) the limitations in the art of formulating such an active compound for the treatment of sensitivity in individuals.

An exemplary non-limiting range of a therapeutically or prophylactically effective amount of an antibody molecule is 0.1-30 mg/kg, more preferably 1-25 mg/kg. One of skill in the art can determine dosages and treatment regimens for the anti-LAG-3 antibody molecule. In certain embodiments, the anti-LAG-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, 1 to 10 mg/kg, 5 to 15 mg/kg, 10 to 20 mg/kg, 15 to 25 mg/kg, or approximately 3 mg/kg. The dosing schedule may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 10 to 20 mg/kg once every two weeks. The antibody molecule can be administered by intravenous infusion at a rate greater than 20 mg/min, such as 20-40 mg/min and preferably greater than or equal to 40 mg/min to give a dose of about 35 to 440 mg/m ² , preferably about 70 to 310 mg/m ² and more preferably from about 110 to 130 mg/m ² . In embodiments, an infusion rate of about 110 to 130 mg/m ² provides a level of about 3 mg/kg. In one embodiment, the anti-LAG-3 antibody molecule is administered (eg, intravenously) at a dose of about 3 to 800 mg, eg, about 3, 20, 80, 240, or 800 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered alone at a dose of about 20 to 800 mg, such as about 3, 20, 80, 240, or 800 mg. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 3 to 240 mg, such as about 3, 20, 80, or 240 mg, in combination with a second agent or treatment, such as a second agent or treatment described herein. . In one embodiment, an anti-LAG-3 antibody molecule is administered every 2 weeks (eg, for 1, 3, 5, 7 weeks) for each cycle of 8 weeks, eg up to 96 weeks.

The antibody molecule can be administered by intravenous infusion at a rate greater than 20 mg/min, such as 20-40 mg/min and preferably greater than or equal to 40 mg/min to give a dose of about 35 to 440 mg/m ² , preferably about 70 to 310 mg/m ² and more preferably from about 110 to 130 mg/m ² . In embodiments, an infusion rate of about 110 to 130 mg/m ² provides a level of about 3 mg/kg. In other embodiments, the antibody molecule is administered by intravenous infusion at a rate of less than 10 mg/min, such as less than or equal to 5 mg/min to give a dose of about 1 to 100 mg/m ² , such as about 5 to 50 mg/m ² , from about 7 to 25 mg/m ² and more preferably about 10 mg/m ² . In some embodiments, the antibody is administered by infusion over a period of approximately 30 minutes.

It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated. It should also be further understood that for any particular individual, it is necessary to select specific dosing regimens over a certain period of time in accordance with the needs of the individual and the professional judgment of the specialist conducting the administration or supervising the administration of the compositions, and that the dosage ranges established in the present description are only illustrative and are not intended to limit the scope or practical use of the composition described in the application.

Pharmaceutical compositions of the invention may contain a therapeutically effective amount or a prophylactically effective amount of an antibody or antibody region of the invention. A therapeutically effective amount refers to an amount effective at the dosages and for periods of time necessary to obtain the desired therapeutic result. The therapeutically effective amount of the modified antibody or antibody fragment may vary depending on factors such as the disease state, age, sex and weight of the individual, and the ability of the antibody or antibody region to elicit the desired response in the individual. A therapeutically effective amount is also an amount at which any toxic or deleterious effects of the modified antibody or antibody fragment are less significant than the therapeutic benefit. A therapeutically effective dose preferably inhibits

- 54 040295 measurable parameter, for example, a tumor growth rate of at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% relative to untreated individuals. The ability of a compound to inhibit a measurable parameter, such as cancer, can be evaluated in an animal model system for predicting efficacy in human tumors. Alternatively, this property of the composition can be assessed by assaying the ability of the compound to inhibit, such inhibition by in vitro assays being known to the person skilled in the art.

A prophylactically effective amount refers to an amount effective at dosages and for periods of time necessary to obtain the desired prophylactic result. Typically, due to the fact that a prophylactic dose is used in individuals before or at an early stage of the disease, the prophylactically effective amount is less than the therapeutically effective amount.

Also within the scope of the invention is a kit containing an antibody molecule as described herein. The kit may contain one or more other elements, including: instructions for use; other reagents, for example a label, a therapeutic agent or an agent suitable for chelation or otherwise binding, an antibody to the label or a therapeutic agent or radioprotective compositions; devices or other substances for preparing antibodies for administration; pharmaceutically acceptable carriers and devices or other substances for administration to an individual.

Use of an anti-LAG-3 antibody molecule.

Anti-LAG-3 antibody molecules described herein may have diagnostic as well as therapeutic and prophylactic utility in vitro and in vivo. For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to an individual, eg a human subject, eg in vivo, to enhance immunity. In one embodiment, anti-LAG-3 antibody molecules enhance the immune response in an individual, eg, by blockade of LAG-3 (eg, by blockade of LAG-3 binding to an MHC molecule or other ligands).

Thus, in one aspect, the invention relates to a method for modulating an immune response in an individual, comprising administering to the individual an antibody molecule described herein in a manner that modifies the immune response in the individual. In one embodiment, the immune response is enhanced, stimulated or activated. In some embodiments, the anti-LAG-3 antibody molecule restores, enhances, or stimulates an antigen-specific T cell response, such as the production of interleukin 2 (IL-2) or interferon-γ (IFN-γ) in an antigen-specific T cell response in an individual. In some embodiments, the implementation of the immune response is an antitumor response. The methods and compositions described herein are suitable for the treatment of human patients suffering from a disorder that can be treated by enhancing a T-cell mediated immune response. For example, anti-LAG-3 antibody molecules, alone or in combination, can be administered to an individual for the treatment, prevention, and/or diagnosis of a number of disorders, such as cancers (melanoma or liver cancer) or infectious disorders.

As used herein, the term individual is intended to include human and non-human animals. In one embodiment, the individual is a human individual, such as a human patient suffering from a disorder or condition characterized by abnormal functioning of LAG-3. The term non-human animals of the invention includes mammals and non-mammals such as non-human primates. In one embodiment, the individual is a human. In one embodiment, the subject is a human patient in need of an enhanced immune response. In one embodiment, the individual suffers from or is at risk for a disorder described herein, such as a cancer or infectious disorder as described herein. In certain embodiments, the individual is immunocompromised or at risk of being immunocompromised. For example, the individual is receiving or has received chemotherapy treatment and/or radiation therapy. Alternatively, or in combination, the individual is immunocompromised or at risk of being immunocompromised as a result of infection. For example, the methods and compositions described herein can increase a number of immunological activities. In one embodiment, the individual has an increased number or activity of tumor infiltrating T-lymphocytes (TILs). In another embodiment, the individual has increased expression or activity of interferon-γ (IFN-γ). In yet another embodiment, the individual has reduced expression or activity of PD-L1. Thus, in certain embodiments, any (e.g., one, two, three, or all) of TILs, IFN-γ, CD8, or PD-L1 can be used as biomarkers for immunotherapies based on anti-LAG-3 antibody, opioid

- 55 040295 mentioned in the present description.

Therapeutic applications.

Malignant tumor.

Blockade of LAG-3 by antibodies can enhance the immune response against malignant cells in an individual. Like CD4, LAG-3 interacts with MHC class II molecules, but unlike CD4, LAG-3 does not interact with the human immunodeficiency virus gp120 protein (Baixeras et al., (1992) J. Exp. Med., 176:327-337 ). Studies have demonstrated direct and specific binding of LAG-3 to MHC class II on the cell surface (Huard et al., (1996) Eur. J. Immunol., 26:1180-1186). The LAG-3/MHC class II interaction plays a role in the suppression of antigen-dependent stimulation of CD4+ and CD8+ T lymphocytes. The addition of anti-LAG-3 antibodies can lead to increased T cell proliferation, higher expression of activation antigens such as CD25, and higher concentrations of cytokines such as interferon-γ and interleukin 4 (Huard et al., (1994) Eur. J Immunol. 24:3216-3221).

The intracytoplasmic region of LAG-3 can also interact with LAP, a signaling molecule involved in suppression of the CD3/TCR activation pathway (Iouzalen et al., (2001) Eur. J. Immunol., 31:2885-2891). In addition, LAG-3 contributes to the suppressive activity of regulatory T cells (T _reg ) CD4+CD25+. Treg cells express LAG-3 when activated, and anti-LAG-3 antibodies inhibit suppression by induced Treg cells (Huang C. et al., (2004) Immunity, 21:503-513). LAG-3 can also negatively regulate T cell homeostasis via regulatory T cells in both T cell dependent and independent mechanisms (Workman CJ and Vignali DA (2005) J. Immunol., 174:688-695). Thus, inhibition of LAG-3 can lead to an increase in the immune response.

Thus, one aspect relates to a method of treating (eg, reducing or inhibiting) a cancer or tumor in an individual. The method includes administering to an individual an anti-LAG-3 antibody molecule as described herein, eg, a therapeutically effective amount of an anti-LAG-3 antibody molecule alone or in combination, eg, with one or more agents or methods. In one embodiment, an anti-LAG-3 antibody molecule can be used alone to inhibit the growth of malignant tumors. Alternatively, an anti-LAG-3 antibody can be used in combination with one or more of: standards of care (eg, for cancers or infectious disorders), another antibody, an immunomodulator (eg, an activator of a co-stimulatory molecule or an inhibitor of an inhibitory molecule); vaccines, for example a therapeutic cancer vaccine or other forms of cellular immunotherapy, as described below. In certain embodiments, an anti-LAG-3 antibody molecule is administered in combination with a co-stimulatory molecule modulator (eg, a co-stimulatory molecule agonist) or an inhibitory molecule modulator (eg, an immune checkpoint inhibitor inhibitor), for example, as described herein.

In one embodiment, the methods are suitable for treating cancer in vivo. An anti-LAG-3 antibody molecule can be co-administered with an antigen of interest to obtain antigen-specific immunity enhancement. When anti-LAG-3 antibodies are administered in combination with one or more agents, the combination may be administered in any order or simultaneously.

Types of malignant tumor; medical and diagnostic methods.

Certain embodiments relate to a method of treating a subject, such as reducing or ameliorating a hyperproliferative condition or disorder (eg, cancer), such as a solid tumor, hematologic cancer, soft tissue tumor, or metastatic lesion in the subject. The method includes administering to an individual one or more of the anti-LAG-3 antibody molecules described herein, alone or in combination with other agents or therapeutic methods.

As used herein, the term cancer is intended to include all types of malignant growth or oncogenic process, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness. Examples of malignant disorders include, but are not limited to, solid tumors, hematologic malignancies, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignancies such as sarcomas and carcinomas (including adenocarcinomas and squamous cell carcinomas) of various organ systems such as sarcomas and carcinomas affecting the liver, lung, breast, lymphoid tissue, gastrointestinal tract (e.g. colon) , urinary tract (eg, kidney cells, urothelial cells), prostate, and pharynx. Adenocarcinomas include malignancies such as most colon cancers, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung carcinoma, small intestine cancer, and esophageal cancer. Squamous cell carcinomas include malignant

- 56 040295 neoplasms such as malignant neoplasms affecting the lung, esophagus, skin, head and neck regions, oral cavity, anus and cervix. Metastatic lesions of the above malignant tumors can also be treated or prevented using the methods of the compositions of the invention.

Exemplary cancers whose growth can be inhibited using the antibody molecules described herein include cancers that are generally responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., advanced stage melanoma (e.g., stage II-IV) or HLA-A2 positive melanoma), pancreatic cancer (e.g., advanced stage pancreatic cancer), solid tumors, breast cancer (eg, metastatic breast carcinoma, breast cancer that does not express one, two, or all of the estrogen receptor, progesterone receptor, or Her2/neu, eg, triple negative breast cancer) and renal cell carcinoma (eg, renal cell carcinoma advanced stage (e.g., stage IV) or metastatic renal cell carcinoma (MRCC)). In addition, resistant or recurrent cancers can be treated using the antibody molecules described herein.

Examples of other cancers that can be treated include, for example, a solid tumor, such as prostate cancer (eg, hormone-resistant prostate adenocarcinoma), colon cancer, lung cancer (eg, non-small cell lung cancer), bone cancer, skin cancer, cancer head or neck (eg, HPV+ squamous cell carcinoma), malignant melanoma of the skin or malignant intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, malignant Merkel cell tumor, childhood solid tumors, bladder cancer, malignant tumor of the kidney or ureter, carcinoma of the renal pelvis, neoplasia of the central nervous system (CNS), neoplastic angiogenesis, tumor spine, brain stem glioma, adenoma pituitary gland, Kaposi's sarcoma, epidermoid or squamous cell carcinoma, or hemoblastosis, eg Hodgkin's lymphoma, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma soft tissue, urethral cancer, penile cancer, chronic or acute leukemias, including acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia (eg, relapsed or resistant chronic lymphocytic leukemia), childhood solid tumors, lymphocytic lymphoma , multiple myeloma, myelodysplastic syndrome, bladder cancer, kidney or ureter cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasia, primary lymphoma CNS, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced malignancies, including asbestos-induced malignancies (eg, mesothelioma), and combinations of these malignant tumors. Treatment of metastatic cancers, such as metastatic cancers that express MHC class II molecules or LAG-3, can be carried out using the antibody molecules described herein.

Without wishing to be bound by theory, in some embodiments, a patient is more likely to respond to treatment with an anti-LAG-3 antibody alone or in combination with anti-PD-1 or PD-L1 antibody molecules (optionally in combination with one or more agents as described herein) if the patient suffers from a cancer that highly expresses PD-L1 and/or the cancer is permeable to anti-tumor immune cells, eg TIL.

Antitumor immune cells may be positive for CD8, PD-L1, and/or IFN-γ; thus, CD8, PD-L1 and/or IFN-γ levels can serve as an indicator of TIL levels in the microenvironment. In certain embodiments, the cancer microenvironment is designated as triple positive for PD-L1/CD8/IFN-y.

Thus, in certain aspects, this invention relates to methods for determining whether a tumor sample is positive for one or more of PD-L1, CD8 and IFN-γ, and if the tumor sample is positive for one or more, for example, two or all three markers, then administering to the patient a therapeutically effective amount of the anti-PD-1 antibody molecule, optionally in combination with one or more other immunomodulators or anti-cancer agents.

In the following indications, a large proportion of patients are triple positive for PD-57 040295

Ll/CD8/IFN-y: lung cancer (squamous); lung cancer (adenocarcinoma); head and neck cancer; stomach cancer; NSCLC; HNSCC; gastric cancer (eg, MSIhi and/or EBV+); CRC (for example, MSIhi); malignant tumor of the nasopharynx (NPC); cervical cancer (eg, squamous cell); thyroid cancer, eg papillary thyroid; melanoma; TN breast cancer and DLBCL (diffuse large B-cell lymphoma). Mostly in breast cancer and mostly in colon cancer, a moderate proportion of patients are triple positive for PD-L1/CD8/IFN-y. In the following indications, a small proportion of patients are triple positive for PDL1/CD8/IFN-y: ER+ breast cancer and pancreatic cancer. These findings are further described in Example 4. Regardless of whether a large or small proportion of patients are triple positive for these markers, patient screening for these markers has identified the proportion of patients for whom there is a particularly high likelihood of a favorable response to anti-LAG-3 antibody therapy alone or in combination with an anti-PD-1 antibody (e.g., an anti-PD-1 inhibitory antibody) optionally in combination with one or more other immunomodulators (e.g., an anti-TIM-3 antibody molecule or an anti-PD-L1 antibody molecule) and/or an anti-cancer agent tumors, for example, the funds listed in the table. 7 and described in the publications listed in table. 7.

In some embodiments, the cancer sample is classified as triple positive for PDL1/CD8/IFN-y. This measurement can be roughly divided into two thresholds: an individual cell is classified as positive, and the sample as a whole is classified as positive. First, the level of PD-L1, CD8 and/or IFN-y can be measured in a single cell. In some embodiments, a cell that is positive for one or more of these markers is a cell that contains a higher level of the marker than a control cell or reference value. For example, in some embodiments, a high level of PD-L1 in a given cell is a level higher than the level of PD-L1 in a corresponding non-cancerous tissue in a patient. As another example, in some embodiments, a high level of CD8 or IFN-y in a given cell is the level of such a protein typically seen in TIL. Secondly, it is also possible to measure the percentage of cells in a sample that are positive for PD-L1, CD8 and/or IFN-y. (It is optional that one cell expresses all three markers.) In some embodiments, a triple positive sample is a sample that contains a high percentage of cells, such as higher than a reference value or higher than a control sample, that are positive for these markers.

In other embodiments, PD-L1, CD8 and/or IFN-y levels can be measured in the entire sample. In this case, a high level of CD8 or IFN-y in the sample may represent the level of such a protein typically seen in a tumor invaded by TILs. Likewise, a high level of PD-L1 may be a protein typically seen in a tumor sample, such as the tumor microenvironment.

The identification of subgroups of patients that are triple positive for PDL1/CD8/IFN-y, as demonstrated in Example 4 herein, has identified certain patient subpopulations that are likely to be particularly responsive to anti-PD-1 antibody therapy. For example, many patients with IM-TN (immunomodulatory, triple negative) breast cancer are triple positive for PDL1/CD8/IFN-y. IM-TN breast cancer is described, for example, in Brian D. Lehmann et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies, J. Clin. Invest., 1 Jul 2011; 121(7): 2750-2767. Triple negative breast cancers are cancers that do not express estrogen receptor (ER), progesterone receptor (PR), and Her2/neu. These malignant tumors are difficult to treat because they they generally do not respond to agents that target ER, PR, and Her2/neu. Types of triple negative breast cancer can be further divided into different classes, one of which is immunomodulatory. As described by Lehmann et al., IM-TN breast cancer is characterized by high levels of factors involved in immune cell processes, e.g., one or more of immune cell signaling (e.g., TH1/TH2 pathway, NK cell pathway, B signal transduction pathway). α-cell receptor pathway, DC pathway and T cell receptor signaling), cytokine signaling (eg, cytokine pathway, IL-12 pathway, and IL-7 pathway), antigen processing and presentation, signaling via central immune system signaling pathways (eg, signaling NFKB, TNF, and JAK/STAT), genes involved in T cell function, immune transcription, interferon (IFN) response, and antigen processing. Thus, in some embodiments, the cancer being treated is a cancer that is, or is determined to be positive for one or more breast cancer IM-TN markers, e.g., a factor that contributes to one or more from immune cell signaling (eg, TH1/TH2 pathway, NK cell pathway, B-cell receptor signaling pathway, DC pathway and T-cell receptor signaling), cytokine signaling (eg, cytokine pathway, IL-12 pathway and IL-7 pathway), antigen processing and presentation, signaling through central immune system signaling pathways (eg, NFKB, TNF, and JAK/STAT signaling), genes involved in T cell function, immune transcription, interferon (IFN) response and antigen processing.

As another example, the present description demonstrates that a subset of colon cancer patients with high MSI (microsatellite instability) is also triple positive for PD-L1/CD8/IFN-y. Thus, in some embodiments, an anti-LAG-3 antibody, such as an anti-LAG-3 antibody as described herein, alone or in combination with an anti-PD-1 antibody (optionally in combination with one or more immunomodulators, such as an antibody anti-TIM-3 or anti-PD-L1 antibody, and one or more anti-cancer agents, e.g., the anti-cancer agent described in Table 7 or in the publication in Table 7) are administered to a patient who suffers from or has been identified colon cancer with high MSI, thus treating cancer. In some embodiments, the high MSI cell is a cell with an MSI level higher than a reference value or a control cell, such as a non-cancerous cell of the same tissue type as the cancer.

As another example, it is demonstrated herein that a subset of gastric cancer patients with high MSI and/or who are EBV+ are also triple positive for PD-Ll/CD8/IFN-y. Thus, in some embodiments, an anti-LAG-3 antibody, such as an anti-LAG-3 antibody as described herein, alone or in combination with an anti-PD-1 antibody (optionally in combination with one or more immunomodulators, such as an antibody anti-TIM-3 or anti-PD-L1 antibody, and one or more anti-cancer agents, e.g., the anti-cancer agent described in Table 7 or in the publication in Table 7) are administered to a patient who suffers from or has been identified that he is suffering from stomach cancer with high MSI and/or EBV+, thus undergoing cancer treatment. In some embodiments, the high MSI cell is a cell with an MSI level higher than a reference value or control cell, such as a non-cancerous cell of the same tissue type as the cancer.

The present disclosure further describes methods for assaying a cancer for PDL1 and then treating the cancer with an anti-LAG-3 antibody alone or in combination with an anti-PD-1 antibody. As described in Example 5 herein, a cancer sample can be analyzed for protein levels or mRNA levels of PD-L1. A sample with PD-L1 (protein or mRNA) levels higher than the reference value or a control cell (eg, a non-cancerous cell) can be classified as PD-L1 positive. Thus, in some embodiments, an anti-LAG-3 antibody, such as an anti-LAG-3 antibody as described herein, alone or in combination with an anti-PD-1 antibody, (optionally in combination with one or more anti-cancer agents) ) is administered to a patient who suffers from or has been identified as suffering from a cancer that is positive for PD-L1.

The malignant tumor may be, for example, non-small cell adenocarcinoma (ASA) of the lung (NSCLC), NSCLC squamous cell carcinoma (SCC) or hepatic cell carcinoma (HCC).

In some embodiments, the methods herein comprise using an anti-LAG-3 antibody, e.g., an anti-LAG-3 antibody as described herein, e.g., in combination with an anti-PD-1 antibody, to treat a cancer that is (or identified as being) positive for PD-L1. In some embodiments, the cancer is colorectal cancer (eg, high MSI), gastric cancer (eg, high MSI and/or EBV+), NPC, cervical cancer, breast cancer (eg, TN breast cancer), and ovarian cancer. In some embodiments, the cancer is NSCLC, melanoma, or HNSCC. In some embodiments, the anti-LAG-3 antibody is administered at a dose of, for example, 1, 3, 10, or 20 mg/kg.

Based on, for example, Example 4 herein, certain gastric cancers that are triple positive for PDL1/CD8/IFN-y are also positive for PIK3CA. Thus, in some embodiments, a cancer may be treated with an anti-LAG-3 antibody alone or in combination with an anti-PD1 antibody molecule (optionally in combination with one or more immunomodulators, e.g., an anti-TIM-3 antibody or an anti-PD-L1 antibody molecule) and an agent that inhibits PIK3CA. Illustrative means in this category are described in Stein R.C. (September 2001). Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment. Endocrine-related Cancer 8 (3): 237-48 and Marone R., Cmiljanovic V., Giese B., Wymann M.P. (January 2008). Targeting phosphoinositide 3-kinase: moving towards therapy. Biochimica et Biophysica Acta 1784 (1): 159-85.

Based on, for example, Example 4 in the present description of CRC, for example, a patient who

- 59 040295 suffering from (or identified as suffering from) CRC with high MSI, can be treated with an anti-LAG-3 antibody alone or in combination with an anti-PD-1 antibody, optionally in combination with a therapeutic agent that targets one or both RNF43 and BRAF. For example, such cancers can be treated with an anti-LAG-3 antibody and an anti-PD-1 antibody, optionally in combination with one or more therapeutic agents that target one or more of RNF4 3 and BRAF. In embodiments, the one or more therapeutic agents include an anti-cancer agent described in Table 1. 7 or the publication given in table. 7. Inhibitors of PD-1, such as antibodies, are described herein. RNF43 can be inhibited, for example, by an antibody, a small molecular weight compound (for example, 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)N-(5-(pyrazin-2-yl)pyridin- 2-yl)acetamide (compound A28)), miRNA or Rspo ligand, or a derivative thereof. BRAF inhibitors (eg, vemurafenib or dabrafenib) are described herein.

Based on, for example, Example 4 herein, a patient who suffers from (or is identified as having) squamous cell lung cancer can be treated with an anti-LAG-3 antibody molecule in combination with a therapeutic agent that targets PD-1, such as antibodies against PD-1; and optionally one or more anti-cancer agents, eg, the anti-cancer agent described in Table 1. 7 or in the publication in table. 7 or a therapeutic agent that targets TIM-3, such as an anti-TIM-3 antibody.

Based on, for example, Example 4 herein, a patient who suffers from (or is identified as suffering from) thyroid cancer can be treated with an anti-LAG-3 antibody molecule alone or in combination with an anti-PD-1 antibody molecule, optionally in combination. with a therapeutic agent that targets BRAF, and optionally in combination with one or more immunomodulators, for example an anti-TIM-3 antibody molecule and an anti-PD-L1 antibody molecule. BRAF inhibitors (eg, vemurafenib or dabrafenib) are described herein, for example, in Table. 7 and publications listed in table. 7.

In some embodiments, therapies herein may be used to treat a patient who is suffering from (or identified as suffering from) a cancer associated with an infection, such as a viral or bacterial infection. Illustrative malignancies include cervical cancer, anal cancer, HPV-associated head and neck squamous cell carcinoma, HPV-associated esophageal papillomas, HHV6-associated lymphoma, EBV-associated lymphomas (including Burkitt's lymphoma), gastric MALT lymphoma, other associated with MALT infection - lymphoma, HCC, Kaposi's sarcoma. In other embodiments, the cancer is a hematological cancer, including, but not limited to, leukemia or lymphoma. For example, an anti-LAG-3 antibody molecule can be used to treat cancers and malignancies, including, but not limited to, for example, acute leukemias, including, but not limited to, for example, B-cell acute lymphoid leukemia (BALL) , T-cell acute lymphoid leukemia (TALL), acute lymphoid leukemia (ALL); one or more chronic leukemias, including but not limited to, for example, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic malignancies or hematologic conditions, including but not limited to, for example, B-cell prolymphocytic leukemia, blast plasmacytoid dendritic cell neoplasia, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasia, Waldenström macroglobulinia, and preleukemia, which are another grouping of hematological conditions , united by inefficient production (or dysplasia) of myeloid blood cells, etc.

In one embodiment, the cancer is a melanoma, such as advanced melanoma. In one embodiment, the cancer is an advanced myeloma or inoperable melanoma that has not responded to other therapies. In other embodiments, the cancer is a melanoma with a BRAF mutation (eg, a BRAF V600 mutation). In other embodiments, the anti-LAG-3 antibody molecule is administered following treatment with an anti-CTLA4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib).

The methods and compositions described herein are useful in the treatment of metastatic lesions associated with the above cancers.

Combining anti-LAG-3 antibodies with cancer vaccines.

Anti-LAG-3 antibody molecules can be combined with an immunogenic agent such as cancer cells, purified tumor antigens (including recombinant proteins, peptides (eg, HLA-A2 peptides), and carbohydrate molecules), cells, and cells transfected with a gene

- 60 040295 mi encoding immune stimulatory cytokines (He et al., (2004) J. Immunol., 173:4919-28). Non-limiting examples of tumor vaccines that can be used include, for example, melanoma antigen peptides such as gp100 peptides, MAGE, Trp-2, MART1 antigens and/or tyrosinase or tumor cells transfected to express the cytokine GM-CSF, vaccines for DNA-based, RNA-based and virus-transduced vaccines. A cancer vaccine may be prophylactic or therapeutic.

LAG-3 blockade can be combined with a vaccination protocol. Many experimental tumor vaccination strategies have been developed (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis C, 2000, ASCO Educational Book Spring: 300-302; Khayat D. 2000, ASCO Educational Book Spring: 414-428, Foon K. 2000, ASCO Educational Book Spring: 730-738, see also Restifo N. and Sznol M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita V. et al (eds.), 1997, Cancer: Principles and Practice of Oncology Fifth Edition). In one such strategy, the vaccine is produced using autologous or allogeneic tumor cells. Such cell vaccines have been shown to be most effective when tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be an effective antigen presentation activator for tumor vaccination (Dranoff et al., (1993) Proc. Natl. Acad. Sci. USA, 90: 3539-43).

Blockade of LAG-3 can be used in combination with a group of recombinant proteins and/or peptides expressed in a tumor to generate an immune response to these proteins. Such proteins are usually recognized by the immune system as self-antigens, and thus it is tolerant to them. The tumor antigen may also include protein telomerase, which is necessary for the synthesis of chromosome telomeres and which is expressed in more than 85% of human malignant tumors and only in a limited number of somatic tissues (Kim N. et al., (1994) Science, 266: 2011-2013 ). (Such somatic tissues can be protected from immune attack in various ways). The tumor antigen can also be neoantigens expressed in malignant cells due to somatic mutations that alter the protein sequence or result in fusion proteins between two unrelated sequences (e.g., bcr-abl on the Philadelphia chromosome) or an idiotype from B cell tumors.

Other cancer vaccines may contain proteins from viruses involved in the formation of malignant tumors in humans, such as human papillomaviruses (HPV), hepatitis viruses (HBV and HCV), Epstein-Barr virus and Kaposi's sarcoma herpesvirus (KHSV). Other forms of tumor-specific antigens that can be used in conjunction with LAG-3 blockade are purified heat shock proteins (HSPs) isolated from the tumor tissue itself. These heat shock proteins contain fragments of tumor cell proteins and such HSPs are highly effective in delivering them to antigen presenting cells to induce antitumor immunity (Suot, R and Srivastava, P (1995) Science, 269:1585-1588; Tamura Y. et al., (1997) Science, 278:117-120).

Dendritic cells (DC) are efficient antigen presenting cells that can be used to stimulate antigen specific responses. DC can be produced ex vivo and can be loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle F. et al. (1998) Nature Medicine 4: 328-332). DCs can also be genetically transduced to give them the ability to express tumor antigens as well. DCs have also been directly fused to tumor cells for immunization purposes (Kugler A. et al. (2000) Nature Medicine, 6:332-336). As a vaccination method, DC immunization can be effectively combined with LAG-3 blockade to activate stronger antitumor responses.

In some embodiments, the combination further comprises an immune checkpoint modulator inhibitor or activator (e.g., PD-1 inhibitor (e.g., anti-PD-1 antibody molecule), PD-L1 inhibitor (e.g., anti-PD-L1 antibody molecule), TIM- 3 (eg, a TIM-3 activator or inhibitor, eg, an anti-TIM-3 antibody molecule) or a CTLA-4 inhibitor (eg, an anti-CTLA4 antibody), or any combination thereof.

LAG-3 blockade can also be combined with standard cancer treatment. Blockade of LAG-3 can be effectively combined with chemotherapy regimens. In these cases, it may be possible to reduce the dose of the injected chemotherapeutic agent (Mokyr M. et al., (1998) Cancer Research, 58: 5301-5304). In certain embodiments, the methods and compositions described herein are administered in combination with one or more other antibody molecules, chemotherapy, other cancer therapies (e.g., targeted cancer therapies or oncolytic drugs), cytotoxic means, types of immunological therapy (for example, cytokines), surgical methods and/or methods of radiation therapy. Illustrative cytotoxic agents that can be administered in combination include antimicrotubulin agents, topoisomerase inhibitors, antimetabolites, mitosis inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalators, agents capable of disrupting the signal transduction pathway, agents that promote apoptosis, proteasome inhibitors; and irradiation (eg, local or whole body irradiation).

Alternatively, or in combination with the above combinations, the methods and compositions described herein may be administered in combination with one or more of: an immunomodulator (eg, an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule); vaccines, for example a therapeutic cancer vaccine or other forms of cellular immunotherapy.

Illustrative non-limiting combinations and uses of anti-LAG-3 antibody molecules include the following.

In certain embodiments, an anti-LAG-3 antibody molecule is administered in combination with a co-stimulatory molecule or inhibitory molecule modulator, such as a co-inhibitory ligand or receptor.

In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with a modulator, such as an agonist, of a costimulatory molecule. In one embodiment, the costimulatory molecule agonist is selected from an agonist (e.g., agonist antibody or soluble fusion) ligand OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4- 1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83.

In another embodiment, an anti-LAG-3 antibody molecule is used in combination with a co-stimulatory molecule, eg, a positive signal-associated agonist, which contains the CD28, CD27, ICOS and GITR co-stimulatory domain.

Exemplary GITR agonists include, for example, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies) such as, for example, the GITR fusion protein described in US Pat. PCT Nos. WO 2010/003118 and 2011/090754, or an anti-GITR antibody as described in, for example, US Pat. No. 7,025,962, EP No. 1,947,183B1, US Pat. 1866339, PCT Publication No. WO 2011/028683, PCT Publication No. WO 2013/039954, PCT Publication No. WO 2005/007190, PCT Publication No. WO 2007/133822, PCT Publication No. WO 2005/055808, PCT Publication No. WO 99/40196, PCT Publication No. WO 2001/03720; PCT Publication No. WO 99/20758; PCT Publication No. WO2006/083289; PCT Publication No. WO 2005/115451; One exemplary anti-GITR antibody is TRX518.

In one embodiment, an anti-LAG-3 antibody molecule is administered in combination with an inhibitor of an inhibitory molecule (eg, an inhibitor of an immune checkpoint molecule). Those skilled in the art will understand that the term immune checkpoints refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can effectively serve as brakes, reducing or inhibiting the antitumor immune response. Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and TIM-3, which directly inhibit immune cells, immunotherapeutic agents that may act as immune checkpoint inhibitors useful in the methods of the present invention include, but are not limited to, PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, VISTA inhibitors , BTLA, TIGIT, LAIR1, CD160, 2B4, SEACAM (eg, SEACAM-1 and/or SEACAM-5) and/or TGFR-β. Inhibition of the inhibitory molecule can be carried out by inhibition at the level of DNA, RNA or protein. In embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA, or shRNA) can be used to inhibit expression of the inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, such as a soluble ligand or an antibody or antibody fragment that binds to an inhibitory molecule. Illustrative anti-TIM-3 antibody molecules include, but are not limited to, MBG220, MBG227, and MBG219. Exemplary TIGIT inhibitors include, but are not limited to, 10A7 and 1F4 (Roche).

Additional examples of modulators include, but are not limited to, B7-H5, ENTPD1, ENTPD2, SIGGIR, B7-1, B7-2, VSIG4, TIM-1, CD200, RANKL, and P2X7.

In one embodiment, the inhibitor is a soluble ligand (eg, CTLA-4-Ig or TIM-3-Ig) or an antibody or antibody fragment that binds to PD-L1, PDL2, or CTLA4. For example, an anti-LAG-3 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, such as ipilimumab. Exemplary anti-CTLA4 antibodies include tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP675,206) and ipilimumab (anti-CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9). In one embodiment, the anti-LAG-3 antibody molecule is administered post-treatment, eg, after treatment of melanoma with an anti-CTLA4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib). In one embodiment, an anti-CTLA-4 anti-body, eg, ipilimumab, is administered at a dose of approximately 3 mg/kg. The anti-LAG-3 antibody molecule can be administered in combination at a dose of about 20 to 800 mg, such as about 20, 80, 240, or 800 mg. In one embodiment, an anti-LAG-3 antibody molecule is administered every 2 weeks (eg, during weeks 1, 3, 5, 7) for each cycle of 8 weeks, eg up to 96 weeks.

In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody molecule. Exemplary doses that may be used include a dose of the anti-PD-1 antibody molecule from about 1 to 10 mg/kg, eg 3 mg/kg. The anti-LAG-3 antibody molecule can be administered in combination at a dose of about 20 to 800 mg, such as about 20, 80, 240, or 800 mg. In one embodiment, an anti-LAG-3 antibody molecule is administered every 2 weeks (eg, during weeks 1, 3, 5, 7) for each cycle of 8 weeks, eg up to 96 weeks.

Inhibitory immune molecules, eg, PD-1 and LAG-3, can regulate, eg, synergistically, T cell function, such that tumors can escape immunological surveillance. In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with an anti-TIM-3 antibody molecule. In yet another embodiment, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-L1 antibody molecule. In other embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody and an anti-TIM-3 antibody. In certain embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody and an anti-PD-L1 antibody. In certain embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-TIM-3 antibody and an anti-PD-L1 antibody. The combination of antibodies described herein may be administered separately, eg as single antibodies or linked, eg as a bispecific or trispecific antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with a CEACAM inhibitor (eg, a CEACAM-1 and/or a CEACAM-5 inhibitor), eg, an anti-CEACAM antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with a CEACAM-1 inhibitor, such as an anti-CEACAM-1 antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule is administered in combination with a CEACAM-5 inhibitor, such as an anti-CEACAM-5 antibody molecule. In one embodiment, a bispecific antibody is administered that comprises an anti-LAG-3 antibody molecule and an anti-PD-1 antibody or an anti-LAG-3 antibody. In certain embodiments, the antibody combination described herein is used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor). The efficacy of the above combinations can be tested in animal models known in the art. For example, animal models for testing the synergistic effect of an anti-LAG-3 antibody and an anti-PD-1 antibody are described in, for example, Woo et al., (2012) Cancer Res., 72(4):917-27. In one embodiment, the CEACAM inhibitor (eg, CEACAM-1 and/or CEACAM-5) is an anti-CEACAM antibody molecule. Without wishing to be bound by theory, CEACAM-1 has been described as a ligand and partner of TIM-3 (see, for example, WO 2014/022332). The in vivo synergistic effect of the combination of an anti-TIM-3 antibody and an anti-CEACAM-1 antibody has been detected in cancer xenograft models (see, for example, WO 2014/022332). Tumors are believed to use CEACAM-1 or CEACAM-5 to inhibit the immune system, as described, for example, in Markel et al., J. Immunol., 2002 Mar 15; 168(6): 2803-10; Markel et al., J. Immunol., 2006 Nov 1;177(9):6062-71; Markel et al., Immunology. 2009 Feb;126(2):186-200; Markel et al., Cancer Immunol. Immunother. 2010 Feb;59(2):215-30; Ortenberg et al., Mol. Cancer Ther. 2012 Jun;11(6):1300-10; Stern et al., J. Immunol., 2005 Jun 1;174(11):6692-701; Zheng et al., PLoS One. 2010 Sep 2;5(9).pii: el2529. Thus, CEACAM inhibitors can be used in conjunction with other immunomodulators described herein (e.g., inhibitors of anti-LAG-3 antibody, anti-PD-1 antibody, or anti-TIM-3 antibody) to enhance the immune response against cancer, e.g., melanoma, cancer. lung (eg, NSCLC), bladder, colon, or ovarian cancer, or other malignancies as described herein. In one embodiment, the CEACAM inhibitor is an anti-CEACAM-1 antibody as described in WO 2010/125571, WO 2013/82366 and WO 2014/022332, e.g. a 34B1, 26H7 and 5F4 monoclonal antibody or a recombinant form thereof, as described, for example , in US 2004/0047858, US 7132255 and WO 99/52552. In other embodiments, the anti-CEACAM antibody is an anti-CEACAM-1 antibody and/or an anti-CEACAM-5 antibody molecule as described, for example, in WO 2010/125571, WO 2013/054331 and US 2014/0271618.

In some embodiments, LAG-3 and PD-1 inhibitory immune molecules (eg, antibody molecules) are administered in combination with each other, eg, for the treatment of cancer. In some embodiments, the patient is a patient whose disease progresses (e.g., tumor growth occurs) during therapy with a PD-1 inhibitor (e.g., an antibody molecule as described herein) and/or a PD-L1 inhibitor (e.g.,

- 63 040295 antibody molecule). In some embodiments, therapy with an anti-PD-1a antibody molecule and/or an anti-PDL1 antibody molecule is continued and a LAG-3 inhibitory immune molecule (eg, antibody) is added to the therapy. In other embodiments, an anti-LAG-3 antibody molecule is administered in combination with a cytokine, e.g., interleukin-21, interleukin-2, or interleukin 15. In certain embodiments, the combination of an anti-LAG-3 antibody molecule and a cytokine described herein is used to treating a cancer, eg a cancer as described herein (eg a solid tumor or melanoma).

Illustrative immunomodulators that can be used in combination with anti-LAG-3 antibody molecules include, but are not limited to, for example, afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimide (CC4047) and cytokines such as IL-21 or IRX-2 (human cytokine mixture containing interleukin 1, interleukin 2 and interferon y, CAS 951209-71-5, available from IRX Therapeutics).

Another example of such a combination is an anti-LAG-3 antibody in combination with decarbazine for the treatment of melanoma. Another example of such a combination is an anti-LAG-3 antibody molecule in combination with interleukin 2 (IL-2) for the treatment of melanoma. In one embodiment, an anti-LAG-3 antibody molecule can be combined with IL-21. Without being bound by theory, it is believed that the combined use of LAG-3 blockade and cell death chemotherapy promotes cell death, which is a consequence of the cytotoxic effect of most chemotherapeutic compounds, which can lead to elevated levels of tumor antigen in the antigen presentation pathway. Other combination therapies that may synergize with LAG-3 blockade through cell death are radiation, surgery, and endocrine shutdown. Each of these protocols contributes to the formation of a source of tumor antigen in the host. Angiogenesis inhibitors can also be combined with LAG-3 blockade. Inhibition of angiogenesis results in the death of tumor cells that can supply tumor antigen in the host antigen presentation pathway.

Blocking antibodies against LAG-3 can also be used in combination with bispecific antibodies. Bispecific antibodies can be used to target two different antigens. For example, anti-Fc receptor/anti-tumor antigen bispecific antibodies (eg, Her-2/neu) have been used to target macrophages to tumor foci. Such targeted delivery may more effectively activate tumor-specific responses. The use of LAG-3 blockade can enhance the T-cell component of these responses. Alternatively, the use of bispecific antibodies that bind to the tumor antigen and a dendritic cell-specific cell surface marker antigen can deliver directly to the DC.

Escape of tumors from the immune surveillance of the host occurs through various mechanisms of a wide spectrum. Many of these mechanisms can be established by inactivating proteins that are expressed by tumors and that are immunosuppressive. These include, along with other TGF-β (Kehrl J. et al., (1986) J. Exp. Med., 163: 1037-1050), IL-10 (Howard M. and O'Garra A. (1992) Immunology Today, 13: 198-200) and Fas ligand (Hahne M. et al., (1996) Science, 274: 1363-1365). Antibodies against each of these compounds can be used in combination with an anti-LAG-3 antibody to inhibit the action of an immunosuppressive agent and promote antitumor responses in the host.

Other antibodies that can be used to activate the host's immunological reactivity can be used in combination with an anti-LAG-3 antibody. They include molecules on the surface of dendritic cells that activate DC function and antigen presentation. Anti-CD40 antibodies can serve as an effective substitute for T helper cell activity (Ridge J. et al., (1998) Nature, 393: 474-478) and can be used in combination with anti-LAG-3 antibodies (Ito N. et al. ., (2000) Immunobiology, 201(5)527-40). Activating antibodies against T-cell co-stimulatory molecules such as CTLA-4 (e.g. US Pat. No. 5,811,097), OX-40 (Weinberg A. et al., (2000) Immunol., 164: 2160-2169), 4-1BB (Melero I. et al., (1997) Nature Medicine, 3: 682-685 (1997) and ICOS (Hutloff A. et al., (1999) Nature, 397: 262-266) can also be used to increase activation levels T cells.

Additional exemplary treatments that can be used in combination with anti-LAG-3 antibody molecules are described in the section below entitled Combination Treatment Methods.

In all of the above methods, LAG-3 blockade can be combined with other forms of immunotherapy, such as cytokine therapy (eg, interferons, GM-CSF, GCSF, IL-2, IL-21) or bispecific antibody therapy, which provides increased presentation tumor antigens (see, for example, Holliger (1993) Proc. Natl. Acad. Sci. USA, 90:6444-6448; Poljak, (1994) Structure, 2:1121-1123).

Methods for introducing anti-LAG-3 antibody molecules are known in the art and are described below.

- 64 040295

Suitable doses of molecules used depend on the age and weight of the individual and the particular drug used. One skilled in the art can determine dosages and treatment regimens for anti-LAG-3 antibody molecules. In certain embodiments, the anti-LAG-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg , about 1 to 5 mg/kg, or about 3 mg/kg, or about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, or about 40 mg/kg. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 1-3 mg/kg, or about 310 mg/kg. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 0.5-2, 2-4, 2-5, 5-15, or 5-20 mg/kg. The dosing schedule may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 10 to 20 mg/kg once every two weeks.

The antibody molecule can be used in conjugated forms or conjugated to a second agent, such as a cytotoxic drug, a radioactive isotope, or a protein, such as a protein toxin or a virus protein. The method includes: administering an antibody molecule or a cytotoxic drug conjugated molecule to an individual in need of such treatment. An antibody molecule can be used to deliver a variety of therapeutic agents, such as a cytotoxic molecule, such as a therapeutic drug, a radioactive isotope, a molecule of plant, fungal, or bacterial origin, or biological proteins (e.g., protein toxins) or particles (e.g., recombinant viral particles, e.g., via viral envelope protein) or mixtures thereof.

Additional combined treatment.

The anti-LAG-3 antibody molecule can be used in combination with other therapies. For example, a combination treatment may include a composition of the present invention co-formulated with and/or co-administered with one or more additional therapeutic agents, such as one or more anti-cancer agents, cytotoxic or cytostatic agents, hormonal treatments, vaccines, and/or other types of immunotherapy. In other embodiments, the antibody molecules are administered in combination with other therapies, including surgery, radiation, cryosurgery, and/or thermotherapy. Such combination treatments can advantageously use lower doses of administered therapeutic agents, thus avoiding the potential toxicities or complications associated with various monotherapies. In one embodiment, the anti-LAG-3 antibody is administered in combination with the therapies described herein at a dose of about 20 to 800 mg, such as about 20, 80, 240, or 800 mg. In one embodiment, the anti-LAG-3 antibody molecule is administered every week, every 2 weeks (eg, at 1, 3, 5, 7 weeks) for each cycle of 8 weeks, eg, up to 96 weeks.

In one embodiment, the composition described herein is administered in combination with other antibody molecules, such as one or more of: an antibody described herein, a chemotherapeutic agent, a cytotoxic agent, surgical methods, and/or radiation therapy methods. Illustrative chemotherapeutic and/or cytotoxic agents that can be administered in combination include anti-microtubulin agents, topoisomerase inhibitors, antimetabolites, mitosis inhibitors, alkylating agents, intercalators, agents capable of disrupting the signal transduction pathway, agents that promote apoptosis, and radiation. Illustrative other antibody molecules that can be administered in combination include, but are not limited to, checkpoint inhibitors (eg, PD-1, PD-L1); antibodies that stimulate an immune cell (eg, anti-GITR or CD137 agonist antibodies); anti-cancer antibodies (eg, rituximab (Rituxan® or MabThera®), trastuzumab (Herceptin®), cetuximab (Erbitux®).

By in combination with does not imply that the therapy or therapeutic agents must be administered simultaneously and/or formulated for co-delivery, although these delivery methods are included in the scope described in the present description. Anti-LAG-3 antibody molecules can be administered simultaneously, before or after one or more other adjunctive therapies or therapeutic agents. The anti-LAG-3 antibody molecule and the other agent or therapeutic protocol may be administered in any order. In general, each agent is administered at a dose and/or time schedule predetermined for that agent. It should also be understood that the additional therapeutic agent used in this combination may be administered together in the same composition or administered separately in different compositions. In general, additional therapeutic agents used in combination are expected to be used at levels that do not exceed the levels at which they are used individually. In some embodiments, levels used in combination will be lower than levels used individually. The effect of the two treatments may be partially additive, fully additive, or more than additive. Delivery may be

- 65 040295 that the effect of the first treatment administered is still detectable when the second treatment is administered.

The antibody molecules can be administered in combination with one or more of the existing cancer treatments, including but not limited to: surgery; radiation therapy (for example, external beam radiation therapy, which includes three-dimensional conformal radiation therapy, where the radiation field is designed.

In certain embodiments, the anti-LAG-3 antibody molecules described herein are administered in combination with one or more PD-1, PD-L1 and/or PD-L2 inhibitors known in the art. The antagonist may be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide.

In some embodiments, another anti-PD-1 antibody is selected from MDX-1106, Merck 3475, or CT-011.

In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin containing an extracellular or PD-1 binding region of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence).

In some embodiments, the PD-L1 inhibitor is an anti-PDL1 antibody. In some embodiments, the PD-L1 binding antibody antagonist is selected from YW243,55.S70, MPDL3280A, MEDI-4736, MSB-OO1O718C, or MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874. The YW243,55.S70 antibody (heavy and light chain variable region sequences shown in SEQ ID NOs: 20 and 21, respectively) is an anti-PD-L1 antibody described in WO 2010/077634.

In some embodiments, the anti-PD-1 antibody is nivolumab. Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. In some embodiments, the anti-PD-1 antibody is nivolumab (CAS accession number: 946414-94-4). Nivolumab (also referred to as BMS-936558 or MDX1106; Bristol-Myers Squibb) is a wholly human IgG4 monoclonal antibody that blocks PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are described in US 8008449, EP2161336 and WO 2006/121168.

Pidilizumab (CT-011, Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD-1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are described in WO 2009/101611.

In other embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (trade name Keytruda, formerly lambrolizumab, also known as MK-3475) is described, for example, in Hamid O. et al., (2013) New England Journal of Medicine, 369 (2): 134-44.

Other anti-PD-1 antibodies include AMP 514 (amplyimmune), LZV178 and LZV181 among others, for example the anti-PD1 antibodies described in US 8609089, US 2010028330 and/or US 20120114649.

In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1. Pembrolizumab and other humanized anti-PD-L1 antibodies are described in WO 2013/079174.

MDPL3280A (Genentech/Roche) is an Fc-optimized human IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies against PD-L1 are described in US Pat. No. 7,943,743 and US Publication No. 20120039906. Other PD-L1 binding agents include YW243.55.S70 (heavy and light chain variable regions are shown in SEQ ID NOs 20 and 21 WO 2010/077634) and MDX-1105 (also referred to as BMS936559 and, for example, the PD-L1 binding agents described in WO 2007/005874).

In some embodiments, the PD-1 inhibitor is AMP-224. AMP-224 (B7-DCIg; Amplimmune; eg described in WO 2010/027827 and WO 2011/066342) is a Fc-fused soluble PD-L2 receptor that blocks the interaction between PD1 and B7-H1.

In some embodiments, the PD-1 inhibitor is MEDI4736.

Types of cancer therapy.

Exemplary combinations of anti-LAG-3 antibody molecules (alone or in combination with other stimulants) and standards of cancer therapy include at least the following.

In certain embodiments, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule described herein, is used in combination with a standard cancer chemotherapeutic agent, including, but not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU ®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytarabinoside (Cytosar-U®), liposomal cytarabine injection ( DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), liposomal daunorubicin citrate injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamyc in®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), calcium leucovorin, melphalan (Alkeran®), 6mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone) ®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polypheprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa , tirapazamine (Tirazone®), topotecan hydrochloride injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), ibrutinib, idelisib, and brentuximab vedotin.

Exemplary alkylating agents include, but are not limited to, nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas, and triazenes): uramustine (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen mustard®, Uracillost ®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®) , chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®) , carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); temozolomide (Temodar® and Temodal®); dactinomycin (also known as Actinomycin-D, Cosmegen®); melphalan (also known as L-PAM, L-sarcolysin and phenylalanine, Alkeran®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); lomustine (also known as CCNU, CeeNU®); cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); chlorambucil (Leukeran®); cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, DTIC-Dome®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosfamide (Ifex®); prenumustine; procarbazine (Matulane®); mechlorethamine (also known as nitric acid, mustine, and mechlorethamine hydrochloride, Mustargen®); streptozocin (Zanosar®); thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®) and bendamustine HCl (Treanda®).

Illustrative anthracyclines include, for example, doxorubicin (Adriamycin® and Rubex®); bleomycin (lenoxane®); daunorubicin (daurubicin hydrochloride, daunomycin and rubidomucin hydrochloride, Cerubidine®); daunorubicin in lysosomal form (liposome with daunorubicin citrate, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimucin; ravidomucin and dezaacetyl ravidomucin.

Exemplary vinca alkaloids that can be used in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g., anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) include, but are not limited to, vinorelbine tartrate (Navelbine®), vincristine (Oncovin®) and vindesine (Eldisine®)); vinblastine (also known as vinblastine sulfate, vincaleukoblastin and VLB, Alkaban-AQ® and Velban®) and vinorelbine (Navelbine®).

Exemplary proteasome inhibitors that can be used in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g., anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) include, but are not limited to, bortezomib (Velcade®); carfilzomib (PX-171-007, (S)-4-methyl-N-((S)-1-(((S)-4-metul-1-((R)-2-metuloxuran-2-yl) -1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4phenylbutanamido)pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770) and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2- methyl-2oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX-0912).

In some embodiments, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule). ), is used in combination with a tyrosine kinase inhibitor (eg, a receptor tyrosine kinase (RTK) inhibitor). Exemplary tyrosine kinase inhibitors include, but are not limited to, an inhibitor of the epidermal growth factor (EGF) pathway (e.g., an inhibitor of the epidermal factor receptor

- 67 040295 growth factor (EGFR)), an inhibitor of the vascular endothelial growth factor (VEGF) pathway (for example, an inhibitor of the vascular endothelial growth factor receptor (VEGFR) (for example, a VEGFR-1 inhibitor, a VEGFR-2 inhibitor, a VEGFR-3 inhibitor)), a platelet growth factor (PDGF) pathway inhibitor (eg, a platelet growth factor receptor (PDGFR) inhibitor (eg, a PDGFR-β inhibitor)), a RAF-1 inhibitor, a KIT inhibitor, and an RET inhibitor. In some embodiments, the cancer agent used in combination with the hedgehog protein inhibitor is selected from the group consisting of: axitinib (AG013736), bosutinib (SKI-606), sederanib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS -354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272) , nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®) , bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF04217903, PF-02341066, PF -299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozaniba (AV-951), OSI-930 , MM-121, XL-184, XL-647, XL228, AEE788, AG-490, AST-6, BMS-599626, CUDC-101, PD153035, Pelitinib (EKB-569), Vandetanib (Zaktima), WZ3146, WZ4002 , WZ8040, ABT-869 (linifaniba), AEE788, AP24534 (ponatinib), AV-951 (tivozaniba), axitinib, BAY 73-4506 (regorafenib), brivanib alaninate (BMS-582664), brivanib (BMS-540215), sederanib (AZD2171), CHIR-258 (dovitinib), CP 673451, CYC116, E7080, Ki8751, mazitinib (AB1010), MGCD-265, motesanib diphosphate (AMG-706), MP-470, OSI-930, pazopanib hydrochloride, PD173074, sorafenib tosylate (Bay 43-9006), SU 5402, TSU-68(SU6668), vatalanib, XL880 (GSK1363089, EXEL-2880).

Selective tyrosine kinase inhibitors are selected from sunitinib, erlotinib, gefitinib or sorafenib.

In certain embodiments, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) used in combination with vascular endothelial growth factor (VEGF) receptor inhibitors including, but not limited to, bevacizumab (Avastin®), axitinib (Inlyta®); brivanib alaninate (BMS582664, (S)-((R)-1 -(4-(4-fluoro-2-methyl-1 H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1 ,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (Nexavar®); pazopanib (Votrient®); sunitinib malate (Sutent®); cediranib (AZD2171, CAS 288383-20-1); vargatef (BIBF1120, CAS 928326-83-4); foretinib (GSK1363089); telatinib (BAY57-9352, CAS 332012-40-5); apatinib (YN968D1, CAS 811803-05-1); imatinib (Gleevec®); ponatinib (AP24534, CAS 943319-70-8); tivozanib (AV951, CAS 475108-18-0); regorafenib (BAY73-4506, CAS 755037-03-7); vatalanib dihydrochloride (RTK787, CAS 212141-51-0); brivanib (BMS-540215, CAS 649735-46-6); vandetanib (Caprelsa® or AZD6474); motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]3-pyridinecarboxamide, described in PCT Publication No. WO 02/066470); dovitinib dilactic acid (TKI258, CAS 852433-84-2); linfanib (ABT869, CAS 796967-16-3); cabozantinib (XL184, CAS 849217-68-1); lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-N1,2,4]triazin-5-yl)methyl)piperidin-3-ol ( BMS690514); N-(3,4-dichloro-2fluorophenyl)-6-methoxy-7-[[(3aa,5c,6aa)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647 , CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide (BHG712, CAS 940310-85-0) and aflibercept (Eylea®).

Exemplary anti-VEGF antibodies include, but are not limited to, a monoclonal antibody that binds to the same epitope as the anti-VEGF monoclonal antibody A4.6.1 produced by ATCC HB 10709 hybridoma; recombinant humanized anti-VEGF monoclonal antibody prepared according to Presta et al., (1997) Cancer Res., 57:4593-4599. In one embodiment, the anti-VEGF antibody is bevacizumab (BV), also known as rhuMAb VEGF or AVASTIN®. It contains mutant human IgG1 framework regions and antigen-binding complementarity-determining regions from the mouse anti-hVEGF monoclonal antibody A.4.6.1, which blocks the binding of human VEGF to its receptors. Bevacizumab and other humanized anti-VEGF antibodies are further described in US Pat. No. 6,884,879 published Feb. 26, 2005. Additional antibodies include antibodies of the G6 or B20 series (e.g., G6-31, B20-4.1) as described in PCT Publication No. WO 2005/012359, PCT Publication No. WO 2005/044853, the contents of these patent applications are expressly incorporated herein by

- 68 040295 by reference. For additional antibodies, see US patents No. 7060269, 6582959, 6703020, 6054297; W098/45332; WO 96/30046; WO94/10202; EP 0666868B1; U.S. Patent Application Publication Nos. 2006009360, 20050186208, 20030206899, 20030190317, 20030203409 and 20050112126; and Popkov et al, Journal of Immunological Methods, 288: 149-164 (2004). Other antibodies include antibodies that bind to a functional epitope on human VEGF containing residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103 and C104, or alternatively containing residues F17, Y21, Q22, Y25, D63 , 183 and Q89.

In some embodiments, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule). ), used in combination with a PI3K inhibitor. In one embodiment, the PI3K inhibitor is an inhibitor of the δ and γ isoforms of PI3K. Exemplary PI3K inhibitors that can be used in combination are described, for example, in WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556. Exemplary PI3K inhibitors that can be used in combination include, for example, GSK 2126458, GDC-0980, GDC-0941, XL147 from Sanofi, XL756, XL147, PF-46915032, VKM 120, CAL-101, CAL 263, SF1126, PX -886 and dual PI3K (e.g. BEZ235 from Novartis).

In some embodiments, an anti-LAG-3 antibody molecule described herein alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used in combination with an mTOR inhibitor, for example, one or more mTOR inhibitors selected from one or more of rapamycin, temsirolimus (TORISEL®), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE- 354, Palomid 529 (P529), PF-04691502 or PKI-587.

Ridaforolimus (formerly known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R, 19R,21R,23S,24E,26E,28Z,30S ,32S,35R)-1,18-dihydroxu-19,30-dimethoxu-15,17,21,23,29,35-hexamethyl2,3,10,14,20-pentaoxo-11,36-dioxa-4- azatricyclo[30.3.1.0 ^4,9 ]hexatriaconta-16,24,26,28-tetraen-12yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03/064383); everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); emsirolimus, (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidine-7(8H)- he (PF04691502, CAS 1013101 -36-4) and N ² -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4 -yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartyl-L-serine, internal salt (SF1126, CAS 936487-67-1) and XL765.

In some embodiments, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) , is used in combination with a BRAF inhibitor such as GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720 and sorafenib tosylate (Bay 43-9006).

In some embodiments, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) , used in combination with a MEK inhibitor. In some embodiments, the combination of an anti-LAG-3 antibody and a MEK inhibitor is used to treat a cancer (eg, the cancer described herein). In some embodiments, the cancer being treated with the combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hemoblastosis, or renal cell carcinoma. In certain embodiments, the cancer contains a BRAF mutation (eg, BRAF V600E mutation), wild-type BRAF, wild-type KRAS, or an activating KRAS mutation. A malignant tumor may be at an early, middle or late stage. Any MEK inhibitor can be used in combination, including but not limited to ARRY-142886, G02442104 (also known as GSK1120212), RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (also known as AZD6244 orselumetinib), BIX 02188, BIX 02189, CI-1040 (PD-184352), PD0325901, PD98059, U0126, GDC-0973 (Methanone, [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy -3-(25)-2-piperidinyl-1-azetidinyl]), G-38963, G02443714 (also known as AS703206) or a pharmaceutically acceptable salt or solvate thereof. Additional examples of MEK inhibitors are described in WO 2013/019906, WO 03/077914, WO 2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, the contents of which are incorporated herein by reference.

In another embodiment, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used in combination with one, two, or all of oxaliplatin, leucovorin or 5-FU

- 69 040295 (eg co-administration of FOLFOX preparations). Alternatively, or in combination, the combination further comprises a VEGF inhibitor (eg, a VEGF inhibitor as described herein). In some embodiments, a combination of an anti-LAG-3 antibody, co-administration of FOLFOX drugs, and a VEGF inhibitor is used to treat a cancer (eg, the cancer described herein). In some embodiments, the cancer being treated with the combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hemoblastosis, or renal cell carcinoma. A malignant tumor may be at an early, middle or late stage.

In some embodiments, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule described herein alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule). ), used in combination with a JAK2 inhibitor, eg CEP-701, INCB18424, CP-690550 (tazocytinib).

In some embodiments, a pharmaceutical composition described herein alone or in combination with another immunomodulator (e.g., anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used in combination with paclitaxel or a paclitaxel-based agent, eg TAXOL®, protein-bound paclitaxel (eg ABRAXANE®). Exemplary paclitaxel-based agents include, but are not limited to, nanoparticle albumin-bound paclitaxel (Abraxane, commercially available from Abraxis Bioscience), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin, commercially available from Protarga), polyglutaminate-bound paclitaxel (PG-paclitaxel, paclitaxel polyglumex, CT-2103, XYOTAX, commercially available from Cell Therapeutic), tumor-activated prodrug (TAP), ANG105 (angiopep 2 linked to three molecules of paclitaxel, commercially available from ImmunoGen), paclitaxel- EC-1 (paclitaxel coupled to erbB2 recognition peptide EC-1; see Li et al., Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g., 2'paclitaxelmethyl-2-glucopyranosyl succinate, see Liu et al., Bioorganic and Medicinal Chemistry Letters, (2007) 17:617-620).

Radiation therapy can be delivered by one of several methods or a combination of methods, including, but not limited to, external beam radiation therapy, internal radiation therapy, implantable radiation source, stereotaxic radiosurgery, systemic radiation therapy, radiation therapy, and permanent or temporary interstitial brachytherapy. The term brachytherapy refers to radiation therapy delivered by a spatially confined radioactive substance injected into the body at or near a tumor or other site of proliferative tissue disease. The term is intended to include, without limitation, exposure to radioactive isotopes (eg, At211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu radioactive isotopes). Suitable radiation sources for use as cell conditioning in the present invention include both solids and liquids. As a non-limiting example, the radiation source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a liquid source, or other radionuclides that emit photons, β particles , γ-radiation or other types of therapeutic radiation. The radioactive material may also be a liquid obtained from any solution of the radionuclide(s), such as a solution of I-125 or I-131, or the radioactive liquid may be obtained using a slurry of a suitable liquid containing small particles of solid radionuclides such as Au-198 , Y-90. In addition, the radionuclide(s) can be formed into a gel or radioactive microspheres.

The anti-LAG-3 antibody molecules, alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) can be administered in combination with one or more of the existing cancer therapies, including, but not limited to: surgery; radiation therapy (eg, external beam radiation therapy, which includes three-dimensional conformal radiation therapy, where the irradiation field is designed, local irradiation (eg, irradiation directed to a preselected target or organ), or focused irradiation).

Focused radiation can be selected from the group consisting of stereotactic radiosurgery, fractionated stereotaxic radiosurgery, and intensity modulated radiation therapy. Focused irradiation may be characterized by a radiation source selected from the group consisting of a particle beam (proton), cobalt 60 (photon) and a linear accelerator (X-rays), for example, as described in WO 2012/177624.

In certain embodiments, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used with an anti-killer cell immunoglobulin-like receptor antibody (also referred to herein as an anti-KIR antibody), an anti-KIR broad spectrum antibody, an anti-NKG2D antibody, and an anti-MICA antibody. In certain embodiments

- 70 040295 a combination of an anti-LAG-3 antibody molecule, an anti-PD-1 antibody molecule, and an anti-KIR antibody, an anti-KIR broad spectrum antibody, an anti-MICA antibody, or an anti-NKG2D antibody described herein is used to treat cancer, e.g. a tumor as described herein (eg a solid tumor, eg an advanced solid tumor).

In one embodiment, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used in conjunction with a cellular immunotherapy (e.g., provenge (e.g., sipuleucel)) and optionally in combination with cyclophosphamide. In certain embodiments, the combination of an anti-LAG-3 antibody molecule, an anti-PD-1 antibody molecule, provenge, and/or cyclophosphamide is used to treat a cancer, e.g., a cancer as described herein (e.g., prostate cancer, e.g., cancer prostate at an advanced stage).

In another embodiment, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used with a vaccine, for example, a dendritic cell vaccine against renal cell carcinoma (DC-RCC). In certain embodiments, the combination of an anti-LAG-3 antibody molecule, an anti-PD-1 antibody molecule, and/or a DC-RCC vaccine is used to treat a cancer, e.g., a cancer as described herein (e.g., renal cell carcinoma, e.g., metastatic renal cell carcinoma (RCC)).

In one embodiment, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used in combination with chemotherapy to treat lung cancer, for example, non-small cell lung cancer. In one embodiment, an anti-LAG-3 antibody molecule is used in conjunction with platinum doublet therapy for the treatment of lung cancer.

In yet another embodiment, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used to treat a kidney cancer, such as renal cell carcinoma (RCC). ) or metastatic RCC. The anti-LAG-3 antibody molecule can be administered in combination with one or more of: an immunological strategy (eg, interleukin 2 or interferon-α), a targeted delivery agent (eg, a VEGF inhibitor such as an anti-VEGF monoclonal antibody); a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib; an RNAi inhibitor) or an inhibitor of downstream mediators of the VEGF signaling cascade, such as the mammalian target inhibitor of rapamycin (mTOR), such as everolimus and temsirolimus.

Example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) described herein for the treatment of cancer pancreas includes, but is not limited to, a chemotherapeutic agent such as paclitaxel or a paclitaxel-based agent (eg, a paclitaxel-based formulation such as taxol, an albumin-stabilized paclitaxel nanoparticulate formulation (eg, abraxane), or a paclitaxel liposomal formulation); gemcitabine (eg, gemcitabine alone or in combination with AChP107-11); other chemotherapeutic agents such as oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicin hydrochloride, NC-6004, cisplatin, docetaxel (eg taxotere), mitomycin C, ifosfamide; interferon; tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, erlotinib, panitumumab, cetuximab, nimotuzumab); HER2/neu receptor inhibitor (eg, trastuzumab); dual kinase inhibitor (eg, bosutinib, saracatinib, lapatinib, vandetanib); multikinase inhibitor (eg, sorafenib, sunitinib, XL184, pazopanib); VEGF inhibitor (eg, bevacizumab, AV-951, brivanib); radioimmunotherapy (eg, XR303); cancer vaccine (eg, GVAX, survivin peptide); COX-2 inhibitor (eg, celecoxib); IGF-1 receptor inhibitor (eg, AMG 479, MK-0646); mTOR inhibitor (eg, everolimus, temsirolimus); IL-6 inhibitor (eg, CNTO 328); cyclin-dependent kinase inhibitor (eg, P276-00, UCN-01); compound targeting altered energy metabolism (AEMD) (eg CPI-613); HDAC inhibitor (eg vorinostat); TRAIL 2 receptor (TR-2) agonist (eg conatumumab); MEK inhibitor (eg , AS703026, selumetinib, GSK1120212); double and kinase inhibitor Raf/MEK (eg RO5126766); an inhibitor of the Notch signaling cascade (eg, MK0752); fusion protein monoclonal antibody-antibody (for example, L19IL2); curcumin; an HSP90 inhibitor (eg tanespimucin, STA-9090); rIL-2; denileukin diftitox; a topoisomerase 1 inhibitor (eg, irinotecan, PEP02); a statin (eg simvastatin); a factor VIIa inhibitor (eg, PCI-27483); an AKT inhibitor (eg RX-0201); hypoxia-activated prodrug (eg, TH-302); metformin hydrochloride, γ-secretase inhibitor (eg RO4929097); a ribonucleotide reductor tase inhibitor (eg, 3-AR); immunotoxin (eg HuC242-DM4); a PARP inhibitor (eg KU0059436, veliparib); a CTLA-4 inhibitor (eg CP-675.206, ipilimumab); AdV-tk therapy; a proteasome inhibitor (eg, bortezomib (Velcade), NPI-0052); thiazolidinedione (eg pioglitazone); NPC-1C; Aurora kinase inhibitor (eg R763/AS703569), CTGF inhibitor (eg FG-3019); siG12D LODER and radiation therapy (eg, tomotherapy, stereotactic radiation, proton therapy), surgery, and a combination thereof. In certain embodiments, a combination of paclitaxel or a paclitaxel and gemcitabine agent can be used with the anti-PD-1 antibody molecules described herein.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of small cell lung cancer includes, but not limited to, a chemotherapeutic agent, for example, etoposide, carboplatin, cisplatin, oxaliplatin, irinotecan, topotecan, gemcitabine, liposomal SN-38, bendamustine, temozolomide, belotecan, NK012, FR901228, flavopiridol); tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor (eg, sorafenib, sunitinib); VEGF inhibitor (eg, bevacizumab, vandetanib); cancer vaccine (eg, GVAX); inhibitor Bcl-2 (eg, oblimersen sodium, ABT-263), proteasome inhibitor (eg, bortezomib (Velcade), NPI-0052), paclitaxel or paclitaxel-based agent, docetaxel, IGF-1 receptor inhibitor (eg, AMG 479); HGF/SF inhibitor (eg, AMG 102, MK-0646); chloroquine; Aurora kinase inhibitor (eg, MLN8237); radioimmunotherapy (eg, TF2); HSP90 inhibitor (eg, tanespimucin, STA-9090); mTOR inhibitor (eg, everolimus), an Ep-CAM/CD3 bispecific antibody (eg, MT110), a CK-2 inhibitor (eg, Cx-4945);

an HDAC inhibitor (eg, belinostat); an SMO antagonist (eg BMS 833923); cancer peptide vaccine and radiation therapy (eg, intensity modulated radiation therapy (IMRT), hypofractionated radiation therapy, hypoxic radiation therapy), surgery, and combinations thereof.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of non-small cell lung cancer includes, but not limited to, chemotherapeutic agent, e.g. vinorelbine, cisplatin, docetaxel, pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine, irinotecan, tegafur-gimeracil-oteracil potassium, capacitabine) ; tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804, nimotuzumab, RO5083945), MET inhibitor (eg, PF-02341066, ARQ 197), PI3K kinase inhibitor (eg, XL147, GDC-0941), Raf/MEK kinase dual inhibitor (eg, RO5126766), PI3K/mTOR kinase dual inhibitor (eg, XL765), SRC inhibitor (eg, dasatinib), dual inhibitor (eg, BIBW 2992, GSK1363089, ZD6474, AZD0530 , AG-013736, lapatinib, MEHD7945A, linifanib), multikinase inhibitor (eg, sorafenib, sunitinib, pazopanib, AMG 706, XL184, MGCD265, BMS-690514, R935788), VEGF inhibitor (eg, endostar, endostatin, bevacizumab, cederanib, BIBF 1120, axitinib, tivozanib, AZD2171), cancer vaccine (eg, BLP25 lysosomal vaccine, GVAX, recombinant DNA and adenovirus expressing L523S protein), Bcl-2 inhibitor (eg, oblimersen sodium), proteasome inhibitor (eg, bortezomib , carfilzomib, NP I0052, MLN9708), paclitaxel or paclitaxel-based agent, docetaxel, IGF-1 receptor inhibitor (eg, cixitumumab, MK-0646, OSI 906, CP-751,871, BIIB022), hydroxychloroquine, HSP90 inhibitor (eg, tanespimucin, STA-9090 , AUY922, XL888), mTOR inhibitor (eg, everolimus, temsirolimus, ridaforolimus), Ep-CAM/CD3 bispecific antibody (eg, MT110), CK-2 inhibitor (eg, CX-4945), HDAC inhibitor (eg, MS 275, LBH589, vorinostat, valproic acid, FR901228), DHFR inhibitor (eg, pralatrexate), retinoid (eg, bexarotene, tretinoin), antibody drug conjugate (eg, SGN-15), bisphosphonate (eg, zoledronic acid) , cancer vaccine (eg, belagenpumatucel-L), low molecular weight heparin (LMWH) (eg, tinzaparin, enoxaparin), GSK1572932A, melatonin, talactoferrin, dimesna, topoisomerase inhibitor (eg, amrubicin, etoposide, carenitecin), nelfinavir, cilengitide, an ErbB3 inhibitor (eg. MM-121, U3-1287), survivin inhibitor (eg, YM155, LY2181308), eribulin mesilate, COX-2 inhibitor (eg, celecoxib), pegfilgrastim, Polo-like kinase 1 inhibitor (eg, BI 6727), TRAIL receptor agonist 2 (TR-2) (e.g. CS1008), CNGRC peptide conjugate (SEQ ID NO: 293)-TNF-a, dichloroacetate (DCA), HGF inhibitor (e.g. SCH 900105), SAR240550, PPAR-γ agonist (e.g., CS-7017), γ-secretase inhibitor (eg, RO4929097), epigenetic therapy (eg, 5-azacytidine), nitroglycerin, MEK inhibitor (eg, AZD6244), cyclin-dependent kinase inhibitor (eg, UCN-01), cholesterol-Fus1, antitube

- 72 040295 line agent (eg E7389), farnesyl OH transferase inhibitor (eg lonafarnib), immunotoxin (eg BB-10901, SSI (dsFv) PE38), fondaparinux, vasoconstrictor (eg AVE8062), inhibitor PD-L1 (eg, MDX-1105, MDX-1106), β-glucan, NGR-hTNF, EMD 521873, MEK inhibitor (eg, GSK1120212), epothilone analog (eg, ixabepilone), spindle kinesin inhibitor (eg, 4SC- 205), telomere targeting agent (eg, KML-001), P70 pathway inhibitor (eg, LY2584702), AKT inhibitor (eg, MK-2206), angiogenesis inhibitor (eg, lenalidomide), Notch signaling cascade inhibitor (eg, OMR-21M18), radiation therapy, surgery and combinations thereof.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of ovarian cancer includes, but does not limited to, a chemotherapeutic agent (e.g., paclitaxel or paclitaxel-based agent; docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin; irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, melphalan, pemetrexed disodium, SJG-136, cyclophosphamide, etoposide, decitabine); ghrelin antagonist (eg, AEZS-130), immunotherapy (eg, APC8024, oregovomab, ORT-821), tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, erlotinib), dual inhibitor (eg, E7080), multikinase inhibitor (eg, AZD0530 , JI-101, sorafenib, sunitinib, pazopanib), ON 01910.Na), VEGF inhibitor (eg, bevacizumab, BIBF 1120, sederanib, AZD2171), PDGFR inhibitor (eg, IMC-3G3), paclitaxel, topoisomerase inhibitor (eg, carenitecin, irinotecan), HDAC inhibitor (eg, valproate, vorinostat), folic acid receptor inhibitor (eg, farletuzumab), angiopoietin inhibitor (eg, AMG 386), epothilone analog (eg, ixabepilone), proteasome inhibitor (eg, carfilzomib), IGF-1 receptor inhibitor (eg, OSI 906, AMG 479), PARP inhibitor (eg, veliparib, AG014699, iniparib, MK-4827), Aurora kinase inhibitor (eg, MLN8237, ENMD-2076), angiogenesis inhibitor (eg, lenalidomide ), DHFR inhibitor (e.g. pralatrexate), RA dioimmunotherapeutic agent (eg Hu3S193), statin (eg lovastatin), topoisomerase 1 inhibitor (eg NKTR-102), cancer vaccine (eg p53 synthetic long peptide vaccine, autogenous OC-DC vaccine), mTOR inhibitor (eg, temsirolimus, everolimus), BCR/ABL inhibitor (eg, imatinib), ET-A receptor antagonist (eg, ZD4054), TRAIL 2 (TR-2) receptor agonist (eg, CS-1008), HGF/SF inhibitor (e.g. AMG 102), EGEN-001, Polo-like kinase 1 inhibitor (e.g. BI 6727), γ-secretase inhibitor (e.g. RO4929097), Wee-1 inhibitor (e.g. MK-1775), antitubulin agent (e.g. , vinorelbine, E7389), immunotoxin (eg, denileukin diftitox), SB-485232, vascular disruptor (eg, AVE8062), integrin inhibitor (eg, EMD 525797), spindle kinesin inhibitor (eg, 4SC-205), revlimid, inhibitor HER2 (eg MGAH22), ErrB3 inhibitor (eg MM-121), radiotherapy and their combinations.

In one exemplary embodiment, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used to treat myeloma alone or in combination with one or more from: chemotherapy or other anticancer agents (e.g. thalidomide analogues e.g. lenalidomide), HSCT (Cook R. (2008) J. Manag. Care Pharm., 14(7 Suppl):19-25), anti-TIM3 antibodies (Hallett WHD et al., (2011) J. of American Society for Blood and Marrow Transplantation 17(8):1133-145), tumor antigen-activated dendritic cells, fusions (eg, electrofusions) of tumor cells and dendritic cells, or idiotype vaccinations immunoglobulin produced by malignant plasma cells (reviewed in Yi Q. (2009) Cancer J. 15(6):502-10).

In yet another embodiment, an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) is used to treat a kidney cancer, such as renal cell carcinoma ( RCC) or metastatic RCC. The anti-PD-1 antibody molecule can be administered in combination with one or more of: an immunological strategy (eg, interleukin-2 or interferon-α), a targeted delivery agent (eg, a VEGF inhibitor such as an anti-VEGF monoclonal antibody, such as bevacizumab ( Rini B. I. et al., (2010) J. Clin. Oncol., 28(13):2137-2143)); a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib, and pazopanib (reviewed in Pal S.K. et al., (2014) Clin. Advances in Hematology and Oncology, 12(2):90-99)); an RNAi inhibitor) or an inhibitor of downstream mediators of the VEGF signaling cascade, such as the mammalian target of rapamycin (mTOR) inhibitor, such as everolimus and temsirolimus (Hudes G. et al., (2007) N. Engl. J. Med., 356 (22): 2271-2281, Motzer R. J. et al., (2008) Lancet, 372: 449-456).

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of chronic myelogenous leukemia

- 73 040295 for (AML) according to the invention includes, but is not limited to, a chemotherapeutic agent (for example, cytarabine, hydroxyurea, clofarabine, melphalan, thiotepa, fludarabine, busulfan, etoposide, cordycepin, pentostatin, capecitabine, azacitidine, cyclophosphamide, cladribine, topotecan ), tyrosine kinase inhibitor (eg, BCR/ABL inhibitor (eg, imatinib, nilotinib), ON 01910.Na, dual inhibitor (eg, dasatinib, bosutinib), multikinase inhibitor (eg, DCC-2036, ponatinib, sorafenib, sunitinib, RGB -286638)), interferon-α, steroids, apoptosis-inducing agent (eg, omacetaxin mepesuccinate), immunotherapy (eg, allogeneic CD4+ Th1-like memory T cells/microparticle-associated anti-CD3/anti-CD28 antibody, autologous cell-inducible cytokine- killer (CIK), AHN-12), CD52 targeting agent (eg, alemtuzumab), HSP90 inhibitor (eg, tanespimucin, STA-9090, AUY922, XL888), mTOR inhibitor (eg, everolima c), SMO antagonist (eg BMS 833923), ribonucleotide reductase inhibitor (eg 3-AP), JAK-2 inhibitor (eg INCB018424), Hydroxychloroquine, retinoid (eg fenretinide), cyclin-dependent kinase inhibitor (eg UCN-01 ), HDAC inhibitor (eg, belinostat, vorinostat, JNJ-26481585), PARP inhibitor (eg, veliparib), MDM2 antagonist (eg, RO5045337), Aurora kinase B inhibitor (eg, TAK-901), radioimmunotherapy (eg, actinium labeled -225 anti-CD33 antibody HuM195), Hedgehog inhibitor (eg PF-04449913), STAT3 inhibitor (eg ORV-31121), KB004, cancer vaccine (eg AG858), bone marrow transplant, stem cell transplant, radiotherapy and their combinations.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of chronic lymphocytic leukemia (CLL) includes, but is not limited to, a chemotherapeutic agent (e.g., fludarabine, cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, 5-azacytidine, pemetrexed disodium), a tyrosine kinase inhibitor (e.g., a EGFR (eg, erlotinib), BTK inhibitor (eg, PCI32765), multikinase inhibitor (eg, MGCD265, RGB-286638), CD-20 targeting agent (eg, rituximab, ofatumumab, RO5072759, LFB-R603), agent targeting CD52 (eg, alemtuzumab), prednisolone, darbepoetin α, lenalidomide, Bc1-2 inhibitor (eg, ABT-263), immunothermo anti-CD3/CD28 antibody (eg, allogeneic CD4+ Th1-like memory T cells/microparticle-associated antibody against CD3/CD28, autologous cytokine-inducible killer (CIK) cells), HDAC inhibitor (eg, vorinostat, valproic acid, LBH589, JNJ-26481585, AR- 42), an XIAP inhibitor (eg, AEG35156), a CD-74 targeting agent (eg, milatuzumab), an mTOR inhibitor (eg, everolimus), AT-101, an immunotoxin (eg, CAT-8015, anti-Tac( Fv)-PE38 (LMB-2)), CD37 targeting agent (eg, TRU-016), radioimmunotherapy (eg, 131-tositumomab), hydroxychloroquine, perifosine, SRC inhibitor (eg, dasatinib), thalidomide, PI3K inhibitor delta (eg, CAL-101), retinoid (eg, fenretinide), MDM2 antagonist (eg, RO5045337), plerixaphor, Aurora kinase inhibitor (eg, MLN8237, TAK-901), proteasome inhibitor (eg, bortezomib), targeted delivery to CD-19 medium (e.g. MEDI-551, MO R208), MEK inhibitor (eg, ABT-348), JAK-2 inhibitor (eg, INCB018424), hypoxia-activated prodrug (eg, TH-302), paclitaxel or paclitaxel-based agent, HSP90 inhibitor, AKT inhibitor (eg, MK2206 ), an HMG-CoA inhibitor (eg, simvastatin), GNKG186, radiation therapy, bone marrow transplantation, stem cell transplantation, and combinations thereof.

Example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of acute lymphocytic leukemia (ALL) includes, but is not limited to, a chemotherapeutic agent (e.g., prednisolone, dexamethasone, vincristine, asparaginase, daunorubicin, cyclophosphamide, cytarabine, etoposide, thioguanine, mercaptopurine, clofarabine, liposomal annamycin, busulfan, etoposide, capecitabine, decitabine, azacitidine, topotecan, temozolomide ), a tyrosine kinase inhibitor (eg, a BCR/ABL inhibitor (eg, imatinib, nilotinib), ON 01910.Na, a multikinase inhibitor (eg, sorafenib)), a CD-20 targeting agent (eg, rituximab), a targeting agent targeting CD52 (eg, alemtuzumab), HSP90 inhibitor (eg, STA-9090), mTOR inhibitor (eg, everolimus, rapamycin), inhibition JAK-2 inhibitor (eg, INCB018424), HER2/neu receptor inhibitor (eg, trastuzumab), proteasome inhibitor (eg, bortezomib), methotrexate, asparaginase, CD-22 targeting agent (eg, epratuzumab, inotuzumab), immunotherapy (eg, autologous cytokine-inducible killer (CIK), AHN-12), blinatumomab, cyclin-dependent kinase inhibitor (eg, UCN-01), CD45 targeting agent (eg, BC8), MDM2 antagonist (eg,

- 74 040295

RO5045337), immunotoxin (eg, CAT-8015, DT2219ARL), HDAC inhibitor (eg, JNJ26481585), JVRS-100, paclitaxel or paclitaxel-based agent, STAT3 inhibitor (eg,

ORV-31121), a PARP inhibitor (eg, veliparib), EZN-2285, radiation therapy, a steroid, bone marrow transplantation, stem cell transplantation, or a combination thereof.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (eg, an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of acute myeloid leukemia (AML) includes but not limited to, a chemotherapeutic agent (e.g., cytarabine, daunorubicin, idarubicin, clofarabine, decitabine, vozaroxin, azacitidine, clofarabine, ribavirin, CPX-351, treosulfan, elacytarabine, azacitidine), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor ( e.g. imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (e.g. midostaurin, SU 11248, quisartinib, sorafinib)), immunotoxin (e.g. gemtuzumab ozogamicin), DT388IL3 fusion protein, HDAC inhibitor (e.g. vorinostat, LBH589), plerixaphor, mTOR inhibitor (eg, everolimus), SRC inhibitor (eg, dasatinib), HSP90 inhibitor (eg, STA-9090), retinoid (eg, bexarotene, Aurora kinase inhibitor (eg, B I 811283), JAK-2 inhibitor (eg, INCB018424), Polo-like kinase inhibitor (eg, BI 6727), cenersen, CD45 targeting agent (eg, BC8), cyclin-dependent kinase inhibitor (eg, UCN-01 ), MDM2 antagonist (eg, RO5045337), mTOR inhibitor (eg, everolimus), LY573636-sodium, ZRx-101, MLN4924, lenalidomide, immunotherapy (eg, AHN-12), histamine dihydrochloride, radiotherapy, bone marrow transplantation, transplantation stem cells and their combination.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of multiple myeloma (MM) includes but not limited to, a chemotherapeutic agent (e.g., melphalan, amifostine, cyclophosphamide, doxorubicin, clofarabine, bendamustine, fludarabine, adriamycin, SyB L-0501), thalidomide, lenalidomide, dexamethasone, prednisone, pomalidomide, proteasome inhibitor (e.g., bortezomib, carfilzomib, MLN9708), cancer vaccine (eg, GVAX), CD-40 targeting agent (eg, SGN-40, CHIR-12,12), perifosin, zoledronic acid, immunotherapy (eg, Mage-Az , NY-ESO-1, HuMax-CD38), HDAC inhibitor (eg, vorinostat, LBH589, AR-42), aplidine, cyclin-dependent kinase inhibitor (eg, PD0332991, dinaciclib), arsenic trioxide, CB3304, HSP90 inhibitor (nap example, KW-2478), tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, cetuximab), multikinase inhibitor (eg, AT9283)), VEGF inhibitor (eg, bevacizumab), plerixaphor, MEK inhibitor (eg, AZD6244), IPH2101, atorvastatin , immunotoxin (eg, BB-10901), NPI-0052, radioimmunotherapy (eg, yttrium Y90 ibritumomab tiuxetan), STAT3 inhibitor (eg, ORV-31121), MLN4924, Aurora kinase inhibitor (eg, ENMD-2076), IMGN901 , ACE-041, a CK-2 inhibitor (eg, CX-4945), radiation therapy, bone marrow transplantation, stem cell transplantation, and combinations thereof.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of prostate cancer includes, but not limited to, chemotherapy (eg, docetaxel, carboplatin, fludarabine), abiraterone, hormone therapy (eg, flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, degarelix, leuprolide, goserelin, triptorelin, buserelin), inhibitor tyrosine kinase (eg, dual kinase inhibitor (eg, lapatanib), multikinase inhibitor (eg, sorafenib, sunitinib)), VEGF inhibitor (eg, bevacizumab), TAK-700, cancer vaccine (eg, BRX-101, PEP223), lenalidomide, TOK-001, IGF-1 receptor inhibitor (eg cixutumumab), TRC105, Aurora A kinase inhibitor (eg MLN8237), proteasome inhibitor (eg p, bortezomib), OGX-011, radioimmunotherapy (eg, HuJ591-GS), HDAC inhibitor (eg, valproic acid, SB939, LBH589), hydroxychloroquine, mTOR inhibitor (eg, everolimus), dovitinib lactate, diindolylmethane, efavirenz, OGX- 427, genistein, IMC-3G3, bafetinib, CP-675,206, radiation therapy, surgery, or a combination thereof.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (eg, an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of HNSCC includes, but is not limited to them, one or both of Compound A8 as described herein (or the compound described in PCT Publication No. WO 2010/029082) and cetuximab (eg Erbitux, commercially available from BMS). In some embodiments, the therapeutic agent (eg, an A8 compound or an A8 related compound) is a PI3K modulator, such as a PI3K inhibitor. In some embodiments, the therapeutic agent (eg, cetuximab) modulates, for example, inhibits EGFR. In some embodiments, the cancer has, or is identified to have, elevated levels or activity of PI3K or EGFR compared to a control cell or reference value.

Example of suitable therapeutic agents for use in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g. anti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) for the treatment of gastric cancer, e.g. high MSI and/or EBV+ gastric cancer includes, but is not limited to, Compound A8 as described herein (or the compound described in PCT Publication No. WO 2010/029082). In some embodiments, the therapeutic agent (eg, an A8 compound or an A8 related compound) is a PI3K modulator, eg, a PI3K inhibitor. In some embodiments, the cancer has, or is identified to have, elevated PI3K levels or activity compared to a control cell or reference value.

An example of suitable therapeutic agents for use in combination with an anti-LAG-3 antibody molecule alone or in combination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of gastric cancer, for example, with high MSI and/or RNF43-inactivated gastric cancer includes, but is not limited to, compound A28 as described herein (or the compound described in PCT Publication No. WO2010/101849). In some embodiments, the therapeutic agent (eg, compound A28 or an A28-related compound) is a modulator, eg, a porcupine inhibitor. In some embodiments, the cancer has, or is identified to have, increased levels or activity of porcupin compared to a control cell or reference value.

Example of suitable therapeutic agents for use in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g. anti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) for the treatment of GI stromal tumor (GIST) includes, but is not limited to, compound A16 as described herein (or the compound described in PCT Publication No. WO 1999/003854). In some embodiments, the therapeutic agent (eg, an A16 compound or an A16-related compound) is a modulator, eg, a tyrosine kinase inhibitor. In some embodiments, the cancer has, or is identified to have, elevated tyrosine kinase levels or activity compared to a control cell or reference value.

Example of suitable therapeutic agents for use in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g. anti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) for the treatment of NSCLC, e.g. squamous cell carcinoma or adenocarcinomas, includes, but is not limited to, one or both of compound A17 as described herein (or compound described in US Pat. Nos. 7,767,675 and 8,420,645) and compound A23 as described herein (or compounds described in PCT Publication No. WO 2003/077914). In some embodiments, a compound (eg, an A17 compound or an A17-related compound) modulates, eg, inhibits c-MET. In some embodiments, a compound (eg, an A23 compound or an A23-related compound) modulates, eg, inhibits Alk. In some embodiments, the cancer has, or is identified to have, elevated levels or activity of one or both of cMET or Alk compared to a control cell or reference value. In some embodiments, the cancer has, or is identified to have, an EGFR mutation.

Example of suitable therapeutic agents for use in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g. anti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) for the treatment of melanoma (e.g. NRAS melanoma ) includes, but is not limited to, one or both of Compound A24 as described herein (or the compound described in US Pat. Nos. 8,415,355 and 8,685,980) and Compound A34 as described herein (or PCT Publication No. WO 2003/077914). In some embodiments, a compound (eg, an A24 compound or an A24-related compound) modulates, eg, inhibits one or more of JAK and CDK4/6. In some embodiments, a compound (eg, an A34 compound or an A34-related compound) modulates, eg, inhibits MEK. In some embodiments, the cancer has, or is identified to have, elevated levels or activity of one or more of JAK, CDK4/6, and MEK compared to a control cell or reference value.

Example of suitable therapeutic agents for use in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g. anti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) for the treatment of melanoma (e.g. NRAS melanoma ) includes, but is not limited to, one or both of Compound A29 as described herein (or the compound described in PCT Publication No. WO 2011/025927) and Compound A34 as described herein (or the compound described in PCT Publication No. WO 2003/077914).

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In some embodiments, a compound (eg, an A29 compound or an A29-related compound) modulates, eg, inhibits BRAF. In some embodiments, a compound (eg, an A34 compound or an A34-related compound) modulates, eg, inhibits, MEK. In some embodiments, the cancer has, or is identified to have, elevated levels or activity of one or both of BRAF and MEK compared to a control cell or reference value.

An example of suitable therapeutic agents for use in combination with anti-LAG-3 antibody molecules, alone or in combination with another immunomodulator (e.g., anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of squamous NSCLC includes, but not limited to, the compound A5 as described in the present description (or the compound described in US patent No. 8552002). In some embodiments, a compound (eg, an A5 compound or an A5 related compound) modulates, eg, inhibits FGFR. In some embodiments, the cancer has, or is identified to have, increased FGFR levels or activity compared to a control cell or reference value.

An example of suitable therapeutic agents for use in combination with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g., anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of colorectal cancer includes, but does not limited to, one or both of Compound A29 as described herein (or Compound PCT Publication No. WO 2011/025927) and Cetuximab (eg, Erbitux, commercially available from BMS). In some embodiments, the therapeutic agent (eg, compound A29 or an A29 related compound) modulates, eg, inhibits BRAF. In some embodiments, the therapeutic agent (eg, cetuximab) modulates, eg, inhibits EGFR. In some embodiments, the cancer has, or is identified to have, elevated levels or activity of BRAF or EGFR compared to a control cell or reference value.

The present invention also relates to a method of treating cancer with compound A8, cetuximab and an anti-LAG-3 antibody molecule (optionally in combination with an anti-PD-1a antibody or an anti-TIM-3 antibody molecule). In some embodiments, the patient is first treated with compound A8 and cetuximab. This treatment is continued for a period of time, eg a predetermined period, eg for about 1, 2, 4, 6, 8, 10 or 12 months. An anti-LAG-3 antibody molecule is then administered (optionally in combination with an anti-PD-1a antibody molecule or an anti-TIM-3 antibody molecule). The anti-LAG-3 antibody may optionally be administered in combination with cetuximab.

In some embodiments, the patient first receives treatment with all three of compound A8, cetuximab, and an anti-LAG-3 antibody molecule (optionally in combination with an anti-PD-1a antibody or an anti-TIM-3 antibody molecule). Such treatment is continued for a period of time, eg a predetermined period of time, eg approximately 6, 8, 10 or 12 months. The dose of compound A8 and/or cetuximab is then reduced such that the maintenance phase includes treatment with an anti-LAG-3 antibody molecule (eg, as monotherapy or in combination with an anti-PD-1a antibody or an anti-TIM-3 antibody molecule), but not compound A8 or cetuximab.

In other embodiments, the three compounds (compound A8, cetuximab, and an anti-LAG-3 antibody molecule, optionally in combination with an anti-PD-1a antibody or a TIM-3 antibody molecule) are administered sequentially at the start of treatment. For example, Compound A8 and cetuximab may be administered first as described above. An anti-LAG-3 antibody molecule (optionally in combination with an anti-PD-1a antibody or an anti-TIM3 antibody molecule) is then added to the treatment regimen. The dose of compound A8 and/or cetuximab can then be reduced as described above.

Exemplary dosages for three (or more) agents of the treatment regimen are as follows. The anti-LAG-3 antibody molecule can be administered, for example, at a dose of about 1 to 40 mg/kg, such as 1 to 30 mg/kg, such as about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg. In some embodiments, Compound A8 is administered at a dose of about 200-300, 300-400, or 200-400 mg. In some embodiments, cetuximab is administered at an initial dose of 400 mg/m ² as a 120-minute intravenous infusion followed by 250 mg/m ² every week infused over 60 minutes. In embodiments, one or more of compound A8, cetuximab, and a LAG-3 antibody molecule is administered at a dose that is lower than the dose at which such an agent would typically be administered as monotherapy, e.g., about 0-10%, 10 -20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower than the dose at which such an agent is typically administered as monotherapy. In embodiments, one or more of compound A8, cetuximab, and an anti-LAG-3 antibody molecule is administered at a dose that is lower than the dose of such an agent given in this paragraph, e.g., about 0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower than the dose of such agent given in this paragraph. In certain embodiments of the concentrate

The ratio of Compound A8 that is necessary to obtain inhibition, eg growth inhibition, is lower when Compound A8 is administered in combination with one or both of cetuximab and an anti-LAG-3 antibody molecule than when Compounds A8 is administered alone. In certain embodiments, the concentration of cetuximab that is necessary to obtain inhibition, e.g., growth inhibition, is lower when cetuximab is administered in combination with one or both of Compound A8 and an anti-LAG-3 antibody molecule than when cetuximab is administered alone. In certain embodiments, the concentration of the anti-LAG-3 antibody molecule that is necessary to obtain inhibition, e.g., growth inhibition, is lower when the anti-LAG-3 antibody molecule is administered in combination with one or both of cetuximab and Compound A8 than when the anti-LAG-3 antibody molecule is administered separately.

Additionally described herein is a method of treating cancer with anti-LAG-3 antibody molecules alone or in combination with another immunomodulator (e.g., anti-PD-1, anti-PD-L1, or anti-TIM-3 antibody molecule) and a cancer targeted agent. , for example, an agent that targets one or more proteins. In some embodiments, an anti-LAG-3 antibody molecule (and optionally other immunomodulator(s)) is administered first, followed by an anti-cancer targeting agent. The time interval between administration of the anti-LAG-3 antibody molecule and the cancer targeting agent may be, for example, 10, 20, or 30 minutes, 1, 2, 4, 6, or 12 hours, or 1, 2, 3, 4, 5 , 6 or 7 days, or any period of time in this range. In certain embodiments, the anti-LAG-3 antibody molecule is administered repeatedly over a period of time (e.g., 1, 2, 3, 4, 5, or 6 days, or 1, 2, 4, 8, 12, 16, or 20 weeks, or any interval time within this range) before the cancer targeting agent is administered. In other embodiments, the anti-LAG-3 antibody molecule and the cancer targeting agent are administered substantially simultaneously.

Infectious diseases.

Other methods of the invention are used to treat patients who have been exposed to specific toxins or pathogens. Thus, another aspect of the invention relates to a method of treating an infectious disease in a subject, comprising administering to the subject an anti-LAG-3 antibody molecule such that the infectious disease is treated in the subject.

In the treatment of infection (eg, acute and/or chronic), the administration of anti-LAG-3 antibody molecules (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-TIM-3 antibody molecule) can be combined with conventional therapies. in addition to or instead of stimulating the body's natural immune defenses against infection. The host's natural immune defenses against infection include, but are not limited to, inflammation, fever, antibody-mediated host defenses, T-lymphocyte-mediated host defenses, including lymphokine secretion and cytotoxic T cells (especially during viral infection), complement-mediated lysis, and opsonization (facilitated phagocytosis) and phagocytosis. The ability of anti-LAG-3 antibody molecules to reactivate dysfunctional T cells is useful in the treatment of chronic infections, in particular chronic infections in which cellular immunity is essential for complete recovery.

Similar to its use in tumors as noted above, LAG-3 mediated blockade can be used alone or as an adjuvant in combination with vaccines to stimulate an immune response to pathogens, toxins and self antigens. Examples of pathogens for which such a therapeutic approach may be particularly useful include pathogens for which no effective vaccine currently exists or pathogens for which conventional vaccines are not fully effective. These include, but are not limited to, hepatitis (A, B, and C), influenza, HIV, herpes, giardia, malaria, leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa. Blockade of LAG-3 is particularly useful against established infections with agents such as HIV that present altered antigens when infections occur. These new epitopes are recognized as foreign at the time of administration of the anti-human LAG-3 antibody, thus inducing a strong T cell response that is not attenuated by negative signals through LAG-3.

Viruses.

For infections caused by viruses, anti-LAG-3 antibody molecules (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody or anti-TIM-3 antibody molecule) can be combined by application simultaneously, before or after standard therapies treatment of viral infections. Such standard therapies vary depending on the type of virus, although in most cases it may be effective to administer human serum containing antibodies (eg, IgA, IgG) specific to the virus.

Some examples of pathogenic viruses that cause infections that can be treated include hepatitis (A, B, or C), influenza virus (A, B, or C), HIV, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, CMV, Epstein-Barr virus), adenovirus, flaviviruses, echovirus, rhinovirus, coxsackievirus, coronovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus , HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, and arbovirus encephalitis virus.

In one embodiment, the infection is an influenza infection. Influenza infection can lead to fever, cough, myalgia, headache, and general malaise, which often occur during seasonal outbreaks. Influenza is also associated with a number of postinfectious disorders such as encephalitis, myopericarditis, Goodpasture's syndrome, and Reye's syndrome. Influenza infection also suppresses normal pulmonary antibacterial defenses, such that patients recovering from influenza are at increased risk of developing bacterial pneumonia. The surface of influenza virus proteins is characterized by marked antigenic variability resulting from mutation and recombination. Thus, cytolytic T-lymphocytes are the host's primary means of eliminating the virus after infection. Influenza is classified into three main types: A, B, and C. Influenza A is unique in that it infects both humans and many other animals (such as pigs, horses, birds, and seals) and is a major cause of influenza pandemics. Also, when a cell is infected with two different strains of influenza A, the segmented RNA genomes of the two types of parental viruses mix during replication to form a hybrid replicant, resulting in new pandemic strains. Influenza B does not replicate in animals and thus has less genetic variation, and influenza C has only one serotype.

Most conventional therapies are to relieve the symptoms associated with the infection, while the host's immune response actually clears the disease. However, certain strains (such as influenza A) can cause more serious illness and death. Influenza A can be treated clinically and prophylactically with the cyclic amine inhibitors amantadine and rimatadine, which inhibit viral replication. However, the clinical utility of such drugs is limited due to the relatively high incidence of adverse reactions, their narrow antiviral spectrum (influenza A only), and the ability of the virus to become resistant. Administration of serum IgG antibodies to the major influenza surface proteins hemagglutinin and neuraminidase can prevent lung infection, while mucosal IgA is essential to prevent upper respiratory and tracheal infections. The most effective treatment currently available for influenza is vaccination with formalin or β-propiolactone inactivated virus. In one embodiment, the LAG-3 antibody molecule is administered in combination with an influenza antigen or influenza vaccine.

In another embodiment, the infection is a hepatitis infection, such as hepatitis B or C infection.

Hepatitis B virus (HB-V) is the best known infectious blood-borne pathogen. It is the main cause of acute and chronic hepatitis and hepatic carcinoma, as well as lifelong chronic infection. After infection, the virus replicates in hepatocytes, which then also secrete the HBsAg surface antigen. Detection of excessive serum HBsAg levels is used as a standard method for diagnosing hepatitis B infection. An acute infection may resolve or it may develop into a chronic resistant infection. Current treatments for chronic HBV include α-interferon, which upregulates human leukocyte class I antigen (HLA) expression on the surface of hepatocytes, thus facilitating their recognition by cytotoxic T-lymphocytes. In addition, the nucleoside analogs ganciclovir, famciclovir, and lamivudine have also shown some efficacy in treating HBV infection in clinical trials. Additional treatments for HBV include pegylated interferon-alpha, adenfovir, entecavir, and telbivudine. While passive immunity can be obtained by initial administration of serum anti-HBsAg antibodies, vaccination with inactivated or recombinant HBsAg also confers resistance to infection. For therapeutic benefit, an anti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-TIM-3 antibody) molecule can be combined with conventional therapies for hepatitis B infections. In one embodiment, the anti-LAG-3 antibody molecule is administered in combination with a hepatitis B antigen or hepatitis B vaccine, and optionally in combination with an aluminum-containing adjuvant.

Infection with hepatitis C virus (HC-V) can lead to chronic hepatitis leading to cirrhosis. Although symptoms are similar to hepatitis B infections, unlike HB-V, infected hosts may be asymptomatic for 10 to 20 years. An anti-LAG-3 antibody molecule can be administered as monotherapy (or in combination with an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-TIM-3 antibody), or all of the above can be combined with a standard of care for hepatitis C infection. For example , the anti-LAG-3 antibody molecule can be administered with one or more of Sovaldi (sofosbuvir) Olysio (simeprevir) plus ribavirin or pegylated interferon. Although regimens that include Incivek (telaprevir) or Victrelis (boceprevir) plus ribavirin and pegylated interferon are also approved, they are associated with an increased incidence of side effects and longer duration of treatment, and thus are not considered the preferred treatment regimens.

Conventional treatment for HC-V infection involves the administration of a combination of α-interferon and ribavirin. A promising potential therapy for HC-V infections is the protease inhibitor telaprevir (VX-960). Additional treatments include: anti-PD-1 antibody (eg, MDX-1106, Medarex), bavituximab (antibody that binds to the anionic phosphatidylserine phosphatidylserine in a B2-glycoprotein I dependent manner, Peregrine Pharmaceuticals), anti-E2 coat protein antibody(ala) HPV virus (eg ATL 6865-Ab68+Ab65, XTL Pharmaceuticals) and Civacir® (human anti-HCV polyclonal immunoglobin). Anti-LAG-3 antibody molecules can be combined with one or more of these treatments for hepatitis C infections to provide a therapeutic benefit. Protease, polymerase and NS5A inhibitors that can be used in combination with anti-LAG-3 antibody molecules for the specific treatment of hepatitis C infection include those described in US 2013/0045202, incorporated herein by reference.

In another embodiment, the infection is a measles virus. After an incubation of 9-11 days, hosts infected with the measles virus develop fever, cough, rhinitis, and conjunctivitis. Within 1-2 days, an erythematous, maculopapular rash develops, which quickly spreads throughout the body. Because the infection also suppresses cellular immunity, the host is at higher risk for bacterial superinfections, including otitis media, pneumonia, and postinfectious encephalomyelitis. Acute infection is associated with significant morbidity and mortality, especially in malnourished adolescents.

Treatment of measles involves the passive administration of pooled human IgG, which can prevent infection in non-immunized individuals, even if more than one week has passed since exposure. However, pre-immunization with live, attenuated virus is the most effective treatment and prevention of disease in more than 95% of those immunized. Because there is a single serotype of this virus, a single immunization or infection usually results in lifelong immunity to subsequent infection.

In a small proportion of infected hosts, measles can develop into SSPE, which is a chronic progressive neurological disorder resulting from persistent infection of the central nervous system. SSPE is caused by clonal variants of the measles virus with defects that impair virion assembly and budding. For such patients, reactivated T cells with anti-LAG-3 antibody molecules are desirable to facilitate clearance of the virus.

In another embodiment, the infection is HIV. HIV attacks CD4+ cells, including T lymphocytes, monocyte macrophages, follicular dendritic cells, and Langerhans cells, and CD4+ helper/inducing cells are depleted. As a result, the host acquires a severe defect in cellular immunity. HIV infection leads to AIDS in at least 50% of individuals and is transmitted through sexual contact, ingestion of infected blood or blood products, artificial insemination with infected semen, exposure to blood-containing needles or syringes, and transmission from an infected mother to her child during childbirth.

An HIV-infected host may not show symptoms or may develop an acute illness that is similar to mononucleosis fever, headache, sore throat, general malaise, and rash. Symptoms may progress to progressive immune dysfunction, including persistent fever, night sweats, weight loss, unexplained diarrhea, eczema, psoriasis, seborrheic dermatitis, herpes zoster, oral candidiasis, and oral hairy leukoplakia. Opportunistic host infections with parasites are common in patients who develop infections into AIDS.

HIV treatments include antiviral therapies including nucleoside analogues, zidovudine (AST) alone or in combination with didanosine or zalcitabine, dideoxyinosine, dideoxycytidine, lamidvudine, stavudine; reverse transcriptase inhibitors such as delavirdine, nevirapine, loviride; and proteinase inhibitors such as saquinavir, ritonavir, indinavir and nelfinavir. For therapeutic benefit, an anti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody or anti-TIM-3 antibody molecule) can be combined with conventional treatments for HIV infections.

In another embodiment, the infection is a cytomegalovirus (CMV). CMV infection is often associated with persistent, latent, and recurrent infection. CMV infects and remains latent in monocytes and granulocyte-monocyte precursor cells. Clinical symptoms of CMV include mononucleosis-like symptoms (ie, fever, swollen glands, general malaise) and a tendency to develop allergic skin rashes in response to antibiotics. The virus is spread by direct contact. The virus is shed in urine, saliva, seminal fluid and, to a lesser extent, other body fluids. Transmission can also occur from an infected mother to her fetus or newborn, and through blood transfusion and organ transplantation. CMV infection mainly results in a disorder of cellular immunity characterized by

- 80 040295 weakened reactions of blast transformation to non-specific mitogens and specific CMV antigens, reduced cytotoxic ability and an increased number of CD8 lymphocytes relative to CD4+ lymphocytes.

Treatments for CMV infection include the antivirals ganciclovir, foscarnet, and cidovir, but these drugs are generally reserved for immunosuppressed patients. For therapeutic benefit, an anti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-TIM-3 antibody) molecule can be combined with conventional treatments for cytomegalovirus infections.

In another embodiment, the infection is an Epstein-Barr virus (EBV). EBV can cause persistent and latent infections and predominantly attacks B cells. EBV infection results in the clinical condition of infectious mononucleosis, which includes fever, sore throat, often with exudate, generalized lymphadenopathy, and splenomegaly. Hepatitis is also present, against which jaundice can develop.

Although conventional treatments for EBV infections aim to relieve symptoms, EBV has been associated with the development of certain cancers such as Burkitt's lymphoma and nasopharyngeal cancer. Thus, clearing the viral infection before these complications occur would be of significant benefit. For therapeutic benefit, an anti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-TIM-3 antibody molecule) can be combined with conventional treatments for Epstein-Barr virus infections.

In another embodiment, the infection is a herpes simplex virus (HSV). HSV is transmitted by direct contact with an infected host. Contact infection may be asymptomatic but usually results in blisters containing infectious particles. The disease manifests itself in the form of cycles of active periods of the disease, during which lesions appear and disappear, because. the virus latently infects the nerve ganglion until subsequent outbreaks. The lesions may be on the face, genitals, eyes and/or hands. In some cases, the infection can also cause encephalitis.

Treatments for herpes infections are primarily aimed at resolving symptomatic outbreaks and include systemic antiviral drugs such as: acyclovir (eg, Zovirax®), valocyclovir, famciclovir, penciclovir, and topical drugs such as docosanol (Abreva®), tromantadine, and zilactin. Clearance of latent herpes infections would bring significant clinical benefit. For therapeutic benefit, an anti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-TIM-3 antibody molecule) can be combined with conventional treatments for herpes virus infections.

In another embodiment, the infection is human T-lymphotropic virus (HTLV-1, HTLV-2). HTLV is transmitted through sexual contact, breastfeeding, or through exposure to toxic blood. The virus activates a subgroup of Th cells called Th1 cells, leading to their overproliferation and overproduction of Th1-related cytokines (eg, IFN-γ and TNF-α). This in turn leads to suppression of Th2 lymphocytes and decreased production of Th2 cytokines (eg, IL-4, IL-5, IL-10, and IL-13), which causes a decrease in the ability of the infected host to develop an adequate immune response to invasive organisms, for which requires a Th2-dependent response for clearance (eg, parasitic infections, production of mucosal and humoral antibodies).

HTLV infections lead to opportunistic infections leading to bronchiectasis, dermatitis, and superinfections with Staphylococcus spp. and Strongyloides spp., leading to death from polymicrobial sepsis. HTLV infection can also lead directly to adult T-cell leukemia/lymphoma and to progressive upper motor neuron demyelinating disease known as HAM/TSP. Clearance of latent HTLV infections would bring significant clinical benefit. For therapeutic benefit, anti-LAG-3 antibody molecules (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-TIM-3 antibody molecule) can be combined with conventional treatments for HTLV infections.

In another embodiment, the infection is human papillomavirus (HPV). HPV predominantly affects keratinocytes and appears in two forms: cutaneous and genital. Transmission is believed to occur through direct contact and/or sexual activity. Skin and genital infection HPV infection can lead to warts and latent infections, and in some cases recurrent infections, which are suppressed by the host's immune system, which suppresses symptoms and blocks the onset of warts, but leaves the host able to transmit the infection to others.

HPV infection can also lead to certain cancers such as cervical cancer, anal cancer, vulvar cancer, penile cancer, and oropharyngeal cancer. There are no known

- 81 040295 drugs for HPV infection, but the current treatment is the topical application of imiquimod, which stimulates the immune system to attack the affected area. Clearance of latent HPV infections would bring significant clinical benefit. For therapeutic benefit, an anti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1 antibody, anti-PD-L1 antibody or anti-TIM-3 antibody molecule) can be combined with conventional treatments for HPV infections.

bacterial infections.

Some examples of pathogenic bacteria that can be treated with the methods of the invention include syphilis, chlamydia, rickettsia bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and gonococci, Klebsiella, proteus, serratia, Pseudomonas aeruginosa, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis and Lyme disease bacteria. An anti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-TIM-3 antibody molecule) can be used in combination with existing treatments for the above infections. For example, treatments for syphilis include penicillin (eg, penicillin G), tetracycline, doxycycline, ceftriaxone, and azithromycin.

Lyme disease, caused by Borrelia burgdorferi, is transmitted to humans through tick bites. The disease first presents as a localized rash followed by flu-like symptoms, including general malaise, fever, headache, neck stiffness, and arthralgia. Further manifestations may include migratory and polyarticular arthritis, neurological and cardiac lesions with cranial nerve palsy and radiculopathy, myocarditis, and arrhythmia. Some cases of Lyme disease become resistant, resulting in permanent damage similar to tertiary syphilis. The current therapy for Lyme disease mainly involves the administration of antibiotics. Antibiotic-resistant strains can be treated with hydroxychloroquine or methotrexate. Antibiotic-resistant patients with neuropathic pain can be treated with gabapentin. Minocycline may be useful in advanced Lyme disease/chronic Lyme disease with neurological or other inflammatory manifestations.

Other forms of borreliosis, such as forms of borreliosis caused by B. recurentis, B. hermsii, B. turicatae, B. parikeri., B. hispanica, B. duttonii and B. persica, as well as leptospirosis (for example, L. interrogans), usually resolve spontaneously unless blood titers reach concentrations that cause intrahepatic obstruction.

fungi and parasites.

Some examples of pathogenic fungi that cause infections that can be treated alone with the methods of the invention include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales ( mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Some examples of pathogenic parasites that cause infections that can be treated with the methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp. , Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Nippostrongylus brasiliensis.

Additional methods of combined treatment.

Provided herein are combinations of anti-LAG-3 antibody molecules with one or more second therapeutic agents. Many of the combinations in this section are useful in the treatment of cancer, and other indications are also described. This section focuses on combinations of anti-LAG-3 antibody molecules, optionally in combination with one or more immunomodulators (e.g., anti-PD-1 antibody molecule, anti-TIM-3 antibody molecule, or anti-PD-L1 antibody molecule), with one or more of the agents described in table. 7. In the combinations herein below, in one embodiment, an anti-LAG-3 antibody molecule comprises (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 286; the amino acid sequence of VHCDR2SEQ ID NO: 2 and the amino acid sequence of VHCDR3 SEQ ID NO: 3 and (ii) a light chain variable region (VL) containing the amino acid sequence of VLCDR SEQ ID NO: 10, the amino acid sequence of VLCDR2 SEQ ID NO: 11 and the amino acid sequence of VLCDR3 SEQ ID NO: 12.

In one embodiment, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PKC inhibitor, sotrastaurine (compound A1), or a compound described in PCT Publication No. WO 2005/039549 for the treatment of a disorder, for example the disorder described herein. In one embodiment, the PKC inhibitor is sotrastaurine (compound A1) or the compound described in PCT Publication No. WO 2005/039549. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with sotrastaurine (Compound A1) or a compound as described in PCT Publication No. WO 2005/039549 to treat a disorder such as cancer, melanoma, non-Hodgkin's lymphoma, inflammatory bowel disease, transplant rejection, ophthalmic disorder, or psoriasis.

In certain embodiments, sotrastaurine (Compound A1) is administered at a dose of about 20 to about 600 mg, such as about 200 to about 600 mg, about 50 mg to about 450 mg, about 100 mg to about 400 mg, about 150 mg to about 350 mg. or about 200 mg to about 300 mg, such as about 50, 100, 150, 200, 300, 400, 500, or 600 mg. The dosing schedule can be changed, for example, every other day - every day, twice or three times a day.

In one embodiment, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the BCR-ABL inhibitor, TASIGNA (compound A2 or a compound described in PCT Publication No. WO 2004/005281 for the treatment of a disorder, such as the disorder described herein.In one embodiment, the BCR-ABL inhibitor is TASIGNA or a compound described in PCT Publication No. WO 2004/005281. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with TASIGNA (Compound A2) or a compound as described in PCT Publication No. WO 2004/005281 for the treatment of a disorder such as lymphocytic leukemia, Parkinson's disease, nervous system cancer. , melanoma, malignant tumor of the digestive/gastrointestinal tract, colorectal cancer, myeloid leukemia, head and neck or lung cancer th hypertension.

In one embodiment, the BCR-ABL inhibitor or TASIGNA is administered at a dose of about 300 mg (e.g., twice daily, e.g., for newly diagnosed Ph+ CML-CP) or about 400 mg, e.g., twice daily, e.g. resistant or Ph+ CML-CP and intolerant CML-AP). The BCR-ABL inhibitor or Compound A2 is administered at a dose of approximately 300-400 mg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an HSP90 inhibitor such as 5-(2,4 -dihydroxy5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (compound A3), or the compound described in PCT Publication No. WO 2010/060937 or WO 2004/072051, for the treatment violations, such as violations described in the present description. In one embodiment, the HSP90 inhibitor is 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4(morpholinomethyl)phenyl)isoxazole-3-carboxamide (Compound A3) or a compound described in PCT Publication No. WO 2010/060937 or WO 2004/072051. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4(morpholinomethyl)phenyl)isoxazole-3-carboxamide (compound A3 ) or a compound as described in PCT Publication No. WO 2010/060937 or WO 2004/072051 for the treatment of a disorder such as cancer, multiple myeloma, non-small cell lung cancer, lymphoma, gastric cancer, breast cancer, digestive/gastric cancer -intestinal tract, pancreatic cancer, colorectal cancer, solid tumor or impaired hematopoiesis.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the PI3K and/or mTOR inhibitor, dactolisib (compound A4 ) or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3dihydroimidazo[4,5-c]quinolin-2-one ( compound A41) or a compound described in PCT Publication No. WO 2006/122806 for the treatment of a disorder, for example the disorder described herein. In one embodiment, the PI3K and/or mTOR inhibitor is dactolisib (compound A4), 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl) 1,3-dihydroimidazo[4,5-c]quinolin-2-one (compound A41) or the compound described in PCT Publication No. WO 2006/122806. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with dactolisib (compound A4), 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1yl-3-trifluoromethylphenyl) -1,3-dihydroimidazo[4,5-c]quinolin-2-one (compound A41) or the compound described in PCT Publication No. WO 2006/122806 for the treatment of a disorder such as cancer, prostate cancer, leukemia ( eg, lymphocytic leukemia), breast cancer, brain cancer, bladder cancer, pancreatic cancer, kidney cancer, solid tumor, or liver cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR inhibitor, 3-(2,6-dichloro -3,5dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea (Compound A5) or the compound described in US Pat. No. 8,552,002 , for the treatment of a disorder, for example, the disorder described herein. In one embodiment, the FGFR inhibitor is 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4 -yl)-1-methylurea (compound A5) or the compound described in US Pat. No. 8,552,002. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with compound A5 or a compound as described in US Pat. such as malignant tumor of the digestive/gastrointestinal tract, hematological malignancy or solid tumor.

In one embodiment, an FGFR inhibitor or 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl )-1-methylurea (compound A5) is administered at a dose of about 100-125 mg (eg once daily), eg about 100 mg or about 125 mg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PI3K inhibitor, buparlisib (Compound A6), or a compound described in PCT Publication No. WO 2007/084786 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the PI3K inhibitor is buparlisib (Compound A6) or the compound described in PCT Publication No. WO 2007/084786. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with buparlisib (Compound A6) or a compound described in PCT Publication No. WO 2007/084786 to treat a disorder such as prostate cancer, non-small cell lung cancer, endocrine malignancy tumor, leukemia, ovarian cancer, melanoma, bladder cancer, breast cancer, malignant tumor of the female reproductive system, malignant tumor of the digestive / gastrointestinal tract, colorectal cancer, glioblastoma multiforme, solid tumor, non-Hodgkin's lymphoma, hematopoietic disorder or head cancer and neck.

In one embodiment, the PI3K inhibitor or buparlisib (compound A6) is administered at a dose of approximately 100 mg (eg, once daily).

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR inhibitor, 8-(2,6-difluoro -3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-III-imidazol-2-yl)quinoxalin-5-carboxamide (compound A7) or the compound described in PCT Publication No. WO 2009/141386 for treating a disorder, such as the disorder described herein. In one embodiment, the FGFR inhibitor is 8-(2,6-difluoro-3,5-dimethoxyphenyl)-K-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxalin-5-carboxamide (Compound A7) or the compound described in PCT Publication No. WO 200 9/141386. In one embodiment, the FGFR inhibitor is 8-(2,6-difluoro-3,5-dimethoxyphenyl)-M-(4-((dimethylamino)methyl)-III-imidazol-2-yl)quinoxalin-5-carboxamide (compound A7). In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 8-(2,6-difluoro-3,5-dimethoxyphenyl)-K-(4-((dimethylamino)methyl)-1H-imidazol-2yl)quinoxaline α-5-carboxamide (Compound A7) or the compound described in PCT Publication No. WO 2009/141386 for the treatment of a disorder such as an angiogenetic cancer.

In one embodiment, the FGFR inhibitor or 8-(2,6-difluoro-3,5-dimethoxyphenyl)-M(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxalin-5-carboxamide (compound A7) is administered at a dose of, for example, from about 3 mg to about 5 g, more preferably from about 10 mg to about 1.5 g per individual per day, optionally divided into 1 to 3 single doses, which may be, for example, the same size.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PI3K inhibitor, (S)-N1-(4 -methyl-5-(2-(1,1,1trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidin-1,2-dicarboxamide (compound A8) or the compound described in PCT Publication No. WO 2010/029082, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the PI3K inhibitor is (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4yl)thiazol-2- yl)pyrrolidine-1,2-dicarboxamide (compound A8) or the compound described in PCT Publication No. WO 2010/029082. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin- 4-yl)thiazol-2-yl)pyrrolidin-1,2-dicarboxamide (Compound A8) or the compound described in PCT Publication No. WO 2010/029082 for the treatment of a disorder such as gastric cancer, breast cancer, pancreatic cancer , malignant tumor of the digestive/gastrointestinal tract, solid tumor, and head and neck cancer.

In one embodiment, the PI3K inhibitor or (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl )pyrrolidine-1,2-dicarboxamide (compound A8) is introduced into

- 84 040295 dose of about 150-300, 200-300, 200-400 or 300-400 mg (for example, once a day), for example, about 200, 300 or 400 mg.

In another embodiment, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a cytochrome P450 inhibitor (e.g., a CYP17 inhibitor) or a compound described in PCT Publication No. WO 2010/149755 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the cytochrome P450 inhibitor (eg, CYP17 inhibitor) is a compound described in PCT Publication No. WO 2010/149755. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with a compound described in PCT Publication No. WO 2010/149755 for the treatment of prostate cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an HDM2 inhibitor, (S)-1-(4 -chlorophenyl)-7isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1 ,2-dihydroisoquinolin-3(4H)-one (compound A10) or the compound described in PCT Publication No. WO 2011/076786 for the treatment of a disorder, for example, the disorder described herein). In one embodiment, the HDM2 inhibitor is (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3 -oxopiperazin-1 -yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (compound A10) or the compound described in PCT Publication No. WO 2011/076786. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)- 4(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (Compound A10) or the compound described in PCT Publication No. WO 2011/ 076786, for the treatment of a disorder such as a solid tumor.

In one embodiment, the HDM2 inhibitor or (S)-1-(4-chlorophenyl)-7-isopropoxy-6methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3- oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (compound A10) is administered at a dose of about 400 to 700 mg, for example administered three times a week, administered 2 weeks and one week break. In some embodiments, the dose is about 400, 500, 600, or 700 mg; about 400-500, 500-600 or 600-700 mg, for example, the dose is administered three times a week.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an iron chelating agent, deferasirox (also known as EXJADE; compound A11) or a compound described in PCT Publication No. WO 1997/049395 for the treatment of a disorder, for example, the disorder described herein. In one embodiment, the iron chelating agent is deferasirox or a compound described in PCT Publication No. WO 1997/049395. In one embodiment, the iron chelating agent is deferasirox (compound A11). In one embodiment, an anti-LAG-3 antibody molecule is used in combination with deferasirox (Compound All) or a compound described in PCT Publication No. WO 1997/049395 to treat iron overload, hemochromatosis, or myelodysplasia.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an aromatase inhibitor, letrozole (also known as femara; compound A12) or a compound described in US 4,978,672 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the aromatase inhibitor is letrozole (Compound A12) or the compound described in US Pat. No. 4,978,672. No. 4,978,672 for treating a disorder such as cancer, leiomyosarcoma, endometrial cancer, breast cancer, female reproductive system cancer, or hormone deficiency.

In another embodiment, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PI3K inhibitor, e.g., a PI3K broad spectrum inhibitor, (4S ,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one (Compound A13) or a compound described in PCT Publication No. WO 2013/124826 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the PI3K inhibitor is (4S,5R)-3-(2'-amino-2morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl)-4-(hydroxymethyl )-5-methyloxazolidin-2-one (compound A13) or the compound described in PCT Publication No. WO2013/124826. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with (4S,5R)-3-(2'-amino-2morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidine] -6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one (compound A13) or the compound described in PCT Publication No. WO2013/124826 for the treatment of a disorder such as a malignant tumor or an advanced stage solid tumor.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a p53 inhibitor and/or an inhibitor of the p53/Mdm2 interaction, (8)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl )-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (compound A14) or a compound described in PCT Publication No. WO 2013/111105 for the treatment of a disorder, e.g. described in the present description. In one embodiment, the p53 inhibitor and/or the p53/Mdm2 interaction inhibitor is (S)-5-(5-chloro-1-methyl-2-oxo-1,2dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (compound A14) or the compound described in PCT Publication No. WO 2013/111105. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (compound A14) or the compound described in PCT Publication No. WO 2013/111105, for the treatment of a disorder such as a malignant tumor or soft tissue sarcoma.

In another embodiment, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a CSF-1R tyrosine kinase inhibitor, 4-(( 2(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide (Compound A15) or the compound described in PCT Publication No. WO 2005/073224 for the treatment of the disorder , for example, the violation described in the present description. In one embodiment, the CSF-1R tyrosine kinase inhibitor is 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide (compound A15) or a compound described in PCT Publication No. WO 2005/073224. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N- methylpicolinamide (Compound A15) or the compound described in PCT Publication No. WO 2005/073224 for the treatment of a disorder such as cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an apoptosis inducer and/or angiogenesis inhibitor such as imatinib. mesylate (also known as Gleevec; Compound A16) or a compound described in PCT Publication No. WO 1999/003854 for the treatment of a disorder, such as the disorder described. In one embodiment, the apoptosis inducer and/or angiogenesis inhibitor is imatinib mesylate (Compound A16) or the compound described in PCT Publication No. WO 1999/003854. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with imatinib mesylate (Compound A16) or a compound described in PCT Publication No. WO 1999/003854 to treat a disorder such as cancer, multiple myeloma, prostate cancer, non-small cell lung cancer, lymphoma, gastric cancer, melanoma, breast cancer, pancreatic cancer, gastrointestinal/gastrointestinal malignancy, colorectal cancer, glioblastoma multiforme, liver cancer, head and neck cancer, asthma, multiple sclerosis, allergies, Alzheimer's dementia , amyotrophic lateral sclerosis or rheumatoid arthritis.

In certain embodiments, imatinib mesylate (compound A16) is administered at a dose of about 100 to 1000 mg, such as about 200 to 800 mg, about 300 to 700 mg, or about 400 to 600 mg, such as about 200, 300, 400, 500, 600 or 700 mg. The dosing schedule can be changed, for example from every other day to once a day, two or three times a day. In one embodiment, imatinib mesylate is administered at an oral dose of about 100 to 600 mg once daily, such as about 100, 200, 260, 300, 400, or 600 mg once daily.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a JAK inhibitor, 2-fluoro-K-methyl- 4-(7-(quinolin6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (compound A17) or its hydrochloric acid salt, or the compound described in PCT Publication No. WO 2007/070514, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the JAK inhibitor is 2-fluoro-K-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2b][1,2,4]triazin-2-yl)benzamide ( compound A17) or its hydrochloric acid salt or the compound described in PCT Publication No. WO 2007/070514. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1, 2,4]triazin-2-yl)benzamide (Compound A17) or its hydrochloric acid salt, or the compound described in PCT Publication No. WO 2007/070514, for the treatment of a disorder such as colorectal cancer, myeloid leukemia, hematological malignancy, autoimmune disease, non-Hodgkin's lymphoma, or thrombocythemia.

In one embodiment, a JAK inhibitor or 2-fluoro-K-methyl-4-(7-(quinolin-6-ylmethyl)umidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (Compound A17) or its hydrochloric acid salt is administered at a dose of about 400-600 mg (e.g. once daily), for example about 400, 500 or 600 mg or about 400-500 or 500-600 mg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the JAK inhibitor, ruxolitinib phosphate (also known as JAKAFI; compound A18) or a compound described in PCT Publication No. WO 2007/070514 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the JAK inhibitor is ruxolitinib phosphate (Compound A18) or the compound described in PCT Publication No. WO 2007/070514. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with ruxolitinib phosphate (Compound A18) or a compound described in PCT Publication No. WO 2007/070514 to treat a disorder such as prostate cancer, lymphocytic leukemia, multiple myeloma, lymphoma, lung cancer, leukemia, cachexia, breast cancer, pancreatic cancer, rheumatoid arthritis, psoriasis, colorectal cancer, myeloid leukemia, hematologic malignancy, autoimmune disease, non-Hodgkin's lymphoma, or thrombocythemia.

In one embodiment, the JAK inhibitor or ruxolitinib phosphate (Compound A18) is administered at a dose of about 15-25 mg, eg, twice daily. In some embodiments, the dose is about 15, 20, or 25 mg, or about 15-20 or 20-25 mg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a deacetylase (DAC) inhibitor, panobinostat (Compound A19) or a compound described in PCT Publication No. WO 2014/072493 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the DAC inhibitor is a panobinostat (compound A19) or a compound described in PCT Publication No. WO 2014/072493. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with panobinostat (Compound A19), a compound described in PCT Publication No. WO 2014/072493, to treat a disorder such as small cell lung cancer, airway/chest cancer , prostate cancer, multiple myeloma, myelodysplastic syndrome, bone cancer, non-small cell lung cancer, endocrine malignancy, lymphoma, nervous system malignancy, leukemia, HIV/AIDS, immune disorder, transplant rejection, gastric cancer, melanoma, breast cancer, pancreatic cancer, colorectal cancer, glioblastoma multiforme, myeloid leukemia, hematological malignancy, kidney malignancy, non-Hodgkin's lymphoma, head and neck cancer, hematopoietic disorders, or liver cancer.

In one embodiment, the DAC inhibitor or panobinostat (compound A19) is administered at a dose of approximately 20 mg (eg, once a day).

In another embodiment, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an inhibitor of one or more of the cytochrome P450s (e.g., 11B2 ), aldosterone or angiogenesis, silodrostat (compound A20), or a compound described in PCT Publication No. WO 2007/024945, for the treatment of a disorder, for example, the disorder described herein. In one embodiment, the inhibitor of one or more of cytochrome P450 (eg, 11B2), aldosterone, or angiogenesis is osilodrostat (compound A20) or the compound described in PCT Publication No. WO 2007/024945. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with osilodrostat (Compound A20) or a compound described in PCT Publication No. WO 2007/024945 for the treatment of a disorder such as Cushing's syndrome, hypertension, or therapy for heart failure.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an IAP inhibitor, (S)-N-(( S)-1-cyclohexyl-2-((S)2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide (compound A21 ) or a compound described in US 8,552,003 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the IAP inhibitor is (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1 -yl)-2-oxoethyl)-2(methylamino)propanamide (Compound A21) or the compound described in US Pat. No. 8,552,003. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with (S)- N((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino) propanamide (compound A21) or the compound described in US Pat. No. 8,552,003 for the treatment of a disorder such as multiple myeloma, breast cancer, ovarian cancer, pancreatic cancer, or hematopoietic disorder.

In one embodiment, an IAP inhibitor or (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl) -2-oxoethyl)-2-(methylamino)propanamide (compound A21) or the compound described in US 8552003 is administered at a dose of approximately 1800 mg, for example once a week.

In another embodiment, an anti-LAG-3 antibody molecule, e.g. an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the Smoothened (SMO) inhibitor, sonidegib phosphate (Compound A22) , (R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol (compound A25) or a compound described in PCT Publication No. WO 2007/131201 or WO 2010/007120 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the SMO inhibitor is sonidegiba phosphate (compound A22), (R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1yl) pyrazin-2-yl)propan-2-ol (compound A25) or the compound described in PCT Publication No. WO 2007/131201 or WO 2010/007120. In one embodiment, an anti-LAG3 antibody molecule is used in combination with sonidegiba phosphate (compound A22), (R)-2-(5-(4-(6-benzyl-4,5dimethylpyridazin-3-yl)-2-methylpiperazin- 1-yl)pyrazin-2-yl)propan-2-ol (Compound A25) or the compound described in PCT Publication No. WO 2007/131201 or WO 2010/007120 for the treatment of a disorder such as cancer, medulloblastoma, small cell carcinoma lung, prostate cancer, basal cell carcinoma, pancreatic cancer, or inflammation.

In certain embodiments, sonidegib phosphate (compound A22) is administered at a dose of about 20 to 500 mg, such as about 40 to 400 mg, about 50 to 300 mg, or about 100 to 200 mg, such as about 50, 100, 150, 200, 250 or 300 mg. The dosing regimen can be changed, for example, from every other day to once a day, two or three times a day.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the Alk inhibitor, ceritinib (also known as Zycadia; compound A23) or a compound described in PCT Publication No. WO 2007/131201 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the Alk inhibitor is ceritinib (Compound A23) or the compound described in PCT Publication No. WO 2007/131201. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with ceritinib (Compound A23) or a compound described in PCT Publication No. WO 2007/131201 to treat a disorder such as non-small cell lung cancer or solid tumors.

In one embodiment, the Alk inhibitor or ceritinib (compound A23) is administered at a dose of approximately 750 mg, eg, once daily.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a JAK inhibitor and/or CDK4/6, 7- cyclopentyl N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6carboxamide (compound A24) or the compound described in US Pat. No. 8,415,355 or US Pat. No. 8,685,980 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the JAK and/or CDK4/6 inhibitor is 7-cyclopentylN,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2 ,3-d]pyrimidine-6-carboxamide (compound A24) or the compound described in US 8415355 or US 8685980. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 7cyclopentyl-N,N-dimethyl- 2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6carboxamide (compound A24) or a compound described in US 8415355 or US 8685980, for the treatment of a disorder such as lymphoma, malignant tumor of the nervous system, melanoma, breast cancer or solid tumor.

In one embodiment, a JAK and/or CDK4/6 inhibitor or 7-cyclopentyl-N,Ndimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxamide (compound A24) is administered at a dose of about 200-600 mg, eg once a day. In one embodiment, the compound is administered at a dose of about 200, 300, 400, 500, or 600 mg, or about 200-300, 300-400, 400-500, or 500-600 mg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a prolactin receptor (PRLR) inhibitor, mono- a human clonal antibody molecule (Compound A26) as described in US Pat. No. 7,867,493) for the treatment of a disorder, such as the disorder described herein. In one embodiment, the PRLR inhibitor is a human monoclonal antibody (compound A26) described in US 7,867,493. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with a human monoclonal antibody molecule (compound A26) described in US Pat. 7,867,493 for treating a disorder such as cancer, prostate cancer, or breast cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PIM kinase inhibitor, N-(4-(( 1R,3S,5S)-3amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (compound A27) or the compound described in PCT Publication No. WO 2010/026124, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the PIM kinase inhibitor is N-(4-((1R, 3S, 5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6(2,6-difluorophenyl)-5- fluoropicolinamide (compound A27) or the compound described in PCT Publication No. WO 2010/026124. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6 -difluorophenyl)-5fluoropicolinamide (compound A27) or the compound described in PCT Publication No. WO 2010/026124 for the treatment of a disorder such as multiple myeloma, myelodysplastic syndrome, myeloid leukemia or non-Hodgkin's lymphoma.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a Wnt signaling cascade inhibitor, 2-(2',3dimethyl -[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide (compound A28) or the compound described in PCT Publication No. WO 2010/101849 , for the treatment of a disorder, such as the disorder described herein. In one embodiment, the Wnt signaling cascade inhibitor is 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2yl)pyridin-2-yl )acetamide (compound A28) or the compound described in PCT Publication No. WO 2010/101849. In one embodiment, the Wnt signaling cascade inhibitor is 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2 -yl)acetamide (compound A28). In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl )pyridin-2-yl)acetamide (Compound A28) or a compound described in PCT Publication No. WO 2010/101849 for the treatment of a disorder such as a solid tumor (e.g. head and neck cancer, squamous cell carcinoma, breast cancer, pancreatic cancer gland or colon cancer).

In certain embodiments, 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2yl)pyridin-2-yl)acetamide (compound A28) is administered at a dose of about 1 to 50 mg, such as about 2 to 45 mg, about 3 to 40 mg, about 5 to 35 mg, 5 to 10 mg, or about 10 to 30 mg, such as about 2.5, 10, 20, 30 or 40 mg. The dosing schedule may vary, for example, from every other day to once a day, two or three times a day.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a BRAF inhibitor, encorafenib (Compound A29) or a compound described in PCT Publication No. WO 2011/025927, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the BRAF inhibitor is encorafenib (Compound A29) or the compound described in PCT Publication No. WO 2011/025927. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with encorafenib (Compound A29) or a compound described in PCT Publication No. WO 2011/025927 to treat a disorder such as non-small cell lung cancer, melanoma, or colorectal cancer.

In one embodiment, the BRAF inhibitor or encorafenib (Compound A29) is administered at a dose of about 200-300, 200-400, or 300-400 mg, eg, once daily. In one embodiment, the compound is administered at a dose of about 200, about 300, or about 400 mg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a CDK4/6 inhibitor, 7-cyclopentyl-N,N -dimethyl2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo [2,3d]pyrimidine-6-carboxamide (Compound A30) or the compound described in PCT Publication No. WO 2011/101409 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the CDK4/6 inhibitor is 7-cyclopentyl-N,N-dimethyl 2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1] nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3

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d]nupuMuguH-6-Kap6oKcaMug (Compound A30) or the compound described in PCT Publication No. WO 2011/101409. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9- diazabicyclo[4.2.1]nonan-3yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (compound A30) or the compound described in PCT Publication No. WO 2011/101409 , for the treatment of a disorder such as cancer, mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell carcinoma of the esophagus, or breast cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an HER3 inhibitor, an A31 compound, or a compound described in the publication PCT No. WO 2012/022814, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the HER3 inhibitor is Compound A31 or the compound described in PCT Publication WO 2012/022814. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with Compound A31 or a compound described in PCT Publication WO 2012/022814 to treat a disorder such as gastric cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, cancer stomach, breast cancer (eg, metastatic breast cancer), or malignant tumor of the digestive/gastrointestinal tract.

In some embodiments, Compound A31 is a human monoclonal antibody molecule.

In one embodiment, the HER3 inhibitor or Compound A31 is administered at a dose of about 3, 10, 20, or 40 mg/kg, such as once a week (QW). In one embodiment, the compound is administered at a dose of about 3-10, 10-20, or 20-40 mg/kg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR2 and/or FGFR4 inhibitor, Compound A32, or Compound described in PCT Publication No. WO 2014/160160 (eg, a conjugate of an anti-FGFR2 and/or FGFR4 antibody molecule and a drug, eg, mAb 12 425), for the treatment of a disorder, eg, the disorder described herein. In one embodiment, the FGFR2 and/or FGFR4 inhibitor is an A32 compound or a compound described in PCT Publication No. WO 2014/160160. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with Compound A32 or a compound as described in Table 1. 7 for treating a disorder such as cancer, gastric cancer, breast cancer, rhabdomyosarcoma, liver cancer, adrenal cancer, lung cancer, esophageal cancer, colon cancer, or endometrial cancer.

In some embodiments, compound A32 is a conjugate of an anti-FGFR2 and/or FGFR4 antibody molecule and a drug, such as mAb 12425.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an M-CSF inhibitor, compound A33, or a compound described in PCT Publication No. WO 2004/045532 (eg, an anti-M-CSF antibody or Fab fragment), for the treatment of a disorder, such as the disorder described herein. In one embodiment, the M-CSF inhibitor is Compound A33 or the compound described in PCT Publication No. WO 2004/045532. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with an A33 compound or a compound as described in PCT publication no. synovitis (PVNS).

In embodiments, Compound A33 is an anti-M-CSF monoclonal antibody molecule or a fragment (eg, a Fab fragment) thereof. In embodiments, the M-CSF inhibitor or Compound A33 is administered at an average dose of about 10 mg/kg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a MEK inhibitor, binimetinib (Compound A34) or a compound described in PCT Publication No. WO 2003/077914 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the MEK inhibitor is binimetinib (Compound A34) or the compound described in PCT Publication No. WO 2003/077914. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with binimetinib (compound A34) or a compound described in PCT Publication No. WO 2003/077914 to treat a disorder such as non-small cell lung cancer, multisystem genetic disorder, melanoma, cancer ovarian cancer, gastrointestinal/gastrointestinal malignancy, rheumatoid arthritis, or colorectal cancer.

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In one embodiment, the MEK inhibitor or binimetinib (compound A34) is administered at a dose of approximately 45 mg, eg, twice daily.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg, FLK2/STK1) or PKC, midostaurin (compound A35), or a compound described in PCT Publication No. WO 2003/037347, for the treatment of a disorder, eg, the disorder described herein. In one embodiment, the inhibitor is midostaurin (Compound A35) or a compound described in PCT Publication No. WO 2003/037347. In one embodiment, the inhibitor of one or more of c-KIT, histamine release, Flt3 (eg, FLK2/STK1), or PKC is midostaurin. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with midostaurin (compound A35) or a compound described in PCT Publication No. WO 2003/037347 to treat a disorder such as cancer, colorectal cancer, myeloid leukemia, myelodysplastic syndrome, age-related macular degeneration, a complication of diabetes, or a dermatological disorder.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a TOR inhibitor (e.g., an mTOR inhibitor), everolimus ( also known as an afinitor; compound A36) or a compound described in PCT Publication No. WO 2014/085318 for the treatment of a disorder, for example, the disorder described herein). In one embodiment, the TOR inhibitor is everolimus (Compound A36) or the compound described in PCT Publication No. WO 2014/085318. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with everolimus (compound A36) to treat a disorder such as interstitial lung disease, small cell lung cancer, respiratory/chest cancer, prostate cancer, multiple myeloma, sarcoma , age-related macular degeneration, bone cancer, tuberous sclerosis, non-small cell lung cancer, endocrine malignancy, lymphoma, neurological disorders, astrocytoma, cervical cancer, nervous system malignancy, leukemia, immune disorder, transplant rejection, gastric cancer, melanoma, epilepsy, breast cancer or bladder cancer.

In one embodiment, the TOR inhibitor or everolimus (compound A36) is administered at a dose of about 2.5-20 mg/day. In one embodiment, the compound is administered at a dose of about 2.5, 5, 10, or 20 mg/day, eg, about 2.5-5, 5-10, or 10-20 mg/day.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an inhibitor of one or more of VEGFR-2, PDGFR- β, KIT or Raf-kinase C, 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl )phenyl)-1H-benzo[d]imidazol-2-amine (Compound A37) or the compound described in PCT Publication No. WO 2007/030377 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the inhibitor of one or more of VEGFR-2, PDGFR-β, KIT, or Raf kinase C is 1-methyl-5-((2-(5-(trifluoromethyl)-1-nimidazol-2-yl)pyridine -4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine (Compound A37) or the compound described in PCT Publication No. WO 2007/030377. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N -(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine (Compound A37) or the compound described in PCT Publication No. WO 2007/030377 for the treatment of a disorder such as cancer, melanoma or solid tumor.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a somatostatin agonist and/or growth hormone releasing inhibitor, pasireotide diaspartate. (also known as signifor; compound A38) or the compound described in PCT Publication No. WO 2002/010192 or US Pat. No. 7,473,761 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the somatostatin agonist and/or growth hormone releasing inhibitor is pasireotide diaspartate (Compound A38) or the compound described in PCT Publication No. WO 2002/010192 or US Pat. No. 7,473,761. In one embodiment, an anti-LAG- 3 is used in combination with pasireotide diaspartate (Compound A38) or the compound described in PCT Publication No. WO 2002/010192 or US Pat. skin (eg, melanoma), pancreatic cancer, liver cancer, Itsenko-Cushing syndrome, gastrointestinal disease, acromegaly, liver disease, and

- 91 040295 biliary tract or cirrhosis of the liver.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the signal transduction modulator and/or angiogenesis inhibitor, dovitinib ( compound A39) or a compound described in PCT Publication No. WO 2009/115562 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the signal transduction modulator and/or angiogenesis inhibitor is dovitinib (Compound A39) or the compound described in PCT Publication No. WO 2009/115562. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with dovitinib (Compound A39) or a compound described in PCT Publication No. WO 2009/115562 to treat a disorder such as cancer, airway/chest cancer, multiple myeloma, prostate cancer, non-small cell lung cancer, endocrine malignancy, or neurological genetic disorder.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an EGFR inhibitor, (R,E)-N- (7-Chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (compound A40) or a compound described in PCT Publication No. WO 2013/184757 for the treatment of a disorder, for example the disorder described herein. In one embodiment, the EGFR inhibitor is (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1Hbenzo[d] imidazol-2-yl)-2-methylisonicotinamide (compound A40) or the compound described in PCT Publication No. WO 2013/184757. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepane-3-yl )-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (compound A40) or the compound described in PCT Publication No. WO 2013/184757 for the treatment of a disorder such as a malignant tumor, for example a solid tumor.

In one embodiment, an EGFR inhibitor or (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d ]imidazol-2-yl)-2-methylisonicotinamide (compound A40) is administered at a dose of 150-250 mg, for example once a day. In one embodiment, the compound is administered at a dose of about 150, 200, or 250 mg, or about 150-200 or 200-250 mg.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an ALK inhibitor, N ⁶ -(2-isopropoxy- 5-methyl-4(1-methylpiperidin-4-yl)phenyl)-N ⁴ -(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4,6diamine (compound A42) or compound described in PCT Publication No. WO 2008/073687 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the ALK inhibitor is N ⁶ -(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4yl)phenyl)-N ⁴ -(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3 ,4-d]pyrimidine-4,6-diamine (compound

A42) or a compound described in PCT Publication No. WO 2008/073687. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with +-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N ⁴ -(2-(isopropylsulfonyl)phenyl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6diamine (compound A42) or the compound described in PCT Publication No. WO 2008/073687 for the treatment of a disorder such as cancer, anaplastic large cell lymphoma (ALCL), non-small cell carcinoma lung (NSCLC) or neuroblastoma.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an IGF-1R inhibitor, 3-(4-( 4-((5-chloro-4-((5-methyl1 H-pyrazol-3 -yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thiethan- 1,1-dioxide (compound A43), 5-chloro-N ² -(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4yl)phenyl)-N ^4- (5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A44) or 5-chloro-Ni-(4(1-ethylpiperidin-4-yl)-2-fluoro-5 -methylphenyl)-N ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or a compound described in PCT Publication No. WO 2010/002655, for the treatment of a disorder, for example described violations. In one embodiment, the IGF1R inhibitor is 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- 5fluoro-2-methylphenyl)piperidin-1-yl)thiethan-1,1-dioxide (compound A43), 5-chloro-N ² -(2-fluoro-5-methyl-41-(tetrahydro-2H-pyran-4 -yl)piperidin-4-yl)phenyl)-N ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A44), 5-chloro-N2-(4-( 1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N ⁴ -(5-methyl-1Hpyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or a compound described in PCT Publication No. WO 2010/002655. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2 -yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thiethan-1,1-dioxide (compound A43), 5-chloro-N ² -(2-fluoro-5-methyl-4- (1(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamin- 92 040295 nom ( compound A44), 5-chloro-M2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-M ⁴ -(5-methyl-1Hpyrazol-3-yl)pyrimidin-2, 4-diamine (compound A45) or a compound described in the publication

PCT No. WO 2010/002655, for the treatment of a disorder such as cancer or sarcoma.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the P-glycoprotein 1 inhibitor, valspodar (also known as amdray; compound A46) or a compound described in EP 296122 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the P-glycoprotein 1 inhibitor is valspodar (compound A46) or a compound described in EP 296122. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with valspodar (compound A46) or a compound described in EP 296122, for the treatment of a disorder such as cancer or a drug-resistant tumor.

In another embodiment, an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with one or more of the VEGFR inhibitor, vatalanib succinate (compound A47) or a compound described in EP 296122 for the treatment of a disorder, such as the disorder described herein. In one embodiment, the VEGFR inhibitor is vatalanib succinate (compound A47) or a compound described in EP 296122. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with vatalanib succinate (compound A47) or a compound described in EP 296122, for the treatment of cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an IDH inhibitor or a compound described in WO 2014/141104 , for the treatment of a disorder, such as the disorder described herein. In one embodiment, the IDH inhibitor is a compound described in PCT Publication No. WO 2014/141104. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with a compound described in WO 2014/141104 to treat a disorder such as cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a BCL-ABL inhibitor or a compound described in a PCT publication. No. WO 2013/171639, WO 2013/171640, WO 2013/171641 or WO 2013/171642, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the BCL-ABL inhibitor is a compound described in PCT Publication No. WO 2013/171639, WO 2013/171640, WO 2013/171641, or WO 2013/171642. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with a compound described in PCT Publication No. WO 2013/171639, WO 2013/171640, WO 2013/171641, or WO 2013/171642 to treat a disorder such as cancer. .

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a c-RAF inhibitor or a compound described in a PCT publication. No. WO 2014/151616, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the c-RAF inhibitor is an A50 compound or a compound described in PCT Publication No. WO 2014/151616. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with a compound described in PCT Publication No. WO 2014/151616 to treat a disorder such as cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a competitive ERK1/2 ATP inhibitor or a compound described in International Patent Application No. PCT/US2014/062913, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the competitive ERK1/2 ATP inhibitor is a compound described in International Patent Application No. PCT/US2014/062913. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with Compound A51 or a compound described in International Patent Application No. PCT/US2014/062913 to treat a disorder such as cancer.

In another embodiment, an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a tyrosine kinase inhibitor (compound A52) or a compound described in PCT Publication No. WO 2005/073224, for the treatment of a disorder, such as the disorder described herein. In one embodiment, the tyrozine kinase inhibitor is 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)N-methylpicolinamide (compound A52) or a compound described in PCT Publication No. WO 2005/073224. In one embodiment, an anti-LAG-3 antibody molecule is used in combination with 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N- methylpicolinamide (Compound A52) or the compound described in PCT Publication No. WO 2005/073224 for the treatment of a disorder such as cancer.

In some embodiments, the anti-LAG-3 antibody molecule is administered in combination with one or more of Compound A8, Compound A17, Compound A23, Compound A24, Compound A27, Compound A29, and Compound A33.

In some embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-cancer agent with known activity in an immune cell assay, e.g., in one or more of a huMLR assay, a T cell proliferation assay, and a B cell proliferation assay. Illustrative assays are described below. Based on the analysis, IC ₅₀ can be calculated for each tested agent. In embodiments, the anti-cancer agent has an IC50, eg 0-1 µM, 1-4 µM, or greater than 4 µM, eg 4-10 µM or 420 µM. In embodiments, the second therapeutic agent is selected from one or more of: Compound A9, Compound A16, Compound A17, Compound A21, Compound A22, Compound A25, Compound A28, Compound A48, and Compound 49.

In some embodiments, Compound A28 (or a related compound to Compound A28) is administered at a dose of about 5-10 or 10-30 mg. In some embodiments, Compound A22 (or a related compound to Compound A22) is administered at a dose of approximately 200 mg. In some embodiments, compound A17 (or a compound related to compound A17) is administered at a dose of about 400-600 mg. In some embodiments, compound A16 (or a compound related to compound A16) is administered at a dose of about 400-600 mg p/o once a day. In some embodiments, Compound A29 (or a related compound to Compound A29) is administered at a dose of about 200-400 or 300-400 mg. In some embodiments, Compound A24 (or a related compound to Compound A24) is administered at a dose of about 200-600 mg. In some embodiments, compound A23 (ceritinib) (or a ceritinib-related compound) is administered at a dose of approximately 750 mg once daily. In some embodiments, Compound A8 (or a compound related to Compound A8) is administered at a dose of about 200-400 or 300-400 mg. In some embodiments, Compound A5 (or a related compound to Compound A5) is administered at a dose of about 100-125 mg. In some embodiments, Compound A6 (or a related compound to Compound A6) is administered at a dose of approximately 100 mg. In some embodiments, compound A1 (or a compound related to compound A1) is administered at a dose of about 200-300 or 200-600 mg. In some embodiments, Compound A40 (or a related compound to Compound A40) is administered at a dose of about 150-250 mg. In some embodiments, Compound A10 (or a compound related to Compound A10) is administered at a dose of about 400 to 700 mg, eg, administered three times per week for 2 weeks and off for one week. In some embodiments, the BCR-ABL inhibitor is administered at a dose of about 20 mg twice daily - 80 mg twice daily.

An exemplary huMLR assay and B or T cell proliferation assay are provided below.

The reaction of a mixed culture of human lymphocytes.

The mixed lymphocyte culture reaction (MLR) is a functional assay that measures the proliferative response of lymphocytes from one individual (responder) to lymphocytes from another individual (stimulator). To obtain allogeneic MLR, peripheral blood mononuclear cells (PBMCs) from three donors were isolated from buffy coats of an unknown HLA type (Kantonspital Blutspendezentrum from Bern and Aarau, Switzerland). Cells were obtained at 2x105 in 0.2 ml culture medium containing RPMI 1640 GlutaMAX™ with 10% fetal calf serum (FCS), 100 U. penicillin/100 µg streptomycin, 50 µM 2-mercaptoethanol. Individual 2-way reactions were performed by mixing PBMCs from two different donors in a 1:1 ratio and co-cultured in triplicate in flat-bottomed 96-well tissue culture plates for 6 days at 37° C., 5% CO ₂ , in the presence of or without test compounds in the concentration range of 8 points. Cells were pulsed with 3H-TdR (1 μCi/0.2 ml) during the last 16 h of culture and radioactivity incorporated was used as a measure of cell proliferation. For each compound, the concentration that inhibited 50% of the maximum huMLR response (IC50) was calculated. Cyclosporine was used as a positive control for huMLR inhibition.

Human B cell proliferation assay.

Received freshly isolated in a density gradient ficoll-pak PBMC from human blood and subjected to negative selection of b-cells. B cells were resuspended in culture medium (RPMI 1640, HEPES, 10% FCS, 50 μg/ml gentamicin, 50 μM 2-mercaptoethanol, 1x ITS (insulin,

- 94 040295 transferrin and sodium selenite), 1x non-essential amino acids) at a concentration of 9104 per well in a flat-bottomed 96-well culture plate. B cell stimulation was performed with an anti-human IgM antibody molecule (30 µg/mL) and IL-4 (75 ng/mL) or CD40 ligand (3 µg/mL) and IL-4 (75 ng/mL) with or without test subjects. compounds in a concentration range of 7 points. After 72 hours of culture at 37°C, 10% CO ₂ cells were pulsed with 3H-TdR (1 μCi/well) during the last 6 hours of culture. B cells were then harvested and the thymidine administered was measured using a scintillation counter. An average was calculated from each duplicate treatment and plotted in XLfit 4 to determine the corresponding IC50 values.

Human T cell proliferation assay.

Received freshly isolated in a density gradient ficoll-pak PBMC from human blood and subjected to negative allocation of T cells. T cells were obtained in culture medium (RPMI 1640, HEPES, 10% FCS, 50 μg/ml gentamicin, 50 μM 2-mercaptoethanol, 1xITS (insulin, transferrin and sodium selenite), 1x non-essential amino acids) at a concentration of 8104 per well in a flat-bottomed 9-well culture plate. T cell stimulation was performed with an anti-human CD3 antibody molecule (10 µg/mL) or an anti-human CD3 antibody molecule (5 µg/mL) and an anti-CD28 antibody molecule (1 µg/mL) with or without test compounds in a concentration range of 7 points. After 72 hours of culture at 37°C, 10% CO ₂ cells were pulsed with 3H-TdR (1 μCi/well) during the last 6 hours of culture. Cell proliferation was measured by thymidine incorporation, which provided an IC ₅₀ determination for each test compound.

Decreased immune response.

Anti-LAG-3 antibodies can be used to modulate, for example, activate and enhance an immune response, such as an autoimmune response. For example, blockade of LAG-3 in combination with various autoproteins can be used to develop vaccination protocols to effectively induce immune responses against such autoproteins to treat disease. In fact, many antitumor responses involve certain types of autoreactivity (van Elsas et al., (2001) J. Exp. Med., 194:481-489; Overwijk et al., (1999) Proc. Natl. Acad. Sci. USA, 96: 2982-2987 Rosenberg and White (1996) J. Immunother Emphasis Tumor Immunol., 19(1):81-4). In addition, Alzheimer's disease includes inappropriate accumulation of AB peptide in amyloid deposits in the brain; the formation of antibodies against amyloid can lead to the removal of such deposits of amyloid (Schenk et al., (1999) Nature, 400: 173-177).

Other autoproteins can also be used as targets such as IgE for allergy and asthma and TNFc for rheumatoid arthritis. The formation of antibodies to various hormones can be induced by using an antibody against LAG-3. The formation of neutralizing antibodies to reproductive hormones can be used for contraception. The formation of neutralizing antibodies to hormones and other soluble factors that are necessary for the growth of specific tumors can also be considered as candidates for vaccination.

Similar methods as described above using anti-LAG-3 antibodies can be used to induce therapeutic autoimmune responses to treat patients suffering from inadequate accumulation of other autoantigens such as amyloid deposits, including AB, in Alzheimer's disease, cytokines such as TNFa, and IgE.

In other embodiments, anti-LAG-3 antibody molecules are administered to an individual in combination with (e.g., before, concurrently, or after) one or more of: bone marrow transplantation, T cell ablation therapy using chemotherapeutic agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide and/or antibodies such as OKT3 or CAMPATH. In one embodiment, anti-LAG-3 antibody molecules are administered following B cell ablation therapy, such as agents that interact with CD20, such as Rituxan. For example, in one embodiment, individuals may receive standard treatment with high dose chemotherapy followed by transplantation of stem cells into peripheral blood. In certain embodiments, after transplantation, individuals receive anti-LAG-3 antibody molecules. In a further embodiment, the anti-LAG-3 antibody molecules are administered before or after surgery.

Applications in diagnostics.

In one aspect, the present invention relates to a diagnostic method for detecting the presence of a LAG-3 protein in vitro (e.g., in a biological sample, such as a tissue biopsy, e.g., from malignant tissue) or in vivo (e.g., in vivo imaging in an individual). The method includes: (i) bringing the sample into contact with the antibody molecule described in the present description, or introduction to the individual of the antibody molecule; (optional) (ii) contacting a reference sample, e.g., a control sample (e.g., a biological control sample such as plasma, tissue, biopsy) or a control individual)) and (iii) detecting the formation of a complex between the antibody molecule and the sample, or an individual or a control sample or control individual, wherein a change, eg, a statistically significant change in complex formation in the sample or individual relative to the control sample or individual, is indicative of the presence of LAG-3 in the sample. The antibody molecule can be directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent substances, luminescent substances and radioactive substances, as described above and described in more detail below.

The term sample as it refers to samples used to detect polypeptides includes, but is not limited to, cells, cell lysates, protein or membrane extracts, body fluids, or tissue samples.

The formation of a complex between an antibody molecule and LAG-3 can be detected by measuring or visualizing the binding molecule bound to the LAG-3 antigen or the unbound binding molecule. Conventional detection assays can be used, such as enzyme-linked immunosorbent assays (ELISA), radioimmunoassay (RIA), or tissue immunohistochemistry. As an alternative to labeling an antibody molecule, the presence of LAG-3 can be assessed in a sample by a competitive immunoassay using detectable labeled standards and an unlabeled antibody molecule. In such an assay, the biological sample, labeled standards, and antibody molecule are combined and the amount of labeled standard bound to the unlabeled binding molecule is determined. The amount of LAG-3 in a sample is inversely proportional to the amount of labeled standard bound to the antibody molecule.

Nucleic acids.

The invention also relates to nucleic acids containing nucleotide sequences that encode the variable regions and heavy and light chain CDRs of anti-LAG-3 antibody molecules as described herein. For example, the invention relates to first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an anti-LAG-3 antibody molecule selected from one or more of the antibody molecules described herein. A nucleic acid may comprise a nucleotide sequence as specified in the tables herein, or a sequence substantially identical to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it, or that differs by no more than 3, 6, 15, 30 or 45 nucleotides from the sequences presented in the tables in the present description.

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region containing an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous to it (e.g., a sequence at at least about 85%, 90%, 95%, 99% or more identical to it and/or containing one or more substitutions, eg conservative substitutions). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a light chain variable region containing an amino acid sequence as set forth in the tables herein, or a sequence substantially homologous to it (e.g., a sequence at at least about 85%, 90%, 95%, 99% or more identical to it and/or containing one or more substitutions, eg conservative substitutions). In yet another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions containing the amino acid sequence as set forth in the tables herein, or the sequence substantially homologous to it (eg, sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or containing one or more substitutions, eg conservative substitutions).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region containing a nucleotide sequence as specified in the tables herein, a sequence substantially homologous to it (e.g., a sequence at least at least about 85%, 90%, 95%, 99% or more identical and/or capable of hybridizing under the stringency conditions described herein). In another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a light chain variable region comprising a nucleotide sequence as set forth in the tables herein, or a sequence substantially homologous to it (e.g., a sequence of at least at least about 85%, 90%, 95%, 99% or more identical and/or capable of hybridizing under the stringency conditions described herein). In yet another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions, comprising a nucleotide sequence as set forth in the tables herein or a sequence according to substantially homologous to it (eg, a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridizing under the stringent conditions described herein).

In another aspect, the invention relates to host cells and vectors containing the nucleic acids described in the present description. Nucleic acids can be contained in the same vector or different vectors contained in the same host cell or in different host cells, as described in more detail in the present description below.

Vectors.

The present description further discloses vectors containing nucleotide sequences encoding the antibody molecule described in the present description. In one embodiment, the implementation of the vectors contain nucleotides encoding the antibody molecule described in the present description. In one of the embodiments, the implementation of the vectors contain the nucleotide sequences described in the present description. Vectors include, but are not limited to, a virus, plasmid, cosmid, λ phage, or yeast artificial chromosome (YAC).

Many vector systems can be applied. For example, one class of vectors uses DNA elements that are derived from animal viruses such as, for example, bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (Rous sarcoma virus, MMTV or MOMLV), or SV40. Another class of vectors uses RNA elements derived from RNA viruses such as Semliki forest virus, eastern equine encephalitis virus, and flavivirus.

In addition, cells that contain stably chromosomally integrated DNA can be selected by introducing one or more markers that allow selection of transfected host cells. The marker may confer, for example, prototropy to an auxotrophic host, resistance to biocides (eg antibiotics), or resistance to heavy metals such as copper or the like. The selectable marker gene can be directly linked to DNA sequences to be expressed or introduced into the same cell via co-transformation. Additional elements may also be necessary for optimal mRNA synthesis. Such elements may include splicing signals as well as transcriptional promoters, enhancers, and termination signals.

Once prepared for expression, the expression vector or constructs containing the DNA sequence, the expression vectors can be transfected or introduced into an appropriate host cell. Various techniques can be used to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, virus transfection, gene gun, lipid-based transfection, or other conventional methods. In the case of protoplast fusion, cells are grown in medium and screened for suitable activity.

Methods and conditions for culturing the resulting transfected cells and isolating the resulting antibody molecule are known to those skilled in the art and can be modified or optimized depending on the particular expression vector used and the mammalian host cell based on the present disclosure.

Cells.

The invention also relates to host cells containing a nucleic acid encoding an antibody molecule as described herein.

In one embodiment, host cells are genetically engineered to contain nucleic acids encoding an antibody molecule.

In one embodiment, host cells are obtained by genetic engineering using an expression cassette. The phrase expression cassette refers to nucleotide sequences that are capable of influencing gene expression in host organisms that are compatible with such sequences. Such cassettes may contain a promoter, an open reading frame with or without introns, and termination signals. You can also use additional factors necessary or suitable to influence the expression, such as, for example, an inducible promoter.

The invention also relates to host cells containing the vectors described in the present description.

The cell may be, without limitation, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells, MDCKII cells, and the Per C6 cell line (eg, PER C6 cells from Crucell). Suitable insect cells include, but are not limited to, Sf9 cells.

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Table 1. Amino acid and nucleotide sequences for mouse, chimeric and humanized antibody molecules. Antibody molecules include BAP050 mouse mAbs, BAP050-chi chimeric mAbs, BAP050-hum01 humanized BAP050-hum20 mAbs, BAP050-hum01-Ser to BAP050-hum15-Ser humanized mAbs, BAP050-hum18-Ser to BAP050-hum20-Ser humanized mAbs BAP050-Clone-F BAP050-Clone-J. The amino acid and nucleotide sequences of the heavy and light chain CDRs, the heavy and light chain variable regions, and the heavy and light chains are shown below.

NS VAR050 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 6 vh QIQLVQSGPELKRPGETVRISCKASGFTL TNYGMNWVRQTPGRGLRWMGWINTDTGEP TYADDFRGAFAFSLETSASTASLQINNLK NADTATYFCARNPPYYYGTNNAEAMDYWG QGTAVTVSS SEQ ID NO: 7 DNA VH CAGATCCAGTTGGTGCAGTCTGGACCTGA GOT GAAGAAGCC T GGAGAGACAGT CAAGA TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGAGGCA GACTCCAGGAAAGGGTTTAAAGTGGATGG GCTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGACGGTT TGCCTTCTCTTTGGAGACCTCTGCCAGCA СTGССTСTTTGCAGATСAACAACСTCAAA AATGCGGACACGGCTACATATTTCTGTGC AAGAAAC CCCCCTTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGT CAAGGAACCGCAGTCACCGTCTCCTCA LC BAP050 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 16 VL DIQMTQTTSSLSASLGDRVTISCSSSQDI SNYLNWYQQRPDGTVRVLIYYTSTLHLGV PSRFSGSGSGTDYSLTISNLELEDIATYY CQQYYNLPWTFGGGTRLEIR SEQ ID NO: 17 DNA VL GAT AT С C AGAT GAG AC AGAC TAG AT С С T C CCTGTCTGCCTCTCTGGGAGACAGAGTCA С CAT CAG T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGATGGAACTGTTAAAGTССTGATСT AT TAGACAT CAAC С T ТАСAC T TAG GAG T C CCATCAAGGTTCAGTGGCAGTGGGTCTGG GACAGAT TATTCTCT CAC CAT CAG CAAC C T GGAAC T C GAAGATAT T GC CACATAC TAT T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGTGGAGGCACCAAGTTGGAAATCA AA HC BAP050-chi SEQ ID NO: 1 (Rabat) HCDR1 NYGMN

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SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 20 vh QIQLVQSGPELRRPGETVRISCRASGFTL TNYGMNWVRQTPGRGLRWMGWINTDTGEP TYADDFRGAFAFSLETSASTASLQINNLR NADTATYFCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 21 DNA VH CAGATCCAGTTGGTGCAGTCTGGACCTGA GOT GAAGAAGCC T GGAGAGACAGT CAAGA TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGAGGCA GACTCCAGGAAAGGGTTTAAAGTGGATGG GCTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGACGGTT TGCCTTCTCTTTGGAGACCTCTGCCAGCA СTGССTСTTTGCAGATСAACAACСTCAAA AATGCGGACACGGCTACATATTTCTGTGC AAGAAAC CCCCCTTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 22 HC QIQLVQSGPELRRPGETVRISCRASGFTL TNYGMNWVRQTPGRGLRWMGWINTDTGEP TYADDFRGRFAFSLETSASTASLQINNLR NADTATYFCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

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SEQ ID NO: 23 NA DNA CAGATCCAGTTGGTGCAGTCTGGACCTGA GOT GAAGAAGCC T GGAGAGACAGT CAAGA TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGAGGCA GACTCCAGGAAAGGGTTTAAAGTGGATGG GCTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGACGGTT TGCCTTCTCTTTGGAGACCTCTGCCAGCA СTGССTСTTTGCAGATСAACAACСTCAAA AATGCGGACACGGCTACATATTTCTGTGC AAGAAAC CCCCCTTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T C GAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCACAGCACGTACCGTGTGTGTCAGCG TCCTCACCGTCC TGCACCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-chi SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

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SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 24 VL DIQMTQTTSSLSASLGDRVTISCSSSQDI SNYLNWYQQRPDGTVRVLIYYTSTLHLGV PSRFSGSGSGTDYSLTISNLELEDIATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 25 DNA VL GAT AT С C AGAT GAC AC AGAC TAG AT С С T C CCTGTCTGCCTCTCTGGGAGACAGAGTCA С CAT CAG T T G CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGATGGAACTGTTAAAGTССTGATСT AT TAGACAT СAAC С T ТАСAC T TAG GAG T C CCATCAAGGTTCAGTGGCAGTGGGTCTGG GACAGAT TATTCTCT CAC CAT CAG CAAC C T GGAAC T C GAAGATAT T GC CACATAC TAT T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 26 LC DIQMTQTTSSLSASLGDRVTISCSSSQDI SNYLNWYQQRPDGTVRVLIYYTSTLHLGV PSRFSGSGSGTDYSLTISNLELEDIATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 27 DNA LC GAT AT С C AGAT GAC AC AGAC TAG AT С С T C CCTGTCTGCCTCTCTGGGAGACAGAGTCA С CAT CAG T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGATGGAACTGTTAAAGTССTGATСT AT TAGACAT CAAC С T ТАСAC T TAG GAG T C CCATCAAGGTTCAGTGGCAGTGGGTCTGG GACAGAT TATTCTCT CAC CAT CAG CAAC C T GGAAC T C GAAGATAT T GC CACATAC TAT T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum01 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

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SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS S TERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 102 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGAGTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACCCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCAC CAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum01 SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 103 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 32 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 33 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 34 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKNGDSTYS LSSTLTLSKADVGLEKHKVY SEQ ID NO: 35 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum02 SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 104 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCWVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 105 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGAGTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum02 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 106 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T СACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT TAC T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSKDS PVTHVEKHKK SEQ ID NO: 39 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T CACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT ТАС T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum03 SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 107 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGAGTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTRPREEQFNSTYRWSVLTVLHQDWL NGREYKCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 108 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGAGTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T C GAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCAC CAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GOTO T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum03 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 109 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 41 DNA VL GAAAT T G T G T T GAGACAG T С T C GAG C GAG CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT GAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAG CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 43 DNA LC GAAAT T G T G T T GACACAG T С T C GAG C GAG CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT GAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAG CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAG TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAG TGC GAG GAGAG T G T GAGAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum04 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 110 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATAT GC T GAT GAC T T CAAGGGAAGAT T TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 111 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum04 SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 112 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 44 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 45 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GACAGAC T T СAC T С T CAC CAT CAG CAGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 46 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYGRSSVYACEVACEV SEQ ID NO: 47 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GACAGAC T T СAC T С T CAC CAT CAG CAGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum05 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 113 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKKPGATVKISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 114 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCAC CAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum05 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 115 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 48 VL EIVLTQSPATLSLSPGERATLSCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 49 DNA VL GAAAT T G T G T T GAC AC AG T С T С C AG С C AC CCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGTTCAAGTCAGGACATC AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 50 LC EIVLTQSPATLSPGERATLSCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSECTYS LSSTLTLSKADYEKHKSSPVACE SEQ ID NO: 51 DNA LC GAAAT T G T G T T GAC AC AG T С T С C AG С C AC CCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGTTCAAGTCAGGACATC AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum06 SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 116 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 117 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC С С T С С С TAT TAC TAC G G TAC TA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC C C C GAG G T C CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCT CACCGTCCTGCACCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATССCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCACTACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum06 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 118 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 52 VL DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTRVEIK SEQ ID NO: 53 DNA VL GATATTGTGAT GAG С CAGAC T С САС T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GAGAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GAGAGAAT T САС T С T GAG CAT CAG GAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 54 LC DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRPVSFTHQGL SEQ ID NO: 55 DNA LC GATATTGTGAT GAC С C AGAC T С С AC T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T САС T С T GAG CAT CAG GAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T GAGAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum07 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 119 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGOTGATGAGTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKKPGATVKISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 120 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum07 SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 121 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 57 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYGLSSVYACEVACEVACEV SEQ ID NO: 59 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAG T CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum08 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 122 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKKPGATVKISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 123 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum08 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 124 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 63 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum09 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 125 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 64 vh QVQLVQS GAEVKKPGASVKVS CKAS G FT L SEQ ID NO: 65 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HC QVQLVQS GAEVKKPGASVKVS CKAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 126 040295

SEQ ID NO: 67 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum09 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 127 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T СACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT TAC T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSKDS PVTHVEKHKK SEQ ID NO: 39 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T CACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT ТАС T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml0 SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 128 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 64 vh QVQLVQS GAE VRRPGAS VRVS ORAS G FT L SEQ ID NO: 65 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGOTGATGAGTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HC QVQLVQS GAEVRRPGASVRVS ORAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 129 040295

SEQ ID NO: 67 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATAT GC T GAT GAC T T CAAGGGAAGAT T TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G GAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T C GAG T T CA GTCCTGCACCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC AT С C GAG GAG GAGAT GAC CAAGAAC GAG G TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml0 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 130 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAAT T G T G T T GACACAG T С T С CAG С CAC CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLECADYGLQKVYACE SEQ ID NO: 43 DNA LC GAAAT T G T G T T GACACAG T С T С CAG С CAC CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-humll SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 131 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 64 vh QVQLVQS GAEVRRPGASVKVSGRAS G FT L SEQ ID NO: 65 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HC QVQLVQS GAEVRRPGASVRVS CRAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS S TERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 132 040295

SEQ ID NO: 67 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G GAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T C GAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-humll SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 133 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 57 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYGLSSVYACEVACEVACEV SEQ ID NO: 59 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAG T CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T САС T С T GAG CAT CAG GAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml2 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 134 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 64 vh QVQLVQS GAEVKKPGASVKVS CKAS G FT L SEQ ID NO: 65 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HC QVQLVQS GAEVKKPGASVKVS CKAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 135 040295

SEQ ID NO: 67 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml2 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 136 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 63 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml3 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 137 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 68 vh QVQLVQS GAE VRRPGAS VRVS GRAS G FT L SEQ ID NO: 69 DNA VH CAGGTTCAGCTGGTGCAGTCCGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 70 HC QVQLVQS GAEVRRPGASVRVS CRAS G FT L TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 138 040295

SEQ ID NO: 71 NA DNA CAGGTTCAGCTGGTGCAGTCCGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGAGTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGACССCGAGGT CGAGT T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCACCAGGACT GGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GOTO T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml3 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 139 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T CACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT TAC T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSKDS PVTHVEKHKK SEQ ID NO: 39 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T CACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT ТАС T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml4 SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 140 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 72 vh EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 73 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 74 HC EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTRPREEQFNSTYRWSVLTVLHQDWL NGREYKCRVSNRGLPS SIEKTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 141 040295

SEQ ID NO: 75 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml4 SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 142 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAAT T G T G T T GAC AC AG T С T С C AG С C AC CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLECADYGLQKVYACE SEQ ID NO: 43 DNA LC GAAAT T G T G T T GAC AC AG T С T С C AG С C AC CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml5 SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 143 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 72 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 73 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAAC TAT GGAAT GAAC TGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 74 HC EVQLVQSGAEVRRPGATVRISCRVSGFTL TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 144 040295

SEQ ID NO: 75 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC С ТАСAC С T G СAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml5 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 145 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT T CAG T С T G T GAC T С CAAAG GAGAAAGT CA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC TTACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAG T G T CAG CAG TAT TATAACCTTCCGTGGAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 63 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT T CAG T С T G T GAC T С CAAAG GAGAAAGT CA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC TTACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAG T G T CAG CAG TAT TATAACCTTCCGTGGAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAGTCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml6 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 146 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 76 vh EVQLVQSGAEVKKPGESLRISCRGSGFTL TNYGMNWVRQATGQGLEWMGWINTDTGEP TYADDFRGRVTISADRSIS TAYLQWS S LR ASDTAMYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 77 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGA GGTGAAAAAGCCCGGGGAGTCTCTGAGGA TCTCCTGTAAGGGTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCACTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATAT GC T GAT GAC T T CAAGGGAAGAGT СAC CAT С T CAG С C GACAAG T С CAT CAG CA CCGCCTACCTGCAGTGGAGCAGCCTGAAG GCCTCGGACACCGCCATGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 78 HC EVQLVQSGAEVRRPGESLRISCRGSGFTL TNYGMNWVRQATGQGLEWMGWINTDTGEP TYADDFRGRVTISADRSIS TAYLQWS S LR ASDTAMYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 147 040295

SEQ ID NO: 79 NA DNA GAAGTGCAGCTGGTGCAGTCTGGAGCAGA GGTGAAAAAGCCCGGGGAGTCTCTGAGGA TCTCCTGTAAGGGTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCACTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATAT GC T GAT GAC T T CAAGGGAAGAGT СAC CAT С T CAG С C GACAAG T С CAT CAG CA CCGCCTACCTGCAGTGGAGCAGCCTGAAG GCCTCGGACACCGCCATGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG WITH CAG GAAGAC WITH C GAG G T WITH CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCAAGACAAAGTGCCGGGAGGAGCA GTTCAGCA G TCCTCACCGTCCTGCACCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml6 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 148 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 63 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml7 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 149 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 80 vh QVQLVQSGSELKKPGASVKVSCKASGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISTLR AEDTATYFCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 81 DNA VH CAGGTGCAGCTGGTGCAATCTGGGTCTGA GTTGAAGAAGCCTGGGGCCTCAGTGAAGG TTTCCTGCAAGGCTTCTGGATTCACCCTG ACTAACTATGGCATGAATTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GATGGATCAACACCGACACTGGGGAGCCA ACGTATGCCGATGACTTCAAGGGACGGTT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCACGCTAAAG GCTGAGGACACTGCTACATATTTCTGTGC AAGAAAC CCCCCTTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 82 HC QVQLVQSGSELKKPGASVKVSCKASGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISTLR AEDTATYFCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 150 040295

SEQ ID NO: 83 NA DNA CAGGTGCAGCTGGTGCAATCTGGGTCTGA GTTGAAGAAGCCTGGGGCCTCAGTGAAGG TTTCCTGCAAGGCTTCTGGATTCACCCTG ACTAACTATGGCATGAATTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GATGGATCAACACCGACACTGGGGAGCCA ACGTATGCCGATGACTTCAAGGGACGGTT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCACGCTAAAG GCTGAGGACACTGCTACATATTTCTGTGC AAGAAAC CCCCCTTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAC СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml7 SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 151 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 84 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQRPGRAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLQPEDIATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 85 DNA VL GAGAT С CAGAT GAG C GAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCTCCTCTAGTCAGGACATT AGCAAC TAT T ТАЛАТ T GGTAT CAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCT ACTATACATCCACTTTGCACCTGGGGGTC CCATCAAGGTTCAGTGGAAGTGGATCTGG GACAGAT T T ТАС T T T CAC CAT CAGCAGC C T GCAGCC T GAAGATAT T GCAACATAT TAG T G T CAACAG TATTATAATCTCCCTTG GAG GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 86 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGRAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLQPEDIATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSTLTLSKADYEKTHKSSVY SEQ ID NO: 87 DNA LC GAGAT С CAGAT GAG C GAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCTCCTCTAGTCAGGACATT AGCAAC TAT T ТАЛАТ T GGTAT CAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCT ACTATACATCCACTTTGCACCTGGGGGTC CCATCAAGGTTCAGTGGAAGTGGATCTGG GACAGAT T T ТАС T T T CAC CAT CAGCAGC C T GCAGCC T GAAGATAT T GCAACATAT TAG T G T CAACAG TATTATAATCTCCCTTG GAG GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC TGC GAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml8 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 152 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 153 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAG G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T C GAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml8 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 154 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 88 VL AIQLTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 89 DNA VL GCCATCCAGTTGACCCAGTCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 90 LC AIQLTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSRGTYS LSSTLTLSKADYGLQKVYACE SEQ ID NO: 91 DNA LC GCCATCCAGTTGACCCAGTCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml9 SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 155 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 28 vh EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 29 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACCCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC EVQLVQSGAEVRRPGATVRISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 156 040295

SEQ ID NO: 31 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml9 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 157 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 92 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 93 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GAC AGAT T T С AC С T T T AC C AT C AG T AG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 94 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYERHRVYACEVTHQGL SEQ ID NO: 95 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum20 SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFKG

- 158 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 64 vh QVQLVQS GAE VRRPGAS VRVS GRAS G FT L SEQ ID NO: 65 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HC QVQLVQS GAEVRRPGASVRVS ORAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQICSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 159 040295

SEQ ID NO: 67 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCTGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum20 SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 160 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 96 VL DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 97 DNA VL GATATTGTGAT GAC С C AGAC T С С AC T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GAC AGAC T T С AC T С T C AC CAT C AG C AGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 98 LC DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSECTYS LSSSTLTLSKADYEKHKSSFQPVACE SEQ ID NO: 99 DNA LC GATATTGTGAT GAC С C AGAC T С С AC T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GACAGAC T T СAC T С T CAC CAT CAG CAGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum01-Ser SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 161 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVKRPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 162 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAG G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T C GAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum01-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 163 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 32 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGRAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 33 DNA VL GAGAT С CAGAT GAG C GAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA COAT CAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T ТАЛАС T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T ОАО С T T TAC CAT GAG TAG С C TGGAAGCTGAAGATGOTGCAACATATTAG T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 34 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGV PSRFSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYERGLNSVY PVTHQACEVTHQACEV SEQ ID NO: 35 DNA LC GACAT С CAGAT GAC C GAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA COAT CAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T ТАЛАС T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T ОАО С T T TAC CAT GAG TAG С C TGGAAGCTGAAGATGOTGCAACATATTAG T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum02-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 164 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQS GAEVKKPGATVKIS CKVS G FT L TNYGMNWVRQAPGQGLEWMGWINT DT GE P TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG G T T G GATAAACAC C GACAC T G GAGAG С CA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQS GAEVKKPGATVKIS CKVS G FT L TNYGMNWVRQAPGQGLEWMGWINT DT GE P TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 165 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAACССTСССTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCAC CAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCACTACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum02-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 166 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T СACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT TAC T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSKDS PVTHVEKHKK SEQ ID NO: 39 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T CACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT ТАС T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum03-Ser SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 167 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVRRPGATVRISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 168 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum03-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 169 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 41 DNA VL GAAAT T G T G T T GAC AC AG T С T С C AG C GAG CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 43 DNA LC GAAAT T G T G T T GAC AC AG T С T С C AG C GAG CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T GAGAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum04-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 170 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVKKPGATVKISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 171 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA G С С CAG CAACAC CAAG G T G GACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T C CAG T T CA CGTCCTGCACCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC AT С С CAG GAG GAGAT GAC CAAGAAC CAG G TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG G С T С T G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum04-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 172 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 44 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQKPGQSPQLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 45 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GAC AGAC T T С AC T С T C AC CAT C AG C AGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 46 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQKPGQSPQLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSSTYPVSFTLVSKADYEKHKK SEQ ID NO: 47 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GACAGAC T T СAC T С T CAC CAT CAG CAGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum05-Ser SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 173 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 174 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum05-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 175 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 48 VL EIVLTQSPATLSLSPGERATLSCSSSQDI SNYLNWYQQKPGKAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 49 DNA VL GAAAT T G T G T T GAC AC AG T С T C GAG C GAG CCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGTTCAAGTCAGGACATC AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAG CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 50 LC EIVLTQSPATLSPGERATLSCSSSQDI SNYLNWYQQKPGKAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLRGSRADYERHRVYACEVTHQGLSS SEQ ID NO: 51 DNA LC GAAAT T G T G T T GAC AC AG T С T C GAG C GAG CCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGTTCAAGTCAGGACATC AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAG CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T GAGAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum06-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 176 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVRRPGATVRISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 177 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum06-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 178 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 52 VL DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 53 DNA VL GATATTGTGAT GAC С CAGAC T С СAC T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 54 LC DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSECTYS LSSTLTLSKADYEKHKSSFQPVACE SEQ ID NO: 55 DNA LC GATATTGTGAT GAC С CAGAC T С СAC T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum07-Ser SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 179 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PE VT CVWDVS QE DPE VQ FNW YVDGVE VH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS S TERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 180 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum07-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 181 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 57 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYGLSSVYACEVACEVACEV SEQ ID NO: 59 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAG T CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum08-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 182 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 183 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum08-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 184 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA COAT CAC С T G CAG T T CAAGT CAGGACAT C AGCAAT TAT T ТАЛАС T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T CAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 63 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT CAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T ТАЛАС T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T CAC T С T CAC CAT CAG GAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum09-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 185 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104 vh QVQLVQS GAEVKKPGASVKVS CKAS G FT L SEQ ID NO: 105 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HC QVQLVQS GAEVKKPGASVKVS CKAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 186 040295

SEQ ID NO: 107 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA BAP050-hum09-Ser LC SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 187 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGRAPRLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 37 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T СACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT ТАС T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGRAPRLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYTHERGLSSVYACEVACEVACEV SEQ ID NO: 39 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGAT T T TAC С С T CACAAT TAATAACA TAGAAT С T GAGGAT GC T GCATAT ТАС T T C T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml0-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 188 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104 vh QVQLVQS GAE VRRPGASVRVS GRAS G FT L SEQ ID NO: 105 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HC QVQLVQS GAEVRRPGASVRVS CRAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS S TERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 189 040295

SEQ ID NO: 107 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G GAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T C GAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml0-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 190 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAAT T G T G T T GAC AC AG T С T С C AG С C AC CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLECADYGLQKVYACE SEQ ID NO: 43 DNA LC GAAAT T G T G T T GAC AC AG T С T С C AG С C AC CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-humll-Ser SEQ ID NO: (Kabat) HCDR1 NYGMN SEQ ID NO: (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 191 040295

SEQ ID NO: (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: (Chothia) HCDR1 GFTLTNY SEQ ID NO: (Chothia) HCDR2 NTDTGE SEQ ID NO: (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104 vh QVQLVQS GAEVKKPGASVKVS CKAS G FT L SEQ ID NO: 105 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HC QVQLVQS GAEVKKPGASVKVS CKAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 192 040295

SEQ ID NO: 107 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G GAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-humll-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 193 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 57 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAG T CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQRPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYGLSSVYACEVACEVACEV SEQ ID NO: 59 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С TAT САС T T GCAG T T CAAG T CAGGACAT C AGCAAT TAT T TAAAC T GGTACC T GCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAAT T СAC T С T CAC CAT CAG CAG С C T GCAGCC T GAT GAT T T T GCAAC T TAT TAG T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml2-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 194 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104 vh QVQLVQS GAEVKKPGASVKVS CKAS G FT L SEQ ID NO: 105 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HC QVQLVQS GAEVKKPGASVKVS CKAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 195 040295

SEQ ID NO: 107 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml2-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 196 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA COAT СAC С T G GAG T T CAAGT GAGGACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T САС T С T GAG CAT CAG GAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 63 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT САС С T G GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T САС T С T GAG CAT CAG GAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T GAGAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml3-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 197 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 108 vh QVQLVQS GAEVRRPGASVRVS GRAS G FT L TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 109 DNA VH CAGGTTCAGCTGGTGCAGTCCGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 110 HC QVQLVQS GAEVRRPGASVRVS CRAS G FT L TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 198 040295

SEQ ID NO: 111 NA DNA CAGGTTCAGCTGGTGCAGTCCGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml3-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 199 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPRLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 37 DNA VL GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC TTACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGATT T TACСС T СACAATTAATAACA TAGAATС T GAGGAT GC T GCATAT ТАС T T C T G T CAG GAG TAT TATAACCTTCCGTGGAC GTTCGGCCAAGGGACCAAGGTGGAAATCA ΆΆ SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPRLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYQRSFYNSVACEVACEVACEV SEQ ID NO: 39 DNA LC GACAT С CAGAT GAC С CAG TCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT СAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAT CAGCAGAA ACCAGGGAAAGCTCCTAAGCTCCTGATCT AT TACACAT CAACC TTACAC T TAGGGAT C CCACCTCGATTCAGTGGCAGCGGGTATGG AACAGATT T TACСС T CACAATTAATAACA TAGAATС T GAGGAT GC T GCATAT ТАС T T C T G T CAG CAG TAT TATAACCTTCCGTGGAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAGTCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml4-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 200 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 8 vh EVQLVQS GAEVKKPGATVKIS CKVS G FT L TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 9 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG G T T G GATAAACAC C GACAC T G GAGAG С CA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 18 HC EVQLVQS GAEVKKPGATVKIS CKVS G FT L TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 201 040295

SEQ ID NO: 19 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml4-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 202 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 41 DNA VL GAAAT T G T G T T GAC AC AG T С T C GAG C GAG CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 43 DNA LC GAAAT T G T G T T GAC AC AG T С T C GAG C GAG CCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTG GAG T T CAAG T GAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T САС С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T GAG GAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T GAGAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAACACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml5-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 203 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 8 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 9 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 18 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWIRQSPSRGLEWLGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 204 040295

SEQ ID NO: 19 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGATCAGGCA GTCCCCATCGAGAGGCCTTGAGTGGCTGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml5-Ser SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 205 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPRERVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 63 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T СAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml8-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 206 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVRRPGATVRISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 207 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G CAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml8-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 208 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 88 VL AIQLTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 89 DNA VL GCCATCCAGTTGACCCAGTCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA COAT CAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T ТАЛАС T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T CAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 90 LC AIQLTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTLTISSLQPEDFATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLECPVRGTRSFTHQ SEQ ID NO: 91 DNA LC GCCATCCAGTTGACCCAGTCTCCATCCTC CCTGTCTGCATCTGTAGGAGACAGAGTCA С CAT CAC T T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T ТАЛАС T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAT T T CAC T С T CAC CAT CAG CAG С C TGCAGCCTGAAGATTTTGCAACTTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-huml9-Ser SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 209 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 101 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLGK

- 210 040295

SEQ ID NO: 103 NA DNA GAGGTCCAGCTGGTACAGTCTGGGGCTGA GGTGAAGAAGCCTGGGGCTACAGTGAAAA TCTCCTGCAAGGTTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCCCCTGGACAAGGGCTTGAGTGGATGG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G GAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG С CAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-huml9-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 211 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 92 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 93 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 94 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDI SNYLNWYQQKPGQAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYGLQKVYACE SEQ ID NO: 95 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTT TCAGTСTGTGACTСCAAAGGAGAAAGTCA С CAT СAC С T G CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTAGCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGGT C CCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGAT T T СAC С T T TAC CAT CAG TAG С C TGGAAGCTGAAGATGCTGCAACATATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-hum20-Ser SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 212 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104 vh QVQLVQS GAE VRRPGAS VRVS CRAS G FT L SEQ ID NO: 105 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HC QVQLVQS GAEVRRPGASVRVS CRAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLGR

- 213 040295

SEQ ID NO: 107 NA DNA CAGGTTCAGCTGGTGCAGTCTGGAGCTGA GGTGAAGAAGCCTGGGGCCTCAGTGAAGG TCTCCTGCAAGGCTTCTGGATTTACCCTC ACAAACTATGGAATGAACTGGGTGCGACA GGCTCGTGGACAACGCCTTGAGTGGATAG GTTGGATAAACACCGACACTGGAGAGCCA ACATATGCTGATGACTTCAAGGGAAGATT TGTCTTCTCCTTGGACACCTCTGTCAGCA CGGCATATCTGCAGATCAGCAGCCTAAAG GCTGAGGACACTGCCGTGTATTACTGTGC AAGAAAC CCTCCCTATTACTACGGTACTA ATAACGCGGAGGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGC TTCCACCAAGGGCCCATCCGTCTTCCCCC TGGCGCCCTGCTCCAGGAGCACCTCCGAG AGCACAGCCGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGT CGTGGAACTCAGGCGCCCTGACCAGCGGC GTGCACACCTTCCCGGCTGTCCTACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGG TGACCGTGCCCTCCAGCAGCTTGGGCACG AAGAC C TACAC С T G GAAC G TAGAT СACAA GCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGG ACCATCAGTCTTCCTGTTCCCCCCAAAAC CCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGT GAG C GAG GAAGAC С С C GAG G T С CAG T T CA ACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAACAGCACGTACCGTGTGGTCAGCG TCCTCACCGTCCTGCA CCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTGTC CAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCC ATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTC TACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTAAC CGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAG GC T С T GCACAACCAC TACACACAGAAGAG CCTCTCCCTGTCTCTGGGTAAA LC BAP050-hum20-Ser SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 214 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 96 VL DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 97 DNA VL GATATTGTGAT GAC С C AGAC T С С AC T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG CAG T T CAAGT CAGGACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GAC AGAC T T С AC T С T C AC CAT C AG C AGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AA SEQ ID NO: 98 LC DIVMTQTPLSLPVTPGEPASISCSSSQDI SNYLNWYQQRPGQAPRLLIYYTSTLHLGI PDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYERHRVYACEVTHQGL SEQ ID NO: 99 DNA LC GATATTGTGAT GAC С C AGAC T С С AC T С T C CCTGCCCGTCACCCCTGGAGAGCCGGCCT CCATCTCCTG CAG T T CAAG T CAG GACAT C AGCAAT TAT T TAAAC T GGTACCAGCAGAA ACCTGGCCAGGCTCCCAGGCTCCTCATCT AT TACACAT CAACC T TACAC T TAGGGAT C CCAGACAGGTTCAGTGGCAGTGGGTCTGG GACAGAC T T СAC T С T CAC CAT CAG CAGAC TGGAGCCTGAAGATTTTGCAGTGTATTAC T G T CAG CAG TAT TATAAC CTTCCGTG GAC GTTCGGCCAAGGGACCAAGGTGGAAATCA AACGTACGGTGGCTGCACCATCTGTCTTC ATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGC T GAATAAC TTCTATCC CAGAGAG G С CAAA GTACAGTGGAAGGTGGATAACGCCCTCCA AT C G G G TAAC T С С CAG GAGAG T G T CACAG AGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGC AGAC TAG GAGAAAGACAAAG TCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGA GTGT HC BAP050-Clone-F SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 215 040295

SEQ ID NO: 3 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 112 DNA VH GAAGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCCGGCGCTACCGTGAAGA TCTCCTGCAAGGTGTCCGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCCCTGGACAGGGCCTGGAATGGATGG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 113 HC EVQLVQSGAEVKKPGATVKISCKVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLG

- 216 040295

SEQ ID NO: 114 NA DNA GAAGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCCGGCGCTACCGTGAAGA TCTCCTGCAAGGTGTCCGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCCCTGGACAGGGCCTGGAATGGATGG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCTGC TTCTACCAAGGGGCCCAGCGTGTTCCCCC TGGCCCCCTGCTCCAGAAGCACCAGCGAG AGCACAGCCGCCCTGGGCTGCCTGGTGAA GGACTACTTCCCCGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCAGCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAG CAGCGGCCTGTACAGCCTGAGCAGCGTGG TGACCGTGCCCAGCAGCAGCCTGGGCACC AAGAC C TACAC С T G TAAC G T G GAC СACAA GCCCAGCAACACCAAGGTGGACAAGAGGG TGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTGGGCGG ACCCAGCGTGTTCCTGTTCCCCCCCAAGC С CAAGGACAC С С T GAT GAT CAGCAGAACC CCCGAGGTGACCTGTGTGGTGGTGGACGT GTCCCAGGAGGACCCCGAGGTCCAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCAC AACGCCAAGACCAAGCCCAGAGAGGAGCA GTTTAACAGCACCTACCGGGTGGTGTCCG TGCTGACCGTGCTGCACCAGGA CTGGCTG AACGGCAAAGAGTACAAGTGTAAGGTCTC CAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCT AGAGAG С С С CAG G T C TACAC С С T G С СAC C CAGCCAAGAGGAGATGACCAAGAACCAGG TGTCCCTGACCTGTCTGGTGAAGGGCTTC TACCCAAGCGACATCGCCGTGGAGTGGGA GAGCAACGGCCAGCCCGAGAACAACTACA AGAC С AC С С С С С C AG T G С T G GAC AG C GAC GGCAGCTTCTTCCTGTACAGCAGGCTGAC CGTGGACAAGTCCAGATGGCAGGAGGGCA ACGTCTTTAGCTGCTCCGTGATGCACGAG G С С С T G CACAAC CAC TACAC С CAGAAGAG CCTGAGCCTGTCCCTGGGC LC BAP050-Clone-F SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 217 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 32 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIR SEQ ID NO: 115 DNA VL GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCGTG CCCTCCAGATTTTCCGGCTCTGGCTCTGG СAC C GAC T T TAC С T T CAC CAT CAG С T С С C TGGAAGCCGAGGACGCCGCCACCTACTAC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AG SEQ ID NO: 34 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQRPGRAPRLLIYYTSTLHLGV PSRFSGSGSGTDFTFTISSLEAEDAATYY CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYERHRVYACEVTHQGL SEQ ID NO: 117 DNA LC GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCGTG CCCTCCAGATTTTCCGGCTCTGGCTCTGG СAC C GAC T T TAC С T T CAC CAT CAG С T С С C TGGAAGCCGAGGACGCCGCCACCTACTAC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCAAGCGACGAGCAGCTGAA GAGCGGCACCGCCAGCGTGGTGTGTCTGC TGAACAACTTCTACCCCAGGGAGGCCAAG GTGCAGTGGAAGGTGGACAACGCCCTGCA GAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGC CTGAGCAGCACCCTGACCCTGAGCAAGGC CGACTACGAGAAGCACAAGGTGTACGСST GTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC HC BAP050-Clone-G SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 218 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 100 vh EVQLVQSGAEVKKPGATVKISCRVSGTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 112 DNA VH GAAGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCCGGCGCTACCGTGAAGA TCTCCTGCAAGGTGTCCGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCCCTGGACAGGGCCTGGAATGGATGG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 113 HC EVQLVQSGAEVKKPGATVKISCRVSGFTL TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLG

- 219 040295

SEQ ID NO: 114 NA DNA GAAGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCCGGCGCTACCGTGAAGA TCTCCTGCAAGGTGTCCGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCCCTGGACAGGGCCTGGAATGGATGG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCTGC TTCTACCAAGGGGCCCAGCGTGTTCCCCC TGGCCCCCTGCTCCAGAAGCACCAGCGAG AGCACAGCCGCCCTGGGCTGCCTGGTGAA GGACTACTTCCCCGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCAGCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAG CAGCGGCCTGTACAGCCTGAGCAGCGTGG TGACCGTGCCCAGCAGCAGCCTGGGCACC AAGAC C TACAC С T G TAAC G T G GAC СACAA GCCCAGCAACACCAAGGTGGACAAGAGGG TGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTGGGCGG ACCCAGCGTGTTCCTGTTCCCCCCCAAGC С CAAG GACAC С С T GAT GAT GAG CAGAAC C CCCGAGGTGACCTGTGTGGTGGTGGACGT GTCCCAGGAGGACCCCGAGGTCCAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCAC AACGCCAAGACCAAGCCCAGAGAGGAGCA GTTTAACAGCACCTACCGGGTGGTGTCCG TGCTGACCGTGCTGCACCA GGACTGGCTG AACGGCAAAGAGTACAAGTGTAAGGTСTC CAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCT AGAGAG С С С CAG G T C TACAC С С T G С СAC C CAGCCAAGAGGAGATGACCAAGAACCAGG TGTCCCTGACCTGTCTGGTGAAGGGCTTC TACCCAAGCGACATCGCCGTGGAGTGGGA GAGCAACGGCCAGCCCGAGAACAACTACA AGAC САС С С С С C GAG T G С T G GACAG C GAC GGCAGCTTCTTCCTGTACAGCAGGCTGAC CGTGGACAAGTCCAGATGGCAGGAGGGCA ACGTCTTTAGCTGCTCCGTGATGCACGAG G С С С T G GAGAAC CAC TACAC С CAGAAGAG CCTGAGCCTGTCCCTGGGC LC BAP050-Clone-G SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 220 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPRLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIR SEQ ID NO: 118 DNA VL GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCATC CCCCCTAGATTCTCCGGCTCTGGCTACGG СAC C GAC T T СAC С С T GAC CAT CAACAACA TCGAGTCCGAGGACGCCGCCTACTACTTC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AG SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPRLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTRVEIRRTVAAPSVF IFPSDEQLRSGTASWCLLNNFYPREAR VQWRVDNALQSGNSQESVTEQDSRDSTYS LSSSTLTLSRADYQRSFYNSVACEVACEVACEV SEQ ID NO: 120 DNA LC GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCATC CCCCCTAGATTCTCCGGCTCTGGCTACGG СAC C GAC T T СAC С С T GAC CAT CAACAACA TCGAGTCCGAGGACGCCGCCTACTACTTC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCAAGCGACGAGCAGCTGAA GAGCGGCACCGCCAGCGTGGTGTGTCTGC TGAACAACTTCTACCCCAGGGAGGCCAAG GTGCAGTGGAAGGTGGACAACGCCCTGCA GAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGC CTGAGCAGCACCCTGACCCTGAGCAAGGC CGACTACGAGAAGCACAAGGTGTACGCCT GTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGA GTGCTGATGAATTC HC BAP050-Clone-H SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG

- 221 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104 vh QVQLVQS GAEVRRPGASVRVS CRAS G FT L SEQ ID NO: 121 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCTGGCGCCTCCGTGAAGG TGTCCTGCAAGGCCTCTGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCAGGGGCCAGCGGCTGGAATGGATCG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 122 HC QVQLVQS GAEVRRPGASVRVS CRAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLG

- 222 040295

SEQ ID NO: 123 NA DNA CAGGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCTGGCGCCTCCGTGAAGG TGTCCTGCAAGGCCTCTGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCAGGGGCCAGCGGCTGGAATGGATCG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCTGC TTCTACCAAGGGGCCCAGCGTGTTCCCCC TGGCCCCCTGCTCCAGAAGCACCAGCGAG AGCACAGCCGCCCTGGGCTGCCTGGTGAA GGACTACTTCCCCGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCAGCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAG CAGCGGCCTGTACAGCCTGAGCAGCGTGG TGACCGTGCCCAGCAGCAGCCTGGGCACC AAGAC C TACAC С T G TAAC G T G GAC СACAA GCCCAGCAACACCAAGGTGGACAAGAGGG TGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTGGGCGG ACCCAGCGTGTTCCTGTTCCCCCCCAAGC С CAAG GACAC С С T GAT GAT CAG CAGAAC C CCCGAGGTGACCTGTGTGGTGGTGGACGT GTCCCAGGAGGACCCCGAGGTCCAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCAC AACGCCAAGACCAAGCCCAGAGAGGAGCA GTTTAACAGCACCTACCGGGTGGTGTCCG TGCTGACCGTGCTGCACCA GGACTGGCTG AACGGCAAAGAGTACAAGTGTAAGGTСTC CAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCT AGAGAG С С С CAG G T C TACAC С С T G С CAC C CAGCCAAGAGGAGATGACCAAGAACCAGG TGTCCCTGACCTGTCTGGTGAAGGGCTTC TACCCAAGCGACATCGCCGTGGAGTGGGA GAGCAACGGCCAGCCCGAGAACAACTACA AGAC CAC С С С С С CAG T G С T G GACAG C GAC GGCAGCTTCTTCCTGTACAGCAGGCTGAC CGTGGACAAGTCCAGATGGCAGGAGGGCA ACGTCTTTAGCTGCTCCGTGATGCACGAG G С С С T G CACAAC CAC TACAC С CAGAAGAG CCTGAGCCTGTCCCTGGGC LC BAP050-Clone-H SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 223 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 118 DNA VL GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCATC CCCCCTAGATTCTCCGGCTCTGGCTACGG СAC C GAC T T СAC С С T GAC CAT CAACAACA TCGAGTCCGAGGACGCCGCCTACTACTTC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AG SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSKDS PVTHVEKHKK SEQ ID NO: 120 DNA LC GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCATC CCCCCTAGATTCTCCGGCTCTGGCTACGG СAC C GAC T T СAC С С T GAC CAT CAACAACA TCGAGTCCGAGGACGCCGCCTACTACTTC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCAAGCGACGAGCAGCTGAA GAGCGGCACCGCCAGCGTGGTGTGTCTGC TGAACAACTTCTACCCCAGGGAGGCCAAG GTGCAGTGGAAGGTGGACAACGCCCTGCA GAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGC CTGAGCAGCACCCTGACCCTGAGCAAGGC CGACTACGAGAAGCACAAGGTGTACGCCT GTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC HC BAP050-Clone-I SEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG

- 224 040295

SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104 vh QVQLVQS GAEVRRPGASVRVS GRAS G FT L SEQ ID NO: 124 DNA VH CAAGTGCAGCTGGTGCAGTCGGGAGCCGA AGTGAAGAAGCCTGGAGCCTCGGTGAAGG TGTCGTGCAAGGCATCCGGATTCACCCTC ACCAATTACGGGATGAACTGGGTCAGACA GGCCCGGGGTCAACGGCTGGAGTGGATCG GATGGATTAACACCGACACCGGGGAGCCT ACCTACGCGGACGATTTCAAGGGACGGTT CGTGTTCTCCCTCGACACCTCCGTGTCCA CCGCCTACCTCCAAATCTCCTCACTGAAA GCGGAGGACACCGCCGTGTACTATTGCGC GAGGAACCCGCCCTACTACTACGGAACCA ACAACGCCGAAGCCATGGACTACTGGGGC CAGGGCACCACTGTGACTGTGTCCAGC SEQ ID NO: 125 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCTGGCGCCTCCGTGAAGG TGTCCTGCAAGGCCTCTGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCAGGGGCCAGCGGCTGGAATGGATCG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 122 HC QVQLVQS GAEVRRPGASVRVS GRAS G FT L TNYGMNWVRQARGQRLEWIGWINTDTGEP TYADDFRGRFVFSLDTSVSTAYLQISSLR AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSE STAALGCLVRDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT RTYTCNVDHRPSNTRVDRRVESRYGPPCP PCPAPEFLGGPSVFLFPPRPRDTLMISRT PE VT CVWDVS QE DPE VQ FNW YVDGVE VH NARTRPREEQFNSTYRWSVLTVLHQDWL NGREYRCRVSNRGLPS SIERTISRARGQP REPQVYTLPPSQEEMTRNQVSLTCLVRGF YPSDIAVEWESNGQPENNYRTTPPVLDSD GSFFLYSRLTVDRSRWQEGNVFSCSVMHE ALHNHYTQRSLSLSLG

- 225 040295

SEQ ID NO: 126 NA DNA CAAGTGCAGCTGGTGCAGTCGGGAGCCGA AGTGAAGAAGCCTGGAGCCTCGGTGAAGG TGTCGTGCAAGGCATCCGGATTCACCCTC ACCAATTACGGGATGAACTGGGTCAGACA GGCCCGGGGTCAACGGCTGGAGTGGATCG GATGGATTAACACCGACACCGGGGAGCCT ACCTACGCGGACGATTTCAAGGGACGGTT CGTGTTCTCCCTCGACACCTCCGTGTCCA CCGCCTACCTCCAAATCTCCTCACTGAAA GCGGAGGACACCGCCGTGTACTATTGCGC GAGGAACCCGCCCTACTACTACGGAACCA ACAACGCCGAAGCCATGGACTACTGGGGC CAGGGCACCACTGTGACTGTGTCCAGCGC GTCCACTAAGGGCCCGTCCGTGTTCCCCC TGGCACCTTGTAGCCGGAGCACTAGCGAA TCCACCGCTGCCCTCGGCTGCCTGGTCAA GGATTACTTCCCGGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCTCCGGA GTGCACACCTTCCCCGCTGTGCTGCAGAG CTCCGGGCTGTACTCGCTGTCGTCGGTGG TCACGGTGCCTTCATCTAGCCTGGGTACC AAGAC C TACAC T T G CAAC G T G GAC СACAA GCCTTCCAACACTAAGGTGGACAAGCGCG TCGAATCGAAGTACGGCCCACCGTGCCCG CCTTGTCCCGCGCCGGAGTTCCTCGGCGG TCCCTCGGTCTTTCTGTTCCCACCGAAGC CCAAGGACACTTTGATGATTTCCCGCACC CCTGAAGTGACATGCGTGGTCGTGGACGT GTCACAGGAAGATCCGGAGGTGCAGTTCA ATTGGTACGTGGATGGCGTCGAGGTGCAC AACGCCAAAACCAAGCCGAGGGAGGAGCA GTTCAACTCCACTTACCGCGTCGTGTCCG TGCTGACGGTGCTGCATCAGGACTGGCTG AACGGGAAGGAGTACAAGTGCAAAGTGTC CAACAAGGGACTTCCTAGCTCAATCGAAA AGACCATCTCGAAAGCCAAGGGACAGCCC CGGGAACCCCAAGTGTATACCCTGCCACC GAG С CAG GAAGAAAT GAC TAAGAAC CAAG TCTCATTGACTTGCCTTGTGAAGGGCTTC TACCCATCGGATATCGCCGTGGAATGGGA GTCCAACGGCCAGCCGGAAAACAACTACA AGACCACCCCTCCGGTGCTGGACTCAGAC GGATCCTTCTTCCTCTACTCGCGGCTGAC CGTGGATAAGAGCAGATGGCAGGAGGGAA ATGTGTTCAGCTGTTCTGTGATGCATGAA G С С С T G CACAAC CAC TACAC T CAGAAG T C CCTGTCCCTCTCCCTGGGA

- 226 040295

SEQ ID NO: 127 NA DNA CAGGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCTGGCGCCTCCGTGAAGG TGTCCTGCAAGGCCTCTGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCAGGGGCCAGCGGCTGGAATGGATCG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCTGC TTCTACCAAGGGGCCCAGCGTGTTCCCCC TGGCCCCCTGCTCCAGAAGCACCAGCGAG AGCACAGCCGCCCTGGGCTGCCTGGTGAA GGACTACTTCCCCGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCAGCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAG CAGCGGCCTGTACAGCCTGAGCAGCGTGG TGACCGTGCCCAGCAGCAGCCTGGGCACC AAGAC C TACAC С T G TAAC G T G GAC СACAA GCCCAGCAACACCAAGGTGGACAAGAGGG TGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTGGGCGG ACCCAGCGTGTTCCTGTTCCCCCCCAAGC С CAAG GACAC С С T GAT GAT CAG CAGAAC C CCCGAGGTGACCTGTGTGGTGGTGGACGT GTCCCAGGAGGACCCCGAGGTCCAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCAC AACGCCAAGACCAAGCCCAGAGAGGAGCA GTTTAACAGCACCTACCGGGTGGTGTCCG TGCTGACCGTGCTGCACCA GGACTGGCTG AACGGCAAAGAGTACAAGTGTAAGGTСTC CAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCT AGAGAG С С С CAG G T C TACAC С С T G С СAC C CAGCCAAGAGGAGATGACCAAGAACCAGG TGTCCCTGACCTGTCTGGTGAAGGGCTTC TACCCAAGCGACATCGCCGTGGAGTGGGA GAGCAACGGCCAGCCCGAGAACAACTACA AGAC СAC С С С С С CAG T G С T G GACAG C GAC GGCAGCTTCTTCCTGTACAGCAGGCTGAC CGTGGACAAGTCCAGATGGCAGGAGGGCA ACGTCTTTAGCTGCTCCGTGATGCACGAG G С С С T G CACAAC CAC TACAC С CAGAAGAG CCTGAGCCTGTCCCTGGGC LC BAP050-Clone-I SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 227 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQKPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 128 DNA VL GATAT T CAGAT GAC T CAG T СAC С TAG TAG CCTGAGCGCTAGTGTGGGCGATAGAGTGA СТАТ САС CTGTAGCTCTAGT CAG GATAT C TCTAACTACCTGAACTGGTATCTGCAGAA GCCCGGTCAATCACCTCAGCTGCTGATCT ACTACACTAGCACCCTGCACCTGGGCGTG CCCTCTAGGTTTAGCGGTAGCGGTAGTGG CACCGAGTTCACCCTGACTATCTCTAGCC TGCAGCCCGACGACTTCGCTACCTACTAC T G T CAG CAG TAG TATAAC CTGCCCTG GAC CTTCGGTCAAGGCACTAAGGTCGAGATTA AG SEQ ID NO: 129 DNA VL GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC TCCAACTACCTGAACTGGTATCTGCAGAA GCCCGGCCAGTCCCCTCAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCGTG CCCTCCAGATTTTCCGGCTCTGGCTCTGG CACCGAGTTTACCCTGACCATCAGCTCCC TGCAGCCCGACGACTTCGCCACCTACTAC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AG SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYLQKPGQSPQLLIYYTSTLHLGV PSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSSTYPVSFSFTLSKADYEKHKKK

- 228 040295

SEQ ID NO: 130 DNA LC GATAT T CAGAT GAC T CAG T СAC C TAG TAG CCTGAGCGCTAGTGTGGGCGATAGAGTGA СТАТ САС CTGTAGCTCTAGT CAG GATAT C TCTAACTACCTGAACTGGTATCTGCAGAA GCCCGGTCAATCACCTCAGCTGCTGATCT ACTACACTAGCACCCTGCACCTGGGCGTG CCCTCTAGGTTTAGCGGTAGCGGTAGTGG CACCGAGTTCACCCTGACTATCTCTAGCC TGCAGCCCGACGACTTCGCTACCTACTAC TGTCAGCAGTACTATAACCTGCCCTGGAC CTTCGGTCAAGGCACTAAGGTCGAGATTA AGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCCAGCGACGAGCAGCTGAA GAGCGGCACCGCCAGCGTGGTGTGCCTGC TGAACAACTTCTACCCCCGGGAGGCCAAG GTGCAGTGGAAGGTGGACAACGCCCTGCA GAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGC CTGAGCAGCACCCTGACCCTGAGCAAGGC CGACTACGAGAAGCATAAGGTGTACGCCT GCGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC SEQ ID NO: 131 DNA LC GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC TCCAACTACCTGAACTGGTATCTGCAGAA GCCCGGCCAGTCCCCTCAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCGTG CCCTCCAGATTTTCCGGCTCTGGCTCTGG CACCGAGTTTACCCTGACCATCAGCTCCC TGCAGCCCGACGACTTCGCCACCTACTAC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCAAGCGACGAGCAGCTGAA GAGCGGCACCGCCAGCGTGGTGTGTCTGC TGAACAACTTCTACCCCAGGGAGGCCAAG GTGCAGTGGAAGGTGGACAACGCCCTGCA GAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGC CTGAGCAGCACCCTGACCCTGAGCAAGGC CGACTACGAGAAGCACAAGGTGTACGCCT GTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC HC BAP050-Clone-J SEQ ID NO: 1 (Rabat) HCDR1 NYGMN SEQ ID NO: 2 (Rabat) HCDR2 WINTDTGEPTYADDFRG SEQ ID NO: 3 (Rabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGE

- 229 040295

SEQ ID NO: 3 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 108 vh QVQLVQS GAEVKKPGASVKVS CKAS G FT L TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSS SEQ ID NO: 132 DNA VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGA AGTGAAGAAACCCGGCGCTAGTGTGAAAG TCAGCTGTAAAGCTAGTGGCTTCACCCTG ACTAACTACGGGATGAACTGGGTCCGCCA GGCCCCAGGTCAAGGCCTCGAGTGGATGG GCTGGATTAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTTAAGGGCAGATT CGTGTTTAGCCTGGACACTAGTGTGTCTA CCGCCTACCTGCAGATCTCTAGCCTGAAG GCCGAGGACACCGCCGTCTACTACTGCGC TAGAAAC CCCCCCTACTACTACGG GAG TA ACAACGCCGAGGCTATGGACTACTGGGGT CAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 133 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCTGGCGCCTCCGTGAAGG TGTCCTGCAAGGCCTCTGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCCCTGGACAGGGCCTGGAATGGATGG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 134 HC QVQLVQS GAEVKKPGASVKVS CKAS G FT L TNYGMNWVRQAPGQGLEWMGWINTDTGEP TYADDFKGRFVFSLDTSVSTAYLQISSLK AEDTAVYYCARNPPYYYGTNNAEAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRT PEVTCVWDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRWSVLTVLHQDWL NGKEYKCKVSNKGLPS SIEKTISKAKGQP REPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHE ALHNHYTQKSLSLSLG

- 230 040295

SEQ ID NO: 135

NA DNA

CAGGTGCAGCTGGTGCAGTCAGGCGCCGA AGTGAAGAAACCCGGCGCTAGTGTGAAAG TCAGCTGTAAAGCTAGTGGCTTCACCCTG ACTAACTACGGGATGAACTGGGTCCGCCA GGCCCCAGGTCAAGGCCTCGAGTGGATGG GCTGGATTAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTTAAGGGCAGATT CGTGTTTAGCCTGGACACTAGTGTGTCTA CCGCCTACCTGCAGATCTCTAGCCTGAAG GCCGAGGACACCGCCGTCTACTACTGCGC TAGAAAC CCCCCCTACTACTACGG CAC TA ACAACGCCGAGGCTATGGACTACTGGGGT CAAGGCACTACCGTGACCGTGTCTAGCGC TAGCACTAAGGGCCCGTCCGTGTTCCCCC TGGCACCTTGTAGCCGGAGCACTAGCGAA TCCACCGCTGCCCTCGGCTGCCTGGTCAA GGATTACTTCCCGGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCTCCGGA GTGCACACCTTCCCCGCTGTGCTGCAGAG CTCCGGGCTGTACTCGCTGTCGTCGGTGG TCACGGTGCCTTCATCTAGCCTGGGTACC AAGAC C TACAC T T G CAAC G T G GAC СACAA GCCTTCCAACACTAAGGTGGACAAGCGCG TCGAATCGAAGTACGGCCCACCGTGCCCG CCTTGTCCCGCGCCGGAGTTCCTCGGCGG TCCCTCGGTCTTTCTGTTCCCACCGAAGC CCAAGGACACTTTGATGATTTCCCGCACC CCTGAAGTGACATGCGTGGTCGTGGACGT GTCACAGGAAGATCCGGAGGTGCAGTTCA ATTGGTACGTGGATGGCGTCGAGGTGCAC AACGCCAAAACCAAGCCGAGGGAGGAGCA GTTCAACTCCACTTACCGCGTCGTGTCCG TGCTGACGGTGCTGCATCAGGACTGG CTG AACGGGAAGGAGTACAAGTGCAAAGTGTC CAACAAGGGACTTCCTAGCTCAATCGAAA AGACCATCTCGAAAGCCAAGGGACAGCCC CGGGAACCCCAAGTGTATACCCTGCCACC GAG С CAG GAAGAAAT GAC TAAGAAC CAAG TCTCATTGACTTGCCTTGTGAAGGGCTTC TACCCATCGGATATCGCCGTGGAATGGGA GTCCAACGGCCAGCCGGAAAACAACTACA AGACCACCCCTCCGGTGCTGGACTCAGAC GGATCCTTCTTCCTCTACTCGCGGCTGAC CGTGGATAAGAGCAGATGGCAGGAGGGAA ATGTGTTCAGCTGTTCTGTGATGCATGAA G С С С T G CACAAC CAC TACAC T CAGAAG T C CCTGTCCCTCTCCCTGGGA

- 231 040295

SEQ ID NO: 136 NA DNA CAGGTGCAGCTGGTGCAGTCTGGCGCCGA AGTGAAGAAACCTGGCGCCTCCGTGAAGG TGTCCTGCAAGGCCTCTGGCTTCACCCTG ACCAACTACGGCATGAACTGGGTGCGACA GGCCCCTGGACAGGGCCTGGAATGGATGG GCTGGATCAACACCGACACCGGCGAGCCT ACCTACGCCGACGACTTCAAGGGCAGATT CGTGTTCTCCCTGGACACCTCCGTGTCCA CCGCCTACCTGCAGATCTCCAGCCTGAAG GCCGAGGATACCGCCGTGTACTACTGCGC CCGGAACCCCCCTTACTACTACGGCACCA ACAACGCCGAGGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCTGC TTCTACCAAGGGGCCCAGCGTGTTCCCCC TGGCCCCCTGCTCCAGAAGCACCAGCGAG AGCACAGCCGCCCTGGGCTGCCTGGTGAA GGACTACTTCCCCGAGCCCGTGACCGTGT CCTGGAACAGCGGAGCCCTGACCAGCGGC GTGCACACCTTCCCCGCCGTGCTGCAGAG CAGCGGCCTGTACAGCCTGAGCAGCGTGG TGACCGTGCCCAGCAGCAGCCTGGGCACC AAGAC C TACAC С T G TAAC G T G GAC СACAA GCCCAGCAACACCAAGGTGGACAAGAGGG TGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTGGGCGG ACCCAGCGTGTTCCTGTTCCCCCCCAAGC C CAAG GACAC С С T GAT GAT CAG CAGAAC C CCCGAGGTGACCTGTGTGGTGGTGGACGT GTCCCAGGAGGACCCCGAGGTCCAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCAC AACGCCAAGACCAAGCCCAGAGAGGAGCA GTTTAACAGCACCTACCGGGTGGTGTCCG TGCTGACCGTGCTGCACCA GGACTGGCTG AACGGCAAAGAGTACAAGTGTAAGGTСTC CAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCT AGAGAG С С С CAG G T C TACAC С С T G С СAC C CAGCCAAGAGGAGATGACCAAGAACCAGG TGTCCCTGACCTGTCTGGTGAAGGGCTTC TACCCAAGCGACATCGCCGTGGAGTGGGA GAGCAACGGCCAGCCCGAGAACAACTACA AGAC СAC С С С С С CAG T G С T G GACAG C GAC GGCAGCTTCTTCCTGTACAGCAGGCTGAC CGTGGACAAGTCCAGATGGCAGGAGGGCA ACGTCTTTAGCTGCTCCGTGATGCACGAG G С С С T G CACAAC CAC TACAC С CAGAAGAG CCTGAGCCTGTCCCTGGGC LC BAP050-Clone-J SEQ ID NO: 10 (Rabat) LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Rabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Rabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY

- 232 040295

SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIK SEQ ID NO: 137 DNA VL GAT AT T C AGAT GAC T C AG T С AC C TAG TAG CCTGAGCGCTAGTGTGGGCGATAGAGTGA СТАТ САС CTGTAGCTCTAGT CAG GATAT C T С TAAC ТАС С T GAAC T GG TAT CAGCAGAA GCCCGGTAAAGCCCCTAAGCTGCTGATCT ACTACACTAGCACCCTGCACCTGGGAATC CCCCCTAGGTTTAGCGGTAGCGGCTACGG СAC C GAC T T СAC С С T GAC TAT TAACAATA TCGAGTCAGAGGACGCCGCCTACTACTTC TGTCAGCAGTACTATAACCTGCCCTGGAC CTTCGGTCAAGGCACTAAGGTCGAGATTA AG SEQ ID NO: 118 DNA VL GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCATC CCCCCTAGATTCTCCGGCTCTGGCTACGG СAC C GAC T T СAC С С T GAC CAT CAACAACA TCGAGTCCGAGGACGCCGCCTACTACTTC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AG SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDI SNYLNWYQQKPGKAPKLLIYYTSTLHLGI PPRFSGSGYGTDFTLTINNIESEDAAYYF CQQYYNLPWTFGQGTKVEIKRTVAAPSVF IFPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSKDS PVTHVEKHKK

- 233 040295

SEQ ID NO: 138 DNA LC GAT AT T C AGAT GAC T C AG T CAC C TAG TAG CCTGAGCGCTAGTGTGGGCGATAGAGTGA СТАТ CAC CTGTAGCTCTAGT CAG GATAT C T С TAAC ТАС С T GAAC T GG TAT CAGCAGAA GCCCGGTAAAGCCCCTAAGCTGCTGATCT ACTACACTAGCACCCTGCACCTGGGAATC CCCCCTAGGTTTAGCGGTAGCGGCTACGG CAC C GAC T T CAC С С T GAC TAT TAACAATA TCGAGTCAGAGGACGCCGCCTACTACTTC T G T CAG CAG TAG TATAAC CTGCCCTG GAC CTTCGGTCAAGGCACTAAGGTCGAGATTA AGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCCAGCGACGAGCAGCTGAA GAGCGGCACCGCCAGCGTGGTGTGCCTGC TGAACAACTTCTACCCCCGGGAGGCCAAG GTGCAGTGGAAGGTGGACAACGCCCTGCA GAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGC CTGAGCAGCACCCTGACCCTGAGCAAGGC CGACTACGAGAAGCATAAGGTGTACGCCT GCGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC SEQ ID NO: 139 DNA LC GACAT С CAGAT GAC С CAG TCCCCCTC CAG CCTGTCTGCTTCCGTGGGCGACAGAGTGA CCATCACCTGTTCCTCCAGCCAGGACATC T С CAAC TAC С T GAAC T G G TAT CAG CAGAA GCCCGGCAAGGCCCCCAAGCTGCTGATCT ACTACACCTCCACCCTGCACCTGGGCATC CCCCCTAGATTCTCCGGCTCTGGCTACGG CAC C GAC T T CAC С С T GAC CAT CAACAACA TCGAGTCCGAGGACGCCGCCTACTACTTC TGCCAGCAGTACTACAACCTGCCCTGGAC CTTCGGCCAGGGCACCAAGGTGGAAATCA AGCGTACGGTGGCCGCTCCCAGCGTGTTC ATCTTCCCCCCAAGCGACGAGCAGCTGAA GAGCGGCACCGCCAGCGTGGTGTGTCTGC TGAACAACTTCTACCCCAGGGAGGCCAAG GTGCAGTGGAAGGTGGACAACGCCCTGCA GAGCGGCAACAGCCAGGAGAGCGTCACCG AGCAGGACAGCAAGGACTCCACCTACAGC CTGAGCAGCACCCTGACCCTGAGCAAGGC CGACTACGAGAAGCACAAGGTGTACGCCT GTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGA GTGC NS BAP050 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA

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SEQ ID NO: 142 (Rabat) HDDR3 AAC CCCCCTTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 142 (Chothia) HDDR3 AAC CCCCCTTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-chi SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 142 (Rabat) HDDR3 AAC CCCCCTTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 142 (Chothia) HDDR3 AAC CCCCCTTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-chi SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum01 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum01 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT

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SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum02 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum02 SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum03 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum03 SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum04 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC

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LC BAP050-hum04 SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum05 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum05 SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum06 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum06 SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum07 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA

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SEQ ID NO: 151 (Rabat) HDDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum07 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum08 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum08 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum09 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum09 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT

- 238 040295

SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml0 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml0 SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-humll SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-humll SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml2 SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC

- 239 040295

LC BAP050-huml2 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml3 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml3 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml4 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml4 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml5 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA

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SEQ ID NO: 151 (Rabat) HDDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml5 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-huml6 HC SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml6 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml7 SEQ ID NO: 152 (Rabat) HCDR1 AACTATGGCATGAAT SEQ ID NO: 153 (Rabat) HCDR2 TGGATCAACACCGACACTGGGGAGCCAAC GTATGCCGATGACTTCAAGGGA SEQ ID NO: 142 (Rabat) HDDR3 AAC CCCCCTTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 154 (Chothia) HCDR1 G GAT T CAC C C T GAC TAAC TAT SEQ ID NO: 155 (Chothia) HCDR2 AACACCGACACTGGGGAG SEQ ID NO: 142 (Chothia) HDDR3 AAC CCCCCTTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml7 SEQ ID NO: 156 (Rabat) LCDR1 T C C T C TAG T CAGGACAT TAGCAAC TAT T T AAAT SEQ ID NO: 157 (Rabat) LCDR2 TATACAT C CAC T T T G CAC C T G SEQ ID NO: 158 (Rabat) LCDR3 CAACAG TATTATAATCTCCCTTG GAC G SEQ ID NO: 159 (Chothia) LCDR1 AGT CAGGACAT TAGCAAC TAT

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SEQ ID NO: 160 (Chothia) LCDR2 TATACATCC SEQ ID NO: 161 (Chothia) LCDR3 TATTATAATCTCCCTTGG HC BAP050-huml8 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml8 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T GAG GACAT CAG CAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml9 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml9 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T GAG GACAT CAG CAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum20 SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AAC AC C GAC AC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC

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LC BAP050-hum20 SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum01-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum01-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum02-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum02-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum03-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA

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SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum03-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum04-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum04-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum05-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum05-Ser SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT

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SEQ ID NO 149 (Chothia) LCDR2 TACACATCA SEQ ID NO 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG NS BAP050- -hum06 -ser SEQ ID NO 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO 151 (Rabat) HDDR3 AAC C C T C C C TAT TAC TAC G G TAC TAATAA CGCGGAGGCTATGGACTAC SEQ ID NO 143 (Chothia) HCDR1 GGATTTACCCT CACAAACTAT SEQ ID NO 144 (Chothia) HCDR2 AACACCGACAC T GGAGAG SEQ ID NO 151 (Chothia) HDDR3 AAC C C T C C C TAT TAC TAC G G TAC TAATAA CGCGGAGGCTATGGACTAC LC BAP050- -hum06 -ser SEQ ID NO 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO 147 (Rabat) LCDR3 CAG CAG TAT TATAACCTTCCGTGGACG SEQ ID NO 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO 149 (Chothia) LCDR2 TACACATCA SEQ ID NO 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050- -hum07 -ser SEQ ID NO 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO 151 (Rabat) HDDR3 AAC C C T C C C TAT TAC TAC G G TAC TAATAA CGCGGAGGCTATGGACTAC SEQ ID NO 143 (Chothia) HCDR1 GGATTTACCCT CACAAACTAT SEQ ID NO 144 (Chothia) HCDR2 AACACCGACAC T GGAGAG SEQ ID NO 151 (Chothia) HDDR3 AAC C C T C C C TAT TAC TAC G G TAC TAATAA CGCGGAGGCTATGGACTAC LC BAP050- -hum07 -ser SEQ ID NO 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO 147 (Rabat) LCDR3 CAG CAG TAT TATAACCTTCCGTGGACG SEQ ID NO 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO 149 (Chothia) LCDR2 TACACATCA SEQ ID NO 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050- -hum08 -ser SEQ ID NO 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO 151 (Rabat) HDDR3 AAC C C T C C C TAT TAC TAC G G TAC TAATAA CGCGGAGGCTATGGACTAC SEQ ID NO 143 (Chothia) HCDR1 GGATTTACCCT CACAAACTAT SEQ ID NO 144 (chothia) HCDR2 AACACCGACAC T GGAGAG SEQ ID NO 151 (Chothia) HDDR3 AAC C C T C C C TAT TAC TAC G G TAC TAATAA CGCGGAGGCTATGGACTAC

- 245 040295

LC BAP050-hum08-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum09-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum09-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml0-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml0-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 GAG GAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-humll-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA

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SEQ ID NO: 151 (Kabat) HDDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-humll-Ser SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml2-Ser SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml2-Ser SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml3-Ser SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml3-Ser SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT

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SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml4-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml4-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml5-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml5-Ser SEQ ID NO: 145 (Rabat) LCDR1 AG T T CAAG T CAGGACAT CAGCAAT TAT T T AAAC SEQ ID NO: 146 (Rabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Rabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml8-Ser SEQ ID NO: 140 (Rabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Rabat) HCDR2 TGGATAAACACCGACACTGGAGAGСCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Rabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACACCGACAC T GGAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC

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LC BAP050-huml8-Ser SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAG GACAT CAG CAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-huml9-Ser SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-huml9-Ser SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAG GACAT CAG CAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAAC CTTCCGTG GAC G SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-hum20-Ser SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAAC ATATGCTGATGACTTCAAGGGA SEQ ID NO: 151 (Kabat) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCT CACAAAC TAT SEQ ID NO: 144 (Chothia) HCDR2 AACAC C GACAC T G GAGAG SEQ ID NO: 151 (Chothia) HDDR3 AAC CCTCCCTATTACTACGGTACTAATAA CGCGGAGGCTATGGACTAC LC BAP050-hum20-Ser SEQ ID NO: 145 (Kabat) LCDR1 AG T T CAAG T CAG GACAT CAG CAAT TAT T T AAAC SEQ ID NO: 146 (Kabat) LCDR2 TACACAT CAAC C T TACAC T TA SEQ ID NO: 147 (Kabat) LCDR3 CAG CAG TAT TATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1 AGT CAGGACAT CAGCAAT TAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCA SEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG HC BAP050-Clone-F SEQ ID NO: 162 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 163 (Kabat) HCDR2 T G GAT CAACAC C GACAC C G G C GAG C C TAC CTACGCCGACGACTTCAAGGGC

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SEQ ID NO: 164 (Rabat) HDDR3 AACCCCCCTTACTACTACGGCACCAACAA CGCCGAGGCCATGGACTAT SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 164 (Chothia) HDDR3 AAC CCCCCTTACTACTACGG САС CAACAA CGCCGAGGCCATGGACTAT LC BAP050-Clone-F SEQ ID NO: 167 (Rabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCT GAAC SEQ ID NO: 168 (Rabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 169 (Rabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 170 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG HC BAP050-Clone-G SEQ ID NO: 162 (Rabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 163 (Rabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTAC CTACGCCGACGACTTCAAGGGC SEQ ID NO: 164 (Rabat) HDDR3 AAC CCCCCTTACTACTACGG САС CAACAA CGCCGAGGCCATGGACTAT SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 164 (Chothia) HDDR3 AAC CCCCCTTACTACTACGG САС CAACAA CGCCGAGGCCATGGACTAT LC BAP050-Clone-G SEQ ID NO: 167 (Rabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCT GAAC SEQ ID NO: 168 (Rabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 169 (Rabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 170 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG HC BAP050-Clone-H SEQ ID NO: 162 (Rabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 163 (Rabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTAC CTACGCCGACGACTTCAAGGGC SEQ ID NO: 164 (Rabat) HDDR3 AAC CCCCCTTACTACTACGG САС CAACAA CGCCGAGGCCATGGACTAT SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 164 (Chothia) HDDR3 AAC CCCCCTTACTACTACGG САС CAACAA CGCCGAGGCCATGGACTAT LC BAP050-Clone-H SEQ ID NO: 167 (Rabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCT GAAC SEQ ID NO: 168 (Rabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 169 (Rabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 170 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC

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SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG HC BAP050-Clone-I SEQ ID NO: 173 (Kabat) HCDR1 AATTACGGGATGAAC SEQ ID NO: 162 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 174 (Kabat) HCDR2 TGGATTAACACCGACACCGGGGAGCCTAC CTACGCGGACGATTTCAAGGGA SEQ ID NO: 163 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTAC CTACGCCGACGACTTCAAGGGC SEQ ID NO: 175 (Kabat) HDDR3 AAC CCGCCCTACTACTACG GAAC CAACAA CGCCGAAGCCATGGACTAC SEQ ID NO: 164 (Kabat) HDDR3 AAC CCCCCTTACTACTACGG CAC CAACAA CGCCGAGGCCATGGACTAT SEQ ID NO: 176 (Chothia) HCDR1 G GAT T CAC C C T CAC CAAT TAG SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 177 (Chothia) HCDR2 AACACCGACACCGGGGAG SEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 175 (Chothia) HDDR3 AAC CCGCCCTACTACTACG GAAC CAACAA CGCCGAAGCCATGGACTAC SEQ ID NO: 164 (Chothia) HDDR3 AAC CCCCCTTACTACTACGG CAC CAACAA CGCCGAGGCCATGGACTAT LC BAP050-Clone-I SEQ ID NO: 178 (Kabat) LCDR1 AGC T C TAG T CAGGATAT C T C TAAC TAC C T GAAC SEQ ID NO: 167 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCT GAAC SEQ ID NO: 179 (Kabat) LCDR2 TACAC TAG CAC C C T G CAC C T G SEQ ID NO: 168 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 180 (Kabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACC SEQ ID NO: 169 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 181 (Chothia) LCDR1 AG T CAGGATAT C T C TAAC TAG SEQ ID NO: 170 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 182 (Chothia) LCDR2 TACACTAGC SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 183 (Chothia) LCDR3 TACTATAACCTGCCCTGG SEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG HC BAP050-Clone-J SEQ ID NO: 184 (Kabat) HCDR1 AACTACGGGATGAAC SEQ ID NO: 162 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 185 (Kabat) HCDR2 TGGATTAACACCGACACCGGCGAGCCTAC CTACGCCGACGACTTTAAGGGC SEQ ID NO: 163 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTAC CTACGCCGACGACTTCAAGGGC SEQ ID NO: 186 (Kabat) HDDR3 AAC CCCCCCTACTACGG CAC TAACAA CGCGGAGGCTATGGACTAC SEQ ID NO: 164 (Kabat) HDDR3 AAC CCCCCTTACTACTACGG CAC CAACAA CGCCGAGGCCATGGACTAT SEQ ID NO: 287 (Chothia) HCDR1 GGCTTCACCCTGACTAACTAC

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SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 177 (Chothia) HCDR2 AACACCGACACCGGGGAG SEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 186 (Chothia) HDDR3 AAC CCCCCCTACTACTACGG CAC TAACAA CGCGGAGGCTATGGACTAC SEQ ID NO: 164 (Chothia) HDDR3 AAC CCCCCTTACTACTACGG CAC CAACAA CGCCGAGGCCATGGACTAT LC BAP050-Clone-J SEQ ID NO: 178 (Rabat) LCDR1 AGC T C TAG T CAGGATAT C T C TAAC TAC C T GAAC SEQ ID NO: 167 (Rabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCT GAAC SEQ ID NO: 179 (Rabat) LCDR2 TACAC TAG CAC C C T G CAC C T G SEQ ID NO: 168 (Rabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 180 (Rabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACC SEQ ID NO: 169 (Rabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 181 (Chothia) LCDR1 AG T CAGGATAT C T C TAAC TAG SEQ ID NO: 170 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 182 (Chothia) LCDR2 TACACTAGC SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 183 (Chothia) LCDR3 TACTATAACCTGCCCTGG SEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG

Table 2. Amino acid and nucleotide sequences of heavy and light chain framework regions for humanized mAbs BAP050-hum0l - BAP050-hum20, BAP050-hum01-Ser BAP050-hum15-Ser, BAP050-hum18-Ser - BAP050-hum20-Ser and BAP050-Clone -F - BAP050-Clone-J

Amino acid sequence Nucleotide sequence VHFW1 (type a) EVQLVQSGAEVRRPGATVRI SCRVS (SEQ ID NO: 187) GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAG TGAAGAAACCCGGCGCTACCGTGAAGATCTC CTGCAAGGTGTCC (SEQ ID NO: 188) VHFW1 (type b) QVQLVQSGAEVRRPGASVRV SCRAS (SEQ ID NO: 190) CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAG TGAAGAAGCCTGGAGCCTCGGTGAAGGTGTC GTGCAAGGCATCC (SEQ ID NO: 191) CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAG TGAAGAAACCTGGCGCCTCCGTGAAGGTGTC CTGCAAGGCCTCT (SEQ ID NO: 192) CAGGTTCAGCTGGTGCAGTCCGGAGCTGAGG TGAAGAAGCCTGGGGCCTCAGTGAAGGTCTC CTGCAAGGCTTCT (SEQ ID NO: 193)

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VHFWl (type c) EVQLVQSGAEVKKPGESLRI SCKGS (SEQ ID NO: 194) GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGG TGAAAAAGCCCGGGGAGTCTCTGAGGATCTC CTGTAAGGGTTCT (SEQ ID NO: 195) VHFWl (type d) QVQLVQSGSELKKPGASVKV SCKAS (SEQ ID NO: 196) CAGGTGCAGCTGGTGCAATCTGGGTCTGAGT TGAAGAAGCCTGGGGCCTCAGTGAAGGTTTC CTGCAAGGCTTCT (SEQ ID NO: 197) VHFW2 (type a) WVRQAPGQGLEWMG (SEQ ID NO: 198) TGGGTCCGCCAGGCCCCAGGTCAAGGCCTCG AGTGGATGGGC (SEQ ID NO: 199) TGGGTGCGACAGGCCCCTGGACAGGGCCTGG AATGGATGGGC (SEQ ID NO: 200) TGGGTGCGACAGGCCCCTGGACAAGGGCTTG AGTGGATGGGT (SEQ ID NO: 201) VHFW2 (type b) WVRQARGQRLEWIG (SEQ ID NO: 202) TGGGTCAGACAGGCCCGGGGTCAACGGCTGG AGTGGATCGGA (SEQ ID NO: 203) TGGGTGCGACAGGCCAGGGGCCAGCGGCTGG AATGGATGGGC (SEQ ID NO: 204) TGGGTGCGACAGGCTCGTGGACAACGCCTTG AGTGGATAGGT (SEQ ID NO: 205) VHFW2 (type c) WIRQSPSRGLEWLG (SEQ ID NO: 206) TGGATCAGGCAGTCCCCATCGAGAGGCCTTG AGTGGCTGGGT (SEQ ID NO: 207) VHFW2 (type d) WVRQATGQGLEWMG (SEQ ID NO: 208) TGGGTGCGACAGGCCACTGGACAAGGGCTTG AGTGGATGGGT (SEQ ID NO: 209) VHFW3 (type a) RFVFSLDTSVSTAYLQICSL KAEDTAVYYCAR (SEQ ID NO : 210) AGATTTGTCTTCTCCTTGGACACCTCTGTCA GCACGGCATATCTGCAGATCTGCAGCCTAAA GGCTGAGGACACTGCCGTGTATTACTGTGCA AGA (SEQ ID NO: 211) VHFW3 (type a Ser) RFVFSLDTSVSTAYLQISSL KAEDTAVYYCAR (SEQ ID NO: 212) CGGTTCGTGTTTCTCCCTCGACACCTCCGTGT CCACCGCCTACCTCCAAATCTCCTCACTGAA AGCGGAGGACACCGCCGTGTACTATTGCGCG AGG SEQ ID NO: 213) AGATTCGTGTTTAGCCTGGACACTAGTGTGT CTACCGCCTACCTGCAGATCTCTAGCCTGAA GGCCGAGGACACCGCCGTCTACTACTGCGCT AGA SEQ ID NO: 214) AGATTCGTGTTCTCCCTGGACACCTCCGTGT CCACCGCCTACCTGCAGATCTCCAGCCTGAA GGCCGAGGATACCGCCGTGTACTACTGCGCC CGG (SEQ ID NO: 215) AGATTTGTCTTCTCCTTGGACACCTCTGTCA GCACGGCATATCTGCAGATCAGCAGCCTAAA GGCTGAGGACACTGCCGTGTATTACTGTGCA AGA (SEQ ID NO: 216) VHFW3 (type b) RVTISADKSISTAYLQWSSL KASDTAMYYCAR (SEQ ID NO: 217) AGAG T CAC CAT C T CAG C C GACAAG T C CAT CA GCACCGCCTACCTGCAGTGGAGCAGCCTGAA GGCCTCGGACACCGCCATGTATTACTGTGCA AGA (SEQ ID NO: 218) VHFW3 (type c) RFVFSLDTSVSTAYLQISTL KAEDTATYFCAR (SEQ ID NO : 219) CGGTTTGTCTTCTCCTTGGACACCTCTGTCA GCACGGCATATCTGCAGATCAGCACGCTAAA GGCTGAGGACACTGCTACATATTTCTGTGCA AGA (SEQ ID NO: 220)

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VHFW4 WGQGTTVTVSS (SEQ ID NO: 221) TGGGGCCAGGGCACCACTGTGACTGTGTCCA GC (SEQ ID NO: 222) TGGGGTCAAGGCACTACCGTGACCGTGTCTA GC (SEQ ID NO: 223) TGGGGCCAGGGCACCACCGTGACCGTGTCCT CT (SEQ ID NO: 224) TGGGGCCAGGGCACCACCGTGACCGTGTCCT CO (SEQ ID NO: 225) VLFW1 (type a) DIQMTQSPSSLSASVGDRVT ITC (SEQ ID NO: 226) GATAT T CAGAT GAC T CAG T CAC C TAG TAG C C TGAGCGCTAGTGTGGGCGATAGAGTGACTAT CACCTGT (SEQ ID NO: 227) GACATCCAGATGACCCAGTCCCCCTCAGCC TGTCTGCTTCCGTGGGCGACAGAGTGACCAT CACCTGT (SEQ ID NO: 228) GACATCCAGATGACCCAGTCTCCATCCTCCC TGTCTGCATCTGTAG GAGAGAGAG T GAG CAT CACTTGC(SEQ ID NO: 229) VLFW1 (type b) EIVLTQSPATLPVTLGQPAS ISC (SEQ ID NO: 230) GAAATTGTGTTGACACAAGTCTCCAGCCACCC TGCCCGTCACCCTTGGACAGCCGGCCTCCAT CTCCTGC(SEQ ID NO: 231) VLFW1 (type c) EIVLTQSPATLSLSPGERAT LSC (SEQ ID NO: 232) GAAATTGTGTTGACACAGTCTCCAGCCACCC TGTCTTTGTCTCCAGGGGAAAGAGCCACCCT CTCCTGC (SEQ ID NO: 233) VLFW1 (type d) DIVMTQTPLSLPVTPGEPAS ISC (SEQ ID NO: 234) GATATTGTGATGACCAGACTCCACTCTCCC TGCCCGTCACCCCTGGAGAGCCGGCCTCCAT CTCCTGC (SEQ ID NO: 235) VLFW1 (type e) EIVLTQSPDFQSVTPKEKVT ITC (SEQ ID NO: 236) GAAATTGTGCTGACTCAGTCTCAGACTTTC AG T C T G T GAC T C CAAAG GAGAAAG T CAC CAT CACCTGC (SEQ ID NO: 237) VLFW1 (type f) AIQLTQSPSSLSASVGDRVT ITC (SEQ ID NO: 238) GCCATCCAGTTGACCAGTCTCCATCCTCCC TGTCTGCATCTGTAG GAGACAGAG T CAC CAT CACTTGC (SEQ ID NO: 239) VLFW2 (type a) WYQQKPGKAPKLLIY (SEQ ID NO: 240) TGGTATCAGCAGAAGCCCGGTAAAGCCCCTA AGOTGOTGATOTAG (SEQ ID NO: 241) TGGTATCAGCAGAAGCCCGGCAAGGCCCCCA AGOTGOTGATOTAG (SEQ ID NO: 242) VLFW2 (type b) WYQQKPGQAPRLLIY (SEQ ID NO: 244) TGGTACCAGCAGAAACCTGGCCAGGCTCCCA GGCTCCTCATCTAT (SEQ ID NO: 245) VLFW2 (type c) WYLQKPGQSPQLLIY (SEQ ID NO: 246) TGGTACCTGCAGAAGCCAGGGCAGTCTCAC AGCTCCTGATCTAT (SEQ ID NO: 247) VLFW2 (type d) WYLQKPGQSPQLLIY (SEQ ID NO: 248) TGGTATCTGCAGAAGCCCGGTCAATCACCTC AGOTGOTGATOTAG (SEQ ID NO: 249) TGGTATCTGCAGAAGCCCGGCCAGTCCCCTC AGOTGOTGATOTAG (SEQ ID NO: 250)

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VLFW3 (type a) GVPSRFSGSGSGTDFTFTIS SLEAEDAATYYC (SEQ ID NO: 252) GGCGTGCCCTCCAGATTTTCCGGCTCTGGCT C T G G CAC C GAC T T TAC C T T CAC CAT CAG C T C CCTGGAAGCCGAGGACGCCGCCACCTACTAC TGC (SEQ ID NO: 253) GGGGTCCCCTCGAGGTTCAGTGGCAGTGGAT C T G G GACAGAT T T CAC C T T TAC CAT CAG TAG CCTGGAAGCTGAAGATGCTGCAACATATTAG TGT (SEQ ID NO: 254) VLFW3 (type b) GIPPRFSGSGYGTDFTLTIN NIESEDAAYYFC (SEQ ID NO: 255) GGAATCCCCCCTAGGTTTAGCGGTAGCGGCT AC G G CAC C GAC T T CAC C C T GAC TAT TAACAA TACGAGTCAGAGGACGCCGCCTACTACTTC TGT (SEQ ID NO: 256) GGCATCCCCCCTAGATTTCTCCGGCTCTGGCT AC G G CAC C GAC T T CAC C C T GAC CAT CAACAA CATCGAGTCCGAGGACGCCGCCTACTACTTC TGC (SEQ ID NO: 257) GGGATCCCACCTCGATTCAGTGGCAGCGGGT AT G GAACAGATT T TACCC T CACAATTAATAA CATAGAAT C T GAGGAT GC T GCATAT TAC T T C TGT (SEQ ID NO: 258) VLFW3 (type c) GIPDRFSGSGSGTDFTLTIS RLEPEDFAVYYC (SEQ ID NO: 259) GGGATCCCAGACAGGTTCAGTGGCAGTGGGT C T GGGACAGAC T T CAC TOT CACCAT CAGCAG AC T GGAGCС T GAAGAT T T T GCAGT GTAT TAG TGT (SEQ ID NO: 260) VLFW3 (type d) GVPSRFSGSGSGTEFTLTIS SLQPDDFATYYC (SEQ ID NO: 261) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTA GTGGCACCGAGTTCACCCTGACTATCTCTAG CCTGCAGCCCGACGACTTCGCTACCTACTAC TGT (SEQ ID NO: 262) GGCGTGCCCTCCAGATTTTCCGGCTCTGGCT CTGGCACCGAGTTTACCCTGACCATCAGCTC CCTGCAGCCCGACGACTTCGCCACCTACTAC TGC (SEQ ID NO: 263) GGGGTCCCATCAAGGTTCAGCGGCAGTGGAT C T GGGACAGAATT CAC TOT CACCAT CAGCAG CCTGCAGCCTGATGATTTTGCAACTTATTAC TGT (SEQ ID NO: 264) VLFW3 (type e) GVPSRFSGSGSGTDFTLTIS SLQPEDFATYYC (SEQ ID NO: 265) GGGGTCCCATCAAGGTTCAGCGGCAGTGGAT C T GGGACAGAT T T CAC TOT CACCAT CAGCAG CCTGCAGCCTGAAGATTTTGCAACTTATTAC TGT (SEQ ID NO: 266) VLFW3 (type f) GVPSRFSGSGSGTDFTFTIS SLQPEDIATYYC (SEQ ID NO: 267) GGGGTCCCATCAAGGTTCAGTGGAAGTGGAT C T GGGACAGAT T T TAC T T T CACCAT CAGCAG CC T GCAGCC T GAAGATAT T GCAACATAT TAG TGT (SEQ ID NO: 268) VLFW3 (type d) GIPDRFSGSGSGTDFTLTIS RLEPEDFAVYYC (SEQ ID NO: 269) GGGATCCCAGACAGGTTCAGTGGCAGTGGGT C T GGGACAGAC T T CAC T C T CACCAT CAGCAG AC T GGAGC C T GAAGAT T T T GCAGT GTAT TAG TGT (SEQ ID NO: 270) VLFW4 FGQGTKVEIK (SEQ ID NO: 271) TTCGGTCAAGGCACTAAGGTCGAGATTAAG (SEQ ID NO: 272) TTCGGCCAGGGCACCAAGGTGGAAATCAAG (SEQ ID NO: 273) TTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 274)

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Table 3. Constant region of amino acid sequences of human IgG heavy chains and human κ-light chain

ns Amino acid sequence of mutant IgG4 constant region (S228P) (EU numbering) ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVWDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY RWSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK (SEQ ID NO: 275) LC Amino acid sequence of human kappa chain constant region RTVAAPSVFI FPPSDEQLKS GTASWCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC (SEQ ID NO: 276) NS Amino acid sequence of the mutant constant region, not containing C-terminal lysine (K), IgG4 (S228P) (EU numbering) ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVWDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY RWSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLG (SEQ ID NO: 277) NS wild-type IgGl ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 278) NS Amino acid sequence of mutant IgGl constant region (N297A) (EU numbering) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYA STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 279) NS Amino acid sequence of the mutant IgGl constant region (D265A, P329A) (EU numbering) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWAVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LAAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 280) NS Amino acid sequence of the mutant IgGl constant region (L234A, L235A) (EU numbering) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 281)

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Table 4. Amino acid sequences of heavy and light chain leader sequences for humanized mAbs BAP050-Clone-F-BAP050-Clone-J

VAR050-S1one-E HC MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) VAR050-S1one-E LC MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-G HC MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) BAP050-Clone-G LC MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-H HC MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) BAP050-Clone-H LC MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-I HC MAWVWTLPFLMAAAQSVQA (SEQ ID NO: 284) MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) BAP050-Clone-I LC MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 285) MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-J HC MAWVWTLPFLMAAAQSVQA (SEQ ID NO: 284) MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) BAP050-Clone-J LC MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 285) MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283)

Table 5. See examples.

Table 6. See examples.

Table 7. Selected therapeutic agents that can be administered in combination with anti-LAG-3 antibody molecules, for example, as a single agent or in combination with other immunomodulators described in the present description.

Each publication listed in this table is hereby incorporated by reference in its entirety, including all structural formulas therein.

No. conn. International non-proprietary name Trade name Connection structure Patents / publications of patent applications Al Sotrastaurin O O zr and . / ¢9 ^/ ιΤ -° 1 ? G j o j / sl EP 1682103 US 2007/142401 WO 2005/039549 A2 Nilotinib HC1 monohydrate TASIGNA® CHJ rt N gy+A ΗΟ1 Η ₂ Ο WO 2004/005281 US 7169791 A3 H ₃ C but J ^CH3 AND R ^HO N ++ o A / NV O WO 2010/060937 WO 2004/072051 EP 1611112 US 8450310

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- 258 040295

A7 -Π 0-0 \ / I o ,----. Ί--Ζ ω ο f ^~\ X # \ JI i /—χ / \ Η Ή Ο Ζ ο ^ζ “I ω W0 2009/141386 US 2010/0105667 A8 τ Yu ο /X ΣΖ \/^ ι 1 u--\ I ο I 1 χ f* W0 2010/029082 A9 CYP17 inhibitor W0 2010/149755 US 8263635 B2 ΕΡ 2445903 B1 AYu ZC*ZE* (J Q Oh wow! Q-Οσ X. r>!—y—ί r-o Q-Z zll'i ο W0 2011/076786

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All Deferasirox EXJADE® .3 .: i i o T W0 1997/049395 Al 2 Letrozole FEMARA® j Y 1 ^z —\ z^/ \__ o 4 US 4978672 A13 X X ΰ o i °οι5 C.J.X W0 2013/124826 US 2013/0225574 Al 4 O Yu O OOO / X O W0 2013/111105

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Al 5 sn _e HN / 6 N^.S NH ^-'' ^ύ 0Η WO 2005/073224 _χ 0Η ₃ /~\ w ^=o Al 6 Imatinib mesylate GLEEVEC® HN HN CH ₃ WO 1999/003854 N^4 \=N Mesylate

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- 262 040295

A20 Osilodrostat N t-N F WO 2007/024945 A21 F O' Ν Ί / Λ us-sn ₃ WO2008/016893 EP 2051990 US 8546336 A22 Sonidegiba phosphate V ^F o yy (U CH ₃ y ° HN d' H ₃ C * n WO 2007/131201 EP 2021328 US 8178563

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A2 3 ceritinib ZYKADIA™ vxU ² ' 0=3=0 ^{and and} WO 2008/073687 US 8039479 A24 aXW N-CH ₃ ψ δ “ 0 N Η US 8415355 US 8685980 A25 O ζ-Ζ ,--y Ζ-Ζ uw , ^ζ Λ >λ Ο J- ⁷ )—( λ—k τ o o f wm τη \ / τ τ τ ⁴⁼⁷ WO 2010/007120 A26 Human anti-PRLR monoclonal antibody US 7867493 Ά2 7 L J a I i G | h CT T N WO 2010/026124 EP 2344474 US 2010/0056576 WO2008/106692

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A2 8 N \u003d n ₃ s4} ^CH 3 o O \u003d (NH h NN WO 2010/101849 A29 Encorafenib n ,0^ ^g + H ₃ С γ %'ΝΗ o SN ₃ 1 Ν' N L k ^ch j n V An CHj o ACh V kJ >SN ₃ γ Cl g WO 2011/025927 AZO n^s HOA o b N N - H ₃ d WO 2011/101409 A31 Human monoclonal antibody against HER3 W02012/022814 EP 2606070 US 8735551

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AZ 2 Antibody-conjugate medicinal product (ADC) WO 2014/160160 AB: 12425 (see table 1, paragraph [00191]) Linker: SMCC (see paragraph [00117] Load: DM1 (see paragraph [00111] See also paragraph 29 AZZ Monoclonal antibody or Fab against M-CSF WO 2004/045532 AZ 4 Binimetinib X ABOUT I ( h -πXX %' [L WO 2003/077914 AZ 5 Midostaurin Eh /^\ x\yj gSt^ \ X__J D-SNe /n _e n /'Ώ oD WO2003/037347 EP 1441737 US 2012/252785

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AZ 6 Everolimus AFINITOR® —OH 0—' \ /— ⁰ )—''bshch / ^m s C O--( )---l G T _ 0 Λ CH ₃ ^ns 1/ SC but \=o o=/ /\ /— ^CHJ '-\ /- ^{CHJ 0} -( /=^ Mjt/ \=Z H ₃ C wo 2014/085318 AZ 7 X WO 2007/030377 US 7482367 AZ 8 Pasireotide Diaspartate SIGNIFOR® JL ^Η Ν Ύ I g 1 MJ4 a-hH HN^ J_nn _jr n Ίτ WO2002/010192 US 7473761

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AZ 9 dovitinib C / - ^F HN O K ^ NH c / N 1 SN ₃ wo 2009/115562 US 8563556 A4 0 O n ₃ s ³ X H1C Ύ ---Y 0 WO 2013/184757 A41 o o o* ^3 I n-O η WO 2006/122806

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CH ₃ N _sn r ^: fl ι ³ A42 V'o'ch ₃ N^N NH ν ρ g VJ^n WO 2008/073687 US 8372858 ΗΝ. ο 1 1] h ₃ c .?s;^ Τ 'ο 0Η ₃ Η ,Ν CHj _/ ^cl yr ΝNH ΗΝ WO A43 ^F ^^ ^CH 3 2010/002655 US 8519129 µ, Q. ο ο Λ WO A44 ^NZS \/ ^F 2010/002655 ΝΗ US 8519129 ΗΝ—Ρ Ν JT N SH H ₃ C^N' Η

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H ₃ C - N ^ H ₃ C-^~Vf A4 5 NH , ^N =< w Cl NH WO 2010/002655 N=^ HnJ A sn _e n ₃ e-—\ kc > HN N—chj A4 6 Valspodar AMDRAY™ _Q EP 296122 / SN ₃ V—“\ r+^'N G il A4 7 Watalaniba succinate y—y < W098/35958 ίι ΊΓ II 1 SG' '^ succinate A4 8 IDH inhibitor WO2014/141104 WO2013/171639 A4 9 BCR-ABL inhibitor WO2013/171640 WO2013/171641 WO2013/171642 A50 cRAF inhibitor WO2014/151616 A51 Competitive inhibitor ERK1/2ATP PCT/US2014/06 2913

Examples

The following examples are given to facilitate understanding of the invention, but they are not intended to limit the scope of the invention in any way, nor are they intended to limit the scope of the invention in any way.

Example 1 Humanization of the anti-LAG-3 antibody, BAP050.

An anti-mouse LAG-3 monoclonal antibody, BAP050, was humanized. Received sequences and test samples of twenty clones of humanized BAP050 with unique sequences of the variable region. These clones were further analyzed for their biological functions (eg, antigen binding and ligand blocking), structural features, and transient expression in CHO cells.

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Example 1.1. Technology and method of humanization.

Humanization of BAP050 was performed using a combinatorial library of human germline variable region (FW) frameworks. The technology involves the transfer of in-frame mouse CDRs into a human variable region (VR) library that is constructed by random combination of human germline FW1, FW2 and FW3 sequences. Only one FW4 sequence is used, which is WGQGTTVTVSS (SEQ ID NO: 221) for the heavy chain (HC) (human HC subgroup I of Rabat, #21) and FGQGTKVEIK (SeQ ID NO: 271) for the light chain (LC) (subgroup I of the human k-chain according to Rabat, No. 5). The VR sequence library was fused with human constant region (CR), human IgG4 (S228P) HC, and human LC κ-chain CR sequences, and the resulting complete IgG library was expressed in CHO cells for screening. Screening was performed with tissue culture supernatants by measuring binding specificity on antigen expressing cells in whole cell ELISA format or by FACS.

The humanization method was performed step by step, starting with the construction and expression of a suitable chimeric mAb (mouse VR, IgG4 (S228P), human κ chain) that can serve as a reference antibody for screening humanized clones. The amino acid sequences of the constant region for the human IgG4 heavy chain (S228P) and the human κ light chain are shown in Table 1. 6.

Humanization of VR LC and HC was carried out in two independent steps.

The humanized LC (huLC) library was paired with chimeric HC (mouse VR, IgG4(S228P)) and the resulting semi-humanized mAbs were screened for binding activity by ELISA.

huLC clones with suitable binding activity (>chimeric mAb binding) were selected. Similarly, a humanized HC (huHC) library was paired with a chimeric LC (murine VR, human κ chain) and screened for binding activity by ELISA. Chose huHC clones with suitable binding activity (>binding chimeric mAb).

The variable regions of the selected huLCs and huHCs were then sequenced to identify huLCs and huHCs with unique sequences (some clones from their initial selection process may contain the same LC or HC). The unique huLC and huHC were then randomly combined to generate a small humAb library that was expressed in CHO cells and screened on antigen expressing cells by ELISA and FACS. The end product of the humanization process are clones with binding activities that were equal to or better than the binding of the chimeric reference mAb.

Example 1.2. Mouse BAP050 mAb sequence.

The sequences of the LC variable region and HC mAb against mouse LAG-3 were determined. The sequences obtained from two independent assays were identical and are shown in FIG. 1.

The germline was analyzed and part of the results are shown in Figure 2 as an amino acid sequence alignment. For the light chain, the V gene is 96.88% identical to mIGkV10-94*01F (279/288 nt) and the J gene is 97.30% identical to mIGkJ1*01F (36/37 nt). For the heavy chain, the V gene is 96.88% identical to mIGHV9-3-1*01F (279/288 nucleotides), the J gene is 86.79% identical to mIGHJ4*01F, and the D gene is mIGHD11*01F .

Example 1.3. Clones of the humanized antibody.

As shown in FIG. 3, the humanization method resulted in twenty humanized clones with binding affinities comparable to those of the chimeric antibody. In addition to binding data, VR sequences are provided for each clone along with a sample mAb. Samples were obtained by transient transfection of CHO cells and tissue culture supernatants were concentrated. mAb concentrations in solutions were determined by IgG4 specific ELISA.

As shown in FIG. 4, twenty unique clones are combinations of six unique HCs and twelve unique LCs. The amino acid and nucleotide sequences of the heavy and light chain variable domains for the humanized BAP050 clones are shown in Table 1. 1. The amino acid and nucleotide sequences of the CDRs of the heavy and light chains of the humanized BAP050 clones are shown in Table 1. 1.

Limited diversity was generated for the FW3 region of the HC with eighteen clones containing the same FWH3 that is derived from human germline IGHV7-4 and contains an available Cys residue at position 84 of the humanized clones. Closely related VHFW3 sequences typically contain a Ser or Ala residue at this position. Thus, in the selected humanized clones, Cys84 was replaced by Ser.

In FIG. 4 indicates that the samples had various mAb concentrations ranging from 3.2 μg/ml to 35.8 μg/ml. These numbers were representative of several transient expression experiments.

Example 1.4. Analysis of humanized clones.

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Example 1.4.1. Analysis of Binding Activity and Binding Specificity of Humanized Clones

Binding activity and specificity was measured in a competitive binding assay using a constant concentration of mouse FITC-labeled mAb, serial dilutions of test mAbs, and LAG-3 expressing CHO cells. Incubations with mAb mixtures with different concentration ratios of test mAb to labeled mAb were performed at 4° C. for 30 min. Bound labeled mouse mAb was then quantified using a FACS machine. The experiment was carried out twice. The results are shown in FIG. 5A-5B.

Within experimental accuracy, all humanized clones have similar activity in competing for binding of labeled mouse mAb. The activity is also comparable to that of the original mouse mAb and the chimeric mAb. mAbs were ranked relative to each other. For example, it may be a weaker competitor if the particular clone curve is to the right of the chimeric mAb curve in both experiments, or it may be a better competitor if the particular clone curve is to the left of the chimeric mAb curve. Such ranking systems have been used in FIG. 6.

Example 1.4.2. Sequence analysis of humanized clones.

Based on structural features, twenty humanized mAbs were divided into six groups and ranked from A to F. The results are shown in FIG. 6.

Example 1.4.3. Selection of humanized clones and generation of new variants with the C84S mutation.

In FIG. 6 summarizes the data that was taken into account in the selection of humanized clones. Expression data (2nd column), diversity of variable region composition (3rd column), relative rankings in binding studies (4th and 5th columns) and structural analysis (6th column) were considered. Certain characteristics that lead to the selection of individual clones are highlighted in gray.

Certain clones were mutated at position 84 of VHFW3 from Cys to Ser (see example 1.3 above). The new variants are referred to as clones #1S, 2S, 5S, 9S, 11S, 12S and 13S and collectively huBAP050(Ser) clones.

Example 1.4.4. Analysis of binding activity and binding specificity of huBAP050(Ser) clones.

New variants of selected clones with C84S mutations in VHFW3 were subjected to a similar competition binding assay as described in Example 1.4.1. The original humanized clones with the Cys84 residue, the new humanized clones with the Ser84 residue, the chimeric mAb and the original mouse mAb were included in the experiment. The results are shown in FIG. 7.

All variants tested were comparable to the parent mouse mAb in blocking labeled mouse mAb binding to LAG-3 expressing CHO cells. Therefore, the behavior of the new humanized clones with the Ser84 residue did not differ from the behavior of the original humanized clones with the Cys84 residue.

Example 1.4.5. Blocking of LAG-3-Ig binding to MHC class II on Daudi cells.

LAG-3 binds to MHC class II, so selected huBAP050(Ser) clones were tested for their ability to block soluble LAG-3-Ig from binding to Daudi cells (a Burkitt's lymphoma cell line) that express MHC class II. The blocking ability of the mAb was assessed in a competitive binding assay using a constant concentration of LAG-3huIgG1 Fc fusion protein (2 μg/ml), serial dilutions of the mAb to be tested, and Daudi cells. Incubation was carried out at 4°C for 30 min. The bound ligand fusion protein was detected using a PE-conjugated goat anti-human IgG F(ab')2 fragment that does not recognize IgG4 mAb (Southern Biotech 2043-09) and flow cytometry. The results are shown in FIG. 8.

Within experimental precision, the seven huBAP050(Ser) clones, the chimeric mAb and the parent mAb of the mouse showed comparable LAG-3-Ig blocking activity.

Example 1.4.6. T-cell epitope analysis.

Humanized mAbs were analyzed for T-cell epitopes using Epibase™. The algorithm analyzes every possible (every 10 monomeric units throughout the protein, advancing one amino acid) for binding to HLA class II. It evaluates the binding free energy (AGbind) for each peptide and calculates the possible KD (AG _bin d=RTlnK _D ). The peptides are then labeled with S, M, or N for strong, medium, and non-binding agents. The thresholds used for such a classification differ for each allotype.

Data were normalized for risk. The overall risk score is the sum of all possible epitopes to all tested alleles, weighted by the affinities of the respective peptides, but excluding all possible epitopes in the germline sequences (the lower the value, the better).

There are approximately three categories of mAbs derived from a large array of different composition mAbs, as described below.

Risk score approximately 500: fully human mAbs derived from humans, humanized mice, and from phage libraries (values below 500 are indeed good even for fully human antibodies). Humanized mAbs specifically engineered (even CDRs) to have a low score tend to be at risk

500-700.

Risk score approximately 900: characteristic CDR-grafted antibodies that contain a wholly murine CDR with or without changes in the FW region (Gary Queen technology); approved CDR-grafted mAbs are generally all in this category.

Risk score approximately 1500: chimeric mAb.

The results for selected humanized BAP050 mAbs are as follows:

clone number Degree of risk 01 999 02 1006 05 967 09 998 eleven 1042 12 1042 13 950

The risk scores of the seven selected humanized clones correspond to the characteristic CDR-grafted mAb category. For example, the human mAb, adalimumab (Humira®), has a score of 654, which is relatively high for a human mAb (at the upper end of the Gaussian curve), but low compared to the representative CDR-grafted mAb.

Scores are obtained from mouse CDRs, in particular Y residues. They represent acceptable scores for antibodies for cancer treatment. Changing the score would mean constructing a mouse CDR, specifically deleting Y residues.

Generalization and conclusion.

A mouse anti-LAG-3 monoclonal antibody, BAP050, was humanized. The technology involves cloning in-frame mouse CDRs into an ordered library of human germline variable region scaffolds, expressing the library of cloned variable regions as intact humanized IgG4 mAb (S228P) in CHO cells, and selecting clones that bind with comparable or greater affinity to the target, thereby and the original mAb. Thus, for CDRs, it has been proposed to select the best human germline framework sequences that retain their conformations and thus the binding affinity and specificity of the parent mouse mAb. Twenty humanized variants with unique variable region sequences were prepared for sequences and test samples, which were also subjected to binding testing with LAG-3 transfected CHO cells. Eighteen clones contained the same germline FW3 HC sequence that contains the rare Cys at position 84. In seven selected clones, Cys was replaced with Ser, generating new mAbs designated as clones huBAP050(Ser) . These clones were further analyzed for their biological functions (eg, antigen binding and ligand blocking), structural features, and transient expression in CHO cells.

Example 2 Expression of humanized anti-LAG-3 antibody, BAP050.

Five humanized clones described in Example 1 were selected to evaluate expression in Chinese hamster (CHO) cells.

Single gene vectors (SGVs) were constructed using Lonza's GS Xceed vectors (IgG4proAK for the heavy chain and k for the light chain). SGV was amplified and transiently co-transfected into CHOK1SV GS-KO cells for expression in a volume of 2.8 L.

Expression cultures were harvested on day 6 post-transfection and clarified by centrifugation and sterile filtration. The clarified cell culture supernatant was purified using one-step protein A chromatography. Product quality analysis was carried out in the form of SE-HPLC, SDS-PAGE, IEF and LAL using the purified substance at a concentration of 1 mg/ml, including the antibody as a control sample.

Example 2.1. Vector design.

The sequences of the light and heavy chain variable domain coding regions were synthesized by GeneArt AG. The light chain variable domain coding regions were subcloned into pXC-Karr and the heavy chain variable domain coding regions into pXC-IgG4proΔκ vectors, respectively, using the Hind III N-terminal restriction site and the BsiWI (light chain) and ApaI (heavy chain) C-terminal restriction sites. . Positive clones were screened by PCR amplification (primers 1053: GCTGACAGACTAACAGACTGTTCC (SEQ ID NO: 288) and 1072: CAAATGTGGTATGGCTGA (SEQ ID NO: 289)) and confirmed by restriction enzyme digestion (using 273 040295 double digestion with EcoRI-EF and HindIII-RF-EF and HindIII ) and the nucleotide sequence of the gene of interest.

Example 2.2. DNA amplification.

One bacterial colony was placed in 15 ml Luria-Bertani (LB) medium (LB broth, SigmaAldrich, L7275) containing 50 μg/ml ampicillin and incubated at 37° C. overnight with shaking at 220 rpm. The resulting starter culture was used to inoculate 1 L of Luria-Bertani (LB) medium containing 50 μg/ml ampicillin and incubated at 37° C. overnight with shaking at 220 rpm. Vector DNA was isolated using the QIAGEN Plasmid Plus Gigaprep system (QIAGEN, 12991). In all cases, the DNA concentration was measured using a Nanodrop 1000 spectrophotometer (Thermo-Scientific) and adjusted to 1 mg/ml with EB buffer (10 mM Tris-Cl, pH 8.5). DNA quality for single gene vectors was assessed by measuring the A260/A280 absorbance ratio. It was found that it ranged from 1.88 to 1.90.

Example 2.3. Cultivation of CHOK1SV GS-KO cells.

CHOK1SV GS-KO cells were cultured in CD-CHO medium (Invitrogen, 10743-029) supplemented with 6 mM glutamine (Invitrogen, 25030-123). Cells were incubated in a shaker incubator at 36.5°C, 5% CO ₂ , 85% humidity, 140 rpm. Cells were routinely subcultured every 3-4 days, seeded at 2x105 cells/ml, and grown to have a sufficient number of cells available for transfection. Cells were removed at passage 20.

Example 2.4. Transient transfections of CHOK1SV GS-KO cells.

Transient transfections were performed using CHOK1SV GS-KO cells that had been in culture for a minimum of two weeks. Cells were subcultured 24 h prior to transfection and cell viability was >99 during transfection.

All transfections were performed by electroporation using the Gene Pulse MXCell (Bio-Rad), an electroporation plate based system. For each transfection, viable cells were resuspended in prewarmed medium to 2.86x107 cells/ml. An aliquot of 80 µg of DNA (ratio of heavy and light chains SGV1:1) and 700 µl of cell suspension were placed in each cuvette/well. Cells were electroporated at 300 W, 1300 uF. The transfected cells were transferred to prewarmed medium in Erlenmeyer flasks and the cuvette/wells were washed twice with prewarmed medium, which was also transferred to the flasks. The transfected cell cultures were incubated in a shaker incubator at 36.5°C, 5% CO ₂ , 85% humidity, 140 rpm. within 6 days. Cell viability and viable cell concentrations were measured at the time of collection using a Cedex HiRes automatic cell counter (Roche).

Example 2.5. Protein A affinity chromatography The cell culture supernatant was collected and clarified by centrifugation at 2000 rpm for 10 min, then filtered through a 0.22 μm PES membrane filter. The clarified supernatant was purified using a preloaded 5 ml HiTrap MabSelect SuRE column (GE Healthcare, 11-0034-94) on an AKTA purifier (10 ml/min). The column was equilibrated with 50 mM sodium phosphate, 125 mM sodium chloride, pH 7.0 (equilibration buffer) for 5 column volumes (CV). After sample loading, the column was washed with 2 CV of equilibration buffer, followed by a 3 CV wash of 50 mM sodium phosphate, 1 M sodium chloride pH 7.0, and repeated with 2 CV of equilibration buffer. The product was then eluted with 10 mM sodium formate, pH 3.5 over 5 CV. The protein-containing eluted fractions were immediately adjusted to pH 7.2 and filtered through a 0.2 μm filter.

During the elution phase, a peak containing one protein was observed. When analyzed by SE-HPLC and SDSPAGE, this peak was shown to contain mAb. The output of the isolated protein is given in table. 5. Clones transiently expressed in the range of 21.9 to 29.4 mg/l.

Table 5 Summary of Yield, Titer, Monomers, and Endotoxin Levels

Product Yield* (mg) Titer* (mg/l) Monomer content (%) Endotoxin Levels (U/mg) Clone F 79.1 28.25 95, 63 0.22 Clone G 61.3 21.88 95, 31 0.15 Clone H 76.0 27.13 97.07 0.20 Clone I 82.3 29, 38 97.82 0.05 Clone J 64.0 24.631 96, 97 0.27

*After purification with protein A purification;

^ from a 2.6 L expression culture.

Example 2.6. SE-HPLC analysis.

Protein A purified antibody samples were analyzed in duplicate by SE-HPLC on an Agilent 1200 series HPLC system using a Zorbax GF-250 4 μm 9.4 mm IDx250 mm column (Agilent). Before injection, an aliquot of the sample at a concentration of 1 mg/ml was filtered through a 0.2 μm filter. Injected 80 µl aliquots respectively and measured 1 ml/min in

- 274 040295 for 15 min. Soluble aggregate levels were analyzed using Chemstation software (Agilent).

Received chromatographic characteristics with a retention time showing the percentage of all areas of detectable peaks for test antibodies and control antibodies IgG4. The products show a single protein peak of approximately 8.59 to 8.61 minutes, comparable to the human IgG4 antibody control (approximately 8.64 minutes) and consistent with the monomeric antibody. Small amounts (up to approximately 3-4%) of high molecular weight impurities corresponding to soluble aggregates were detected at a retention time of approximately 7.90 minutes.

Example 2.1. SDS-PAGE analysis.

Reconstituted assay samples were prepared by mixing with NuPage 4x LDS Sample Buffer (Invitrogen, NP0007) and NuPage 10x Sample Reconstitute (Invitrogen, NP0009) and incubated at 70° C. for 10 min. For unrecovered samples, the reducing agent and heat incubation were excluded. Samples were electrophoresed in precast 1.5 mm NuPage 4-12% Bis-Tris Novex gels (Invitrogen, NP0335PK2) with NuPage MES SDS reaction buffer under denaturing conditions. A 10 µl aliquot of SeeBlue Plus 2 pre-stained molecular weight standard (Invitrogen, LC5925) and an IgG4 control antibody at 1 mg/ml were included in the gel. 1 μl of each sample at 1 mg/ml was applied to the gel. After electrophoresis, the gels were stained with InstantBlue (TripleRed, ISB01L) for 30 min at room temperature. Images of stained gels were analyzed on a BioSpectrum Imaging (UVP) system.

The analysis confirmed the presence of antibodies, products and good levels of purity. Under non-reducing conditions, a predominant protein band of about 98 kDa was observed, comparable to the control IgG4 antibody. The IgG4 control antibody and one test clone showed an additional weaker band corresponding to the heavy plus light chain half-antibody at approximately 70 kDa under non-reducing conditions. This is expected for a control antibody. Under reducing conditions, two bands were observed corresponding in size to the heavy (close to position 49 kDa marker) and light chains (close to position 2 of the 8 kDa marker) and comparable to the bands detected for the control IgG4 antibody.

Example 2.8. Isoelectric Focusing (IEF) Analysis Non-reduced antibody samples purified using Protein A were electrophoresed as described below.

Electrophoresis of 5 μg protein A purified samples was performed on a 1.0 mm Novex pH 3-10 gel gradient (Invitrogen, EC66552BOX) using the manufacturer's recommended reaction conditions. A 10 μl aliquot of IEF markers pH 3-10 (Invitrogen, 39212-01) was included in the gel. After electrophoresis, the gels were fixed with 10% TCA for 30 min and then stained with InstantBlue (TripleRed, ISB01L) overnight at room temperature. Images of stained gels were analyzed on a BioSpectrum Imaging (UVP) system.

As shown in Table. 6, the tested clones show charged isoforms at pH in the range of 6.0 and 7.45. The charged isoforms detected are comparable to the theoretically calculated pIs for these antibodies, which were theoretically calculated to be between 6.35 and 6.82. Clones F and G had a theoretically calculated pI of 6.35 and show comparable charged isoforms, which is also consistent with the theoretically calculated pI being the same for both (6.35). The behavior of the control IgG4 antibody was as expected.

Table 6 Charged isoforms as detected by Novex IEF assay

Product R! predominant charged isoform* Acidic charged isoforms* Main charged isoforms* Clone F 6, 2 2x; 6.0 to 6.1 6, 3 Clone G 6, 2 2x; 6.0 to 6.1 6, 3 Clone H 7.4 2x; 6.9 to 7.3 7.45 Clone I 7.0 2x; 6.7 to 6.9 7.3 Clone J 6, 5 2x; 6.0 to 6.4 6, 8

*pI registrations were evaluated from initial positions correlated with the IEF 3-10 marker.

Example 2.9. Endotoxin analysis.

The edotoxin levels of the purified proteins were measured at final concentrations (up to 3.44 mg/mL) using the Endosafe-PTS device, a cartridge based method based LAL assay (Charles River).

As shown in Table. 8, the content of endotoxin was detected in the range from 0.05 to 0.27 U. end./mg.

Conclusion.

GS vectors were designed to express a single gene for selected humanized mAbs

- 275 040295 against LAG-3 and used for transient transfection of CHOK1SV GS-KO cells. From 2.6 to 2.8 liters of expression culture was incubated under standard conditions for 6 days and the resulting cell culture supernatant was purified using protein A chromatography. Titers after purification are shown in table. 8 and found to be in the range of 21.88 to 29.38 mg/l. The yields of the useful component range from 61.3 to 82.3 mg.

SDS-PAGE and SE-HPLC analyzes indicated the presence of a small amount (up to 4.69%) of soluble aggregates contained in the products, predominantly corresponding to the mAb dimeric antibody. The mAb also showed high molecular weight impurities for a retention time corresponding to the retention time of trimeric antibodies.

Isoelectric focusing detected a number of charged isoforms for all mAbs. For mAbs, isoforms were shown to be generally more basic when based on the theoretically calculated pI for these molecules, indicating some level of post-translational modification. The mAbs were found to be comparable to their terrorist calculated pI values.

Endotoxin levels for all samples were measured prior to sample submission and found to be below 0.63 U. end./mg.

Example 3 Characterization of mouse anti-LAG-3 antibody and humanized anti-LAG-3 antibody.

Example 3.1. Characterization of mouse anti-LAG-3 antibody.

The binding affinity of the mouse anti-LAG-3 antibody BAP050 to LAG-3 was studied. As demonstrated by FACS assays, mouse anti-LAG-3 antibody binds to human LAG3 transfected CHO cells with a KD of 0.2 nM, to human T cells with a KD of 0.26 nM, and to human LAG-3 transfected 300.19 cells with a KD of 13.6 nM. .

The blocking activity of the mouse anti-LAG-3 antibody BAP050 was examined by competitive binding assays. Mouse anti-LAG-3 antibody blocked binding of LAG-3-Ig to MHC class II molecules on Raji cells with an IC50 of 2.3 nM.

The effect of mouse anti-LAG-3 antibody BAP050 on interferon-γ (IFN-γ) expression was tested. In mice, anti-LAG-3 antibody resulted in a 3.0 ± 2.1-fold increase in IFN-γ expression in cells stimulated with anti-CD3 antibody (0.1 μg/ml), a 1.6 ± 0.4-fold increase in cells stimulated with staphylococcal enterotoxin B (SEB) (3 pg/ml), and a 1.4±0.3-fold increase in cells stimulated with CMV peptides.

Investigated areas in LAG-3 that can bind to the mouse anti-LAG-3 antibody BAP050. As demonstrated by ELISA, a mouse anti-LAG-3 antibody binds to the LAG-3 Ig fusion protein (sLAG-3 D1-D4Ig), which contains all four extracellular Ig-like domains (D1-D4), as well as to the LAG-3 fusion protein. Ig (sLAG-3 D1-D2Ig), which contains only domain 1 (D1) - domain 2 (D2). Additional analysis demonstrates that this anti-LAG-3 antibody binds to CHO cells that express full-length LAG-3, LAG-3 with a D2 deletion (CHO-LAG-3AD2) and LAG-3 with a partial deletion of the additional D1 loop (CHO-LAG -3AP48A60). Thus, the anti-LAG-3 antibody binds to D1 LAG-3.

The mouse anti-LAG-3 antibody BAP050 was found to increase IFN-γ secretion in stimulated CD3 PBMCs compared to a mouse IgG1 control and a non-antibody control. The fold increase is in the range from 1.4 to 2.9 times for four donors.

Example 3.2. Characterization of the humanized anti-BLAG-3 antibody.

Binding affinity and specificity.

The binding of an exemplary humanized anti-LAG-3 antibody to human LAG-3 protein was measured by the Biacore method. The results are as follows: Ka=6.41x10 ⁵ M' ¹ s'¹; Kd=7.00x10 ⁵ s ^-1 ; KD=0.109±0.008 nM. The anti-LAG-3 antibody also binds to cynomolgus monkey LAG-3 as measured by the Biacore method.

Binding of the same humanized anti-LAG-3 antibody to human LAG-3 expressing CHO cells and LAG-3 expressing cynomolgus monkey HEK 209 cells was measured using FACS analysis. The result demonstrates that the anti-LAG-3 antibody (human IgG4) binds with high affinity to human LAG-3 compared to the human IgG4 isotype control. The anti-LAG-3 antibody binds to human LAG-3 expressing cells with a KD of 1.92 nM and binds to cynomolgus monkey LAG-3 expressing cells with a KD of 2.3 nM.

The binding of anti-LAG-3 antibodies to rhesus monkey LAG-3 expressing 300.19 cells was also measured. The results demonstrate that the anti-LAG-3 antibody binds to rhesus monkey LAG-3 with a KD of 8.03 nM.

Additional binding assays demonstrate that the exemplary humanized anti-LAG-3 antibody does not cross-react with mouse LAG-3 or cross-react with the original cell line.

Blocking the interaction of LAG-3 and its ligands.

The ability of an exemplary humanized anti-LAG-3 antibody to block interactions between LAG-3 and its known ligand, class II MHC molecules, was investigated. The results demonstrate that the anti-LAG-3 antibody blocks the interaction between LAG-3 and MHC class II molecules on Daudi cells with an IC50 of 5.5 nM compared to a human IgG4 isotype control.

Stimulation of LAG-3 cytokine release in vitro in the absence of T-cell receptor involvement.

Anti-LAG-3 antibody is not expected to stimulate detectable cytokine responses without specific T-cell receptor stimulation. An anti-LAG-3 antibody was immobilized and air dried crosslinked on a tissue culture plate and tested for its ability to stimulate cytokine production in the manner described by Stebbings R. et al. (J. Immunol. 2007 179(5):3325-3331). He was induced to produce IL-2 or IFN-γ with an anti-LAG-3 antibody or an IgG control in the absence of whole blood staphylococcal enterotoxin B (SEB) stimulation.

Example 4 Selection of Patients Based on PD-L1/CD8/IFN-Y Status.

For each of several types of cancer, samples from many patients were tested for PD-L1/CD8/IFN-Y status. Each sample was classified as triple negative for PD-L1/CD8/IFN-y, single or double positive for these markers, or triple positive for these markers. In FIG. 11 demonstrates that in this experiment, in the patient population, the following types of malignancies are usually triple positive for PDL1/CD8/IFN-y: lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell ), gastric cancer, thyroid cancer, melanoma and malignant tumor of the nasopharynx. Patients suffering from these types of cancers are good candidates for therapy with anti-PD-1 antibodies in combination therapies as described herein, for example with anti-LAG-3 antibodies. The likelihood of effective treatment can be further enhanced by determining which patients are PD-L1/CD8/IFN-y triple positive and treating triple positive patients with anti-PD-1 antibodies or anti-PD-L1 antibodies and combination treatments as described herein. description, for example antibodies against LAG-3.

In FIG. 12 demonstrates that the following types of cancer are rarely triple positive for PD-L1/CD8/IFN-y in the patient population: ER+ breast cancer and pancreatic cancer. It should be noted that even for cancers that are not typically PD-L1/CD8/IFN-Y positive, it is possible to increase the likelihood of effective treatment by determining which patients are PD-L1/CD8/triple positive. IFN-Y, and treating triple positive patients with anti-PD-1 antibodies or anti-PD-L1 antibodies and combination treatments as described herein, eg, with anti-LAG-3 antibodies.

In FIG. 13 shows the proportion of breast cancer patients who are triple positive for PDL1/CD8/IFN-Y. Considering mainly breast cancer, the proportion of triple positives is somewhat low. However, if one focuses only on IM-TN breast cancer, one can see that a much larger percentage of patients are triple positive for PD-L1/CD8/IFN-y. IM-TN breast cancer is particularly difficult to treat with conventional therapies. The discovery that IM-TN breast cancer is often triple positive for PD-L1/CD8/IFN-y opens new possibilities for therapy of this malignancy with anti-PD-1 antibodies or anti-PD-L1 antibodies and combination therapies, as described in the present description, for example, antibodies against LAG-3.

In FIG. 14 shows the proportion of colon cancer patients who are triple positive for PD-L1/CD8/IFN-Y. Considering mainly colon cancer, the proportion of triple positives is somewhat low. However, if one focuses only on breast cancers with high MSI (high microsatellite instability), one can see that a much higher percentage of patients are triple positive for PD-L1/CD8/IFN-Y. MSI levels can be analyzed, for example, using commercially available PCR methods.

Gastric cancer samples were tested for PD-L1/CD8/IFN-y levels (data not shown). It was found that in high MSI gastric cancer or EBV+ gastric cancer, approximately 49% were positive for PD-L1, and a high proportion of PD-L1 positive cells were triple negative for PD-L1/CD8/IFN-y. It was also found that the proportion of PD-L1-positive cells and positive for PD-L1/CD8/IFN-Y cells was also positive for PIK3CA. This finding suggests that such cancers can be treated with an anti-PD-1 antibody or an anti-PD-L1 antibody, for example in combination with an anti-LAG-3 antibody, optionally in combination with a therapeutic agent directed at PIK3.

High MSI CRC samples were tested for a combination of markers (data not shown). In high MSI-high CRC samples, a high proportion of PD-L1/CD8/IFN-Y samples were also found to be positive for LAG-3, PD-1 (all referred to as PDCD1), RNF43, and BRAF. This discovery allows

- 277 040295 suggest that these cancers can be treated with an anti-LAG-3 antibody, optionally in combination with a therapeutic agent that targets one or more of PD-1, PD-L1,

PDCD1, RNF43 and BRAF.

Squamous cell lung cancer was tested for a combination of markers (data not shown). It was found that in samples of squamous cell lung cancer, a large proportion of samples with PD-L1/CD8/IFN-y is also positive for LAG-3. This finding suggests that these cancers can be treated with an anti-LAG-3 antibody, optionally in combination with a therapeutic agent that targets PD-1 or PD-L1, such as an anti-PD-1 antibody or an anti-PD-L1 antibody.

Papillary thyroid cancer was tested for a combination of markers including the BRAF V600E mutation (data not shown). It has been found that a large proportion of thyroid cancer specimens that are positive for PD-L1 are also positive for BRAF V600E. This finding suggests that these cancers can be treated with an anti-PD1 antibody or an anti-PD-L1 antibody, for example in combination with an anti-LAG-3 antibody, optionally in combination with a BRAF-targeted therapeutic agent.

Example 5 Selection of Patients Based on PD-L1 Status.

In order to provide a broad study of cancer indications for immunomodulator-based therapies (e.g., LAG-3 alone or in combination with PD1/PD-L1), PD-L1 expression at protein and mRNA levels was assessed in human cancers, including tumors of the lung and liver.

PD-L1 protein expression was assessed in a group of formalin-fixed paraffin-embedded non-small cell adenocarcinoma (ASA) lung (NSCLC), NSCLC squamous cell carcinoma (SCC) and hepatic cell carcinoma (HCC) tumors by immunohistochemistry (IHC). The expression of PD-L1 was also semiquantitatively assessed by the method of manual histological assessment (H-score) based on the intensity of staining and the percentage of positive tumor cells. In the authors' IHC analysis, a positive result for PD-L1 (PD-L1+) was defined as Noscore > 20. In parallel, PD-L1 mRNA expression data from the Cancer Genome Atlas (TCGA) were analyzed at the same indications (503 NSCLC ACA, 489 NSCLC SCC and 191 HCC) and analyzed by comparing expression in normal tissues from TCGA.

With RNA sequencing analysis after RSEM normalization, data were calculated as log2 (RPKM+0.1) using OmicSoft systems for RNA sequencing data from TCGA tumor readings. Expression of PD-L1 is increased in NSCLC ACA and SCC relative to expression in HCC. By overlaying distributions and comparing expression levels across all indications in TCGA, the authors ranked the overexpression profiles for PD-L1 and identified a cohort of HCC TCGA that is characterized by significantly reduced levels of PD-L1 mRNA with a median level of -0.8 compared to 1.3 for ACA. and 1.5 for SCC, which is more than a 2-fold change in the median expression level. With RNA sequencing data, the authors' analysis identifies 50% adenocarcinoma NSCLC, 54% squamous cell carcinoma NSCLC, and 6% HCC as highly expressing PD-L1.

Expression of PD-L1 protein in tumor cells was measured in 45 lung adenocarcinoma (ACA), 47 lung squamous cell carcinoma (SCC) and 36 hepatocellular carcinoma (HCC) samples. 16/45 (35.6%) lung ACA, 21/47 (44.7%) lung SCC were PD-L1 positive. In contrast, a positive PD-L1 result was observed in only 2/36 (5.6%) HCC samples.

In summary, using IHC analysis and RNA sequencing data in large and independent sets of NSCLC and human HCC samples, PD-L1 expression was found to be more upregulated in NSCLC than in HCC. For NSCLC, comparable results are observed for adenocarcinoma and squamous cell carcinomas. It should be noted that among the large number of samples (128 for IHC and 1183 for RNA sequencing), very good agreement between protein and mRNA based assays is observed for the 3 indications. Thus, this discovery provides a framework for large-scale data analysis based on mRNA in TCGA by indication and patient population in which responses to immunomodulator-based immune therapies (e.g., PD-1/PD-L1, e.g., in combination) can be enhanced. with LAG-3).

Inclusion by reference.

All publications, patents, and access numbers referred to in this specification are hereby incorporated by reference in their entirety, as if specifically and separately indicating that each individual publication or patent is invoked by reference.

Equivalents.

Although specific embodiments of the invention have been described, the above description is illustrative and non-limiting. Many variations of the invention will become apparent to those skilled in the art upon viewing the present description and the claims below. The full scope of the invention should be defined by the claims together with their full scope of equivalents and the description along with such modifications.

Claims (39)

CLAIM 1. An isolated antibody molecule capable of binding to the human lymphocyte activation gene 3 (LAG-3), containing: (a) a heavy chain variable region (VH) containing the amino acid sequence VHCDR1 SEQ ID NO: 4, the amino acid sequence VHCDR2 SEQ ID NO: 5, and the amino acid sequence VHCDR3 SEQ ID NO: 3, and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 13, the amino acid sequence of VLCDR2 SEQ ID NO: 14, and the amino acid sequence of VLCDR3 SEQ ID NO: 15; (b) a VH comprising the amino acid sequence of VHCDR1 SEQ ID NO: 1, the amino acid sequence of VHCDR2 SEQ ID NO: 2, and the amino acid sequence of VHCDR3 SEQ ID NO: 3, and VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 10, the amino acid sequence of VLCDR2 SEQ ID NO: 11, and the amino acid sequence of VLCDR3 SEQ ID NO: 12; (c) a VH containing the amino acid sequence of VHCDR1 SEQ ID NO: 286, the amino acid sequence of VHCDR2 SEQ ID NO: 5, and the amino acid sequence of VHCDR3 SEQ ID NO: 3, and VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 13, the amino acid sequence of VLCDR2 SEQ ID NO: 14, and the amino acid sequence of VLCDR3 SEQ ID NO: 15; or (d) a VH comprising the amino acid sequence of VHCDR1 SEQ ID NO: 286, the amino acid sequence of VHCDR2 SEQ ID NO: 2, and the amino acid sequence of VHCDR3 SEQ ID NO: 3, and VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 10, the amino acid sequence of VLCDR2 SEQ ID NO: 11, and the amino acid sequence of VLCDR3 SEQ ID NO: 12. 2. An antibody molecule according to claim 1, wherein said antibody molecule is a humanized antibody molecule. 3. An antibody molecule according to claim 1 or 2, wherein said antibody molecule is a monospecific antibody molecule. 4. An antibody molecule according to any one of claims 1 to 3, which contains VH containing four frame (FW) sections containing: (i) FW1 containing any amino acid sequence from SEQ ID NO: 187, 190, 194 or 196, or an amino acid sequence that is at least 90% identical to them, or has no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences of SEQ ID NO: 187, 190, 194, or 196; (ii) FW2 containing any amino acid sequence from SEQ ID NO: 198, 202, 206 or 208, or an amino acid sequence that is at least 90% identical to them, or has no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences of SEQ ID NO: 198, 202, 206 or 208; (iii) FW3 containing any amino acid sequence from SEQ ID NO: 210, 212, 217 or 219, or an amino acid sequence that is at least 90% identical to them, or has no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences of SEQ ID NO: 210, 212, 217, or 219; and (iv) FW4 containing the amino acid sequence of SEQ ID NO: 221, or an amino acid sequence that is at least 90% identical to it, or having no more than two amino acid substitutions, insertions or deletions compared to the amino acid sequence of SEQ ID NO: 221 ; and/or VL containing four FW sections containing: (i) FW1 containing any amino acid sequence from SEQ ID NO: 226, 230, 232, 234, 236, or 2385, or an amino acid sequence that is at least 90% identical to them, or having no more than two amino acid substitutions, insertions, or deletions compared to any - 279 040295 from the amino acid sequences of SEQ ID NO: 226, 230, 232, 234, 236 or 2385; (ii) FW2 containing any amino acid sequence from SEQ ID NO: 240, 244, 246 or 248, or an amino acid sequence that is at least 90% identical to them, or has no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences of SEQ ID NO: 240, 244, 246, or 248; (iii) FW3 containing any amino acid sequence from SEQ ID NO: 252, 255, 259, 261, 265, 267 or 269, or an amino acid sequence that is at least 90% identical to them, or having no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences of SEQ ID NO: 252, 255, 259, 261, 265, 267 or 269; and (iv) FW4 comprising the amino acid sequence of SEQ ID NO: 271, or an amino acid sequence that is at least 90% identical thereto, or has no more than two amino acid substitutions, insertions, or deletions compared to the amino acid sequence of SEQ ID NO: 271 . 5. An antibody molecule according to any one of claims 1 to 4, which contains VH containing any of the amino acid sequences of SEQ ID NO: 8, 28, 64, 68, 72, 76, 80, 100, 104, or 108, or an amino acid sequence that is at least 85% identical to any of the sequences of SEQ ID NO: 8, 28, 64, 68, 72, 76, 80, 100, 104 or 108; and/or VL containing any of the amino acid sequences of SEQ ID NO: 32, 36, 40, 44, 48, 52, 56, 60, 84, 88, 92, or 96, or an amino acid sequence that is at least 85% identical to any of the sequences SEQ ID NO: 32, 36, 40, 44, 48, 52, 56, 60, 84, 88, 92 or 96. 6. An antibody molecule according to any one of claims 1 to 5, which contains VH containing an amino acid sequence selected from SEQ ID NO: 8, SEQ ID NO: 28, SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 76, SEQ ID NO: 80, SEQ ID NO: 100, SEQ ID NO: 104 or SEQ ID NO: 108; and/or VL containing the amino acid sequence of SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO : 60, SEQ ID NO: 84, SEQ ID NO: 88, SEQ ID NO: 92, or SEQ ID NO: 96. 7. An antibody molecule according to any one of claims 1 to 6, which contains a heavy chain containing the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 30, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 74 , SEQ ID NO: 78, SEQ ID NO: 82, SEQ ID NO: 102, SEQ ID NO: 106, SEQ ID NO: 110, SEQ ID NO: 113, SEQ ID NO: 122 or SEQ ID NO: 134; and/or a light chain containing the amino acid sequence EQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 42, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54, SEQ ID NO: 58 , SEQ ID NO: 62, SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 94, or SEQ ID NO: 98. 8. An antibody molecule according to any one of claims 1 to 6, which contains: (a) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 32; (b) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 36; (c) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 40; (d) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 44; (e) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 48; (f) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 52; (g) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 56; (h) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 60; (i) VH containing the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and VL containing the amino acid sequence of SEQ ID NO: 36; (j) VH containing the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and VL containing the amino acid sequence of SEQ ID NO: 40; (k) VH containing the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and VL containing the amino acid sequence of SEQ ID NO: 56; (l) VH containing the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and VL containing the amino acid sequence of SEQ ID NO: 60; (m) VH containing the amino acid sequence of SEQ ID NO: 68 or SEQ ID NO: 108; and VL containing the amino acid sequence of SEQ ID NO: 36; (n) VH containing the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 8; and VL - 280 040295 containing the amino acid sequence of SEQ ID NO: 40; (o) VH containing the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 8; and VL containing the amino acid sequence of SEQ ID NO: 60; (p) VH containing the amino acid sequence of SEQ ID NO: 76 and VL containing the amino acid sequence of SEQ ID NO: 60; (q) VH containing the amino acid sequence of SEQ ID NO: 80 and VL containing the amino acid sequence of SEQ ID NO: 84; (r) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 88; (s) VH containing the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and VL containing the amino acid sequence of SEQ ID NO: 92; or (t) a VH containing the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and VL containing the amino acid sequence of SEQ ID NO: 96. 9. An antibody molecule according to any one of claims 1 to 5, which contains: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 34; (b) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 38; (c) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 42; (d) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 46; (e) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 50; (f) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 54; (g) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 58; (h) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 62; (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106; and a light chain containing the amino acid sequence of SEQ ID NO: 38; (j) a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106; and a light chain containing the amino acid sequence of SEQ ID NO: 42; (k) a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106; and a light chain containing the amino acid sequence of SEQ ID NO: 58; (l) a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106; and a light chain containing the amino acid sequence of SEQ ID NO: 62; (m) a heavy chain containing the amino acid sequence of SEQ ID NO: 70 or SEQ ID NO: 110; and a light chain containing the amino acid sequence of SEQ ID NO: 38; (n) a heavy chain containing the amino acid sequence of SEQ ID NO: 74 or SEQ ID NO: 18; and a light chain containing the amino acid sequence of SEQ ID NO: 42; (o) a heavy chain containing the amino acid sequence of SEQ ID NO: 74 or SEQ ID NO: 18; and a light chain containing the amino acid sequence of SEQ ID NO: 62; (p) a heavy chain containing the amino acid sequence of SEQ ID NO: 78 and a light chain containing the amino acid sequence of SEQ ID NO: 62; (q) a heavy chain containing the amino acid sequence of SEQ ID NO: 82 and a light chain containing the amino acid sequence of SEQ ID NO: 86; (r) a heavy chain containing the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chain containing the amino acid sequence of SEQ ID NO: 94; (s) a heavy chain containing the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106; and a light chain containing the amino acid sequence of SEQ ID NO: 98; (t) a heavy chain containing the amino acid sequence of SEQ ID NO: 113 and a light chain containing the amino acid sequence of SEQ ID NO: 34; (u) a heavy chain containing the amino acid sequence of SEQ ID NO: 113 and a light chain containing the amino acid sequence of SEQ ID NO: 38; (v) a heavy chain containing the amino acid sequence of SEQ ID NO: 122 and a light chain containing the amino acid sequence of SEQ ID NO: 38; (w) a heavy chain containing the amino acid sequence of SEQ ID NO: 122 and a light chain containing the amino acid sequence of SEQ ID NO: 58; or (x) a heavy chain containing the amino acid sequence of SEQ ID NO: 134 and a light chain containing the amino acid sequence of SEQ ID NO: 38. - 281 040295 10. An antibody molecule according to any one of claims 1 to 9, which is a full length monoclonal antibody. 11. An antibody molecule according to any one of claims 1 to 9, which is an antibody fragment, which is a Fab, F(ab') ₂ , Fv or a single chain Fv fragment (scFv). 12. An antibody molecule according to any one of claims 1 to 11, which contains a heavy chain constant region selected from IgG1, IgG2, IgG3 and IgG4 and/or a light chain constant region selected from k or λ. 13. An antibody molecule according to claim 10, which contains: (a) a human IgG4 heavy chain constant region of SEQ ID NO: 275 or 277 and a k light chain constant region; (b) human IgG1 heavy chain constant region of SEQ ID NO: 279 and k light chain constant region; (c) human IgG1 heavy chain constant region of SEQ ID NO: 280 and k light chain constant region; or (d) a human IgG1 heavy chain constant region of SEQ ID NO: 281 and a k light chain constant region. 14. An antibody molecule according to any one of claims 1 to 13, which: (a) capable of binding to human LAG-3 with a dissociation constant (KD) of less than about 0.2 nM; (b) binds to the extracellular Ig-like domain of LAG-3; (c) is able to reduce the binding of LAG-3 to a major histocompatibility complex (MHC) class II molecule; or a cell that expresses an MHC class II molecule; or (d) capable of enhancing an antigen-specific T cell response. 15. An isolated bispecific antibody having (i) a first binding specificity for LAG3 and (ii) a second binding specificity for PD-1, TIM-3, CEACAM, CEACAM-1, CEACAM-5, PD-L1, or PD-L2, wherein the first LAG-3 binding specificity portion of a bispecific antibody molecule contains: (a) a heavy chain variable region (VH) comprising VHCDR1 with the amino acid sequence of SEQ ID NO: 4, VHCDR2 with the amino acid sequence of SEQ ID NO: 5, and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising VLCDR1 with the amino acid sequence of SEQ ID NO: 13, VLCDR2 with the amino acid sequence of SEQ ID NO: 14, and VLCDR3 with the amino acid sequence of SEQ ID NO: 15; (b) VH containing VHCDR1 with the amino acid sequence of SEQ ID NO: 1; VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; and VL containing VLCDR1 with the amino acid sequence of SEQ ID NO: 10, VLCDR2 with the amino acid sequence of SEQ ID NO: 11, and VLCDR3 with the amino acid sequence of SEQ ID NO: 12; (c) VH containing VHCDR1 with the amino acid sequence of SEQ ID NO: 286; VHCDR2 with the amino acid sequence of SEQ ID NO: 5 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; and VL containing VLCDR1 with the amino acid sequence of SEQ ID NO: 13, VLCDR2 with the amino acid sequence of SEQ ID NO: 14, and VLCDR3 with the amino acid sequence of SEQ ID NO: 15; or (d) VH containing VHCDR1 with the amino acid sequence of SEQ ID NO: 286; VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; and a VL comprising VLCDR1 with the amino acid sequence of SEQ ID NO: 10, VLCDR2 with the amino acid sequence of SEQ ID NO: 11, and VLCDR3 with the amino acid sequence of SEQ ID NO: 12, and/or wherein said antibody molecule comprises an antigen-binding antibody fragment, or a semi-antibody or antigen-binding semi-antibody fragment. 16. A pharmaceutical composition for stimulating an immune response in an individual, comprising an isolated antibody molecule according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, excipient or stabilizer. 17. A pharmaceutical composition for treating cancer in an individual, comprising the isolated antibody molecule according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, excipient or stabilizer. 18. A pharmaceutical composition for the treatment of an infectious disease in an individual, comprising an isolated antibody molecule according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, excipient or stabilizer. 19. An isolated nucleic acid encoding an antibody molecule according to any one of claims 1-14, comprising a heavy chain CDR1-3 and a light chain CDR1-3, wherein said nucleic acid comprises any nucleotide sequence from SEQ ID NOs: 140-287. 20. An isolated nucleic acid encoding a bispecific antibody molecule according to claim 15, - 282 040295 containing CDR1-3 of the heavy chain and CDR1-3 of the light chain, where the specified nucleic acid contains any nucleotide sequence from SEQ ID NO: 140-287. 21. An isolated nucleic acid encoding an isolated antibody molecule according to claim 16, comprising a heavy chain CDR1-3 and a light chain CDR1-3, wherein said nucleic acid comprises any nucleotide sequence from SEQ ID NOs: 140-287. 22. Nucleic acid according to claim 19, containing: a nucleotide sequence encoding a VH, wherein said nucleotide sequence comprises any of SEQ ID NOs: 9, 29, 65, 69, 73, 77, 81, 101, 105, 109, 112, 121, 124, 125, 132, or 133, or which at least 85% identical to any of SEQ ID NOs: 9, 29, 65, 69, 73, 77, 81, 101, 105, 109, 112, 121, 124, 125, 132, or 133; and/or a nucleotide sequence encoding VL, wherein said nucleotide sequence contains any of SEQ ID NOs: 33, 37, 41, 45, 49, 53, 57, 61, 85, 89, 93, 97, 115, 118, 128, 129 or 137 or which is at least 85% identical to any of SEQ ID NOs: 33, 37, 41, 45, 49, 53, 57, 61, 85, 89, 93, 97, 115, 118, 128, 129, or 137. 23. Nucleic acid according to claim 19 or 22, containing a nucleotide sequence encoding a heavy chain, where the specified nucleotide sequence contains any of SEQ ID NO: 19, 31, 67, 71, 75, 79, 83, 103, 107, 111, 114, 123, 126, 127, 135 or 136 or which is at least 85% identical to any of ID NOs: 19, 31, 67, 71, 75, 79, 83, 103, 107, 111, 114, 123, 126 , 127, 135 or 136; and/or a nucleotide sequence encoding a light chain, wherein said nucleotide sequence comprises any of SEQ ID NOs: 35, 39, 43, 47, 51, 55, 59, 63, 87, 91, 95, 99, 117, 120, 130 , 131, 138 or 139 or which is at least 85% identical to any of SEQ ID NOs: 35, 39, 43, 47, 51, 55, 59, 63, 87, 91, 95, 99, 117, 120, 130 , 131, 138 or 139. 24. An isolated nucleic acid encoding the VH of an antibody molecule according to any one of claims 1-14. 25. An isolated nucleic acid encoding the VH of the bispecific antibody molecule according to claim 15. 26. An isolated nucleic acid encoding the VL of an antibody molecule according to any one of claims 1-14. 27. An isolated nucleic acid encoding the VL of the bispecific antibody molecule according to claim 15. 28. An isolated nucleic acid encoding the VH and VL of an antibody molecule according to any one of claims 1-14. 29. An isolated nucleic acid encoding the VH and VL molecules of the bispecific antibody of claim 15. 30. An expression vector containing a nucleic acid according to any one of claims 19-28. 31. A host cell containing a nucleic acid according to any one of claims 19-28, for the production of an antibody molecule according to any one of claims 1-15. 32. A method for producing an antibody molecule or fragment thereof, comprising culturing a host cell according to claim 31 under conditions suitable for nucleic acid expression. 33. A method for detecting LAG-3 in a biological sample, comprising (i) bringing the sample into contact with the selected antibody molecule according to any one of claims 1 to 15 under conditions that ensure the interaction of the antibody molecule and the polypeptide; and (ii) detecting the formation of a complex between the antibody molecule and the sample. 34. The method of claim 33, further comprising: (i) contacting a control sample with an isolated antibody molecule according to any one of claims 1 to 15 under conditions that allow interaction between the antibody molecule and the polypeptide; and (ii) detecting the formation of a complex between the antibody molecule and the control sample. 35. The use of an antibody molecule according to any one of claims 1 to 15 to stimulate an immune response. 36. The use of an antibody molecule according to any one of claims 1 to 15 for the treatment of a cancer in an individual. 37. The use of an antibody molecule according to any one of claims 1 to 15 for the treatment of an infectious disease in an individual. 38. Use according to claim 35 or 36, wherein the cancer is selected from lung cancer, melanoma, kidney cancer, liver cancer, prostate cancer, breast cancer, head and neck cancer, colorectal cancer, pancreatic cancer, brain cancer, hematological malignant tumor or metastatic lesion caused by malignant tumor. 39. Application according to claim 38, where: (a) the lung cancer is non-small cell lung cancer (NSCLC), KRAS mutated lung cancer, pulmonary adenocarcinoma, squamous cell lung carcinoma, or small cell lung cancer; (b) the melanoma is advanced melanoma, inoperable melanoma, metastatic melanoma, HLA-A2 positive melanoma, BRAF-mutated melanoma, NRAS-mutated melanoma, cutaneous melanoma, or intraocular melanoma; (c) the kidney cancer is renal cell carcinoma (RCC), metastatic renal cell carcinoma or clear cell renal cell carcinoma (CCRCC); or (d) the hematologic tumor is lymphoma, non-Hodgkin's lymphoma, myeloma - 283 040295 or leukemia. 40. Use according to any one of claims 35-39, wherein the use further comprises the use of a second therapeutic agent, wherein the second therapeutic agent is a chemotherapeutic agent, a targeted antitumor therapy agent, an oncolytic drug, a cytotoxic agent, an immunotherapy agent, a cytokine, an activator a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy agent. 41. The use according to any one of claims 35-40, where the use further includes the use of: (a) a co-stimulatory molecule agonist which is one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30 , CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand; or (b) an immune response checkpoint inhibitor that is one or more of PD-1, PD-L1, PD-L2, CTLA4, TIM3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, or TGFR. 42. Use according to any one of claims 35-41, where the use further includes the use of one or more of the following: (a) a PD-1 inhibitor; (b) a TIM-3 inhibitor; (c) a GITR agonist; or (d) a PD-L1 inhibitor. 43. Application according to claim 42, where: (a) the PD-1 inhibitor is an anti-PD-1 antibody molecule or nivolumab, pembrolizumab, pidilizumab, AMP-224, or AMP 514; (b) the TIM-3 inhibitor is an anti-TIM-3 antibody molecule; (c) the GITR agonist is an anti-GITR antibody molecule or a GITR fusion protein; or (d) the PD-L1 inhibitor is an antibody molecule or YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105. 44. Use according to any one of claims 35-43, where the use further includes the use of one or more of the following: (a) a tumor antigenic peptide for the treatment of melanoma; (b) a chemotherapeutic agent for the treatment of pancreatic cancer; or (c) a chemotherapeutic agent for the treatment of breast cancer. 45. Use according to claim 44, including one or more of the following: (a) the tumor antigenic peptide is an HLA-A2 peptide; (b) the chemotherapeutic agent is gemcitabine; or (c) the chemotherapeutic agent is paclitaxel. 46. Use according to any one of claims 39 to 44, wherein the subject suffers from or is diagnosed with one or more of the following: (a) a cancer that expresses PD-L1; (b) a cancer that is positive for one, two, or all of: PD-L1, CD8, or IFN-γ; (c) a cancer that is triple positive for PD-L1, CD8, and IFN-α; or (d) a cancer that is positive for tumor infiltrating lymphocytes (TIL). 47. Use according to any one of claims 35-46, wherein the antibody molecule is used at a dose of about 1-30 mg/kg or 1-5 mg/kg, or the antibody molecule is used from once a week to once every 2, 3 or 4 weeks or at a dose of approximately 10 to 20 mg/kg every week thereafter. 48. The use according to any one of claims 35-47, where the use further includes the use of one or more of: 1) protein kinase C inhibitor (PKC); 2) heat shock protein inhibitor 90 (HSP90); 3) a phosphoinositide 3-kinase inhibitor (PI3K) and/or a rapamycin target (mTOR); 4) a cytochrome P450 inhibitor (for example, a CYP17 inhibitor or a 17-a-hydroxylase/C17-20 lyase inhibitor); 5) an iron chelating agent; 6) an aromatase inhibitor; 7) a p53 inhibitor, eg an inhibitor of the p53/Mdm2 interaction; 8) apoptosis inducer; 9) an angiogenesis inhibitor; 10) an aldosterone synthase inhibitor; 11) protein receptor inhibitor smoothened (SMO); 12) a prolactin receptor (PRLR) inhibitor; - 284 040295 13) an inhibitor of the Wnt signaling cascade; 14) a CDK4/6 inhibitor; 15) fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) an inhibitor of macrophage colony stimulating factor (M-CSF); 17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (eg, FLK-1/KDR), PDGFRbeta, c-KIT, or Raf kinase C; 19) a somatostatin agonist and/or a growth hormone releasing inhibitor; 20) an anaplastic lymphoma kinase (ALK) inhibitor; 21) inhibitor of insulin-like growth factor receptor 1 (IGF-1R); 22) P-glycoprotein 1 inhibitor; 23) an inhibitor of vascular endothelial growth factor receptor (VEGFR); 24) BCR-ABL kinase inhibitor; 25) an FGFR inhibitor; 26) CYP11B2 inhibitor; 27) an HDM2 inhibitor, eg an HDM2-p53 interaction inhibitor; 28) a tyrosine kinase inhibitor; 29) c-MET inhibitor; 30) a JAK inhibitor; 31) DAC inhibitor; 32) Πβ-hydroxylase inhibitor; 33) an IAP inhibitor; 34) a PIM kinase inhibitor; 35) porcupine inhibitor; 36) BRAF inhibitor, BRAF V600E or wild-type BRAF; 37) HER3 inhibitor; 38) MEK inhibitor; or 39) a lipid kinase inhibitor. 49. Use according to any one of claims 35-48, where the use further includes the use of one or more compounds A1-A51, as described in table. 7. 50. Use according to any one of claims 35-49, wherein the use further comprises the use of an anti-PD-1 antibody molecule and/or carboplatin. 51. Use according to any one of claims 35-50, wherein the cancer is triple negative breast cancer (TNBC). 52. An antibody molecule capable of binding to LAG-3, containing a VH containing the amino acid sequence of SEQ ID NO: 104 and a VL containing the amino acid sequence of SEQ ID NO: 56. 53. An antibody molecule capable of binding to LAG-3, containing a VH containing the amino acid sequence of SEQ ID NO: 108 and a VL containing the amino acid sequence of SEQ ID NO: 36. 54. An antibody molecule capable of binding to LAG-3, containing a heavy chain containing the amino acid sequence of SEQ ID NO: 122 and a light chain containing the amino acid sequence of SEQ ID NO: 58. 55. An antibody molecule capable of binding to LAG-3, containing a heavy chain containing the amino acid sequence of SEQ ID NO: 134 and a light chain containing the amino acid sequence of SEQ ID NO: 38. 56. Use of an antibody molecule capable of binding to LAG-3 containing a VH containing the amino acid sequence of SEQ ID NO: 104 and a VL containing the amino acid sequence of SEQ ID NO: 56 to stimulate an immune response. 57. Use of an antibody molecule capable of binding to LAG-3 comprising a VH comprising the amino acid sequence of SEQ ID NO: 104 and a VL comprising the amino acid sequence of SEQ ID NO: 56 for the treatment of a cancer or infectious disease in an individual. 58. Use of an antibody molecule capable of binding to LAG-3 containing a VH containing the amino acid sequence of SEQ ID NO: 108 and a VL containing the amino acid sequence of SEQ ID NO: 36 to stimulate an immune response. 59. Use of an antibody molecule capable of binding to LAG-3 comprising a VH comprising the amino acid sequence of SEQ ID NO: 108 and a VL comprising the amino acid sequence of SEQ ID NO: 36 for the treatment of a cancer or infectious disease in an individual. - 285 040295 60. Use of an antibody molecule capable of binding to LAG-3 containing a heavy chain containing the amino acid sequence of SEQ ID NO: 122 and a light chain containing the amino acid sequence of SEQ ID NO: 58 to stimulate an immune response. 61. Use of an antibody molecule capable of binding to LAG-3 containing a heavy chain containing the amino acid sequence of SEQ ID NO: 122 and a light chain containing the amino acid sequence of SEQ ID NO: 58 for the treatment of a cancer or an infectious disease in an individual. 62. Use of an antibody molecule capable of binding to LAG-3 containing a heavy chain containing the amino acid sequence of SEQ ID NO: 134 and a light chain containing the amino acid sequence of SEQ ID NO: 38 to stimulate an immune response. 63. Use of an antibody molecule capable of binding to LAG-3 containing a heavy chain containing the amino acid sequence of SEQ ID NO: 134 and a light chain containing the amino acid sequence of SEQ ID NO: 38 for the treatment of a cancer or an infectious disease in an individual.