EA045940B1 - ANTI-PD-1 ANTIBODY MOLECULES AND THEIR APPLICATIONS - Google Patents

Description

Cross reference to related applications

This patent application claims the benefit of US Provisional Application No. 61/931512, filed January 24, 2014, US Provisional Application No. 62/059676, filed October 3, 2014, and US Provisional Application No. 62/094834, filed December 19, 2014. and the contents of the above applications are incorporated herein by reference in their entirety.

List of sequences

The invention contains a sequence listing that has been provided electronically in ASCII format and is incorporated herein by reference in its entirety. The specified copy of the ASCII file, created on January 12, 2015, called C2160-7000WO_SL.txt, is 191589 bytes in size.

Level of invention

The ability of T cells to mediate an immune response to antigen requires two distinct signaling interactions (Viglietta, V. et al. (2007) Neurotherapeutics 4:666-675; Korman, A. J. et al. (2007) Adv. Immunol. 90:297- 339). First, the antigen that is exposed on the surface of antigen presenting cells (APCs) is presented to antigen-specific naïve CD4' T cells. This presentation delivers a signal through the T cell receptor (TCR), which directs T cells to initiate an immune response specific to the presented antigen. Second, various costimulatory and inhibitory signals, mediated through interactions between APC and various T cell surface molecules, trigger T cell activation and proliferation and, ultimately, their inhibition.

The immune system is tightly controlled by a network of costimulatory and coinhibitory ligands and receptors. These molecules provide a second signal to activate T cells and provide a balanced mix of positive and negative signals to maximize the immune response against infection while limiting autoimmunity (Wang, L. et al. (Epub Mar. 7, 2011) J. Exp Med 208(3):577-92 Lepenies, B. et al (2008) Endocrine, Metabolic & Immune Disorders Drug Targets 8:279-288). Examples of costimulatory signals include binding between ligands B7.1 (CD80) and B7.2 (CD86) in APC cells and between CD28 and CTLA-4 receptors on CD4+ T cells (Sharpe, A. H. et al. (2002) Nature Rev. Immunol. 2:116-126; Lindley, P. S. et al (2009) Immunol. Rev. 229:307-321). Binding of B7.1 or B7.2 to CD28 stimulates T cell activation, and binding of B7.1 or B7.2 to CTLA-4 inhibits such activation (Dong, S. et al. (2003) Immunolog. Res. 28(1 ):39-48; Greenwald, R. J. et al. (2005) Ann. Rev. Immunol. 23:515-548). The CD28 molecule is constitutively expressed on the surface of T cells (Gross, J. et al. (1992) J. Immunol. 149: 380-388), while CTLA-4 expression is rapidly upregulated following T cell activation (Linsley, P. et al. al (1996) Immunity 4: 535-543).

Other ligands of the CD28 receptor include a group of related B7 molecules, also called the B7 superfamily (Coyle, A. J. et al. (2001) Nature Immunol. 2(3): 203-209; Sharpe, A. H. et al. (2002) Nature Rev. Immunol 2:116-126; Collins, M. et al. (2005) Genome Biol. 6:223.1-223.7; Korman, A. J. et al. (2007) Adv. Immunol. 90:297-339). Several members of the B7 superfamily are known, including B7.1 (CD80), B7.2 (CD86), inducible costimulatory ligand (ICOS-L), programmed death ligand-1 (PD-L1; B7-H1), programmed death ligand-2 (PD-L2; B7-DC), B7-NZ, H4-B7 and B7-H6 (Collins, M. et al. (2005) Genome Biol. 6:223.1-223.7).

Programmed death protein-1 (PD-1) is an inhibitory member of the expanded CD28/CTLA-4 family of T-cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 39177982; Bennett et al. (2003) J. Immunol. 170:711-8). Other members of the CD28 family include CD28, CTLA-4, ICOS, and BTLA. The PD-1 protein is predicted to exist as a monomer lacking the unpaired cysteine residue, a feature shared by other CD28 family members. The PD-1 protein is expressed on activated B cells, T cells and monocytes.

The PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:76572). Despite its structural similarity to CTLA-4, the PD-1 protein lacks the MYPPY motif (SEQ ID NO: 236), which is important for binding to B7-1 and B7-2. Two ligands for PD-1 have been identified, namely PD-L1 (B7-H1) and PD-L2 (B7-DC), which significantly suppress T cell activation after binding to PD-1 (Freeman et al. (2000) J Exp Med 192:1027-34 Carter et al (2002 Eur J Immunol 32:63443). Both PD-L1 and PD-L2 ligands are B7 homologs that bind to PD-1 but not to other CD28 family members. PD-L1 is found in excess in various human malignancies (Dong et al. (2002) Nat. Med. 8:787-9).

The PD-1 protein is an immunoinhibitory protein that negatively regulates TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother 56(5):739–745). The interaction between PD-1 and PD-L1 may act as an immune checkpoint, and may cause, for example, decreased tumor lymphocyte infiltration, decreased T-cell receptor-mediated proliferation, and/or escape of cancer cells from immunosurveillance (Dong et al. (2003) J Mol Med 81:281-7 Blank et al (2005 Cancer Immunol Immunother 54:307-314 Konishi et al (2004 Clin Cancer Res 10:5094-100) ). Reversal of immunosuppression can be achieved by inhibiting the local interaction of PD-1 with PD-L1 or PD

- 1 045940

L2; this effect is additive if the interaction of PD-1 with PD-L2 is also blocked (Iwai et al. (2002) Proc. Natl. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol 170:1257–66).

Given the importance of immune checkpoint signaling pathways in regulating the immune response, there is a need to develop new substances that modulate the activity of immunoinhibitory proteins such as PD-1, thereby causing activation of the immune system. Such substances may have applications, for example, in cancer immunotherapy and the treatment of other diseases such as chronic infections.

The essence of the invention

The present invention relates to antibody molecules (eg, humanized antibody molecules) that bind to programmed death-1 (PD-1) proteins with a high degree of affinity and specificity. In one embodiment, anti-PD-1 antibody molecules comprise a novel combination of framework regions (eg, FW1, FW2, FW3 and/or FW4), for example, novel combinations of heavy chain framework regions and/or light chain framework regions. The invention also relates to nucleic acid molecules encoding said antibody molecules, expression vectors, host cells and methods for producing antibody molecules. The invention also relates to immunoconjugates, multispecific or bispecific antibody molecules and pharmaceutical compositions containing antibody molecules. The anti-PD-1 antibody molecules described herein can be used (as a single agent or in combination with other substances or therapeutic agents) for the treatment, prevention and/or diagnosis of diseases such as malignancies (eg, solid and soft tissue tumors ), as well as infectious diseases (for example, chronic infectious diseases or sepsis). Thus, the present invention relates to compositions and methods for detecting PD-1, as well as methods for treating various diseases, including cancer and/or infectious diseases, using anti-PD-T antibody molecules.

Accordingly, in one aspect, the present invention provides an antibody molecule (e.g., an isolated or recombinant antibody molecule) that has one or more of the following properties:

(I) binds to PD-1, e.g., human PD-1, with high affinity, e.g., with an affinity constant of at least about 10 ⁷ M ^-1 , typically about 10 ⁸ M ^-1 , and more typically, from about 10 ⁹ M ^-1 to 10 ¹⁰ M ^-1 , or higher affinity;

(ii) does not substantially bind to CD28, CTLA-4, ICOS or BTLA;

(III) inhibits or reduces the binding of PD-1 to a PD-1 ligand, for example, PD-L1 or PD-L2, or two of these ligands;

(IV) specifically binds to an epitope on PD-1, for example, the same or a similar epitope that is recognized by the mouse monoclonal antibody BAP049 or a chimeric BAP049 antibody, for example, BAP049-chi or BAP049-chi-Y;

(V) exhibits the same or similar binding affinity or specificity, or both, as any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07 , BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP0 49 -iltoh-G. BAP049-iltoh-D or BAP049-clone-E;

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

(VII) exhibits the same or similar binding affinity or specificity, or both, as antibody molecules (eg, heavy chain variable region and light chain variable region) having the amino acid sequence that is shown in table. 1;

(VIII) exhibits 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 that is shown in table. 1;

(IX) inhibits, for example competitively inhibits, the binding of a second antibody molecule to PD-1, wherein the second antibody molecule is an antibody molecule described in the present invention, for example, an antibody molecule selected, for example, from any of the antibodies BAP049hum01, BAP049- hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049hum13, B AP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP049-cloneG, BAP049-clone-O, or BAP049-clone-E;

(X) binds to a second anti-PD-1 antibody molecule via the same epitope or an overlapping epitope, wherein the second antibody molecule is an antibody molecule described in the present invention, for example, an antibody molecule selected, for example, from any of the antibodies BAP049- hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049

- 2 045940 hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-cloneB, BAP049-clone-C, BAP049-KaOH-D or BAP049-clone-E;

(XI) competes for binding and/or binds to a second anti-PD-1 antibody molecule via the same epitope, wherein the second antibody molecule is an antibody molecule described in the invention, for example an antibody molecule selected from, for example, any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,

BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,

BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP04 9-clone-A, BAP049-clone-B, BAP049-clone-C, BAP049-clone-E, or BAP049-clone-E;

(XII) has one or more biological properties of an antibody molecule described in the invention, for example, an antibody molecule selected, for example, from any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049 -hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone- A, VAR049 -clone-B, VAR049-clone-O, VAR049-clone-O or VAR049-clone-E;

(XIII) has one or more pharmacokinetic properties of an antibody molecule described in the invention, for example, an antibody molecule selected, for example, from any of the antibodies BAP049hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06 , BAP049hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP04 9-clone-B, VAR049 -cloneG, BAP049-clone-O or BAP049-clone-E;

(XIV) inhibits one or more actions of PD-1, resulting in, for example, one or more of the following: increased tumor infiltration by lymphocytes, increased T-cell receptor-mediated proliferation, or decreased evasion of cancer cells from immunosurveillance;

(XV) binds to human PD-1 and cross-reacts with cynomolgus monkey PD-1;

(XVI) binds to one or more residues within the C chain, CC' loop, C' chain, or FG loop of PD-1, or a combination of two, three, or all of these from the C- chain, CC' loop, C' chains or FG loops of PD-1, for example, wherein binding is analyzed by ELISA or Biacore assay; or (XVII) has a VL region that is more significant for binding to PD-1 than a VH region.

In some embodiments of the present invention, the antibody molecule binds to PD-1 with high affinity, for example, with a dissociation constant K _D that is approximately the same as, or higher or lower by at least about 10, 20, 30, 40, 50, 60 , 70, 80 or 90% than the KD of a mouse or chimeric anti-PD-1 antibody molecule, for example, a mouse or chimeric anti-PD-1 antibody molecule described in the present invention. In some embodiments, the KD of the murine or chimeric anti-PD-1 antibody molecule is less than about 0.4, 0.3, 0.2, 0.1, or 0.05 nmol, as measured, for example, by the Biacore method. In some embodiments, the KD of the murine or chimeric anti-PD-1 antibody molecule is less than about 0.2 nmol, such as about 0.135 nmol. In other embodiments, the KD of a murine or chimeric anti-PD-1 antibody molecule is less than about 10, 5, 3, 2, or 1 nmol, as measured, for example, by binding to cells expressing PD-1 (e.g., 300.19 cells ). In some embodiments, the KD of the murine or chimeric anti-PD-1 antibody molecule is less than about 5 nmol, such as about 4.60 nmol (or about 0.69 μg/ml).

In some embodiments, the anti-PD-1 antibody molecule binds to PD-1 with a dissociation constant _Koff that is lower than 1x10 ^-4 , 5x10 ^-5 or 1x10 ^-5 s ^-1 , such as approximately 1.65x10 ^-5 s ^-1 . In some embodiments, the anti-PD-1 antibody molecule binds to PD-1 with an association rate constant K _on that is greater than 1 x 10 ⁴ , 5 x 10 ⁴ , 1 x 10 ⁵ or 5 x 105 M ^-1 s ^-1 , for example, approximately 1.23x105 M ^-1 s ^-1 .

In some embodiments, the expression level of the antibody molecule is, for example, at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the expression level of the murine or chimeric antibody molecule , for example, a mouse or chimeric anti-PD-1 antibody molecule described in the invention. In some embodiments, the antibody molecule is expressed in CHO cells.

In some embodiments, the anti-PD-1 antibody molecule reduces one or more PD-1-associated activities with an IC ₅₀ value (concentration at 50% inhibition) that is approximately equal to or lower, for example, by at least about 10, 20, 30, 40, 50, 60, 70, 80 or 90% than the IC ₅₀ value of a mouse or chimeric anti-PD-1 antibody molecule, for example, a mouse or chimeric anti-PD-1 antibody molecule described in the invention. In some embodiments, the IC50 value of a mouse or chimeric anti-PD-1 antibody molecule

- 3045940 is less than about 6, 5, 4, 3, 2 or 1 nmol, as measured, for example, by binding to cells expressing PD-1 (eg, 300.19 cells). In some embodiments, the IC ₅₀ value of a mouse or chimeric anti-PD-1 antibody molecule is less than about 4 nmol, such as about 3.40 nmol (or about 0.51 μg/ml). In some embodiments, the reduction in PD-1-associated activity is the binding of PD-L1 and/or PD-L2 to PD-1. In some embodiments, the anti-PD-1 antibody molecule binds to peripheral blood mononuclear cells (PBMCs) activated by staphylococcal enterotoxin B (SEB). In other embodiments, the anti-PD-1 antibody molecule increases interleukin IL-2 expression in SEB-activated whole blood. For example, an anti-PD-1 antibody increases IL-2 expression by at least about 2-, 3-, 4-, or 5-fold compared to IL-2 expression using an isotype control (eg, IgG4).

In some embodiments, the anti-PD-1 antibody molecule has improved stability, such as being at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times more stable. conditions in vivo or in vitro than a mouse or chimeric anti-PD-1 antibody molecule, for example, a mouse or chimeric anti-PD-1 antibody molecule described in the invention.

In one embodiment, the anti-PD-1 antibody molecule is a humanized antibody molecule and has a T cell epitope assay-based risk score of 300 to 700, 400 to 650, 450 to 600, or a risk score of the invention.

In another embodiment, the anti-PD-1 antibody molecule comprises at least one antigen binding region, e.g., a variable region, or an antigen binding fragment thereof, from an antibody of the invention, e.g., an antibody selected from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP0 49-hum14, BAP049- hum15, BAP049-hum16, BAP04 9-clone-A, BAP049-clone-B, BAP049-ikioh-G, BAP049-kioh-D or BAP049-clone-E; or according to the description from table. 1; or the sequence encoded by the nucleotide sequence from the table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences.

In yet another embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three, or four variable regions from an antibody of the invention, for example, an antibody selected from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP0 49-hum15, BAP049- hum16, BAP049-clone-A, BAP049-clone-B, BAP049-clone^, BAP049-clone-O, or BAP049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences.

In yet another embodiment, the anti-PD-1 antibody molecule comprises at least one or two heavy chain variable regions from an antibody of the invention, for example, an antibody selected from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049- hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10,

BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16,

VAR049-clone-A, VAR049-clone-B, VAR049-clone^, VAR049-clone-O, or VAR049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences.

In yet another embodiment, the anti-PD-1 antibody molecule comprises at least one or two light chain variable regions from an antibody of the invention, for example, an antibody selected from any of BAP049-hum01, BAP049-1m02. BAP049-hum03, BAP049-hum04, BAP049hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049hum11, BAP049-hum12, BAP049-hum13, BAP049 -hum14, BAP049-hum15, BAP049- hum16, BAP049-cloneA, BAP049-clone-B, BAP049-clone^, BAP049-clone-O, or BAP049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences.

In yet another embodiment, the anti-PD-1 antibody molecule includes a heavy chain constant region for IgG4, such as human IgG4. In one embodiment, human IgG4 includes a substitution at position 228, in accordance with the EU numbering system (eg, replacing Ser with Pro). In yet another embodiment, the anti-PD-1 antibody molecule includes con

- 4 045940 heavy chain constant region for IgG1, for example human IgG1. In one embodiment, human IgG1 includes a substitution at position 297 in accordance with EU numbering (eg, replacing Asn with Ala). In one embodiment, human IgG1 includes a substitution at position 265 according to the EU numbering, a substitution at position 329 according to the EU numbering, or both substitutions (e.g., replacing Asp with Ala at position 265 and/or replacing Pro with Ala at position 329 ). In one embodiment, human IgG1 includes a substitution at position 234, consistent with the EU numbering, a substitution at position 235, consistent with the EU numbering, or both substitutions (e.g., substituting Leu for Ala at position 234 and/or substituting Leu for Ala at position 235). In one embodiment, the heavy chain constant region contains the amino acid sequence presented in table. 3, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% identical or greater) to said sequence.

In yet another embodiment, the anti-PD-1 antibody molecule comprises a kappa light chain constant region, for example, a human kappa light chain constant region. In one embodiment, the light chain constant region comprises the amino acid sequence presented in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% identical or greater) in relation to the specified sequence.

In another embodiment, the anti-PD-1 antibody molecule includes a heavy chain constant region for IgG4, e.g., human IgG4, and a kappa light chain constant region, e.g., a human kappa light chain constant region, e.g., a heavy and light chain constant region, containing the amino acid sequence presented in table. 3, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% identical or greater) to said sequence. In one embodiment, human IgG4 includes a substitution at position 228, in accordance with the EU numbering (eg, replacing Ser with Pro). In yet another embodiment, the anti-PD-1 antibody molecule includes a heavy chain constant region for IgG1, e.g., human IgG1, and a kappa light chain constant region, e.g., a human kappa light chain constant region, e.g., a heavy and light chain constant region comprising an amino acid the sequence presented in table. 3, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% identical or greater) to said sequence. In one embodiment, human IgG1 includes a substitution at position 297 in accordance with EU numbering (eg, replacing Asn with Ala). In one embodiment, human IgG1 includes a substitution at position 265 according to the EU numbering, a substitution at position 329 according to the EU numbering, or both substitutions (e.g., replacing Asp with Ala at position 265 and/or replacing Pro with Ala at position 329 ). In one embodiment, human IgG1 includes a substitution at position 234, consistent with EU numbering, a substitution at position 235, consistent with EU numbering, or both substitutions (e.g., replacing Leu with Ala at position 234 and/or replacing Leu with Ala at position 235).

In another embodiment, the anti-PD-1 antibody molecule comprises a heavy chain variable domain and constant region, a light chain variable domain and constant region, or both, which comprises the amino acid sequence of BAP049-clone-A, BAP049-clone-B, BAP049-clone -C, VAR049-clone-E or VAR049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% identical or greater) to any of the above sequences. Optionally, the anti-PD-1 antibody molecule contains a leader sequence from a heavy chain, a light chain, or both, as shown in Table 1. 4, or a substantially identical sequence.

In yet another embodiment, the anti-PD-1 antibody molecule includes at least one, two or three hypervariable regions (CDRs, complementarity determining regions) from the heavy chain variable region of an antibody of the invention, for example, an antibody selected from any of the antibodies BAP049- hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12 , BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP049-ktoh-G. VAR049-clone-E or VAR049-clone-E; or according to the description from the table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences.

In yet another embodiment, the anti-PD-1 antibody molecule includes at least one, two or three CDR regions (or collectively all CDR regions) from the heavy chain variable region that contain the amino acid sequence presented in table. 1, or encoded by the nucleotide sequence presented in table. 1. In one embodiment, one or more CDR regions (or collectively all CDR regions) carry one, two, three, four, five, six, or more than six changes, such as amino acid substitutions or deletions, compared

- 5 045940 with the amino acid sequence presented in table. 1, or the encoded nucleotide sequence presented in table. 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes at least one, two or three CDRs from the light chain variable region of an antibody of the invention, for example, an antibody selected from any of BAP049-hum01, BAP049-hum02, BAP049-hum03 , BAP049hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP0 49-hum15, BAP049hum16, VAR049-clone -A, BAP049-clone-B, BAP049-k.toh-G. VAR049-clone-O or VAR049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences.

In yet another embodiment, the anti-PD-1 antibody molecule includes at least one, two or three CDRs (or collectively all CDR regions) from the light chain variable region that contain the amino acid sequence presented in table. 1, or encoded by the nucleotide sequence presented in table. 1. In one embodiment, one or more CDRs (or collectively all CDR regions) carry one, two, three, four, five, six, or more than six changes, such as amino acid substitutions or deletions, compared to the amino acid sequence presented in table 1, or the encoded nucleotide sequence presented in table. 1. In some embodiments, the anti-PD-1 antibody molecule includes a substitution in the light chain of a CDR, such as one or more substitutions in the light chain CDR1, CDR2, and/or CDR3. In one embodiment, the anti-PD-1 antibody molecule includes a light chain substitution of CDR3 at position 102 of the light chain variable region, for example, a substitution of cysteine residues with tyrosine or cysteine residues with serine residues, at position 102 of the light chain variable region, as shown in Table. 1 (e.g., SEQ ID NO: 16 or 24 for a murine or chimeric, unmodified sequence, or any of SEQ ID NO: 34, 42, 46, 54, 58, 62, 66, 70, 74, or 78 for a modified sequence).

In another embodiment, an anti-PD-1 antibody molecule includes at least one, two, three, four, five, or six CDR regions (or collectively all CDR regions) from a heavy chain variable region and a light chain variable region that comprise the amino acid sequence set forth in table 1, or encoded by the nucleotide sequence presented in table. 1. In one embodiment, one or more CDRs (or collectively all CDR regions) carry one, two, three, four, five, six, or more than six changes, such as amino acid substitutions or deletions, compared to the amino acid sequence presented in table 1, or encoded by the nucleotide sequence presented in table. 1.

In one embodiment, the anti-PD-1 antibody molecule includes all six CDRs from an antibody of the invention, for example, from an antibody selected from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049 -hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone- A, VAR049 -clone-B, VAR049-clone-O, VAR049-clone-E or VAR049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1, or closely related CDR regions, eg, CDRs that are identical or have at least one amino acid alteration, but no more than two, three or four alterations (eg, substitutions, deletions or insertions, eg, conservative substitutions). In one embodiment, the anti-PD-1 antibody molecule may include any CDR described in the invention. In some embodiments, the anti-PD-1 antibody molecule includes a substitution in the light chain of a CDR, such as one or more substitutions in CDR1, CDR2, and/or CDR3 of the light chain. In one embodiment, the anti-PD-1 antibody molecule includes a light chain substitution of CDR3 at position 102 of the light chain variable region, such as a substitution of cysteine to tyrosine or cysteine to serine residues at position 102 of the light chain variable region according to Table 1 (e.g. , SEQ ID NO: 16 or 2 4 for a mouse or chimeric unmodified sequence, or any of SEQ ID NO: 34, 42, 46, 54, 58, 62, 66, 70, 74 or 78 for a modified sequence). In another embodiment, the anti-PD-1 antibody molecule includes at least one, two or three CDR regions, in accordance with the numbering system of Kabat et al. (e.g., at least one, two or three CDRs, as defined by Kabat as set forth in Table 1), from the heavy chain variable region of an antibody of the invention, e.g., an antibody selected from any of BAP049- 1шш01. BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049humll, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049- hum15, BAP049-hum16, VAR049-cloneA, VAR049-clone-B, VAR049-cloneYu. VAR049-cloneY or VAR049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (e.g., at least 80, 85, 90, 92, 95, 97, 98, 99%

- 6 045940 or higher identity) to any of the above sequences; or a sequence that carries at least one amino acid alteration, but no more than two, three, or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) compared to one, two, or three CDR regions according to Kabat et al., as indicated in table. 1.

In another embodiment, the anti-PD-1 antibody molecule includes at least one, two or three CDRs according to the numbering of Kabat et al. (e.g., at least one, two or three CDRs as defined by Kabat as set forth in Table 1) from the light chain variable region of an antibody of the invention, e.g., an antibody selected from any one of antibodies BAP049hum01, BAP049-hum02 , BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049hum13, BAP0 49-hum14, BAP049-hum15, BAP049 -hum16, BAP049-clone-A, BAP049-clone-B, BAP049-cloneG, BAP049-kioh-D, or BAP049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences; or a sequence that carries at least one amino acid alteration, but no more than two, three, or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) compared to one, two, or three CDR regions according to Kabat et al., as indicated in table. 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes at least one, two, three, four, five, or six CDR regions as numbered by Kabat et al. (e.g., at least one, two, three, four, five or six CDRs, as defined by Kabat as set forth in Table 1) from the heavy and light chain variable regions of an antibody of the invention, e.g., an antibody selected from any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-Sht03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12 , BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, BAP049-clone-B, or BAP049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences; or a sequence that carries at least one amino acid alteration, but no more than two, three, or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) compared to one, two, three, four, five, or six CDR regions in accordance with Kabat et al., as indicated in table. 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes all six CDRs as numbered by Kabat et al. (e.g., all six CDRs as defined by Kabat as set forth in Table 1) from the heavy and light chain variable regions of an antibody of the invention, e.g., an antibody selected from any one of BAP049-hum01, BAP049-hum02, BAP049hum03 , VAR049-Iit04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP 049hum15, BAP049-hum16, VAR049 -clone-A, BAP049-clone-B, BAP049-ikioh-G, BAP049-k.yun-1) or BAP049clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences; or a sequence that carries at least one amino acid alteration, but no more than two, three or four alterations (eg, substitutions, deletions or insertions, eg, conservative substitutions) compared to all six CDRs, according to Kabat et al. , as indicated in table. 1. In one embodiment, the anti-PD-1 antibody molecule may include any CDR region described in the present invention.

In another embodiment, the anti-PD-1 antibody molecule includes at least one, two, or three hypervariable loops as defined by Chothia (e.g., at least one, two, or three hypervariable loops as defined by Chothia as defined in table 1), from the variable region of the heavy chain of an antibody of the invention, for example, an antibody selected from any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07 , BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, VAR049-clone-A, VAR049-clone-B, VAR0 49 -clone-S. VAR049-clone-E or VAR049-clone-E; or according to the description from table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or at least amino acids from these hypervariable loops that contact PD1; or loops carrying at least one amino acid alteration, but no more than two, three or four alterations (eg, substitutions, deletions and insertions, such as conservative substitutions), compared to one, two or three hypervariable loops, in accordance with Cho definition

- 7 045940 thia et al., as indicated in table. 1.

In another embodiment, the anti-PD-1 antibody molecule includes at least one, two, or three Chothia hypervariable loops (e.g., at least one, two, or three Chothia hypervariable loops as defined in Table 1) from the light chain variable region of an antibody of the invention, for example, an antibody selected from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049 -hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, VAR049-clone-A, VAR049-clone-B, VAR049-clone-C VAR049- clone-E or VAR049-clone-E; or according to the description from table. 1, or encoded by the nucleotide sequence from table. 1 or at least amino acids from these hypervariable loops that contact PD-1; or loops carrying at least one amino acid alteration, but no more than two, three or four alterations (eg, substitutions, deletions and insertions, such as conservative substitutions), compared to one, two or three hypervariable loops, in accordance with definition by Chothia et al., as indicated in table. 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes 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 by detecting Chothia as set forth in Table 1) from the heavy and light chain variable regions of an antibody of the invention, for example, an antibody selected from any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05 V AR049-clone-A , BAP049-clone-B, BAP049-clone-6, BAP049-ikioh-D or BAP049-clone-E; or according to the description from the table. 1, or encoded by the nucleotide sequence from table. 1 or at least amino acids from these hypervariable loops that contact PD-1; or loops carrying at least one amino acid alteration, but no more than two, three, or four alterations (e.g., substitutions, deletions, and insertions, e.g., conservative substitutions), compared with one, two, three, four, five, or six hypervariable loops, as defined by Chothia et al., as indicated in table. 1.

In one embodiment, the anti-PD-1 antibody molecule comprises all six hypervariable loops (e.g., all six hypervariable loops as defined by Chothia as defined in Table 1) from an antibody of the invention, e.g., an antibody selected from any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP04 9hum12, BAP049-hum13, BAP049- hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-cloneB, BAP049-clone^, BAP049-clone-E or BAP049-clone-E, or closely related hypervariable loops, e.g. identical hypervariable loops, or having at least one amino acid alteration, but not more than two, three or four alterations (eg, substitutions, deletions or insertions, eg, conservative substitutions); or loops carrying at least one amino acid alteration, but no more than two, three or four alterations (eg, substitutions, deletions or insertions, eg, conservative substitutions) compared to all six hypervariable loops as defined by Chothia et al. , as indicated in table. 1. In one embodiment, the anti-PD-1 antibody molecule may include any hypervariable loop described in the invention.

In yet another embodiment, the anti-PD-1 antibody molecule includes at least one, two or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody of the invention, for example, an antibody selected from any of the BAP049- hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12 , BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP049-clone^, BAP049-clone-E or BAP049-clone-E, 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 of the invention. For a description of canonical hypervariable loop structures, see, for example, Chothia et al., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798. These structures can be determined by analyzing the tables provided in these references.

In some embodiments, the anti-PD-1 antibody molecule includes a combination of CDR regions or hypervariable loops as defined by the systems of Kabat et al. and Chothia et al.

In one embodiment, the anti-PD-1 antibody molecule includes at least one, two or three CDR regions or hypervariable loops from the heavy chain variable region of an antibody of the invention, for example, an antibody selected from any of BAP049-hum01, BAP049hum02, BAP049- hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049hum14, B AP049-hum15, BAP049-hum16, BAP049-kioh-A, BAP049-clone-B, BAP049-clone-O, BAP049-clone-D, or BAP049-kioh-E, as defined by Kabat and Chothia (e.g., at least

- 8 045940 at least one, two or three CDR regions or hypervariable loops in accordance with the definitions of Kabat and Chothia, as indicated in table. 1); or the sequence encoded by the nucleotide sequence from table. 1; or a sequence substantially identical (eg, at least 80, 85, 90, 92, 95, 97, 98, 99% or greater identity) to any of the above sequences; or having at least one amino acid alteration, but no more than two, three or four alterations (e.g., substitutions, deletions and insertions, e.g., conservative substitutions) compared to one, two or three CDR regions or hypervariable loops, in accordance with definitions according to Kabat and Chothia, as indicated in table. 1).

For example, an anti-PD-1 antibody molecule may include VH CDR1 according to the system of Kabat et al., or hypervariable loop 1 of VH according to the system of Chothia et al., or combinations thereof, for example, as shown in table. 1. In one embodiment, the combination of CDRs from Kabat and Chothia's VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 224), or an amino acid sequence substantially identical thereto (e.g., bearing at least one amino acid alteration, but not more than two , three or four alterations (eg substitutions, deletions or insertions, eg conservative substitutions)). The anti-PD-1 antibody molecule may further include, for example, VH CDR 2-3 regions according to Kabat et al., and VL CDR 1-3 regions according to Kabat et al., for example, as shown in table. 1. Thus, in some embodiments, framework regions are defined based on a combination of CDRs defined by the system of Kabat et al., and hypervariable loops are defined by the system of Chothia et al. For example, an anti-PD1 antibody molecule may include a VH FR1 region defined based on hypervariable loop 1 from VH according to the system of Chothia et al., and the VH FR2 region determined on the basis of VH CDR 1-2 according to the system of Rabat et al., for example, as shown in table. 1. The anti-PD-1 antibody molecule may further include, for example, VH FR 3-4 regions defined on the basis of VH CDR 2-3 regions according to the system of Kabat et al., and VL FR 1-4 regions defined on the basis of VL CDR 1-3 according to the Kabat et al. system.

An anti-PD-1 antibody molecule may contain any combination of CDR regions or hypervariable loops as defined by Kabat and Chothia. In one embodiment, the anti-PD-1 antibody molecule includes at least one, two or three CDR regions from the light chain variable region of an antibody of the invention, for example, an antibody selected from any of BAP049-hum01, BAP049-hum02, BAP049-hum03 , BAP049-hum04, BAP049-hum05, BAP049hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049hum12, BAP049-hum13, BAP049-hum14, BAP0 49-hum15, BAP049-hum16, VAR049 -clone-A, BAP049-cloneB, BAP049-ictoh-G. BAP049-clone-O or BAP049-clone-E, as defined by Kabat and Chothia (eg, at least one, two or three CDR regions as defined by Kabat and Chothia, as set forth in Table 1).

In one embodiment, for example, an embodiment comprising a variable region, a CDR region (eg, Chothia CDR or Kabat CDR), or other sequence mentioned in the invention, for example, in table. 1, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, or an antibody molecule that contains an antigen binding fragment of an antibody, such as a half-antibody or an antigen binding fragment of a semi-antibody. In some embodiments, the antibody molecule is a bispecific antibody molecule having a first binding specificity for PD-1 and a second binding specificity for TIM-3, LAG-3, SEACAM (e.g., SEACAM-1 and/or SEACAM-5), PD- L1 or PD-L2.

In one embodiment, the anti-PD-1 antibody molecule includes:

(a) a heavy chain variable region (VH) which comprises VHCDR1 having the amino acid sequence SEQ ID NO: 4, VHCDR2 having the amino acid sequence SEQ ID NO: 5 and VHCDR3 having the amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) which comprises VLCDR1 having the amino acid sequence SEQ ID NO: 13, VLCDR2 having the amino acid sequence SEQ ID NO: 14, and VLCDR3 having the amino acid sequence SEQ ID NO: 33;

(b) VH, which contains VHCDR1 with the amino acid sequence of SEQ ID NO: 1; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and VL, which contains VLCDR1 having the amino acid sequence SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 11 and VLCDR3 having the amino acid sequence SEQ ID NO: 32;

(c) VH, which contains VHCDR1 with the amino acid sequence SEQ ID NO: 224, VHCDR2 with the amino acid sequence SEQ ID NO: 5, and VHCDR3 with the amino acid sequence SEQ ID NO: 3; and VL, which contains VLCDR1 having the amino acid sequence SEQ ID NO: 13, VLCDR2 having the amino acid sequence SEQ ID NO: 14, and VLCDR3 having the amino acid sequence SEQ ID NO: 33; or (d) VH, which contains VHCDR1 with the amino acid sequence of SEQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and VL, which contains VLCDR1 with the amino acid sequence

- 9 045940

SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 11, and VLCDR3 having the amino acid sequence SEQ ID NO: 32.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising VHCDR1 having the amino acid sequence of SEQ ID NO: 4, VHCDR2 having the amino acid sequence of SEQ ID NO: 5, and VHCDR3 having the amino acid sequence of SEQ ID NO: 3; and VL comprising VLCDR1 having the amino acid sequence SEQ ID NO: 13, VLCDR2 having the amino acid sequence SEQ ID NO: 14 and VLCDR3 having the amino acid sequence SEQ ID NO: 33.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising VHCDR1 with the amino acid sequence of SEQ ID NO: 1; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and VL comprising VLCDR1 having the amino acid sequence SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 11 and VLCDR3 having the amino acid sequence SEQ ID NO: 32.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising VHCDR1 having the amino acid sequence of SEQ ID NO: 224, VHCDR2 having the amino acid sequence of SEQ ID NO: 5, and VHCDR3 having the amino acid sequence of SEQ ID NO: 3; and VL comprising VLCDR1 having the amino acid sequence SEQ ID NO: 13, VLCDR2 having the amino acid sequence SEQ ID NO: 14 and VLCDR3 having the amino acid sequence SEQ ID NO: 33.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH comprising VHCDR1 with the amino acid sequence of SEQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and VL comprising VLCDR1 having the amino acid sequence SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 1 and VLCDR3 having the amino acid sequence SEQ ID NO: 32.

In one embodiment, the antibody molecule is a humanized antibody molecule. In another embodiment, the antibody molecule is a monospecific antibody molecule. In yet another embodiment, the antibody molecule is a bispecific antibody molecule.

In one embodiment, the anti-PD-1 antibody molecule includes:

(I) a heavy chain variable region (VH) which includes the amino acid sequence of VHCDR1 selected from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and (II) a light chain variable region (VL), which includes VLCDR1 having the amino acid sequence of SEQ ID NO: 10, VLCDR2 having the amino acid sequence of SEQ ID NO: 11, and VLCDR3 having the amino acid sequence of SEQ ID NO: 32.

In another embodiment, the anti-PD-1 antibody molecule comprises:

(I) a heavy chain variable region (VH) which includes the amino acid sequence of VHCDR1 selected from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 5 and VHCDR3 with amino acid sequence SEQ ID NO: 3; and (II) a light chain variable region (VL), which includes VLCDR1 having the amino acid sequence of SEQ ID NO: 13, VLCDR2 having the amino acid sequence of SEQ ID NO: 14, and VLCDR3 having the amino acid sequence of SEQ ID NO: 33.

In one embodiment, the anti-PD-1 antibody molecule contains VHCDR1 with the amino acid sequence SEQ ID NO: 1. In another embodiment, the anti-PD-1 antibody molecule contains VHCDR1 with the amino acid sequence SEQ ID NO: 4. In yet another embodiment, the anti-PD-1 antibody molecule contains VHCDR1 with the amino acid sequence SEQ ID NO: 4. In yet another embodiment, the anti-PD-1 antibody molecule contains VHCDR1 with the amino acid sequence SEQ ID NO: 4. PD-1 contains VHCDR1 with the amino acid sequence SEQ ID NO: 224.

In one embodiment, the light or heavy chain variable framework (e.g., the region spanning at least FR1, FR2, FR3, and optionally FR4) in the anti-PD-1 antibody molecule may be selected from: (a) a light or heavy variable framework a chain containing at least 80, 85, 87, 90, 92, 93, 95, 97, 98% or preferably 100% of the amino acid residues from the human variable framework light or heavy chain, for example, a residue from the variable framework light or a heavy chain from a human mature antibody, a human germline sequence or a human consensus sequence; (b) a light or heavy chain variable framework comprising from 20 to 80%, from 40 to 60%, from 60 to 90%, or from 70 to 95% amino acid residues from the human light or heavy chain variable framework, e.g. from a light or heavy variable framework region from a human mature antibody, human germline sequence or human con

- 10 045940 sensus sequence; (c) a non-human framework region (eg, a rodent framework region); or (d) a non-human framework region that has been modified, for example, to remove antigenic or cytotoxic determinants, for example, deimmunized or partially humanized. In one embodiment, the light or heavy chain variable framework (specifically, FR1, FR2, and/or FR3) comprises a light or heavy chain variable framework sequence that is at least 70, 75, 80, 85, 87, 88 identical , 90, 92, 94, 95, 96, 97, 98, 99% or identical to the frame regions of the human germline VL or VH gene regions.

In some embodiments, the anti-PD-1 antibody molecule comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, such as amino acid substitutions or deletions, from the chimeric amino acid sequence BAP049-chi-HC, for example, the FR amino acid sequence throughout the variable region, for example, as shown in FIG. 9A-9B, or SEQ ID NO: 18, 20, 22 or 30. In one embodiment, the anti-PD-1 antibody molecule contains a heavy chain variable domain having one or more of the following: E at position 1, V at position 5, A in position 9, V in position 11, K in position 12, K in position 13, E in position 16, L in position 18, R in position 19, I or V in position 20, G in position 24, I in positions 37, A or S in position 40, T in position 41, S in position 42, R in position 43, M or L in position 48, V or F in position 68, T in position 69, I in position 70, S in position 71, A or R in position 72, K or N in position 74, T or K in position 76, S or N in position 77, L in position 7 9, L in position 81, E or Q in position 82, M at position 83, S or N at position 84, R at position 87, A at position 88, or T at position 91 in the amino acid sequence of BAP049-chi-HC, for example, the FR amino acid sequence throughout the variable region, for example, shown in FIG. 9A-9B, or SEQ ID NO: 18, 20, 22 or 30.

Alternatively, or in combination with the BAP049chi-HC heavy chain substitutions described herein, the anti-PD-1 antibody molecule comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen , twenty or more amino acid changes, such as amino acid substitutions or deletions, from the BAP049-chi-LC amino acid sequence, such as the amino acid sequence shown in FIG. 10A-10B, or SEQ ID NO: 24 or 26. In one embodiment, the anti-PD-1 antibody molecule contains a heavy chain variable domain having one or more of the following: E at position 1, V at position 2, Q at position 3 , L in position 4, T in position 7, D or L or A in position 9, F or T in position 10, Q in position 11, S or P in position 12, L or A in position 13, S in position 14 , P or L or V in position 15, K in position 16, Q or D in position 17, R in position 18, A in position 19, S in position 20, I or L in position 21, T in position 22, L in position 43, K in position 48, A or S in position 49, R or Q in position 51, Y in position 55, I in position 64, S or P in position 66, S in position 69, Y in position 73, G in position 74, E in position 7 6, F in position 79, N in position 82, N in position 83, L or I in position 84, E in position 85, S or P in position 86, D in position 87, A or F or I at position 89, T or Y at position 91, F at position 93, or Y at position 102 in the amino acid sequence of BAP049-chi-LC, for example the amino acid sequence shown in FIG. 10A-10B, or SEQ ID NO: 24 or 26.

In other embodiments, the anti-PD-1 antibody molecule includes 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 essentially identical to it.

In other embodiments, the anti-PD-1 antibody molecule includes 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 the sequence , essentially identical to it.

In other embodiments, the anti-PD-1 antibody molecule includes 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 essentially identical to it; and one, two, three or four light chain framework regions (eg, the amino acid sequence VLFW shown in Table 2, or encoded by the nucleotide sequence shown in Table 2), or a sequence substantially identical thereto.

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework 1 (VHFW1) of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049- hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum15, BAP049-hum16, VAR049-clone-A, VAR049-clone-B, VAR049-clone-C, VAR049- clone-E or BAP049-clone-E (eg, SEQ ID NO: 147). In some embodiments, said antibody molecule comprises heavy chain framework 1 (VHFW1) from BAP049-hum14 or BAP049-hum15 (eg, SEQ ID NO: 151).

- 11 045940

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework 2 (VHFW2) of BAP049-hum01, BAP049-hum02, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum09, BAP049-hum11, BAP049- hum12, BAP049-hum13, BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, or BAP049-clone-E (eg, SEQ ID NO: 153). In some embodiments, the antibody molecule comprises heavy chain framework 2 (VHFW2) of BAP049-hum03, BAP049-hum04, BAP049-hum08, BAP049-hum10, BAP049-hum14, BAP049-hum15, or BAP049-clone-E (e.g., SEQ ID NO: 157). In some embodiments, the antibody molecule comprises heavy chain framework 2 (VHFW2) from BAP049-hum16 (eg, SEQ ID NO: 160).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework 3 (VHFW3) of BAP049-hum01, BAP049-hum02, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum09, BAP049-hum11, BAP049- hum12, BAP049-hum13, BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, or BAP049-clone-E (eg, SEQ ID NO: 162). In some embodiments, the antibody molecule comprises heavy chain framework 3 (VHFW3) of BAP049-hum03, BAP049-hum04, BAP049-hum08, BAP049-hum10, BAP049-hum14, BAP049-hum15, BAP049-hum16, or BAP049-k.toh- D (eg SEQ ID NO: 166).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework 4 (VHFW4) of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049- hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, VAR04 9-clone-A, VAR049-clone-B, VAR049-clone -C, BAP049-clone-B, or BAP049-clone-C (eg, SEQ ID NO: 169).

In some embodiments, the anti-PD-1 antibody molecule comprises light chain framework 1 (VLFW1) from BAP049-hum08, BAP049-hum09, BAP049-hum15, BAP049-hum16, or BAP049-clone-C (e.g., SEQ ID NO: 174) . In some embodiments, the antibody molecule comprises light chain framework region 1 (VLFW1) of BAP049-hum01, BAP049-hum04, BAP049-hum05, BAP049-hum07, BAP049-hum10, BAP049-hum11, BAP049-hum14, BAP049-clone-A, BAP049-clone-B, BAP049-k.toh-D, or BAP049-clone-E (eg, SEQ ID NO: 177). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP049-hum06 (eg, SEQ ID NO: 181). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP049-hum13 (eg, SEQ ID NO: 183). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP049hum02, BAP049-hum03, or BAP049-hum12 (eg, SEQ ID NO: 185).

In some embodiments, the anti-PD-1 antibody molecule comprises light chain framework 2 (VLFW2) of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum06, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049- hum11, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP04 9-clone-A, BAP049-clone-B, BAP049-k.toh-D or BAP049-clone-C (eg, SEQ ID NO: 187). In some embodiments, the antibody molecule comprises light chain framework 2 (VLFW2) regions from BAP049-hum04, BAP049-hum05, BAP049-hum07, BAP049-hum13, or BAP049 clone-C (eg, SEQ ID NO: 191). In some embodiments, the antibody molecule comprises the light chain framework 2 (VLFW2) regions of BAP049-hum12 (eg, SEQ ID NO: 194).

In some embodiments, the anti-PD-1 antibody molecule comprises light chain framework 3 (VLFW3) of BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049- hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-C, BAP049-clone-E, or BAP049-clone-E (eg, SEQ ID NO: 196). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) from BAP049-hum02 or BAP049-hum03 (eg, SEQ ID NO: 200). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) from BAP049hum01 or BAP049-clone-A (eg, SEQ ID NO: 202). In some embodiments, the antibody molecule comprises VLFW3 light chain framework 3 of BAP049-hum04, BAP049-hum05, or BAP049-clone-B (eg, SEQ ID NO: 205).

In some embodiments, the anti-PD-1 antibody molecule comprises light chain framework 4 (VLFW4) of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049- hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, VAR04 9-clone-A, VAR049-clone-B, VAR049-clone -C, BAP049-khoh-D or BAP049-khoh-G (for example, SEQ ID NO: 208).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavy chain framework regions 1-3 of BAP049-hum01, BAP049-hum02, BAP049-hum05, BAP049-hum06, BAP-hum07, BAP049-hum09, BAP049-hum11, BAP049-hum12 , BAP049-hum13, BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, or BAP049-clone-E (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2) and SEQ ID NO: 162 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 of BAP049-hum03, BAP049-hum04, BAP049-hum08, BAP049-hum10, or

- 12 045940

VAR049-clone-E (for example, SEQ ID NO: 147 (VHFW1), SEQ ID NO: 157 (VHFW) and SEQ ID NO: 166 (VHFW3)). In some embodiments, the antibody molecule comprises the 13 heavy chain framework regions of BAP049-hum14 or BAP049-hum15 (e.g., SEQ ID NO: 151 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3) ). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum16 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 160 (VHFW2), and SEQ ID NO: 166 (VHFW3)). In some embodiments, the antibody molecule further comprises heavy chain framework 4 (VHFW4) of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049 -hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, VAR04 9-clone-A, VAR049-clone-B,

BAP049-clone-C, BAP049-k.toh-D, or BAP049-k.toh-G (eg, SEQ ID NO: 169).

In some embodiments, the anti-PD-1 antibody molecule comprises light chain framework regions 1-3 from BAP049-hum01 or BAP049-clone-A (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 202 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP049-hum02 or BAP049-hum03 (e.g., SEQ ID NO: 185 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 200 (VLFW3 )). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP049-hum04, BAP049-hum05, or BAP049-clone-B (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 205 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP049-hum06 (e.g., SEQ ID NO: 181 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP049-hum07 (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP049-hum08, BAP049-hum09, BAP049hum15, BAP049-hum16, or BAP049-clone-C (e.g., SEQ ID NO: 174 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP049-hum10, BAP049-hum11, BAP049-hum14, BAP049clone-D, or BAP049clone-C (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP049-hum12 (e.g., SEQ ID NO: 185 (VLFW1), SEQ ID NO: 194 (VLFW2), and SEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP049-hum13 (e.g., SEQ ID NO: 183 (VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody molecule further comprises light chain framework 4 (VLFW4) of BAP049-hum01, BAP049hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049hum08, BAP049-hum09, BAP 049 -hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049hum14, BAP049-hum15, BAP049-hum16, VAR04 9-clone-A, VAR049-clone-B, VAR049-clone-C, VAR049clone-D or VAR049- clone-E (eg, SEQ ID NO: 208).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum01 or BAP049-clone-A (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)), and light chain framework regions 1-3 of BAP049hum01 or BAP049-clone-A (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO: 202 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum02 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum02 (eg, SEQ ID NO: 185 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 200 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum03 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum03 (eg, SEQ ID NO: 185 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 200 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum04 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum04 (eg, SEQ ID NO: 177 (VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 205 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum05 or BAP049-clone-B (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)), and light chain framework regions 1-3 of BAP049-hum05 or BAP049-clone-B (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 191 (VLFW2) and SEQ ID NO : 205 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum06 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2)

- 13 045940 and SEQ ID NO: 162 (VHFW3)), and light chain framework regions 1-3 of BAP049-hum06 (for example, SEQ ID NO: 181 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO : 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum07 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum07 (eg, SEQ ID NO: 177 (VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum08 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum08 (eg, SEQ ID NO: 174 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum09 or BAP049-clone-C (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)), and light chain framework regions 1-3 from BAP049hum09 or BAP049-clone-C (e.g., SEQ ID NO: 174 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum10 or BAP049-clone-E (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)), and light chain framework regions 1-3 from BAP049hum10 or BAP049-clone-E (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum11 or BAP049-clone-E (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)), and light chain framework regions 1-3 from BAP049hum11 or BAP049-clone-E (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum12 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum12 (eg, SEQ ID NO: 185 (VLFW1), SEQ ID NO: 194 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavy chain framework regions 1-3 of BAP049-hum13 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum13 (eg, SEQ ID NO: 183 (VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum14 (e.g., SEQ ID NO: 151 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum14 (eg, SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2) and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum15 (e.g., SEQ ID NO: 151 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum15 (eg, SEQ ID NO: 174 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises heavy chain framework regions 1-3 from BAP049-hum16 (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 160 (VHFW2), and SEQ ID NO: 166 (VHFW3 )), and light chain framework regions 1-3 of BAP049-hum16 (eg, SEQ ID NO: 174 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule further comprises heavy chain framework 4 (VHFW4) of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049 -hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP049-clone -C, BAP049-clone-E or BAP049-i<.toh-G (e.g., SEQ ID NO: 169), and light chain framework 4 (VLFW4) of BAP049-hum01, BAP049hum02, BAP049-hum03, BAP049-hum04 , BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049hum14, BAP049-hum15, BAP0 49-hum16, VAR049-clone-A , BAP049-clone-B, BAP049-icioh-G. BAP049clone-D or BAP049-clone-C (eg, SEQ ID NO: 208).

In some embodiments, the anti-PD-1 antibody molecule comprises a heavy chain framework region bearing a combination of the FW1, FW2 and FW3 framework regions, as shown in FIG. 5 or 7. In another embodiment, the antibody molecule comprises a light chain framework region bearing a combination of framework regions FW1, FW2 and FW3, as shown in FIG. 5 or 7. In other embodiments, the antibody molecule comprises a heavy chain framework region bearing a combination of framework regions FW1, FW2 and FW3, as shown in FIG. 5 or 7, and a light chain framework region carrying a combination of framework regions FW1, FW2 and FW3, as shown in FIG. 5 or 7.

- 14 045940

In one embodiment, the heavy or light chain variable domain, or both, of an anti-PD-1 antibody molecule comprises an amino acid sequence that is substantially identical to the amino acid sequence disclosed herein, e.g., at least 80, 85, 90 identical , 92, 95, 97, 98, 99% or a higher degree, of the variable region of an antibody according to the invention, for example, an antibody selected from any of the antibodies BAP049hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049hum13, BAP049-hum14, BAP049-hum15, BAP049-clone-A, BAP049- clone-B, VAR049- clone-C, BAP049clone-D or BAP049-clone-E; or as described in table. 1, or the sequence encoded by the nucleotide sequence from table. 1; or a sequence that differs by at least 1 or 5 residues, but less than 40, 30, 20 or 10 residues, from the variable region of an antibody of the invention.

In one embodiment, the heavy or light chain variable region, or both, of an anti-PD-1 antibody molecule comprises an amino acid sequence encoded by a nucleic acid sequence described in the invention, or a nucleic acid sequence that hybridizes to a nucleic acid sequence described in the invention (eg, the nucleic acid sequence shown in Tables 1 and 2), or its complement, eg, under low stringency, medium stringency or high stringency conditions, or other hybridization conditions described in the invention.

In another embodiment, the anti-PD-1 antibody molecule contains at least one, two, three or four antigen binding regions, for example, variable regions having the amino acid sequence as set forth in table. 1, or a sequence substantially identical to that sequence (e.g., a sequence identical to at least about 85, 90, 95, 99% or more, or different from the sequences presented in Table 1 by no more than 1, 2 , 5, 10, or 15 amino acid residues. In another embodiment, the anti-PD-1 antibody molecule includes a VH domain and/or a VL domain encoded by a nucleic acid that has the nucleotide sequence set forth in Table 1, or a sequence substantially identical to the specified sequences (for example, a sequence identical to at least about 85, 90, 95, 99% or more, or different from the sequences presented in Table 1 by no more than 3, 6, 15, 30 or 45 nucleotides In yet another embodiment, the anti-PD-1 antibody molecule comprises at least one, two or three heavy chain variable region CDR regions that have the amino acid sequence set forth in Table. 1, or a sequence substantially homologous to said sequences (e.g., a sequence identical to at least about 85, 90, 95, 99% or more, and/or having one, two, three or more substitutions, deletions or insertions, e.g. , conservative substitutions). In yet another embodiment, the anti-PD-1 antibody molecule comprises at least one, two or three light chain variable region CDR regions that have the amino acid sequence set forth in Table. 1, or a sequence substantially homologous to said sequences (e.g., a sequence identical to at least about 85, 90, 95, 99% or more, and/or having one, two, three or more substitutions, deletions or insertions, e.g. , conservative substitutions). In yet another embodiment, the anti-PD-1 antibody molecule comprises at least one two, three, four, five or six CDR regions of the heavy and light chain variable regions that have the amino acid sequence presented in table. 1), or a sequence substantially homologous to said sequences (e.g., a sequence identical to at least about 85, 90, 95, 99% or more, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conservative substitutions).

In one embodiment, the anti-PD-1 antibody molecule comprises at least one, two or three CDRs, and/or heavy chain variable region hypervariable loops that have the amino acid sequence of an antibody of the invention, for example, an antibody selected from any of BAP049- hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049hum12, B AP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP04 9-clone-A, BAP049-cloneB, BAP049-clone-C, BAP049-clone-E or BAP049-clone-E, as presented in table. 1, or a sequence substantially identical to said sequences (e.g., a sequence identical to at least about 85, 90, 95, 99% or more, and/or having one, two, three or more substitutions, insertions or deletions, for example, conservative substitutions). In another embodiment, the anti-PD-1 antibody molecule contains at least one, two or three CDRs, and/or light chain variable region hypervariable loops that have the amino acid sequence of an antibody of the invention, for example, an antibody selected from any of the BAP049 antibodies -hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,

BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,

- 15 045940

BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, BAP049-clone-O or BAP049-clone-E, as presented in the table , or a sequence substantially identical to said sequences (e.g., a sequence identical to at least 85, 90, 95, 99% or more, and/or having one, two, three or more substitutions, insertions and deletions, such as conservative replacements). In one embodiment, the anti-PD-1 antibody molecule contains all six CDRs and/or hypervariable loops described in the invention, for example, those presented in table. 1.

In one embodiment, the anti-PD-1 antibody molecule has a variable region whose sequence is identical to or differs by 1, 2, 3 or 4 amino acids from the variable region of the invention (eg, the FR region disclosed in the invention).

In one embodiment, the anti-PD-1 antibody molecule is a complete antibody or a fragment thereof (eg, Fab, F(ab') ₂ , Fv, or single chain Fv fragment (ScFv)). In some embodiments, the anti-PD-1 antibody molecule is a monoclonal antibody or a single specificity antibody. The anti-PD-1 antibody molecule may also be a humanized, chimeric, camel, shark, or in vitro generated antibody molecule. In one embodiment, such an anti-PD-1 antibody molecule is a humanized antibody molecule. The heavy and light chains of an anti-PD-1 antibody molecule may be full-length (e.g., the antibody may include at least one, and preferably two, full-length heavy chains and at least one, and preferably two, full-length light chains) or may include an antigen-binding moiety (e.g. , Fab, F(ab') ₂ , Fv, single chain Fv fragment, single domain antibody, diabody (dAb), bivalent antibody or bispecific antibody or fragment thereof, single domain variant thereof or camel antibody).

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

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

In other embodiments, the anti-PD-1 antibody molecule has a heavy chain constant region (Fc) selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, and more particularly from the heavy chain constant region of IgG1 or IgG2 (eg, human IgG1, IgG2 or IgG4). In one embodiment, the heavy chain constant region is human IgG1. In another embodiment, the anti-PD-1 antibody molecule has a light chain constant region selected, for example, from kappa or lambda light chain constant regions, preferably from a kappa chain (eg, human kappa chain). In one embodiment, the constant region is modified, e.g., mutated, to modify the properties of the anti-PD-1 antibody molecule (e.g., to increase or decrease one or more of the following properties: Fc receptor binding, antibody glycosylation, number of cysteine residues , effector cell function or complement function). For example, the 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 alter binding to the Fc receptor ( for example, the 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) from

- 16 045940

SEQ ID NO: 215, 216, 217 or 218). In another embodiment, the heavy chain constant region of an IgG4, eg, human IgG4, is mutated at position 228 according to EU numbering (eg, S to P), for example, as shown in Table 1. 3. In some embodiments, the anti-PD-1 antibody molecules comprise human IgG4 with a mutation at position 228, according to EU numbering (eg, S to P), for example, as shown in Table. 3, and a kappa light chain constant region, for example, as shown in Table. 3. In yet another embodiment, the heavy chain constant region of an IgG1, e.g., human IgG1, is mutated at one or more positions: at EU numbering position 297 (e.g., N to A), at EU numbering position 265 (e.g., D to A), at position 329 according to the EU numbering (for example, P to A), at position 234 according to the EU numbering (for example, L to A), or at position 235 according to the EU numbering (for example, L to A), for example, as shown in table. 3. In some embodiments, the anti-PD-1 antibody molecules comprise human IgG1 with a mutation at one or more of these positions, for example, as shown in table. 3, and a kappa light chain constant region, for example, as shown in Table. 3.

In one embodiment, the anti-PD-1 antibody molecule is isolated or recombinant.

In one embodiment, the anti-PD-1 antibody molecule is a humanized antibody molecule. In one embodiment, the anti-PD-1 antibody molecule has a T cell epitope assay-based risk score of less than 700, 600, 500, 400, or less.

In one embodiment, the anti-PD-1 antibody molecule is a humanized antibody molecule and has a T cell epitope assay-based risk score of 300 to 700, 400 to 650, 450 to 600, or a risk score of the invention.

The invention also relates to a nucleic acid molecule containing one or both nucleotide sequences that encode heavy and light chain variable regions, CDR regions, hypervariable loops, framework regions of anti-PD-1 antibody molecules according to the invention. In some embodiments, the nucleotide sequence that encodes the anti-PD-1 antibody molecule is a codon optimized molecule. For example, the present invention provides first and second nucleic acids encoding heavy and light chain variable regions, respectively, in an anti-PD-1 antibody molecule selected from one or more antibodies, for example, any of BAP049-hum01, BAP049-hum02, BAP049-hum03, VAR049-1pc04. BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP0 49-hum16, VAR04 9 -clone-A, VAR049-clone-B, VAR049-clone-C, VLR049-k.yun-1) or VAR049-clone-E, as indicated in table. 1, or a sequence substantially identical to the above sequences. For example, the nucleic acid may contain the nucleotide sequence shown in table. 1 and 2, or a sequence substantially identical to those sequences (e.g., a sequence that is at least 85, 90, 95, 99% or more identical, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides shown in Tables 1 and 2).

In other embodiments, the nucleic acid molecule contains a nucleotide sequence that encodes a heavy chain variable domain and/or a heavy chain constant region comprising the amino acid sequence of BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, BAP049- clone-E or VAR049-clone-E; or, as described in table. 1; or nucleotide sequence from table. 1; or a sequence substantially identical (eg, a sequence identical to at least about 85%, 90%, 95%, 99% or more) to any of the above sequences.

In other embodiments, the nucleic acid molecule comprises a nucleotide sequence that encodes a light chain variable domain and/or a light chain constant region comprising the amino acid sequence of BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, BAP049- clone-E or VAR049-clone-E; or, as described in table. 1; or nucleotide sequence from table. 1; or a sequence substantially identical (eg, a sequence identical to at least about 85%, 90%, 95%, 99% or more) to any of the above sequences.

These nucleotide sequences encoding the variable domain and heavy and light chain constant regions of an anti-PD-1 antibody may be present as a separate nucleic acid molecule or within the same nucleic acid molecule. In some embodiments, the nucleic acid molecules contain a nucleotide sequence that encodes a leader sequence, for example, the leader sequence shown in table. 4, or a sequence substantially identical to said sequence.

In some embodiments, the nucleic acid molecule comprises a nucleotide sequence encoding at least one, two or three CDR regions, or hypervariable loops, from a heavy chain variable region that has the amino acid sequence set forth in Table. 1, or a sequence substantially homologous to said sequence

- 17 045940 identity (for example, a sequence that is at least about 85, 90, 95, 99% identical or more, and/or having one, two, three or more substitutions, insertions or deletions, for example, conservative substitutions).

In another embodiment, the nucleic acid molecule contains a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a light chain variable region that has the amino acid sequence shown in table. 1, or a sequence substantially homologous to said sequence (e.g., a sequence identical to at least about 85, 90, 95, 99% or more, and/or having one, two, three or more substitutions, deletions or insertions, e.g. , conservative substitutions).

In yet another embodiment, the nucleic acid molecule contains a nucleotide sequence encoding at least one, two, three, four, five or six CDRs, or hypervariable loops, from heavy and light chain variable regions that have the amino acid sequence as set forth in Table . 1, or a sequence substantially homologous to said sequences (e.g., a sequence identical to at least about 85, 90, 95, 99% or more and/or having one, two, three or more substitutions, insertions or deletions, e.g. conservative substitutions).

In one embodiment, the nucleic acid molecule comprises a nucleotide sequence encoding an anti-PD-1 antibody molecule that includes a change in the light chain of CDR3 at position 102 of the light chain variable region, for example, a change of a cysteine residue to a tyrosine, or a cysteine residue to a serine, at position 102 variable region of the light chain, in accordance with table. 1 (e.g., SEQ ID NO: 16 or 24 for a murine or chimeric, unmodified sequence, or any of SEQ ID NO: 34, 42, 46, 54, 58, 62, 66, 70, 74, or 78 for a modified sequence) .

In another embodiment, the nucleic acid molecule includes one or more heavy chain framework regions (e.g., any of VHFW1 (type a), VHFW1 (type b), VHFW2 (type a), VHFW2 (type b), VHFW2 (type c), VHFW3 (type a), VHFW3 (type b), or VHFW4, or any combination thereof, for example, a combination of framework regions described in the invention) for any of the antibodies BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP0 49-hum16, VAR049- clone-A, VAR049-clone-B, VAR049-clone-C, VAR049-clone-E or VAR049-clone-E, given in table. 1 and 2, or a sequence substantially identical to these sequences. For example, a nucleic acid molecule may contain the nucleotide sequence presented in table. 1 and 2, or a sequence substantially identical thereto (e.g., a sequence that is at least about 85, 90, 95, 99% or more identical, or differs from the sequences presented in Tables 1 and 2 by no more than than 3, 6, 15, 30 or 45 nucleotides).

In another embodiment, the nucleic acid molecule includes one or more light chain framework regions (e.g., any of VLFW1 (type a), VLFW1 (type b), VLFW1 (type c), VLFW1 (type d), VLFW1 (type e), VLFW2 (type a), VLFW2 (type b), VLFW2 (type c), VLFW3 (type a), VLFW3 (type b), VLFW3 (type c), VLFW3 (type d), or VLFW4, or any combination thereof, for example, a combination of framework regions described in the invention) for any of the antibodies BAP049-hum01, BAP049hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-humO7, BAP049hum08, BAP049-hum09, BAP049-hum10 , BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049hum14, BAP049-hum15, BAP049-hum16, BAP049-clone-A, BAP049-clone-B, BAP049-clone-C, BAP049-clone-D or BAP049-clone-E, as indicated in table. 1 and 2, and a sequence substantially identical to said sequences. For example, a nucleic acid molecule may contain the nucleotide sequence shown in table. 1 and 2, or a sequence that is essentially identical to it (for example, a sequence that is at least 85, 90, 95, 99% or more% identical, or differs from the sequences from Tables 1 and 2 by no more than 3, 6, 15, 30 or 45 nucleotides).

In another embodiment, the nucleic acid molecule includes one or more heavy chain framework regions and one or more light chain framework regions described in the present invention. The heavy and light chain framework regions may be in the same vector or in different vectors.

In another aspect, the present application relates to host cells and vectors carrying the nucleic acids described herein. The nucleic acids may be in the same vector or in different vectors present in the same host cell or in 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, the mammalian cell may be a cultured cell or a cell line. Examples of mammalian cells include lymphocytic cell lines (eg, NSO), Chinese hamster ovary (CHO) cells, COS cells, oocyte cells, and cells from a transgenic animal, e.g.

- 18 045940 mammalian epithelial cells.

In one aspect, the present invention relates to a method for producing an antibody molecule of the invention. This method includes the following: obtaining a PD-1 antigen (eg, an antigen containing at least a portion of a PD-1 epitope); providing an antibody molecule that specifically binds to a PD-1 polypeptide; and determining whether the antibody molecule specifically binds to the PD-1 polypeptide, or assessing the effectiveness of the antibody molecule to modulate, for example, inhibit PD-1 activity. The method may further include administering the antibody molecule to a subject, such as a human or non-human animal.

In another aspect, the present invention relates to compositions, for example, pharmaceutical compositions, which include a pharmaceutically acceptable carrier, excipient or stabilizer, and at least one of the anti-PD-1 antibody molecules of the invention. In one embodiment, the composition, for example, a pharmaceutical composition, includes a combination of an antibody molecule, and one or more substances, for example, a therapeutic agent or another antibody molecule, according to the invention. In one embodiment, the antibody molecule is conjugated to a label or therapeutic agent.

The anti-PD-1 antibody molecules of the invention can inhibit, reduce or neutralize one or more of the actions of PD-1, resulting in blockade or reduction of the immune checkpoint. In one embodiment, the antibody molecule causes one or more of the following effects: increased tumor infiltration by lymphocytes, increased T-cell receptor-mediated proliferation, decreased immune evasion of cancer cells, restoration of effector cell function (e.g., one or more of the following: T -cell proliferation, IFN-gamma secretion or cytolytic function), suppression of regulatory T cell function or effects on the activity of various cell types such as regulatory T cells, effector T cells and NK cells). Thus, these antibody molecules can be used to treat or prevent diseases in which it is desirable to enhance the immune response in a subject.

Applications of anti-PD-1 antibody molecules.

Accordingly, in another aspect, the invention relates to a method of modulating an immune response in a subject. The method includes administering to a subject an anti-PD-1 antibody molecule described in the invention (e.g., a therapeutically effective amount of an anti-PD-1 antibody molecule), as a single formulation, or in combination with one or more substances or procedures, such that modulation occurs immune response in the subject. In one embodiment, the antibody molecule enhances, stimulates, or enhances the immune response in a subject. The subject may be a mammal, such as a primate, preferably a great ape, such as a human (eg, a patient suffering from or at risk of developing a disease described in the invention). In one embodiment, the subject requires an enhanced immune response.

In one embodiment, the subject suffers from or is at risk of developing a disease mentioned in the invention, such as cancer or an infectious disease mentioned in the invention. In some embodiments, the subject is immunocompromised or is at risk for immunodeficiency. For example, the subject is undergoing or has previously undergone chemotherapy treatment and/or radiation therapy. Alternatively or in combination, the subject has an immunodeficiency or is at risk of developing an immunodeficiency as a result of an infection.

In one aspect, the invention relates to a method of treating cancer or a tumor in a subject (eg, one or more of the following effects: reducing, inhibiting or slowing progression). The method comprises administering to a subject an anti-PD-1 antibody molecule of the invention, for example, a therapeutically effective amount of an anti-PD-1 antibody molecule, either alone or in combination with one or more substances or procedures. In some embodiments, the anti-PD-1 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, according to the present invention.

In some embodiments, the cancer that is treated with the anti-PD-1 antibody molecule includes, but is not limited to, solid tumors, hematologic cancers (eg, leukemia, lymphoma, myeloma, eg, multiple myeloma), and metastatic disease. In one embodiment, the cancer is a solid tumor. Examples of solid tumors include malignant tumors, such as sarcomas and carcinomas, such as adenocarcinomas of various organs and systems, such as tumors affecting the lungs, breasts, ovaries, lymphoid tissue, gastrointestinal tract (eg, colon), anal, genital and genitourinary tract (eg, kidney, urothelium, bladder cells, prostate), pharynx, central nervous system (eg, brain, nerve or glial cells), tumors of the head and neck, skin (eg, melanoma), and pancreas, and also adenocarcinomas, which include malignant tumors such as colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small

- 19 045940 cell lung cancer, small intestine cancer and esophageal cancer. The cancer may be early, intermediate, advanced, or metastatic.

In one embodiment, the cancer is selected from the following: lung cancer (eg, non-small cell lung cancer (NSCLC) (eg, NSCLC squamous histological type and/or non-squamous histological type or NSCLC adenocarcinoma)), melanoma (eg, advanced melanoma), kidney cancer ( eg, renal cell carcinoma), liver cancer, myeloma (eg, multiple myeloma), prostate cancer, breast cancer (eg, breast cancer that lacks expression of one, two, or all of the estrogen receptors, progesterone receptors, or HER2/ neu, eg, triple negative breast cancer), colorectal cancer, pancreatic cancer, head and neck cancer (eg, (HNSCC), anal cancer, gastroesophageal cancer, thyroid cancer, cervical cancer, lymphoproliferative disease (eg, post-transplant lymphoproliferative disease) or hematologic cancer, T-cell lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, or leukemia (eg, myeloid leukemia or lymphocytic leukemia).

In another embodiment, the cancer is selected from carcinoma (eg, advanced or metastatic carcinoma), melanoma, or lung carcinoma, eg, non-small cell lung carcinoma.

In one embodiment, the cancer is a lung cancer, such as non-small cell lung cancer or small cell lung cancer.

In one embodiment, the cancer is melanoma, for example, advanced melanoma. In one embodiment, the cancer is an advanced or inoperable melanoma that does not respond to other treatments. In other embodiments, the cancer is BRAF mutation melanoma (eg, BRAF V600 mutation). In other embodiments, the anti-PD-1 antibody molecule is administered following treatment with an anti-CTLA4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib).

In another embodiment, the cancer is a hepatocarcinoma, such as advanced hepatocarcinoma, with or without viral infection, such as chronic viral hepatitis.

In another embodiment, the cancer is prostate cancer, such as advanced prostate cancer.

In yet another embodiment, the cancer is myeloma, such as multiple myeloma.

In yet another embodiment, the cancer is a kidney cancer, such as renal cell carcinoma (RCC) (eg, metastatic RCC or clear cell renal cell carcinoma (CCRCC)).

In one embodiment, there is an increased level of PD-L1 expression in the cancer microenvironment. Alternatively, or in combination, there may be increased expression levels of IFN-gamma and/or CD8 in the cancer microenvironment.

In some embodiments, the subject has a tumor, or is identified as having a tumor that exhibits one or more properties, such as high levels of PD-L1 or increased expression of PD-L1, or the tumor is leaky lymphocyte (TIL)+ (e.g., it has an increased number of tumor-infiltrating lymphocytes (TILs)), or both. In some embodiments, the subject has a tumor, or is identified as having a tumor, that exhibits high levels of PD-L1 or increased expression of PD-L1 and is a TIL+ tumor. In some embodiments, the methods described in the invention further include identifying the subject based on whether the subject has a tumor that exhibits one or more properties, such as high levels of PD-L1 or increased expression of PD-L1, or the tumor is TIL+, or both of these properties. In some embodiments, the methods described in the invention further include identifying a subject based on whether the subject has a tumor that exhibits one or more properties, such as high levels of PD-L1 or increased expression of PD-L1, or the tumor is TIL+. In some embodiments, tumors that are TIL+ tumors are positive for CD8 and IFN-gamma. In some embodiments, the subject has, or is identified as having, a high percentage of cells that are positive for the presence of one, two, or more than two of PD-L1, CD8, and/or IFN-gamma. In some embodiments, the subject has or is identified as having a high percentage of cells that are positive for all of PD-L1, CD8, and IFN-gamma.

In some embodiments, the methods described in the invention further include identifying a subject based on the presence of a high percentage of cells that are positive for one, two, or more than two of PD-L1, CD8, and/or IFN-gamma. In some embodiments, the methods described in the invention further include identifying the subject based on

- 20 045940 evidenced by the presence of a high percentage of cells that are positive for all of PD-L1, CD8 and IFN-gamma. In some embodiments, the subject is detected, or the subject is identified as having one, two, or more than two of PD-L1, CD8, and/or IFN-gamma, and one or more pathologies, such as lung cancer, such as squamous cell lung cancer or adenocarcinoma lung, head and neck cancer, squamous cell carcinoma of the cervix, stomach cancer, esophageal cancer, thyroid cancer, melanoma, and/or nasopharyngeal cancer (NPC). In some embodiments, the methods described in the invention further describe identifying a subject based on the presence of one, two, or more than two of PD-L1, CD8, and/or IFN-gamma, and one or more pathologies, such as lung cancer, for example, squamous cell lung cancer or lung adenocarcinoma, head and neck cancer, squamous cell carcinoma of the cervix, gastric cancer, thyroid cancer, melanoma and/or nasopharyngeal cancer.

The methods and compositions disclosed herein are useful for the treatment of metastatic lesions caused by the above-mentioned types of cancer.

In another aspect, the present invention provides a method of treating an infectious disease in a subject, which method comprises administering to the subject a therapeutically effective amount of an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more agents or procedures. In one embodiment, the infectious disease is selected from hepatitis (eg, infectious hepatitis C) or sepsis.

Furthermore, the present invention provides a method of enhancing a subject's immune response to an antigen, which method comprises administering to the subject: (I) an antigen, and (II) an anti-PD-1 antibody molecule such that the subject's immune response to an antigen is enhanced. antigen. The antigen may be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen from a pathogen.

The route of administration of the anti-PD-1 antibody molecule to a subject may be systemic (e.g., oral, parenteral, subcutaneous, intravenous, rectal, intramuscular, intraperitoneal, intranasal, transdermal, or inhalational or intracavitary), topical, or mucosal. , for example, mucous membranes of the nose, throat and bronchi.

Dosages and schedules of administration of the anti-PD-1 antibody molecule can be determined by one skilled in the art. In some embodiments, the anti-PD-1 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. The schedule of administration may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-PD-1 antibody molecule is administered at a dose of approximately 10 to 20 mg/kg every two weeks.

The antibody molecules described herein are preferred for use in the methods described herein, although other anti-PD-1 antibodies may be used instead of or in combination with the anti-PD-1 antibody molecule of the invention.

Combination therapy.

The methods and compositions described in the invention may be used in combination with other substances or therapeutic techniques. In one embodiment, the methods described herein include administering to a subject an anti-PD-1 antibody molecule of the invention, in combination with a substance or therapeutic procedure or technique, in an amount effective to treat or prevent a disease. The anti-PD-1 antibody molecule and agent, or therapeutic procedure or technique, can be administered simultaneously or sequentially in any order. Any combination and sequence of anti-PD-1 antibody molecules and other therapeutic agents, procedures or techniques (eg, those described in the invention) can be used. The antibody molecule and/or other therapeutic agents, procedures and techniques can be used during a period of disease activity, or during a period of remission or decreased disease activity. The antibody molecule can be administered before another treatment, simultaneously with another treatment, after treatment, or during remission of the disease.

In some embodiments, the methods and compositions described in the invention are used in combination with one or more techniques, such as administration of other antibody molecules, chemotherapy, other anticancer therapies (e.g., targeted anticancer drugs, gene therapy, viral therapy, RNA therapy , bone marrow transplantation, nanotherapy or oncolytic drugs), cytotoxic agents, immune drugs (eg, cytokines or cell-based immune drugs), surgery (eg, lumpectomy or mastectomy) or radiation therapy procedures, or a combination of any of the above. Additional treatments may be in the form of an adjuvant or neoadjuvant agent. In some embodiments, the additional drug is an enzyme inhibitor (eg, a small molecule enzyme inhibitor) or a metastatic inhibitor. Examples of cytotoxic agents that may be administered in combination include antimicrotubule agents, topoisomerase inhibitors, antimetabolites,

- 21 045940 mitosis inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, substances capable of disrupting signal transduction pathways, substances that stimulate apoptosis, proteasome inhibitors, as well as irradiation (for example, local irradiation or total body irradiation (for example, gamma -irradiation).In other embodiments, the additional treatment is surgery or radiation, or a combination thereof. In other embodiments, the additional treatment is a therapy targeting one or more targets, such as the PI3K/AKT/mTOR pathway, an HSP90 inhibitor, or tubulin inhibitor.

Alternatively, or in combination with the above combinations, the methods and compositions of the invention may be used in combination with one or more of the following: an immunomodulator (e.g., a co-stimulatory molecule activator or an inhibitor of an inhibitory molecule, e.g., an immune checkpoint molecule), a vaccine, e.g. , a therapeutic tumor vaccine, or other forms of cellular immunotherapy.

Exemplary, non-limiting combinations and uses of anti-PD-1 antibody molecules include the following.

In some embodiments, the anti-PD-1 antibody molecule is administered in combination with a co-stimulatory molecule or inhibitory molecule modulator, such as a coinhibitory ligand or receptor.

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

In one embodiment, the anti-PD-1 antibody molecule is administered in combination with an inhibitory molecule (or immune checkpoint molecule) selected from PD-L1, PDL2, CTLA-4, TIM-3, LAG-3, SEACAM (e.g., SEACAM -1, SEACAM-3, and/or SEACAM-5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR-beta. Inhibition of an inhibitory molecule can be accomplished by inhibition at the DNA, RNA or protein level. In embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA, or shRNA) may be used to inhibit expression of the inhibitory molecule. In other embodiments, an inhibitory signal inhibitor is a polypeptide, such as a soluble ligand, or an antibody or antigen-binding fragment thereof that binds to an inhibitory molecule. In one embodiment, the inhibitor is a soluble ligand (eg, CTLA-4-Ig) or antibody or antibody fragment that binds PD-L1, PD-L2, or CTLA-4. For example, an anti-PD-1 antibody molecule may be administered in combination with an anti-CTLA-4 antibody, e.g., the drug ipilimumab, e.g., for the treatment of cancer (e.g., cancer selected from: melanoma, e.g., metastatic melanoma, lung cancer, e.g. non-small cell lung carcinoma or prostate cancer). In one embodiment, the anti-PD-1 antibody molecule is administered following treatment with an anti-CTLA-4 antibody (such as ipilimumab) with or without a BRAF inhibitor (such as vemurafenib or dabrafenib).

In another embodiment, the anti-PD-1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof.

In another embodiment, the anti-PD-1 antibody molecule is administered in combination with an anti-TIM-3 antibody or an antigen-binding fragment thereof.

In other embodiments, the anti-PD-1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody (or antigen-binding fragments thereof).

In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a SEACAM inhibitor (eg, a SEACAM-1 and/or SEACAM-5 inhibitor), for example, an anti-CEACAM antibody molecule. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a CEACAM-1 inhibitor, for example, an anti-CEACAM-1 antibody molecule. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a CEACAM-5 inhibitor, for example, an anti-CEACAM-5 antibody molecule.

The combination of antibodies mentioned in the invention can be administered separately, for example, in the form of individual antibodies or antigen-binding fragments thereof, or in combined form, for example, in the form of a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody is administered that includes an anti-PD-1 antibody molecule and an anti-TIM-3 antibody, an anti-SEACAM antibody (e.g., an anti-SEACAM-1, an anti-SEACAM-3, and/or an anti-SEACAM-5 antibody), or an anti-LAG- 3 or antigen-binding fragments of these antibodies. In some embodiments, a combination of antibodies mentioned in the invention is used to treat a cancer, for example, a cancer specified in the invention (eg, a solid tumor or a hematological malignancy).

- 22 045940

In other embodiments, the anti-PD-1 antibody molecule is administered in combination with a cytokine. The cytokine can be administered as a molecule fused to an anti-PD-1 antibody molecule or in separate compositions. In one embodiment, the anti-PD-1 antibody is administered in combination with one, two, three or more cytokines, for example, as a fusion molecule or in separate compositions. In one embodiment, the cytokine is an interleukin (IL) selected from one, two, three, or more of the interleukins 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 (for example, for PD-1), a second binding specificity for a second target (for example, for LAG-3 or TIM-3), and is optionally associated with an interleukin domain ( for example, IL12), for example, full-length IL-12 or with part thereof. In some embodiments, a combination of an anti-PD-1 antibody molecule and a cytokine of the invention is used to treat a cancer, such as a cancer of the invention (eg, a solid tumor).

In some embodiments, the anti-PD-1 antibody molecule is administered in combination with an anti-human leukocyte antigen C (HLA C)-specific antibody, such as a killer cell immunoglobulin-like receptor-specific antibody (also referred to herein as an anti-KIR antibody). In some embodiments, a combination of an anti-PD-1 antibody molecule and an anti-KIR antibody is used to treat a cancer, such as a cancer of the invention (eg, a solid tumor, eg, an advanced solid tumor).

In one embodiment, the anti-PD-1 antibody molecule is administered in combination with a cellular immunotherapy (eg, Provenge®, e.g., SipuleucelT), and optionally in combination with cyclophosphamide. In some embodiments, a combination of an anti-PD-1 antibody molecule, Provenge® and/or cyclophosphamide is used to treat a cancer, such as a cancer of the invention (eg, prostate cancer, eg, advanced prostate cancer).

In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a vaccine, e.g., a tumor vaccine (e.g., dendritic cell renal carcinoma (DC-RCC) vaccine. In one embodiment, the vaccine is made from a peptide based DNA-based, RNA-based or antigen-based, or a combination thereof. In some embodiments, the vaccine contains one or more peptides, nucleic acids (e.g., DNA or RNA), antigens, or a combination thereof. In some embodiments, the combination of an anti-PD antibody molecule -1 and the DC-RCC vaccine are used to treat cancer, for example, the cancer specified in the invention (for example, kidney cancer, for example, metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).

In another embodiment, the anti-PD-1 antibody molecule is administered in combination with an adjuvant.

In yet another embodiment, the anti-PD-1 antibody molecule is administered in combination with a chemotherapeutic and/or immunotherapy agent. For example, an anti-PD-1 antibody molecule may be used to treat myeloma, either alone or in combination with one or more of the following: chemotherapeutic or other antineoplastic agents (eg, thalidomide analogues, eg, lenalidomide), anti-TIM-3 antibodies , tumor antigen - pulsed dendritic cells, fusions (eg, electrofusion) of tumor cells and dendritic cells, or vaccination using an immunoglobulin idiotype produced by malignant plasma cells. In one embodiment, an anti-PD-1 antibody molecule is used in combination with an anti-TIM-3 antibody to treat myeloma, such as multiple myeloma.

In one embodiment, the anti-PD-1 antibody molecule is used in combination with chemotherapy to treat lung cancer, such as non-small cell lung cancer. In one embodiment, the anti-PD-1 antibody molecule is used with standard pulmonary chemotherapy, such as that used for NSCLC, such as platinum doublet therapy, to treat lung cancer. In other embodiments, the anti-PD-1 antibody molecule is used in combination with an indoleamine-pyrrole-2,3 dioxygenase (IDO) inhibitor (e.g., (4E)-4-[(3-chloro-4fluoroanilino)-nitrosomethylidene]-1, 2,5-Oxadiazol-3-amine (also known as INCB24360), indoximod (1-methyl-E-tryptophan), α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), etc.) for use in a subject with advanced or metastatic cancer (eg, a patient with metastatic and recurrent NSCL cancer).

In other embodiments, the anti-PD-1 antibody molecule is used in combination with one or more of the following techniques: an immunological approach (e.g., interleukin-2 or interferon-α), a targeted agent (e.g., a VEGF inhibitor, such as an anti-VEGF monoclonal antibody ); a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib; RNA interference inhibitor; or an inhibitor of a mediator located downstream of the VEGF signaling pathway, for example, a mammalian target of rapamycin (mTOR) inhibitor,

- 23 045940 e.g. everolimus and temsirolimus. Any of these combinations may be used to treat kidney cancer, such as renal cell carcinoma (RCC) (eg, clear cell renal carcinoma (CCRCC)) or metastatic RCC.

In some embodiments, an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody molecule of the invention, is used in combination with a MEK inhibitor (eg, a MEK inhibitor of the invention). In some embodiments, a combination of an anti-PD-1 antibody and a MEK inhibitor is used to treat cancer (eg, a cancer of the invention). In some embodiments, the cancer that is subject to the combination treatment is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell carcinoma. In some embodiments, the cancer includes a BRAF mutation (eg, BRAF V600E mutation), wild-type BRAF, wild-type KRAS, or an activating KRAS mutation. Cancer can be early, intermediate or late stage.

In another embodiment, the anti-PD-1 antibody molecule is used in combination with one, two, or all of the following: oxaliplatin, leucovorin, or 5-FU (eg, FOLFOX co-treatment). Alternatively or in combination, the combination further includes a VEGF inhibitor (eg, a VEGF inhibitor of the invention). In some embodiments, a combination of an anti-PD-1 antibody, a FOLFOX co-treatment, and a VEGF inhibitor is used to treat cancer (eg, a cancer of the invention). In some embodiments, the cancer that is subject to the combination treatment is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell carcinoma. Cancer can be at an early, middle or late stage.

In other embodiments, the anti-PD-1 antibody molecule is administered with a tyrosine kinase inhibitor (eg, axitinib) for the treatment of renal cell carcinoma and other solid tumors.

In other embodiments, the anti-PD-1 antibody molecule is administered with an agent that targets the 4-1BB receptor (eg, an antibody that stimulates 41BB signaling (CD-137), eg, PF-2566). In one embodiment, the anti-PD-1 antibody molecule is administered in combination with a tyrosine kinase inhibitor (eg, axitinib) and an agent targeting the 4-1BB receptor.

The anti-PD-1 antibody molecule may be associated with a substance, for example, a cytotoxic substance or component (for example, a therapeutic drug, a radiation-emitting compound, molecules of plant, fungal or bacterial origin, or a biological protein (for example, a protein toxin) or particle (e.g., a recombinant viral particle, e.g., via a viral envelope protein). For example, the antibody may be coupled to a radioactive isotope such as an α-, β-, or γ-emitter, or a β- or γ-emitter .

Any combination and sequence of anti-PD-1 antibody molecules and other therapeutic agents, procedures or techniques (eg, those described in the invention) can be used. The antibody molecule and/or other therapeutic agents, procedures or techniques can be used during a period of active disease, or during a period of remission or decrease in disease activity. The antibody molecule can be administered before another treatment, in parallel with that treatment, after treatment, or during remission of the disease.

Additional combination treatments.

The methods and compositions described in the invention (eg, anti-PD-1 antibodies and methods of using them) can be used in combination with other substances or therapeutic techniques, for example, with a second therapeutic agent selected from one or more of the agents listed in table. 7. In one embodiment, the methods described in the invention include administering to a subject an anti-PD-1 antibody molecule of the invention (optionally in combination with one or more PD-L1, LAG-3, TIM-3, SEACAM inhibitors (e.g., SEACAM- 1 and/or SEACAM-5), or CTLA-4)), and additionally include the introduction of a second therapeutic agent selected from one or more of the agents listed in table. 7, in an amount effective for treating or preventing a disease, for example, a disease mentioned in the invention, such as cancer. When administered in combination, an anti-PD-1 antibody molecule, an additional agent (e.g., a second or third agent), or all of the agents may be administered in an amount or dose that is higher, lower, or the same as the amount or the dose of each substance used separately, for example, as monotherapy. In some embodiments, the administered amount or dose of the anti-PD-1 antibody, an additional substance (e.g., a second or third substance), or all of the substances, is lower (e.g., by at least 20%, by at least 30%, at least 40% or at least 50%) than the amount or dose of each substance used separately, for example, as monotherapy. In other embodiments, the amount or dose of anti-PD-1 antibody,

- 24 045940 additional substance (for example, a second or third substance), or all of the mentioned substances that cause the desired effect (for example, cancer treatment) are lower (for example, by at least 20%, by at least 30%, at least 40% or at least 50% lower).

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

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

In one embodiment, the second therapeutic agent is selected from one or more of the following compounds: compound A5, compound A8, compound A17, compound A23, compound A24, compound A29 and compound A40.

In one embodiment, the second therapeutic agent is selected from one or more of the following compounds: 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 a therapeutic dose or at a subtherapeutic dose. In some embodiments, the concentration of the second therapeutic agent that is required to achieve inhibition, such as growth inhibition, is lower when the second therapeutic agent is administered in combination with an anti-PD-1 antibody molecule than when the second therapeutic agent is administered as a separate drug. In some embodiments, the concentration of the anti-PD-1 antibody molecule that is required to achieve inhibition, e.g., growth inhibition, is lower when the anti-PD-1 antibody molecule is administered in combination with a second therapeutic agent than when the anti-PD-1 antibody molecule is administered as a separate drug. In some embodiments, in a combination therapy, the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second drug administered as monotherapy, e.g., 10-20%, 20-30% lower. , 3040%, 40-50%, 50-60%, 60-70%, 70-80% or lower by 80-90%. In some embodiments, in a combination therapy, the concentration of the anti-PD-1 antibody molecule that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the anti-PD-1 antibody molecule administered as monotherapy, e.g., 10-10% lower. 20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or lower by 80-90%.

Detection.

In another aspect, the present invention provides methods for detecting the presence of PD-1 in a sample, e.g., in vitro or in vivo (e.g., a biological sample, e.g., serum, semen, or urine, or a tissue biopsy, e.g., tissue from an area of hyperproliferative or cancer). The subject method can be used for evaluation (eg, to monitor the progress of treatment or the progression, diagnosis and/or stage of a disease mentioned in the invention, for example, a hyperproliferative or cancerous disease in a subject). This method includes: (I)

- 25 045940 contacting a sample with an antibody molecule of the invention (and, optionally, a reference, for example, a control sample), or administering to the subject an antibody molecule of the invention, under conditions that allow interaction to occur, and (ii) detecting the formation of a complex between the antibody molecule and sample (and optionally with a reference, for example, with a control sample). Formation of the complex indicates the presence of PD-1, and may indicate the acceptability or need for the treatment described in the invention. The method may include immunohistochemical, immunocytochemical techniques, fluorescence excited cell sorter (FACS) analysis, complexation of antibody molecules and magnetic beads, ELISA assays, PCR technologies (eg, reverse transcription-PCR (RT-PCR)).

Typically, an antibody molecule used in in vivo and in vitro diagnostic methods is labeled directly or indirectly with a detectable substance, which facilitates the detection of bound or unbound binder. Suitable detectable substances include various biologically active enzymes, prosthetic groups, fluorescent materials, luminescent materials, paramagnetic (eg, nuclear magnetic resonance active materials) and radioactive materials.

Additional embodiments relate to a method of treating cancer, which comprises: determining in a subject or sample (for example, a sample from the subject containing cancer cells and, optionally, cells of the immune system, such as TIL cells) the presence of one, two or all of PDL1, CD8, or IFN-γ, thereby providing indicators for one, two, or all of PD-L1, CD8, and IFN-γ. The method may further include comparing the PD-L1, CD8 and/or IFN-γ value with a reference value, such as a control value. If the PD-L1, CD8+ and/or IFN-γ values are higher than a reference value, e.g., control values, then the subject is administered a therapeutically effective amount of an anti-PD-1 antibody (e.g., an anti-PD-1 antibody of the invention), optionally in combination with one or more other substances, and thereby treat cancer. The cancer may be, for example, a cancer mentioned in the invention, for example, lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), stomach cancer, thyroid cancer, melanoma, nasopharyngeal cancer or breast cancer, such as triple negative (TN) breast cancer, such as immunomodulatory triple negative (IM-TN) breast cancer. In some embodiments, the cancer is ER+ breast cancer or pancreatic cancer.

The present invention also provides a method of treating cancer, which comprises: testing a subject or a sample (eg, a sample from a subject containing cancer cells) for the presence of PD-L1, thereby determining the PD-L1 value, comparing the PD-L1 value with a control value, and if the PD-L1 value exceeds the control value, administering to the subject a therapeutically effective amount of an anti-PD-1 antibody (e.g., an anti-PD-1 antibody of the invention), optionally in combination with one or more other substances, and thereby cancer treatment. The cancer may be, for example, a cancer mentioned in the invention, for example, the cancer is non-small cell lung cancer (NSCLC)-adenocarcinoma (ACA), NSCLC squamous cell carcinoma (SCC) or hepatocellular carcinoma (HCC).

In another aspect, the present invention provides diagnostic or therapeutic kits that include antibody molecules of the invention and instructions for use.

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

Other features, objects and advantages of the present invention will be apparent from the description and drawings, as well as from the claims.

Brief description of the figures

In fig. 1 shows the amino acid sequences of the light and heavy chain variable regions of the mouse anti-PD-1 monoclonal antibody mAb BAP049. The sequences shown above and below were obtained from two independent analyses. Light and heavy chain CDR sequences based on Kabat numbering are underlined. The light and heavy chain CDR sequences shown in bold italics are based on Chothia numbering. The unpaired Cys residue at position 102 of the light chain sequence is shown in the box. SEQ ID NOs: 8, 228, 16 and 229 are shown, respectively, in order of appearance.

In fig. 2A shows the amino acid sequences of the light and heavy chain variable regions of the murine monoclonal antibody (Mu mAb) anti-PD-1 mAb BAP049 aligned with germline sequences. The sequences indicated at the top and bottom are germline (GL) and BAP049 (Mu mAb) sequences, respectively. Light and heavy chain CDR sequences based on Kabat numbering are underlined. Bold italics indicate light and heavy chain CDR sequences based on Chothia numbering. Identical amino acid residues are shown in quotation marks. Sequences SEQ ID NOs: 230, 8, 231 and 16 are presented, respectively, in order of appearance.

- 26 045940

In fig. 2B shows the sequence of the mouse kJ2 gene and the corresponding mutation in the mouse monoclonal antibody against PD-1 mAb BAP049. Quotation marks indicate an identical nucleotide residue. The sequences shown as SEQ ID NO: 233, 232, 234 and 235 are shown in order of appearance, respectively.

In fig. 3A-3B show competitive binding between the fluorescently labeled mouse monoclonal antibody against PD-1 mAb BAP049 (Mu mAb) and three chimeric versions of BAP049 (Chi mAb). The experiment was carried out twice and the results are shown in Fig. 3A and 3B respectively. The three chimeric BAP049 antibodies (Chi mAb (Cys), Chi mAb (Tyr) and Chi mAb (Ser)) have Cys, Tyr and Ser residues at position 102 of the light chain variable region, respectively. Also Chi mAb (Cys), Chi mAb (Tyr) and Chi mAb (Ser) are designated as BAP049-chi, BAP049-chi-Y and BAP049-chi-S, respectively.

Fig. 4 is a bar graph showing the results of FACS binding analysis for sixteen humanized BAP049 clones (BAP049-hum01 - BAP049-hum16). Antibody concentrations are 200, 100, 50, 25, and 12.5 ng/mL from leftmost column to leftmost column for each mAb tested.

In fig. 5 shows structural analysis of humanized BAP049 clones (a, b, c, d and e represent different types of framework sequences). The mAb concentrations in the samples are also shown.

In fig. 6A-6B show the binding affinity and specificity of humanized mAb BAP049 measured in a competitive binding assay using murine mAb BAP049 at a constant concentration with Alexa 488 tag, serial dilutions of test antibodies and PD-1 expressing 300.19 cells. The experiment was performed twice and the results are shown in FIG. 6A and 6B respectively.

In fig. 7 shows the ranking of humanized BAP049 clones based on FACS, competitive binding, and structural analyses. The mAb concentrations in the samples are also shown.

Fig. 8A-8B show blocking of ligand binding to PD-1 by selected humanized BAP049 clones.

The blocking of PD-L1-Ig and PD-L2-Ig binding to PD-1 is shown in FIG. 8A. Blocking PD-L2-Ig binding to PD-1 is shown in FIG. 8B. BAP049-hum01, BAP049-hum05, BAP049hum08, BAP049-hum09, BAP049-hum10 and BAP049-hum11 were analyzed. Also included in the analysis were mouse mAb BAP049 and chimeric mAbs having a Tyr at position 102 of the light chain variable region.

Fig. 9A-9B show the sequence alignment of the heavy chain variable domains for sixteen humanized BAP049 clones and chimeric BAP049 (BAP049-chi). In fig. 9A all sequences, (SEQ ID NO: 22, 38, 38, 38, 38, 38, 38, 38, 38, 38, 50, 50, 50, 50, 82, 82 and 86 are shown, respectively, in order of appearance) . In fig. 9B shows only amino acid sequences that differ from the mouse sequence (SEQ ID NOs: 22, 38, 38, 38, 38, 38, 38, 38, 38, 38, 50, 50, 50, 50, 82, 82 and 86 indicated , respectively, in order of appearance).

Fig. 10A-10B show a light chain variable domain sequence alignment for sixteen humanized BAP049 clones and chimeric BAP049 (BAP049-chi). In fig. 10A all sequences (SEQ ID NOs: 24, 66, 66, 66, 66, 70, 70, 70, 58, 62, 78, 74, 46, 46, 42, 54 and 54 are shown, respectively, in order of appearance). In fig. 10B shows only amino acid sequences that differ from the mouse sequence (SEQ ID NOs: 24, 66, 66, 66, 66, 70, 70, 70, 58, 62, 78, 74, 46, 46, 42, 54 and 54 indicated , respectively, in order of appearance).

In fig. 11 shows exemplary cancers in which there is a relatively large proportion of patients who are triple positive for PD-L1/CD8/IFN-Y.

In fig. Figure 12 shows an example of ER+ breast cancer and pancreatic cancer, which have a relatively low proportion of patients who are triple positive for PD-L1/CD8/IFN-Y.

In fig. Figure 13 shows the proportion of typical breast cancer patients who are triple positive for PD-L1/CD8/IFN-Y.

In fig. Figure 14 shows the proportion of typical colon cancer patients who are triple positive for PD-L1/CD8/IFN-Y.

In fig. 15 graphically presents the results of flow cytometry of surface expression of PD-L1 in EBC-1 cells in vitro with or without administration of Compound A17. EBC-1 cells are non-small cell lung cancer (NSCLC) cancer cells with cMET amplification.

In fig. 16 graphically shows the expression of PD-L1 mRNA in Hs.746.T cells in a tumor xenograft model with or without administration of Compound A17. Hs.746.T cells are gastric cancer cells with c-MET amplification and c-MET mutation.

In fig. 17 graphically shows the expression of PD-L1 mRNA in H3122 cells in vitro with or without administration of Compound A23. H3122 cells are non-small cell lung cancer (NSCLC) cells with ALK translocation.

In fig. 18 graphically shows the expression of PD-L1 mRNA in LOXIMV1 cells (melano cells

- 27 045940 we with BRAF mutation) in a tumor xenograft model after administration of compound A29 or without such administration.

In fig. 19 graphically depicts PD-L1 mRNA expression in HEYA8 cells (KRAS mutation ovarian cancer cells) in a tumor xenograft model with or without administration of Compound A34.

In fig. 20 graphically depicts PD-L1 mRNA expression in UKE-1 cells (JAK2 V617F mutant myeloproliferative neoplasm cells) in a tumor xenograft model with or without administration of Compound A18.

Brief description of tables

In table Figure 1 shows the amino acid and nucleotide sequences for mouse, chimeric and humanized antibody molecules against PD-1. These antibody molecules include the mouse monoclonal antibodies mAb BAP049, the chimeric mAbs BAP049-chi and BAP049-chi-Y, and the humanized mAbs BAP049-hum01 - BAP049-hum16 and BAP049-clone-A - BAP049-clone-E. In table 1 shows the amino acid and nucleotide sequences of the heavy and light chain CDR regions, 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 Figure 2 shows the amino acid and nucleotide sequences of the heavy and light chain framework regions for the humanized mAbs BAP049-hum01 - BAP049-hum16 and BAP049-clone-A BAP049-clone-E.

In table Figure 3 shows the amino acid sequences of the constant regions of the heavy chains of human IgG and the human kappa light chain.

In table Figure 4 shows the amino acid sequences of the heavy and light chain leader sequences from the humanized mAbs BAP049-clone-A - BAP049-clone-E.

In table 5 shows the amounts obtained, titers, monomer content and endotoxin levels for selected humanized monoclonal antibodies BAP049 expressed in CHO cells.

In table 6 shows the charged isoforms detected by the Novex IEF isoelectric focusing assay for selected humanized mAbs BAP049 expressed in CHO cells.

In table 7 depicts selected therapeutic agents that can be administered in combination with an anti-PD-1 antibody molecule and other immunomodulators (eg, one or more of the following: costimulatory molecule activator and/or immune checkpoint molecule inhibitor) described in the present invention. In table 7 shows the following (from left to right): the designation of the second therapeutic agent compound, the structure of this compound, and the published patent application (publication) disclosing this compound.

Detailed description

Programmed death protein 1 (PD-1) is a member of the CD28/CTLA-4 family and is expressed on activated CD4' and CD8+ T cells, T regulatory cells (T _reg ), and B cells. This protein negatively regulates the signaling pathway and function of effector T cells. PD-1 is induced on tumor-infiltrating T cells, resulting in functional exhaustion or dysfunction ((Keir et al. (2008) Annu. Rev. Immunol. 26:677-704; Pardoll et al. (2012) Nat. Rev. Cancer 12(4):252–64).

The PD-1 protein delivers a coinhibitory signal upon binding to either of its two ligands, programmed death ligand 1 (PD-L1) or programmed death ligand 2 (PD-L2). The PD-L1 protein is expressed on T cells, natural killer (NK) cells, macrophages, dendritic cells (DC), B cells, epithelial cells, vascular endothelial cells, and in many types of tumors. High expression of PD-L1 on murine and human tumor cells is associated with adverse clinical outcomes in various forms of cancer ((Keir et al. (2008) Annu. Rev. Immunol. 26:677-704; Pardoll et al. (2012) Nat. Rev. Cancer 12(4):252–64) PD-L2 is expressed on dendritic cells, macrophages, and some tumors.

Preliminary preclinical and clinical evaluation of PD-1 pathway blockade has been performed for antitumor immunotherapy purposes. In both preclinical and clinical studies, blockade of the PD-1 pathway has been shown to restore effector T cell activity and induce a robust antitumor response. For example, blockade of the PD-1 signaling pathway when T cell effector functions are exhausted/dysfunction restores these functions (e.g., proliferation, IFNγ secretion, or cytolytic function) and inhibits Tr^ cell functions (Keir et al. (2008) Annu. Rev. Immunol 26:677–704 Pardoll et al (2012) Nat Rev Cancer 12(4):252–64

Accordingly, the present invention relates, at least in part, to antibody molecules (eg, humanized antibody molecules) that bind to programmed death proteins 1 (PD-1) with high affinity and specificity. In one embodiment, the invention discloses humanized anti-PD-1 antibodies that exhibit surprisingly low immunogenicity. For example, humanized BAP049 antibodies have been found to have a risk score of less than 650, 600, 550, or less than 500 based on T cell epitope assays described in ISO

- 28 045940 Bretting. In other embodiments, it has been shown that a selected combination of frame regions, such as those shown in FIG. 5 and 7, has different product performance indicators and binding properties.

Additional aspects of the present invention include nucleic acid molecules encoding antibody molecules, expression vectors, host cells, and methods for producing antibody molecules. The invention also relates to immunoconjugates, multispecific or bispecific molecules and pharmaceutical compositions containing antibody molecules. The anti-PD-1 antibody molecules of the invention can be used for the treatment, prevention and/or diagnosis of cancer or malignant diseases (such as solid and soft tissue tumors, melanoma, e.g. advanced melanoma, hepatocellular carcinoma, pancreatic cancer, renal cell carcinoma (RCC), such as metastatic RCC or clear cell RCC, gliomas or glioblastomas, multiple myeloma, colon cancer, and lung cancer, such as non-small cell carcinoma), and infectious diseases (such as infectious diseases such as hepatitis, e.g. C (for example, chronic viral hepatitis), sepsis). Thus, the invention discloses methods for detecting PD-1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-1 antibody molecules.

The term programmed death protein-1 or PD-1 includes isoforms of mammalian PD-1, for example, human PD-1, species homologs of human PD-1, and analogues thereof containing at least one common epitope with PD-1.

The amino acid sequence of PD-1, for example human PD-1, is known in the art, see, for example, the publications of Shinohara T et al. (1994) Genomics 23(3):704-6; Finger LR, et al. Gene (1997) 197(1-2):177-87.

Definitions of additional terms are given below and further in the text of the present invention.

As used in the invention, the singular forms refer to one or more than one (eg, at least one) grammatical entity from a paragraph of the invention.

As used herein, the conjunction or means and/or and is used interchangeably with the above conjunctions unless the context clearly indicates otherwise.

Near and approximately usually mean an acceptable degree of error for the quantity being measured, taking into account the nature or accuracy of the measurements. The approximate degree of error is within 20 percent (%), typically within 10%, and more typically within 5% of a specified value or range of values.

The compositions and methods of the present invention include polypeptides and nucleic acids having the specified sequences, or sequences substantially identical or similar to the specified ones, for example, sequences that are at least 85, 90, 95% identical or with a higher degree of identity to the specified sequence. With respect to an amino acid sequence, the term substantially identical is used herein to mean a first amino acid containing a sufficient or minimal number of amino acid residues that: i) are identical, or ii) are conservative substitutions of aligned amino acid residues in a second amino acid sequence, such that that the first and second amino acid sequences may have a common structural domain and/or a common functional activity. For example, amino acid sequences that contain a common structural domain are at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% identical, or 99% identical to a reference sequence, e.g. sequence presented in the invention.

With respect to a nucleotide sequence, the term substantially identical is used herein to mean a first nucleic acid sequence containing 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 nucleic acid sequences encode a polypeptide having common functional activity, or encode a common structural domain of a polypeptide, or a common functional polypeptide activity. For example, nucleotide sequences that are at least about 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to a reference sequence, for example, the sequence provided in the invention.

The term functional variant refers to polypeptides that have an amino acid sequence substantially identical to the natural sequence, or are encoded by a substantially identical nucleotide sequence, and which are capable of having one or more actions characteristic of the natural sequence.

Calculation of the degree of homology or sequence identity between sequences (these terms are used interchangeably in the invention) is performed as follows.

To determine the percentage identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison (for example, gaps may be introduced in one or both, that is, in the first and second amino

- 29 045940 acid sequence or nucleic acid sequences for optimal alignment, and non-homologous sequences can be neglected for comparison purposes). In a preferred embodiment, the length of the reference sequence aligned for comparison 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 original sequence. Comparisons are then made between amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules at that position are identical (according to the invention, the identity of an amino acid or nucleic acid is equivalent to homology of the amino acid or nucleic acid).

The percentage identity between two sequences depends on the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that must be introduced to optimally align the two sequences.

Comparing sequences and determining the percent identity between two sequences can be done using a mathematical algorithm. In a preferred embodiment, the percentage identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453), which is included in the GAP program in the GCG software package (available at http: //www.gcg.com), using either the Blossum 62 matrix or the RAM250 matrix, and the following parameters: a penalty for opening a gap of 16, 14, 12, 10, 8, 6 or 4, and a penalty for continuing a gap equal to 1, 2, 3, 4, 5 or 6. In another preferred embodiment, the percentage identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using the NWSgapdna matrix. CMP, a penalty for opening a gap of 40, 50, 60, 70, or 80, and a penalty for opening a gap of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the set that should be used unless otherwise noted) is a Blossum 62 substitution matrix with the following parameters: omission penalty 12, gap extension penalty 4, and frameshift omission penalty 5.

The percentage of identity between 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 included in the ALIGN program (version 2.0), using the PAM120 residue substitution weight table , the penalty for extending the gap is 12 and the penalty for missing is 4.

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

As used herein, the term hybridizes under low stringency, medium stringency, high stringency, or very high stringency conditions describes the hybridization and washing conditions. Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated herein by reference. This publication describes aqueous and non-aqueous methods, and any of them can be used. The specific hybridization conditions referenced in the invention are as follows: 1) low stringency hybridization conditions are 6xsodium chloride/sodium citrate (SSC) at approximately 45°C, followed by two washes in 0.2xSSC, 0.1 % SDS, at least 50°C (for low severity, wash temperatures can be increased to 55°C); 2) medium stringency hybridization conditions are 6xSSC at approximately 45°C, followed by one or more washes in 0.2xSSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions are 6xSSC at approximately 45°C, followed by one or more washes in 0.2xSSC, 0.1% SDS at 65°C; and, preferably 4) very high stringency hybridization conditions are 0.5 M sodium phosphate, 7% SDS at 65°C, followed by one or more washes at

- 30 045940

0.2xSSC, 1% SDS at 65°C. The preferred conditions are the very high stringency conditions (4) and the conditions that should be used unless otherwise noted.

It should be understood that the molecules of the present invention may have additional conservative substitutions or substitutions of nonessential amino acids that do not significantly affect their functions.

The term amino acid is intended to encompass all molecules, both natural and synthetic, that include both amino functionality and acid functionality and can be incorporated into a polymer of naturally occurring amino acids. Examples of amino acids include natural amino acids, analogs, derivatives and related amino acids; amino acid analogues having variant side chains; and all stereoisomers of any of the above examples. As used herein, the term amino acid includes both D- and L-optical isomers and peptidomimetics.

A conservative amino acid substitution is a substitution in which an amino acid residue is replaced by an amino acid residue having a similar side chain. In this area, families of amino acid residues having similar side chains have been identified. 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), non-polar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g. threonine, valine, isoleucine) and aromatic side chains (e.g. tyrosine, phenylalanine , tryptophan, histidine).

The terms polypeptide, peptide and protein (when single chain) are used interchangeably in the invention to refer to amino acid polymers of any length. Such a polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids. These 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 to a labeling moiety. The polypeptide may be isolated from natural sources, may be produced recombinantly from a eukaryotic or prokaryotic host, or may be the product of synthesis.

The terms nucleic acid, nucleic acid sequence, nucleotide sequence or polynucleotide sequence and polynucleotide are used interchangeably. These terms refer to the polymeric form of nucleotides of any length, or deoxyribonucleotides or ribonucleotides, or analogs thereof. The polynucleotide may be single-stranded or double-stranded, and if 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 analogues. The nucleotide sequence may be interrupted by non-nucleotide components. The polynucleotide may be further modified after polymerization, for example, by conjugation with a labeling component. The nucleic acid may be a recombinant polynucleotide, may be derived from cDNA, or may be a polynucleotide of genomic, semisynthetic, or synthetic origin that is either not naturally occurring or is linked to another polynucleotide in an unnatural configuration.

The term isolated, as used herein, refers to material that has been removed from its original or native environment (eg, from the natural environment if the material is of natural origin). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide separated by human intervention from some or all of the co-existing materials in the natural system is isolated. Such polynucleotides may be part of a vector, and/or such polynucleotides or polypeptides may be part of a composition and yet be isolated in such a vector or composition that are not part of the environment in which they naturally occur.

Various aspects of the present invention are described in more detail below. Additional definitions are set out in the description text.

Antibody molecules.

In one embodiment, the antibody molecule binds to PD-1 of a mammal, such as a human. For example, the antibody molecule specifically binds to an epitope on PD-1, such as a linear or conformational epitope (eg, an epitope described in the invention).

As used herein, the term antibody molecule refers to a protein, for example an immunoglobulin 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 has an immunoglobulin Fc region). IN

- 31 045940 In one embodiment, the antibody molecule contains a full-length antibody, or a full-length immunoglobulin chain. In one embodiment, the antibody molecule contains an antigen-binding fragment or a 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 may have multiple immunoglobulin variable domain sequences, each of which binds to the same epitope.

In one embodiment, the antibody molecule is a multispecific antibody molecule, for example, it contains a plurality of immunoglobulin variable region sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope, and a second immunoglobulin variable domain sequence of the plurality has binding specificity for the second epitope. In one embodiment, the first and second epitopes are located on the same antigen, for example, 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 each other. In one embodiment, the first and second epitopes are located on different antigens, for example, on different proteins (or on different subunits of a multimeric protein). In one embodiment, the multispecific antibody molecule comprises a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, 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 having 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 located on the same antigen, for example, 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 each other. In one embodiment, the first and second epitopes are located on different antigens, for example, on 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 half-antibody having binding specificity for a first epitope and a half-antibody having binding specificity for a second epitope. In one embodiment, a bispecific antibody molecule comprises a half-antibody or fragment thereof having a binding specificity for a first epitope and a half-antibody or fragment thereof having a binding specificity for a second epitope. In one embodiment, the bispecific antibody molecule comprises a ScFv or fragment thereof having binding specificity for a first epitope, and a ScFv or fragment thereof having binding specificity for a second epitope. In one embodiment, the first epitope is located on PD-1 and the second epitope is located on TIM-3, LAG-3, SEACAM (eg, SEACAM-1 and/or SEACAM-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 fragment of the antibody (eg, Fab, F(ab') ₂ and Fv). For example, an antibody molecule may include a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light chain variable domain (L) 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, an antibody molecule includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen binding regions, such as Fab, Fab', F(ab') ₂ , Fc, Fd, Fd', Fv, single chain antibodies (ScFv, for example), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific) and chimeric (for example, humanized) antibodies, which can be obtained by modifying whole antibodies or synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind to their corresponding antigen or receptor. Antibodies and antibody fragments can be of any type

- 32 045940 antibodies, including without limitation IgG, IgA, IgM, IgD and IgE, and to any subtype of antibodies (for example, IgG1, IgG2, IgG3 and IgG4). The antibody molecule preparation may be monoclonal or polyclonal. The antibody molecule may also be a human, humanized, CDR-transplanted or in vitro generated antibody. The antibody may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3 or IgG4. The antibody may also have a light chain selected from, for example, kappa or lambda chains. The term immunoglobulin (Ig) is used interchangeably with the term antibody.

Examples of antigen binding fragments of an antibody molecule include: (I) Fab fragment, a monovalent fragment consisting of VL, VH, CL and CH1 domains; (II) F(ab') ₂ fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (III) Fd fragment consisting of VH and CH1 domains; (IV) Fv fragment consisting of the VL and VH domains of one arm of the antibody; (V) a diabody fragment (dAb), which consists of a VH domain; (VI) camelized 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: 5879-5883); (VIII) single domain antibody. These antibody fragments are prepared using conventional methods known to those skilled in the art, and these fragments are screened for utility in the same manner as intact antibodies.

The term antibody includes intact molecules as well as functional fragments thereof. Antibody constant regions may be altered, eg, mutated, to change properties of the antibody (eg, to increase or decrease one or more of the following properties: Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or complement function).

Antibody molecules can also be single domain antibodies. Single domain antibodies may include antibodies in which the hypervariable regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies that do not naturally have light chains, single domain antibodies derived from conventional 4 chain antibodies, engineered antibodies, and single domain scaffolds other than antibody scaffolds. Single domain antibodies can be any antibodies in the prior art, or any single domain antibodies produced in the future. Single domain antibodies can be obtained from any species, including, without limitation, mouse, human, camel, llama, fish, shark, goat, rabbit and cattle. According to another aspect of the present invention, the single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking light chains. Such single-domain antibodies are described, for example, in WO 9404678. For clarity, such a variable domain derived from the heavy chain of an antibody that does not naturally have a light chain is referred to in the invention as a VHH or nanobody, in contrast to the conventional VH of four-chain immunoglobulins. Such a VHH molecule can be derived from antibodies produced in Camelidae species such as camels, llamas, dromedary camels, alpacas and guanacos. Species other than Camelidae can produce heavy chain antibodies that do not naturally have a light chain; such VHH are included within the scope of the present invention.

The VH and VL regions are divided into regions of hypervariability, called hypervariable regions (CDR), interspersed with regions that are more conserved, called framework regions (FR or FW).

The extent of the framework and CDR regions has been accurately determined by a number of methods (see Kabat, 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 196:901917 and the definition of AbM used in Oxford Molecular software for modeling AbM antibodies See general information, e.g. Protein Sequence and Structure Analysis of Antibody Variable Domains in: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

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

The precise boundaries of the amino acid sequence of the CDR in question can be determined using any of a number of well-known schemes, including the systems described by Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (numbering scheme no Kabat), Al-Lazikani et al., (1997) JMB 273,927-948 (numbering scheme no. Chothia). According to the invention, CDR regions defined using the Chothia numbering system are also sometimes referred to as hypervariable loops.

For example, according to the Kabat system, the CDR amino acid residues in the heavy chain variable region (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3); and amino acids

- 33 045940 The CDRs in the light chain variable region (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to the Chothia system, the CDR amino acid residues 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). When combining the CDR definitions according to the Kabat numbering and the Chothia numbering, the following numbering scheme is obtained: CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3) in human VH, and from amino acid residues 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.

In general, unless specifically stated, anti-PD-1 antibody molecules may include any combination of one or more Kabat CDR regions and/or Chothia hypervariable loops, such as those listed in Table 1. 1. In one embodiment, the following definitions are used for the anti-PD-1 antibody molecules listed in Table. 1: HCDR1 according to the combined Kabat and Chothia CDR definitions, and HCCDR 2-3 and LCCDR 1-3 regions according to the Kabat CDR definition. By all definitions, each of VH and VL typically includes three CDR regions and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

As used herein, the term immunoglobulin variable domain sequence refers to an amino acid sequence that can form the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a natural variable domain. For example, the sequence may not include or may include one, two or more N- or C-terminal amino acids, or may include 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 containing surface-forming determinants that binds to a PD-1 polypeptide or an epitope thereof. For proteins (or protein mimics), the antigen-binding site typically includes one or more loops (of at least four amino acids or amino acid mimics) forming a surface that binds to the PD-1 polypeptide. Typically, the antigen binding site of an antibody molecule includes at least one or two CDR regions and/or hypervariable loops, or more typically at least three, four, five or six CDR regions and/or hypervariable loops.

The terms compete or cross-compete are used interchangeably herein to refer to the ability of an antibody molecule to interfere with the binding of an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody molecule of the invention, to a target, such as human PD-1. The interference with binding may be direct or indirect (eg, through allosteric modulation of the antibody molecule or target). The extent to which an antibody molecule can interfere with the binding of another antibody molecule to a target, and therefore whether it can be considered competition, can be determined using a competitive binding assay, such as a FACS assay, ELISA or BIACORE assay. In some embodiments, the competitive binding assay is a quantitative competition assay. In some embodiments, the first anti-PD-1 antibody molecule is considered to compete for target binding with a second anti-PD-1 antibody molecule if binding of the first anti-PD-1 antibody molecule to the target is reduced by 10% or more, such as by 20% or more, by 30% or more, by

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 greater, 98% or greater, 99% or greater, according to a competitive binding assay (eg, a competitive binding assay described herein).

The terms monoclonal antibody or monoclonal antibody composition in the context of the present invention refer to a preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. Monoclonal antibodies can be produced by hybridoma technology or by methods that do not use hybridoma technology (eg, recombinant methods).

Effectively, a human protein is a protein that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. In some cases, the use of NAMA can be problematic, for example, if the antibody molecule is repeatedly administered, for example, in the treatment of a chronic or recurrent pathological condition.

The HAMA response may render repeated antibody administration potentially ineffective due to increased antibody clearance from serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)), as well as potential 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 antibody may be produced recombinantly, such as by phage display or combinatorial methods.

- 34 045940

Phage display methods and combinatorial methods for generating antibodies are known in the art (and are described, for example, in the following publications: Ladner et al. US Patent No. 5223409; Kang et al. International Published Application No. WO 92/18619; Dower et al. International Published Application Application No. WO 91/17271; Winter et al. International Published Application WO 92/20791; Markland et al. International Published Application No. WO 92/15679; Breitling et al. International Published Application WO 93/01288; McCafferty et al. International Published Application WO 92/01047 Garrard et al International Published Application WO 92/09690 Ladner et al International Published Application WO 90/02809 Fuchs et al (1991) Bio/Technology 9:1370-1372 Hay et al al (1992) Hum Antibod Hybridomas 3:81-85 Huse et al (1989) Science 246:1275-1281 Griffths et al (1993) EMBO J 12:725-734 Hawkins et al ( 1992) 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 Res. 19:4133-4137; and Barbas et al. (1991) PNAS 88:7978-7982, and the contents of all of these publications are incorporated by reference).

In one embodiment, the antibody is a fully human antibody (e.g., an antibody produced in mice that have been genetically engineered to produce the antibody from a human immunoglobulin sequence), or a non-human antibody, such as an antibody from a rodent (mice or rat) ), goats, primates (e.g. monkeys), camels. Preferably, the non-human antibody is a rodent antibody (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

Human monoclonal antibodies can be produced using transgenic mice carrying human immunoglobulin genes, as opposed to the mouse system. Splenocytes from such transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs with specific affinities for epitopes from human proteins (see, for example, Wood et al. International Application WO 91/00906, Kucherlapati et al. Published Application 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. 1994 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 part thereof, such as a CDR, is generated in a non-human body, such as a rat or mouse. The present invention includes chimeric, CDR-grafted and humanized antibodies. The present invention includes antibodies that are produced in a non-human body, for example in a rat or mouse, and then modified, for example in the variable framework or constant region, to reduce antigenicity in humans.

Chimeric antibodies can be produced by methods in recombinant DNA known in the art (see Robinson et al., International Patent Application Published PCT/US86/02269; Akira, et al., European Patent Application 184187; Taniguchi, M., European Patent Application 171496; Morrison et al., European Patent Application 173494; Neuberger et al., International Application WO 86/01533; Cabilly et al., US Patent No. 4816567; Cabilly et al., European Patent Application 125023; Better et al (1988 Science 240:1041-1043) Liu et al (1987) PNAS 84:3439-3443 Liu et al 1987 J Immunol 139:35213526 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 will have at least one or two, but typically all three, recipient CDR regions (from immunoglobulin heavy and/or light chains) that are replaced by donor CDR regions. Substitutions can be introduced into an antibody that are at least a portion of the non-human CDR, or only some of the CDR regions can be replaced with non-human CDRs. It is only necessary to replace certain CDR regions required for the humanized antibody to bind to PD-1. Preferably, the donor is a rodent antibody, such as a rat or mouse antibody, and the recipient is a human scaffold or human consensus scaffold. Typically, the immunoglobulin carrying the CDR is called the donor, and the immunoglobulin bearing the scaffold is called the acceptor. In one embodiment, the donor immunoglobulin is non-human (eg, derived from rodents). The acceptor framework has a naturally occurring (eg, human) framework or consensus framework or sequence that is approximately 85% or greater identical thereto, preferably 90, 95, 99% or higher identical.

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 of proteins, each position in the consensus sequence is occupied by the amino acid most frequently found at that position in that family.If two

- 35 045940 amino acids are equally common, each of them can be included in the consensus sequence. The term consensus framework refers to a framework region in an immunoglobulin consensus sequence.

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

Humanized or CDR-grafted antibodies can be produced by CDR grafting or CDR replacement, wherein one, two, or all of the CDR regions 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 Pat. No. 5,225,539, and the contents of all of these publications are incorporated herein by reference. Winter has described a method for transplanting CDRs that can be used to produce humanized antibodies of the present invention (GB Patent Application GB 2188638A, filed March 26, 1987, Winter US Patent 5,225,539), the contents of which are incorporated by reference herein.

Also included within the scope of the present invention are humanized antibodies in which specific amino acids have been replaced, deleted, or added. Criteria for selecting amino acids from a donor are described in US Pat. No. 5,585,089, for example in columns 12-16 of US Pat. No. 5,585,089, for example in columns 12-16 of US Pat. No. 5,585,089, the contents of which are incorporated herein by reference. Other methods for humanizing antibodies are described by Padlan et al., EP 519596 A1, publication date December 23, 1992.

The antibody molecule may be a single chain antibody. A single chain antibody (ScFv) can be generated by genetic engineering (see, for example, Colcher, D. et al. (1999) All. N. Y. Acad. Sci. 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245-52). A single chain antibody can undergo dimerization or multimerization to create multivalent antibodies that have specificity for different epitopes of the same target protein.

In other embodiments, the antibody molecule has a heavy chain constant region that is selected, for example, from the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular, selected from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4 (eg, human sequences). In another embodiment, the antibody molecule has a light chain constant region that is selected, for example, from kappa light chain or lambda chain constant regions (eg, human sequences). The constant region may be altered, e.g., mutated, to modify properties of the antibody (e.g., to increase or decrease one or more of the following properties: Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, and/or complement function) . In one embodiment, the antibody has 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 absent ability to bind to the Fc receptor. For example, it is an isotype or subtype, fragment or other mutant that lacks the ability to bind to the Fc receptor, for example, it has a mutant Fc receptor binding region or a deletion of this region.

Methods for altering the constant region of an antibody are known in the art. Antibodies with altered function, for example, with altered affinity for an effector ligand, such as an FcR on a cell, or a C1 complement component, can be obtained by replacing at least one amino acid residue in the constant portion of the antibody with another residue (see, for example, the patent EP 388151 A1, US Patent 5624821 and US Patent No. 5648260, the contents of which are incorporated by reference herein). It is possible to describe a similar type of change, the introduction of which into murine immunoglobulin or other types of immunoglobulin will lead to a decrease or elimination of these functions.

The antibody molecule may be derivatized or attached to another functional molecule (eg, another peptide or protein). As used herein, the term derivatized antibody molecule refers to a modified molecule. Derivatization methods include, but are not limited to, the addition of a fluorescent moiety, radionuclide, toxin, enzyme, or affinity ligand such as biotin. Thus, it is intended that the antibody molecules of the invention include derivatized and otherwise modified forms of the antibodies of the invention, including immunoadhesion molecules. For example, an antibody molecule may be operably linked (by chemical coupling, genetic fusion, non-covalent association, or other means) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable substance, a cytotoxic substance, a pharmaceutical substance and/or protein or peptide that can mediate the association of anti

- 36 045940 body or part of an antibody with another molecule (for example, with a streptavidin core region or a polyhistidine tag).

One type of derivatized antibody molecule is made by linking two or more antibodies (of the same type or different types, for example to create bispecific antibodies). Suitable cross-linking agents include heterobifunctional agents that have two different reactive groups separated by a suitable spacer (such as tmaleimidobenzoyl-N-hydroxysuccinimide ester), or homobifunctional agents (for example, disuccinimidyl suberate). Such linkers are available from Pierce Chemical, III.

Useful detectable substances with which the antibody molecule of the invention can be derivatized (or labeled) include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, metal atoms that emit fluorescent radiation, such as europium (Eu), and others antanides and radioactive substances (described below). Exemplary fluorescent detectable substances include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-chloride-naphthalene sulfonyl 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, its detection is accomplished by adding additional reagents that the enzyme uses to produce the detectable reaction product. For example, if the detectable substance horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that can be detected. The antibody molecule can also be derivatized with a prosthetic group (eg, streptavidin/biotin and avidin/biotin). For example, the antibody can be derivatized using biotin, and detection is carried out by indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, fluorescein dichlorotriazinylamine, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; and examples of bioluminescent materials include luciferase, luciferin and aequorin.

The labeled antibody molecule can be used, for example, for the following diagnostic and/or experimental purposes, including:

(I) isolating a given antigen by standard methods such as affinity chromatography or immunoprecipitation;

(ii) detection of a given antigen (eg, in a cell lysate or cell supernatant) to assess the relative abundance and expression pattern of the protein;

(III) monitoring protein levels in tissues as part of a clinical analysis technique, for example, to determine the effectiveness of a given treatment regimen.

The antibody molecules may be conjugated to another molecular entity, typically a label, or to a therapeutic (eg, cytotoxic or cytostatic) agent or functional moiety. Radioactive isotopes can be used for diagnostic or therapeutic purposes. Radioactive isotopes that can be attached to the anti-PD-1 antibody include, but are not limited to, α-, β-, or γ-ray emitters. Such radioactive isotopes include, but are not limited to, iodine ( ¹³¹ I or ¹²⁵ I), yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ Ac), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re), bismuth ( ²¹² Bi or ²¹³ Bi), indium (111In), technetium ( ⁹⁹ mTC), phosphorus ( ³² P), 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 used as therapeutic agents include yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ Ac), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re), bismuth ( ²¹² Bi or ²¹³ Bi), and rhodium ( ¹⁸⁸ Rh). Radioactive isotopes used as tracers, for example for diagnostic applications, include iodine ( ¹³¹ I or ¹²⁵ I), indium (111B), technetium ( ⁹⁹ mTC), phosphorus ( ³² P), carbon ( ¹⁴ C) and tritium ( ³ H), or one or more of the above therapeutic isotopes.

The present invention relates to radiolabeled antibody molecules and methods for labeling them. In one embodiment, a method of labeling an antibody molecule is disclosed. The method involves contacting an antibody molecule with a chelating agent, resulting in a conjugated antibody. A radiolabel with a radioisotope, for example, 111 indium, ⁹⁰ yttrium and ¹⁷⁷ lutetium, is attached to the conjugated antibody, thereby obtaining a labeled antibody molecule.

As described above, the antibody molecule can be conjugated to a therapeutic agent. Therapeutic active radioisotopes are mentioned above. Examples of other therapeutic agents include taxol, cytochalasin, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracinedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, for example, maytansinol (see US patent 5208020), CC1065 (see US patents 5475092, 5585499, 5846545) and their analogs or homologues. Therapeutics include, but are not limited to, antimetabolites (eg, methotrexate, 6-mercaptopurine, 6-thioguanine,

- 37 045940 cytarabine, 5-fluorouracil, dacarbazine), alkylating agents (e.g. mechlorethamine, thiotepa, chlorambucil, CC-1065, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C and platinum(II) cis-dichlorodiamine (DDP) cisplatin), anthracyclines (eg, daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (eg, dactinomycin (formerly actinomycin), bleomycin, mithramycin and anthramycin (AMC)), and antimitotic agents ( e.g. vincristine, vinblastine, taxol and maytansinoids).

In one aspect, the present invention provides a method for producing a targeted binding molecule that specifically binds to the PD-1 receptor. For example, the targeting binding molecule is an antibody molecule. The method includes: obtaining a target protein that contains at least a portion of the non-human protein, a portion that is homologous (at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96, 97 identical) , 98%) of the corresponding portion of the human target protein, but differs in at least one amino acid (eg, by at least one, two, three, four, five, six, seven, eight, nine or amino acids); producing an antibody molecule that specifically binds to an antigen; and assessing the effectiveness of the binder in modulating the activity of the target protein. The method may further include administering to a human a binder (eg, an antibody molecule) or a derivative thereof (eg, a humanized antibody molecule).

In some embodiments, the antibody molecule is a multispecific (eg, bispecific or trispecific) antibody molecule. Protocols for creating bispecific or heterodimeric antibody molecules are known in the art and include, but are not limited to, for example, the prong-to-valley approach described, for example, in US Pat. No. 5,731,168; pairing Fc by electrostatic interaction, as described, for example, in applications WO 09/089004, WO 06/106905 and WO 2010/129304; formation of a heterodimer by the SEED (Strand Exchange Engineered Domains) method, as described, for example, in WO 07/110205; replacing the Fab arm as described, for example, in WO 08/119353, WO 2011/131746 and WO 2013/060867; a double antibody conjugate, for example, cross-linking an antibody with an amino-reactive group and a sulfhydryl-reactive group to create a bispecific structure using a heterobifunctional reagent, as described, for example, in US Pat. No. 4,433,059; bispecific antibody determinants created by recombination of semi-antibodies (heavy-light chain pairs or FABS) from different antibodies through a cycle of reduction and oxidation of disulfide bonds between two heavy chains, as described, for example, in US patent 4444878; trifunctional antibodies, for example, three Fab' fragments cross-linked through sulfhydryl reactive groups, as described, for example, in US patent 5273743; biosynthetic binding proteins, for example, a pair of scFvs cross-linked through terminal tails, preferably by chemical cross-linking in reaction with a disulfide or amine, as described, for example, in US patent 5534254; bifunctional antibodies, eg, Fab fragments with different binding specificities, dimerized through leucine zippers (eg, c-fos and c-jun), which replace the constant domain, as described, for example, in US patent 5582996; bispecific and oligospecific mono- and oligovalent receptors, for example, the VH-CH1 region of two antibodies (two Fab fragments), connected through a polypeptide spacer between the CH1 region of one antibody and the VH region of another antibody, usually with associated light chains, as described, for example, in US patent 559182 8; bispecific DNA-antibody conjugates, for example, cross-linking antibodies or Fab fragments using a double-stranded DNA region, as described, for example, in US patent 5635602; bispecific fusion proteins, for example, an expression construct containing two scFvs with a hydrophilic coiled-coil peptide linker between them and a full constant region, as described, for example, in US Pat. No. 5,637,481; multivalent and multispecific binding proteins, for example, a dimer of polypeptides having 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, which are commonly referred to as dimers (higher order structures forming bispecific, trispecific or tetraspecific molecules, as described, for example, in US patent 5837242); minibody constructs with linked VL and VH chains, further attached via peptide spacers to the antibody hinge region and the CH3 region, which can be dimerized to form a bispecific/multivalent molecule, as described, for example, in US Pat. No. 5,837,821; VH and VL domains linked via a short peptide linker (eg, 5 or 10 amino acids long), or no linker at all, in any orientation, which can form dimers to form bispecific diabodies; trimers and tetramers, as described, for example, in US patent 5844094; a string of VH domains (or VL domains in family members) linked by peptide bonds with stitchable groups at the C-terminus, further linked to VL domains to form a series of FVs (or scFvs), as described, for example, in US Pat. No. 5,864,019; and single chain VH domain and VL domain binding polypeptides linked through a peptide linker are combined into multivalent structures by non-covalent or chemical cross-linking to form, for example, homobivalent, heterobivalent, trivalent and tetravalent structures involving both the ScFv-type format or the diabody-type format , How

- 38 045940 is described, for example, in US patent 5869620. Additional examples of multispecific and bispecific molecules and methods for their preparation can be found, for example, in patents and published patent applications Nos. US 5910573, US 5932448, US 5959083, US 5989830, US 6005079, US 6239259, US

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9323537 A1, WO 9409131 A1, WO 9412625 A2, WO 9509917 A1, WO 9637621 A2, WO 9964460 A1. The contents of the above applications are incorporated in the invention by reference in their entirety.

In other embodiments, the anti-PD-1 antibody molecule (e.g., a monospecific, bispecific, or multispecific antibody molecule) is covalently linked, e.g., fused, to another partner, e.g., a protein, e.g., one, two, or more cytokines, e.g. form of a fusion molecule, for example a fusion protein. In other embodiments, 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 interleukins 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 (eg, PD-1), a second binding specificity for a second target (eg, LAG-3 or TIM-3), and is optionally associated with an interleukin domain (eg IL-12), eg full-length IL-12 or a portion thereof.

The terms fusion protein and fusion polypeptide refer to a polypeptide having at least two moieties covalently linked to each other, each moiety being a polypeptide with different properties. The property may be a biological property, such as activity in vitro or in vivo. The property may also be a simple chemical or physical property, such as binding to a target molecule, catalyzing a reaction, etc. The two moieties may be linked directly through a single peptide bond or through a peptide linker but be in frame with each other.

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

Examples of anti-PD-1 antibody molecules.

In one embodiment, the anti-PD-1 antibody molecule includes:

(a) a heavy chain variable region (VH) which comprises VHCDR1 having the amino acid sequence SEQ ID NO: 4, VHCDR2 having the amino acid sequence SEQ ID NO: 5 and VHCDR3 having the amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) which comprises VLCDR1 having the amino acid sequence of SEQ ID NO: 13, VLCDR2 having the amino acid sequence of SEQ ID NO: 14 and VLCDR3 having the amino acid sequence of SEQ ID NO: 33;

(b) VH, which contains VHCDR1 with an amino acid sequence selected from SEQ ID NO: 1, VHCDR2 with an amino acid sequence of SEQ ID NO: 2, and VHCDR3 with an amino acid sequence of SEQ ID NO: 3; and VL, which contains VLCDR1 having the amino acid sequence SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 11 and VLCDR3 having the amino acid sequence SEQ ID NO: 32;

(c) VH, which contains VHCDR1 with the amino acid sequence of SEQ ID NO: 224, 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, which contains VLCDR1 with the amino acid sequence SEQ ID NO: 13, VLCDR2 with the amino acid sequence SEQ ID NO: 14 and VLCDR3 with the amino acid sequence SEQ ID NO: 33; or (d) VH, which contains VHCDR1 with the amino acid sequence of SEQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and VL, which contains VLCDR1 having the amino acid sequence SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 11, and VLCDR3 having the amino acid sequence SEQ ID NO: 32.

- 39 045940

In some embodiments, the anti-PD-1 antibody molecule comprises:

(I) a heavy chain variable region (VH) that contains the amino acid sequence of VHCDR1 selected from SEQ ID NO: 1, SEQ ID NO: 4 or SeQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and (II) a light chain variable region (VL) which comprises VLCDR1 having the amino acid sequence of SEQ ID NO: 10, VLCDR2 having the amino acid sequence of SEQ ID NO: 11, and VLCDR3 having the amino acid sequence of SEQ ID NO: 32.

In other embodiments, the anti-PD-1 antibody molecule comprises:

(I) a heavy chain variable region (VH) which contains the amino acid sequence of VHCDR1 selected from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224, VHCDR2 with the amino acid sequence of SEQ ID NO: 5, VHCDR3 with the amino acid sequence sequence SEQ ID NO: 3; and (II) a light chain variable region (VL) which comprises VLCDR1 having the amino acid sequence of SEQ ID NO: 13, VLCDR2 having the amino acid sequence of SEQ ID NO: 14, and VLCDR3 having the amino acid sequence of SEQ ID NO: 33.

In embodiments of the above antibody molecules, the VHCDR1 region comprises the amino acid sequence SEQ ID NO: 1. In other embodiments, VHCDR1 comprises the amino acid sequence SEQ ID NO: 4. In other embodiments, VHCDR1 comprises the amino acid sequence SEQ ID NO: 224.

In embodiments, the above antibody molecules have a heavy chain variable region comprising at least one framework (FW) region that contains any amino acid sequence of SEQ ID NO: 147, 151, 153, 157, 160, 162, 166, or 169, or an amino acid sequence that is at least 90% identical to the specified sequences, or having no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences of SEQ ID NO: 147, 151, 153, 157, 160, 162, 166 or 169 .

In other embodiments, the above antibody molecules have a heavy chain variable region that contains at least one framework region comprising any amino acid sequence of SEQ ID NO: 147, 151, 153, 157, 160, 162, 166, or 169.

In other embodiments, the above antibody molecules have a heavy chain variable region that contains at least two, three, or four framework regions containing any amino acid sequence of SEQ ID NO: 147, 151, 153, 157, 160, 162, 166, or 169.

In other embodiments, the above antibody molecules comprise VHFW1 having amino acid sequence SEQ ID NO: 147 or 151, VHFW2 having amino acid sequence SEQ ID NO: 153, 157 or 160, and VHFW3 having amino acid sequence SEQ ID NO: 162 or 166, and optionally , additionally contain VHFW4 with the amino acid sequence SEQ ID NO: 169.

In other embodiments, the above antibody molecules have a light chain variable region comprising at least one framework region that contains any amino acid sequence of SEQ ID NO: 174, 177, 181, 183, 185, 187, 191, 194, 196, 200 , 202, 205 or 208, or an amino acid sequence that is at least 90% identical to these sequences, or having no more than two amino acid substitutions, insertions or deletions compared to any amino acid sequence of 174, 177, 181, 183, 185, 187, 191, 194, 196, 200, 202, 205 or 208.

In other embodiments, the above antibody molecules have a light chain variable region that contains at least one framework region comprising any amino acid sequence of SEQ ID NO: 174, 177, 181, 183, 185, 187, 191, 194, 196, 200 , 202, 205 or 208.

In other embodiments, the above antibody molecules have a light chain variable region that contains at least two, three, or four framework regions containing any of the amino acid sequences of SEQ ID NO: 174, 177, 181, 183, 185, 187, 191, 194, 196, 200, 202, 205 or 208.

In other embodiments, the above antibody molecules comprise the amino acid sequence of VLFW1 from SEQ ID NO: 174, 177, 181, 183, or 185, the amino acid sequence of VLFW2 from SEQ ID NO: 187, 191, or 194, and the amino acid sequence of VLFW3 from SEQ ID NO: 196, 200, 202 or 205, and optionally further comprises VLFW4 with the amino acid sequence of SEQ ID NO: 208.

In other embodiments, the above antibodies comprise a heavy chain variable domain comprising an amino acid sequence that is at least 85% identical to any of SEQ ID NO: 38, 50, 82, or 86.

In other embodiments, the above antibody molecules comprise a variable

- 40 045940 heavy chain domain containing the amino acid sequences of SEQ ID NO: 38, 50, 82 or 86.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising an amino acid sequence that is at least 85% identical to any of SEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74, or 78.

In other embodiments, the above antibody molecules comprise a light chain variable domain comprising the amino acid sequences of SEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74, or 78.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38.

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

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 91.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 or SEQ ID NO: 102.

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

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

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

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

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

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

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

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

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

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

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

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

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

In other embodiments, the above antibodies comprise a light chain comprising the amino acid sequence of SEQ ID NO: 64.

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

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

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

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

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

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

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

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

In other embodiments, the above antibody molecules comprise a variable

- 41 045940 a heavy chain domain containing the amino acid sequence of SEQ ID NO: 38, and a light chain variable domain containing the amino acid sequence of SEQ ID NO: 42.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain containing 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: 38 and a light chain variable domain containing 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: 50 and a light chain variable domain 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: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 46.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 46.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 54.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 54.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the above antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain variable domain 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: 38 and a light chain variable domain 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: 38 and a light chain variable domain 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: 82 and a light chain variable domain 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: 82 and a light chain variable domain 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: 86 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain containing the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain containing the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain containing 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: 91 and a light chain containing 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: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 72.

- 42 045940

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 48.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 48.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain containing the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the above antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain 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: 52 and a light chain containing 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: 40 and a light chain containing 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: 52 and a light chain 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: 40 and a light chain 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: 40 and a light chain containing 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: 40 and a light chain 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: 84 and a light chain containing 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: 84 and a light chain containing 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: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the above antibody molecules are selected from Fab, 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 kappa or lambda light chain constant regions.

In other embodiments, the above antibody molecules comprise a human IgG4 heavy chain constant region mutated at position 228 according to EU numbering, or at position 108 in SEQ ID NO: 212 or 214, and a kappa light chain constant region.

In other embodiments, the above antibody molecules comprise a human IgG4 heavy chain constant region with a serine to proline substitution mutation at position 228 according to EU numbering, or at position 108 in SEQ ID NO: 212 or 214, and a kappa light chain constant region.

- 43 045940

In other embodiments, the above antibody molecules comprise a human IgG1 heavy chain constant region with an asparagine to alanine substitution mutation at position 297 according to EU numbering, or at position 180 in SEQ ID NO: 216, and a kappa 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 in accordance with EU numbering, or at position 148 in SEQ ID NO: 217, and a proline-to-alanine mutation at position 329 in according to EU numbering, or at position 212 in SEQ ID NO: 217, and a kappa light 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 in accordance with EU numbering, or at position 117 in SEQ ID NO: 218, and a leucine-to-alanine mutation at position 235 in according to the EU numbering, or at position 118 in SEQ ID NO: 218, and the kappa light chain constant region.

In other embodiments, the above antibody molecules are capable of binding to human PD-1 with a dissociation constant ( _KD ) of less than about 0.2 nmol.

In some embodiments, the above antibody molecules bind to human PD-1 with a K _D that is lower than about 0.2, 0.15, 0.1, 0.05, or 0.02 nmol, such as about 0. 13 nmol to 0.03 nmol, for example about 0.077 nmol to 0.088 nmol, for example about 0.083 nmol, and the K _D value is measured, for example, by the Biacore method.

In other embodiments, the above antibody molecules bind to cynomolgus PD-1 with a K _D that is lower than about 0.2, 0.15, 0.1, 0.05 or 0.02 nmol, for example, is about 0 11 to 0.08 nmol, for example approximately 0.093 nmol, and the KD value is measured, for example, by the Biacore method.

In some embodiments, the above antibody molecules bind to both human PD-1 and cynomolgus monkey PD-1 with the same K _D , eg, in nmol order, and the K _D is measured, eg, by the Biacore method. In some embodiments, the above antibody molecules bind to a human PD-1-Ig fusion protein with a K _D that is lower than about 0.1, 0.075, 0.05, 0.025, or 0.01 nmol, such as about 0.04 nmol , and the K _D value is measured, for example, using an ELISA assay.

In some embodiments, the above antibody molecules bind to Jurkat cells that express human PD-1 (e.g., Jurkat cells transfected with human PD-1) with a KD value of less than about 0.1, 0.075, 0.05, 0.025 or 0.01 nmol, for example approximately 0.06 nmol, and the KD value is measured, for example, by FACS analysis.

In some embodiments, the above antibody molecules bind to cynomolgus monkey T cells with a K _D value that is lower than about 1, 0.75, 0.5, 0.25 or 0.1 nmol, for example, is about 0.4 nmol, for example, when measured using FACS analysis.

In some embodiments, the above antibody molecules bind to cells that express cynomolgus PD-1 (e.g., cells transfected with cynomolgus PD-1) with a KD value of less than about 1, 0.75, 0.5, 0 .25 or 0.01 nmol, for example, is approximately 0.6 nmol, for example, when measured by FACS analysis.

In some embodiments, the above antibody molecules do not cross-react with murine or rat PD-1. In other embodiments, the above antibodies cross-react with rhesus macaque PD-1. For example, cross-reactivity can be measured using the Biacore method or using a binding assay using cells that express PD-1 (eg, human PD-1-expressing 300.19 cells). In other embodiments, the above antibody molecules bind to the extracellular Ig-like domain of PD-1.

In other embodiments, the above antibody molecules are capable of reducing the binding of PD-1 to PD-L1, PD-L2, or both ligands, or to cells that express PD-L1, PD-L2, or both cell types. In some embodiments, the above antibody molecules reduce (e.g., block) the binding of PD-L1 to a PD-1-expressing cell (e.g., human PD-1-expressing 300.19 cells) with an IC ₅₀ value of less than about 1.5. 1, 0.8, 0.6, 0.4, 0.2 or 0.1 nmol, for example, is from about 0.79 nmol to about 1.09 nmol, for example, about 0.94 nmol, or about 0 .78 nmol or less, for example approximately 0.3 nmol. In some embodiments, the above antibodies reduce (eg, block) the binding of PD-L2 to a PD-1-expressing cell (eg, human PD-1-expressing 300.19 cells) with an IC ₅₀ value that is lower than about 2.1 .5, 1, 0.5 or 0.2 nmol, for example, is between approximately 1.05

- 44045940 nmol to about 1.55 nmol, or about 1.3 nmol or less, for example about 0.9 nmol.

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

In some embodiments, the antibody molecule is a monospecific antibody molecule or a bispecific antibody molecule. In some embodiments, the antibody molecule has a first binding specificity for PD-1 and a second binding specificity for TIM-3, LAG-3, SEACAM (e.g., SEACAM-1, SEACAM-3, and/or SEACAM-5), PD-L1, or PD-L2. In some 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 from staphylococcal enterotoxin B (SEB)-activated cells (e.g., at a concentration of 25 μg/ml) by at least about 2-fold, 3-fold, 4-fold, 5-fold, such as about 2 to 3 times, e.g., about 2 to 2.6 times, e.g., about 2.3 times, compared to IL-2 expression using an isotype control (e.g., IgG4) e.g., as measured in a T-assay cellular activation by SEB or in ex vivo human whole blood assays.

In some embodiments, the above antibody molecules increase IFN-γ expression from T cells stimulated with an anti-CD3 antibody (e.g., at a dose of 0.1 μg/ml) by at least about 2-fold, 3-fold, 4-fold, 5-fold, e.g. approximately 1.2- to 3.4-fold, e.g., approximately 2.3-fold, compared to IFN-γ expression using an isotype control (e.g., IgG4), as measured, for example, in an IFN-γ activity assay .

In some embodiments, the above antibody molecules increase IFN-γ expression from SEB-activated T cells (e.g., at a concentration of 3 μg/ml) by at least about 2-fold, 3-fold, 4-fold, 5-fold, such as from about 0. 5 to 4.5-fold, eg, approximately 2.5-fold, compared to IFN-γ expression using an isotype control (eg, IgG4), as measured, for example, in an IFN-γ activity assay.

In some embodiments, the above antibody molecules increase IFN-γ expression from cytomegolovirus (CMV) peptide-activated T cells by at least about 2-fold, 3-fold, 4-fold, 5-fold, e.g., about 2-fold to 3.6-fold, e.g. , approximately 2.8-fold compared to IFN-γ expression when using an isotype control (eg, IgG4), as determined, for example, when measured in an IFN-γ activity assay.

In some embodiments, the above antibody molecules increase the proliferation of CMV peptide-activated CD8' T cells by at least about 1-, 2-, 3-, 4-, 5-fold, such as about 1.5-fold, compared to CD8' proliferation T cells using an isotype control (eg, IgG4), which is determined, for example, by measuring the percentage of CD8+ T cells that have undergone at least n cell divisions (eg, n=2 or 4).

In some embodiments, the maximum concentration ( _Cmax ) of the above antibody molecules is from about 100 μg/ml to about 500 μg/ml, from about 150 μg/ml to about 450 μg/ml, from about 250 μg/ml to about 350 μg /ml, or from about 200 μg/ml to about 400 μg/ml, for example, about 292.5 μg/ml, for example, when measured in monkeys.

In some embodiments, the above antibody molecules have a T1 _/2 half-life of about 250 hours to about 650 hours, about 300 hours to about 600 hours, about 350 hours to about 550 hours, or about 400 hours to about 500 hours , for example, approximately 465.5 hours, for example, when measured in monkeys.

In some embodiments, the above antibody molecules bind to PD-1 with a dissociation constant Kd that is lower than 5x10 ^-4 , 1x 10 ^-4 , 5x10 ^-5 or 1x 10 ^-5 s ^-1 , such as about 2.13x10 ^{- 4} s ^-1 , for example, when measured using the Biacore method. In some embodiments, the above antibody molecules bind to PD-1 with an association constant Ka that is greater than ^1x104 , ^5x104 , ^1x105, or ^5x105 M ^-1 s ^-1 , such as approximately ^2.78x105 M ^{- 1} s ^-1 , for example, when measuring using the Biacore method.

In some embodiments, the above anti-PD-1 antibody molecules bind to one or more residues within the C chain, CC' loop, C' chain, and FG loop of PD-1. A description of the domain structure of PD-1 can be found, for example, in Cheng et al., Structure and Interactions of the Human Programmed Cell Death 1 Receptor J. Biol. Chem. 2013, 288:11771-11785. As described by Cheng et al., the C strand contains residues F43-M50, the CC' loop contains residues S51-N54, the C' strand contains residues B55-F62, and the FG loop contains residues L108-I114 from PD-1 (amino acid numbers are given according to Cheng et al., supra). Accordingly, in some embodiments, an anti-PD-1 antibody of the invention binds to at least one residue in one or more of the F43-M50, S51-N54, B55-F62, and L108-I114 spans of PD-1. In some embodiments, an anti-PD-1 antibody of the invention binds to at least one

- 45 045940 tatcom in two, three or all four spaces F43-M50, S51-N54, Q55-F62 and L108-I114 from PD-1. In some embodiments, the anti-PD-1 antibody binds to a residue in PD-1 that is also part of the binding site for one of PD-L1 and PD-L2 or both ligands.

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

The invention also relates to an isolated nucleic acid encoding the heavy chain variable region or the light chain variable region of an antibody, or both, in any of the above antibody molecules.

In one embodiment, the isolated nucleic acid encodes the heavy chain CDR 1-3 regions, wherein said nucleic acid comprises the nucleotide sequences of SEQ ID NOs: 108-112, 223, 122-126, 133-137, or 144-146.

In another embodiment, the isolated nucleic acid encodes the light chain CDR-1-3 regions, wherein said nucleic acid comprises the nucleotide sequences of SEQ ID NOs: 113-120, 127-132, or 138-143.

In other embodiments, said 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 SEQ ID NO: 39, 51, 83, 87, 90, 95 or 101.

In other embodiments, said nucleic acid further comprises a nucleotide sequence encoding a heavy chain variable domain, said nucleotide sequence comprising any of SEQ ID NO: 39, 51, 83, 87, 90, 95, or 101.

In other embodiments, said nucleic acid further comprises a nucleotide sequence encoding a heavy chain, wherein said nucleotide sequence is at least 85% identical to any of SEQ ID NO: 41, 53, 85, 89, 92, 96, or 103.

In other embodiments, said nucleic acid further comprises a nucleotide sequence encoding a heavy chain, wherein said nucleotide sequence comprises any of SEQ ID NO: 41, 53, 85, 89, 92, 96, or 103.

In other embodiments, the aforementioned 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 SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105 or 107.

In other embodiments, said nucleic acid further comprises a nucleotide sequence encoding a light chain variable domain, said nucleotide sequence comprising any of SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105 or 107.

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 SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105 or 107.

In other embodiments, said nucleic acid further comprises a nucleotide sequence encoding a light chain, wherein said nucleotide sequence comprises any of SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105 or 107.

In some embodiments, the invention relates to one or more expression vectors and host cells containing the above nucleic acids.

The invention also relates to a method for producing an antibody molecule or fragment thereof, which method comprises culturing a host cell as described in the invention under conditions suitable for gene expression.

Pharmaceutical compositions and kits.

In another aspect, the present invention relates to compositions, for example, pharmaceutically acceptable compositions, which include an antibody molecule of the invention, formulated together with a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable carrier includes any and all solvents, dispersion media, isotonic and absorption retarding agents, and the like that are physiologically compatible. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal, or epidermal administration (eg, by injection or infusion).

The compositions of the present invention can be in various forms. These include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (eg injections and infusions), dispersions or suspensions, liposomes and suppositories.

The preferred form depends on the intended route of administration and therapeutic use. The dosage form of typical preferred compositions are injections or infusion solutions. The preferred route of administration is parenteral (e.g.

- 46 045940 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 by intramuscular or subcutaneous injection.

The expressions parenteral administration and parenterally administered as used in the invention mean methods of administration other than enteral and topical administration and are typically injection administration and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal , intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrathoracic injections and infusions.

Compositions intended for treatment generally must be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high concentrations of antibodies. Sterile injection solutions can be prepared by introducing the active compound (ie, antibody or portion of an antibody) in the required amount into a suitable solvent with one ingredient or a combination of the above ingredients, followed by sterilization by filtration, if necessary. Typically, dispersions are made by introducing the active compound into a sterile vehicle that contains the basic dispersion medium and other necessary ingredients listed above. When using sterile powders to prepare sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying, resulting in a powder of the active ingredient plus any additional desired ingredient from a solution that has previously been sterilized by filtration. Proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of surfactants. Delayed absorption of injectable compositions can be achieved by including in the composition a substance that retards absorption, for example monostearate and gelatin salts.

Antibody molecules can be administered in a variety of ways known in the art, however, for many therapeutic applications, the preferred route/mode of administration is intravenous injection or infusion. For example, antibody molecules can be administered by intravenous infusion at a rate greater than 20 mg/min, such as 20 to 40 mg/min, and typically at a rate equal to or greater than 40 mg/min, to achieve a dose of approximately 35 to 440 mg/m ² , typically about 70 to 310 mg/m ² , and more typically about 110 to 130 mg/m ² In some embodiments, the antibody molecules may be administered by intravenous infusion at a rate of less than 10 mg/minute, preferably at a rate equal to or less than 5 mg/min until a dose of about 1 to 100 mg/ ^m2 , preferably about 5 to 50 mg/ ^m2 , about 7 to 25 mg/ ^m2 , or more is achieved preferably from about 10 mg/m ² . One skilled in the art will appreciate that the route of administration and/or mode of administration may vary depending on the desired results. In some embodiments, the active compound may be formulated with a carrier that will protect the compound from rapid release, for example, in controlled release formulations including implants, transdermal patches, and microcapsule 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 compositions are patented or generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In some embodiments, the antibody molecule can be administered orally, for example, with an inert diluent or digestible edible carrier. The compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or directly included in the subject's diet. For oral administration of a compound for the purpose of treatment, the compound can be combined with excipients and used in the form of oral tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers and the like. To administer a compound of the invention by routes other than parenteral administration, it may be necessary to coat the compound, or co-administer the compound with a material to prevent inactivation. Compositions intended for treatment can also be administered using medical devices known in the art.

Dosing regimens are selected to provide the optimal desired response (eg, therapeutic response). For example, a single bolus may be administered, multiple divided doses may be administered over a period of time, or the dose may be proportionally decreased or increased as required by the clinical situation. Particularly preferred is the formulation of parenteral compositions in unit dosage form for ease of administration and dose uniformity. The unit dosage form used in the invention refers to physically discrete units suitable as unitary dosages for the subjects being treated.

- 47 045940 nuyu, wherein each unit contains a predetermined amount of the active compound, calculated to achieve the desired therapeutic effect, in combination with the necessary pharmaceutical carrier. The specification of the unit dosage forms of the invention is determined by and is directly dependent on: (a) the unique characteristics of the active compound and the specific therapeutic effect intended to achieve, and (b) the limitations inherent in the field of formulating this active compound for the treatment of sensitivity in humans.

As a non-limiting example, the range of a therapeutically effective or prophylactically effective amount of an antibody molecule is from 0.1 to 30 mg/kg, more preferably from 1 to 25 mg/kg. One of ordinary skill in the art can determine treatment regimens and dosages of the anti-PD-1 antibody molecule. In some embodiments, the anti-PD-1 antibody molecule is administered by injection (eg, subcutaneously or intravenously) 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. kg, approximately 10 to 20 mg/kg, approximately 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 kg, or approximately 3 mg/kg. The administration schedule may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-PD-1 antibody molecule is administered at a dose of approximately 10 to 20 mg/kg every two weeks. The antibody molecule can be administered by intravenous infusion at a rate greater than 20 mg/minute, for example, at a rate of 20 to 40 mg/minute, and typically at a rate equal to or greater than 40 mg/minute, to achieve a dose of approximately 35 to 440 mg /m ² , typically from about 70 to 310 mg/m ² , and more typically from about 110 to 130 mg/m ² . In some embodiments, the infusion rate of about 110 to 130 mg/m ² reaches a level of about 3 mg/kg. In other embodiments, the antibody molecule can be administered by intravenous infusion at a rate of less than 10 mg/minute, such as at a rate of 5 mg/minute or less, to achieve a dose of from about 1 to 100 mg/m ² , for example, from about 5 up to 50 mg/m ² , approximately 7 to 25 mg/m ² , or approximately 10 mg/m ² . In some embodiments, the antibody infusion is administered over approximately 30 minutes. It should be noted that the dose may vary depending on the type and severity of the condition being alleviated. It should also be understood that for any particular subject, the specific dosage regimen will need to be adjusted over time according to individual need and the professional judgment of the person prescribing or directing the administration of the compositions, and that the dosage ranges set forth in the invention are given by way of example only and are not intended to to limit the scope or use of the claimed composition.

The pharmaceutical compositions of the present invention may include a therapeutically effective amount or a prophylactically effective amount of an antibody or antibody portion of the invention. The term therapeutically effective amount refers to an amount effective in doses and for periods of time necessary to achieve the desired therapeutic result. The therapeutically effective amount of the modified antibody or antibody fragment may vary depending on factors such as the clinical condition, age, sex and weight of the individual, as well as the ability of the antibody or antibody portion to elicit the desired response in the individual. A therapeutically effective amount is also an amount at which the therapeutically beneficial effects of the modified antibody or antibody fragment outweigh any toxic or harmful effects thereof. The therapeutically effective dose preferably inhibits a measurable parameter, e.g., tumor growth rate, by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and even more preferably by at least at least approximately 80% higher than in untreated subjects. The ability of a compound to inhibit a measurable parameter, such as cancer, can be assessed using an animal model system to predict efficacy in human tumors. Alternatively, this property of the composition can be assessed by analyzing the inhibitory ability of the compound, and such inhibition is analyzed in vitro by methods known to one skilled in the art.

A prophylactically effective amount refers to an amount effective in doses and for periods of time necessary to achieve the desired prophylactic result. Typically, the prophylactically effective amount will be less than the therapeutically effective amount because the prophylactic dose is administered to subjects pre-disease or early stage of the disease.

Also included within the scope of the present invention is a kit containing an antibody molecule described in the invention. One or more other components may be included in the kit, including: instructions for use, other reagents such as a tag, a therapeutic agent or substance useful for chelating or other mode of attachment, an antibody to the tag or therapeutic agent, or a radioprotective composition , devices or other materials for preparing the antibody for administration, pharmaceutically acceptable carriers, and devices or other materials for administration to a subject.

- 48 045940

Applications of anti-PD-1 antibody molecules.

The anti-PD-1 antibody molecules of the invention have diagnostic as well as therapeutic and prophylactic applications in vitro and in vivo. For example, these molecules can be introduced into cell cultures under in vitro or ex vivo conditions, or they can be administered to a subject, such as a human, for the treatment, prevention and/or diagnosis of various diseases, such as cancer and infectious diseases.

Accordingly, in one aspect, the present invention provides a method for modifying an immune response in a subject, the method comprising administering to the subject an antibody molecule of the invention such that the immune response is modified in the subject. In one embodiment, the immune response is enhanced, stimulated, or upregulated. In one embodiment, the antibody molecules enhance the immune response in a subject by blocking PD-1.

As used herein, the term subject includes human and non-human animals. In one embodiment, the subject is a human, for example, a diseased human having a disease or condition characterized by abnormal functioning of PD-1. Non-human animals include mammals and non-mammals, such as non-human primates. In one embodiment, the subject is a human. In one embodiment, the subject is a sick person in need of an enhanced immune response. In one embodiment, the subject has an immunodeficiency, for example, the subject is undergoing chemotherapy or radiation therapy, or has previously been subjected to such treatment. Alternatively, or in combination, the subject has an immunodeficiency or is at risk of developing an immunodeficiency as a result of an infection. The methods and compositions described in the invention are suitable for the treatment of sick people suffering from a disease that can be treated by enhancing the immune response mediated by T cells. For example, the methods and compositions described in the invention can quantitatively increase immune actions. In one embodiment, the subject has an increase in the number and/or activity of tumor infiltrating lymphocytes (TILs). In another embodiment, the subject has increased interferon-gamma (IFN-γ) expression or activity. In yet another embodiment, the subject has decreased PD-L1 expression or activity.

Therapeutic applications.

Cancer.

Blockade of PD-1 may enhance a subject's immune response to cancer cells. The ligand for PD-1, PD-L1, is not expressed in normal human cells, but is widely distributed in various human malignancies (Dong et al. (2002) Nat. Med. 8:787-9). The interaction between PD-1 and PD-L1 may cause decreased tumor lymphocyte infiltration, decreased receptor-mediated T-cell proliferation, and/or evasion of cancer cells from immune surveillance (Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Reversal of immunosuppression can be achieved by inhibiting the local interaction of PD-1 with PD-L1; this effect is additive if the interaction of PD-1 with PD-L2 is simultaneously blocked (Iwai et al. (2002) PNAS 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).

Thus, inhibition of PD-1 may lead to an enhanced immune response.

In one aspect, the present invention relates to treating a subject in vivo by using an anti-PD-1 antibody molecule in such a way that the growth of cancerous tumors is inhibited or reduced. An anti-PD-1 antibody can be used as a single agent to inhibit the growth of cancerous tumors. Alternatively, an anti-PD-1 antibody may be used in combination with one or more of the following: standard medical care (eg, cancer or infectious diseases), another antibody or antigen-binding fragment thereof, an immunomodulator (eg, co-stimulatory molecule activator or inhibitory molecule inhibitor). ), a vaccine, such as a therapeutic tumor vaccine, or other forms of cellular immunotherapy, as described below.

Accordingly, in one embodiment, the present invention provides a method of inhibiting the growth of tumor cells in a subject, which method comprises administering to the subject a therapeutically effective amount of an anti-PD-1 antibody molecule of the invention.

In one embodiment, these methods are suitable for treating cancer in vivo. To achieve antigen-specific enhancement of immunity, the anti-PD-1 antibody molecule can be administered together with the antigen of interest. When administering anti-PD-1 antibodies in combination with one or more agents, the combination may be administered in any order or simultaneously.

Types of cancer; therapeutic and diagnostic methods.

In another aspect, the invention relates to a method of treating a subject, for example, reducing or ameliorating a hyperproliferative condition or disease (eg, cancer) in a subject, such as a solid tumor, hematologic cancer, soft tissue tumor, or metastatic lesion. Spo

- 49 045940 involves administering to a subject one or more anti-PD-1 antibody molecules of the invention, either alone or in combination with other agents or therapeutic modalities.

As used herein, the term cancer includes all types of cancerous neoplasms or oncogenic phenomena, metastatic tissues or malignantly transformed cells, tissues or organs, regardless of the histological type or stage of the lesion. Examples of cancers include, but are not limited to, solid tumors, hematologic cancers, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignancies arising in various organs and systems, such as sarcomas and carcinomas (including adenocarcinomas and squamous cell carcinomas), such as those affecting the liver, lungs, breasts, lymphoid tissue, gastrointestinal tract (eg, colon), genitourinary tract (eg, kidneys, urothelial cells), prostate and pharynx. Adenocarcinomas include malignant tumors such as most colon cancers, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung carcinoma, small bowel cancer, and esophageal cancer. Squamous cell carcinomas include malignant tumors such as those affecting the lungs, esophagus, skin, head and neck, mouth, anus, and cervix. In one embodiment, the cancer is melanoma, for example, advanced melanoma. Using the methods and compositions of the invention, it is also possible to treat or prevent metastatic lesions in the above types of cancer.

Typical cancers whose growth can be inhibited by the antibody molecules of the invention include cancers typically responsive to immunotherapy.

Non-limiting examples of cancers preferred for treatment include melanoma (eg, metastatic malignant melanoma), kidney cancer (eg, clear cell carcinoma), prostate cancer (eg, hormone-refractory prostate adenocarcinoma), breast cancer, colon cancer, and lung cancer (eg, non-small cell lung cancer). Additionally, refractory or relapsed cancers can be treated with the antibody molecules described in the invention.

Other cancers may be treated, including, by way of example, the following cancers: bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastroesophageal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Merkel cell cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer , thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, bladder cancer, multiple myeloma, myelodysplastic syndrome, kidney or ureter cancer, renal pelvic carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmental cancers, including asbestos-induced cancers (eg, mesothelioma), and combinations of these cancers.

Treatment of metastatic cancers, for example, metastatic cancers expressing PD-L1 (Iwai et al. (2005) Int. Immunol. 17:133-144), can be carried out using the antibody molecules described in the invention. In one embodiment, increased expression levels of PD-L1, IFN-γ and/or CD8 are observed in cancer.

Without being bound by any theory, in some embodiments, a patient will presumably respond to treatment with an immunomodulator (optionally in combination with one or more substances mentioned in the invention) if the patient has a cancer with high expression of PD-L1, and/or if the cancerous tumor is infiltrated with antitumor immune cells, such as TIL cells. Antitumor immune cells may be positive for CD8, PDL1, and/or IFN-γ; thus, CD8, PD-L1, and/or IFN-γ levels may serve as indicators of TIL levels in the microenvironment. In some embodiments, the cancer microenvironment has a triple positive phenotype for PD-L1/CD8/IFN-Y.

Thus, in some aspects, the present application provides methods for determining whether a tumor sample is positive for one or more of PD-L1, CD8 and IFN-γ, and, if positive for one or more, for example, two , or all three of these markers in a tumor sample, the patient is administered a therapeutically effective amount of an anti-PD-1 antibody molecule, optionally in combination with one or more other immunomodulators or antitumor agents.

The following are indications for use in a large proportion of triple positive patients:

- 50 045940 phenotype in relation to PD-L1/CD8/IFN-y, representing: lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, gastric cancer, NSCLC, HNSCC, gastric cancer (for example, with high microsatellite instability MSIhi and/or positive for Epstein-Barr virus EBV+); colorectal cancer (CRC, e.g. MSIhi), nasopharyngeal cancer (NPC), cervical cancer (e.g. squamous cell), thyroid cancer, e.g. papillary thyroid cancer, melanoma, triple negative (TN) breast cancer and DLBCL (diffuse B-cell lymphoma). Typically in breast cancer and typically in colon cancer, a moderate proportion of patients have a triple positive phenotype for PD-L1/CD8/IFN-Y.

Additional indications in a small proportion of patients with the PD-L1/CD8/IFN-Y triple positive phenotype are: ER+ breast cancer, pancreatic cancer. These results are discussed in Example 4. Regardless of whether a large or small proportion of patients have a triple positive phenotype for these markers, screening patients for these markers allows us to determine the proportion of patients who are particularly likely to respond positively to treatment with an anti-PD-1 antibody (e.g. , blocking PD-1), optionally in combination with one or more other immunomodulators (such as an anti-TIM-3 antibody molecule, an anti-LAG-3 antibody molecule or an anti-PD-L1 antibody molecule) and/or anti-tumor agents, e.g. indicated in table. 7 and disclosed in the publications listed in table. 7.

In some embodiments, the cancer sample is classified as a PD-L1/CD8/IFN-Y triple positive phenotype. This classification can be roughly broken down into two threshold levels: when an individual cell is classified as positive, and when the sample as a whole is classified as positive. First, PD-L1, CD8, and/or IFN-γ levels can be measured at the single-cell scale. In some embodiments, a cell that is positive for one or more of these markers is a cell that has a higher level of the marker compared to a control cell or reference value. For example, in some embodiments, the high level of PD-L1 in a given cell is a higher level than the level of PD-L1 in the corresponding noncancerous tissue in the patient. As another example, in some embodiments, the high level of CD8 or IFN-γ in a given cell represents the level of this protein typically observed in TIL cells. Second, the percentage of cells in the sample that are positive for PD-L1, CD8, and/or IFN-γ can also be measured. (One cell does not necessarily express all three markers.) In some embodiments, a triple positive sample is a sample that has a high percentage of cells positive for specified markers, eg, higher than a reference value or higher than a control sample.

In other embodiments, the levels of PD-L1, CD8 and/or IFN-γ in the sample as a whole can be measured. In this case, the high level of CD8 or IFN-γ in the sample may represent the level of this protein that is typically observed in a TIL-infiltrated tumor. Likewise, a high level of PD-L1 may represent the level of this protein that is typically observed in a tumor sample, such as in the tumor microenvironment.

By identifying subgroups of patients who have a triple positive PDLl/CD8/IFN-y phenotype, as shown in Example 4 of the present invention, certain subpopulations of patients with a possible response to anti-PD-1 antibody treatment have been identified. For example, many patients with IM-TN (immunomodulatory, triple-negative) breast cancer have a triple-positive phenotype for PD-L1/CD8/IFN-γ. IM-TN breast cancer is described, for example, by Brian D. Lehmann et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies, J Clin. Invest. July 1, 2011; 121(7): 2750-2767. Triple negative breast cancer refers to cancers that lack expression of estrogen receptor (ER), progesterone receptor (PR), and HER2/Neu. These cancers are difficult to treat because they typically do not respond to agents that target the ER, PR, and HER2/Neu. Triple negative breast cancer can be further subdivided into various classes, one of which is immunomodulatory cancer. As described by Lehmann et al., in IM-TN breast cancer, factors involved in immune cell function, such as one or more immune cell signaling pathways (eg, Th1/Th2 pathway, NK cell pathway, B cell receptor pathway, dendritic cell (DC) pathway, and T cell receptor signaling pathway), cytokine signaling pathway (e.g., cytokine pathway, IL-12 pathway, and IL-7 pathway), antigen processing and presentation, core signaling immune signal transduction pathways (eg, TNF (tumor necrosis factor), NFkB, and JAK/STAT signaling pathways), genes involved in T cell function, immune transcription, interferon (IFN) responses, and antigen processing. Accordingly, in some embodiments, the cancer being treated is a cancer that is positive or determined to be positive for one or more breast cancer IM-TN markers, e.g., a factor that stimulates one or

- 51 045940 multiple immune cell signaling pathways (eg Th1/Th2 pathway, NK cell pathway, B cell receptor signaling pathway, DC pathway and T cell receptor signaling pathway), cytokine signaling pathway (eg cytokine pathway, IL pathway -12 and IL-7 pathway), antigen processing and presentation, signaling through core immune signal transduction pathways (e.g., NFKB, TNF, and JAK/STAT signaling pathways), genes involved in T cell function, immune transcription, interferon responses (IFN) and antigen processing.

As another example, the invention shows that patients in the high MSI (microsatellite instability) subgroup of colon cancer also have a triple PD-L1/CD8/IFN-Y positive phenotype. Accordingly, in some embodiments, an anti-PD1 antibody, such as an anti-PD-1 antibody of the invention (optionally in combination with one or more immunomodulators, such as an anti-LAG-3 antibody, an anti-TIM-3 antibody, or an anti-PD-L1 antibody, and with one or more antitumor agents, e.g., an antineoplastic agent listed in Table 7 or the list of publications in Table 7), is administered to a patient who has or is determined to have high MSI colon cancer, thereby treating cancer. In some embodiments, a high MSI cell is a cell whose MSI level is greater than a reference value, or higher than a control cell, such as a non-cancerous cell from the same tissue type as the cancer cell.

As another example, the invention shows that patients in the high MSI and/or Epstein-Barr virus (EBV+) subset of gastric cancer also have a triple PD-L1/CD8/IFN-Y positive phenotype. Accordingly, in some embodiments, an anti-PD-1 antibody, such as an anti-PD-1 antibody of the invention (optionally in combination with one or more immunomodulators, such as an anti-LAG-3 antibody, an anti-TIM-3 antibody, or an anti-PD-L1 antibody , and one or more antineoplastic agents, for example, an antineoplastic agent specified in Table 7 or in the list of publications in Table 7) is administered to a patient who has or is determined to have gastric cancer with a high level of MSI and/or EBV+, performing thereby treating cancer. In some embodiments, a high MSI cell is a cell whose MSI level is greater than a reference value, or higher than a control cell, such as a non-cancerous cell from the same tissue type as the cancer cell.

Additionally, the invention discloses methods of assessing cancer for PD-L1 and then treating that cancer with an anti-PD-1 antibody. As described in Example 5 of the present invention, a cancer sample can be analyzed for PD-L1 protein content or mRNA content. If a sample has a level of PD-L1 (protein or mRNA) that is higher than the reference value or higher than a control cell (for example, a non-cancerous cell), then the sample can be classified as PDL1-positive. Accordingly, in some embodiments, an anti-PD-1 antibody, such as an anti-PD-1 antibody of the invention (optionally in combination with one or more antineoplastic agents) is administered to a patient who has or is determined to have PD-L1 positive cancer. The cancer may be, for example, non-small cell lung cancer (NSCLC)-adenocarcinoma (ACA), NSCLC-squamous cell carcinoma (SCC), or hepatocellular carcinoma (HCC).

In some embodiments, the methods of the invention include the use of an anti-PD-1 antibody, e.g., an anti-PD-1 antibody of the invention, e.g., as a monotherapy, to treat cancer that is PD-L1 positive (or determined to be PD-L1 positive ). In some embodiments, the cancer is colon cancer (eg, high MSI), gastric cancer (eg, high MSI and/or EBV+), nasopharyngeal NPC cancer, 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-PD-1 antibody is administered at a dose of, for example, 1, 3, 10, or 20 mg/kg.

As shown, for example, in Example 4 of the present invention, it has been found that some PD-L1/CD8/IFN-Y triple positive gastric cancers are also PIK3CA positive. Accordingly, in some embodiments, cancer can be treated with an anti-PD-1 antibody molecule (optionally in combination with one or more immunomodulators, such as an anti-LAG-3 antibody molecule, an anti-TIM-3 antibody molecule, or an anti-PD-L1 antibody molecule) and a substance , which inhibits PIK3CA. Examples of substances in this category are described in publications by Stein RC (September 2001). Prospects for phosphoinositide 3kinase inhibition as a cancer treatment. Endocrine-related Cancer 8(3): 237-48 and Marone R, Cmiljanovic V, Giese B, Wymann MP (January 2008). Targeting phosphoinositide 3-kinase: moving towards therapy. Biochimica et Biophysica Acta 1784(1):159-85.

As shown, for example, in Example 4 of the present invention, colorectal cancer (CRC), for example, in a patient who has or is determined to have colorectal cancer with a high MSI score, can be treated with an anti-PD-1 antibody, optionally in combination with a therapeutic agent that targets one or more of LAG-3, RNF43 and BRAF. For example,

- 52 045940 these cancers can be treated with an anti-PD-1 antibody, optionally in combination with one or more therapeutic agents that target one or more of LAG-3, PD-1, RNF43 and BRAF. In some embodiments, the one or more therapeutic agents include immunomodulators, such as anti-LAG-3 antibody molecules, as well as an antitumor agent set forth in Table. 7 or in the list of publications from table. 7. The invention describes inhibitors of LAG-3, for example antibodies. Inhibition of RNF43 can be accomplished, for example, using a small molecule antibody (eg, 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-H-(5-(pyrazin-2- yl)pyridin-2yl)acetamide (compound A28)), siRNA or Rspo ligand or derivative thereof. The invention describes BRAF inhibitors (eg vemurafenib or dabrafenib).

As shown, for example, in Example 4 of the present invention, a patient who has (or is determined to have) squamous cell lung cancer can be treated with an anti-PD-1 antibody molecule in combination with a therapeutic agent that targets LAG-3, e.g. , an anti-LAG-3 antibody molecule, and optionally one or more antitumor agents, such as the antitumor agent listed in table. 7 or in the list of publications from table. 7.

In some embodiments, a subject who has (or is determined to have) squamous cell lung cancer may be treated with an anti-PD-1 antibody, optionally in combination with a therapeutic agent that targets TIM-3, e.g., an anti-TIM-3 antibody . The invention describes TIM-3 inhibitors, for example antibodies.

As shown, for example, in Example 4 of the present invention, a patient who has (or is determined to have) thyroid cancer may be treated with an anti-PD-1 antibody molecule, optionally in combination with a BRAF-targeted therapeutic agent, and , optionally in combination with one or more immunomodulators, such as an anti-LAG-3 antibody molecule, an anti-TIM-3 antibody molecule and an anti-PD-L1 antibody molecule. The invention describes BRAF inhibitors (eg, vemurafenib or dabrafenib), for example, as indicated in table. 7 and in the list of publications from table. 7.

In some embodiments, therapeutic agents of the invention may be used to treat a patient who has (or is determined to have) cancer associated with an infection, such as a viral or bacterial infection. Common cancers include cervical cancer, anal cancer, human papillomavirus (HPV)-associated squamous cell carcinoma of the head and neck, HPV-associated esophageal papillomas, HHV6-associated lymphomas (associated with herpes virus type 6), EBV-associated lymphomas ( including Burkitt's lymphoma), gastric MALT lymphoma (gastric mucosa-associated lymphoid tissue), other infection-associated MALT lymphomas, HCC hepatocellular carcinoma and Kaposi's sarcoma.

In other embodiments, the cancer is a hematologic malignancy or cancer, including but not limited to leukemias or lymphomas. For example, an anti-PD-1 antibody molecule can be used to treat cancers and malignancies, including, but not limited to, acute leukemia, including, for example, B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia ( T-ALL), acute lymphocytic leukemia (ALL); one or more chronic leukemias, including, but not limited to, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic conditions including, but not limited to, B-cell prolymphocytic leukemia, plasmacytoid dendritic cell blast tumor, 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 tumor, Waldenström's macroglobulinemia and pre-leukemias, which represent a heterogeneous collection of hematological conditions united by effective products (or dysplasia) of myeloid blood cells, and the like.

In one embodiment, the cancer is selected from the following types: lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC squamous histological type, and/or non-squamous histological type, or NSCLC adenocarcinoma)), melanoma (e.g., advanced melanoma), kidney cancer (eg, renal cell carcinoma, eg clear cell renal cell carcinoma), liver cancer, myeloma (eg, multiple myeloma), prostate cancer, breast cancer (eg, breast cancer that lacks expression of one, two or all of estrogen receptors, progesterone receptors, or HER2/Neu, eg, triple negative breast cancer), colorectal cancer, pancreatic cancer, head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC), anal cancer, gastroesophageal cancer, thyroid cancer, cervical cancer, lymphoproliferative disease (eg, post-transplant lymphoproliferative disease) or hematologic cancer, T

- 53 045940 cellular lymphoma, non-Hodgkin's lymphoma or leukemia (for example, myeloid leukemia).

In another embodiment, the cancer is selected from carcinoma (eg, advanced or metastatic), melanoma, or lung carcinoma, eg, non-small cell lung carcinoma.

In one embodiment, the cancer is a lung cancer, such as non-small cell lung cancer.

In another embodiment, the cancer is a hepatocarcinoma, eg, advanced hepatocarcinoma, without or with a viral infection, eg, chronic viral hepatitis.

In another embodiment, the cancer is prostate cancer, such as advanced prostate cancer.

In yet another embodiment, the cancer is myeloma, such as multiple myeloma.

In yet another embodiment, the cancer is a kidney cancer, such as renal cell carcinoma (RCC) (eg, metastatic RCC or clear cell renal cell carcinoma).

In one embodiment, the cancer is melanoma, for example, advanced melanoma. In one embodiment, the cancer is an advanced or inoperable melanoma that does not respond to other therapies. In other embodiments, the cancer is BRAF mutation melanoma (eg, BRAF V600 mutation). In other embodiments, the anti-PD-1 antibody molecule is administered following treatment with an anti-CTLA-4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib).

The methods and compositions disclosed herein are useful for treating metastatic lesions associated with the types of cancer mentioned above.

Combining anti-PD-1 antibodies with antitumor vaccines.

Anti-PD-1 antibody molecules can be combined with an immunogenic substance such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes encoding immunostimulatory cytokines (He et al. (2004) , J Immunol 173: 4919-28). Non-limiting examples of possible tumor vaccines include peptides with melanoma antigens such as gp100 peptides, MAGE, Trp-2, MART1 and/or tyrosinase antigens, tumor cells transfected to express the cytokine GM-CSF, DNA-based vaccines, RNA and vaccines based on viral transduction. A tumor vaccine can be prophylactic or therapeutic.

PD-1 blockade can be combined with a vaccination protocol. Many strategies have been developed for tumor vaccination experiments (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; also see 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). According to one of the mentioned strategies, vaccines are produced using autologous or allogeneic tumor cells. Such cell-based vaccines have been shown to be most effective after transducing tumor cells to express granulocyte-macrophage colony-stimulating factor (GMCSF). GM-CSF has been found to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43).

PD-1 blockade can be used in combination with a set of tumor-expressed recombinant proteins and/or peptides to produce an immune response to these proteins. Typically, the immune system considers these proteins to be self-antigens and therefore develops tolerance to them. Tumor antigen may also include the protein telomerase, which is required for the synthesis of chromosomal telomeres and is expressed in more than 85% of human cancers and only in a limited number of somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013). (These somatic tissues can be protected from immune attack in a variety of ways.) Tumor antigen may also be neo-antigens that are expressed in cancer cells due to somatic mutations that change the protein sequence, or create fusion proteins between two unrelated sequences (namely, the bcr-abl gene on the Philadelphia chromosome), or an idiotype from B-cell tumors .

Other cancer vaccines may include proteins from viruses implicated in human cancers, such as human papillomaviruses (HPV), hepatitis viruses (HBV and HCV), Kaposi's sarcoma herpes virus (KHSV), and Epstein-Barr virus (EBV). Another form of tumor-specific antigen that can be used in combination with PD-1 blockade is purified heat shock proteins (HSPs) isolated directly from tumor tissue. These heat shock proteins contain protein fragments from tumor cells, and such HSPs are highly effective

- 54 045940 useful in the delivery of antigen presenting cells to induce antitumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al. (1997) Science 278:117-120).

Dendritic cells (DCs) are potent antigen-presenting cells that can be used to prime antigen-specific responses. Dendritic cells can be obtained ex vivo and administered with various protein and peptide antigens, as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). Dendritic cells can also be genetically transduced to express these tumor antigens. Dendritic cells have also been fused directly with tumor cells for immunization purposes (Kugler, A. Et al. (2000) Nature Medicine 6: 332-336). As a vaccination method, DC immunization may be effective in combination with PD-1 blockade to induce more potent antitumor responses.

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

PD-1 blockade can also be combined with standard cancer treatment. PD-1 blockade may be effective in combination with chemotherapy regimens. In these cases, it becomes possible to reduce the administered dose of the chemotherapeutic reagent (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). In some embodiments, the methods and compositions described in the invention are administered in combination with one or more of the following modalities: other antibody molecules, chemotherapy, other antineoplastic therapies (eg, targeted antineoplastic agents or oncolytic agents), cytotoxic agents, immunological therapeutic agents (eg, cytokines), surgery, and/or radiation procedures. Examples of cytotoxic agents that may be administered in combination include antimicrotubule agents, topoisomerase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents capable of disrupting signal transduction pathways, agents promoting apoptosis, proteasome inhibitors, and irradiation (for example, local or total body irradiation).

Alternatively, or in combination with the above combinations, the methods and compositions described in the invention can be used in combination with one or more of the following: an immunomodulator (e.g., a co-stimulatory molecule activator or an inhibitory molecule inhibitor), a vaccine, e.g., a therapeutic cancer vaccine, or other forms of cellular immunotherapy.

Below, by way of example and without limitation, combinations and uses of anti-PD-1 antibody molecules are provided.

In some embodiments, the anti-PD-1 antibody molecule is administered in combination with a co-stimulatory molecule or inhibitory molecule modulator, such as a coinhibitory ligand or receptor.

In one embodiment, the anti-PD-1 antibody molecule is administered in combination with a modulator, such as a costimulatory molecule agonist. In one embodiment, the costimulatory molecule agonist is selected from the following agonists (such as an agonist antibody, or an antigen binding fragment, or a soluble fusion thereof): OX40, CD2, CD27, CDS, ICAM-1, LFA-1, (CD11a/CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAPFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.

In another embodiment, the anti-PD-1 antibody molecule is used in combination with a costimulatory molecule, eg, a positive signal associated agonist, comprising a costimulatory domain of CD28, CD27, ICOS and GITR.

Examples of GITR (familial glucocorticoid-induced TNF receptor) agonists include, for example, GITR fusion proteins and anti-GITR antibodies (eg, bivalent anti-GITR antibodies), such as the GITR fusion protein described in the following documents: US Patent No. 6,111,090, European Patent No. 090505B1, US Patent No. 8586023, PCT WO Published Applications Nos. 2010/003118 and 2011/090754, or anti-GITR antibodies described, for example, in the following documents: US Patent No. 7025962, European Patent No. 1947183B1, US Patent No. 7812135, US Patent No. 8388967, US Patent No. 8591886, European Patent No. EP 1866339, published applications RST No. Wo 2011/028683, PCT No. Wo 2013/039954, PCT No. WO 2005/007190, PCST No. Wo 2007/133822, PCT No. WO 2005 /055808, PCT No. WO 99/40196, PCT No. WO 2001/03720, PCT No. WO 99/20758, PCT No. WO 2006/083289, PCT WO No. 2005/115451, US Patent No. 7618632 and PCT Published Application No. WO 2011/ 051726. In one embodiment, the anti-PD-1 antibody molecule is administered in combination with an inhibitory immune checkpoint molecule inhibitor. Those skilled in the art will understand that the term immune checkpoint refers to a group of molecules on the surface of CD4 and CD8 T cells. These molecules can effectively serve as brakes for the down-mode

- 55 045940 lation or suppression of the antitumor immune response. Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, LAG-3, and TIM-3, which directly inhibit immune cells. Immunotherapeutic agents useful in the methods of the invention that can act as immune checkpoint inhibitors include, but are not limited to, PD-L1, PD-L2, CTLA4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, SEASAM (for example, SEASAM-1 and/or SEASAM-5) and/or TGFR-beta. Inhibition of an inhibitory molecule can be accomplished by inhibition at the DNA, RNA or protein level. In embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA, or shRNA) may be used to inhibit expression of the inhibitory molecule. In other embodiments, the inhibitory signal inhibitor is a polypeptide, such as a soluble ligand, or an antibody or antigen-binding fragment thereof that binds to an inhibitory molecule.

In one embodiment, the inhibitor is a soluble ligand (eg, CTLA-4-Ig or TIM-3-Ig), or antibody or antibody fragment that binds PD-L1, PD-L2, or CTLA4. For example, an anti-PD-1 antibody molecule may be administered in combination with an anti-CTLA-4 antibody, e.g., the drug ipilimumab, e.g., for the treatment of cancer (e.g., cancer selected from melanoma, e.g., metastatic melanoma, lung cancer, e.g., non-small cell lung carcinoma or prostate cancer). Examples of anti-CTLA4 antibody include Tremelimumab (an IgG2 monoclonal antibody obtained from Pfizer, formerly known as ticilimumab, CP-675206), and ipilimumab (anti-CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9) . In one embodiment, the anti-PD-1 antibody molecule is administered following treatment, for example, after treatment of melanoma with an anti-CTLA4 antibody (eg, ipilimumab) without or with a BRAF inhibitor (eg, vemurafenib or dabrafenib). Dosages that may be used include, by way of example, a dose of an anti-PD-1 antibody molecule of about 1 to 10 mg/kg, such as 3 mg/kg, and a dose of an anti-CTLA antibody such as ipilimumab of about 3 mg. /kg.

Immune inhibitory molecules, such as PD-1 and LAG-3, may exert regulation, such as synergistic regulation of T cell function, which promotes tumor cell immune evasion. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with an anti-TIM-3 antibody or an antigen-binding fragment thereof. In other embodiments, the anti-PD-1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody, or an antigen-binding fragment thereof. The antibody combination of the invention may be administered separately, for example, as individual antibodies, or as linked antibodies, such as bispecific or trispecific antibody molecules. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a SEACAM inhibitor (eg, a SEACAM-1, SEACAM-3, and/or SEACAM-5 inhibitor), for example, an anti-CEACAM antibody molecule. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a SEACAM-1 inhibitor, for example, an anti-CEACAM-1 antibody molecule. In another embodiment, the anti-PD-1 antibody molecule is administered in combination with a CEACAM-5 inhibitor, for example, an anti-CEACAM-5 antibody molecule. In one embodiment, a bispecific antibody is administered that includes an anti-PD-1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody, or an antigen-binding fragment thereof. In some embodiments, a combination of antibodies mentioned in the invention is used to treat cancer, for example, a cancer mentioned in the invention (eg, a solid tumor). The effectiveness of the above combinations can be tested in animal models known in the art. For example, animal models for testing the synergistic effects of anti-PD-1 and anti-LAG-3 antibodies are described, for example, by Woo et al. (2012) Cancer Res. 72(4): 917-27).

In one embodiment, a SEACAM inhibitor (eg, SEACAM-1 and/or SEACAM-5) is an anti-CEACAM antibody molecule. Without wishing to be bound by any theory, SEACAM-1 has been described as a ligand and partner of TIM-3 (see, for example, WO 2014/022332). The combination of anti-TIM-3 and anti-CEACAM-1 antibodies exhibits a synergistic effect in vivo, found in tumor xenograft models (see, for example, WO 2014/022332). It is assumed that tumors involve SEACAM-1 or SEACAM-5 to inhibit the immune system, as described, for example, in the publications of 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. Feb 2009; 126(2):186-200; Markel et al. Cancer Immunol. Immunother. Feb 2010; 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: e12529. Thus, CEACAM inhibitors can be used in conjunction with other immunomodulators described in the invention (eg, PD-1 or TIM-3 inhibitors) to enhance the immune response against cancer, for example, melanoma, lung cancer (eg, NSCLC), bladder cancer , colon or cancer

- 56 045940 ovarian, or other types of cancer mentioned in the invention. 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, for example monoclonal antibody 34B1, 26H7 and 5F4 or a recombinant form thereof as described for example, in applications US 2004/0047858, US 7132255 and WO 99/52552. In other embodiments, the anti-CEACAM antibody is an anti-CEACAM-1 antibody molecule 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, immune molecules that inhibit PD-1 and LAG-3 (eg, antibody molecules) are administered in combination with each other, for example, to treat cancer. In some embodiments, the patient is a patient who has experienced progression (eg, tumor growth) during treatment with a PD-1 inhibitor (eg, an antibody molecule of the invention) and/or a PD-L1 inhibitor (eg, an antibody molecule). In some embodiments, treatment with an anti-PD-1 antibody molecule and/or an anti-PD-L1 antibody molecule is continued, and a LAG-3 inhibitory immune molecule (eg, an antibody) is added to said treatment.

In some embodiments, immune molecules that inhibit PD-1 and TIM-3 (eg, antibody molecules) are administered in combination with each other, for example, to treat cancer. In some embodiments, the patient is a patient who has experienced progression (eg, tumor growth) during treatment with a PD-1 inhibitor (eg, an antibody molecule of the invention) and/or a PD-L1 inhibitor (eg, an antibody molecule). In some embodiments, treatment with an anti-PD-1 antibody molecule and/or an anti-PD-L1 antibody molecule is continued, and an immune molecule that inhibits TIM-3 (eg, an antibody) is added to said treatment.

In other embodiments, the anti-PD-1 antibody molecule is administered in combination with a cytokine such as interleukin-21, interleukin-2, interleukin-12, or interleukin-15. In some embodiments, a combination of an anti-PD-1 antibody molecule and a cytokine of the invention is used to treat a cancer, such as a cancer of the invention (eg, solid tumor or melanoma).

By way of example and without limitation, immunomodulators that can be used in combination with an anti-PD-1 antibody molecule include, for example, afutuzumab (Roche®); Pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimide (CC4047); and cytokines, for example, IL-21 or IRX-2 (a mixture of human cytokines including interleukin 1, interleukin-2 and interferon γ, CAS 951209-71-5, obtained from IRX Therapeutics).

In other embodiments, the anti-PD-1 antibody molecule is used in combination with an indoleamine pyrrole 2,3 dioxygenase (IDO) inhibitor (eg, INCB24360) in a subject with advanced or metastatic cancer (eg, a patient with metastatic and recurrent NSCL cancer).

In other embodiments, anti-PD-1 antibody molecules are administered to a subject in combination with one or more of the following (e.g., before, concurrently, or after): bone marrow transplant, T-cell ablative therapy using chemotherapeutic agents such as fludarabine, topical External beam radiation therapy (XRT), administration of cyclophosphamide and/or antibodies such as OKT3 or Campath/CAMPATH. In one embodiment, anti-PD-1 antibody molecules are administered following B-cell ablation therapy, for example, following CD20-reactive agents such as Rituxan. For example, in one embodiment, patients may receive standard treatment with high-dose chemotherapy followed by a peripheral blood stem cell transplant. In some embodiments, patients are administered anti-PD-1 antibody molecules following transplantation. In a further embodiment, anti-PD-1 antibody molecules are administered before or after surgery.

Another example of combination use is anti-PD-1 antibodies in combination with decarbazine for the treatment of melanoma. Without being bound by specific theory, the combined use of PD-1 blockade and chemotherapy is believed to promote cell death, which is a consequence of the cytotoxic effects of most chemotherapeutic compounds, which can cause increased levels of tumor antigen in the antigen presentation pathway. Other combination treatments that may be synergistic with PD-1 blockade via cell death are radiation, surgery, and hormonal deprivation. In each of these protocols, a source of tumor antigen is created in the host. Angiogenesis inhibitors may also be used in combination with PD-1 blockade. Inhibition of angiogenesis results in the death of tumor cells that can deliver tumor antigen to the antigen presentation pathway.

Antibodies that block PD-1 can also be used in combination with bispecific antibodies. Bispecific antibodies can be used to target two separate antigens. On

- 57 045940 example, anti-Fc receptor/anti-tumor antigen (eg Her2/Neu) bispecific antibodies are used to target macrophages to the tumor site. This targeting may more effectively activate tumor-specific responses. The T cell arm of these responses will be enhanced by the application of PD-1 blockade. Alternatively, the antigen can be delivered directly to dendritic cells using bispecific antibodies that bind to the tumor antigen and a specific cell surface marker of the dendritic cells.

There are a wide variety of mechanisms by which tumors evade immunosurveillance. Many of these mechanisms can be overcome by inactivating proteins that are expressed by tumors and are immunosuppressive. These include, among others, transforming growth factor TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200) and Fas ligand (Hahne, M. et al. (1996) Science 274: 13631365).

Antibodies or antigen-binding fragments thereof against each of these molecules can be used in combination with an anti-PD-1 antibody to counteract the effects of the immunosuppressive agent and improve antitumor immune responses of the host.

Other antibodies that can be used to activate an immune response in the host can be used in combination with an anti-PD-1 antibody. These include molecules on the surface of dendritic cells (DCs) that activate DC function and antigen presentation. Antibodies against CD40 can effectively replace the action of helper T cells (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in combination with antibodies against PD-1 (Ito, N. et al. (2000) Immunobiology 201(5)527-40). Antibodies against T cell costimulatory molecules such as CTLA-4, OX-40 (Weinberg, A. Et al. (2000) Immunol. 164: 2160-2169) (eg US Pat. No. 5811097), 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 create increased levels of T cell activation.

An additional illustrative standard of care is described in the section entitled Types of Combination Treatments below.

In all methods described herein, PD-1 blockade can be combined with other types of immunotherapy, such as cytokine administration (eg, interferons, GM-CSF, G-CSF, IL-2, IL-21), or bispecific antibody treatment, which results in is to increase the presentation of tumor antigens (see Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123).

Methods for administering antibody molecules are known in the art and are described below. Suitable dosages of the molecules used depend on the age and weight of the subject and the specific drug used. Dosages and treatment regimens for the anti-PD-1 antibody molecule can be determined by one skilled in the art. In some embodiments, the anti-PD-1 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. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 1 mg/kg, about 3 mg/kg or 10 mg/kg, about 20 mg/kg, about 30 mg/kg, or about 40 mg/kg. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 1 to 3 mg/kg, or about 3 to 10 mg/kg. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 0.5 to 2, 2 to 4, 2 to 5, 5 to 15, or 5 to 20 mg/kg. The administration schedule may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-PD-1 antibody molecule is administered at a dose of approximately 10 to 20 mg/kg every two weeks.

Antibody molecules can be used in unconjugated forms or in conjugation with a second substance, for example, a cytotoxic drug, a radioisotope, or a protein, for example, a protein toxin or a viral protein. This method includes: administering to a subject in need of such treatment an antibody molecule, either as a single molecule or conjugated to a cytotoxic drug. Antibody molecules can be used to deliver various therapeutic agents, for example, a cytotoxic moiety, e.g., a drug, a radioisotope, molecules of plant, fungal or bacterial origin, or biological proteins (e.g., protein toxins) or particles (e.g., recombinant viral particles, e.g. , through the viral envelope protein) or a mixture thereof.

Additional Combination Treatments The anti-PD-1 antibody molecule may be used in combination with other treatments. For example, a combination treatment may include a composition of the present invention in a single formulation, and/or administered in conjunction with one or more additional therapeutic agents, such as one or more antineoplastic agents, cytotoxic or cytostatic agents, hormonal therapies, vaccines, and/or other treatments. immunotherapy. In other embodiments, the antibody molecules are administered in combination with other treatment modalities, including surgery

- 58 045940 mischief, radiation therapy, cryosurgery and/or thermotherapy. These combination treatments may have the advantage of using lower doses of therapeutic agents administered to avoid possible complications or toxic effects associated with different monotherapies.

The expression in combination with does not mean that the treatment or therapeutic agents must be administered simultaneously and/or be in a single formulation for co-delivery, although such delivery methods are within the scope of the present invention. The anti-PD-1 antibody molecules can be administered simultaneously, before or after one or more other additional treatments or therapeutic agents. The anti-PD-1 antibody molecule and the other agent or therapeutic protocol can be administered in any order. In general, each substance will be administered at a dose and/or according to an administration schedule established for that substance. It should also be understood that the additional therapeutic agent used in this combination may be administered together in a single composition or administered separately in different compositions. In general, it is contemplated that the additional therapeutic agents used in combination may be administered at concentrations that do not exceed the concentration levels if they were administered separately. In some embodiments, the concentration levels used in combination will be lower than those used separately.

In some embodiments, the anti-PD-1 antibody molecules described herein are administered in combination with one or more other 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, the other 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 comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-GPAT binding antagonist is selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105 MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874 Antibody YW243.55.S70 (heavy and light chain variable region sequences SEQ ID NO: 20 and 21, respectively) is an anti-PD-L1 antibody described in WO 2010/077634.

MDX-1106, also known as MDX-1106-04, ONO-4538 or BMS-936558, is an anti-PD-1 antibody described in WO 2006/121168. Merck-3745 antibody, also known as MK3475 or SCH-900475, is an anti-PD-1 antibody described in WO 2009/114335. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD-1. Pidilizumab and other humanized anti-PD1 monoclonal antibodies are described in WO 2009/101611. In other embodiments, the anti-PD-1 antibody is pemrolizumab. Pemrolizumab (trade name: Keytruda, formerly known as lambrolizumab, also called MK-3475) is described, for example, in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44. AMP-224 (B7-DCIg; Amplimmune, for example, disclosed in WO 2010/027827 and WO 2011/066342), is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD-1 and B7-H1. Other anti-PD-1 antibodies include AMP 514 (Amplimmune), among others, for example, the anti-PD-1 antibodies disclosed in US patents US 8609089, US 2010028330 and/or US 20120114649.

In some embodiments, the other anti-PD-1 antibody is MDX-1106. Alternative names for MDX-1106 include MDX-1106-04, ONO-4538, BMS-936558, or Nivolumab. In some embodiments, the anti-PD-1 antibody is Nivolumab (CAS registration number: 946414-94-4). Nivolumab (also called BMS-936558 or MDX1106, Bristol-Myers Squibb) is a fully human human IgG4 monoclonal antibody that specifically blocks PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are described in US patents 8008449 and WO 2006/121168. Lambrolizumab (also called pemrolizumab or MK03475; Merck) is a humanized monoclonal IgG4 antibody that binds to PD-1. Pemrolizumab and other humanized anti-PD-1 antibodies are described in US patents 8354509 and WO 2009/114335. MDPL3280A (Genentech/Roche) is a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies against PD-L1 are disclosed in US Patent No. 7943743 and US Patent Application Published No. 20120039906. Other anti-PBA1 binders include YW243.55.S70 (heavy and light chain variable regions shown in SEQ ID NO: 20 and 21, see WO 2010/077634) and MDX-1105 (also known as BMS-936559, and for example, anti-PD-L1 binders disclosed in WO 2007/005874).

Types of cancer treatment.

Exemplary combinations of anti-PD-1 antibody molecules (as a single agent

- 59 045940 or in combination with other stimulants) and standard cancer treatment include at least the following.

In some embodiments, an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody molecule of the invention, is used in combination with a standard of care cancer treatment chemotherapy agent including, but not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxan®), busulfan (Mileran®), busulfan injection (Busilvex®), capecitabine (Xeloda®), N-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil ( Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC- Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidin®), daunorubicin citrate in liposomes for injection (Daunoxom®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide ( Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adricil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarucibin (Idamycin®), ifosfamide (IFEX ®), irinotecan (Camtosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purenetol®), methotrexate (Folex®), mitoxantrone (Novantron®), Mylotarg, paclitaxel ( Taxol®), Phoenix (Yttrium90/MX-ETRA), pentostatin, polypheprosan 20 with carmustine, implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®) , topotecan hydrochloride injection (Hycamtin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), ibrutinib, idelalisib, and brentuximab vedotin.

Alkylating agents include, by way of example and without limitation, mustargens, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes: uracil mustard (Aminouracil mustard®, Chlortaminacyl®, Demethyldopane®, Desmethyldopane®, Hemantamine®, Nordopan®, Uracil nitrogen mustard®, Uracillost®, Uracilmostaza®, Uramustin/Uramustin®, Uramustine/Uramustine®), Chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Heocap®, Klafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), chlorambucil (Leukeran®), pipobromane (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, Temozolamide (Temodar®), thiotepa (Thioplex ®), Busulfan (Busilvex®, Mileran®), Carmustine (BiCNU®), Lomustine (CeeNU®), Streptozocin (Zanosar®) and Dacarbazine (DTICDome®). Additional illustrative alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®), Temozolamide (Temodar® and Temodal®), Dactinomycin (also known as Actinomycin-D, Cosmegen®), Melphalan (also known as L-PAM, L-sarcolysine and phenylalanine mustard , Alkeran®), Altretamine (also known as hexamethylmelamine (HMM), Hexalene®), Carmustine (BiCNU®), Bendamustine (Treanda®), Busulfan (Busilvex® and Mileran®), 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 imidazole carboxamide, DTIC-Dome®), Altratemine (also known as hexamethylmelamine (HMM), Hexalene®), Ifosfamide (Iflex®), Prenumustine,

Procarbazine (Matulan®), Mechlorethamine (also known as mustargen, mustine and mechlorethamine hydrochloride, Mustargen®), Streptozocin (Zanosar®), Thiotepa (also known as thiophosphamide, TESPA and TSPA, Thioplex®), Cyclophosphamide (Endoxan®, Cytoxan® , Neosar®, Pocytox®, Revimmune®) and Bendamustine hydrochloride (Treanda®).

Examples of anthracyclines include, for example, doxorubicin (Adriamycin® and Rubex®), bleomycin (Lenoxan®), daunorubicin (daunorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, Cerubidin®), liposomal daunorubicin (daunorubicin citrate in liposomes, DaunoXome®), mitoxantrone (DHAD , Novantrone®), epirubicin (Ellens™), idarucibin (idamycin®, idamycin PFS®), mitomycin C (Mutamycin®), geldanamycin, herbimycin, ravidomycin and desacetylravidomycin.

Examples of vinca alkaloids that can be used in combination with anti-PD-1 antibody molecules, either alone or in combination with another immunomodulator (such as an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule) include: restrictions vinorelbine tartrate (Navelbine®), vincristine (Oncovin®) and Vindesine (Eldizine®)), vinblastine (also known as vinblastine sulfate, vincaleucoblastine and VLB, Alkaban-AQ® and Velban®) and vinorelbine (Navelbine®).

Examples of proteasome inhibitors that can be used in combination with anti-PD-1 antibody molecules, either alone or in combination with another immunomodulator (eg, with an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule) include without limitation bortezomib (Velcad®), carfilzomib (PX-171-007, ^)-4-methyl-N-(^)-1-((^)-4-methyl-1-N)-2methyloxiran-2-yl )-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-(^)-2-(2

- 60 045940 morpholinaceamido)-4-phenylbutanamido)-pentanamide), marizomib (NPI-0052), ixazomib citrate (MLN9708), delanzomib (CEP-18770) and O-methyl-H-[(2-methyl-5-thiazolyl) carbonyl|-G-seryl-O-methyl-H-[(^)2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX -0912).

In some embodiments, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, is used alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1, or anti-PD-1 antibody molecule). TIM-3), in combination with a tyrosine kinase inhibitor (eg, a receptor tyrosine kinase (RTK) inhibitor). A tyrosine kinase inhibitor includes, by way of example and without limitation, an epidermal growth factor (EGF) pathway inhibitor (e.g., an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor (VEGF) pathway inhibitor (e.g., a vascular endothelial growth factor receptor (EGF) inhibitor). VEGFR) (eg, VEGFR-1 inhibitor, VEGFR-2 inhibitor, VEGFR-3 inhibitor)), platelet-derived growth factor (PDGF) pathway inhibitor, (eg, platelet-derived growth factor receptor (PDGFR) inhibitor (eg, PDGFR-β inhibitor) ), a RAF-1 inhibitor, a KIT inhibitor, and a RET inhibitor. In some embodiments, the antineoplastic agent is used in combination with a hedgehog inhibitor selected from the group consisting of the following drugs: axitinib (AG013736), bosutinib (SKI-606), cediranib (Recentin ™, AZD2171), dasatinib (Spricel®, BMS -354825), erlotinib (Tarceva®), gefitinib (Iressa®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (Tykerb®, Tiverb®), lestaurtinib ( CEP-701), neratinib (HKI-272), nilotinib (Tasigna®), semakanib (semaxanib, SU5416), sunitinib (Sutent®, SU11248), toceranib (Palladia®), vandetanib (Zactima®, ZD6474), vatalinib (PTK787 , PTK/ZK), trastuzumab (Herceptin®), bevacizumab (Avastin®), rituximab (Rituxan®), cetuximab (Erbitux®), panitumumab (Vectibix®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib ( Nexavar®), alemtuzumab (Kampat®), gemtuzumab ozogamicin (Mylotarg®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (Vargatef®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tizovib (AV-9 51 ), OSI-930, MM-121, XL-184, XL-647, XL228, AEE788, AG-490, AST-6, BMS-599626, CUDC-101, PD153035, pelitinib (EKB-569), vandatenib (Zactima ), WZ3146, WZ4002, WZ8040, АВТ869 (линифаниб), АЕЕ788, АР24534 (понатиниб), AV-951 (тивозаниб), акситиниб, BAY 73-4506 (регорафениб), бриваниб аланинат (BMS-582664), бриваниб (BMS-540215 ), cediranib (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), vatalinib, XL880 (GSK1363089, EXEL-2880). Select tyrosine kinase inhibitors are selected from sunitinib, erlotinib, gefitinib or sorafenib.

In some embodiments, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1, or anti-3 -TIM), is used in combination with vascular endothelial growth factor (VEGF) receptor inhibitors, including, but not limited to, Bevacizumab (Avastin®), axitinib (Inlyta®), brivanib alaninate (BMS582664, ^)-((P)-1-(4 -(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2.1-G|[1.2.4|triazin-6yloxy)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 81180305-1), Imatinib (Gleevec), Ponatinib (AP24534, CAS 943319-70-8), Tivozanib (AV951, CAS 475108-180), Regorafenib (BAY73- 4506, CAS 755037-03-7), VALATALINIB dihydrochloride (PTK787, CAS 212141-510), Brivanib (BMS-540215, CAS 649735-46-6), Vandetanib (Kaprelesa® or AZD6474), MOTESNIB DIFOSPHATE (AMG706, CAS 857 876 -30-3, No.(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4pyridinylmethyl)amino|-3-pyridinecarboxamide, described in published PCT application WO 02/066470 ), Dovitinib dilactate (TKI258, CAS 852433-84-2), Linfanib (ABT869, CAS 796967-16-3) Cabozantinib (XL184, CAS 849217-68-1), Lestaurtinib (CAS 111358-88-4), ^[ 5-[[[5-(1,1-dimethylethyl)-2oxazolyl|methyl|thio|-2-thiazolyl|-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7), (3R,4R)-4amino-1 -((4-((3-methoxyphenyl)amino)pyrrolo[2,1-G|[1,2,4|triazin-5-yl)methyl)piperidin-3-ol (BMS690514), No.(3,4 -dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aa,5b,6aa)-octahydro-2methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23- 8), 4-methyl-3-[[1methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4d]pyrimidin-4-yl]amino]-H-[3-(trifluoromethyl)phenyl]benzamide ( BHG712, CAS 940310-85-0) and Aflibercept (Eylea®).

Examples of the anti-VEGF antibody 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 hybridoma ATCC HB 10709; a recombinant humanized anti-VEGF monoclonal antibody generated as described in Presta et al. (1991). Cancer Res. 57: 4593-4599. In one embodiment, the anti-VEGF antibody is bevacizumab (BV), also known as

- 61 045940 rhuMAb VEGF or Avastin®. This drug contains mutant human IgG1 framework regions and antigen-binding complementarity-determining regions from the murine 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 Patent No. 6,884,879, published February 26, 2005. Additional antibodies include G6 or B20 series antibodies (eg, G6-31, B20-4.1), as described in PCT published application WO 2005/ 012359, published PCT application WO 2005/044853, and the contents of these patent applications are expressly incorporated herein by reference. Information on additional antibodies can be found in US Patent Nos. 7060269, 6582959, 6703020, 6054297, WO 98/45332, WO 96/30046, WO 94/10202, EP 0666868B1, Published US Patent Applications No. 2006009360 , 20050186208, 20030206899, 20030190317, 20030203409 and 20050112126, and in 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, Ml 8, D19, Y21, Y25, Q89, 191, Kl 01, E1 03 and C104, or alternatively containing residues F17 , Y21, B22, Y25, D63, 183 and Q89.

In some embodiments, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1, or anti-TIM antibody molecule -3), used in combination with a PI3K inhibitor. In one embodiment, the PI3K inhibitor is an inhibitor of the delta and gamma isoforms of PI3K. Examples of 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, and are GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL756, XL147, PF46915032, BKM 120, CAL-101, CAL 263, SF1126, PX-886 and dual PI3K inhibitor (eg, Novartis BEZ235).

In some embodiments, anti-PD-1 antibody molecules of the invention, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-3-TIM antibody molecule), are used in combination with an inhibitor mTOR, for example, with one or more mTOR inhibitors selected from one or more of the following: rapamycin, temsirolimus (Torisel®), AZD8055, BEZ235, BGT226, XL765, PF4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794 , WYE-354, Palomide 529 (P529), PF04691502 or PKI-587, ridaforolimus (official name deferolimus, (1R,2R,4S)-4-[(2R)2[(1Κ,9842845Κ,16Ε,18Κ,19Κ, 21Κ,238,24Ε,26Ε,28Ζ,308,328,35K)-1,18-^ή.4ΡΟκμ-19,30-^€τοκ^15,17,21,23,29,35-hexamethyl-2,3, 10,14,20-pentaoxo-11,36-dioxa-4azatricyclo[30.3.1.0 ^4,9 ]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in published PCT application WO 03/064383), everolimus (Afinitor® or RAD001), rapamycin (AY22989, Sirolimus®), simapimod (CAS 164301-51-3), emsirolimus, (5- {2,4-bis[^)-3-methylmorpholin-4-yl]pyrido[2,3d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055), (PF04691502, CAS 1013101-36-4) , and N ² -[1,4dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholin-4-yl]methoxy]butyl]-L-arginylglycyl- Lα-aspartyl-E-serine- (SEQ ID NO: 237), internal salt (SF1126, CAS 936487-67-1) and XL765.

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

In some embodiments, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, is used alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1, or anti-PD-1 antibody molecule). TIM-3) in combination with a MEK inhibitor. In some embodiments, a combination of an anti-PD-1 antibody and a MEK inhibitor is used to treat cancer (eg, a cancer described in the invention). In some embodiments, the cancer treated with the combination is selected from the following cancers: melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell cancer. In some embodiments, the cancer includes BRAF mutations (eg, BRAF V600E mutation), wild-type BRAF, wild-type KRAS, or an activating KRAS mutation. Cancer can be early, intermediate or late stage. Any MEK inhibitor may 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 AZD-6244 or selumetinib), BIX 02188, BIX 021 89 , CI-1040 (PD184352), PD0325901, PD98059, U0126, GDC-0973 (Methanone, [3,4-difluoro-2-[(2-fluoro-4iodophenyl)amino]phenyl][3-hydroxy-3-(25 )-2-piperidinyl-1-azetidinyl]-), G-38963, G02443714 (also

- 62 045940 known as AS703206), or pharmaceutically acceptable salts or solvates thereof. Additional examples of MEK inhibitors are disclosed 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 some embodiments, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, is used alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1, or anti-PD-1 antibody molecule). TIM-3) in combination with a JAK2 inhibitor, for example, CEP-701, INCB18424, CP-690550 (tasocitinib).

In some embodiments, the pharmaceutical composition of the invention, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-3-TIM antibody molecule), is used in combination with paclitaxel or a preparation of paclitaxel , such as Taxol (TAXOL®), protein-bound paclitaxel (eg, ABRAXANE®). Paclitaxel formulations include, by way of example and without limitation, nanoparticle albumin-bound paclitaxel (Abraxane, marketed by Abraxis Bioscience), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin, marketed by Protarga), polyglutamate-bound paclitaxel (PG-paclitaxel , paclitaxel polyglumex, CT-2103, XYOTAX, registered by Cell Therapeutic), tumor-activated prodrug (TAP), ANG105 (Angiopep-2, bound to three molecules of paclitaxel, registered by ImmunoGen), paclitaxel-EC-1 (paclitaxel, bound to erbB2 recognition peptide EC-1, see Li et al., Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (eg, 2'-paclitaxel methyl 2-glucopyranosyl succinate, see Liu et al. , Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620).

Radiation therapy can be administered by one of several modalities or a combination of modalities, including, but not limited to, external beam radiation therapy, internal beam radiation therapy, implantation radiation, stereotactic radiosurgery, systemic radiation therapy, radiation therapy, and permanent or temporary interstitial brachytherapy. The term brachytherapy refers to radiation therapy that is delivered using a spatially confined radioactive material introduced into the body, into or near a tumor, or other site of abnormal proliferative tissue. The term is intended to include, without limitation, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and radioactive Lu isotopes). Suitable radiation sources for use as a cell conditioner according to the invention include both solids and liquids. As a non-limiting example, the radiation source may be a radioactive isotope such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other photon-emitting radionuclides, beta -particles, gamma radiation, or other therapeutic rays. The radioactive material may also be a liquid which is prepared from any solution of radionuclide(s), for example a solution of I-125 or I-131, or the radioactive liquid may be prepared using a suspension of a suitable liquid containing fine particles of solid radionuclides such as Au- 198, Y-90. Moreover, the radionuclide(s) can be placed in a gel or radioactive microspheres.

Anti-PD-1 antibody molecules, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), can be administered in combination with one or more of the existing techniques treatment of cancer, including but not limited to surgery, radiation therapy (eg, external beam radiation therapy, which includes three-dimensional, conformal radiation therapy with a designated radiation field, local radiation therapy (eg, radiation aimed at a preselected target or organ), or focused irradiation). Focused radiation may be selected from the group consisting of stereotactic radiosurgery, fractionated stereotactic radiosurgery, and intensity-modulated radiation therapy. Focused irradiation may have a radiation source selected from the group consisting of a particle beam (protons), cobalt-60 (photons) and a linear accelerator (x-rays), for example, as described in WO 2012/177624.

In some embodiments, an anti-PD-1 antibody molecule, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), is administered in combination with an anti-immunoglobulin-like antibody molecule. killer cell receptor (also called anti-KIR antibody in the invention), with pan-KIR antibody, anti-NKG2D antibody and anti-MICA antibody. In some embodiments, a combination of an anti-PD-1 antibody molecule and an anti-KIR antibody, pan-KIR antibody, or anti-NKG2D antibody mentioned in the invention is used to treat a cancer, such as a cancer described in the invention (e.g., a solid tumor, such as advanced solid tumor).

- 63 045940

In one embodiment, an anti-PD-1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), is administered in combination with a cellular immunotherapy ( for example, with the drug Provenge, for example, Sipuleucel), and, optionally, in combination with cyclophosphamide. In some embodiments, a combination of an anti-PD-1 antibody molecule, Provenge, and/or cyclophosphamide is used to treat a cancer, such as a cancer of the invention (eg, prostate cancer, eg, advanced prostate cancer).

In another embodiment, an anti-PD-1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), is administered in combination with a vaccine, e.g. , with a dendritic cell-based vaccine against renal cell carcinoma (DC-RCC). In some embodiments, the combination of an anti-PD-1 antibody molecule and a DC-RCC vaccine is used to treat cancer, such as a cancer mentioned in the invention (e.g., kidney cancer, such as metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).

In yet another embodiment, an anti-PD-1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), is administered in combination with chemotherapy and /or immunotherapy. For example, an anti-PD-1 antibody molecule may be used to treat myeloma, either alone or in combination with one or more of the following: chemotherapy or other antineoplastic agents (such as thalidomide analogues, e.g., lenalidomide), anti-TIM-3 antibody, tumor antigen - pulsed dendritic cells, fusions (eg, electrofusion) of tumor cells and dendritic cells, or vaccination using an immunoglobulin idiotype produced by malignant plasma cells. In one embodiment, an anti-PD-1 antibody molecule is used in combination with an anti-TIM-3 antibody to treat myeloma, such as multiple myeloma.

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

In yet another embodiment, an anti-PD-1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), is used to treat kidney cancer , for example, renal cell carcinoma (RCC) (for example, clear cell renal cell carcinoma (CCRCC) or metastatic RCC. The anti-PD-1 antibody molecule can be administered in combination with one or more of the following: an immunological strategy (for example, interleukin-2 or interferon-α), a targeting 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 RNA interference inhibitor), or an inhibitor of a downstream neurotransmitter VEGF pathways, such as mammalian target of rapamycin (mTOR) inhibitors, such as everolimus and temsirolimus.

Examples of suitable therapeutic agents for use in combination with the anti-PD-1 antibody molecules of the invention, either alone or in combination with another immunomodulator (eg, with an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of pancreatic cancer include, but are not limited to, a chemotherapeutic agent, e.g., paclitaxel or a paclitaxel formulation (e.g., a paclitaxel formulation such as Taxol, an albumin-stabilized nanoparticle formulation of paclitaxel (e.g., Abraxane), or a liposomal paclitaxel formulation), gemcitabine (e.g., gemcitabine alone or in combination with AChR107-11), 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, bosutilinib, saracatinib, lapatinib, vandetanib); multikinase inhibitor (eg , sorafenib, sunitinib, XL184, pazopanib); VEGF inhibitor (eg, bevacizumab, AV-951, brivanib); radioimmunotherapy (eg, XR303), tumor 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 receptor 2 (TR-2) agonist (eg, conatumumab); MEK inhibitor (eg AS703026, selumetinib, GSK1120212) dual Raf/MEK kinase inhibitor (eg RO5126766); Notch signaling pathway inhibitor (eg MK0752); if

- 64 045940 protein monoclonal antibody - antibody (for example, L19IL2); curcumin; HSP90 inhibitor (eg tanespimycin, STA-9090); RIL-2, denileukin diftitox; topoisomerase 1 inhibitor (eg, irinotecan, PEP02); statin (eg simvastatin); factor VIIa inhibitor (eg PCI27483); AKT inhibitor (eg, RX-0201); hypoxia-activated prodrug (eg, TH302); metformin hydrochloride, a gamma secretase inhibitor (eg RO4929097); ribonucleotide reductase inhibitor (eg 3-AR); immunotoxin (eg HuC242-DM4); PARP inhibitor (eg, KU-0059436, veliparib); CTLA-4 inhibitor (eg, CP-675206, ipilimumab); ADV-tk therapy (using herpes simplex virus thymidine kinase); proteasome inhibitor (eg, bortezomib (Velcad), NPI-0052); thiazolidinedione (eg pioglitazone); NPC-1C; Aurora kinase inhibitor (eg R763/AS703569), CTGF inhibitor (eg FG-3019); siG12DLODER; and radiation therapy (eg, tomotherapy, stereotactic radiation, proton therapy), surgery, and combinations thereof. In some embodiments, a combination of paclitaxel or a drug of paclitaxel and gemcitabine with an anti-PD-1 antibody molecule of the invention may be used.

Examples of suitable therapeutic agents for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, with an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of small cell lung cancer include, but are 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); tumor vaccine (eg, GVAX); Bcl-inhibitor 2 (eg, oblimersen sodium, ABT-263); proteasome inhibitor (eg, bortezomib (Velcad), NPI-0052), paclitaxel or paclitaxel preparation; 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, tanespimycin, STA-9090); mTOR inhibitor (eg, everolimus); bispecific Ep-CAM-/CD3 antibody (eg, MT110); CK-2 inhibitor (eg, CX-4945); HDAC inhibitor (eg, belinostat); SMO antagonist (eg, BMS 833923); peptide tumor vaccine and radiation therapy (eg , intensity-modulated radiation therapy (IMRT), hypofractionated radiation therapy, hypoxia-guided radiation therapy), surgery, and combinations thereof.

Examples of suitable therapeutic agents for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule) for the treatment of non-small cell lung cancer include, but are not limited to, a chemotherapy agent, for example, vinorelbine, cisplatin, docetaxel, pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal SN38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine, irinotecan, tegafurgimeracil-oteracil potassium, sapacitabine); 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), dual Raf/MEK kinase inhibitor (eg, RO5126766), dual PI3K/mTOR kinase 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, cediranib, BIBF 1120, axitinib, tivozanib, AZD2171), tumor vaccine (eg, BLP25 liposomal vaccine, GVAX, recombinant DNA and L523S adenovirus), Bcl-2 inhibitor (eg, oblimersen sodium), proteasome inhibitor (eg, bortezomib, carfilzomib , NPI0052, MLN9708), paclitaxel or paclitaxel preparation, docetaxel, IGF-1 receptor inhibitor (eg, cixutumumab, MK-0646, OSI 906, CP-751871, BIIB022), hydroxychloroquine, HSP90 inhibitor (eg, tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor (eg, everolimus, temsirolimus, ridaforolimus), Ep-CAM/CD3 bispecific antibody (eg, MT110), CK2 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), tumor vaccine (eg , belagenpumatucel-L), low molecular weight heparin (LMWH) (eg, tinzaparin, enoxaparin), GSK1572932A, melatonin, talactoferrin, dimesna, topoisomerase inhibitor (eg, amrubicin, etoposide, carenitcin), nelfinavir, cilengitide, ErbB3 inhibitor (eg, MM- 121, U3-1287), survivin inhibitor (e.g. YM155, LY2181308), eribulin mesylate, COX-2 inhibitor (e.g. celecoxib), pegfilgrastim, Polo-like kinase 1 inhibitor (e.g. BI 6727), TRAIL receptor 2 agonist (TR-2) (e.g. CS-1008), pepti conjugate

- 65 045940 yes CNGRC (SEQ ID NO: 225) - TNF alpha, dichloroacetate (DCA), HGF inhibitor (eg SCH 900105), SAR240550, PPAR gamma agonists (eg CS-7017), gamma secretase inhibitor (eg , RO4929097), epigenetic agents (e.g., 5-azacytidine), nitroglycerin, MEK inhibitor (e.g., AZD6244), cyclin-dependent kinase inhibitor (e.g., UCN-01), cholesterol-HS1, antimicrotubule agent (e.g., E7389), inhibitor farnesyl OH transferase (eg, lonafarnib), immunotoxin (eg, BB-10901, SS1 (dsFv) PE38), fondaparinux, vascular disruptor (eg, AVE8062), PD-L1 inhibitor (eg, MDX-1105, MDX -1106), betaglucan, NGR-hTNF, EMD 521873, MEK inhibitor (eg, GSK1120212), epothilone analog (eg, ixabepilone), kinesin spindle 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 inhibitor (eg, OMP-21M18), radiation therapy, surgery, and combinations thereof .

Examples of suitable therapeutic agents for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of ovarian cancer include, but are not limited to, a chemotherapy agent (eg, paclitaxel or a paclitaxel preparation; 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, cediranib, AZD2171), PDGFR inhibitor (eg, IMC-3G3), paclitaxel, topoisomerase inhibitor (eg , carenitcin, irinotecan), HDAC inhibitor (eg, valproate, vorinostat), folate receptor inhibitor (eg, farletuzumab), angiopoietin inhibitor (eg, AMG 386), epothilone analogue (eg, ixabepilone), proteasome inhibitor (eg, carflizomib) , 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 (eg, pralatrexate), radioimmunotherapies (eg, Hu3S193), statins (eg, lovastatin), topoisomerase 1 inhibitor (eg, NKTR-102), tumor vaccine (eg, long synthetic p53 peptide vaccine , autologous OC-DC vaccine), mTOR inhibitor (eg, temsirolimus, everolimus), BCR/ABL inhibitor (eg, imatinib), ET-A receptor antagonist (eg, ZD4054), TRAIL-2 receptor (TR-2) agonist ( e.g. CS-1008), HGF/SF inhibitor (e.g. AMG 102), Egen-001, Polo-like kinase 1 inhibitor (e.g. BI 6121), gamma secretase inhibitor (e.g. RO4929097), Wee-1 inhibitor ( e.g., MK-1775), antimicrotubule agent (e.g., vinorelbine, E7389), immunotoxin (e.g., Denileukin diftitox), SB-485232, vascular disruptor (e.g., AVE8062), integrin inhibitor (e.g., EMD 525797), kinesin inhibitor spindle (eg, 4SC-205), Revlimid, HER2 inhibitor (eg, MGAH22), ErrB3 inhibitor (eg, MM-121), radiation therapy; and their combinations.

In one illustrative embodiment, an anti-PD-1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), is used to treat myeloma, in as a single agent or in combination with one or more of the following: chemotherapy or other antineoplastic agents (e.g. thalidomide analogs, e.g. lenalidomide), hematopoietic stem cell transplant (HSCT) (Cook, R. (2008) J. Manag. Care Pharm. 14(7 Suppl):19-25), anti-TIM-3 antibody (Hallett, WHD et al. (2011) J. of American Society for Blood and Marrow Transplantation 17 (8):1133-145), tumor antigen - pulsed dendritic cells, fusions (eg electrofusion) of tumor cells and dendritic cells, or vaccination using an immunoglobulin idiotype produced by malignant plasma cells (reviewed by Yi, Q. (2009) Cancer J. 15 (6): 502-10 ).

In yet another embodiment, an anti-PD-1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), is used to treat kidney cancer. for example, renal cell carcinoma (RCC) or metastatic RCC. The anti-PD-1 antibody molecule can be used in combination with one or more of the following: an immunological strategy (e.g. interleukin-2 or interferon-α), a targeted agent (e.g. a VEGF inhibitor such as an anti-VEGF monoclonal antibody, e.g. 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 & Oncology 12(2):9099)); RNA interference inhibitor), or an inhibitor of a downstream VEGF signaling pathway, such as a mammalian target of rapamycin (mTOR) inhibitor, such as EVE

- 66 045940 rolimus 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) .

Examples of suitable therapeutic agents for use in combination with the anti-PD-1 antibody molecules of the invention, either alone or in combination with another immunomodulator (eg, with an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of chronic myeloid leukemia (AML) in accordance with the present invention include, without limitation, a chemotherapeutic agent (such as cytarabine, hydroxyurea, clorafabine, melphalan, thiotepa, fludarabine, busulfan, etoposide, cordycepin, pentostatin, capecitabine, azacitidine, cyclophosphamide, cladribine, topotecan) , tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON 01910.Na, dual inhibitor (e.g., dasatinib, bosutinib), multikinase inhibitor (e.g., DCC-2036, ponatinib, sorafenib, sunitinib, RGB- 286638)), interferon-alpha, steroids, apoptotic agent (e.g., omacetaxine mepesuccinate), immunotherapeutic agent (e.g., anti-CD3/anti-CD28 antibodies associated with allogeneic CD4+ Th1-like memory T cells/microparticles, autologous cytokine-induced killer cells ( CIK), AHN-12), CD52-targeting agent (eg, alemtuzumab), HSP90 inhibitor (eg, tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor (eg, everolimus), SMO antagonist (eg, BMS 833923), ribonucleotide reductase inhibitor (e.g. 3-AP), JAK-2 inhibitor (e.g. INCB018424), hydroxychloroquine, retinoid (e.g. fenretinide), cyclin-dependent kinase inhibitor (e.g. UCN-01), HDAC inhibitor (e.g. belinostat, vorinostat, JNJ26481585), PARP inhibitor (eg, veliparib), MDM2 antagonist (eg, RO5045337), Aurora B kinase inhibitor (eg, TAK-901), radioimmunotherapy (eg, actinium-225 labeled anti-CD33 antibody HuM195), hedgehog inhibitor (eg, PF-04449913), STAT3 inhibitor (eg, ORV-31121), KB004, tumor vaccine (eg, AG858), bone marrow transplant, stem cell transplant, radiation therapy, and combinations thereof.

Examples of suitable therapeutic agents for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of chronic lymphocytic leukemia (CLL) include, but are not limited to, a chemotherapy agent (eg, fludarabine, cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, 5-azacytidine, disodium pemetrexed), a tyrosine kinase inhibitor (eg, EGFR inhibitor (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 alfa, lenalidomide, Bcl-2 inhibitor (eg, ABT-263), immunotherapy (eg, anti-CD3/anti-CD28 associated with allogeneic CD4+ Th1-like T cells memory/microparticles, autologous cytokinin-induced killer (CIK) cells), HDAC inhibitor (eg, vorinostat, valproic acid, LBH589, JNJ-26481585, AR-42), XIAP inhibitor (eg, AEG35156), CD-74 targeting agent (eg, milatuzumab), mTOR inhibitor (eg, everolimus), AT-101, immunotoxin (eg, CAT-8015, anti-Tac(Ty)-PE38 (LMB-2)), CD37-targeting agent (eg, TRU -016), radioimmunotherapy (eg, 131-tositumomab), hydroxychloroquine, perifosine, SRC inhibitor (eg, dasatinib), thalidomide, PI3K delta inhibitor (eg, CAL-101), retinoid (eg, fenretinide), MDM2 antagonist (eg , RO5045337), plerixafor, Aurora kinase inhibitor (eg, MLN8237, TAK-901), proteasome inhibitor (eg, bortezomib), CD-19-targeting agent (eg, MEDI-551, MOR208), MEK inhibitor (eg, ABT -348), JAK-2 inhibitor (eg, INCB018424), hypoxia-activated prodrug (eg, TH-302), paclitaxel or paclitaxel preparation, HSP90 inhibitor, AKT inhibitor (eg, MK2206), HMG-CoA reductase inhibitor (eg, simvastatin), GNKG186, radiation therapy, bone marrow transplantation, stem cell transplantation and a combination thereof.

Examples of suitable therapeutic agents for use in combination with the anti-PD-1 antibody molecules of the invention, either alone or in combination with another immunomodulator (eg, with an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of acute lymphocytic leukemia (ALL) include, but are 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), tyrosine kinase inhibitor (eg, BCR/ABL inhibitor (eg, imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (eg, sorafenib)), CD-20-targeting agent (eg, rituximab), substance CD52-targeting (eg, alemtuzumab), HSP90 inhibitor (eg, STA-9090), mTPOR inhibitor (eg, everolimus, rapamycin), JAK-2 inhibitor (eg, INCB018424), HER2/Neu receptor inhibitor (eg, trastuzumab) , proteasome inhibitor (eg, bortezomib), methotrexate, asparaginase, CD-22-targeting agent (eg, epratuzumab, inotuzomab), immunotherapy

- 67 045940 agent (autologous cytokine-induced killer (CIK) cells, AHN-12), blinatumomab, cyclin-dependent kinase inhibitor (eg, UCN-01), CD45-targeting agent (eg, BC8), MDM2 antagonist (eg, RO5045337), immunotoxin (eg, CAT-8015, DT2219ARL), HDAC inhibitor (eg, JNJ-26481585), JVRS-100, paclitaxel or paclitaxel preparation, STAT3 inhibitor (eg, ORV-31121), PARP inhibitor (eg , veliparib), EZN-2285, radiation therapy, steroid, bone marrow transplant, stem cell transplant, or a combination thereof.

Examples of suitable therapeutic agents for use in combination with the anti-PD-1 antibody molecules of the invention, either alone or in combination with another immunomodulator (eg, with an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of acute myeloid leukemia (AML) include, but are not limited to, a chemotherapy agent (e.g., cytarabine, daunorubicin, idarubicin, clofarabine, decitabine, vosaroxine, azacitidine, clofarabine, ribavirin, CPX-351, treosulfan, elacytarabine, azacitidine), a tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (eg, imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (eg, midostaurin, SU 11248, quizartinib, sorafinib)), immunotoxin (eg, gemtuzumab ozogamicin), DT388IL3 fusion protein, HDAC inhibitor (eg, vorinostat, LBH589), plerixafor, mTOR inhibitor (eg, everolimus), SRC inhibitor (eg, dasatinib), HSP90 inhibitor (eg, STA-9090), retinoid (eg, bexarotene, Aurora kinase inhibitor (eg, BI 811283), JAK-2 (eg, INCB018424), Polo-like kinase inhibitor (eg, BI6727), 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, radiation therapy, bone marrow transplantation, stem cell transplantation, and their combinations.

Examples of suitable therapeutic agents for use in combination with the anti-PD-1 antibody molecules of the invention, either alone or in combination with another immunomodulator (eg, with an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of multiple myeloma (MM) include, but are not limited to, a chemotherapy agent (eg, melphalan, amifostine, cyclophosphamide, doxorubicin, clofarabine, bendamustine, fludarabine, adriamycin, SyB L-0501), thalidomide, lenalidomide, dexamethasone, prednisolone, pomalidomide, proteasome inhibitor ( e.g., bortezomib, carflizomib, MLN9708), tumor vaccine (e.g., GVAX), CD-40-targeting agent (e.g., SGN-40, CHIR-12.12), perifosine, zoledronic acid, immunotherapy (e.g., MAGE-AZ, NY-ESO-1, HuMax-CD38), HDAC inhibitor (eg, vorinostat, LBH589,-42 AR), aplidine, cyclin-dependent kinase inhibitor (eg, PD-0332991, dinaciclib), arsenic trioxide, CB3304, HSP90 inhibitor ( e.g., KW2478), tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., cetuximab), multikinase inhibitor (e.g., AT9283)), VEGF inhibitor (e.g., bevacizumab), plerixafor, MEK inhibitor (e.g., 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, ACE041, CK-2 inhibitor (eg, CX-4945), radiation therapy, bone marrow transplant, stem cell transplant, and combinations thereof.

Examples of suitable therapeutic agents for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of prostate cancer include, but are not limited to, a chemotherapy agent (e.g., docetaxel, carboplatin, fludarabine), abiraterone, a hormonal agent (e.g., flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, degarelix, leuprolide, goserelin, triptorelin, buserelin) , tyrosine kinase inhibitor (eg, dual kinase inhibitor (eg, lapatanib), multikinase inhibitor (eg, sorafenib, sunitinib)), VEGF inhibitor (eg, bevacizumab), TAK-700, tumor vaccine (eg, BPX-101, PEP223), Lenalidomide, TOK-001, IGF-1 receptor inhibitor (eg, cixutumumab), TRC105, Aurora kinase inhibitor (eg, MLN8237), proteasome inhibitor (eg, bortezomib), OGX-011, radioimmunotherapy (eg, HuJ591-GS), HDAC inhibitor (eg, valproic acid, SB939, LBH589), hydroxychloroquine, mTOR inhibitor (eg, everolimus), dovitinib lactate, diindolemethane, efavirenz, OGX-427, genistein, IMC-3G3, bafetinib, CP-675206, radiation therapy, surgery intervention or a combination thereof.

Examples of suitable therapeutic agents for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of HNSCC includes, without limitation, one or both of compound A8 of the invention (or the compound described in published PCT application No. WO 2010/029082) and cetuximab (eg, Erbitux, registered by BMS). In some embodiments, the therapeutic agent (eg, with

- 68 045940 compound A8 or a compound related to A8) is a PI3K modulator, for example a PI3K inhibitor. In some embodiments, the therapeutic agent (eg, cetuximab) modulates, eg, inhibits, the epidermal growth factor receptor. In some embodiments, the cancer has, or is determined to have, increased levels or activity of PI3K or EGFR compared to a control cell or reference value.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of gastric cancer, for example, high MSI cancer and/or EBV+ gastric cancer, includes, without limitation, the compound A8 of the invention (or the compound described in PCT published application WO 2010/029082). In some embodiments, the therapeutic agent (eg, compound A8 or A8-related compound) is a PI3K modulator, such as a PI3K inhibitor. In some embodiments, the cancer has, or is determined to have, an increased level or activity of PI3K compared to a control cell or reference value.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of gastric cancer, for example, high MSI gastric cancer and/or inactivated RNF4 3 gastric cancer, includes, without limitation, the compound A28 of the invention (or the compound described in PCT published application WO 2010/101849). In some embodiments, the therapeutic agent (eg, compound A28 or A28-related compound) is a modulator, such as a porcupine inhibitor. In some embodiments, the cancer has, or is determined to have, an increased level or activity of porcupine compared to a control cell or reference value.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of gastrointestinal stromal tumors (GIST) includes, without limitation, compound A16 described in the invention (or the compound described in published PCT application WO 1999/003854). In some embodiments, the therapeutic agent (eg, compound A16 or A16-related compound) is a modulator, such as a tyrosine kinase inhibitor. In some embodiments, the cancer has, or is determined to have, an increased level or activity of the tyrosine kinase compared to a control cell or reference value.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of non-small cell lung cancer, such as squamous cell carcinoma or adenocarcinoma, includes, without limitation, one or both of Compound A17 of the invention (or the compound disclosed in U.S. Patent Nos. 7,767,675 and 8,420,645) and Compound A23 of the invention (or the compound disclosed in published PCT application WO 2003/077914). In some embodiments, a compound (eg, compound A17 or a compound related to A17) modulates, eg, inhibits, c-MET. In some embodiments, the compound (eg, compound A23 or a compound related to A23) modulates, eg inhibits, Alk. In some embodiments, the cancer has, or is determined to have, an increased level or activity of one of c-MET or Alk, or both cMET and Alk, compared to a control cell or reference value. In some embodiments, the cancer has, or is determined to have, a mutation in EGFR.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of melanomas (e.g., NRAS mutation melanomas) includes, without limitation, one or both of Compound A24 described in the invention (or the compound described in US Pat. Nos. 8,415,355 and 8,685,980) and Compound A34 described in the invention (or the compound described in published PCT application WO 2003/077914). In some embodiments, a compound (eg, compound A24 or a compound related to A24) modulates, eg, inhibits, one or both of JAK and CDK4/6. In some embodiments, the compound (eg, compound A34 or A34-related compound) modulates, eg, inhibits, MEK. In some embodiments, the cancer has, or is determined to have, an increased level or activity of one or more of JAK, CDK4/6, and MEK compared to a control cell or reference value.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of melanomas (eg, NRAS mutation melanomas) includes, without limitation, one or both of compound A29,

- 69 045940 described in the invention (or the compound described in the published PCT application WO 2011/025927) and compound A34 described in the invention (or the compound described in the published PCT application WO 2003/077914). In some embodiments, the compound (eg, compound A29 or a compound related to A29) modulates, eg inhibits, BRAF. In some embodiments, a compound (eg, compound A34 or an A34-related compound) modulates, eg, inhibits, MEK. In some embodiments, the cancer has, or is determined to have, an increased level or activity of one of BRAF and MEK, or both of BRAF and MEK, compared to a control cell or reference value.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of squamous cell NSCLC includes, without limitation, compound A5 described in the invention (or the compound described in US patent 8552002). In some embodiments, a compound (eg, compound A5 or a compound related to A5) modulates, eg inhibits, FGFR. In some embodiments, the cancer has, or is determined to have, an increased level or activity of FGFR compared to a control cell or reference value.

An example of a suitable therapeutic agent for use in combination with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), for the treatment of colorectal cancer includes, without limitation, one or both of compound A29 described in the invention (or the compound described in published PCT application No. WO 2011/025927) and cetuximab (for example, Erbitux, registered by BMS). In some embodiments, the therapeutic agent (eg, compound A29 or A29-related compound) modulates, eg inhibits, BRAF. In some embodiments, the therapeutic agent (eg, cetuximab) modulates, for example inhibits, EGFR. In some embodiments, the cancer has, or is determined to have, elevated levels or activity of BRAF or EGFR compared to a control cell or reference value.

The present invention also provides methods for treating cancer with Compound A8, cetuximabom, and an anti-PD-1 antibody molecule (optionally in combination with an anti-TIM-3 antibody molecule or an anti-LAG-3 antibody molecule). In some embodiments, the patient first receives treatment with Compound A8 and cetuximab. Such treatment is continued for a period of time, such as a predetermined period of time, such as approximately 1, 2, 4, 6, 8, 10 or 12 months. An anti-PD-1 antibody molecule is then administered (optionally in combination with an anti-TIM-3 antibody molecule or an anti-LAG-3 antibody molecule). The anti-PD-1 antibody may optionally be administered in combination with cetuximab.

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

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

Approximate doses for administration regimens of three (or more than three) substances are as follows. The anti-PD-1 antibody molecule can be administered, for example, at a dose of about 1 to 40 mg/kg, for example, from 1 to 30 mg/kg, for example, about 5 to 25 mg/kg, about 10 to 20 mg/kg 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 to 300, 300 to 400, or 200 to 400 mg. In some embodiments, cetuximab is administered at an initial dose of 400 mg/m ² via a 120-minute intravenous infusion, followed by a dose of 250 mg/m ² as a weekly infusion over 60 minutes. In some embodiments, one or more substances, such as Compound A8, cetuximab, and an anti-PD-1 antibody molecule, is administered at a dose that is lower than the dose at which the substance is typically administered as monotherapy, for example, about 0-10 %, 10-20%, 20-30%, 30-40%, 40-50%, 5060%, 60-70%, 70-80% or 80-90% lower than the dose at which the substance would normally be taken administered as monotherapy. In some embodiments, one or more substances, such as a compound

- 70 045940

A8, cetuximab and an anti-PD-1 antibody molecule, is administered at a dose that is lower than the dose of that substance specified in this paragraph, for example, approximately 0-10%, 10-20%, 20-30%, 30-40 %, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower than the dose of that substance specified in this paragraph. In some embodiments, the concentration of Compound A8 that is required to achieve inhibition, e.g., growth inhibition, is lower when Compound A8 is administered in combination with one or both of cetuximab and an anti-PD-1 antibody molecule than when administered compounds A8 as the only remedy. In some embodiments, the concentration of cetuximab that is required to achieve inhibition, e.g., growth inhibition, is lower when cetuximab is administered in combination with one or both of compound A8 and an anti-PD-1 antibody molecule than when cetuximab is administered as the only remedy. In some embodiments, the concentration of the anti-PD-1 antibody molecule that is required to achieve inhibition, e.g., growth inhibition, is lower when the anti-PD-1 antibody molecule is administered in combination with one or both of cetuximab and Compound A8 than when administering an anti-PD-1 antibody molecule as a single agent.

Additionally, the invention relates to a method of treating cancer with an anti-PD-1 antibody molecule, either alone or in combination with another immunomodulator (for example, an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule) and an antitumor a targeted agent, for example, an agent that targets one or more proteins. In some embodiments, the anti-PD-1 antibody molecule (and optionally other immunomodulator(s)) is administered first and the targeted antitumor agent is administered second. The length of time between administration of the anti-PD-1 antibody molecule and the targeted antitumor 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 within the specified range. In some embodiments, the anti-PD-1 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 for any period of time within this range) before administration of a targeted antitumor agent. In other embodiments, the anti-PD-1 antibody molecule and the targeted antitumor agent are administered substantially simultaneously.

Infectious diseases.

Other methods of the present invention are used to treat patients who have been exposed to certain toxins or pathogens. Accordingly, another aspect of the present invention relates to a method of treating an infectious disease in a subject, the method comprising administering to the subject an anti-PD-1 antibody molecule, thereby treating the subject for the infectious disease.

When treating an infection (eg, acute and/or chronic), the administration of anti-PD-1 antibody molecules can be combined with conventional treatments in addition to or instead of stimulating the host's natural immune defense against infection. Natural host immune defense mechanisms against infection include, but are not limited to, inflammation, fever, antibody-mediated host defense, T-lymphocyte-mediated host defense mechanisms including the secretion of lymphokines and cytotoxic T cells (especially during viral infection), complement-mediated lysis and opsonization (facilitation of phagocytosis), and phagocytosis. The ability of anti-PD-1 antibody molecules to reactivate dysfunctional T cells will be useful for the treatment of chronic infections, particularly in which cellular immunity is important for full recovery.

Antibody-mediated blockade of PD-1, similar to its use in tumors as described above, can be used as a single agent or as an adjuvant, in combination with vaccines, to stimulate an immune response to pathogens, toxins and autoantigens. Examples of pathogens for which this 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. Such pathogens include, but are not limited to, HIV, hepatitis viruses (A, B and C), influenza and herpes viruses, Giardia, malaria, leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa. PD-1 blockade is particularly useful against infections with pathogens such as HIV that present altered antigens throughout the course of the infectious disease. These new epitopes are recognized as foreign when the anti-human PD-1 antibody is administered, thereby inducing a potent T cell response that is not suppressed by negative signals through PD-1.

Viruses.

For infections caused by viral pathogens, anti-PD-1 antibody molecules can be combined by using them simultaneously, before or after standard therapeutic agents for the treatment of viral infections. Such standard therapeutic agents vary

- 71 045940 vary depending on the type of virus, although in almost all cases the administration of human serum containing antibodies (eg IgA, IgG) specific to the virus can be effective.

Some examples of pathogenic viruses that cause infections and can be treated by the methods mentioned include HIV, hepatitis virus (A, B or C), herpes virus (for example, VZV, HSV-1, HAV-6, HSV-II and CMV, Epstein virus- Barr), adenovirus, influenza virus, flaviviruses, ECHO virus, rhinovirus, Coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscan virus, polio virus, rabies virus, JC virus and arboviral encephalitis virus.

In one embodiment, the infection is an influenza infection. Influenza infection can cause fever, cough, myalgia, headache and general malaise, which are often found in seasonal epidemics. Influenza is also associated with a number of post-infectious diseases, such as encephalitis, myopericarditis, Goodpasture's syndrome and Reye's syndrome. Influenza infection also suppresses normal pulmonary antibacterial defense mechanisms, meaning that a patient recovering from influenza has an increased risk of developing bacterial pneumonia. The surface proteins of the influenza virus exhibit pronounced antigenic variability due to mutation and recombination. Thus, cytolytic T lymphocytes are the host's primary means of eliminating the virus after infection. There are three main types of influenza: A, B, and C. What makes the influenza A virus unique is that it infects both humans and many other animals (such as pigs, horses, birds, and seals) and is the leading cause of influenza pandemics. Also, when a cell is infected with two different strains of influenza A virus, the segmented RNA genomes of the two parental virus types are mixed during replication to create a hybrid replicant, resulting in the emergence of new epidemic strains. Influenza B virus does not replicate in animals and therefore has less genetic variability, and influenza C virus has only one serotype.

Most conventional treatments are palliative, targeting symptoms due to the infection, with the disease actually being eliminated by the host's immune response. However, some strains (such as influenza A virus) can cause more severe illness and death. Therapeutic and prophylactic treatment of influenza A can be carried out by administering cyclic amine inhibitors (amantadine and rimantadine), which inhibit viral replication. However, the clinical applicability of these drugs is limited due to the relatively high frequency of adverse reactions, narrow antiviral spectrum (exclusively influenza A virus), and the tendency of the virus to acquire resistance. The use of serum IgG antibodies against most influenza surface proteins, hemagglutinin and neuraminidase can prevent pulmonary infection, while mucosal IgA is necessary to prevent infection of the upper respiratory tract and trachea. The most effective modern treatment for influenza is vaccination with the introduction of a virus inactivated by formaldehyde or β-propiolactone.

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

Hepatitis B virus (HB-V) is the most well-known infectious blood-borne pathogen. This virus is the leading cause of acute and chronic hepatitis and liver carcinoma, as well as lifelong chronic infection. After infection, the virus replicates in hepatocytes, which in turn secrete the surface antigen HBsAg. Detection of elevated serum HBsAg levels is used as a standard method for diagnosing infectious hepatitis. The acute infection may resolve or may develop into a chronic persistent infection. Current treatments for chronic hepatitis include α-interferon, which increases the expression of human leukocyte antigen class I (HLA) on the surface of hepatocytes, thereby promoting their recognition by cytotoxic T lymphocytes. Additionally, the nucleoside analogues ganciclovir, famciclovir, and lamivudine have also shown some efficacy in the treatment of HBV infection in clinical trials. Additional treatments for HBV infection include pegylated interferon-α, adenfovir, entecavir, and telbivudine. Passive immunity can be created by parenteral administration of serum antibodies against HBsAg, but at the same time, resistance to infection is also created by vaccination with inactivated or recombinant HBsAg. Anti-PD-1 antibody molecules can be combined with conventional treatments for hepatitis B infection to achieve therapeutic benefit.

Infection with hepatitis C virus (HC-V) can lead to chronic hepatitis, which results in cirrhosis. Despite the fact that the symptoms are similar to infectious hepatitis B, the striking difference from HB-V is the absence of symptoms in those infected for 10-20 years. The anti-PD-1 antibody molecule can be administered as monotherapy or in combination with standard treatment for infectious hepatitis C. For example, the anti-PD-1 antibody molecule can be administered with one

- 72 045940 or several drugs, such as Sovaldi (sofosbuvir), Olicio (simeprevir), in combination with ribavirin or pegylated interferon. Treatment regimens that include Insivec (Telaprevir) or Victrelis (Boceprevir) plus ribavirin and pegylated interferon are also approved, although they are associated with increased side effects and longer treatment durations and are therefore not considered preferred treatment regimens.

Conventional treatment for HC-V infection involves administering a combination of interferon-α and ribavirin. A promising potential treatment for HC-V infection is the use of the protease inhibitor telaprevir (VX-960). Additional treatments include: anti-PD-1 antibody (MDX-1106, Medarex), bavituximab (an antibody that binds to the anionic phospholipid phosphatidylserine in a B2-glycoprotein 1-dependent manner, Peregrine Pharmaceuticals), anti-HPV viral envelope protein E2 antibody(ies). (eg, ATL 6865-Ab68+Ab65, XTL Pharmaceuticals) and Civacir® (polyclonal human anti-HCV immunoglobulin). The anti-PDL1 antibodies of the invention can be combined with one or more treatments for infectious hepatitis C for therapeutic benefit. Proteases, polymerases and NS5A inhibitors that can be used in combination with anti-PD-1 antibody molecules for specific treatment of hepatitis C include those described in US application 2013/0045202, incorporated herein by reference.

In another embodiment, the infection is a measles virus. After an incubation period of 9-11 days, the body infected with the measles virus develops fever, cough, runny nose 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 patient is at high risk of developing bacterial superinfections, including otitis media, pneumonia, and postinfectious encephalomyelitis. Acute infection is characterized by high morbidity and mortality, especially in malnourished adolescents.

Treatment of measles involves passive administration of a pool of human IgG, which can prevent infection in nonimmunized subjects, even when administered intravenously within one week of infection. However, primary immunization with a live attenuated virus is the most effective treatment and prevents disease in more than 95% of immunized patients. Because there is a single serotype of this virus, a single immunization or infection usually provides lifelong protection against subsequent infection.

In a small proportion of infected people, measles can progress to subacute sclerosing panencephalitis (SSPE), which is a chronic, progressive neurological disorder resulting from chronic infection of the central nervous system. SSPE is caused by clonal variants of the measles virus with defects that impair virion assembly and active viral replication through cell entry (budding). For such patients, reactivation of T cells using anti-PD-1 antibody molecules would be desirable to facilitate viral clearance.

In another embodiment, the infection is due to human immunodeficiency virus (HIV). HIV attacks CD4+ cells, including T cells, monocyte macrophages, follicular dendritic cells, and Langerhans cells, and depletes CD4+ helper/inducer cells. As a result, a person develops a severe defect in cellular immunity. As a result of HIV infection, at least 50% of people are diagnosed with AIDS, which is transmitted sexually, through the ingestion of contaminated blood or blood products, through artificial insemination with contaminated sperm, through contact with needles or syringes containing blood, and through transmission of the virus from an infected mother to the baby during childbirth.

A person infected with HIV may be asymptomatic or may develop an acute illness resembling mononucleosis, with fever, headache, sore throat, malaise, and rash. Symptoms may progress to progressive immune system dysfunction, including persistent fever, night sweats, weight loss, unexplained diarrhea, eczema, psoriasis, seborrheic dermatitis, herpes zoster, oral candidiasis, and oral hairy cell leukoplakia. Opportunistic infections due to parasites are common in patients who have progressed to the AIDS stage.

Treatment of HIV infection includes antiviral therapeutic agents, including nucleoside analogues, zidovudine (AST), either as monotherapy or in combination with the drugs didanosine or zalcitabine, dideoxyinosine, dideoxycytidine, lamivudine, stavudine; reverse transcriptase inhibitors such as delavirdine, nevirapine, loviride, and protease inhibitors such as saquinavir, ritonavir, indinavir and nelfinavir. Anti-PD-1 antibody molecules can be combined with conventional drugs for the treatment of HIV infection for therapeutic benefit.

In another embodiment, the infection is due to cytomegalovirus (CMV). CMV infection is often associated with persistent, occult and recurrent infection. CMV infects monocytes and granulocyte-monocyte precursor cells and remains in them in a latent form. Clinical symptoms of CMV include mononucleosis-like symptoms (eg, fever,

- 73 045940 swelling of the glands, general malaise) and a tendency to develop allergic skin rashes to the administration of antibiotics. The virus spreads through direct contact. The virus is shed in urine, saliva, semen and, to a lesser extent, other body fluids. Transmission of the virus can also occur from an infected mother to the fetus or newborn and through blood transfusions and organ transplants. CMV infection causes a general disorder of cellular immunity, characterized by impaired blast transformation response to nonspecific mitogens and specific CMV antigens, a decrease in cytotoxic ability and an increase in the number of CD8 lymphocytes compared to the number of CD4+ lymphocytes.

Treatment for cytomegalovirus infection includes the antiviral drugs ganciclovir, foscarnet, and cidovir, but these drugs are usually only prescribed to immunocompromised patients. Anti-PD-1 antibody molecules can be combined with conventional treatments for cytomegalovirus infections for therapeutic benefit.

In another embodiment, the infection is due to Epstein-Barr virus (EBV). EBV can cause persistent and latent infections and primarily attacks B cells. EBV infection causes the clinical condition of infectious mononucleosis, which includes fever, sore throat, often with exudate, generalized lymphadenopathy, and splenomegaly. Hepatitis is also detected, which can develop to the symptom of jaundice.

Because conventional treatments for EBV infection are palliative and symptomatic, EBV is associated with the development of some cancers, such as Burkitt's lymphoma and nasopharyngeal cancer. Thus, greater benefit will arise from eliminating the viral infection before these complications occur. Anti-PD-1 antibody molecules can be combined with conventional treatments for Epstein-Barr virus infections for therapeutic benefit.

In another embodiment, the infection is due to herpes simplex virus (HSV). HSV is transmitted through direct contact with an infected person. Direct infection may be asymptomatic, but usually causes the appearance of herpetic blisters containing infectious particles. The disease manifests itself in cycles of active periods of the disease, during which lesions appear, and periods without the manifestation of the disease, but foci of latent viral infection appear in the nerve ganglia for subsequent outbreaks. Lesions may be on the face, genitals, eyes and/or hands. In some cases, the infection can also cause encephalitis.

Therapeutics for the treatment of herpes infections are aimed primarily at controlling symptomatic outbreaks, and include systemic antivirals such as acyclovir (eg, Zovirax®), valacyclovir, famciclovir, penciclovir, and topical medications such as docosanol (Abreva® ), tromantadine and zilactin. Elimination of latent herpes infections will have great clinical benefit. Anti-PD1 antibody molecules can be combined with conventional treatments for herpesvirus infections for therapeutic benefit.

In another embodiment, the infection is caused by human T-lymphotropic virus (HTLV-1, HTLV-2). HTLV viruses are transmitted through sexual contact, breastfeeding, or contact with contaminated blood. The virus activates a subset of TH cells called Th1 cells, which causes them to overproliferate and overproduce Th1-related cytokines (eg, IFN-γ and TNFα). In turn, this leads to suppression of Th2 lymphocytes and a decrease in the production of Th2 cytokines (for example, IL-4, IL-5, IL-10 and IL-13), resulting in a decrease in the ability of the infected organism to form an adequate immune response to introduction of pathogens that require a Th2-dependent response for clearance (for example, to resolve parasitic infections, humoral antibody products and mucosal antibodies).

Infection with HTLV viruses leads to opportunistic infections causing bronchiectasis, dermatitis and superinfections with Staphylococcus spp. and Strongyloides spp., resulting in death from polymicrobial sepsis. HTLV infection can also directly cause T-cell leukemia/lymphoma and progressive upper motor neuron demyelinating disease called HAM/TSP. Elimination of latent HTLV infection would be of great clinical benefit. Anti-PD-1 antibody molecules can be combined with conventional treatments for HTLV infections for therapeutic benefit.

In another embodiment, the infection is caused by human papillomavirus (HPV). HPV primarily affects keratinocytes and occurs in two forms: cutaneous and genital. Transmission of the virus is believed to occur through direct contact and/or sexual contact. Both the cutaneous and genital forms of HPV infection can manifest as warts and latent infections, and sometimes recurrent infections controlled by the body's immune system, whereby a person's immune system controls symptoms and blocks the appearance of warts, but leaves that person capable of transmitting the infection to others.

HPV infection can also cause some types of cancer, such as cervical cancer,

- 74 045940 anal, vulvar, penile and oropharyngeal cancer. There are no known drugs to treat HPV infection, with current treatment being the topical application of the drug Imiquimod, which stimulates the immune system to attack the affected area. Elimination of latent HPV infection will provide greater clinical benefit. The anti-PD-L1 antibodies of the invention can be combined with conventional treatments for HPV infection for therapeutic benefit.

Bacterial infections.

Some examples of pathogenic bacteria causing infections that can be treated by the methods of the present invention include syphilis, chlamydia, rickettsia, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and gonococci, Klebsiella, Proteus, Salmonella, Serratia, Pseudomonas, Legionella, bacilli , the causative agents of diphtheria, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease. Anti-PD-1 antibody molecules can be used in combination with existing treatments for the above infections. For example, treatment for syphilis includes penicillin (eg, penicillin G), tetracycline, doxycycline, ceftriaxone, and azithromycin.

Lyme disease, caused by Borrelia burgdorferi, is transmitted to humans through the bite of a tick. The initial manifestation of the disease is a localized rash, followed by flu-like symptoms including general malaise, fever, headache, stiff neck and arthralgia. Later manifestations may include migratory and polyarticular arthritis, neurological and cardiac disorders with cranial nerve palsies and radiculopathy, myocarditis and arrhythmias. In some cases, Lyme disease becomes persistent, resulting in irreversible damage similar to tertiary syphilis. Current treatment for Lyme disease involves primarily administering antibiotics. Antibiotic-resistant strains can be treated with hydroxychloroquine or methotrexate. Patients who are refractory to antibiotics and have neuropathic pain can be treated with gabapentin. Minocycline may be useful for the treatment of advanced/chronic Lyme disease with neurological or other inflammatory symptoms.

Other forms of borreliosis, such as those caused by infection with B. recurrentis, B. hermsii, B. turicatae, B. parikeri., B. hispanica, B. duttonii and B. persica, as well as leptospirosis (for example, L. interrogans), usually resolve spontaneously if antibody titers in the blood do not reach a concentration that causes intrahepatic obstruction.

Fungi and parasites.

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

Some examples of pathogenic parasites causing infections that are treatable by the methods of the invention are Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi and Nippostrongylus brasiliensis.

Additional combination drugs.

The invention relates to combinations of anti-PD-1 antibody molecules with one or more second therapeutic agents. Many of the combinations listed in this section can be used in the treatment of cancer, but other indications are also described. This section discusses combinations of anti-PD-1 antibody molecules, optionally in combination with one or more immunomodulators (such as an anti-TIM-3 antibody molecule, an anti-LAG-3 antibody molecule, or an anti-PD-L1 antibody molecule), with one or more agents , indicated in table. 7. In one embodiment, in the following combinations of the invention, the anti-PD1 antibody molecule includes:

(a) a heavy chain variable region (VH) which comprises VHCDR1 having the amino acid sequence SEQ ID NO: 4, VHCDR2 having the amino acid sequence SEQ ID NO: 5, and VHCDR3 having the amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) which comprises VLCDR1 having the amino acid sequence SEQ ID NO: 13, VLCDR2 having the amino acid sequence SEQ ID NO: 14, and VLCDR3 having the amino acid sequence SEQ ID NO: 33;

(b) VH, which contains the amino acid sequence of VHCDR1 selected from SEQ ID NO: 1; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and VL, which contains VLCDR1 having the amino acid sequence SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 11, and VLCDR3 having the amino acid sequence SEQ ID NO: 32;

(c) VH, which contains VHCDR1 with the amino acid sequence SEQ ID NO: 224, VHCDR2 with the amino acid sequence SEQ ID NO: 5, and VHCDR3 with the amino acid sequence SEQ ID NO: 3; and VL, which contains VLCDR1 with the amino acid sequence

- 75 045940

SEQ ID NO: 13, VLCDR2 having the amino acid sequence SEQ ID NO: 14, and VLCDR3 having the amino acid sequence SEQ ID NO: 33; or (d) VH, which contains VHCDR1 with the amino acid sequence of SEQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 2; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and VL, which contains VLCDR1 having the amino acid sequence SEQ ID NO: 10, VLCDR2 having the amino acid sequence SEQ ID NO: 11, and VLCDR3 having the amino acid sequence SEQ ID NO: 32.

In another embodiment, in the following combinations of the invention, the anti-PD-1 antibody molecule comprises:

(I) a heavy chain variable region (VH) containing the amino acid sequence of VHCDR1 selected from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224; VHCDR2 with amino acid sequence SEQ ID NO: 2 or SEQ ID NO: 5; and VHCDR3 with amino acid sequence SEQ ID NO: 3; and (II) a light chain variable region (VL) comprising VLCDR1 having amino acid sequence SEQ ID NO: 10 or SEQ ID NO: 13, VLCDR2 having amino acid sequence SEQ ID NO: 11 or SEQ ID NO: 14, and VLCDR3 having amino acid sequence SEQ ID NO: 32 or SEQ ID NO: 33.

In one embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a protein kinase C (PKC) inhibitor, Sotrastaurin (compound A1), or with a compound described in the published PCT application WO 2005/039549, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the PKC inhibitor is Sotrastaurin (compound A1), or a compound described in PCT Published Application No. WO 2005/039549. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Sotrastaurin (compound A1), or with a compound described in PCT Published Application No. WO 2005/039549, for the treatment of a disease such as cancer, melanoma, non-Hodgkin's lymphoma, inflammatory disease intestines, transplant rejection, ophthalmic disease or psoriasis.

In some embodiments, Sotrastaurin (Compound A1) is administered at a dose of about 20 to 600 mg, such as about 200 to about 600 mg, about 50 mg to about 450 mg, about 100 to 400 mg, about 150 to 350 mg, or about 200 to 300 mg, for example about 50, 100, 150, 200, 300, 400, 500 or 600 mg. The schedule of administration may vary, for example, from administration every other day to administration twice or three times a day.

In one embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, 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 published PCT application No. WO 2004/005281, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the BCR-ABL inhibitor is Tasigna, or a compound described in PCT Published Application No. WO 2004/005281. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Tasigna (compound A2) or with a compound described in PCT published application WO 2004/005281 for the treatment of a disease such as lymphoblastic leukemia, Parkinson's disease, neuronal cancer, melanoma , digestive/duodenal cancer, colorectal cancer, myeloid leukemia, head and neck cancer, or pulmonary hypertension.

In one embodiment, the BCR-ABL inhibitor or Tasigna is administered at a dose of approximately 300 mg (e.g., twice daily, e.g., for newly diagnosed Ph+ CML-CP (Philadelphia chromosome positive chronic phase CLL), or approximately 400 mg, e.g. , twice a day, for example, in case of resistance or intolerance in patients with Ph+ CML-SR and CML-AR (in the acute phase)). The BCR-ABL inhibitor or Compound A2 is administered at a dose of approximately 300 to 400 mg.

In another embodiment, an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an HSP90 inhibitor such as 5-(2. 4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (compound A3), or with the compound described in published PCT application WO 2010/060937 or WO 2004/ 072051, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the HSP90 inhibitor is 5-(2,4-dihydroxy-5-isopropylphenyl)-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (compound A3), or a compound described in published PCT application No. WO 2010/060937 or WO 2004/072051. In one embodiment, the anti-PD-1 antibody molecule is used in combination with 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (Compound A3),

- 76 045940 or with a compound described in the published PCT application WO 2010/060937 or WO 2004/072051, for the treatment of a disease such as cancer, multiple myeloma, non-small cell lung cancer, lymphoma, gastric cancer, breast cancer, digestive system cancer/ cancer of the gastrointestinal tract, pancreas, colorectal cancer, solid tumor or disorder of hematopoiesis.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, 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-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5- c]quinolin-2-one (compound A41), or the compound described in published PCT application No. WO 2006/122806, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the PI3K and/or mTOR inhibitor is Dactolisib (compound A4), 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl) -1,3-dihydro-imidazo[4,5-c]quinolin-2-one (compound A41), or the compound described in published PCT application WO 2006/122806. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Dactolisib (compound A4), with the compound 8-(6methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3 -trifluoromethylphenyl)-1,3-dihydro-imidazo[4,5c]quinolin-2-one (compound A41), or with the compound described in PCT Published Application No. WO 2006/122806, for the treatment of a disease 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-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR inhibitor, 3-(2,6dichloro- 3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1 -yl)phenyl)amino)pyrimidin-4-yl)-1 methylurea (compound A5) or with the compound described in the US patent 8552002, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the FGFR inhibitor is 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1yl)phenyl)amino)pyrimidin-4-yl)- 1-methylurea (Compound A5) or the compound described in US Pat. No. 8,552,002. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Compound A5, or the compound described in US Pat. No. 8,552,002, to treat a disease such as cancer digestive system/gastrointestinal cancer, hematological cancer 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 to 125 mg (eg, per day), such as about 100 mg or about 125 mg.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, 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 published PCT application WO 2007/084786, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the PI3K inhibitor is Buparlisib (compound A6) or a compound described in published PCT application WO 2007/084786. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Buparlisib (compound A6) or a compound described in PCT published application WO 2007/084786 for the treatment of a disease such as prostate cancer, non-small cell lung cancer, endocrine system cancer , leukemia, ovarian cancer, melanoma, bladder cancer, breast cancer, female reproductive system cancer, digestive/duodenal cancer, colorectal cancer, glioblastoma multiforme, solid tumor, non-Hodgkin's lymphoma, hematopoietic disorder, or head and neck cancer.

In one embodiment, the PI3K inhibitor or Buparlisib (Compound A6) is administered at a dose of approximately 100 mg (eg, per day).

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR inhibitor, 8-(2,6difluoro- 3,5-dimethoxyphenyl)-H-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5carboxamide (compound A7) or with the compound described in published PCT application WO 2009/141386, for the treatment diseases, for example, the diseases mentioned in the invention. In one embodiment, the FGFR inhibitor is 8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide (compound A7 ) or a compound described in published PCT application WO 2009/141386. In one embodiment, the FGFR inhibitor is 8-(2,6-difluoro-3,5-dimethoxyphenyl)-H-(4-((dimethylamino)methyl)-1H-imidazol-2yl)quinoxaline-5-carboxamide (compound A7) . In one embodiment, the antibody molecule

- 77 045940 against PD-1 is used in combination with 8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5- carboxamide (compound A7) or with a compound described in published PCT application WO 2009/141386, for the treatment of a disease such as cancer characterized by angiogenesis.

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

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a PI3K inhibitor (S)-N1-(4methyl -5 -(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidin-1,2dicarboxamide (compound A8) or with the compound described in published PCT application WO 2010/029082, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the PI3K inhibitor is (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan2-yl)pyridin-4-yl)thiazol-2-yl) pyrrolidine-1,2-dicarboxamide (compound A8) or the compound described in published PCT application WO 2010/029082. In one embodiment, the anti-PD-1 antibody molecule is used in combination with ^)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2yl)pyridin-4-yl) pyridin-2-yl)pyrrolidin-1,2-dicarboxamide (compound A8) or with the compound described in the published PCT application WO 2010/029082, for the treatment of a disease such as stomach cancer, breast cancer, pancreatic cancer, digestive cancer systems/gastrointestinal cancer, solid tumor and head and neck cancer.

In one embodiment, a PI3K inhibitor or γ)-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 administered at a dose of about 150 to 300, 200 to 300, 200 to 400, or 300 to 400 mg (eg, per day), such as about 200, 300, or 400 mg .

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, 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 with a compound described in published PCT application WO 2010/149755, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, a cytochrome P450 inhibitor (eg, a CYP17 inhibitor) is a compound disclosed in PCT Published Application No. WO 2010/149755. In one embodiment, an anti-PD-1 antibody molecule is used in combination with a compound described in PCT Published Application No. WO 2010/149755 for the treatment of prostate cancer.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an HDM2 inhibitor (S)-1-(4chlorophenyl )-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 with the compound described in the published PCT application WO 2011/076786, for the treatment of a disease, for example, the disease mentioned in the invention). 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-1yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (compound A10) or the compound described in PCT Published Application No. WO 2011/076786. In one embodiment, the anti-PD-1 antibody molecule is used in combination with the compound ^)-1-(4-chlorophenyl)-7isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-( 4-methyl-3-oxopiperazin-1yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (compound A10), or the compound described in published PCT application WO 2011/076786, for the treatment of a disease such as a solid tumor.

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

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the iron chelating drug Deferasirox (also known as Exjade , compound A11) or with a compound described in published PCT application WO 1997/049395, for the treatment of a disease, for example, a disease mentioned

- 78 045940 in the invention. In one embodiment, the iron chelating agent is Deferasirox or a compound described in published PCT application WO 1997/049395. In one embodiment, the iron chelating drug is Deferasirox (compound A11). In one embodiment, the anti-PD-1 antibody molecule is used in combination with Deferasirox (compound A11), or with a compound described in PCT published application WO PCT WO 1997/049395, for the treatment of iron overload, hemochromatosis or myelodysplasia.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the aromatase inhibitor Letrozole (also known as Femara; compound A12), or with a compound described in US Pat. No. 4,978,672, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the aromatase inhibitor is Letrozole (Compound A12) or a compound disclosed in US Pat. No. 4,978,672. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Letrozole (Compound A12), or a compound disclosed in US Pat. No. 4,978,672 , for the treatment of a disease such as cancer, leiomyosarcoma, endometrial cancer, breast cancer, cancer of the female reproductive system or hormonal deficiency.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a PI3K inhibitor, e.g., a pan-PKK inhibitor ( 4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl)-4(hydroxymethyl)-5-methyloxazolidin-2-one (compound A13) or with a compound described in published PCT application WO 2013/124826, for the treatment of a disease, for example the disease mentioned in the invention. 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 published PCT application WO 2013/124826. In one embodiment, the anti-PD-1 antibody molecule is used in combination with the compound (4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidine]-6 -yl)-4-(hydroxymethyl)-5methyloxazolidin-2-one (compound A13), or with the compound described in published PCT application WO 2013/124826, for the treatment of a disease such as cancer or advanced solid tumor.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a p53 inhibitor and/or an Mdm2/interaction inhibitor. p53, which is ^)-5-(5-chloro-1-methyl-2-oxo-1,2dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5- yl)-1-isopropyl-5,6dihydropyrrolo[3,4D]imidazol-4(1H)-one (compound A14), or with a compound described in published PCT application WO 2013/111105, for the treatment of a disease, e.g. mentioned in the invention. In one embodiment, the p53 inhibitor and/or the p53/Mdm2 interaction inhibitor is ^)-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[3,4D]imidazol-4(1H)-one (compound A14) or a compound described in a published PCT application WO 2013/111105. In one embodiment, the anti-PD-1 antibody molecule is used in combination with the compound ^)-5-(5-chloro1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)- 2-(2,4-dimethoxypyrimidin-5-yl)-1isopropyl-5,6-dihydropyrrolo[3,4D]imidazol-4(1H)-one (compound A14), or with the compound described in the published PCT application WO 2013 /111105, for the treatment of a disease such as cancer or soft tissue sarcoma.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a CSF-1R tyrosine kinase inhibitor, 4-(( 2-(((^^)-2-hydroxycyclohexyl)amino)benzothiazol-6-yl)oxy)-Nmethylpicolinamide (compound A15), or with the compound described in the published PCT application WO 2005/073224, for the treatment of a disease, e.g. disease mentioned in the invention. In one embodiment, the CSF-1R tyrosine kinase inhibitor is 4-((2-(((1R,2R)-2hydroxycyclohexyl)amino)benzothiazol-6-yl)oxy)-N-methylpicolinamide (compound A15) or a compound described in published PCT application No. WO 2005/073224. In one embodiment, the anti-PD-1 antibody molecule is used in combination with 4-((2-(((1R,2R)-2hydroxycyclohexyl)amino)benzothiazol-6-yl)oxy)-N-methylpicolinamide (compound A15) or a compound described in PCT Published Application No. WO 2005/073224 for the treatment of a disease such as cancer.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an apoptosis inducer and/or an angiogenesis inhibitor, such as Imatinib mesylate (also known as Gleevec, compound A16),

- 79 045940 or with a compound described in published PCT application WO 1999/003854, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the apoptosis inducer and/or angiogenesis inhibitor is Imatinib mesylate (compound A16) or a compound described in PCT published application WO 1999/003854. In one embodiment, the anti-PD-1 antibody molecule is used in combination with the drug Imatinib mesylate (compound A16), or with a compound described in published PCT application WO 1999/003854, for the treatment of a disease such as cancer, multiple myeloma, prostate cancer , non-small cell lung cancer, lymphoma, stomach cancer, melanoma, breast cancer, pancreatic cancer, digestive/gastrointestinal cancer, colorectal cancer, glioblastoma multiforme, liver cancer, head and neck cancer, asthma, multiple sclerosis, allergies, Alzheimer's disease, amyotrophic lateral sclerosis or rheumatoid arthritis.

In some 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 administration schedule may vary, for example, from administration every other day to administration twice or three times a day. In one embodiment, Imatinib mesylate is administered orally at a dose of about 100 to 600 mg per day, such as about 100, 200, 260, 300, 400, or 600 mg per day.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a JAK inhibitor, 2-fluoro-Nmethyl-4 -(7-(quinolin-6-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (compound A17) or its dihydrochloride salt, or with the compound described in the published application PCT No. WO 2007/070514, for the treatment of a disease, for example the disease mentioned in the invention. In one embodiment, the JAK inhibitor is 2-fluoro-N-methyl-4-(7-(quinolin-6yl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (compound A17) or its dihydrochloride salt, or a compound described in published PCT application WO 2007/070514. In one embodiment, the anti-PD-1 antibody molecule is used in combination with 2-fluoro-N-methyl-4-(7-(quinolin-6yl)imidazo[1,2-b][1,2,4]triazine-2 -yl)benzamide (compound A17) or its dihydrochloride salt, or with the compound described in PCT published application WO 2007/070514, for the treatment of a disease such as colorectal cancer, myeloid leukemia, hematological cancer, autoimmune disease, non-Hodgkin's lymphoma or thrombocythemia.

In one embodiment, a JAK inhibitor or 2-fluoro-N-methyl-4-(7-(quinolin-6yl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (compound A17 ) or its dihydrochloride salt is administered at a dose of about 400 to 600 mg (eg, per day), such as about 400, 500 or 600 mg, or about 400 to 500 or 500 to 600 mg.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the JAK inhibitor drug Ruxolitinib phosphate (also known as JAKAFI, compound A18), or with a compound described in published PCT application WO 2007/070514, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the JAK inhibitor is Ruxolitinib phosphate (compound A18) or a compound described in published PCT application WO 2007/070514. In one embodiment, the anti-PD-1 antibody molecule is used in combination with the drug Ruxolitinib phosphate (compound A18), or with a compound described in PCT Published Application No. WO 2007/070514, for the treatment of a disease such as prostate cancer, lymphocytic leukemia, multiple myeloma, lymphoma, lung cancer, leukemia, cachexia, breast cancer, pancreatic cancer, rheumatoid arthritis, psoriasis, colorectal cancer, myeloblastic leukemia, hematologic cancer, 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 to 25 mg, for example, twice daily. In some embodiments, the dose is about 15, 20, or 25 mg, or about 15 to 20, or 20 to 25 mg.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the deacetylase (DAC) inhibitor drug Panobinostat (compound A19) or with a compound disclosed in published PCT application WO 2014/072493, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the DAC inhibitor is Panobinostat (compound A19) or a compound described in published PCT application WO 2014/072493. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Panobinostat (compound A19), a compound described in PCT published application WO 2014/072493, to treat a disease such as small cell lung cancer, respiratory/chest cancer, prostate cancer

- 80 045940 zy, multiple myeloma, myelodysplastic syndrome, bone cancer, non-small cell lung cancer, endocrine system cancer, lymphoma, nervous system cancer, leukemia, HIV/AIDS, immune disease, transplant rejection, stomach cancer, melanoma, breast cancer, pancreatic cancer, colorectal cancer, glioblastoma multiforme, myeloid leukemia, hematological cancer, kidney cancer, non-Hodgkin's lymphoma, head and neck cancer, hematopoietic disorders or liver cancer.

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

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with one or more cytochrome P450 inhibitors (e.g. 11B2), aldosterone or angiogenesis, the drug Osilodrostat (compound A20), or with a compound described in published PCT application WO 2007/024945 for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, one or more of the cytochrome P450 (eg, 11B2), aldosterone, or angiogenesis inhibitors is Osilodrostat (compound A20) or a compound described in PCT published application WO 2007/024945. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Osilodrostat (compound A20) or a compound disclosed in PCT published application WO 2007/024945 to treat a disease such as Cushing's syndrome, hypertension or heart failure.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an IAP inhibitor (S)-N-(( S)-1cyclohexyl-2-(^)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2(methylamino)propanamide (compound A21) or with a compound described in US Pat. No. 8,552,003 for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the IAP inhibitor is ^)-N-(^)-1-cyclohexyl-2-(^)-2-(4-(4-fluorobenzoyl)thiazol-2yl)pyrrolidin-1-yl)-2-oxoethyl )-2-(methylamino)propanamide (compound A21) or the compound disclosed in US Pat. No. 8,552,003. In one embodiment, the anti-PD-1 antibody molecule is used in combination with ^)-H-(^)-1-cyclohexyl-2- (^)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin1-yl)-2-oxoethyl)-2-(methylamino)propanamide (compound A21), or the compound described in US Pat. No. 8,552,003 , for the treatment of a disease such as multiple myeloma, breast cancer, ovarian cancer, pancreatic cancer or a disorder of hematopoiesis.

In one embodiment, an IAP inhibitor, or ^)-N-(^)-1-cyclohexyl-2-(^)-2-(4-(4fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2- Oxoethyl)-2-(methylamino)propanamide (compound A21), or the compound described in US Pat. No. 8,552,003, is administered at a dose of approximately 1800 mg, for example, once a week.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the Smoothened (SMO) inhibitor drug Sonidegib phosphate ( compound A22), with compound (P)-2-(5-(4-(6-benzyl-4.5dimethylpyrazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol (compound A25), or with a compound described in published PCT applications WO 2007/131201 or WO 2010/007120, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the SMO inhibitor is Sonidegib phosphate (compound A22), da-2-(5-(4-(6-benzyl-4,5dimethylpyrazin-3-yl)-2-methyl-piperazin-1-yl)pyrazine -2-yl)propan-2-ol (compound A25), or the compound described in published PCT applications WO 2007/131201 or WO 2010/007120. In one embodiment, the anti-PD-1 antibody molecule is used in combination with the drug Sonidegib phosphate (compound A22), with the compound ^)-2-(5-(4-(6-benzyl-4,5-dimethylpyrazin-3-yl) -2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol (compound A25) or with the compound described in published PCT applications WO 2007/131201 or WO 2010/007120, for the treatment of a disease such as cancer , medulloblastoma, small cell lung cancer, prostate cancer, basal cell carcinoma, pancreatic cancer or inflammation.

In some 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 administration schedule may vary, for example, from administration every other day to daily administration once, twice or three times a day.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the Alk inhibitor, ceritinib (also known as Zykadia/ ZYKADIA; Compound A23) or with a compound disclosed in published PCT application WO 2007/131201, for the treatment of a disease, for example, a disease mentioned in

- 81 045940 invention. In one embodiment, the Alk inhibitor is ceritinib (compound A23) or a compound described in PCT Published Application No. WO 2007/131201. In one embodiment, the anti-PD-1 antibody molecule is used in combination with ceritinib (compound A23) or a compound described in PCT Published Application No. WO 2007/131201 to treat a disease such as non-small cell lung cancer or a solid tumor.

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

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a JAK and/or CDK4/6 inhibitor 7- cyclopentyl-YNdimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3^]pyrimidine6-carboxamide (compound A24), or with the compound described in US patent 8415355 or in US patent 8685980 for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the JAK and/or CDK4/6 inhibitor is 7-cyclopentyl-N,N-dimethyl2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3^ ]pyrimidine-6-carboxamide (compound

A24) or a compound described in US Pat. No. 8,415,355 or US Pat. No. 8,685,980. In one embodiment, the anti-PD-1 antibody molecule is used in combination with 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazine-1 -yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3^]pyrimidine-6-carboxamide (compound A24) or with the compound described in US patents US 8415355 or US 8685980, for the treatment of a disease such as lymphoma, nervous system cancer, melanoma, breast cancer or solid tumor.

In one embodiment, a JAK and/or CDK4/6 inhibitor, or 7-cyclopentyl-N,N-dimethyl2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3 ^]pyrimidine-6-carboxamide (compound A24) is administered at a dose of approximately 200 to 600 mg, for example, per day. In one embodiment, the compound is administered at a dose of about 200, 300, 400, 500, or 600 mg, or about 200 to 300, 300 to 400, 400 to 500, or 500 to 600 mg.

In another embodiment, an antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a prolactin receptor (PRLR) inhibitor, a human monoclonal antibody molecule (compound A26 ), disclosed in US patent 7867493), for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the PRLR inhibitor is a human monoclonal antibody (Compound A26) disclosed in US Pat. No. 7,867,493. In one embodiment, the anti-PD-1 antibody molecule is used in combination with a human monoclonal antibody molecule (Compound A26) disclosed in US Pat. No. 7,867,493 , for the treatment of a disease such as cancer, prostate cancer or breast cancer.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a PIM kinase inhibitor, N-(4(( W^^)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (compound A27) or the compound described in published PCT application WO 2010/026124 , for treating a disease, for example, the disease mentioned in the invention. In one embodiment, the PIM kinase inhibitor is N(4-((N^^)-3-amino-5-methylcyclohexyl)pyridin-3-yl)6-(2,6-difluorophenyl)-5-fluoropicolinamide (compound A27) or a compound described in published PCT application WO 2010/026124. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Na(4-((N^^)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6difluorophenyl)-5- fluoropicolinamide (compound A27) or a compound described in PCT published application WO 2010/026124, for the treatment of a disease such as multiple myeloma, myelodysplastic syndrome, myeloid leukemia or non-Hodgkin's lymphoma.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a Wnt signaling pathway inhibitor, 2-(2' ,3-dimethyl-[2,4'-bipyridin]-5-yl)-N(5-(pyrazin-2-yl)pyridin-2-yl) acetamide (compound A28) or with a compound described in a published PCT application WO 2010/101849, for the treatment of a disease, for example the disease mentioned in the invention. In one embodiment, the Wnt signaling pathway inhibitor is 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N(5-(pyrazin-2yl)pyridin-2-yl)acetamide (compound A28) or a compound described in published PCT application WO 2010/101849. In one embodiment, the Wnt signaling pathway 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, the anti-PD-1 antibody molecule is used in combination with 2-(2',3dimethyl-[2,4'-bipyridin]-5-yl)-N(5-(pyrazin-2-yl)pyridin-2 -yl)acetamide (compound A28) or with the compound described in the published PCT application WO 2010/101849, for the treatment of such a disease

- 82 045940 as a solid tumor (for example, head and neck cancer, squamous cell carcinoma, breast cancer, pancreatic cancer or colon cancer).

In some embodiments, 2-(2'.3-dimethyl-[2.4'-bipyridin|-5-yl)-H-(5-(pyrazin-2yl)pyridin-2-yl)acetamide (Compound A28) is administered at a dose about 1 to 50 mg, for example about 2 to 45 mg, about 3 to 40 mg, about 5 to 35 mg, about 5 to 10 mg, or about 10 to 30 mg, for example about 2, 5, 10, 20, 30 or 40 mg. The administration schedule may vary, for example, from administration every other day to daily administration once, twice or three times a day.

In another embodiment, an anti-PD-i antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the BRAF inhibitor, Encorafenib (Compound A29) or with a compound described in published PCT application WO 2011/025927, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the BRAF inhibitor is Encorafenib (compound A29) or a compound described in PCT Published Application No. WO 2011/025927. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Encorafenib (compound A29) or a compound described in PCT Published Application No. WO 2011/025927 to treat a disease 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 to 300, 200 to 400, or 300 to 400 mg, for example, per day. In one embodiment, the compound is administered at a dose of about 200, about 300, or about 400 mg.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a CDK4/6 inhibitor, 7cyclopentyl-H,No. dimethyl-2-((5-((N^)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2yl)amino)-7H-pyrrolo[2 ,3M]pyrimidine-6-carboxamide (compound A30), or with the compound described in the published PCT application WO 2011/101409, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the CDK4/6 inhibitor is 7-cyclopentyl-N,N-dimethyl-2-((5-((N^)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonane -3yl)pyridin-2-yl)amino)-7H-pyrrolo[2.3M]pyrimidine-6-carboxamide (Compound A30) or the compound described in published PCT application WO 2011/101409. In one embodiment, the anti-PD-1 antibody molecule is used in combination with 7-cyclopentyl-N,N-dimethyl-2-((5-((N^)-9methyl-4-oxo-3,9-diazabicyclo[4.2.1 ]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3^]pyrimidine-6carboxamide (compound A30) or with the compound described in the published PCT application WO 2011/101409, for the treatment of such a disease , 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-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an HER3 inhibitor, compound A31, or a compound disclosed in published PCT application WO 2012/022814, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the HER3 inhibitor is compound A31 or a compound described in published PCT application WO 2012/022814. In one embodiment, the anti-PD-1 antibody molecule is used in combination with compound A31, or a compound described in PCT published application WO 2012/022814, for the treatment of a disease such as gastric cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, stomach cancer, breast cancer (eg metastatic breast cancer) or digestive system/gastrointestinal cancer.

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, for example, once a week (QW). In one embodiment, the compound is administered at a dose of about 3 to 10, 10 to 20, or 20 to 40 mg/kg.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR2 and/or FGFR4 inhibitor, compound A32, or a compound disclosed in published PCT application WO 2014/160160 (eg, an antibody molecule drug conjugate against FGFR2 and/or FGFR4, eg mAb 12425), for treating a disease, eg a disease mentioned in the invention. In one embodiment, the FGFR2 and/or FGFR4 inhibitor is compound A32 or a compound described in published PCT application WO 2014/160160. In one embodiment, the anti-PD-1 antibody molecule is used in combination with compound A32 or a compound specified

- 83 045940 in the table. 7, for the treatment of a disease such as cancer, stomach cancer, breast cancer, rhabdomyosarcoma, liver cancer, adrenal cancer, lung cancer, esophageal cancer, colon cancer or endometrial cancer.

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

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an M-CSF inhibitor, compound A33, or a compound disclosed in published PCT application WO 2004/045532 (eg, an antibody molecule or Fab fragment against M-CSF), for treating a disease, for example, a disease mentioned in the invention. In one embodiment, the M-CSF inhibitor is compound A33 or a compound described in published PCT application WO 2004/045532. In one embodiment, the anti-PD-1 antibody molecule is used in combination with compound A33 or a compound described in PCT published application WO 2004/045532 to treat a disease such as cancer, prostate cancer, breast cancer or pigmented villonodular synovitis (PVNS). ).

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

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, 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 published PCT application WO 2003/077914, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the MEK inhibitor is Binimetinib (compound C34) or a compound described in published PCT application WO 2003/077914. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Binimetinib (compound A34) or a compound described in published PCT application WO 2003/077914 for the treatment of a disease such as non-small cell lung cancer, multisystem genetic disease, melanoma, ovarian cancer , digestive/duodenal cancer, rheumatoid arthritis or colorectal cancer.

In one embodiment, a MEK inhibitor or Binimetinib (Compound A34) is administered at a dose of approximately 45 mg, for example, twice daily.

In another embodiment, an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with one or more inhibitors, such as a c- inhibitor KIT, a histamine release inhibitor, Flt3 (eg FLK2/STK1) or a PKC inhibitor, with the drug Midostaurin (compound A35) or with a compound described in published PCT application WO 2003/037347, for the treatment of a disease, for example, a disease mentioned in the invention . In one embodiment, the inhibitor is Midostaurin (compound A35) or a compound disclosed in PCT Published Application No. WO 2003/037347. In one embodiment, one or more inhibitors, such as a c-KIT inhibitor, a histamine release inhibitor, Flt3 (eg, FLK2/STK1), or a PKC inhibitor, is Midostaurin. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Midostaurin (compound A35) or a compound disclosed in published PCT application WO 2003/037347 for the treatment of a disease such as cancer, colorectal cancer, myeloid leukemia, myelodysplastic syndrome, age-related macular degeneration, diabetic complication or skin disease.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a TOR inhibitor (e.g., an mTOR inhibitor), the drug Everolimus (also known as Afinitor, compound A36) or with a compound disclosed in published PCT application WO 2014/085318, for the treatment of a disease, for example, a disease mentioned in the invention). In one embodiment, the TOR inhibitor is Everolimus (compound A36) or a compound described in published PCT application WO 2014/085318. In one embodiment, the PD-1 antibody molecule is used in combination with Everolimus (compound A36) to treat a disease 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 system cancer, lymphoma, neurological diseases astrocytoma, cervical cancer, nervous system cancer, leukemia, immune diseases, transplant rejection, gastric cancer, melanoma, epilepsy, breast cancer or bladder cancer.

In one embodiment, a TOR inhibitor or Everolimus (compound A36) is administered at a dose of approximately 2.5 to 20 mg/day. In one embodiment, said compound is administered to

- 84 045940 dose of approximately 2.5, 5, 10 or 20 mg/day, for example approximately 2.5-5, 5-10 or 10-20 mg/day.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with one or more inhibitors, such as VEGFR- 2, PDGFR-beta, KIT or Raf kinase C, 1-methyl-5-((2-(5(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-H-(4 -(trifluoromethyl)phenyl)-1Hbenzoshimidazol-2-amine (compound A37) or with the compound described in the published PCT application WO 2007/030377, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, one or more inhibitors, such as VEGFR-2, PDGFR-beta, KIT or Raf kinase C inhibitors, are 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazole2- yl)pyridin-4-yl)oxy)-H-(4-(trifluoromethyl)phenyl)-1H-benzoshimidazol-2-amine (compound A37) or the compound described in PCT published application WO 2007/030377. In one embodiment, the anti-PD-1 antibody molecule is used in combination with 1-methyl-5-((2-(5-(trifluoromethyl)-1Nimidazol-2-yl)pyridin-4-yl)oxy)-H-(4 -(trifluoromethyl)phenyl)-1H-benzoshimidazol-2-amine (compound A37) or with the compound described in the published PCT application WO 2007/030377, for the treatment of a disease such as cancer, melanoma or solid tumor.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a somatostatin agonist and/or a growth hormone release inhibitor, the drug Pasireotide diaspartate (also known as Signifor, compound A38), or with a compound disclosed in published PCT application WO 2002/010192 or US patent No. 7473761, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the somatostatin agonist and/or growth hormone release inhibitor is Pasireotide diaspartate (compound A38) or a compound described in PCT Published Application WO 2002/010192 or US Patent No. 7,473,761. In one embodiment, the anti-PD-1 antibody molecule used in combination with the drug Pasireotide diaspartate (Compound A38) or a compound disclosed in PCT Published Application WO 2002/010192 or US Patent No. 7,473,761 for the treatment of a disease such as prostate cancer, endocrine cancer, nervous system cancer, skin cancer (eg, melanoma), pancreatic cancer, liver cancer, Cushing's syndrome, gastrointestinal disease, acromegaly, liver and biliary tract disease, or cirrhosis.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, 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 with a compound disclosed in published PCT application WO 2009/115562, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the signal transduction modulator and/or angiogenesis inhibitor is Dovitinib (compound A39) or a compound described in PCT Published Application No. WO 2009/115562. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Dovitinib (compound A39) or a compound described in PCT published application WO 2009/115562 to treat a disease such as cancer, respiratory/chest cancer, multiple myeloma, prostate cancer, non-small cell lung cancer, endocrine system cancer, or a neurological genetic disorder.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an EGFR inhibitor, (R,R)-N -(7chloro-1-(1 -(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo A|imidazol-2-yl)-2methylisonicotinamide (compound A40) or with the compound described in the published PCT application WO 2013/184757, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the EGFR inhibitor is (I,K)-K-(7-chloro-1-(1-(4(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzoSchimidazol-2- yl)-2-methylisonicotinamide (compound A40) or the compound described in published PCT application WO 2013/184757. In one embodiment, the anti-PD-1 antibody molecule is used in combination with (I,K)-K-(7-chloro-1-(1-(4(dimethylamino)but-2-enoyl)azepan-3-yl)- 1H-benzoshimidazol-2-yl)-2-methylisonicotinamide (compound A40) or a compound described in published PCT application WO 2013/184757, for the treatment of a disease such as cancer, eg solid tumor.

In one embodiment, an EGFR inhibitor or IgD)-N-(7-chloro-1-(1-(4-(dimethylamino)but2-enoyl)azepan-3-yl)-1H-benzoSchimidazol-2-yl)-2 α-methylisonicotinamide (compound A40) is administered at a dose of 150 to 250 mg, for example, per day. In one embodiment, the compound is administered at a dose of about 150, 200 or 250 mg, or about 150 to 200 or 200 to 250 mg.

In another embodiment, an anti-PD-1 antibody molecule, for example, an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an ALK inhibitor, No. ⁶ - (2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-I ⁴ -(2-(isopropylsulfonyl)phenyl)-Spirazolo[3,4^]pyrimidin-4,6-diamine (compound A42 ) or with a compound described in published PCT application WO 2008/073687, for the treatment of a disease, for example, a disease mentioned in the invention. In one embodiment, the ALK inhibitor is X ³ -(2-isopropoxy-5-methyl-4-(1methylpiperidin-4-yl)phenyl)-N ⁴ -(2-(isopropylsulfonyl)phenyl)-III-pyrazolo[3,4 ^]pyrimidine-4,6diamine (compound A42) or the compound described in published PCT application WO 2008/073687. In one embodiment, the anti-PD-1 antibody molecule is used in combination with N ⁶ -(2isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N ⁴ -(2-(isopropylsulfonyl)phenyl)- Spirazolo[3,4^]pyrimidine-4,6-diamine (compound C42) or with the compound described in the published PCT application WO 2008/073687, for the treatment of a disease such as cancer, anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC) or neuroblastoma. In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, 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-methyl1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thiethane- 1,1 dioxide (compound A43), 5-chloro-N-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4yl)phenyl)-H ⁴ -( 5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound C44) or 5-chloro-N2-(4-(1ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)- H ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45), or with a compound described in published PCT application WO 2010/002655, for the treatment of a disease, e.g. mentioned in the invention. In one embodiment, the IGF-1R inhibitor is 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3yl)amino)pyrimidin-2-yl)amino)-5 -fluoro-2-methylphenyl)piperidin-1-yl)thiethane 1,1-dioxide (compound A43), 5-chloro-H ² -(2-fluoro-5-methyl-4-(1-(tetrahydro-2H- pyran-4-yl)piperidin-4-yl)phenyl)-H ⁴ -(5methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound C44) or 5-chloro-N2-(4- (1-ethylpiperidin-4yl)-2-fluoro-5-methylphenyl)-H ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45), or the compound described in published PCT application WO 2010/002655. In one embodiment, the anti-PD-1 antibody molecule is used in combination with 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3yl)amino)pyrimidin-2-yl) amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thiethane 1,1-dioxide (compound A43), 5-chloro-H ² -(2-fluoro-5-methyl-4-(1-( tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-H ⁴ -(5methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound C44) or 5-chloro-N2 -(4-(1-ethylpiperidin4-yl)-2-fluoro-5-methylphenyl)-H ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or with a compound described in PCT Published Application No. WO 2010/002655 for the treatment of a disease such as cancer or sarcoma.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with the P-glycoprotein 1 inhibitor drug Valspodar (also known as AMDRAY, compound A46) or with the compound described in patent EP 296122, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the P-glycoprotein 1 inhibitor is Valspodar (compound A46) or a compound disclosed in EP 296122. In one embodiment, the anti-PD-1 antibody molecule is used in combination with Valspodar (compound A46) or a compound disclosed in EP 296122. to treat a disease such as cancer or a drug-resistant tumor.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with one or more VEGFR inhibitors, the drug Vatalinib succinate ( compound A47) or with a compound described in patent EP 296122 for the treatment of a disease, for example the disease mentioned in the invention. In one embodiment, the VEGFR inhibitor is Vatalinib succinate (compound A47) or a compound described in EP 296122. In one embodiment, the anti-PD-1 antibody molecule is used in combination with the drug Vatalinib succinate (compound A47) or a compound described in EP 296122 , for the treatment of cancer.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with an isocitrate dehydrogenase (IDH) inhibitor or a compound disclosed in WO 2014/141104, for the treatment of a disease, for example the disease mentioned in the invention. In one embodiment, the IDH inhibitor IDH is a compound disclosed in published PCT application WO 2014/141104. In one embodiment, an anti-PD-1 antibody molecule is used in combination with a compound disclosed in WO 2014/141104 to treat a disease, such as cancer.

In another embodiment, an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more

- 86 045940 how many other immunomodulators, used in combination with a BCL-ABL inhibitor or with a compound described in published PCT applications WO 2013/171639, WO 2013/171640, WO 2013/171641 or WO 2013/171642, for the treatment of a disease, e.g. disease mentioned in the invention. In one embodiment, the BCL-ABL inhibitor is a compound disclosed in PCT Published Application Nos. WO 2013/171639, WO 2013/171640, WO 2013/171641, or WO 2013/171642. In one embodiment, an anti-PD-1 antibody molecule is used in combination with a compound disclosed in PCT Published Application Nos. WO 2013/171639, WO 2013/171640, WO 2013/171641 or WO 2013/171642 to treat a disease such as cancer .

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a c-RAF inhibitor or a compound described in published PCT application WO 2014/151616, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the c-RAF inhibitor is compound A50 or a compound described in published PCT application WO 2014/151616. In one embodiment, an anti-PD-1 antibody molecule is used in combination with a compound disclosed in published PCT application WO 2014/151616 to treat a disease, such as cancer.

In another embodiment, an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibody molecule of the invention, alone or in combination with one or more other immunomodulators, is used in combination with a competitive ERK1/2ATP inhibitor or a compound described in international patent application PCT/US 2014/062913, for the treatment of a disease, for example, the disease mentioned in the invention. In one embodiment, the competitive ERK1/2ATP inhibitor is a compound disclosed in international patent application PCT/US2014/062913. In one embodiment, the anti-PD-1 antibody molecule is used in combination with compound A51 or a compound disclosed in international patent application PCT/US2014/062913 to treat a disease such as cancer.

In some embodiments, the PD-1 antibody molecule is administered in combination with one or more substances selected from Compound A8, Compound A17, Compound A23, Compound A24, Compound A27, Compound A29, and Compound A33.

In some embodiments, the PD-1 antibody molecule is administered in combination with an antineoplastic agent that has been shown to be active in an immune cell assay, such as one or more of the following assays: huMLR assay, T cell proliferation assay, B cell proliferation assay. Examples of analyzes are described below. From the above analyses, the IC ₅₀ for each test substance can be calculated. In some embodiments, the IC ₅₀ value of the anticancer agent is, for example, 0 to 1 μM, 1 to 4 μM, or greater than 4 μM, such as 4 to 10 μM, or 4 to 20 μM. In some embodiments, the second therapeutic agent is selected from one or more of the following compounds: 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 compound related to Compound A28) is administered at a dose of about 5 to 10 or 10 to 30 mg. In some embodiments, compound A22 (or a compound related 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 to 600 mg. In some embodiments, compound A16 (or a compound related to compound A16) is administered at a dose of about 400 to 600 mg orally once daily. In some embodiments, compound A29 (or a compound related to compound A29) is administered at a dose of about 200 to 400 or 300 to 400 mg. In some embodiments, compound A24 (or a compound related to compound A24) is administered at a dose of about 200 to 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 to 400 or 300 to 400 mg. In some embodiments, compound A5 (or a compound related to compound A5) is administered at a dose of about 100 to 125 mg. In some embodiments, compound A6 (or a compound related 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 to 300 or 200 to 600 mg. In some embodiments, compound A40 (or a compound related to compound A40) is administered at a dose of about 150 to 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, for example, administered three times a week for 2 weeks and one week apart. In embodiments, the BCR-ABL inhibitor is administered at a dose of about 20 mg twice daily to 80 mg twice daily.

- 87 045940

The huMLR assay and the B cell or T cell proliferation assay are presented below as an example.

Mixed Lymphocyte Response in Humans The Mixed Lymphocyte Response (MLR) is a functional assay that measures the proliferative response of lymphocytes from one individual (responders) to lymphocytes from another individual (stimulators). To perform allogeneic MLR, peripheral blood mononuclear cells (PBMCs) from three donors were isolated from the clear edge of a blood clot of unknown HLA type (Kantonspital Blutspendezentrum, Bern and Aarau, Switzerland).

Cells were prepared at a concentration of 2x10 ⁵ in 0.2 ml of culture medium containing RPMI 1640 GlutaMAX™ medium supplemented with 10% fetal calf serum (FCS), 100U penicillin/100 μg streptomycin, 50 μM 2-mercaptoethanol. Bidirectional reactions of these individuals were carried out by mixing PBMCs from two different donors in a 1:1 ratio and co-culturing in triplicate in flat-bottomed 96-well culture plates for 6 days at 37°C, 5% CO ₂ , using 8- point range of concentrations of the tested compounds or in their absence. Cells were pulsed with 3H-thymidine (1 μCi/0.2 ml) for the last 16 hours of culture, and radiolabel incorporation was used to measure cell proliferation. The concentration at which 50% inhibition of the maximum huMLR response (IC ₅₀ ) occurs was calculated for each compound. Cyclosporine was used as a positive control for huMLR inhibition.

Human B cell proliferation assay.

PBMCs freshly isolated by Ficoll-Paque density gradient from human blood were used and subjected to negative B cell isolation. B cells were resuspended in culture medium (RPMI 1640, HEPES, 10% FCS, 50 µg/ml gentamicin, 50 µM 2-mercaptoethanol, 1xITS (insulin, transferrin and sodium selenite), 1x nonessential amino acids) at a concentration of 9x10 ⁴ per well in flat-bottomed 96-well culture plates. Stimulation of B cells was performed using a human antibody molecule against IgM (30 μg/ml) and IL-4 (75 ng/ml) or using CD40 ligand (3 μg/ml) and IL-4 (75 ng/ml) with using a 7-point concentration range of test compounds or no concentration range thereof. After 72 h of culture at 37°C, 10% CO ₂ , cells were pulsed with 3H-thymidine (1 μCi/well) for the last 6 h of culture. B cells were then collected and thymidine incorporation was measured using a scintillation counter. The average values from each replicate treatment were calculated and the data entered into XLfit 4 software to determine the corresponding IC ₅₀ values.

Human T cell proliferation assay.

PBMCs freshly isolated by Ficoll-Paque density gradient from human blood were used and subjected to negative T-cell isolation. T cells were prepared in culture medium (RPMI 1640, HEPES, 10% FCS, 50 μg/ml gentamicin, 50 μM 2-mercaptoethanol, 1xITS (insulin, transferrin and sodium selenite), 1x nonessential amino acids) at a concentration of 8x10 ⁴ per well in flat-bottomed 96-well culture plates. T cell stimulation was performed with human anti-CD3 antibody molecule (10 μg/ml) or human anti-CD3 antibody molecule (5 μg/ml), and anti-CD28 antibody molecule (1 μg/ml) using a 7-point test concentration range connections or lack thereof. After 72 h of culture at 37°C, 10% CO ₂ , cells were pulsed with 3H-thymidine (1 μCi/well) for the last 6 h of culture. Cell proliferation was measured by thymidine incorporation, allowing the IC ₅₀ to be determined for each compound tested.

Down-modulators of the immune system.

In an alternative embodiment, the anti-PD-1 antibody molecules disclosed in the invention are used to produce anti-idiotypic peptides or antibodies (Wallmann, J. et al. (2010) Anti-Ids in Allergy: Timeliness of a Classic Concept, World Allergy Organiz. J 3(6):195-201 Nardi, M. et al (2000) Antiidiotype Antibody Against Platelet Anti-Gpiiia Contributes To The Regulation Of Thrombocytopenia In HIV-1-ITP Patients, J. Exp. Med. 191(12 ):2093-2100) or mimetics (Zang, Y. C et al. (2003) Human Anti-Idiotypic T Cells Induced By TCR Peptides Corresponding To A Common CDR3Sequence Motif In Myelin Basic Protein-Reactive T Cells, Int. Immunol. 15 (9):1073-1080; Loiarro, M. et al. (Epub 2010 Apr. 8) Targeting TLR/IL-1R Signaling In Human Diseases, Mediators Inflamm. 2010:674363) B7-H1 or PD-1. Such molecules serve as surrogates for PD-1 and thus, when administered to a subject, down-modulate the immune system in that subject, which mimics or promotes B7-H1 binding to PD-1. These molecules are useful in the treatment of graft-versus-host disease. Likewise, agonist antibodies that i) enhance binding between said antibodies and said receptor/ligand, or ii) trigger signal transduction upon direct binding to B7-H1 or PD-1 are useful as agonists of the B7-H1 signaling pathway - PD-1 and thus can be used in the treatment of inflammatory and autoimmune diseases, through direct or indirect action as an agonist

- 88 045940 hundred receptor.

Bispecific antibodies that exhibit immunospecific binding to both PD-1 and B7-H1 are able to bind to both antigen presenting cells (APCs) and T cells, and thus promote the colocalization of APC and T cells. This colocalization facilitates the ability of such cells to communicate with each other through B7-H1 molecules and PD-1 molecules that do not form a complex with the antibody, or through coinhibitory molecules. Thanks to this binding, down-modulation of the recipient's immune system occurs.

Down-modulation of the immune system is desirable in the treatment of inflammatory and autoimmune diseases, and graft-versus-host disease (GvHD). Examples of autoimmune diseases that can be treated by administering the antibody of the present invention include, but are not limited to: alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune adrenal diseases, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis , autoimmune thrombocytopenia, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue, dermatitis, chronic fatigue and immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathies, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease , discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA neuropathy, juvenile arthritis, lichen planus, systemic erythematosus chunka, Meniere's disease, mixed connective tissue disease, multiple sclerosis, neuromyelitis optica (NMO), diabetes mellitus type 1 or immune-mediated diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, muscle stiffness syndrome, systemic lupus erythematosus, erythematous lupus, Takayasu's arteritis, temporal arteritis/giant cell arteritis, transverse myelitis , ulcerative colitis, uveitis, vasculitis such as vasculitis dermatitis herpetiformis, vitiligo and Wegener's granulomatosis.

Examples of inflammatory diseases that can be prevented, treated or controlled in accordance with the methods of the invention include, but are not limited to, asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), allergic diseases, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathies, undifferentiated arthropathy, arthritis, inflammatory osteolysis and chronic inflammation caused by chronic viral or bacterial infections.

Thus, the antibodies and antigen binding fragments thereof of the present invention are useful in the treatment of inflammatory and autoimmune diseases.

Types of diagnostic applications.

In one aspect, the present invention provides a diagnostic method for detecting the presence of PD-1 protein in vitro (e.g., in a biological sample, e.g., in a tissue biopsy, e.g., from cancer tissue) or in vivo (e.g., in vivo imaging in a subject) . The method includes: (I) contacting the sample with an antibody molecule of the invention, or administering the antibody molecule to the subject; (optional) (II) contacting a reference sample, e.g., a control sample (e.g., a biological control sample, e.g., plasma, tissue, biopsy) or control subject)); and (III) detecting the formation of a complex between the antibody molecule and the sample or subject, or a control sample or subject, wherein a change, such as a statistically significant change, in complex formation in the sample or subject compared to the control sample or subject, indicates the presence of in the PD-1 protein sample. The antibody molecule may be labeled directly or indirectly with a detectable substance to facilitate detection of bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials, as described above and described in more detail below.

The term sample, with respect to samples used for detection of polypeptides, includes, without limitation, cells, cell lysates, proteins or membrane extracts of cells, body fluids or tissue samples.

Formation of a complex between the antibody molecule and PD-1 can be detected by measuring or imaging both the binding molecule attached to the PD-1 antigen or the unattached binding molecule. Conventional detection assays such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA) or tissue immunohistochemistry may be used. As an alternative to labeling the antibody molecule, the presence of PD-1 in a sample can be examined by a competitive immunoassay using analyte-labeled standards and an unlabeled antibody molecule. This analysis combines

- 89 045940 biological sample, labeled standards and antibody molecule, and quantify the labeled standard bound to the unlabeled binding molecule. The amount of PD-1 in a sample is inversely proportional to the amount of labeled standard bound to the antibody molecule.

Nucleic acids.

The invention also relates to a nucleic acid comprising nucleotide sequences that encode heavy and light chain variable regions and CDR regions or hypervariable loops in the anti-PD-1 antibody molecules of the invention. For example, the invention relates to first and second nucleic acids encoding heavy and light chain variable regions, respectively, in an anti-PD-1 antibody molecule selected from one or more antibody molecules disclosed in the invention. The nucleic acid may contain a nucleotide sequence as specified in the tables of the present invention, or a sequence substantially identical thereto (e.g., a sequence identical to the specified sequence with at least about 85, 90, 95, 99% or a greater degree of identity, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences presented in the tables of the present invention.

In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDR regions or hypervariable loops from a heavy chain variable region that has an amino acid sequence set forth in the tables of the present invention, or a sequence that is substantially homologous (e.g. , a sequence identical to the specified sequence by at least about 85, 90, 95, 99% or more, and/or having one or more substitutions, for example, conservative substitutions). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDR regions or hypervariable loops from a light chain variable region, comprising an amino acid sequence set forth in the tables of the present invention, or a sequence substantially homologous (e.g. , a sequence identical to the specified sequence by at least about 85, 90, 95, 99% or more, and/or having one or more substitutions, for example, conservative substitutions). In yet another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five or six CDR regions or hypervariable loops of heavy and light chain variable regions having the amino acid sequence set forth in the tables of the present invention, or a sequence substantially homologous to the specified sequence (eg, a sequence identical to it at least about 85, 90, 95, 99% or more, and/or having one or more substitutions, for example, conservative substitutions).

In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDR regions or hypervariable loops from a heavy chain variable region having a nucleotide sequence set forth in the tables of the present invention, a sequence substantially homologous thereto (e.g. sequence identical to it by at least about 85, 90, 95, 99% or more, and/or capable of hybridization under the stringent conditions described in the invention). In another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs or hypervariable loops from a light chain variable region having a nucleotide sequence set forth in the tables of the present invention or a sequence substantially homologous thereto (e.g. sequence identical to it by at least about 85, 90, 95, 99% or more, and/or capable of hybridization under the stringent conditions described in the invention). In yet another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDR regions or hypervariable loops from heavy and light chain variable regions, having a nucleotide sequence set forth in the tables herein invention, or a sequence substantially homologous thereto (e.g., a sequence identical to it with at least about 85, 90, 95, 99% or a higher degree of identity, and/or a sequence capable of hybridizing under the stringency requirements described in the invention).

In another aspect, the present application relates to host cells and vectors containing nucleic acids of the invention. The nucleic acids may be present in the same vector or in different vectors present in the same host cell or in different host cells, as described in more detail below.

Vectors.

The present invention further relates to vectors containing nucleotide sequences that encode an antibody molecule of the invention. In one embodiment, the vectors contain nucleotides encoding an antibody molecule of the invention. In one embodiment, the vectors contain nucleotide sequences described in the invention. Vectors

- 90 045940 includes, without limitation, a virus, plasmid, cosmid, lambda phage or yeast artificial chromosome (YAC).

Numerous vector systems can be used. 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 (Rouse sarcoma virus, MMTV or MOMLV) or SV40 virus . Another class of vectors uses RNA elements derived from RNA viruses such as Semliki Forest virus, eastern equine encephalitis virus, and flaviviruses.

Additionally, cells that stably integrate this DNA into their chromosomes can be selected by introducing one or more markers that allow selection of transfected host cells. The marker may confer, for example, prototrophy on an auxotrophic host, biocide resistance (eg, to antibiotics), or resistance to heavy metals such as copper, or the like. The selectable marker gene can either be directly linked to the DNA sequences to be expressed or introduced into the same cell by co-transformation. Additional elements may also be required for optimal mRNA synthesis. These elements may include splicing signals, as well as transcriptional promoters, amplifiers, and termination signals.

Once an expression vector or DNA sequence containing these constructs has been prepared for expression, the expression vectors can be transfected or introduced into the appropriate host cell. Various technologies can be used to accomplish this task, such as, for example, protoplast fusions, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun techniques, lipid-based transfection, or other conventional techniques. For protoplast fusion, cells are grown in media and screened for appropriate activity.

Methods and conditions for culturing the resulting transfected cells and recovering the produced antibody molecule are known to those skilled in the art and may be modified or optimized depending on the particular expression vector and mammalian host cell used in the present invention.

Cells.

The present invention also relates to host cells containing a nucleic acid that encodes an antibody molecule of the invention.

In one embodiment, the host cells are genetically engineered to contain nucleic acids encoding the antibody molecule.

In one embodiment, the host cells are genetically engineered using an expression cassette. The term expression cassette refers to nucleotide sequences that are capable of influencing gene expression in host cells compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. Additional factors necessary or beneficial for efficient expression, such as, for example, an inducible promoter, can also be used.

The invention also relates to host cells containing the vectors described in the present invention.

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, and MDCKII cells. 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 mouse mAbs BAP049, chimeric mAbs BAP049-chi and BAP049-chi-Y, and humanized mAbs BAP049-hum01 - BAP049-hum16 and BAP049-clone-A - BAP049clone-E. Amino acid and nucleotide sequences of the heavy and light chain, CDR regions, heavy and light chain variable regions, and heavy and light chains are shown.

VAR049 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 6 VH QVQLQQPGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTTVDTSSTTAYMHLASLTSEDSAVYYC T RWT T GT GAYWGQ GT LVTVSA SEQ ID NO: 7 DNA VH CAGGTCCAGCTGCAGCAACCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 8 VH QVQLQQSGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTTVDTSSTTAYMHLASLTSEDSAVYYC T RWT T GT GAYWGQ GT LVTVSA SEQ ID NO: 9 DNA VH CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAAGGGACTCTGGTCACTGTCTCTGCA BAP049LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 12 (Kabat) LCDR3 QNDYSYPCT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 15 (Chothia) LCDR3 DYSYPC SEQ ID NO: 16 VL DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDS GNQKNFLTWYQQKPGQPPKLLIFWASTRESGV PDRFTGSGSVTDFTLTISSVQAEDLAVYYCQN DYSYPCTFGGGTKLEIK

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SEQ ID NO: 17 DNA VL AGA TTTCACTCTCACCATCAGCAGTGTGCAGG CTGAAGACCTGGCAGTTTATTACTGTCAGAAT GATTATAGTTATCCGTGCACGTTCGGAGGGGG GACCAAGCTGGAAATAAAA BAP049-chi HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 18 VH QVQLQQPGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 19 DNA VH CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCC SEQ ID NO: 20 H.C. QVQLQQPGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S SWT VP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P

- 93 045940

REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 21 DNA NS CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACT CA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCACGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTT CCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCA AGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT

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GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACCAGAAGAGCC TCTCCCTGTCTCTGGGTAAA SEQ ID NO: 22 VH QVQLQQSGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 23 DNA VH CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCC SEQ ID NO: 30 HO QVQLQQSGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HO CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC

- 95 045940

TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGC GGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCACGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCC AAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGG CCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTT CCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-chi LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 12 (Kabat) LCDR3 QNDYSYPCT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 15 (Chothia) LCDR3 DYSYPC SEQ ID NO: 24 VL DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDS

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GNQKNFLTWYQQKPGQPPKLLIFWASTRESGV PDRFTGSGSVTDFTLTISSVQAEDLAVYYCQN DYSYPCTFGQGTKVEIK SEQ ID NO: 25 DNA VL GACATTGTGATGACCCAGTCTCCATCCTCCCT GACT GT GACAGCAGGAGAGAAGGT CACTAT GA GCT GCAAGT CCAGT CAGAGT CT GTTAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCAGGGCAGCCTCCTAAACTGTTGA TCTTCTGGGCATCCACTAGGGAATCTGGGGTC CCTGATCGCTTCACAGGCAGTGGATCTGTAAC AG ATTT CACT CT CACCAT CAGCAGT GT GCAGG CTGAAGACCTGGCAGTTTATTACTGTCAGAAT GATTATAGTTATCCGTGCACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 26 L.C. DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDS GNQKNFLTWYQQKPGQPPKLLIFWASTRESGV PDRFTGSGSVTDFTLTISSVQAEDLAVYYCQN DYSYPCTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSK ADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 27 DNA LC AGA TTTCACTCTCACCATCAGCAGTGTGCAGG CTGAAGACCTGGCAGTTTATTACTGTCAGAAT GATTATAGTTATCCGTGCACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCAGAGAGG CCAAAGTACAGTGGAAG GTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT

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BAP049-chi-Y NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 18 VH QVQLQQPGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 19 DNA VH CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCC SEQ ID NO: 20 H.C. QVQLQQPGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 21 DNA HC CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC

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AAAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAGCCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCT GCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCC CATGCCGA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCG TCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCA ATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA SEQ ID NO: 22 VH QVQLQQSGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 23 DNA VH CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT

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GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAGCCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACT GGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCC SEQ ID NO: 30 H.C. QVQLQQSGSELVRPGASVKLSCKASGYTFTTY WMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKF KNRTSLTVDTSSTTAYMHLASLTSEDSAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HC CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCT GGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCT GCAAGGCGTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGAGGCAGAGGCCTGGACA AGGCCTTGAGTGGATTGGAAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAAAACAGGACCT CACT GACT GTAGACACAT C CTCCACCACAG CCTACATGCACCTCGCCAGCC TGACATCTGAGGACTCTGCGGTCTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACT CA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA

100 045940

TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGC ATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TC TCCCTGTCTCTGGGTAAA BAP049-chi-Y LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 34 VL DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDS GNQKNFLTWYQQKPGQPPKLLIFWASTRESGV PDRFTGSGSVTDFTLTISSVQAEDLAVYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 35 DNA VL AGA TTTCACTCTCACCATCAGCAGTGTGCAGG

101 045940

CTGAAGACCTGGCAGTTTATTACTGTCAGAAT GAT TATAGTTATCCGTACACGTTCGGC CAAG G GACCAAGGTGGAAATCAAA SEQ ID NO: 36 L.C. DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDS GNQKNFLTWYQQKPGQPPKLLIFWASTRESGV PDRFTGSGSVTDFTLTISSVQAEDLAVYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 37 DNA LC AGA TTTCACTCTCACCATCAGCAGTGTGCAGG CTGAAGACCTGGCAGTTTATTACTGTCAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAG GTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum01 HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS

102 045940

SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT GAG GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HO EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HO GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT B ACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC

- 103 045940

TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTG GTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCC G GGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum01 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 42 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTEFTLTISSLQPDDFATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 43 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT CCT GCAAGT CCAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC

104 045940

CCATCAAGGTTCAGCGGCAGTGGATCTGGGAC AGAATTCACTCTCACCATCAGCAGCCTGCAGC CTGATGATTTTGCAACTTATTACTGTCAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 44 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTEFTLTISSLQPDDFATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 45 DNA LC GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCATCAAGGTTCAGCGGCAGTGGATCTG GGAC AGAATTCACTCTCACCATCAGCAGCCTGCAGC CTGATGATTTTGCAACTTATTACTGTCAGAAT GAT TATAGTTATCCGTACACGTTCGGC C AAG G GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCAGAGAGG CCAAAGTA CAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum02 HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF

105 045940

KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT GAG GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HO EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HO GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT B ACGGTGTCGTGGAACTCA

- 106 045940

GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTT CCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCA AGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGGCTCCCGTGCT ACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum02 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 46 VL DIQMTQSPSSLSSASVGDRVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGI PPRFSGSGYGTDFTLTINNIESEDAAYYFCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 47 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCT GT CT GCAT CT GTAGGAGACAGAGT CACCAT CA CTT GCAAGT CCAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA

107 045940

GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGATC CCACCTCGATTCAGTGGCAGCGGGTATGGAAC AGAT TTTACCCT CACAAT TAATAACATAGAAT CTGAGGATGCTGCATATTACTTCTGTCAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 48 L.C. DIQMTQSPSSLSASVGDRVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGI PPRFSGSGYGTDFTLTINNIESEDAAYYFCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLS KADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 49 DNA LC GACATCCAGATGACCCAGTCTCCATCCTCCCT GT CT GCAT CT GTAGGAGACAGAGT CACCAT CA CT T GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGATC CCACCTCGATTCAGTGGCAGCGGGTATGGA AC AGAT TTTACCCT C AC AAT T AAT AAC AT AGAAT CTGAGGATGCTGCATATTACTTCTGTCAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAA GTACAGTGGAAGGTGGATAACGCСCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum03 HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY

108 045940

SEQ ID NO: 50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC

- 109 045940

AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTC CAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTA CCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGC CGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum03 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 46 VL DIQMTQSPSSLSSASVGDRVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGI PPRFSGSGYGTDFTLTINNIESEDAAYYFCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 47 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCT GT CT GCAT CT GTAGGAGACAGAGT CACCAT CA

110 045940

CT T GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGATC CCACCTCGATTCAGTGGCAGCGGGTATGGAAC AGAT TTTACCCT CACAAT TAATAACATAGAAT CTGAGGATGCTGCATATTACTTCTGTCAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 48 L.O. DIQMTQSPSSLSSASVGDRVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGI PPRFSGSGYGTDFTLTINNIESEDAAYYFCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 49 DNA LO GACATCCAGATGACCCAGTCTCCATCCTCCCT GT CT GCAT CT GTAGGAGACAGAGT CACCAT CA CT T GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGATC CCACCTCGATTCAGTGGCAGCGGGTATGGA AC AGAT TTTACCCT CACAAT TAATAACATAGAAT CTGAGGATGCTGCATATTACTTCTGTCAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACA GTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum04 HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY

111 045940

SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCCG

- 112 045940

CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAG ACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTA CGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGG AGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACC ACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum04 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 54 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLQPEDIATYYCQN DYSYPYTFGQGTKVEIK

113 045940

SEQ ID NO: 55 DNA VL A GATTTTACTTTCACCATCAGCAGCCTGCAGC CT GAAGATATT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 56 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLQPEDIATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSK ADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 57 DNA LC A GATTTTACTTTCACCATCAGCAGCCTGCAGC CT GAAGATATT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGGAGG CCAAAGTACAGTGGA AGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum05 HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN

114 045940

SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT

- 115 045940

ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAG TCCTCAGGACTCTACTCCC TCAGCAGCTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGG TC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCC AAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAG CAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum05 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 54 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV

116 045940

PSRFSGSGSGTDFTFTISSLQPEDIATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 55 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAAT CAAAAGAACTT CTT GACCT GGTAT CA GCAGAAACCAGGGAAAGCTCCTAAGCTCCTGA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCATCAAGGTTCAGTGGAAGTGGATC TGGGAC AGATTTTACTTTCACCATCAGCAGCCTGCAGC CT GAAGATATT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 56 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLQPEDIATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 57 DNA L.C. GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAAT CAAAAGAACTT CTT GACCT GGTAT CA GCAGAAACCAGGGAAAGCTCCTAAGCTCCTGA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCATCAAGGTTCAGTGGAAGTGGATC TGGGAC AGATTTTACTTTCACCATCAGCAGCCTGCAGC CT GAAGATATT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCAGAGAGG CCAAAGTA CAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum06 HC

117 045940

SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C

- 118 045940

CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCCGGTG ACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTG GGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGC AAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCAC GCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum06 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY

119 045940

SEQ ID NO: 58 VL DIVMTQTPLSLPPVTPGEPASISCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 59 DNA VL GATATTGTGATGACCCAGACTCCACTCTCCCT GCCCGTCACCCCTGGAGAGCCGGCCTCCATCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGA TTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 60 L.C. DIVMTQTPLSLPPVTPGEPASISCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 61 DNA LC GATATTGTGATGACCCAGACTCCACTCTCCCT GCCCGTCACCCCTGGAGAGCCGGCCTCCATCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGA TTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GAT TATAGTTATCCGTACACGTTCGGC CAAG G GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCAGAGAGG CCAAAGTACAGTG GAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA

120 045940

GCTTCAACAGGGGAGAGTGT BAP049-hum07 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGGGT GAAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA

- 121 045940

AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCCG CTT CCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTAC ACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG G CGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACC AAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACA GAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum07 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT

122 045940

SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 62 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 63 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTATCA GCAGAAACCAGGGAAAGCTCCTAAGCTCCTGA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGG AC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 64 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 65 DNA LC GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAAT CAAAAGAACTT CTT GACCT GGTAT CA GCAGAAACCAGGGAAAGCTCCTAAGCTCCTGA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATC TGGGAC AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCAGAGAGG CCAAA GTACAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA

- 123 045940

GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum08 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGGGT GAAAAAGCCCGGGGAGTCTCTGAGGATCTCCT

- 124 045940

GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CAAGAACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACA AGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCA GGACTCTACTCCC TCAGCACGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATTGGTCCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACG TGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCC AAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGG GCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-hum08 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT

125 045940

SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VL EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 67 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGT CACCAT CA C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 68 L.C. EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 69 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGT CACCAT CA C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACA GTGGAAGGTGGATAACGCCCTC

- 126 045940

CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-hum09 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK

- 127 045940

SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT B ACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTG GGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGC AAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCAC GCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA

128 045940

BAP049-hum09 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VL EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 67 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGT CACCAT CA C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 68 L.C. EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 69 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGT CACCAT CA C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT

- 129 045940

GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAG AGTGT BAP049-huml0 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S SWT VP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP

- 130 045940

ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA NS GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCCGGTGAC GGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACGGGAGTTCCTG GACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAA GGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGC CTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA

131 045940

GGCTCTGCACAACCACTACACACCAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-huml0 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 71 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTG GGAC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 72 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 73 DNA LC GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTG GGAC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG

- 132 045940

CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAG TCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-humll NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV

- 133 045940

SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT B ACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCC TGGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAA CGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGA CCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA

134 045940

GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACCAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-humll LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 71 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTG GGAC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 72 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 73 DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTG GGAC AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT

- 135 045940

GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAG CAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-huml2 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV

- 136 045940

T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHN HYTQKSLSLSSLGK SEQ ID NO: 41 DNA NS GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT B ACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTG GGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGC AAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG

137 045940

GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-huml2 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 74 VL DIQMTQSPSSLSSASVGDRVTITCKSSQSLLDS GNQKNFLTWYLQKPGQSPQLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 75 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCT GT CT GCAT CT GTAGGAGACAGAGT CACCAT CA CT T GCAAGTCCAGT CAGAGT CT GTTAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCT GCAGAAGCCAGGGCAGTCTCCACAGCTCCTGA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGG AC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGATGCT GCAACATATTACTGTCAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 76 L.C. DIQMTQSPSSLSSASVGDRVTITCKSSQSLLDS GNQKNFLTWYLQKPGQSPQLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 77 DNA LC GACATCCAGATGACCCAGTCTCCATCCTCCCT GT CT GCAT CT GTAGGAGACAGAGT CACCAT CA CT T GCAAGTCCAGT CAGAGT CT GTTAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCT GCAGAAGCCAGGGCAGTCTCCACAGCTCCTGA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGG A.C.

- 138 045940

AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTA CAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-huml3 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT C CACGAGCACAGCCTACATGGAGCTGAGCAGCC TGAGATCTGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S

- 139 045940

LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTC LVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HO GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCACTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAGT CAC GAT TAC C G C G GACAAAT B ACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTG GGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGC AAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC

140 045940

CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTC TCTGGGTAAA BAP049-huml3 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 78 VL DWMTQSPLSLPVTLGQPASISCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 79 DNA VL A GATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GAT TATAGTTATCCGTACACGTTCGGC CAAG G GACCAAGGTGGAAATCAAA SEQ ID NO: 80 L.C. DWMTQSPLSLPVTLGQPASISCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 81 DNA LC GATGTTGTGATGACTCAGTCTCCACTCTCCCT GCCCGTCACCCTTGGACAGCCGGCCTCCATCT C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTAACCTGGTATCA GCAGAAACCAGGGAAAGCTCCTAAGCTCCTGA

- 141 045940

TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTT GAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCG TCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-huml4 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 82 VH QVQ LVQ S GAEVKK P GASVKVS CKASGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 83 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGT GAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCT GCAAGGCTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGAACAGCTGTATCTTCAAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTACTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 84 H.C. QVQ LVQ S GAEVKK P GASVKVS CKASGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL

- 142 045940

APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSV LTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 85 DNA HC CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGT GAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCT GCAAGGCTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTACTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCCGGTGAC GGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCAGCACACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTG GACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAA GGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG

143 045940

AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAA TGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-huml4 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 71 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCASSCCT GTCTTTGTCTCCAGGGGAAAGAGCCACCCTCT C CT GCAAGTCCAGT CAGAGT CT GTTAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGG AC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 72 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 73 DNA LC GAAATTGTGTTGACACAGTCTCCAGCCASSCCT gtctttgtctccaggggaaagagccaccctct C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT

- 144 045940

GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GAT TATAGTTATCCGTACACGTTCGGC CAAG G GACCAA GGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGC AAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-huml5 NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 82 VH QVQ LVQ S GAEVKK P GASVKVS CKASGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 83 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGT GAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCT GCAAGGCTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGAACAGCTGTATCTTCAAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTACTG GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 84 H.C. QVQ LVQ S GAEVKK P GASVKVS CKASGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF

- 145 045940

KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISR TPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALH NHYTQKSLSLSSLGK SEQ ID NO: 85 DNA HC CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGT GAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCT GCAAGGCTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGATCAGGCAGTCCCCATCGAG AGGCCTTGAGTGGCTGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CA AGACACGCTGTATCTTCAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTACTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCCGGTGAC GGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATTGGTCCCCCATGCCCA CCGTGCCCAGCACGGGAGTTCCTG GACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAA GGAGTACAAGTGCAAGGTG

146 045940

TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGAT GACCAAGAACCAGGT CAGCCT GAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCC GACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-huml5 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VL EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 67 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGT CACCAT CA C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 68 L.C. EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSK ADY EKHKVYACEVTHQGLS S PVTKS FNRGEC

- 147 045940

SEQ ID NO: 69 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGT CACCAT CA C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACA GTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-huml6 HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 86 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQAPGQGLEWMGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 87 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCCCTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CAAGAACACGCTGTATCTTCAAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG

148 045940

GGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 88 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQAPGQGLEWMGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 89 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGT GAAAAGCCCGGGGAGTCTCTGAGGATCTCCT GTAAGGGTTCTGGCTACACATTCACCACTTAC TGGATGCACTGGGTGCGACAGGCCCCTGGACA AGGGCTTGAGTGGATGGGTAATATTTATCCTG GTACTGGTGGTTCTAACTTCGATGAGAAGTTC AAGAACAGAT T CAC CAT C T C CAGAGACAAT T C CAAGAACACGCTGTATCTTCAAATGAACAGCC TGAGAGCCGAGGACACGGCCGTGTATTACTGT ACAAGATGGACTACTGGGACGGGAGCTTATTG GGGCCAGGGCACCACGTGACCGTGTCCTCCG CTTCCACCAAGGGCCCATCCGTCTTCCCCCTG GCGCCCTGCTCCAGGAGCACCTCCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTCAAGGACTACT TCCCCGAACCCTG ACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCC GGCTGTCCTACAGTCCTCAGGACTCTACTCCC TCAGCAGGTGGTGACCGTGCCCTCCAGCAGC TTGGGCACGAAGACCTACACCTGCAACGTAGA TCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAATATGGTCCCCCATGCCCA CCGTGCCCAGCACCTGAGTTCCTG GGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGG ACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGA CCCCGAGGTCCAGTTCAACTGGTACGTGGATG

149 045940

GCGTGGAGGTGCATAATGCCAAGACAAAGCCG CGGGAGGAGCAGTTCAACAGCACGTACCGTGT GGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTG TCCAACAAAGGCCTCCCGTCCTCCATCGAGAA AACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGA CCAAGAACCAGGTCAGCCTGAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG GAGAACAACTACAAGACCACGCCTCCCGTGCT GGACTCCGACGGCTCCTTCTTCCTCTACAGCA GGCTAACCGTGGACAAGAGCAGGTGGCAGGAG GGGAATGTCTTCTCATGCTCCGTGATGCATGA GGCTCTGCACAACCACTACACACA GAAGAGCC TCTCCCTGTCTCTGGGTAAA BAP049-huml6 LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VL EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 67 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGTCACCAT CA C CT GCAAGTCCAGT CAGAGT CT GTTAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGA TTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAA SEQ ID NO: 68 L.C. EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD

- 150 045940

EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 69 DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCA GT CT GT GACT CCAAAGGAGAAAGT CACCAT CA C CT GCAAGT C CAGT CAGAGT CT GT TAGACAGT GGAAATCAAAAGAACTTCTTGACCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCA TCTATTGGGCATCCACTAGGGAATCTGGGGTC CCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC AGATTTCACCTTTACCATCAGTAGCCTGGAAG CT GAAGAT GCT GCAACATATTACT GT CAGAAT GATTATAGTTATCCGTACACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGTACGGTGGCTG CACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGT GTGCCTGCTGAATAACTTCTATCCCAGAGAGG CCAAAGTACA GTGGAAGGTGGATAACGCCCTC CAAT CGGGTAACT CCCAGGAGAGT GT CACAGA GCAGGACAGCAAGGACAGCACCTACAGCCTCA GCAGCACCCTGACGCTGAGCAAAGCAGACTAC GAGAAACACAAAGTCTACGCCTGCGAAGTCAC CCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGT BAP049-clone-A HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 90 DNA VH GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGT GAAGAAGCCTGGCGAGTCCCTGCGGATCTCCT GCAAGGGCTCTGGCTACACCTTCACCACCTAC TGGATGCACTGGGTGCGACAGGCTACCGGCCA GGGCCTGGAATGGATGGGCAACATCTATCCTG GCACCGGCGGCTCCAACTTCGACGAGAAGTTC AAGAACAGAGT GAC CAT CAC C GC C GACAAG T C

151 045940

CACCTCCACCGCCTACATGGAACTGTCCTCC TGAGATCCGAGGACACCGCCGTGTACTACTGC ACCCGGTGGACAACCGGCACAGGCGCTTATTG GGGCCAGGGCACCACAGTGACCGTGTCCTCT SEQ ID NO: 91 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 92 DNA HC GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGT GAAGAAGCCTGGCGAGTCCCTGCGGATCTCCT GCAAGGGCTCTGGCTACACCTTCACCACCTAC TGGATGCACTGGGTGCGACAGGCTACCGGCCA GGGCCTGGAATGGATGGGCAACATCTATCCTG GCACCGGCGGCTCCAACTTCGACGAGAAGTTC AAGAACAGAGT GAC CAT CAC C GC C GACAAG T C CACCTCCACCGCCTACATGGAACTGTCCTCCC TGAGATCCGAGGACACCGCCGTGTACTACTGC ACCCGTGTGGACAACCGGCACAGGCGCTTATTG GGGCCAGGGCACCACAGTGACCGTGTCCTCTG CTTCTACCAAGGGGCCCAGCGTGTTCCCCCTG GCCCCCTGCTCCAGAAGCACCAGCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTGAAGGACTACT TCCCCGAGCCCG TGACCGTGTCCTGGAACAGC GGAGCCCTGACCAGCGGCGTGCACACCTTCCC CGCCGTGCTGCAGAGCAGCGGCCTGTACAGCC TGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC CTGGGCACCAAGACCTACACCTGTAACGTGGA CCACAAGCCCAGCAACACCAAGGTGGACAAGA GGGTGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTG CGGACC CAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGG ACAC C C T GAT GAT CAG CAGAAC CCCCGAGGTG

152 045940

ACCTGTGTGGTGGTGGACGTGTCCCAGGAGGA CCCCGAGGTCCAGTTCAACTGGTACGTGGACG GCGTGGAGGTGCACAACGCCAAGACCAAGCCC AGAGAGGAGCAGTTTAACAGCACCTACCGGGT GGTGTCCGTGCTGACCGTGCTGCACCAGGACT GGCT GAACGGCAAAGAGTACAAGT GTAAGGT C TCCAACAAGGGCCTGCCAAGCAGCATCGAAAA GACCATCA GCAAGGCCAAGGGCCAGCCTAGAG AGCCCCAGGTCTACACCCTGCCACCCAGCCAA GAGGAGAT GACCAAGAACCAGGT GT CCCT GAC CTGTCTGGTGAAGGGCTTCTACCCAAGCGACA TCGCCGTGGAGTGGGAGAGCAACGGCCAGCCC GAGAACAAC TACAAGAC CACCCCCCCAGTGCT GGACAGCGACGGCAGCTTCTTCCTGTACAGCA GGCTGACCGTGGA CAAGTCCAGATGGCAGGAG GGCAACGTCTTTAGCTGCTCCGTGATGCACGA GGCCCTGCACAACCACTACACCCCAGAAGAGCC TGAGCCTGTCCCTGGGC BAP049-clone-A LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 42 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTEFTLTISSLQPDDFATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 93 DNA VL GAGATCGTGCTGACCCAGTCCCCTGCCACCCT GTCACTGTCTCCAGGCGAGAGCTACCCTGT CCTGCAAGTCCTCCCAGTCCCTGCTGGACTCC GGCAACCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGCCAGCCCCCAGACTGCTGA TCTACTGGGCCTCCACCCGGGAATCTGGCGTG CCCTCTAGATTCTCCGGCTCCGGCTCTGGCAC CGAGTTTACCCTGA CCATCTCCAGCCTGCAGC CCGACGACTTCGCCACCTACTACTGCCAGAAC GACTACTCCTACCCCTACACCTTTCGGCCAGGG GACCAAGGTGGAAATCAAG SEQ ID NO: 44 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV

- 153 045940

PSRFSGSGSGTEFTLTISSLQPDDFATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 94 DNA LC GAGATCGTGCTGACCCAGTCCCCTGCCACCCT GTCACTGTCTCCAGGCGAGAGCTACCCTGT CCTGCAAGTCCTCCCAGTCCCTGCTGGACTCC GGCAACCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGCCAGCCCCCAGACTGCTGA TCTACTGGGCCTCCACCCGGGAATCTGGCGTG CCCTCTAGATTCTCCGGCTCCGGCTCTGGCAC CGAGTTTACCCTGA CCATCTCCAGCCTGCAGC CCGACGACTTCGCCACCTACTACTGCCAGAAC GACTACTCCTACCCCTACACCTTCGGCCAGGG CACCAAGGTGGAAATCAAGCGTACGGTGGCCG CTCCCAGCGTGTTCATCTTCCCCCCAAGCGAC GAGCAGCTGAAGAGCGGCACCGCCAGCGTGGT GTGTCTGCTGAACAACTTCTACCCCAGGGAGG CCAAGGTGCAGTGGAAGGTGGACAACGCCCTG CAGAGCGGCAACAGCCAGGAGAGCGTCACCGA GCAGGACAGCAAGGACTCCACCTACAGCCTGA GCAGCACCCTGACCCTGAGCAAGGCCGACTAC GAGAAGCACAAGGTGTACGCCTGTGAGGTGAC CCACCAGGGCCTGTCCAGCCCCGTGACCAAGA GCTTCAACAGGGGCGAGTGC BAP049-clone-B NS SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 95 DNA VH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGT GAAGAAGCCCCGGCGAGTCACTGAGAATTAGCT GTAAAGGTTCAGGCTACACCTTCACTACCTAC TGGATGCACTGGGTCCGCCAGGCTACCGGTCA AGGCCTCGAGTGGATGGGTAATATCTACCCCG

154 045940

GCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGT GAC TAT СAC C G C C GATAAGT C TACTAGCACCGCCTATATGGAACTGTCTAGCC TGAGATCAGAGGACACCGCCGTCTACTACTGC ACTAGGTGGACTACCGGCACAGGCGCCTACTG GGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 91 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 96 DNA HC GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGT GAAGAAGCCCGGCGAGTCACTGAGAATTAGCT GTAAAGGTTCAGGCTACACCTTCACTACCTAC TGGATGCACTGGGTCCGCCAGGCTACCGGTCA AGGCCTCGAGTGGATGGGTAATATCTACCCCG GCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGT GACTAT СAC C GC GATAAGT C T ACTAGCACCGCCTATATGGAACTGTCTAGCC TGAGATCAGAGGACACCGCCGTCTACTACTGC ACTAGGTGGACTACCGGCACAGGCGCCTACTG GGGTCAAGGCACTACCGTGACCGTGTCTAGCG CTAGCACTAAGGGCCCGTCCGTGTTCCCCCTG GCACCTTGTAGCCGGAGCACTAGCGAATCCAC CGCTGCCCTCGGCTGCCTGGTCAAGGATTACT TCCCGGAGCCCGTGACCG TGTCCTGGAACAGC GGAGCCCTGACCTCCGGAGTGCACACCTTCCC CGCTGTGCTGCAGAGCTCCGGGCTGTACTCGC TGTCGTCGGTGGTCACGGTGCCTTCATCTAGC CTGGGTACCAAGACCTACACTTGCAACGTGGA CCAAAGCCTTCCAACACTAAGGTGGACAAGC GCGTCGAATCGAAGTACGGCCCACGTGCCCG CCTTGTCCCGCGCGGAGTTCCTCGGC TCC

155 045940

CTCGGTCTTTCTGTTCCCACCGAAGCCCAAGG ACACTTTGATGATTTCCCGCACCCCTGAAGTG ACAT GCGT GGT CGT GGACGT GT CACAGGAAGA TCCGGAGGTGCAGTTCAATTGGTACGTGGATG GCGTCGAGGTGCACAACGCCAAAACCAAGCCG AGGGAGGAGCAGTTCAACTCCACTTACCGCGT CGTGTCCGTGCTGACGGTGCTGCATCAGGACT GGC TGAACGGGAAGGAGTACAAGTGCAAAGTG TCCAACAAGGGACTTCCTAGCTCAATCGAAAA GACCATCTCGAAAGCCAAGGGACAGCCCCGGG AAC C C CAAGT GTATACCCTGCCACCGAGCCAG GAAGAAAT GACTAAGAAC CAAGT CT CAT T GAC TTGCCTTGTGAAGGGCTTCTACCCATCGGATA TCGCCGTGGAATGGGAGTCCAACGGCCAGCCG GAAAACAACT ACAAGACCACCCCTCCGGTGCT GGACTCAGACGGATCCTTCTTCCTCTACTCGC GGCTGACCGTGGATAAGAGCAGATGGCAGGAG GGAAATGTGTTCAGCTGTTCTGTGATGCATGA AGCCCTGCACAACCACTACACTCAGAAGTCCC TGTCCCTCTCCCTGGGA BAP049-clone-B LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 54 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLQPEDIATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 97 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCT GAGCCTGAGCCCTGGCGAGCGGGCTACACTGA GCTGTAAATCTAGTCAGTCACTGCTGGATAGC GGTAATCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGA TCTACTGGGCCTCTACTAGAGAATCAGGCGTG CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCAC CGACTTCACCT TCACTATCTCTAGCCTGCAGC CCGAGGATATCGCTACCTACTACTGTCAGAAC GACTATAGCTACCCCTACACCTTCGGTCAAGG CACTAAGGTCGAGATTAAG

156 045940

SEQ ID NO: 56 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGKAPKLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLQPEDIATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSK ADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 98 DNA LC GAGATCGTCCTGACTCAGTCACCCGCTACCCT GAGCCTGAGCCCTGGCGAGCGGGCTACACTGA GCTGTAAATCTAGTCAGTCACTGCTGGATAGC GGTAATCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGA TCTACTGGGCCTCTACTAGAGAATCAGGCGTG CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCAC CGACTTCACCT TCACTATCTCTAGCCTGCAGC CCGAGGATATCGCTACCTACTACTGTCAGAAC GACTATAGCTACCCCTACACCTTCGGTCAAGG CACTAAGGTCGAGATTAAGCGTACGGTGGCCG CTCCCAGCGTGTTCATCTTCCCCCCCAGCGAC GAGCAGCTGAAGAGCGGCACCGCCAGCGTGGT GTGCCTGCTGAACAACTTCTACCCCCGGGAGG CCAAGGTGCAGTGGAAGGTGGACAACGCCC TG CAGAGCGGCAACAGCCAGGAGAGCGTCACCGA GCAGGACAGCAAGGACTCCACCTACAGCCTGA GCAGCACCCTGACCCTGAGCAAGGCCGACTAC GAGAAGCATAAGGTGTACGCCTGCGAGGTGAC CCACCAGGGCCTGTCCAGCCCCGTGACCAAGA GCTTCAACAGGGGCGAGTGC BAP049-clone-C HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 90 DNA VH GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGT GAAGAAGCCCTGGCGAGTCCCTGCGGATCTCCT GCAAGGGCTCTGGCTACACCCTTCACCACCTAC

157 045940

TGGATGCACTGGGTGCGACAGGCTACCGGCCA GGGCCTGGAATGGATGGGCAACATCTATCCTG GCACCGGCGGCTCCAACTTCGACGAGAAGTTC AAGAACAGAGT GAC CAT CAC C GC C GACAAGT C CACCTCCACCGCCTACATGGAACTGTCCTCCC TGAGATCCGAGGACACCGCCGTGTACTACTGC ACCCGGTGGACAACCGGCACAGGCGCTTATTG GGG CCAGGGCACCACAGTGACCGTGTCCTCT SEQ ID NO: 91 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 92 DNA HC GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGT GAAGAAGCCTGGCGAGTCCCTGCGGATCTCCT GCAAGGGCTCTGGCTACACCTTCACCACCTAC TGGATGCACTGGGTGCGACAGGCTACCGGCCA GGGCCTGGAATGGATGGGCAACATCTATCCTG GCACCGGCGGCTCCAACTTCGACGAGAAGTTC AAGAACAGAGT GAC CAT CAC C GC C GACAAG T C CACCTCCACCGCCTACATGGAACTGTCCTCCC TGAGATCCGAGGACACCGCCGTGTACTACTGC ACCCGTGTGGACAACCGGCACAGGCGCTTATTG GGGCCAGGGCACCACAGTGACCGTGTCCTCTG CTTCTACCAAGGGGCCCAGCGTGTTCCCCCTG GCCCCCTGCTCCAGAAGCACCAGCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTGAAGGACTACT TCCCCGAGCCCG TGACCGTGTCCTGGAACAGC GGAGCCCTGACCAGCGGCGTGCACACCTTCCC CGCCGTGCTGCAGAGCAGCGGCCTGTACAGCC TGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC CTGGGCACCAAGACCTACACCTGTAACGTGGA CCACAAGCCCAGCAACACCAAGGTGGACAAGA

158 045940

GGGTGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTGGGCGGACC CAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGG ACAC C C T GAT GAT CAG CAGAAC CCCCGAGGTG ACCTGTGTGGTGGTGGACGTGTCCCAGGAGGA CCCCGAGGTCCAGTTCAACTGGTACGTGGACG GCGTGGAGGTGCACAACGCCAAGACCAAGCCCC AGAGAGGA GCAGTTTAACAGCACCTACCGGGT GGTGTCCGTGCTGACCGTGCTGCACCAGGACT GGCT GAACGGCAAAGAGTACAAGT GTAAGGT C TCCAACAAGGGCCTGCCAAGCAGCATCGAAAA GACCATCAGCAAGGCCAAGGGCCAGCCTAGAG AGCCCCAGGTCTACACCCTGCCACCCAGCCAA GAGGAGAT GACCAAGAACCAGGT GT CCCT GACGG CTGTCTGGTGAA GCTTCTACCCAAGCGACA TCGCCGTGGAGTGGGAGAGCAACGGCCAGCCC GAGAACAAC TACAAGAC CAC C C C C CAGT G C T GGACAGCGACGGCAGCTTCTTCCTGTACAGCA GGCTGACCGTGGACAAGTCCAGATGGCAGGAG GGCAACGTCTTTAGCTGCTCCGTGATGCACGA GGCCCTGCACAACCACTACACCCAGAAGAGCC TGAGCCTGTCCC TGGGC VARO49—clone—C LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VL EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 99 DNA VL GAGATCGTGCTGACCCAGTCCCCCGACTTCCA GT C C GT GAC C C C CAAAGAAAAAGT GACCAT CA CATGCAAGTCCTCCCAGTCCCTGCTGGACTCC GGCAACCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGCCAGGCCCCAGACTGCTGA TCTACTGGGCCTCCACCCGGGAATCTGGCGTG CCCTCTAGATTCTCCGGCTCCGGCTCTGGCAC CGACTTTACCT TCACCATCTCCAGCCTGGAAG CCGAGGACGCCGCCACCTACTACTGCCAGAAC

159 045940

GACTACTCCTACCCTACACCTTCGGCCAGGG CACCAAGGTGGAAATCAAG SEQ ID NO: 68 L.C. EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 100 DNA LC GAGATCGTGCTGACCCAGTCCCCCGACTTCCA GT C C GT GAC C C C CAAAGAAAAAGT GAC CAT CA CATGCAAGTCCTCCCAGTCCCTGCTGGACTCC GGCAACCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGCCAGGCCCCCAGACTGCTGA TCTACTGGGCCTCCACCCGGGAATCTGGCGTG CCCTCTAGATTCTCCGGCTCCGGCTCTGGCAC CGACTTTAC CTTCACCATCTCCAGCCTGGAAG CCGAGGACGCCGCCACCTACTACTGCCAGAAC GACTACTCCTACCCCTACACCTCGGCCAGGG CACCAAGGTGGAAATCAAGCGTACGGTGGCCG CTCCCAGCGTGTTCATCTTCCCCCCAAGCGAC GAGCAGCTGAAGAGCGGCACCGCCAGCGTGGT GTGTCTGCTGAACAACTTCTACCCCAGGGAGG CCAAGGTGCAGTGGAAGGTGGACAACGC CCTG CAGAGCGGCAACAGCCAGGAGAGCGTCACCGA GCAGGACAGCAAGGACTCCACCTACAGCCTGA GCAGCACCCTGACCCTGAGCAAGGCCGACTAC GAGAAGCACAAGGTGTACGCCTGTGAGGT GAC CCACCAGGGCCTGTCCAGCCCCGTGACCAAGA GCTTCAACAGGGGCGAGTGC VAR049-clone-O HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSS

160 045940

SEQ ID NO: 101 DNA VH GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGT GAAGAAGCCTGGCGAGTCCCTGCGGATCTCCT GCAAGGGCTCTGGCTACACCTTCACCACCTAC TGGATGCACTGGATCCGGCAGTCCCCCTCTAG GGGCCTGGAATGGCTGGGCAACATCTACCCTG GCACCGGCGGCTCCAACTTCGACGAGAAGTTC AAGAACAGGTTCACCATCTCCCGGGACAACTC CAAGAACA CCCTGTACCTGCAGATGAACTCCC TGCGGGCCGAGGACACCGCCGTGTACTACTGT ACCAGATGGACCACCGGAACCGGCGCCTATTG GGGCCAGGGCACAACAGTGACCGTGTCCTCC SEQ ID NO: 102 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKF KNRFTISRDNSKNTLYLQMNSLRAEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLV KGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 103 DNA HC GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGT GAAGAAGCCTGGCGAGTCCCTGCGGATCTCCT GCAAGGGCTCTGGCTACACCTTCACCACCTAC TGGATGCACTGGATCCGGCAGTCCCCCTCTAG GGGCCTGGAATGGCTGGGCAACATCTACCCTG GCACCGGCGGCTCCAACTTCGACGAGAAGTTC AAGAACAGGTTCACCATCTCCCGGGACAACTC CAAGAACA CCCTGTACCTGCAGATGAACTCCC TGCGGGCCGAGGACACCGCCGTGTACTACTGT ACCAGATGGACCACCGGAACCGGCGCCTATTG GGGCCAGGGCACAACAGTGACCGTGTCCTCCG CTTCTACCAAGGGGCCCAGCGTGTTCCCCCTG GCCCCCTGCTCCAGAAGCACCAGCGAGAGCAC AGCCGCCCTGGGCTGCCTGGTGAAGGACTACT TCCCCGAGCCCGTGACCGTGTC CTGGAACAGC GGAGCCCTGACCAGCGGCGTGCACACCTTCCC CGCCGTGCTGCAGAGCAGCGGCCTGTACAGCC

- 161 045940

TGAGCAGCGTGGTGACCGTGCCCAGCAGCAGC CTGGGCACCAAGACCTACACCTGTAACGTGGA CCACAAGCCCAGCAACACCAAGGTGGACAAGA GGGTGGAGAGCAAGTACGGCCCACCCTGCCCC CCCTGCCCAGCCCCCGAGTTCCTGGGCGGACC CAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGG ACAC C C T GAT GAT CAG CAGAAC CCCCGAGGTG ACCTGTGTG GTGGTGGACGTGTCCCAGGAGGA CCCCGAGGTCCAGTTCAACTGGTACGTGGACG GCGTGGAGGTGCACAACGCCAAGACCAAGCCC AGAGAGGAGCAGTTTAACAGCACCTACCGGGT GGTGTCCGTGCTGACCGTGCTGCACCAGGACT GGCT GAACGGCAAAGAGTACAAGT GTAAGGT C TCCAACAAGGGCCTGCCAAGCAGCATCGAAAA GACCATCAGCAAGGCCAA GGGCCAGCCTAGAG AGCCCCAGGTCTACACCCTGCCACCCAGCCAA GAGGAGAT GACCAAGAACCAGGT GT CCCT GAC CTGTCTGGTGAAGGGCTTCTACCCAAGCGACA TCGCCGTGGAGTGGGAGAGCAACGGCCAGCCC GAGAACAAC TACAAGAC CAC C C C C C CAGT G C T GGACAGCGACGGCAGCTTCTTCCTGTACAGCA GGCTGACCGTGGA CAAGTCCAGATGGCAGGAG GGCAACGTCTTTAGCTGCTCCGTGATGCACGA GGCCCTGCACAACCACTACACCCCAGAAGAGCC TGAGCCTGTCCCTGGGGC VAR049-clone-O LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 104 DNA VL GAGATCGTGCTGACCCAGTCCCCTGCCACCCT GTCACTGTCTCCAGGCGAGAGAGCTACCCTGT CCTGCAAGTCCTCCCAGTCCCTGCTGGACTCC GGCAACCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGCCAGGCCCCCAGACTGCTGA TCTACTGGGCCTCCACCCGGGAATCTGGCGTG

162 045940

CCCTCTAGATTCTCCGGCTCCGGCTCTGGCAC CGACTTTACCTTCACCATCTCCAGCCTGGAAG CCGAGGACGCCGCCACCTACTACTGCCAGAAC GACTACTCCTACCCTACACCTTCGGCCAGGG CACCAAGGT GGAAAT CAAG SEQ ID NO: 72 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 105 DNA LC GAGATCGTGCTGACCCAGTCCCCTGCCACCCT GTCACTGTCTCCAGGCGAGAGCTACCCTGT CCTGCAAGTCCTCCCAGTCCCTGCTGGACTCC GGCAACCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGCCAGCCCCCAGACTGCTGA TCTACTGGGCCTCCACCCGGGAATCTGGCGTG CCCTCTAGATTCTCCGGCTCCGGCTCTGGCAC CGACTTTACCTTCAC CATCTCCAGCCTGGAAG CCGAGGACGCCGCCACCTACTACTGCCAGAAC GACTACTCCTACCCCTACACCTTCGGCCAGGG CACCAAGGTGGAAATCAAGCGTACGGTGGCCG CTCCCAGCGTGTTCATCTTCCCCCCAAGCGAC GAGCAGCTGAAGAGCGGCACCGCCAGCGTGGT GTGTCTGCTGAACAACTTCTACCCCAGGAGG CCAAGGTGCAGTGGAAGGTGGACAACGCCCTG CA GAGCGGCAACAGCCAGGAGAGCGTCACCGA GCAGGACAGCAAGGACTCCACCTACAGCCTGA GCAGCACCCTGACCCTGAGCAAGGCCGACTAC GAGAAGCACAAGGTGTACGCCTGTGAGGTGAC CCACCAGGGCCTGTCCAGCCCCGTGACCAAGA GCTTCAACAGGGGCGAGTGC BAP049-clone-E HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF

163 045940

KNRVTITADKSSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 95 DNA VH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGT GAAGAAGCCCGGCGAGTCACTGAGAATTAGCT GTAAAGGTTCAGGCTACACCTTCACTACCTAC TGGATGCACTGGGTCCGCCAGGCTACCGGTCA AGGCCTCGAGTGGATGGGTAATATCTACCCCG GCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGT GACTAT СAC C GC GATAAGT C T ACTAGCACCGCCTATATGGAACTGTCTAGCC TGAGATCAGAGGACACCGCCGTCTACTACTGC ACTAGGTGGACTACCGGCACAGGCGCCTACTG GGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 91 H.C. EVQLVQSGAEVKKPGESLRISCKGSGYTFTTY WMHWVRQATGQGLEWMGNIYPGTGGSNFDEKF KNRVTITADKSTSTAYMELSSLRSEDTAVYYC TRWTTGTGAYWGQGTTVTVSSASTKGPSVFPL APCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALT S GVHT FPAVLQ S S GL YS L S S WTVP S S S L GTKTYTCNVDHKPSNTKVDKRVESKYGPPCP PCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV T C VWD VS Q E D P E VQ FNW YVD GVE VHNAKT K P REEQFNSTYRWSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVK GFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 96 DNA HC GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGT GAAGAAGCCCGGCGAGTCACTGAGAATTAGCT GTAAAGGTTCAGGCTACACCTTCACTACCTAC TGGATGCACTGGGTCCGCCAGGCTACCGGTCA AGGCCTCGAGTGGATGGGTAATATCTACCCCG GCACCGGCGGCTCTAACTTCGACGAGAAGTTT AAGAATAGAGT GACTAT СAC C GC GATAAGT C T ACTAGCACCGCCTATATGGAACTGTCTAGCC TGAGATCAGAGGACACCGCCGTCTACTACTGC ACTAGGTGGACTACCGGCACAGGCGCCTACTG GGGTCAAGGCACTACCGTGACCGTGTCTAGCG CTAGCACTAAGGGCCCGTCCGTGTTCCCCCTG GCACCTTGTAGCCGGAGCACTAGCGAATCCAC CGCTGCCCTCGGCTGCCTGGTCAAGGATTACT TCCCGGAGCCCGTGACCG TGTCCTGGAACAGC

- 164 045940

GGAGCCCTGACCTCCGGAGTGCACACCTTCCC CGCTGTGCTGCAGAGCTCCGGGCTGTACTCGC TGTCGTCGGTGGTCACGGTGCCTTCATCTAGC CTGGGTACCAAGACCTACACTTGCAACGTGGA CCACAAGCCTTCCAACACTAAGGTGGACAAGC GCGTCGAATCGAAGTACGGCCCACCGTGCCCG CCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCC CTCGGTC TTTCTGTTCCCACCGAAGCCCAAGG ACACTTTGATGATTTCCCGCACCCCTGAAGTG ACAT GCGT GGT CGT GGACGT GT CACAGGAAGA TCCGGAGGTGCAGTTCAATTGGTACGTGGATG GCGTCGAGGTGCACAACGCCAAAACCAAGCCG AGGGAGGAGCAGTTCAACTCCACTTACCGCGT CGTGTCCGTGCTGACGGTGCTGCATCAGGACT GGCTGAACGAA GGAGTACAAGTGCAAAGTG TCCAACAAGGGACTTCCTAGCTCAATCGAAAA GACCATCTCGAAAGCCAAGGGACAGCCCCGGG AAC C C CAAGT GTATACCCTGCCACCGAGCCAG GAAGAAAT GACTAAGAAC CAAGT CT CAT T GAC TTGCCTTGTGAAGGGCTTCTACCCATCGGATA TCGCCGTGGAATGGGAGTCCAACGGCCAGCCG GAAAACAACTACAAGACCAC CCCTCCGGTGCT GGACTCAGACGGATCCTTCTTCCTCTACTCGC GGCTGACCGTGGATAAGAGCAGATGGCAGGAG GGAAATGTGTTCAGCTGTTCTGTGATGCATGA AGCCCTGCACAACCACTACACTCAGAAGTCCC TGTCCCTCTCCCTGGGA BAP049-clone-E LC SEQ ID NO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 W.A.S. SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIK SEQ ID NO: 106 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCT GAGCCTGAGCCCTGGCGAGCGGGCTACACTGA GCTGTAAATCTAGTCAGTCACTGCTGGATAGC GGTAATCAGAAGAACTTCCTGACCTGGTATCA

165 045940

GCAGAAGCCCGGTCAAGCCCCTAGACTGCTGA TCTACTGGGCCTCTACTAGAGAATCAGGCGTG CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCAC CGACTTCACCTTCACTATCTCTAGCCTGGAAG CCGAGGACGCCGCTACCTACTACTGTCAGAAC GACTATAGCTACCCCTACACCTTCGGTCAAGG CACTAAGGTCGAGATTAAG SEQ ID NO: 72 L.C. EIVLTQSPATLSLSPGERATLSCKSSQSLLDS GNQKNFLTWYQQKPGQAPRLLIYWASTRESGV PSRFSGSGSGTDFTFTISSLEAEDAATYYCQN DYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASWCLLNNFYPREAKVQWKVflHKL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLS S PVTKS FNRGEC SEQ ID NO: 107 DNA LC GAGATCGTCCTGACTCAGTCACCCGCTACCCT GAGCCTGAGCCCTGGCGAGCGGGCTACACTGA GCTGTAAATCTAGTCAGTCACTGCTGGATAGC GGTAATCAGAAGAACTTCCTGACCTGGTATCA GCAGAAGCCCGGTCAAGCCCCTAGACTGCTGA TCTACTGGGCCTCTACTAGAGAATCAGGCGTG CCCTCTAGGTTTAGCGGTAGCGGTAGTGGCAC CGACTTCACCT TCACTATCTCTAGCCTGGAAG CCGAGGACGCCGCTACCTACTACTGTCAGAAC GACTATAGCTACCCCTACACCTTCGGTCAAGG CACTAAGGTCGAGATTAAGCGTACGGTGGCCG CTCCCAGCGTGTTCATCTTCCCCCCCAGCGAC GAGCAGCTGAAGAGCGGCACCGCCAGCGTGGT GTGCCTGCTGAACAACTTCTACCCCCGGGAGG CCAAGGTGCAGTGGAAGGTGGACAACGCCC TG CAGAGCGGCAACAGCCAGGAGAGCGTCACCGA GCAGGACAGCAAGGACTCCACCTACAGCCTGA GCAGCACCCTGACCCTGAGCAAGGCCGACTAC GAGAAGCATAAGGTGTACGCCTGCGAGGTGAC CCACCAGGGCCTGTCCAGCCCCGTGACCAAGA GCTTCAACAGGGGCGAGTGC BAP049HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC

166 045940

SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 115 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GT GCAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 118 (Chothia) LCDR3 GAT TATAGT TAT C C GT GC BAP049-chi HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-chi LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 115 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GT GCAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 118 (Chothia) LCDR3 GAT TATAGT TAT C C GT GC BAP049-chi Y HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-chi Y LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G

- 167 045940

SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum01 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum01 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum02 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum02 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum03 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT

- 168 045940

C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum03 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum04 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum04 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum05 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum05 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA

- 169 045940

TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA gaacttc SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum06 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGTT CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum06 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA gaacttc SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum07 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum07 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAATGATTATAGTTAT CCGTACACG SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAATCAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC

- 170 045940

BAP049-hum08 NS SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGTT CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum08 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA gaacttc SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-hum09 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGTT CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-hum09 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA gaacttc SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-huml0 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 aatatttatcctggtactggtggttctaactt C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT

- 171 045940

SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-huml0 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-humll HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-humll LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-huml2HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-huml2 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA

- 172 045940

GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-huml3 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-huml3 LC SEQ ID NO: 121 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTAACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-huml4HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 223 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAC SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 223 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAC BAP049-huml4 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-huml5 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC

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SEQ ID NO: 223 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAC SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 223 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAC BAP049-huml5 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-huml6 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTT C GAT GAGAAGT T CAAGAAC SEQ ID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGGAGCTTAT SEQ ID NO: 111 (Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2 TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3 TGGACTACTGGGACGGGGAGCTTAT BAP049-huml6 LC SEQ ID NO: 113 (Kabat) LCDR1 AAGT C CAGT CAGAGT CT GT TAGACAGT GGAAA TCAAAAGAACTTCTTGACC SEQ ID NO: 114 (Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3 CAGAAT GAT TATAGT TAT C C GTACAC G SEQ ID NO: 116 (Chothia) LCDR1 AGT CAGAGT CT GTTAGACAGT GGAAAT CAAAA GAACTTC SEQ ID NO: 117 (Chothia) LCDR2 TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GAT TATAGT TAT WITH C GTAC BAP049-clone-A HC SEQ ID NO: 122 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 123 (Kabat) HCDR2 AACATCTATCCTGGCACCCGGCGGCTCCAACTT C GAC GAGAAGT T CAAGAAC SEQ ID NO: 124 (Kabat) HCDR3 TGGACAACCGGCACAGGCGCTTAT SEQ ID NO: 125 (Chothia) HCDR1 GGCTACACCTTCACCACCTAC SEQ ID NO: 126 (Chothia) HCDR2 TATCCTGGCACCGGCGGC SEQ ID NO: 124 (Chothia) HCDR3 TGGACAACCGGCACAGGCGCTTAT VAR049-CLONE-A LC SEQ ID NO: 127 (Kabat) LCDR1 AAGTCCTCCCAGTCCCTGCTGGACTCCGGCAA CCAGAAGAACTTCCTGACC

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SEQ ID NO: 128 (Kabat) LCDR2 TGGGCCTCCACCCGGGAATCT SEQ ID NO: 129 (Kabat) LCDR3 CAGAACGACTACTCCTACCCCTACACC SEQ ID NO: 130 (Chothia) LCDR1 TCCCAGTCCCTGCTGGACTCCGGCAACCAGAA gaacttc SEQ ID NO: 131 (Chothia) LCDR2 TGGGCCTCC SEQ ID NO: 132 (Chothia) LCDR3 GACTACTCCTACCCCTAC BAP049-clone-B NS SEQ ID NO: 133 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 134 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTT C GAC GAGAAGTTTAAGAAT SEQ ID NO: 135 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 136 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 137 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 135 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC VAR049-CLONE-V LC SEQ ID NO: 138 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAA TCAGAAGAACTTCCTGACC SEQ ID NO: 139 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 140 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 141 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAA gaacttc SEQ ID NO: 142 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 143 (Chothia) LCDR3 GACTATAGCTACCCCTAC VAR049-CLONE-S HC SEQ ID NO: 122 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 123 (Kabat) HCDR2 AACATCTATCCTGGCACCCGGCGGCTCCAACTT C GAC GAGAAGTT CAAGAAC SEQ ID NO: 124 (Kabat) HCDR3 TGGACAACCGGCACAGGCGCTTAT SEQ ID NO: 125 (Chothia) HCDR1 GGCTACACCTTCACCACCTAC SEQ ID NO: 126 (Chothia) HCDR2 TATCCTGGCACCGGCGGC SEQ ID NO: 124 (Chothia) HCDR3 TGGACAACCGGCACAGGCGCTTAT VAR049-CLONE-S LC SEQ ID NO: 127 (Kabat) LCDR1 AAGTCCTCCCAGTCCCTGCTGGACTCCGGCAA CCAGAAGAACTTCCTGACC SEQ ID NO: 128 (Kabat) LCDR2 TGGGCCTCCACCCGGGAATCT SEQ ID NO: 129 (Kabat) LCDR3 CAGAACGACTACTCCTACCCCTACACC SEQ ID NO: 130 (Chothia) LCDR1 TCCCAGTCCCTGCTGGACTCCGGCAACCAGAA GAACTTC SEQ ID NO: 131 (Chothia) LCDR2 TGGGCCTCC SEQ ID NO: 132 (Chothia) LCDR3 GACTACTCCTACCCCTAC VAR049-clone-O HC

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SEQ ID NO: 122 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 144 (Kabat) HCDR2 AACATCTACCTGGCACCGGCGGCTCCAACTT C GAC GAGAAGT T CAAGAAC SEQ ID NO: 145 (Kabat) HCDR3 TGGACCACCGGAACCGGCGCCTAT SEQ ID NO: 125 (Chothia) HCDR1 GGCTACACCTTCACCACCTAC SEQ ID NO: 146 (Chothia) HCDR2 TACCCTGGCACCGGCGGC SEQ ID NO: 145 (Chothia) HCDR3 TGGACCACCGGAACCGGCGCCTAT VAR049-clone-O LC SEQ ID NO: 127 (Kabat) LCDR1 AAGTCCTCCCAGTCCCTGCTGGACTCCGGCAA CCAGAAGAACTTCCTGACC SEQ ID NO: 128 (Kabat) LCDR2 TGGGCCTCCACCCGGGAATCT SEQ ID NO: 129 (Kabat) LCDR3 CAGAACGACTACTCCTACCCCTACACC SEQ ID NO: 130 (Chothia) LCDR1 TCCCAGTCCCTGCTGGACTCCGGCAACCAGAA GAACTTC SEQ ID NO: 131 (Chothia) LCDR2 TGGGCCTCC SEQ ID NO: 132 (Chothia) LCDR3 GACTACTCCTACCCCTAC BAP049-clone-E HC SEQ ID NO: 133 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 134 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTT C GAC GAGAAGT T TAAGAAT SEQ ID NO: 135 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 136 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 137 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 135 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC VAR049-CLONE-E LC SEQ ID NO: 138 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAA TCAGAAGAACTTCCTGACC SEQ ID NO: 139 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 140 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 141 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAA GAACTTC SEQ ID NO: 142 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 143 (Chothia) LCDR3 GACTATAGCTACCCCTAC

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table 2

Amino acid and nucleotide sequences of heavy and light chain framework regions for humanized mAbs BAP049-hum01 - BAP049-hum16 and BAP049-clone-A - BAP049-clone-E

Amino acid sequences Nucleotide sequences VHFW1 EVQLVQSGAEVKKPGESLRISCKGS GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAA (type a) (SEQ ID NO: 147) AAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGG GTTCT (SEQ ID NO: 148) GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGG GCTCT (SEQ ID NO: 149) GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAA GAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAG GTTCA (SEQ ID NO: 150) VHFW1 (type b) QVQ LVQ S GAEVKK P GASVKVS C KAS (SEQ ID NO: 151) CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGG CTTCT (SEQ ID NO: 152) VHFW2 (type a) WVRQATGQGLEWMG (SEQ ID NO: 153) TGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTG GATGGGT (SEQ ID NO: 154) TGGGTGCGACAGGCTACCGGCCAGGGCCTGGAATG GATGGGC (SEQ ID NO: 155) TGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTG GATGGGT (SEQ ID NO: 156) VHFW2 (type b) WIRQSPSRGLEWLG (SEQ ID NO: 157) TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTG GCTGGGT (SEQ ID NO: 158) TGGATCCGGCAGTCCCCCTCTAGGGGCCTGGAATG GCTGGGC (SEQ ID NO: 159) VHFW2 (type c) WVRQAPGQGLEWMG (SEQ ID NO: 160) TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTG GATGGGT (SEQ ID NO: 161) VHFW3 (type a) RVTITADKSTSTAYMELSSLRSEDTA VYYCTR (SEQ ID NO: 162) AGAGT CAC GAT TAC C G C G GACAAATСCACGAGCAC AGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGG ACACGGCCGTGTATTACTGTACAAGA (SEQ ID NO: 163) AGAGT GAC CAT CAC C GC C GACAAGTCCASST CCAC CGCCTACATGGAACTGTCCTCCCTGAGATCCGAGG ACACCGCCGTGTACTACTGCACCCGG (SEQ ID NO: 164) AGAGTGACTATCACCGCCGATAAGTCTACTAGCAC CGCCTATATGGAACTGTCTAGCCTGAGATCAGAGG ACACCGCCGTCTACTACTGCACTAGG (SEQ ID NO: 165) VHFW3 (type b) RFTISRDNSKNTLYLQMNSLRAEDTA VYYCTR (SEQ ID NO: 166) AGAT T CAC CAT C T C CAGAGACAATT CCAAGAACAC GCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGG ACCAGGCCGTGTATTACTGTACAAGA (SEQ ID

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NO: 167) AGGTTCACCATCTCCCGGGACAACTCCAAGAACAC CCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGG ACACCGCCGTGTACTACTGTACCAGA (SEQ ID NO: 168) VHFW4 WGQGTTVTVSS (SEQ ID NO: 169) TGGGGCCAGGGCACCACCGTGACCGTGTCCTCC (SEQ ID NO: 170) TGGGGCCAGGGCACCACAGTGACCGTGTCCTCT (SEQ ID NO: 171) TGGGGTCAAGGCACTACCGTGACCGTGTCTAGC (SEQ ID NO: 172) TGGGGCCAGGGCACAACAGTGACCGTGTCCTCC (SEQ ID NO: 173) VLFW1 (type a) EIVLTQSPDFQSVTPKEKVTITC (SEQ ID NO: 174) GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGC (SEQ ID NO: 175) GAGATCGTGCTGACCCAGTCCCCCGACTTCCAGTC C GT GAC C C C CAAAGAAAAAGT GAC CAT CACAT GC (SEQ ID NO: 176) VLFW1 (type b) EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 177) GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTC TTTGTCTCCAGGGGAAAGAGCCACCTCTCCTGC (SEQ ID NO: 178) GAGATCGTGCTGACCCAGTCCCCTGCCACCCTGTC ACTGTCTCCAGGCGAGAGAGCTACCCTGTCCTGC (SEQ ID NO: 179) GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAG CCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGT (SEQ ID NO: 180) VLFW1 (type c) DIVMTQTPLSLPPVTPGEPASISC (SEQ ID NO: 181) GATATTGTGATGACCCAGACTCCACTCTCCCTGCC CGTCACCCCTGGAGAGCCGGCCTCCATCTCCCTGC (SEQ ID NO: 182) VLFW1 (type d) DWMTQSPLSLPVTLGQPASISC (SEQ ID NO: 183) GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCC CGTCACCCTTGGACAGCCGGCCTCCATCTCCCTGC (SEQ ID NO: 184) VLFW1 (type e) DIQMTQSPSSLSSASVGDRVTITC (SEQ ID NO: 185) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTC T GCAT CT GTAGGAGACAGAGT CACCATCACTT GC (SEQ ID NO: 186) VLFW2 (type a) WYQQKPGQAPRLLIY (SEQ ID NO: 187) TGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCT CCTCATCTAT (SEQ ID NO: 188) TGGTATCAGCAGAAGCCCGGCCAGGCCCCAGACT GCTGATCTAC (SEQ ID NO: 189) TGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGACT

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GCTGATCTAC (SEQ ID NO: 190) VLFW2 (type b) WYQQKPGKAPKLLIY (SEQ ID NO: 191) TGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCT CCTGATCTAT (SEQ ID NO: 192) TGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCT GCTGATCTAC (SEQ ID NO: 193) VLFW2 (type c) WYLQKPGQSPQLLIY (SEQ ID NO: 194) TGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCT CCTGATCTAT (SEQ ID NO: 195) VLFW3 (type a) GVPSRFSGSGSGTDFTFTISSLEAED AATYYC (SEQ ID NO: 196) GGGGTCCCTCGAGGTTCAGTGGCAGTGGATCTGG GACAGATTTCACCTTTACCATCAGTAGCCTGGAAG CTGAAGATGCTGCAACATATTACTGT (SEQ ID NO: 197) GGCGTGCCCTCTAGATTCTCCGGCTCCGGCTCTGG CACGACTTTACCTTCACCATCTCCAGCCTGGAAG CCGAGGACGCCGCCACCTACTACTGC (SEQ ID NO: 198) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGG CACCGACTTCACCTTCACTATCTCTAGCCTGGAAG CCGAGGACGCCGCTACCTACTACTGT (SEQ ID NO: 199) VLFW3 (type b) GIPPRFSGSGYGTDFTLTINNIESED AAYYFC (SEQ ID NO: 200) GGGATCCCACCTCGATTCAGTGGCAGCGGGTATGG AACAGATTTTACCCT CACAATTAATAACATAGAAT CTGAGGATGCTGCATATTACTTCTGT (SEQ ID NO: 201) VLFW3 (type c) GVPSRFSGSGSGTEFTLTISSLQPDD FATYYC (SEQ ID NO: 202) GGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGG GACAGAATTCACT CT CACCATCAGCAGCCT GCAGC CTGATGATTTTGCAACTTATTACTGT (SEQ ID NO: 203) GGCGTGCCCTCTAGATTCTCCGGCTCCGGCTCTGG CACCGAGTTTACCCTGACCATCTCCAGCCTGCAGC CCGACGACTTCGCCACCTACTACTGC (SEQ ID NO: 204) VLFW3 (type d) GVPSRFSGSGSGTDFTFTISSLQPED IATYYC (SEQ ID NO: 205) GGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGG GACAGATTTTACTTTCACCATCAGCAGCCTGCAGC CTGAAGATATTGCAACATATTACTGT (SEQ ID NO: 206) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGG CACCGACTTCACCTTCACTATCTCTAGCCTGCAGC CCGAGGATATCGCTACCTACTACTGT (SEQ ID NO: 207) VLFW4 FGQGTKVEIK (SEQ ID NO: 208) TTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 209) TTCGGCCAGGGCACCAAGGTGGAAATCAAG (SEQ ID NO: 210) TTCGGTCAAGGCACTAAGGTCGAGATTAAG (SEQ ID NO: 211)

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Table 3

Amino acid sequences of the constant region of human IgG heavy chains and human kappa light chain_______________________

ns L.C. NS NS NS IgG4 (S228P) mutant constant region amino acid sequence (EU numbering system) 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: 212) amino acid sequence of the human kappa chain constant region RTVAAPSVFI FPPSDEQLKS GTASWCLLN NFYPREAKVQ WKVflHKLQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC (SEQ ID NO : 213) IgG4 (S228P) mutant constant region amino acid sequence, C-terminal lysine (K) cross-linked (EU numbering system) 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: 214) 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: 215) IgGl (N297A) mutant constant region amino acid sequence (EU numbering system) 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: 216) NS IgGl (D265A, P329A) mutant constant region amino acid sequence (EU numbering system) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWAVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYR WSVLT VLHQDWLNGK EYKCKVSNKA LAAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 217) NS IgGl (L234A, L235A) mutant constant region amino acid sequence (EU numbering system) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYR WSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 218)

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Table 4

Amino acid sequences of heavy and light chain leader sequences for humanized mAbs BAP04 9-clone-A - BAP04 9-clone-E________

VAR049-clone-A NS MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 219) L.C. MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 220) VAR049-CLONE-V NS MAWVWTLPFLMAAAQSVQA (SEQ ID NO: 221) L.C. MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 222) VAR049-clone-S NS MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 219) L.C. MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 220) VAR04 E-clone-D NS MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 219) L.C. MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 220) VAR049-clone-E NS MAWVWTLPFLMAAAQSVQA (SEQ ID NO: 221) L.C. MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 222)

Table 5. See examples section.

Table 6. See examples section.

Table 7

Selected therapeutic agents that may be administered in combination with anti-PD-1 antibody molecules, for example, as a single agent, or in combination with other immunomodulators described in the invention. Each publication listed in this table is incorporated by reference in its entirety, including all structural formulas provided therein.

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A8 -VryO / ⁼ \ CT^NH ₂ \\ / ^F _F ^N \ x WO 2010/029082 A9 CYP17 inhibitor W0 2010/149755 US 8263635 B2 EP 2445903 Bl AY O )·ι|2 2-0 / \ / \ / I 0-2 '---f \---f ω '0 » v M 2~Ο o oh oh □Ξ T WO 2011/076786 All Deferasirox Exjade/EXJ ADE® ... O ΞΕ WO 1997/049395 A12 Letrozole Femara/FEMAR A® 0 ^z —\zy\_ US 4978672 A13 co I I o ° I °CD ^z ^0 Λ u- z=( z ZE ¹ WO 2013/124826 US 2013/0225574

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Al 4 CO T CO O T / OOO o ” 0N ⁼ O WO 2013/111105 Al 5 c* WO 2005/073224

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A2 9 Encorafenib ^Н з ^с γ Х\ _Н 0 СН ₃ 1 Ν^Ν СНз F \ , ^N ^\ Η V ^сн з X ν Qi сн ₃ d Cl WO 2011/025927 AZO Н ₃ с jQ^-з ΗΝ^ΝΓ'Ν ^ο ύ ό & Н ₃ с WO 2011/101409 A31 Human monoclonal anti-HER3 antibody WO 2012/022814 EP 2606070 US 8735551 AZ 2 Antibody conjugate - drug (ADC) WO 2014/160160 Ab: 12425 (see Table 1, paragraph [00191]) Linker: SMCC (see paragraph [00117] Payload: DM1 (see paragraph [00111] See also Claims, paragraph 29 AZZ Monoclonal antibody or Fab vs M-CSF WO 2004/045532 AZ 4 Binimetinib N NS) R .O F n I ί Υ Ύ JL \=N WO 2003/077914

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A4 5 НзС ^- \ N—у ^НзС viz NH N=< У Cl NH N=/ HnJ CH ₃ WO 2010/002655 A4 6 Valspodar Amdrey/AMDRA uTM CH ₃ CH ₃ J V-NH / H ₃ C-—\ / H ₃ C / ^HN N—' ^CH 3 \--“CH ₃ NH h ₃ cV CH ₃ \=== ^{0 H3C} \<^ ^NH _X H ₃ C^N Г сн ₃ 7==° y—«, H ₃ CI / H ₃ C / \__CH ₃ / ^c % >-4 / TN II / у ^Н зС 'VV Г ^СНз сн ₃ Н ₃ с- -у сн ₃ EP 296122 A4 7 Vatalanib succinate ΓΎι /uln Succinate WO 98/35958 A4 8 IDH inhibitor WO2014/141104 A4 9 BCR-ABL inhibitor WO2013/171639 WO2013/171640 WO2013/171641 WO2013/171642 A5 0 cRAF inhibitor WO2014/151616 A51 competitive inhibitor of ERK1/2 ATP PCT/US2014/062913

Examples

The following examples are provided to assist in understanding the present invention, but are not intended to be, and should not be construed as, any limitation on its scope.

Example 1: Humanization of BAP049, anti-PD-1 antibodies. The mouse anti-PD-1 monoclonal antibody BAP049 was humanized. Sequences and test samples of sixteen humanized BAP049 clones with unique variable region sequences were obtained. These clones were further analyzed for their biological functions (eg, antigen binding and ligand blocking), structural characteristics, and transient cellular expression

- 194 045940 kah SNO.

Example 1.1: technology and method of humanization.

Humanization of BAP049 was performed using a combinatorial library of human germline framework (FW) variable regions. The technology involves in-frame transfer of mouse CDR regions into a human variable region (VR) library that was constructed by randomly combining human germline sequences FW1, FW2 and FW3. Only one FW4 sequence was used, which was WGQGTTVTVSS (SEQ ID NO: 169) for the heavy chain (HC) (according to the Kabat system, human HC subgroup I, no. 21), and the sequence FGQGTKVEIK (SEQ ID NO: 208) for the light chain ( LC) (according to the Kabat system, human kappa chain, subgroup I, no. 5). The VR sequence library was fused to the human constant region (CR), heavy chain (HC) of human IgG4 (S228P) and human kappa chain CR light chain (LC) sequences, and the resulting full-length IgG library was expressed in CHO cells for screening. Screening was performed with tissue culture supernatants by measuring binding avidity on antigen-expressing cells in a whole-cell ELISA or FACS.

Humanization was carried out in a stepwise manner, starting with the construction and expression of a suitable chimeric mAb (mouse VR, IgG4 (S228P), human kappa chain), which can serve as a comparator for screening humanized clones. The amino acid sequences of the constant region of the human IgG4 heavy chain (S228P) and the human kappa light chain are shown in table. 3.

Humanization of VR from LC and NS was performed in two independent stages. A humanized LC (huLC) library was paired with a chimeric NS (mouse VR, IgG4 (S228P)) and the resulting semi-humanized mAbs were screened for binding activity by ELISA. huLC clones with adequate binding activity (> chimeric mAb binding) were selected. Similarly, a humanized HC (huHC) library was paired with a chimeric LC (mouse VR, human kappa chain) and screened for binding activity by ELISA. huHC clones with suitable binding activity ((> chimeric mAb binding) were selected.

The variable regions of the selected huLCs and huHCs were sequenced to identify huLCs and huHCs with unique sequences (some clones from the initial selection round may have the same LC or HC). The unique huLC and huHC were then randomly combined to generate a small library of humanized monoclonal antibodies (humAb) that were expressed in CHO cells and screened for antigen-expressing cells by ELISA and FACS. Clones with binding activity that was the same as or greater than the binding activity of the chimeric comparator mAb are the final humanization products.

Example 1.2: sequence of mouse mAb BAP049.

The LC and HC variable region sequences of the mouse anti-PD1 mAb were determined. The sequences obtained in two independent analyzes were identical, as shown in Fig. 1.

Germline analysis was performed and the result is shown in part in FIG. 2A as an amino acid sequence alignment. For the light chain, the V gene is 98.65% identical to mIGKV819*01F (293/297 nts) and the J gene is 97.30% identical to mIGKJ2*01F (36/37 nts). For the heavy chain, the V gene is 92.83% identical to mIGHV1S22*01F (259/279 nts), the J gene is 82.98% identical to mIGHJ3*01F (39/47 nts), and the D gene is mIGHD2-14 *01F. As shown in FIG. 2B, the LC sequence of the mouse mAb contains an unpaired Cys at position 102, which is located in CDRL3 and arises through a point mutation in the mouse J2 gene (tac^tgc; Y^C).

Example 1.3: Construction of a chimeric antibody.

Three variants of the chimeric antibody were produced that had a Cys, Tyr or Ser residue at position 102 of the LC sequence. Three chimeric antibodies, i.e. BAP049-chi (Cys), BAP049-chi (Tyr) and BAP049-chi (Ser) (also known as BAP049-chi, BAP049-chi-Y and BAP049-chi-S, respectively) were expressed in CHO cells and tested on their ability to compete with a labeled mouse antibody for binding to PD-1 in Jurkat-expressing cells. As shown in FIG. 3A-3B, the three variants were indistinguishable in the competition experiment. The results show that the three chimeric monoclonal antibodies (Cys, Tyr, Ser) compete equally well in binding to the labeled murine mAb BAP049. The slight difference between the chimeric mAb curves and the mouse mAb curves is likely due to the use of different methods for determining mAb concentration. The concentration of the mouse mAb was determined by measuring OD280, while the concentrations of the chimeric mAb in the supernatants were determined by ELISA using standard IgG4. For the humanized antibodies, the germline Tyr residue was selected.

The amino acid sequences of the heavy and light chains in the chimeric mAb BAP049-chi (Cys) are shown in Table. 1. The nucleotide sequences of the heavy and light chains in the chimeric mAb BAP049-chi (Cys) are shown in table. 1. In antibodies BAP049-chi (Tyr) and BAP049-chi (Ser) unpaired Cys

- 195 045940 the residue at position 102 LC was replaced by a Tyr or Ser residue.

Example 1.4: Humanized Antibody Clones.

As shown in FIG. 4, humanization resulted in sixteen clones with binding affinities comparable to those of the chimeric antibody. In addition to binding scores, VR sequences were provided for each clone along with the mAb sample. Samples were prepared by transient transfection of CHO cells and were tissue culture supernatants. Antibody concentrations in solutions were determined using IgG4-specific ELISA.

As shown in FIG. 5, the sixteen unique clones are combinations of four unique HC sequences and nine unique LC sequences. In the FW regions of the HC, the HC sequences are combinations of one of two different VHFW1, one of three different VHFW2, and one of two different VHFW3 sequences. In the LC FW regions, the LC sequences are combinations of one of five different VLFW1, one of three different VLFW2, and one of four different VLFW3 sequences. The amino acid sequences and nucleotide sequences of the heavy and light chain variable domains from the humanized BAP049 clones are shown in Table. 1. The amino acid and nucleotide sequences of the heavy and light chain CDR regions from the humanized BAP049 clones are also shown in Table. 1.

In fig. Figure 5 shows that samples vary in mAb concentration, ranging from 7.9 to 61.5 μg/ml. These numbers are representative of several transient expression experiments.

Example 1.5: Analysis of Humanized Clones.

Example 1.5.1: Analysis of binding activity and binding specificity.

Binding activity and specificity were measured in a competitive binding assay using a constant concentration of Alexa 488-labeled mouse mAbs, serial dilutions of test mAbs, and PD-1-expressing 300.19 cells. Incubation of mixtures of monoclonal antibodies having different concentration ratios of the tested mAb and labeled mAb was carried out at 4°C for 30 min. Bound labeled mouse mAb was then quantified using a FACS device. The experiment was repeated twice. The results are shown in Fig. 6A-6B.

Within the limits of experimental precision, all humanized clones show similar binding competition activity with the labeled murine mAb. This activity is also comparable to that of the parental murine mAb and the chimeric mAb. The MAbs were ranked in comparison to each other. For example, a clone may be a weaker competitor if in both experiments the curve of a particular clone is located to the right of the chimeric mAb curve, or it may be a stronger competitor if the curve of a particular clone is located to the left of the chimeric mAb curve. Such a ranking system is used in FIG. 7.

Example 1.5.2: Sequence Analysis.

Based on structural characteristics, sixteen humanized monoclonal antibodies were divided into four groups and ranked from A to E. The results are shown in FIG. 7.

Example 1.5.3: selection of humanized clones.

In fig. Table 7 shows the data that was taken into account when selecting humanized clones. Expression data (column 2), variability of variable regions in their composition (column 3), relative performance in binding assays (columns 4 and 5) and also structural analysis (column 6).

Selected clones were further tested for their ability to block PD-L1 and PD-L2 binding to PD-1 and enhance T cell activity in vitro in human PBMC assays.

Example 1.5.4: blocking ligand binding.

A mouse monoclonal antibody against PD-1 blocks the binding of the natural ligands PDL1 and PD-L2 to the PD-1 protein, which is expressed in low concentrations on cells. Comparative experiments were performed with mouse and chimeric antibodies to determine whether the humanized clones retained the ability to block the parental mouse mAb.

The blocking ability of the mAb was assessed in a competitive binding assay at a constant concentration of PD-L1 - huIgG1 Fc fusion protein or PD-L2 - huIgG1 Fc fusion protein, using serial dilutions of the test monoclonal antibodies and PD-1-expressing 300.19 cells. Incubation was carried out at 4°C for 30 min. Detection of ligand-bound fusion proteins was performed with a PE-conjugated F(ab') ₂ fragment of a goat anti-human IgG antibody that does not recognize IgG4 mAb (Southern Biotech 2043-09) and by flow cytometry. The results are shown in Fig. 8A-8B.

Within experimental limits, the humanized clones, chimeric antibodies, and mouse parental mAb exhibited comparable blocking activity against both PD-L1 and PD-L2 ligands.

Example 1.5.5: T cell epitope analysis.

Humanized monoclonal antibodies were analyzed for T cell epitopes using

- 196 045940 using the Epibase™ algorithm. This algorithm analyzes every possible peptide (every 10-mer along the length of the protein, moving forward by one amino acid) for binding to HLA class II. Epibase™ estimates the free energy of binding (bind) for each peptide and calculates the estimated KD ( ^AG bind= ^RT nKD). Peptides are then designated S, M, or N as strong (S), moderate (M), weak, or nonbinding (N). The thresholds used for this classification vary for each allotype.

Data were standardized to risk scores. The overall risk score is the sum of all potential epitopes for all alleles tested, weighted by the affinity of the corresponding peptides, discarding all potential epitopes in germline sequences (thus, lower is better).

There are approximately three categories of mAbs derived from a large group of monoclonal antibodies with different compositions, as described below.

Risk score approximately 500: fully human monoclonal antibodies derived from humans, humanized mice, and phage libraries (values below 500 are actually good even for fully humanized antibodies). Humanized mAbs are specifically designed (even the CDR regions) to have a low score, and are typically in the 500-700 risk category.

Risk score approximately 900: typical CDR-grafted antibodies that have fully murine CDR regions with or without changes in the FW region; this category mainly includes confirmed CDR-transplanted mAbs.

Risk score approximately 1500: chimeric monoclonal antibodies.

Results of selected humanized mAb BAP049:

The selected humanized clones have low scores. Typically, values below 500 indicate a low risk of immunogenicity, even for fully human antibodies. 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 lower than a typical CDR transplant mAb.

Conclusion and conclusions.

A mouse monoclonal antibody against PD-1, BAP049, is humanized. This technology involves cloning in-frame murine CDR regions into a sequenced library of human germline variable region frameworks, expressing the cloned variable region library in CHO cells as intact mAbs humanized IgG4 (S228P), and selecting clones that bind to a target with comparable or with higher affinity than the parent mAb. Thus, mouse CDR regions were tested to select suitable human germline framework sequences that retain their conformation and thus the binding affinity and specificity of the parental mouse mAb. Sixteen humanized monoclonal antibodies with unique variable region sequences were sequenced and tested and tested for binding to PD-1-transfected CHO cells. These clones were further analyzed for their biological functions (eg, antigen binding and ligand blocking), structural characteristics, and transient expression in CHO cells.

Example 2: Expression of BAP049, a humanized anti-PD-1 antibody.

Five humanized clones described in Example 1 were selected to evaluate expression in Chinese hamster ovary (CHO) cells.

Single gene vectors (SGVs) were constructed using Xceed Lonza GS vectors (IgG4pro ^m ' for the heavy chain and kappa for the light chain). SGVs were amplified and transiently cotransfected into CHOK1SV GS-KO cells for expression in a 2.8-L volume.

Expression cultures were harvested on day 6 posttransfection and clarified by centrifugation and sterile filtration. The clarified cell culture supernatant was purified by one-step protein A chromatography. Product quality analyzes by size exclusion high-performance liquid chromatography (SE-HPLC), polyac electrophoresis

- 197 045940 sodium dodecyl sulfate rilamide gel (SDS-PAGE), IEF and LAL procedures were performed using purified material at a concentration of 1 mg/ml, including antibodies as a control sample.

Example 2.1: vector construction.

The sequences of the coding regions of the light and heavy chain variable domains were synthesized using GeneArt AG. The light chain variable domain coding regions were subcloned into pXC-kappa, and the heavy chain variable domain coding regions were subcloned into pXC-IgG4proΔΚ vectors, respectively, using the N-terminal HindIII restriction site and the C-terminal BsiWI (light chain) and ApaI restriction sites ( heavy chain). Positive clones were screened by PCR amplification (primers 1053: GCTGACAGACTAACAGACTGTTCC (SEQ ID NO: 226) and 1072: CAAATGTGGTATGGCTGA (SEQ ID NO: 227)), and verified by restriction digestion (using EcoRI-HF and HindIII double digestion -HF) and nucleotide sequencing of the gene of interest.

Example 2.2: DNA amplification.

A single bacterial colony was picked into 15 ml of Luria Bertani (LB) medium (LB broth, Sigma-Aldrich, 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, 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 absorbance ratio A260/A280. The value was found to range from 1.88 to 1.90.

Example 2.3: Culture 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 shaking incubator at 36.5°C, 5% CO ₂ , 85% humidity, 140 rpm. Cells were routinely subcultured every 3-4 days at a concentration of 2 x 10 ⁵ cells/ml and expanded to ensure sufficient numbers of cells were available for transfection. Cells were discarded after 20 subcultures.

Example 2.4: transient transfections of CHOK1SV GS-KO cells.

Transient transfections were performed using CHOK1SV GS-KO cells, which were cultured for a minimum of two weeks. Cells were subcultured 24 h before transfection, and cell viability during transfection was 99%.

All transfections were performed by electroporation using the Gene Pulse MXCell Electroporation Plate System (Bio-Rad). For each transfection, viable cells were resuspended in prewarmed medium to a concentration of 2.86 x 10 ⁷ cells/ml. An aliquot of 80 μg of DNA (1:1 ratio of SGV heavy to light chains) and 700 μl of cell suspension was added to each cuvette/well. Cells were electroporated at 300 V, 1300 μF. Transfected cells were transferred in prewarmed medium in Erlenmeyer flasks and the cuvette/wells were washed twice with prewarmed medium, which was also transferred to the flasks. Transfected cell cultures were incubated in a shaking incubator at 36.5°C, 5% CO2, 85% humidity, 140 rpm for 6 days. Cell viability and viable cell concentrations were measured at the time of collection using a Cedex HiRes automated cell counter (Roche).

Example 2.5: Protein A affinity chromatography.

Cell culture supernatants were collected and clarified by centrifugation at 2000 rpm for 10 min and 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 ACT 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 loading the sample, the column was washed with 2 column volumes of equilibration buffer, followed by a 3-column wash with 50 mM sodium phosphate, 1 M sodium chloride, pH 7.0, and repeated the procedure with 2 column volumes of equilibration buffer. The product was then eluted with 10 mM sodium formate, pH 3.5 in a volume of 5 columns. Protein-containing eluted fractions were immediately adjusted to pH 7.2 and filtered through a 0.2-μm filter.

A single protein-containing peak was observed during the elution phase. This peak was determined to contain mAb by SE-HPLC and SDS-PAGE analysis. The yield of the reduced protein is shown in table. 5. Transient expression of the clones ranged from 32.4 to 43.0 mg/L.

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Table 5

Protein yield, titer, monomer content and endotoxin levels

Product Yield* (mg) Titer* (mg/l) Monomer content (%) Endotoxin levels (EU/mg) Clone A 107.5 38.38 93.94 0.04 Clone B 93.8 33.50 95.28 0.63 Clone C 90.7 32.38 97.83 0.04 Clone D 108.9 38.88 96, 53 0.35 Clone E 120.4 43.00 97.73 0.14 *After protein A purification

Example 2.6: SE-HPLC analysis.

Protein A-purified antibody samples were analyzed in two SE-HPLC assays on an Agilent 1200 series HPLC system using a Zorbax GF-250 4 μm 9.4 mm IDx250 mm column (Agilent). Before injection, aliquots of 1 mg/mL sample were filtered through a 0.2 μm filter. Accordingly, 80 μl aliquots were injected and run for 15 min at a rate of 1 ml/min. The level of soluble aggregates was analyzed using Chemstation software (Agilent).

Retention time chromatographic profiles were obtained showing the percentage of total peak area detected for test antibodies and control IgG4 antibodies. These products show a single protein peak at approximately 8.65 to 8.72 min, which is comparable to the control human IgG4 antibody (approximately 8.64 min) and consistent with the monomeric antibody. Small amounts (up to approximately 4-5%) of higher molecular weight impurities, consistent with soluble aggregates, were detected, with retention times ranging from approximately 7.43 to 8.08 min.

Example 2.1: SDS-PAGE analysis.

Reduced samples were prepared for analysis by mixing with NuPAGE 4xLDS Sample Buffer (Invitrogen, NP0007) and NuPAGEx10 Sample Reducing Agent (Invitrogen, NP0000), which were incubated at 70°C for 10 min. For unreduced samples, reducing agent and heat incubation were skipped. Samples were electrophoresed on 1.5 mm NuPAGE 4-12% Bis-Tris Novex precast gels (Invitrogen, NP0335PK2), with NuPAGE MES-SDS running buffer under denaturing conditions. A 10 μl aliquot of prestained SeeBlue Plus 2 standard molecular weight antibody (Invitrogen, LC5925) and a control IgG4 antibody at a concentration of 1 mg/ml were injected into 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. Stained gel images were analyzed on a Biospectrum imaging system (UVP).

The analysis confirmed the presence of antibody products and a good level of purity. Under non-reducing conditions, a predominant protein band close to 98 kDa was observed, comparable to the control IgG4 antibody. The control IgG4 antibody and one clone tested additionally exhibited a weaker band corresponding to the approximately 70 kDa heavy plus light chain half-antibody under non-reducing conditions. This is as expected for the control antibody. Two bands were observed under reducing conditions, consistent with the size of the heavy chains (close to the 49 kDa position of the marker) and light chains (close to the 28 kDa position of the marker) and comparable to the bands detected for the control IgG4 antibody.

Example 2.8: Isoelectric focusing (IEF) analysis.

Non-reducing samples of protein A-purified antibody are subjected to electrophoresis as described below.

μg of protein A - purified samples were subjected to electrophoresis on a 1.0 mM Novex pH 3-10 gradient gel (Invitrogen, EC66552BOX) using the manufacturers' recommended assay conditions. The gel was aliquoted with 10 μl of IEF markers, pH 3–10 (Invitrogen, 39212-01). After electrophoresis, the gels were fixed with 10% trichloroacetic acid for 30 min and then stained with InstantBlue dye (TripleRed, ISB01L) overnight at room temperature. Stained gel images were analyzed on a Biospectrum imaging system (UVP).

As shown in table. 6, the tested clones show charged isoforms at marker pH levels between 7.4 and 8.0. The detected charged isoforms had a slightly more basic response than the theoretically calculated pI level for these antibodies, which was predicted to range from 6.99 to 7.56. The general shift towards isoforms with more basic charge suggests the presence of post-translational modifications such as glycosylation on the molecules. Clone C and clone E show comparable isoform charges, which is also consistent with the theoretically calculated pI being the same for both clones (6.99). The IgG4 control antibody has the expected characteristics.

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Table 6

Charged isoforms identified by Novex IEF assay

Product pl preferential charge of isoforms* Acidic charged isoforms* Main charged isoforms* Clone A 7.6 2x; from 7.5 to 7.55 7.7 Clone B 7.75 2x; from 7.5 to 7.6 7.8 Clone C 7.5 2x; from 7.4 to 7.5 7.55 Clone D 8.0 7.9 8.1 Clone E 7.5 2x; from 7.4 to 7.5 7.55 *Evaluation of pl indicators based on colored positions with correlation in comparison with the IEF 3-10 marker

Example 2.9: Endotoxin assay.

Endotoxin levels of purified proteins were measured at final concentrations (up to 3.44 mg/ml) using the Endosafe-PTS, cartridge-based LAL assay method (Charles River).

As shown in table. 5, the endotoxin content was found to range from 0.04 to 0.63 EU/mg.

Conclusion.

Single gene GS expression vectors for selected humanized anti-PD-1 monoclonal antibodies were constructed and used for transient transfection of CHOK1SV GS-KO cells. A 2.6 to 2.8 L expression culture was incubated under standard conditions for 6 days, and the resulting cell culture supernatant was purified using protein A chromatography. Purification titers are shown in Table 1. 5, with a detected range from 32.38 to 43.0 mg/l. The yield under reducing conditions ranged from 90.7 to 120.4 mg.

SDS-PAGE and SE-HPLC analyzes indicated the presence of small amounts (up to 6.06%) of soluble aggregates in the products, largely consistent with dimeric antibody for the mAb. Monoclonal antibodies also exhibit higher molecular weight impurities with retention times consistent with trimeric antibodies.

Using isoelectric focusing, multiple charged isoforms were detected for all mAbs. Among the monoclonal antibodies, isoforms have been identified that are generally more basic in response than the theoretically calculated pI level for these molecules, suggesting the presence of post-translational modifications. The mAbs were found to have pI values comparable to their theoretically calculated pI values.

Endotoxin levels for all samples were measured before sample administration and were found to be below 0.63 EU/mg.

Example 3: Determination of properties of murine and humanized anti-PD-1 antibodies.

Example 3.1: determination of the properties of mouse antibodies against PD-1.

The PD-1 binding affinity of the mouse anti-PD-1 antibody, BAP049, was analyzed. The mouse anti-PD-1 antibody binds to the human PD-1-Ig fusion protein with a KD of 0.04 nmol as measured by ELISA. As shown in FACS analysis, mouse anti-PD-1 antibody binds to Jurkat cells transfected with human PD-1 with a KD of 0.06 nmol, to Cynomolgus monkey cells (eg, CD4 T cells activated by CD3/CD28) with a KD of 0 .4 nmol, and with cells transfected with cynomolgus monkey PD-1 with a KD of 0.6 nmol.

The blocking activity of the mouse anti-PD-1 antibody BAP049 was analyzed by competitive binding. Mouse anti-PD-1 antibody blocked PD-L1 binding to 300.19 cells expressing human PD-1 with an IC _{50 of} 0.3 nmol. This antibody blocked PD-L2 binding to 300.19 cells expressing human PD-1 with an IC _{50 of} 0.9 nmol.

The effect of the mouse anti-PD-1 antibody BAP049 on interferon-gamma (IFN-γ) expression was analyzed. Mouse anti-PD-1 antibody causes a 2.3±1.1-fold increase in IFN-γ expression on cells stimulated with anti-CD3 (0.1 μg/ml), a 2.5±2.0-fold increase in IFNγ expression on cells stimulated with staphylococcal enterotoxin B (SEB) (3 pg/ml), and a 2.8 ± 0.8 fold increase in IFN-γ expression compared to cells stimulated with CMV peptides.

The mouse anti-PD-1 antibody BAP049 was also found to increase the proliferation of CD8+ T cells stimulated with CMV peptides, as measured by the percentage of CD8+ cells that have undergone at least a certain number (n) of cell divisions (eg, n=2, 4 , 6).

Example 3.2: Determination of properties of a humanized anti-PD-1 antibody.

Binding affinity and specificity.

The binding of an exemplary humanized anti-PD-1 antibody to human PD-1 protein is measured by the Biacore method. Results: Ka=2.78x10 ⁵ M ^-1 s ^-1 ; Kd=2.13x10 ⁴ s ^-1 ; KD=0.0827±0.005505

- 200 045940 nmol.

Binding of the same humanized anti-PD-1 antibody to 300.19 cells expressing human PD-1 was measured by FACS analysis. The result shows that anti-PD-1 antibody (human IgG4) binds with high affinity to human PD-1 compared to the human IgG4 isotype control.

An exemplary humanized anti-PD-1 antibody was found to have high affinity for the cynomolgus monkey PD-1 protein and for 300.19 cells expressing cynomolgus monkey PD-1. According to the Biacore assay, anti-PD-1 antibody binds to cynomolgus monkey PD-1 with a KD of 0.093 ± 0.015 nmol. The binding affinity for cynomolgus monkey PD-1 is comparable to the binding affinity of the antibody for human PD-1.

Additional binding assays show that the exemplary humanized anti-PD-1 antibody does not have cross-reactivity with murine PD-1 or cross-reactivity with the parent cell line.

Blocking interactions between PD-1 and its ligands.

The ability of an exemplary humanized anti-PD-1 antibody to block the interaction between PD-1 and both of its known ligands, PD-L1 and PD-L2, was studied. Results show that anti-PD-1 antibody blocks PD-L1 and PD-L2 binding to 300.19 cells expressing human PD-1 compared to human IgG4 isotype control and no antibody control. Anti-PD-1 antibody blocks PD-L1 binding on 300.19 cells with an IC ₅₀ of 0.94 ± 0.15 nmol. The same antibody blocks PD-L2 binding on 300.19 cells with an IC ₅₀ of 1.3 ± 0.25 nmol.

Cellular activity.

The ability of an exemplary humanized anti-PD-1 antibody to increase staphylococcal enterotoxin B (SEB)-stimulated IL-2 expression was examined in an ex vivo human whole blood assay. Diluted human whole blood was incubated with anti-PD-1 antibody in the presence or absence of SEB at 37°C for 48 h before IL-2 measurement. The result shows that anti-PD-1 antibody increases SEB-stimulated IL-2 expression by 2.28 ± 0.32-fold compared to human IgG4 isotype control (SEB 25 μg/ml; n = 5 donors).

Example 4: Patient selection based on PD-L1/CD8/IFN-Y status.

Samples from multiple patients for each of several cancer types were tested for PD-L1/CD8/IFN-Y status. Each sample was classified into the following groups: triple negative phenotype for PD-L1/CD8/IFN-Y, single or double positive phenotype for the specified markers, or triple positive phenotype for the specified markers. In fig. Figure 11 shows that in the patient population in this experiment, the following types of cancer often exhibit a triple positive phenotype for PD-L1/CD8/IFN-Y: lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer uterine (squamous cell), stomach cancer, thyroid cancer, melanoma and nasopharyngeal cancer. Patients with these cancers are good candidates for treatment with anti-PD-1 antibodies and combination therapeutic agents as described in the present invention. The likelihood of successful treatment may be further increased by identifying patients with a triple positive phenotype for PD-L1/CD8/IFN-y, and treating patients with a triple positive phenotype with anti-PD-1 antibodies and combination therapeutics according to the invention.

In fig. 12 shows that in the patient population, the following types of cancer rarely exhibit a triple positive phenotype for PD-L1/CD8/IFN-y: ER+ breast cancer and pancreatic cancer. Notably, even in cancers that are not typically PD-L1/CD8/IFN-Y positive, the likelihood of successful treatment can be increased by identifying a subset of patients with a PD-L1/CD8/IFN-Y triple positive phenotype, and treat patients with a triple positive phenotype with anti-PD-1 antibody and combination therapeutic agents according to the invention.

In fig. Figure 13 shows the proportion of breast cancer patients who have a triple positive phenotype for PD-L1/CD8/IFN-Y. Considering breast cancer as a whole, one can note a fairly low number of triple positive phenotypes. However, when focusing only on IM-TN breast cancer, a much larger percentage of patients have a triple positive PD-L1/CD8/IFN-Y phenotype. IM-TN breast cancer is particularly difficult to treat with conventional therapeutic agents. The discovery that IM-TN breast cancer is often triple positive for PD-L1/CD8/IFN-y opens up new possibilities for treating this cancer with anti-PD-1 antibody and combination therapeutics according to the invention.

In fig. Figure 14 shows the proportion of colon cancer patients who have a triple positive phenotype for PD-L1/CD8/IFN-Y. It has been noted that, in general, colon cancer has a fairly low percentage of the triple positive phenotype. However, if we focus only on high MSI (high microsatellite instability) breast cancers, we see that much

- 201 045940 a higher percentage of patients have a triple positive phenotype for PD-L1/CD8/IFN-Y. MSI levels can be analyzed using, for example, commercially available PCR-based methods.

Gastric cancer samples were tested for PD-L1/CD8/IFN-Y levels (data not shown). In high MSI or EBV+ gastric cancers, approximately 49% of samples were found to be PD-L1 positive, and a high proportion of PD-L1 positive cells had a triple positive PD-Ll/CD8/IFN-Y phenotype. It was also found that a proportion of PD-L1-positive cells and PD-L1/CD8/IFN-Y positive cells are also PIK3CA positive. These data suggest that these cancers can be treated with anti-PD-1 antibody, not necessarily in combination with PIK3 treatment.

Colorectal cancer (CRC) samples with high MSI were tested for a combination of markers (data not shown). In CRC samples with high MSI, a higher proportion of PDL1/CD8/IFN-Y samples were found to also be positive for LAG-3, PD-1 (also called PDCD1), RNF43, and BRAF. The findings suggest that these cancers can be treated with an anti-PD-1 antibody, optionally in combination with a therapeutic agent that targets one or more of LAG-3, PDCD1, RNF43 and BRAF.

Samples from squamous cell lung cancer were tested for a combination of markers (data not shown). In squamous cell lung cancer specimens, a large proportion of PDL1/CD8/IFN-Y specimens were found to also be LAG-3 positive. The findings suggest that these cancers can be treated with an anti-PD-1 antibody, optionally in combination with a therapeutic agent targeting LAG-3, such as an anti-LAG-3 antibody.

Papillary thyroid cancer samples were tested for a combination of markers including BRAF V600E mutations (data not shown). It was found that a high proportion of thyroid cancer samples that are positive for PD-L1 are also positive for BRAF V600E. The findings suggest that these cancers can be treated with an anti-PD-1 antibody, not necessarily in combination with a BRAF-targeting therapeutic.

Example 5: Patient selection based on PD-L1 status.

To enable broad examination of cancer treatment indications with PD-1/PD-L1-based therapeutics, we assessed PD-L1 expression at the protein level and mRNA level in human malignancies including lung and liver tumors.

PD-L1 protein expression was assessed in immunohistochemistry (IHC) analysis of a set of formalin-fixed, paraffin-embedded tumor specimens from non-small cell lung cancer (NSCLC)-adenocarcinoma (ACA), NSCLC squamous cell carcinoma (SCC), and hepatocellular carcinoma (HCC). PD-L1 expression was assessed semiquantitatively using a manual histological scoring technique (H-score) based on staining intensity and the percentage of positive tumor cells. In the IHC analysis of the invention, PD-L1 positivity (PD-L1+) was defined as a histological score of 20. In parallel, PD-L1 mRNA expression data were examined in The Cancer Genome Atlas (TCGA) for the same indications (503 NSCLC ACA, 489 NSCLC SCC and 191 NCC) and analyzed by comparing expression in related normal tissues from the TCGA Atlas.

RNA sequencing analysis calculated data as log2 (RPKM+0.1) after RSEM standardization using OmicSoft RNASeq RNA sequencing information from the TCGA Atlas of tumor properties. PD-L1 expression is increased in NSCLC ACA and SCC, relative to expression in NCC. By overlaying distributions and comparing expression levels across all properties from TCGA, the authors assessed overexpression profiles for PD-L1 and found that the HCC cohort from TCGA had significantly reduced mRNA levels from PD-L1, with a median of -0.8 compared to a median of 1. 3 in ACA and 1.5 in SCC, representing more than a 2-fold change in median expression level. From RNA sequencing analysis, the authors determined that 50% of NSCLC adenocarcinomas, 54% of NSCLC squamous cell carcinomas, and 6% of hepatocellular carcinomas had high expression of PD-L1.

PD-L1 protein expression by tumor cells was measured in 45 lung adenocarcinoma (ACA), 47 lung squamous cell carcinoma (SCC) samples, and 36 hepatocellular carcinoma (HCC) samples. 16/45 (35.6%) lung ACAs, 21/47 (44.7%) lung SCCs were positive for PD-L1. In contrast, PD-L1 positivity was detected in only 2/36 (5.6%) NCC samples.

In summary, using immunohistochemistry (IHC) and RNA sequencing in large and independent sets of human NSCLC and NCC samples, the authors found that PD-L1 expression is more abundant in NSCLC than in HCC. NSCLC showed comparable results between adenocarcinoma and squamous cell carcinomas. It is important to note that among the large number of samples (128 in the IHC analysis and 1183 in the RNA-seq analysis), in 3 cases there was very good agreement between the analysis at the protein level and the analysis at the mRNA level. Thus, the findings may form the basis for large-scale mRNA mining in TCGA regarding indications and patient groups in which it is possible to enhance

- 202 045940 reactions to PD-1/PD-L1 based immune therapeutics.

Example 6: Effect of targeted drugs on PD-L1 modulation.

In this example, the effects of selected therapeutics (such as cMET inhibitor, MEK inhibitor, bRAF inhibitor and ALK inhibitor) on PD-L1 (CD274) modulation were assessed. Compound A17 can be prepared as described in Example 21 of US Pat. No. 8,420,645. The following compounds: Compound A18 (ruxolitinib phosphate), Compound A23 (ceritinib), Compound A34 (Binimetinib) and Compound A29 (Encorafenib) were obtained from Novartis AG. Basel, Switzerland. Selected therapeutics were analyzed by real-time PCR and flow cytometry at the PD-L1 level. Significant inhibition of PD-L1 by compound A17, compound A18, compound A34, compound A29 and compound A23 on tumor cells was observed.

Down-regulation of PD-L1 protein by compound A17 in non-small cell lung cancer cells.

The expression of PD-L1 (CD274) was analyzed in cancer cell lines treated with compound A17. Cells were obtained from ATCC and cultured in vitro according to ATCC instructions. The properties of the cell lines used have been described previously, see Cancer Cell Line Encyclopedia Project (http://www.broadinstitute.org/ccle/home).

Cells were seeded in six-well culture plates and treated with compound A17 at various concentrations (10 nmol, 100 nmol and 1000 nmol) for 24, 48 and 72 h. An equal amount of vehicle (dimethyl sulfoxide, DMSO) was used as a control. The cells were washed with phosphate-buffered saline and then collected using a cell scraper.

For each reaction, 0.5-1 x 10 ⁶ cells were stained with 20 μl of monoclonal PE antibody against human PD-L1, clone M1H1 (BD) for 30-60 min at 4°C. Cells were washed twice. Data were acquired using Canto II with FACSDiva software (BD Bioscience). Data analysis was performed using FlowJo software (Tree Star). Mean fluorescence intensity (MFI) was determined by gating on individual cells. Unstained cells were used as gating controls.

In vitro treatment of EBC-1 cells (non-small cell lung cancer (NSCLC) cells with cMET amplification) with compound A17 resulted in a significant down-regulation of PD-L1 surface expression as detected by flow cytometry (FIG. 15). According to the results presented in the invention, it is assumed that compound A17 acts as an inhibitor of PD-L1/PD-1.

Compound A17, compound A34, compound A18, compound A29 and compound A23 suppress PD-L1 mRNA.

TaqMan-PCR assays were developed to detect changes in PD-L1 (CD274) expression levels in cell lines and tumor xenografts. mRNA was isolated from frozen cell beads or tumor fragments using the Qiagen RNeasy Mini Kit. The isolated RNA was frozen at -80°C. After checking the RNA quality, RNA was quantified using the 2100 Agilent Bioanalyzer according to the Agilent RNA 6000 Nano Kit protocol. cDNA was prepared using the High Capacity RNA-to cDNA Kit (Applied Biosystems Kit).

Real-time PCR reactions were performed in a 20-μl total volume containing 10 μl Universal PCR master mix (Applied Biosystems), 1 μl human PD-L1 (CD274) probe/primer set (Applied Biosystems), and 8 μl cDNA. Each sample was reacted three times. The amount of cDNA obtained from 25–50 ng of RNA in the reverse transcription reaction was used in each PCR reaction. Due to the difference in mRNA levels between PD-L1 and GAPDH, two real-time PCR reactions were performed in separate tubes using the same amount of cDNA. Real-time PCR reactions were performed on a C1000 Thermal Cycle (BioRad) with the following thermal cycle program: 10 min incubation at 95°C, followed by 40 cycles at 95°C for 15 s and 60°C for 1 min . After reaction completion, the mean PD-L1 Ct value was standardized to each Ct value from the GAPDH reference reaction. Each standardized logarithmic value is then converted to a linear value.

Suppression of PD-L1 (mRNA) expression by compound A17 was observed in a tumor cell xenograft Hs.746.T (gastric cancer cells with amplification and c-MET mutations) (Fig. 16). Inhibition of PD-L1 mRNA by compound A23 was observed in vitro in H3122 (non-small cell lung cancer (NSCLC) with ALK translocation) (Fig. 17). Inhibition of PD-L1 mRNA by compound A29 and compound A34 was observed in tumor xenograft models bearing LOXIMV1 (BRAF-mutant melanoma, Fig. 18) and HEYA8 (KRAF-mutant ovarian cancer, Fig. 19) tumors, respectively. Inhibition of PD-L1 mRNA by compound A18 was observed in tumor xenograft models harboring UKE-1 (myeloproliferative neoplasm (MPN) cell line with JAK2V617F mutation, Fig. 20).

The results presented in the invention demonstrate the role of compound A17, compound A34, compound A18, compound A29 and compound A23 in the regulation of immune checkpoint molecules in cancer. The observed inhibition of PD-L1 expression by these compounds suggests that these targeted agents may have immunomodulatory effects.

- 203 045940 fects, in addition to their effects on the cancer signaling pathway. Thus, the results presented in the invention show that by administering targeted substances with inhibitors of immune checkpoint inhibitors such as PD-1, PD-L1, LAG-3 and/or TIM-3, a more potent reversal of immunosuppression will be achieved, mediated point of immune control.

Incorporation by reference

All publications, patents and accession numbers mentioned in the invention are incorporated by reference in their entirety as if each individual publication or patent were specifically and separately identified as being incorporated by reference.

Equivalents

Specific embodiments of the present invention have been discussed, but the above description is intended to be illustrative and not limiting. Many embodiments of the invention will become apparent to those skilled in the art upon consideration of this specification and the following claims. The full scope of the invention is to be determined by the claims, together with the full scope of their equivalents, and the description, along with such variations.

Claims (56)

1. An antibody molecule capable of binding to human programmed death protein-1 (PD-1), containing: (a) a heavy chain variable region (VH) containing: V HCDR1 with amino acid sequence SEQ ID NO: 4; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia; (b) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 1; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; numbering corresponds to the definition of CDR according to Kabat; (c) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat; or (d) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; The numbering corresponds to the definition of CDR according to Kabat, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat. 2. The antibody molecule according to claim 1, wherein the antibody molecule is a monospecific antibody molecule. 3. A bispecific antibody molecule capable of binding to human programmed death protein 1 (PD-1), containing: - 204 045940 (a) a heavy chain variable region (VH) containing: V HCDR1 with amino acid sequence SEQ ID NO: 4; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33, according to Hotia; (b) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 1; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32, according to Kabat; (c) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat; or (d) VH containing: VHCDR1 with amino acid sequence SEQ ID NO: 224; amino acid sequence VHCDR2 SEQ ID NO: 2; And VHCDR3 with amino acid sequence SEQ ID NO: 3; And VL containing: VLC DR1 with amino acid sequence SEQ ID NO: 10; VLC DR2 with amino acid sequence SEQ ID NO: 11; And VLC DR3 with amino acid sequence SEQ ID NO: 32; The numbering corresponds to the definition of CDR according to Kabat, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat. 4. The antibody molecule according to any one of claims 1 to 3, wherein said antibody molecule is a humanized antibody molecule. 5. Antibody molecule according to any one of claims 1-4, in which: VH contains at least one, two, three or four framework regions (FW) containing any amino acid sequence of SEQ ID NO: 147, 151, 153, 157, 160, 162, 166 or 169, or an amino acid sequence that is at least is 90% identical to, or has no more than two amino acid substitutions, insertions or deletions with, any amino acid sequence of SEQ ID NO: 147, 151, 153, 157, 160, 162, 166 or 169; and/or VL contains at least one, two, three or four framework regions containing any amino acid sequence of SEQ ID NO: 174, 177, 181, 183, 185, 187, 191, 194, 196, 200, 202, 205 or 208, or an amino acid sequence that is at least 90% identical to, or has no more than two amino acid substitutions, insertions or deletions with, any amino acid sequence of SEQ ID NO: 174, 177, 181, 183, 185, 187, 191, 194, 196, 200, 202, 205 or 208. 6. Antibody molecule according to any one of claims 1-5, which contains: VH containing the amino acid sequence of SEQ ID NO: 38, 50, 82 or 86, or an amino acid sequence that is at least 85% identical to any of SEQ ID NO: 38, 50, 82 or 86; and/or VL containing the amino acid sequence of SEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74 or 78, or an amino acid sequence that is at least 85% identical to any of SEQ ID NO: 42, 46, 54 , 58, 62, 66, 70, 74 or 78. 7. Antibody molecule according to any one of claims 1-6, which contains: VH containing an amino acid sequence selected from SEQ ID NO: 38; SEQ ID NO: 50, SEQ ID NO: 82 or SEQ ID NO: 86; and/or VL containing an amino acid sequence selected from SEQ ID NO: 42, SEQ ID NO: 46, SEQ ID NO: 54; SEQ ID NO: 58; SEQ ID NO: 62; SEQ ID NO: 66; SEQ ID NO: 70; SEQ ID NO: 74 or SEQ ID NO: 78. - 205 045940 8. Antibody molecule according to any one of claims 1-6, which contains: a heavy chain comprising an amino acid sequence selected from SEQ ID NO: 40, SEQ ID NO: 91, SEQ ID NO: 52, SEQ ID NO: 102, SEQ ID NO: 84, or SEQ ID NO: 88; and/or a light chain containing an amino acid sequence selected from SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 56, SEQ ID NO: 60, SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 76 or SEQ ID NO: 80. 9. Antibody molecule according to any one of claims 1-6, which contains: (a) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 42; (b) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 66; (c) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 70; (d) VH containing the amino acid sequence of SEQ ID NO: 50, and VL containing the amino acid sequence of SEQ ID NO: 70; (e) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 46; (f) VH containing the amino acid sequence of SEQ ID NO: 50, and VL containing the amino acid sequence of SEQ ID NO: 46; (g) VH containing the amino acid sequence of SEQ ID NO: 50, and VL containing the amino acid sequence of SEQ ID NO: 54; (h) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 54; (i) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 58; (j) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 62; (k) VH containing the amino acid sequence of SEQ ID NO: 50, and VL containing the amino acid sequence of SEQ ID NO: 66; (l) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 74; (m) VH containing the amino acid sequence of SEQ ID NO: 38, and VL containing the amino acid sequence of SEQ ID NO: 78; (n) VH containing the amino acid sequence of SEQ ID NO: 82, and VL containing the amino acid sequence of SEQ ID NO: 70; (o) VH containing the amino acid sequence of SEQ ID NO: 82, and VL containing the amino acid sequence of SEQ ID NO: 66; or (p) VH containing the amino acid sequence of SEQ ID NO: 86, and VL containing the amino acid sequence of SEQ ID NO: 66. 10. Antibody molecule according to any one of claims 1 to 9, which contains: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 91, and a light chain containing the amino acid sequence of SEQ ID NO: 44; (b) a heavy chain containing the amino acid sequence of SEQ ID NO: 91, and a light chain containing the amino acid sequence of SEQ ID NO: 56; (c) a heavy chain containing the amino acid sequence of SEQ ID NO: 91, and a light chain containing the amino acid sequence of SEQ ID NO: 68; (d) a heavy chain containing the amino acid sequence of SEQ ID NO: 91, and a light chain containing the amino acid sequence of SEQ ID NO: 72; (e) a heavy chain containing the amino acid sequence of SEQ ID NO: 102, and a light chain containing the amino acid sequence of SEQ ID NO: 72; (f) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 44; (g) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 48; (h) a heavy chain containing the amino acid sequence of SEQ ID NO: 52, and a light chain containing the amino acid sequence of SEQ ID NO: 48; (i) a heavy chain containing the amino acid sequence of SEQ ID NO: 52, and a light chain containing the amino acid sequence of SEQ ID NO: 56; (j) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 56; (k) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 60; - 206 045940 (l) a heavy chain containing the amino acid sequence SEQ ID NO: 40, and a light chain containing the amino acid sequence SEQ ID NO: 64; (m) a heavy chain containing the amino acid sequence of SEQ ID NO: 52, and a light chain containing the amino acid sequence of SEQ ID NO: 68; (n) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 68; (o) a heavy chain containing the amino acid sequence of SEQ ID NO: 52, and a light chain containing the amino acid sequence of SEQ ID NO: 72; (p) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 72; (q) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 76; (r) a heavy chain containing the amino acid sequence of SEQ ID NO: 40, and a light chain containing the amino acid sequence of SEQ ID NO: 80; (s) a heavy chain containing the amino acid sequence of SEQ ID NO: 84, and a light chain containing the amino acid sequence of SEQ ID NO: 72; (t) a heavy chain containing the amino acid sequence of SEQ ID NO: 84, and a light chain containing the amino acid sequence of SEQ ID NO: 68; or (u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain containing the amino acid sequence of SEQ ID NO: 68. 11. The antibody molecule according to any one of claims 1 to 10, which is a monoclonal antibody, Fab, F(ab') ₂ , Fv or single chain Fv fragment (scFv); or contains: a heavy chain constant region selected from IgG1, IgG2, IgG3 or IgG4; and/or a light chain constant region selected from the kappa or lambda light chain constant regions. 12. Antibody molecule according to claim 11, which contains: (a) a human IgG4 heavy chain constant region with a mutation at position 228 according to EC numbering or at position 108 of SEQ ID NO: 212 or 214, and a kappa light chain constant region; (b) a human IgG4 heavy chain constant region with a serine to proline mutation at position 228 according to EC numbering or at position 108 of SEQ ID NO: 212 or 214, and a kappa light chain constant region; (c) a human IgG1 heavy chain constant region with an asparagine to alanine mutation at position 297 according to EC numbering or at position 180 of SEQ ID NO: 216 and a kappa light chain constant region; (d) a human IgG1 heavy chain constant region with an aspartate to alanine mutation at position 265 in accordance with EC numbering or at position 148 of SEQ ID NO: 217 and with a proline to alanine mutation at position 329 in accordance with EC numbering or at position 212 of SEQ ID NO: 217, and kappa light chain constant region; or (e) a human IgG1 heavy chain constant region with a leucine to alanine mutation at position 234 in accordance with EC numbering or at position 117 of SEQ ID NO: 218 and with a leucine to alanine mutation at position 235 in accordance with EC numbering or at position 118 SEQ ID NO: 218, and a kappa light chain constant region. 13. Antibody molecule according to any one of claims 1 to 12, which: (a) is capable of binding to human PD-1 with a dissociation constant (K _D ) that is lower than approximately 0.2 nM; (b) binds to the extracellular Ig-like domain of PD-1; (c) is capable of reducing the binding of PD-1 to PD-L1, PD-L2, or both of these ligands, or to a cell expressing PD-L1, PD-L2, or both of these ligands; and/or (d) is capable of enhancing antigen-specific T-cell responses. 14. The antibody molecule according to any one of claims 3 to 13, which has a first binding specificity for PD-1 and a second binding specificity for TIM-3, LAG-3, SEACAM-1, SEACAM-5, PD-L1 or PD-L2 . 15. The antibody molecule according to any one of claims 1 to 14, wherein said antibody molecule comprises an antigen binding fragment of an antibody, a semi-antibody or an antigen binding fragment of a semi-antibody. 16. A pharmaceutical composition for stimulating an immune response or treating a malignancy or infectious disease in an individual, comprising an antibody molecule according to any one of claims 1 to 15, and a pharmaceutically acceptable carrier, excipient or stabilizer. 17. An isolated nucleic acid molecule encoding an antibody molecule according to any one of claims 1 to 15. 18. Nucleic acid according to claim 17, containing: a nucleotide sequence encoding a VH, wherein the nucleotide sequence contains SEQ ID NO: 39, 51, 83, 87, 90, 95 or 101 or is at least 85% identical to any SEQ ID - 207 045940 NO: 39, 51, 83, 87, 90, 95 or 101; and/or a nucleotide sequence encoding VL, wherein the nucleotide sequence contains SEQ ID NO: 43, 47, 55, 59, 63, 67, 71, 75, 79, 93, 97, 99, 104 or 106 or at least 85 % identical to any SEQ ID NO: 43, 47, 55, 59, 63, 67, 71, 75, 79, 93, 97, 99, 104 or 106. 19. Nucleic acid according to claim 18, containing: a nucleotide sequence encoding a heavy chain, wherein the nucleotide sequence contains SEQ ID NO: 41, 53, 85, 89, 92, 96 or 103 or is at least 85% identical to any SEQ ID NO: 41, 53, 85, 89, 92 , 96 or 103; and/or a nucleotide sequence encoding a light chain, wherein the nucleotide sequence comprises SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105 or 107 or at least 85% identical to any SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105 or 107. 20. An expression vector containing a nucleic acid molecule according to any one of claims 17-19. 21. A host cell producing an antibody molecule or an antigen-binding fragment thereof, comprising a nucleic acid molecule according to any one of claims 17 to 19. 22. A method for producing an antibody molecule or an antigen-binding fragment thereof, comprising culturing the host cell of claim 21 under conditions suitable for gene expression. 23. A method for detecting PD-1 in a biological sample, including: (i) contacting the sample or individual with the antibody molecule of any one of claims 1 to 15 under conditions that allow the antibody molecule and the PD-1 polypeptide to interact; and (ii) detecting the formation of a complex between the antibody molecule and the sample or individual. 24. The method according to claim 23, additionally including: (iii) contacting the reference sample or individual with the antibody molecule of any one of claims 1 to 15 under conditions such that the antibody molecule and the PD-1 polypeptide interact; and (iv) detecting the formation of a complex between the antibody molecule and a reference sample or individual. 25. Use of an antibody molecule according to any one of claims 1 to 15 for stimulating an immune response in an individual. 26. Use according to claim 25, wherein the stimulation of an immune response is for the treatment of cancer in an individual. 27. Use according to claim 25, wherein the stimulation of an immune response is intended to treat an infectious disease in an individual. 28. Use according to claim 26, wherein the malignancy is selected from solid tumor, lung cancer, melanoma, kidney cancer, liver cancer, prostate cancer, breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, thyroid cancer, cancer brain, uterine cancer, nasopharyngeal cancer, head and neck cancer, ovarian cancer, endometrial cancer, endocrine cancer, or hematologic malignancy or cancer metastasis. 29. Application according to claim 28, where: (a) the lung cancer is selected from non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung carcinoma or small cell lung cancer, optionally wherein the NSCLC contains a KRAS mutation; (b) the melanoma is selected from advanced melanoma, unresectable melanoma, metastatic melanoma, BRAF-mutant melanoma, NRAS-mutant melanoma, cutaneous melanoma, or intraocular melanoma; (c) the kidney cancer is selected from renal cell carcinoma (RCC), metastatic renal cell carcinoma, or clear cell renal cell carcinoma (CCRCC); (d) the hematological neoplasm is selected from lymphoma, myeloma or leukemia; (e) the brain cancer is glioblastoma; (f) the breast cancer is triple negative breast cancer; (g) the liver cancer is hepatocellular carcinoma; or (h) the cancer is a high MSI (high microsatellite instability) cancer. 30. Use according to any one of claims 25 to 29, which is carried out in combination with a second therapeutic agent, where the second therapeutic agent is selected from one or more of the following: a chemotherapeutic agent, a targeted antitumor therapy, an oncolytic drug, a cytotoxic agent, an immunotherapeutic agent, a cytokine, a costimulatory molecule activator, an inhibitory molecule inhibitor, a vaccine, or a cellular immunotherapy. 31. Application according to claim 30, which is carried out in combination with: (a) a costimulatory molecule agonist selected from 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 checkpoint molecule inhibitor selected from one or more of PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, SEACAM-1, SEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, - 208 045940 2B4 or TGFR. 32. Use according to any one of claims 25 to 31, which is carried out in combination with one or more of the following: (a) a LAG-3 inhibitor; (b) a TIM-3 inhibitor; (c) a PD-L1 inhibitor; (d) a GITR agonist; (e) interleukin; (f) a MEK inhibitor; or (g) an FGFR inhibitor, for example, for the treatment of hepatocellular carcinoma. 33. Application according to claim 32, where: (a) a LAG-3 inhibitor is an antibody molecule against LAG-3, for example, for the treatment of NSCLC, melanoma, RCC or hematological malignancy; (b) a TIM-3 inhibitor is an antibody molecule against TIM-3, for example, for the treatment of melanoma or RCC; (c) the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, or selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-OO1O718C or MDX-1105, for example, for the treatment of thyroid cancer, NSCLC, triple negative breast cancer, uterine cancer or lymphoma; (d) a GITR agonist is an anti-GITR antibody molecule or fusion protein, for example, for the treatment of NSCLC; (e) the interleukin is IL-15, for example, for the treatment of a solid tumor; or (f) a MEK inhibitor selected from ARRY-142886, G02442104 (GSK1120212), RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (AZD-6244 or selumetinib), BIX 02188, BIX 02189, CI-1040 (PD18 4352), PD0325901, PD98059, U0126, GDC-0973 (Methanonyl [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl] [3-hydroxy-3-(25)-2-piperidinyl-1-azetidinyl ] -), G-3 8963, G02443714 (AS703206) or a pharmaceutically acceptable salt or solvate thereof, for example, for the treatment of triple negative breast cancer, NSCLC or colorectal cancer. 34. Use according to any one of claims 25 to 33, which is carried out in combination with one or more of the following: (a) chemotherapy for the treatment of lung cancer; (b) an indoleamine pyrrole 2,3 dioxygenase (IDO) inhibitor for the treatment of lung cancer; (c) a CTLA-4 inhibitor for the treatment of lung cancer or melanoma; (d) an anti-cancer vaccine; (e) with one or more of the following: an immunotherapy, a targeted agent, a VEGF tyrosine kinase inhibitor, an RNA interference inhibitor, or an inhibitor of a downstream VEGF signaling pathway, for the treatment of kidney cancer. 35. Application according to claim 34, where: (a) the chemotherapy is platinum doublet therapy; (b) the IDO inhibitor is INCB24360; (c) the CTLA-4 inhibitor is an anti-CTLA-4 antibody (eg, ipilimumab) or a soluble CTLA-4 ligand, and/or the use further includes the use of a BRAF inhibitor, such as vemurafenib or dabrafenib; (d) the cancer vaccine is, for example, a dendritic cell renal carcinoma (DC-RCC) vaccine; or (e) one or more of the following are: (i) immunotherapy, which includes interleukin-2 or interferon-α; (ii) a targeting agent that is a VEGF inhibitor, for example an anti-VEGF antibody; (iii) a VEGF tyrosine kinase inhibitor, which is selected from sunitinib, sorafenib, axitinib or pazopanib; (iv) a downstream inhibitor of the VEGF signaling pathway, which is a mammalian target of rapamycin (mTOR) inhibitor, for example, temsirolimus; (f) one, two or all of the drugs: oxaliplatin, leucovorin or 5-FU, for the treatment of melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematological cancer or renal cell cancer carcinomas; or (g) a tyrosine kinase inhibitor (eg, axitinib) for the treatment of kidney cancer. 36. Use according to any one of claims 25 to 35, wherein the individual has or has been diagnosed as having one or more of the following types of cancer: (a) cancer expressing PD-L1; (b) cancers positive for one, two or all PD-L1, CD8, IFN-γ; - 209 045940 (c) cancer that is triple positive for PD-L1, CD8 and IFN-γ; or (d) cancer with a positive tumor lymphocyte permeability response (TIL). 37. Use according to any one of claims 25 to 36, wherein the antibody molecule is at a dose of about 1 to 30 mg/kg, for example, at a dose of about 1 to 5 mg/kg. 38. Use according to claim 37, wherein the antibody molecule is intended for use once a week or once every 2, 3 or 4 weeks. 39. Use according to any one of claims 25 to 38, where the use is carried out in combination with G02442104 (GSK1120212). 40. Use according to any one of claims 25-38, where the use is carried out in combination with dabrafenib. 41. Use according to any one of claims 25 to 38, where the use is in combination with G02442104 (GSK1120212) and dabrafenib. 42. Use according to any one of claims 39-41, wherein the antibody molecule is for the treatment of melanoma. 43. An antibody molecule capable of binding to the human PD-1 protein, containing: VH containing the amino acid sequence SEQ ID NO: 38; And VL containing the amino acid sequence SEQ ID NO: 54. 44. An antibody molecule capable of binding to the human PD-1 protein, containing: VH containing the amino acid sequence SEQ ID NO: 38; And VL containing the amino acid sequence SEQ ID NO: 70. 45. An antibody molecule capable of binding to human PD-1 protein, comprising: a heavy chain containing the amino acid sequence of SEQ ID NO: 91; and a light chain containing the amino acid sequence of SEQ ID NO: 56. 46. An antibody molecule capable of binding to human PD-1 protein, comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 91; and a light chain containing the amino acid sequence of SEQ ID NO: 72. 47. A pharmaceutical composition for stimulating an immune response or treating a malignancy or infectious disease in an individual, comprising an antibody molecule according to any one of claims 43-46 and a pharmaceutically acceptable carrier, excipient or stabilizer. 48. Use of an antibody molecule according to any one of claims 43-46 to stimulate an immune response in an individual. 49. Use according to claim 48, wherein the stimulation of an immune response is for the treatment of cancer in an individual. 50. Use according to claim 48, wherein the stimulation of an immune response is intended to treat an infectious disease in an individual. 51. The use of an antibody molecule capable of binding to human PD-1 in combination with a MEK inhibitor and/or a BRAF inhibitor for the treatment of cancer, where the antibody molecule contains: (a) a heavy chain variable region (VH) comprising; V HCDR1 with amino acid sequence SEQ ID NO: 4; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia; (b) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 1; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; numbering corresponds to the definition of CDR according to Kabat; (c) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; - 210 045940 VLCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat; or (d) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; VLCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; The numbering corresponds to the definition of CDR according to Kabat, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat. 52. The use of an antibody molecule capable of binding to human PD-1 in combination with G02442104 (GSK1120212) and/or dabrafenib for the treatment of malignancy, where the antibody molecule contains: (a) a heavy chain variable region (VH) containing: V HCDR1 with amino acid sequence SEQ ID NO: 4; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia; (b) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 1; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; numbering corresponds to the definition of CDR according to Kabat; (c) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat; or (d) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; VLCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; The numbering corresponds to the definition of CDR according to Kabat, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat. 53. Use according to claim 51 or 52, where the malignant neoplasm is melanoma. 54. The use of an antibody molecule capable of binding to human PD-1 and a MEK inhibitor and/or a BRAF inhibitor in the production of a medicinal product for the treatment of malignancy, where the antibody molecule contains: (a) a heavy chain variable region (VH) containing: V HCDR1 with amino acid sequence SEQ ID NO: 4; V HCDR2 with amino acid sequence SEQ ID NO: 5; And - 211 045940 V HCDR3 with amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia; (b) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 1; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; numbering corresponds to the definition of CDR according to Kabat; (c) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat; or (d) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; The numbering corresponds to the definition of CDR according to Kabat, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat. 55. The use of an antibody molecule capable of binding to human PD-1 and G02442104 (GSK1120212) and/or dabrafenib in the production of a medicament for the treatment of malignancy, where the antibody molecule contains: (a) a heavy chain variable region (VH) containing: V HCDR1 with amino acid sequence SEQ ID NO: 4; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; and a light chain variable region (VL) containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; V LCDR2 with amino acid sequence SEQ ID NO: 14; And V LCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia; (b) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 1; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; numbering corresponds to the definition of CDR according to Kabat; (c) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 5; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 13; - 212 045940 VLCDR2 with amino acid sequence SEQ ID NO: 14; And VLCDR3 with amino acid sequence SEQ ID NO: 33; numbering corresponds to the definition of CDR according to Hotia, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat; or (d) VH containing: V HCDR1 with amino acid sequence SEQ ID NO: 224; V HCDR2 with amino acid sequence SEQ ID NO: 2; And V HCDR3 with amino acid sequence SEQ ID NO: 3; And V L containing: V LCDR1 with amino acid sequence SEQ ID NO: 10; V LCDR2 with amino acid sequence SEQ ID NO: 11; And V LCDR3 with amino acid sequence SEQ ID NO: 32; The numbering corresponds to the definition of CDR according to Kabat, except for VHCDR1, which corresponds to the combined definition of CDR according to Hotia and Kabat. 56. Use according to claim 54 or 55, wherein the malignancy is melanoma.