EA040861B1 - PD-L1 ANTIBODY MOLECULES AND THEIR APPLICATIONS - Google Patents

Description

Cross-reference to related applications

This patent application claims priority of U.S. Provisional Application No. 62/063852, filed October 14, 2014, U.S. Provisional Application No. 62/094847, filed December 19, 2014, U.S. Provisional Application No. 62/198545, filed July 29, 2015 ., and US Interim Application No. 62/213076, filed September 1, 2015, the contents of the above applications are incorporated herein by reference in their entirety.

Sequence list

The invention contains a sequence listing, which is provided in electronic form in ASCII format and is incorporated herein by reference in its entirety. The specified ASCII copy, created on October 13, 2015, is named C2160-7003WO_SL.txt and has a size of 310216 bytes.

State of the art

The ability of T cells to mediate an immune response against an 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 (APC) is presented to an antigen-specific naive CD4+ T cell. This presentation delivers a signal through the T cell receptor (TCR) which instructs the T cell to initiate an immune response specific to the antigen being presented. Second, various costimulatory and inhibitory signals mediated by interactions between APC and certain T cell surface molecules trigger T cell activation and proliferation and ultimately their inhibition.

The immune system is tightly controlled by a network of co-stimulatory and co-inhibitory ligands and receptors. These molecules provide a second signal for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection while limiting immunity to self-components (Wang, L. et al. (Epub Mar. 7, 2011) J. Exp Lepenies, B. et al (2008) Endocrine, Metabolic & Immune Disorders-Drug Targets Targets 8:279-288). Examples of costimulatory signals include binding between the B7.1 (CD80) and B7.2 (CD86) ligands on APC and the CD28 and CTLA-4 receptors on CD4+ T lymphocytes (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, while binding of B7.1 or B7.2 to CTLA-4 inhibits such activation (Dong, C. et al. (2003) Immunolog. Res. 28 (1): 39-48; Greenwald, R. J. et al. (2005) All Rev. Immunol. 23:515-548). CD28 is expressed constitutively on the surface of T cells (Gross, J., et al. (1992) J. Immunol. 149:380-388), while CTLA-4 expression is rapidly upregulated after T cell activation (Linsley, P et al (1996) Immunity 4:535543).

Other CD28 receptor ligands include the B7 group of related molecules, also known as 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 family are known, including B7.1 (CD80), B7.2 (CD86), inducible costimulatory ligand (ICOS-L), programmed death protein ligand 1 (PD-L1; B7-H1), protein ligand 2 programmed death (PD-L2; B7-DC), B7-H3, B7H4 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 an extended family of CD28/CTLA-4 T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol 170:711-8). Other members of the CD28 family include CD28, CTLA-4, ICOS and BTLA. Two cell surface glycoprotein ligands of PD-1 have been identified: programmed death protein ligand 1 (PD-L1) and programmed cell death protein ligand 2 (PD-L2). When bound to PD-1, PD-L1 and PD-L2 have been shown to inhibit T cell activation and cytokine secretion (Freeman et al. (2000) J Exp Med 192:1027-34; Latchman et al. (2001) Nat Immunol 2:261-8 Carter et al (2002) Eur J Immunol 32:634-43 Ohigashi et al (2005) Clin Cancer Res 11:2947-53).

PD-L1 (also known as 274 differentiation cluster protein (CD274) or B7 homologue 1 (B7H1)) is a 40 kDa type 1 transmembrane protein. PD-L1 binds to its receptor, PD-1, found on activated T cells, B cells, and myeloid cells, modulating activation or inhibition. Both PD-L1 and PD-L2 are B7 homologues that bind to PD-1 but do not bind to CD28 or CTLA-4 (Blank et al. (2005) Cancer Immunol Immunother. 54:307-14). Binding of PD-L1 to its PD-1 receptor on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. The mechanism involves inhibition of ZAP70 phosphorylation and its binding to CD3Z, (Sheppard et al. (2004) FEBS Lett. 574:37-41). PD-1 signaling attenuates the phosphorylation of the PKC-9 activating loop by TCR signaling, which is required for the activation of transcription factors NF-kB and AP-1 and for IL-2 production. PD-L1 also binds to the costimulatory molecule CD80 (B7-1) but not CD86 (B7-2)

- 1 040861 (Butte et al. (2008) Mol Immunol. 45:3567-72).

Cell surface expression of PD-L1 has been shown to be activated by IFN-γ stimulation. PD-L1 expression has been found in many cancers, including lung, ovarian, and colon carcinoma, and various human myelomas, and is often associated with poor prognosis (Iwai et al. (2002) PNAS 99:12293-7; Ohigashi et al (2005) Clin Cancer Res 11:2947-53 Okazaki et al (2007) Intern Immun 19:813-24 Thompson et al (2006) Cancer Res 66:3381-5). It has been suggested that PD-L1 plays a role in tumor immunity by increasing the apoptosis of antigen-specific T cell clones (Dong et al. (2002) Nat Med 8:793-800). It has also been suggested that PD-L1 may be involved in inflammation of the intestinal mucosa, and inhibition of PD-L1 suppresses the debilitating disease associated with colitis (Kanai et al. (2003) J Immunol 171:415663).

Given the importance of immune control cascades in the regulation of the immune response, there is a need to develop new agents that modulate the activity of immunoinhibitory proteins such as PD-L1, thus providing activation of the immune system. Such agents can be used, for example, in cancer immunotherapy and in the treatment of other conditions such as chronic infection.

The essence of the invention

Described herein are antibody molecules (eg, humanized antibody molecules) that bind to a programmed death protein 1 (PD-L1) ligand with high affinity and specificity. In one embodiment, anti-PD-L1 antibody molecules comprise a novel combination of framework regions (eg, FW1, FW2, FW3 and/or FW4), eg, novel combinations of heavy chain frameworks and/or light chain frameworks. Also provided are nucleic acid molecules encoding antibody molecules, expression vectors, host cells, and methods for producing antibody molecules. Also contemplated are immunoconjugates, polyspecific or bispecific antibody molecules, and pharmaceutical compositions containing antibody molecules. The anti-PD-L1 antibody molecules described herein can be used (alone or in combination with other therapies and therapies) for the treatment, prevention and/or diagnosis of disorders such as malignant disorders (e.g., solid tumors and soft tissue tumors) , as well as infectious diseases (for example, chronic infectious disorders or sepsis). In addition, the present description describes methods and compositions containing a combination of two, three or more drugs selected from one, two or all of the following categories (i)-(iii):

(i) an agent that enhances antigen presentation (eg, tumor antigen presentation);

(ii) an agent that enhances an effector cell response (eg, activation and/or mobilization of B cells and/or T cells); or (iii) an agent that reduces tumor immunosuppression.

In some embodiments, the combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein). Thus, compositions and methods for detecting PD-L1 as well as methods for treating various disorders, including cancer and/or infectious diseases, are described herein using anti-PD-L1 antibody molecules and combinations thereof.

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

(i) binds to PD-L1, e.g., human PD-L1, with high affinity, e.g., an affinity constant of at least about 10 ⁷ M' ¹ , typically about 108 M' ¹ , and more specifically, about from 109 M ^-1 to 10 ¹⁰ M ^-1 or stronger;

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

(iii) inhibits or reduces the binding of PD-L1 to a receptor, eg PD-1 or CD80 (B7-1), or both;

(iv) specifically binds to an epitope on PD-L1, eg the same or a similar epitope as the epitope recognized by the mouse monoclonal antibody BAP058 or the chimeric BAP058 antibody, eg BAP058-chi;

(v) exhibits the same or similar binding affinity or specificity, or both affinity and binding specificity, as any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058 -hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-Clone-K -Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O;

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

- 2 040861 (vii) demonstrates the same or similar binding affinity or specificity, or both affinity and binding specificity, as an antibody molecule (for example, a heavy chain variable region and a light chain variable region) having the amino acid sequence shown in Table. 1;

(viii) exhibits the same or similar binding affinity or specificity, or both affinity and binding specificity, as an antibody molecule (e.g., heavy chain variable region and light chain variable region) encoded by the nucleotide sequence shown in Table 1. 1;

(ix) inhibits, e.g., competitively inhibits, the binding of a second antibody molecule to PDL1, wherein the second antibody molecule is an antibody molecule as described herein, e.g., an antibody molecule selected, for example, from any of BAP058-hum01, BAP058hum02, BAP058 -hum03 BAP058-hum04 BAP058-hum05 BAP058-hum06 BAP058-hum07 BAP058hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058hum14 , BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058Clone-M, BAP058-Clone-N or BAP058-Clone-O;

(x) binds the same or overlapping epitope to a second anti-PD-L1 antibody molecule, wherein the second antibody molecule is an antibody molecule as described herein, e.g., an antibody molecule selected, for example, from any of BAP058-hum01, BAP058- hum02 BAP058-hum03 BAP058-hum04 BAP058-hum05 BAP058-hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-αone-O;

(xi) competes for binding and/or binds the same epitope as a second anti-PD-L1 antibody molecule, wherein the second antibody molecule is an antibody molecule as described herein, e.g., an antibody molecule selected from, e.g., any of BAP058-hum01 BAP058hum02 BAP058-hum03 BAP058-hum04 BAP058-hum05 BAP058-hum06 BAP058-hum07 BAP058hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058Clone-M, BAP058-Clone-N or BAP058-Clone-O;

(xii) has one or more of the biological properties of an antibody molecule as described herein, e.g., an antibody molecule selected from, for example, any of BAP058hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06 , BAP058hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058- hum17 , BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O;

(xiii) has one or more of the pharmacokinetic properties of an antibody molecule as described herein, e.g., an antibody molecule selected from, for example, any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058 -hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 -K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O;

(xiv) inhibits one or more of the activities of PD-L1, for example, leads to one or more of: an increase in the level of tumor-infiltrating lymphocytes, an increase in T-cell receptor-mediated proliferation, or a decrease in the immune escape of malignant cells; or (xv) binds human PD-L1 and cross-reacts with cynomolgus monkey PD-L1.

In some embodiments, the antibody molecule binds to PD-L1 with high affinity, e.g., a Kd that is about the same, or is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher or lower than the KD of an anti-mouse PD-L1 antibody molecule or a chimeric anti-PD-L1 antibody molecule, e.g., an anti-mouse PD-L1 antibody or a chimeric anti-PD-L1 antibody molecule described herein. In some embodiments, the KD of an anti-PD-L1 mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule is less than about 0.4, 0.3, 0.2, 0.1, or 0.05 nM, e.g., as measured by the method Biacore. In some embodiments, the KD of an anti-murine PD-L1 antibody molecule or a chimeric anti-PD-L1 antibody molecule is less than about 0.2 nM, such as about 0.171 nM. In other embodiments, the KD of an anti-PD-L1 mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule is less than about 10, 5, 3, 2, or 1 nM, e.g., as measured by binding to cells expressing PD-L1 (e.g., , cells 300.19). In some embodiments, the KD of an anti-mouse PD-L1 antibody molecule or a chimeric anti-PD-L1 antibody molecule is less than about 1 nM, such as about 0.285 nM.

In some embodiments, an anti-PD-L1 antibody molecule binds to PD-L1 with Kd

- 3 040861 slower than 1x10 ^-4 , 5x10-5 or 1x10 ^-5 s ^-1 , for example approximately 6.33x10 ^-5 s ^-1 . In some embodiments, an anti-PD-L1 antibody molecule binds to PD-L1 with a K _a faster than 1 x 10 ⁴ , 5 x 10 ⁴ .

1x105 or 5x105 M ^-1 s ^-1 , for example approximately 3.07x105 M ^-1 s ^-1 .

In some embodiments, the expression level of the antibody molecule is higher, such as at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the expression level of the antibody molecule. a mouse antibody or a chimeric antibody molecule, such as a mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule described herein. In some embodiments, the antibody molecule is expressed in CHO cells.

In some embodiments, an anti-PD-L1 antibody molecule reduces one or more PD-L1-associated activities with an IC ₅₀ (50% inhibitory concentration) that is about the same or lower, e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower than the _IC50 of a mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule, e.g. a mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule, described in the present description. In some embodiments, the IC ₅₀ of a mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule is less than about 6, 5, 4, 3, 2, or 1 nM, e.g., as measured by binding to cells expressing PD-L1 (e.g., cells 300.19). In some embodiments, the IC ₅₀ of a mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule is less than about 4 nM, such as about 3.40 nM (or about 0.51 μg/mL). In some embodiments, the reduced activity associated with PD-L1 is the binding of PD-L1 and/or PD-L2 to PD-1. In some embodiments, the anti-PD-L1 antibody molecule binds to staphylococcal enterotoxin B (SEB)-activated peripheral blood mononuclear cells (PBMCs). In other embodiments, the anti-PD-L1 antibody molecule increases IL2 expression in SEB-activated whole blood. For example, an anti-PD-L1 antibody increases IL2 expression by at least about 2, 3, 4, or 5-fold over IL-2 expression when an isotype control (eg, IgG4) is used.

In some embodiments, the anti-PD-L1 antibody molecule has increased stability, e.g., is at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times more stable in vivo or in vitro than a mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule, such as a mouse antibody molecule or a chimeric anti-PD-L1 antibody molecule described herein.

In one embodiment, the anti-PD-L1 antibody molecule is a humanized antibody molecule and has a risk score based on T cell epitope analysis of 300-700, 400-650, 450-600, or a risk score as described herein. description.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02 , BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06,

BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12,

BAP058-hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, an anti-PD-L1 antibody molecule contains at least one, two, three, or four variable regions from an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03 BAP058-hum04 , BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058hum04 BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058hum10 -Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence that is substantially identical (e.g., at least

- 4 040861

80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one or two light chain variable regions from an antibody of the present invention, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058hum04 BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058hum10 -Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain constant region for IgG4, eg, human IgG4. In one embodiment, human IgG4 includes a substitution at position 228 (eg, Ser to Pro substitution). In another embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain constant region for IgG1, eg, human IgG1. In one embodiment, human IgG1 includes a substitution at position 297 (eg, substitution of Asn to Ala). In one embodiment, human IgG1 comprises a substitution at position 265, a substitution at position 329, or both (eg, an Asp to Ala substitution at position 265 and/or a Pro to Ala substitution at position 329). In one embodiment, human IgG1 comprises a substitution at position 234, a substitution at position 235, or both (eg, a Leu to Ala substitution at position 234 and/or a Leu to Ala substitution at position 235). In one embodiment, the heavy chain constant region contains the amino acid sequence shown in table. 3, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to it.

In another embodiment, the anti-PD-L1 antibody molecule comprises a kappa light chain constant region, eg, a human kappa light chain constant region. In one embodiment, the light chain constant region contains the amino acid sequence shown in table. 3, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to it.

In another embodiment, the anti-PD-L1 antibody molecule comprises an IgG4 heavy chain constant region, such as human IgG4, and a kappa light chain constant region, such as a human kappa light chain constant region, such as a heavy and light chain constant region, comprising the amino acid sequence indicated in Table. 3, or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to it. In another embodiment, the anti-PD-L1 antibody molecule comprises an IgG1 heavy chain constant region, such as human IgG1, and a kappa light chain constant region, such as a human kappa light chain constant region, such as a heavy and light chain constant region, comprising the amino acid sequence indicated in Table. 3 or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to it. In one embodiment, human IgG1 includes a substitution at position 297 (eg, an Asn to Ala substitution). In one embodiment, human IgG1 comprises a substitution at position 265, a substitution at position 329, or both (eg, an Asp to Ala substitution at position 265 and/or a Pro to Ala substitution at position 329). In one embodiment, human IgG1 comprises a substitution at position 234, a substitution at position 235, or both (eg, a Leu to Ala substitution at position 234 and/or a Leu to Ala substitution at position 235).

In another embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable domain and constant region, a light chain variable domain and constant region, or both, comprising the amino acid sequence BAP058-Clone-K, BAP058-Clone-L, BAP058Clone -M, BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences. An anti-PD-1 antibody molecule optionally contains a leader sequence from a heavy chain, a light chain, or both.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from the heavy chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058 -hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06,

BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12,

BAP058-hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O ; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, the anti-PD-L1 antibody molecule comprises at least one, two or three CDRs (or collectively all of the CDRs) from the heavy chain variable region containing the amino acid sequence shown in Table 1. 1 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or, collectively, all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three CDRs from the light chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058- hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09,

BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15,

BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, the PD-L1 antibody molecule comprises at least one, two or three CDRs (or collectively all CDRs) from the light chain variable region containing the amino acid sequence shown in Table 1. 1 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or, collectively, all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1. In certain embodiments, the anti-PD-L1 antibody molecule comprises a light chain CDR substitution, eg, one or more light chain CDR1, CDR2 and/or CDR3 substitutions.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, three, four, five, or six CDRs (or, in the aggregate, all of the CDRs) from the heavy and light chain variable region, comprising the amino acid sequence shown in Table 1. . 1 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or, collectively, all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1.

In one embodiment, an anti-PD-L1 antibody molecule comprises all six CDRs from an antibody described herein, e.g., an antibody selected from any of BAP058hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, hum06 BAP058hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1, or highly similar CDRs, eg, CDRs that are identical or that have at least one amino acid change but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, eg, conservative substitutions). In one embodiment, an anti-PD-L1 antibody molecule may include any of the CDRs described herein. In certain embodiments, the anti-PD-L1 antibody molecule comprises a light chain CDR substitution, for example, one or more light chain CDR1, CDR2, and/or CDR3 substitutions. In another embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs as defined by Kabat as listed in Table 1) from the heavy chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02 BAP058-hum03 BAP058-hum04 -hum16, BAP058hum17, BAP058-Clone-R, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences; or having at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, eg, conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table. 1.

In another embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs as defined by Kabat as listed in Table 1) from the light chain variable region of an antibody described in

- 6 040861 of the present invention, for example, an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-Clone-R BAP058-Clone-L BAP058-Clone-M BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences; or having at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, eg, conservative substitutions) relative to one, two, or three CDRs according to Kabat et al. shown in Table. 1.

In another embodiment, the PD-L1 antibody molecule comprises at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs as defined by Kabat as indicated in Table 1) from the heavy and light chain variable regions of an antibody of the present invention, e.g., an antibody selected from any from BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058hum11, BAP058-hum12, BAP058-hum11 -hum14, BAP058-hum15, BAP058-hum16, BAP058hum17, BAP058-Clone-R, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences; or having at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, such as conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Kabat et al. shown in Table. 1.

In another embodiment, the anti-PD-L1 antibody molecule includes all six CDRs according to Kabat et al. (e.g., all six CDRs as defined by Kabat as listed in Table 1) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03 BAP058-hum04 -hum16, BAP058-hum17, BAP058-Clone-R, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences; or having at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, eg, conservative substitutions) relative to all six CDRs according to Kabat et al., shown in table. 1. In one embodiment, an anti-PD-L1 antibody molecule may include any of the CDRs described herein.

In another embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, or three Chothia hypervariable loops (e.g., at least one, two, or three Chothia hypervariable loops, as shown in Table 1) from the variable region an antibody described herein, e.g. an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09 BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15 , BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or at least amino acids from these hypervariable loops that contact PD-L1; or which has at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, such as conservative substitutions) relative to one, two, or three hypervariable loops according to Chothia et al. shown in Table . 1.

In another embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, or three Chothia hypervariable loops (e.g., at least one, two, or three Chothia-defined hypervariable loops as listed in Table 1) of the lung variable region. chain of an antibody described in the present invention, for example, an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-CloneK BAP058-Clone-L BAP058-Clone-M N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or at least amino acids from these hypervariable loops that contact PD-L1; or which has at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, such as conservative substitutions) relative to one, two, or three hypervariable loops according to Chothia et al. presented in table. 1.

In another embodiment, the PD-L1 antibody molecule comprises at least one, two, three, four, five, or six hypervariable loops (e.g., at least one, two, three, four, five, or six hypervariable loops as defined by Chothia, as indicated in Table 1) from the heavy and light chain variable regions of an antibody of the present invention, e.g. an antibody selected from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058 -hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 -K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or at least amino acids from these hypervariable loops that contact PD-L1; or which has at least one amino acid change but no more than two, three or four changes (e.g. substitutions, deletions or insertions, e.g. conservative substitutions) relative to one, two, three, four, five or six hypervariable loops according to Chothia et al., shown in table. 1.

In one embodiment, an anti-PD-L1 antibody molecule comprises all six hypervariable loops (e.g., all six hypervariable loops as defined by Chothia as listed in Table 1) of an antibody described herein, e.g., an antibody selected from any of BAP058- hum01 BAP058-hum02 BAP058-hum03 BAP058-hum04 BAP058-hum05 BAP058hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-CloneK, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O, or highly similar hypervariable loops, e.g. hypervariable loops that are identical or that have at least one amino acid change but no more than two, three or four changes (eg substitutions, deletions or insertions, eg conservative substitutions); or which have at least one amino acid change, but no more than two, three, or four changes (eg, substitutions, deletions, or insertions, eg, conservative substitutions) relative to all six hypervariable loops according to Chothia et al., shown in table. 1. In one embodiment, an anti-PD-L1 antibody molecule may include any of the hypervariable loops described herein.

In another embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody selected from any of BAP058 -hum01 BAP058-hum02 BAP058-hum03 BAP058-hum04 BAP058hum05 BAP058-hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058hum11 BAP058-hum12 , BAP058-hum15, BAP058-hum16, BAP058hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O, for example, the same canonical structures as at least loop 1 and/or loop 2 of the variable domains of the heavy and/or light chains of an antibody described in the present invention. See, for example, Chothia et al. (1992) J. Mol. Biol. 227:799-817; Tomlinson et al. (1992) J. Mol. Biol. 227:776-798 for describing the canonical structures of hypervariable loops. These structures can be determined by examining the tables provided in these links.

In certain embodiments, an anti-PD-L1 antibody molecule comprises a combination of CDRs or hypervariable loops as defined according to Kabat et al. and Chothia et al.

In one embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three CDRs or hypervariable loops from the heavy chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP058-hum01, BAP058-hum02 BAP058-hum03 -hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O, as defined by Kabat and Chothia (e.g., at least one, two or three CDRs or hypervariable loops as defined by Kabat and Chothia as listed in Table 1); or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences; or which have at least one amino acid change but no more than two, three or four changes (e.g. substitutions, deletions or insertions, e.g. conservative substitutions) relative to one, two or three CDRs or hypervariable loops according to Kabat and/or Chothia, shown in table. 1.

For example, an anti-PD-L1 antibody molecule may include VH CDR1 according to Kabat et al., or VH hypervariable loop 1 according to Chothia et al., or a combination thereof, for example, as shown in

- 8 040861 tab. 1. In one embodiment, the combination of CDRs according to Kabat and Chothia for CDR1 VH comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO: 195) or an amino acid sequence substantially identical to it (e.g., having at least one amino acid change, but no more than two, three or four changes (eg substitutions, deletions or insertions, eg conservative substitutions)). In addition, the anti-PD-L1 antibody molecule may include, for example, VH CDR 2-3 according to Kabat et al. and CDR 1-3 VL according to Kabat et al., for example, as presented in table. 1. Thus, in some embodiments, framework regions are determined based on a combination of CDRs as determined by Kabat et al. and hypervariable loops as determined by Chothia et al. For example, an anti-PD-L1 antibody molecule may include VH FR1 as determined from VH hypervariable loop 1 according to Chothia et al. and VH FR2 as determined from VH CDR 1-2 from Kabat et al., for example, as shown in Table . 1. Additionally, an anti-PD-L1 antibody molecule may include, for example, VH FRs 3-4 as determined from VH CDRs 2-3 according to Kabat et al. and FR 1-4 VL, determined on the basis of CDR 1-3 VL according to Kabat et al.

An anti-PD-L1 antibody molecule may contain any combination of CDRs or hypervariable loops as defined by Kabat and Chothia. In one embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three CDRs from the light chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP058hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16 hum17, BAP058-Clone-R, BAP058Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O as defined by Kabat and Chothia (e.g. at least one, two or three CDRs as defined by Kabat and Chothia as listed in Table 1).

In one embodiment, for example, an embodiment comprising a variable region, a CDR (eg, CDR according to Chothia or CDR according to Kabat) or another sequence mentioned in the present description, for example, in table. 1, an antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, or is an antibody molecule that contains an antigen-binding fragment of an antibody, such as a half-antibody or an antigen-binding fragment of a half-antibody. In embodiments, the antibody molecule is a bispecific antibody molecule having a first binding specificity for PD-L1 and a second binding specificity for TIM-3, LAG-3, CEACAM (e.g., CEACAM-1 and/or CEACAM-5), PD -1 or PD-L2. In some embodiments, the second binding specificity for TIM-3, LAG-3, and/or PD-1 comprises an amino acid sequence or is encoded by a nucleotide sequence as described herein (e.g., as described in the section titled Inhibitors of Immune Checkpoint Molecules, starting on page 218 of the present description below (including all publications mentioned therein).

In one embodiment, an anti-PD-L1 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 195; the amino acid sequence of VHCDR2 SEQ ID NO: 2 and the amino acid sequence of VHCDR3 SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 9, the amino acid sequence of VLCDR2 SEQ ID NO: 10, and the amino acid sequence of VLCDR3 SEQ ID NO: 11.

In another embodiment, the anti-PD-L1 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 195; the amino acid sequence of VHCDR2 SEQ ID NO: 5 and the amino acid sequence of VHCDR3 SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 12, the VLCDR2 amino acid sequence of SEQ ID NO: 13, and the VLCDR3 amino acid sequence of SEQ ID NO: 14.

In one embodiment, the anti-PD-L1 antibody molecule contains the amino acid sequence of VHCDR1 SEQ ID NO: 1. In another embodiment, the anti-PD-L1 antibody molecule contains the amino acid sequence of VHCDR1 of SEQ ID NO: 4. In another embodiment, the anti-PD-L1 antibody molecule contains the amino acid sequence VHCDR1 SEQ ID NO: 195.

In one embodiment, the light or heavy chain variable framework (e.g., spanning at least FR1, FR2, FR3, and optionally FR4) of the anti-PD-L1 antibody molecule can be selected from: (a) a light or heavy chain variable framework , comprising at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or preferably 100% of amino acid residues from a human light or heavy chain variable framework region, for example, a mature light or heavy chain variable framework region residue human antibodies,

- 9 040861 human germline value or human consensus sequence; (b) a light or heavy chain variable framework region comprising 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of amino acid residues from a human light or heavy chain variable framework, e.g. a light or heavy chain variable framework region of a mature human antibody, a human germline sequence, or a human consensus sequence; (c) a non-human framework (eg, a rodent framework); or (d) a non-human framework region that has been modified, eg, to remove antigenic or cytotoxic determinants, eg, deimmunized or partially humanized. In one embodiment, the light or heavy chain variable framework (specifically FR1, FR2 and/or FR3) comprises the light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90 , 92, 94, 95, 96, 97, 98, 99% identical, or identical, to the framework regions of the VL or VH segment of the human germline gene.

In certain embodiments, an anti-PD-L1 antibody molecule comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, or more changes, such as amino acid substitutions or deletions in the amino acid sequence. BAP058-CN-HC, for example the amino acid sequence of the FR region from the entire variable region, for example as shown in FIG. 8A-8B or SEQ ID NO: 16. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable domain having one or more of: Q at position 1, I at position 2, T at position 3, V or K in position 5, P in position 9, T in position 10, V in position 11, K in position 12, T in position 15, E or Q in position 16, T in position 17, L in position 18, R or T in position 19, I or V in position 20, T in position 21, T in position 23, G, V or F in position 24, I in position 37, R in position 38, A or P or S in position 40, T or R at position 41, S at position 42, Q or K at position 43, M or L or V at position 48, R at position 67, F or V or L at position 68, I at position 70 , S at position 71, A, K or R at position 72, D or T or N at position 74, T or K at position 76, N at position 77, Q at position 78, F or V or L in position 79, S or V in position 80, L in position 81, E or K or T in position 82, M in position 83, T or N in the floor position 84, N in position 85, V or M in position 86, K or R or D in position 87, T or A or P in position 88, A or V in position 89, T in position 91, or T at position 93, the BAP058chi-HC amino acid sequence, eg, the FR amino acid sequence from the entire variable region, eg, shown in FIG. 8A-8B, or SEQ ID NO: 16.

Alternatively, or in combination with the BAP058-chi-HC heavy chain substitutions described herein, an anti-PD-L1 antibody molecule contains 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, in the BAP058-chi-LC amino acid sequence, such as the amino acid sequence shown in FIG. 9A-9B, or SEQ ID NO: 17. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable domain having one or more of: E or A at position 1, V at position 2, V or Q at position 3, L in position 4, T in position 7, P in position 8, D or L or S or A in position 9, S or T in position 10, Q or L in position 11, P in position 12, V or L or A at position 13, T at position 14, P or L at position 15, K at position 16, Q or E at position 17, K or P at position 18, A at position 19, T at position 20, L at position 21, S at 22, L at 37, A at 43, R or Q at 45, I at 58, A or S or P at 60, S at 63, Y at 67, E at 70, F at 73, K at 74, N at 76, S or R at 77, I or L at 78, E at 79, P or A at 80, D at 81, F , or I, or V, or A at position 83, G at position 84, T, or V, or Y at position 85, and whether Y is at position 87 of the BAP058-chi-LC amino acid sequence, such as the amino acid sequence shown in FIG. 10A-10B or SEQ ID NO: 24 or 26.

In other embodiments, the anti-PD-L1 antibody molecule comprises 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 the sequence essentially identical to them.

In other embodiments, an anti-PD-L1 antibody molecule comprises one, two, three, or four light chain framework regions (e.g., the VLFW amino acid sequence shown in Table 2 or encoded by the nucleotide sequence shown in Table 2), or the sequence essentially identical to them.

In other embodiments, an anti-PD-L1 antibody molecule comprises 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 the sequence essentially identical to them; and one, two, three, or four light chain framework regions (e.g., the VLFW amino acid sequence shown in Table 2 or encoded

- 10 040861 nucleotide sequence presented in table. 2), or a sequence essentially identical to them.

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework 1 (VHFW1) from BAP058-hum01, BAP058-hum02, BAP058-hum07, BAP058-hum14, or BAP058-hum16 (e.g., SEQ ID NO: 124). In some embodiments, the antibody molecule comprises heavy chain framework 1 (VHFW1) of BAP058-hum04, BAP058-hum06, BAP058hum08, BAP058-hum09, BAP058-hum12, BAP058-hum15, BAP058-hum17, BAP058-Clone-L or BAP058Clone- M (for example, SEQ ID NO: 126). In some embodiments, the antibody molecule comprises heavy chain framework 1 (VHFW1) of BAP058-hum03, BAP058-hum05, BAP058-hum11, BAP058-hum13, BAP058-Clone-K, BAP058-Clone-N, or BAP058-Clone-O ( for example, SEQ ID NO: 128). In some embodiments, the antibody molecule comprises heavy chain framework 1 (VHFW1) from BAP058-hum10 (eg, SEQ ID NO: 130).

In some embodiments, an anti-PD-L1 antibody molecule comprises a heavy chain framework region 2 (VHFW2) of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum11, BAP058-hum14, BAP058-Clone-K, or BAP058-Clone- N (for example, SEQ ID NO: 132). In some embodiments, the antibody molecule comprises a heavy chain framework 2 (VHFW2) from BAP058-hum04, BAP058-hum12, or BAP058-Clone-L (eg, SEQ ID NO: 134). In some embodiments, the antibody molecule comprises a heavy chain framework 2 (VHFW2) of BAP058-hum06, BAP058-hum09, BAP058-hum15, or BAP058-αone-M (eg, SEQ ID NO: 136). In some embodiments, the antibody molecule comprises a heavy chain framework region 2 (VHFW2) from BAP058-hum05, BAP058-hum07, or BAP058-hum16 (eg, SEQ ID NO: 138). In some embodiments, the antibody molecule comprises a heavy chain framework 2 (VHFW2) of BAP058-hum08, BAP058-hum13, BAP058-hum17, or BAP058-αone-O (eg, SEQ ID NO: 140). In some embodiments, the antibody molecule comprises heavy chain framework 2 from BAP058-hum10 (eg, SEQ ID NO: 142).

In some embodiments, an anti-PD-L1 antibody molecule comprises a heavy chain framework 3 (VHFW3) from BAP058-hum01, BAP058-hum02, BAP058-hum07, BAP058-hum14, or BAP058-hum16, (e.g., SEQ ID NO: 144). In some embodiments, the antibody molecule comprises a heavy chain framework region 3 (VHFW3) of BAP058-hum03, BAP058-hum06, BAP058hum09, BAP058-hum10, BAP058-hum11, BAP058-hum15, BAP058-Clone-K, BAP058-Clone-M, or BAP058-Clone-N (e.g. SEQ ID NO: 146). In some embodiments, the antibody molecule comprises a heavy chain framework 3 (VHFW3) from BAP058-hum04, BAP058-hum12, or BAP058Clone-L (eg, SEQ ID NO: 148). In some embodiments, the antibody molecule comprises a heavy chain framework 3 (VHFW3) from BAP058-hum05, BAP058-hum08, or BAP058-hum17 (eg, SEQ ID NO: 150). In some embodiments, the antibody molecule comprises a heavy chain framework 3 (VHFW3) from BAP058-hum13 or BAP058-Clone-O (eg, SEQ ID NO: 152). In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework 4 (VHFW4) of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058- hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-Clone-K BAP058-Clone-L BAP058-Clone-M, BAP058-Clone-N or BAP058Clone-O (e.g. SEQ ID NO: 154).

In some embodiments, the anti-PD-L1 antibody molecule comprises light chain framework 1 (VLFW1) of BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058- hum17, BAP058-Clone-K, BAP058-Clone-L or BAP058-Clone-M (e.g. SEQ ID NO: 156). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP058-hum08, BAP058-hum10, BAP058hum11, or BAP058-Clone-N (eg, SEQ ID NO: 158). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP058-hum01 or BAP058hum09 (eg, SEQ ID NO: 160). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP058-hum02 or BAP058-hum12 (eg, SEQ ID NO: 162). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP058-hum07 (eg, SEQ ID NO: 164). In some embodiments, the antibody molecule comprises light chain framework 1 (VLFW1) from BAP058-hum13 or BAP058-Clone-O (eg, SEQ ID NO: 166).

In some embodiments, the anti-PD-L1 antibody molecule comprises light chain framework 2 (VLFW2) of BAP058-hum08, BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058- hum17 or BAP058-Clone-N (e.g. SEQ ID NO: 168). In some embodiments, the antibody molecule comprises light chain framework 2 (VLFW2) of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058hum05, BAP058-hum06, BAP058-hum07, BAP058-hum09, BAP058-hum13, BAP058-Clone-K, BAP058Clone-L, BAP058-Clone-M or BAP058-Clone-O (e.g. SEQ ID NO: 170).

- 11 040861

In some embodiments, the anti-PD-L1 antibody molecule comprises light chain framework 3 (VLFW3) of BAP058-hum08, BAP058-hum10, BAP058-hum11, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17 or BAP058- Clone-N (eg, SEQ ID NO: 172). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) of BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum12, BAP058-Clone-L, or BAP058-Clone-M (e.g., SEQ ID NO: 174). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) from BAP058-hum01 or

BAP058-hum09 (for example, SEQ ID NO: 176). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) from BAP058-hum02 (eg, SEQ ID NO: 178). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) from BAP058-hum03 or BAP058-Clone-K (eg, SEQ ID NO: 180). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) from BAP058-hum07 (eg, SEQ ID NO: 182). In some embodiments, the antibody molecule comprises light chain framework 3 (VLFW3) from BAP058-hum13 or BAP058-Clone-O (eg, SEQ ID NO: 184).

In some embodiments, the anti-PD-L1 antibody molecule comprises light chain framework 4 (VLFW4) of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058- hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-Clone-K BAP058-Clone-M, BAP058-Clone-N or BAP058Clone-O (e.g. SEQ ID NO: 186).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum01, BAP058-hum02, or BAP058-hum14 (e.g., SEQ ID NO: 124 (VHFW1), SEQ ID NO: 132 (VHFW2) and SEQ ID NO: 144 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum07 or BAP058-hum16 (e.g., SEQ ID NO: 124 (VHFW1), SEQ ID NO: 138 (VHFW2) and SEQ ID NO: 144 (VHFW3 )). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum04, BAP058-hum12, or BAP058-Clone-L (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 134 (VHFW2), and SEQ ID NO: 148 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum06, BAP058hum09, BAP058-hum15, or BAP058-Clone-M (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 136 (VHFW2) , and SEQ ID NO: 146 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum08 or BAP058-hum17 (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 140 (VHFW2), and SEQ ID NO: 150 (VHFW3 )). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 of BAP058-hum03, BAP058-hum11, BAP058-Clone-K, or BAP058-Clone-N (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 132 (VHFW2) and SEQ ID NO: 146 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum13 or BAP058-Clone-O (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 140 (VHFW2) and SEQ ID NO: 152 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum05 (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 138 (VHFW2), and SEQ ID NO: 150 (VHFW3)). In some embodiments, the antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum10 (e.g., SEQ ID NO: 130 (VHFW1), SEQ ID NO: 142 (VHFW2) and SEQ ID NO: 146 (VHFW3)). In some embodiments, the antibody molecule further comprises a heavy chain framework region 4 (VHFW4) of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058- hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-Clone-K BAP058-Clone-L BAP058-Clone-M, BAP058-Clone-N or BAP058Clone-O (e.g. SEQ ID NO: 154).

In some embodiments, an anti-PD-L1 antibody molecule comprises light chain framework regions 1-3 from BAP058-hum01 or BAP058-hum09 (e.g., SEQ ID NO: 160 (VLFW1), SEQ ID NO: 170 (VLFW2), and SEQ ID NO: : 176 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP058-hum14, BAP058-hum15, BAP058-hum16, or BAP058-hum17 (e.g., SEQ ID NO: 156 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 of BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-Clone-L, or BAP058-Clone-M (e.g., SEQ ID NO: 156 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 174 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP058-hum08, BAP058-hum10, or BAP058-hum11 (e.g., SEQ ID NO: 158 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: : 172 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP058-hum13 or BAP058-Clone-O (e.g., SEQ ID NO: 166 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 184 (VLFW3)). In some variants, osu

The antibody molecule contains light chain framework regions 1-3 from BAP058-hum02 (eg SEQ ID NO: 162 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 178 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP058hum03 (e.g., SEQ ID NO: 156 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 180 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP058-hum07 (e.g., SEQ ID NO: 164 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 182 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP058-hum12 (e.g., SEQ ID NO: 162 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 174 (VLFW3)). In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP058-Clone-K (e.g., SEQ ID NO: 156 (VLFW1), SEQ ID NO: 168 (VLFW2), and SEQ ID NO: 180 (VLFW3)) . In some embodiments, the antibody molecule comprises light chain framework regions 1-3 from BAP058-Clone-N (e.g., SEQ ID NO: 158 (VLFW1), SEQ ID NO: 170 (VLFW2), and SEQ ID NO: 172 (VLFW3)) . In some embodiments, the antibody molecule further comprises light chain framework 4 (VLFW4) of BAP058-hum01, BAP058hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058hum08, BAP058- hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-Clone-K BAP058-Clone-L BAP058Clone-M Clone-N or BAP058-Clone-O (eg SEQ ID NO: 186).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum01 (e.g., SEQ ID NO: 124 (VHFW1), SEQ ID NO: 132 (VHFW2) and SEQ ID NO: 144 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum01 (eg, SEQ ID NO: 160 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 176 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum02 (e.g., SEQ ID NO: 124 (VHFW1), SEQ ID NO: 132 (VHFW2) and SEQ ID NO: 144 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum02 (eg, SEQ ID NO: 162 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 178 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum03 (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 132 (VHFW2) and SEQ ID NO: 146 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum03 (eg, SEQ ID NO: 156 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 180 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum04 or BAP058-Clone-L (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 134 (VHFW2), and SEQ ID NO: 148(VHFW3)) and light chain framework regions 1-3 from BAP058hum04 or BAP058-αone-L (e.g., SEQ ID NO: 156 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 174 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum05 (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 138 (VHFW2) and SEQ ID NO: 150 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum05 (eg, SEQ ID NO: 156 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 174 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum06 or BAP058-Clone-M (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 136 (VHFW2), and SEQ ID NO: 146 (VHFW3)) and light chain frameworks 1-3 from BAP058hum06 or BAP058-Clone-M (e.g., SEQ ID NO: 156 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 174 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum07 (e.g., SEQ ID NO: 124 (VHFW1), SEQ ID NO: 138 (VHFW2), and SEQ ID NO: 144 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum07 (eg, SEQ ID NO: 164 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 182 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum08 (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 140 (VHFW2) and SEQ ID NO: 150 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum08 (eg, SEQ ID NO: 158 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, an anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum09 (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 136 (VHFW2) and SEQ ID NO: 146 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum09 (eg, SEQ ID NO: 160 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 176 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum10 (e.g., SEQ ID NO: 130 (VHFW1), SEQ ID NO: 142 (VHFW2) and SEQ ID NO: 146 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum10 (eg, SEQ ID NO: 158 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum11 (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 132

- 13 040861 (VHFW2) and SEQ ID NO: 146 (VHFW3)) and light chain frameworks 1-3 from BAP058-hum11 (e.g. SEQ ID NO: 158 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum12 (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 134 (VHFW2) and SEQ ID NO: 148 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum12 (eg, SEQ ID NO: 162 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 174 (VLFW3)).

In some embodiments, an anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum13 or BAP058-Clone-O (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 140 (VHFW2), and SEQ ID NO: 152 (VHFW3)) and light chain frameworks 1-3 from BAP058hum13 or BAP058-Clone-O (e.g. SEQ ID NO: 166 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 184 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum14 (e.g., SEQ ID NO: 124 (VHFW1), SEQ ID NO: 132 (VHFW2), and SEQ ID NO: 144 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum14 (eg, SEQ ID NO: 156 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, an anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum15 (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 136 (VHFW2) and SEQ ID NO: 146 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum15 (eg, SEQ ID NO: 156 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum16 (e.g., SEQ ID NO: 124 (VHFW1), SEQ ID NO: 138 (VHFW2) and SEQ ID NO: 144 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum16 (eg, SEQ ID NO: 156 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-hum17 (e.g., SEQ ID NO: 126 (VHFW1), SEQ ID NO: 140 (VHFW2) and SEQ ID NO: 150 (VHFW3 )) and light chain framework regions 1-3 from BAP058-hum17 (eg, SEQ ID NO: 156 (VLFW1), SEQ ID NO: 168 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule comprises heavy chain framework regions 1-3 from BAP058-Clone-N (e.g., SEQ ID NO: 128 (VHFW1), SEQ ID NO: 132 (VHFW2) and SEQ ID NO: 146 (VHFW3)) and light chain frameworks 1-3 from BAP058-Clone-N (eg, SEQ ID NO: 158 (VLFW1), SEQ ID NO: 170 (VLFW2) and SEQ ID NO: 172 (VLFW3)).

In some embodiments, the anti-PD-L1 antibody molecule further comprises heavy chain framework 4 (VHFW4) of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058- hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-hum17 BAP058-Clone-K Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O (e.g. SEQ ID NO: 154) and light chain framework 4 (VLFW4) from BAP058-hum01, BAP058-hum02, BAP058- hum03 BAP058-hum04 BAP058-hum05 BAP058-hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O (for example, SEQ ID NO: 186).

In some embodiments, an anti-PD-L1 antibody molecule comprises a heavy chain framework having a combination of FW1, FW2, and FW3 frameworks as shown in FIG. 4 or 6. In another embodiment, the antibody molecule comprises a light chain framework having a combination of FW1, FW2, and FW3 frameworks as shown in FIG. 4 or 6. In other embodiments, the antibody molecule comprises a heavy chain framework region having a combination of FW1, FW2, and FW3 framework regions as shown in FIG. 4 or 6 and a light chain framework having a combination of frameworks FW1, FW2 and FW3 as shown in FIG. 4 or 6.

In one embodiment, the heavy or light chain variable domain, or both heavy and light chain, of an anti-PD-L1 antibody molecule comprises an amino acid sequence that is substantially identical to the amino acid sequence described herein, e.g., at least 80, 85, 90, 92, 95, 97, 98, 99% or more identical to the variable region of an antibody described in the present invention, for example, an antibody selected from any of BAP058hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058- hum05 BAP058-hum06 BAP058hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058-hum11 BAP058-hum12 BAP058hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 K, BAP058Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or which differs by at least 1 or 5 residues, but less than 40, 30, 20 or 10 residues, from the variable region of an antibody described in the present invention.

In one embodiment, the heavy or light chain variable region, or both heavy and light chain, of an anti-PD-L1 antibody molecule comprises the amino acid sequence,

- 14 040861 encoded by the nucleic acid sequence described in the present description, or a nucleic acid that hybridizes with the nucleic acid sequence described in the present description (for example, the nucleic acid sequences presented in Tables 1 and 2), or its complementary sequence, for example , under conditions of low stringency, medium stringency, or high stringency, or other hybridization conditions described herein.

In another embodiment, the PD-L1 antibody molecule contains at least one, two, three, or four antigen-binding regions, such as variable regions, having an amino acid sequence as shown in Table 1. 1, or a sequence substantially identical to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it, or which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from sequences presented in Table 1). In another embodiment, the PD-L1 antibody molecule comprises a VH and/or VL domain encoded by a nucleic acid having the nucleotide sequence as shown in Table 1. 1, or a sequence substantially identical to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences presented in Table 1).

In another embodiment, the PD-L1 antibody molecule contains at least one, two, or three CDRs from the heavy chain variable region having the amino acid sequence as shown in Table 1. 1, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or having one, two, three or more substitutions, insertions or deletions, for example, conservative substitutions). In another embodiment, the PD-L1 antibody molecule contains at least one, two, or three CDRs from the light chain variable region having the amino acid sequence as shown in Table 1. 1, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and / or having one, two, three or more substitutions, insertions or deletions, for example, conservative substitutions). In another embodiment, the PD-L1 antibody molecule contains at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions having the amino acid sequence as shown in Table 1. 1), or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conservative substitutions).

In one embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three CDRs and/or hypervariable loops from a heavy chain variable region having the amino acid sequence of an antibody described herein, e.g., an antibody selected from any of BAP058 -hum01 BAP058-hum02 BAP058-hum03 BAP058-hum04 BAP058hum05 BAP058-hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058hum11 BAP058-hum12 , BAP058-hum15, BAP058-hum16, BAP058hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O, as summarized in Table 1, or a sequence substantially identical to them (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to them, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conservative substitutions). In another embodiment, an anti-PD-L1 antibody molecule comprises at least one, two, or three CDRs and/or hypervariable loops from a light chain variable region having the amino acid sequence of an antibody described herein, e.g., an antibody selected from any of BAP058 -hum01 BAP058-hum02 BAP058-hum03 BAP058-hum04 BAP058hum05 BAP058-hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058hum11 BAP058-hum12 , BAP058-hum15, BAP058-hum16, BAP058hum17, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O, as summarized in Table 1, or a sequence substantially identical to them (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to them, and/or having one, two, three or more substitutions, insertions or deletions, e.g. , conservative changes). In one embodiment, the PD-L1 antibody molecule contains all six CDRs and/or hypervariable loops described herein, eg, those described in Table 1. 1.

In one embodiment, an anti-PD-L1 antibody molecule has a variable region that is identical in sequence to, or that differs by 1, 2, 3, or 4 amino acids from, the variable region described herein (e.g., the FR region described herein) .

In one embodiment, the PD-L1 antibody molecule is a full-length antibody or fragment thereof (eg, Fab, F(ab') ₂ , Fv, or single chain Fv fragment (scFv)). In certain embodiments, the anti-PD-L1 antibody molecule is mono

- 15 040861 clonal antibody or antibody with one specificity. The PD-L1 antibody molecule can also be a humanized, chimeric antibody molecule, a camelid antibody molecule, a shark antibody molecule, or an in vitro-produced antibody molecule. In one embodiment, the anti-PD-L1 antibody molecule is a humanized antibody molecule. The heavy and light chains of an anti-PD-L1 antibody molecule may be full-length (for example, an antibody may include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete heavy chains) or may include an antigen-binding fragment ( e.g., Fab, F(ab')2, Fv, single chain Fv fragment, single domain antibody, diantibody (dAb), divalent antibody or bispecific antibody or fragment thereof, single domain variant thereof or camelid animal antibody).

In certain embodiments, the anti-PD-L1 antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity for PD-L1 and a second binding specificity for TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), PD -1 or PD-L2. In one embodiment, the bispecific antibody molecule binds to PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds to PD-L1 and CEACAM (eg, CEACAM-1, CEACAM-3 and/or CEACAM-5). In another embodiment, the bispecific antibody molecule binds to PD-L1 and CEACAM-1. In another embodiment, the bispecific antibody molecule binds to PD-L1 and CEACAM-5. In another embodiment, the bispecific antibody molecule binds to PD-L1 and PD-1. In another embodiment, the bispecific antibody molecule binds to PD-L1 and PD-L2. Any combination of the above molecules can be produced as a multispecific antibody molecule, e.g., a trispecific antibody, which includes a first binding specificity for PD-L1 and a second and third binding specificity for one or more of: TIM-3, LAG-3, CEACAM ( for example, CEACAM-1, CEACAM-3 and/or CEACAM-5), PD-1 or PD-L2. In some embodiments, the second and/or third binding specificity for TIM3, LAG-3, and/or PD-1 involves an amino acid sequence or is encoded by a nucleotide sequence as described herein (e.g., as described in the section titled Immune Point Molecule Inhibitors control, starting on page 218 of the present description below (including all publications mentioned in it).

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

In other embodiments, the anti-PD-L1 antibody molecule has a heavy chain constant region (Fc) selected from, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE heavy chain constant regions; in particular selected, for example, from IgG1, IgG2, IgG3 and IgG4 constant regions, more specifically IgG1 or IgG2 heavy chain constant region (eg human IgG1, IgG2 or IgG4). In one embodiment, the heavy chain constant region is human IgG1. In another embodiment, the anti-PD-L1 antibody molecule has a light chain constant region selected, for example, from kappa or lambda light chain constant regions, preferably kappa (eg, human kappa). In one embodiment, the constant region is altered, e.g., mutated, to modify properties of the anti-PD-L1 antibody molecule (e.g., to increase or decrease one or more of: 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 change binding Fc receptor (e.g., mutant positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) SEQ ID NOs: 212 or 214, or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K), and 317 (N to F) SEQ ID NO: 215, 216, 217 or 218). In another embodiment, the IgG4 heavy chain constant region, eg, human IgG4, is mutated at position 228 (eg, S to P), eg, as shown in Table 1. 3. In certain embodiments, anti-PD-L1 antibody molecules comprise human IgG4 that is mutated at position 228 (eg, S to P), eg, as shown in Table 1. 3; and a kappa light chain constant region, for example, as shown in Table 1. 3. In another embodiment, an IgG1 heavy chain constant region, e.g., human IgG1, is mutated at one or more of position 297 (e.g. N to A), position 265 (e.g. D to A), position 329 (e.g. , from P to A), provisions

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234 (for example, from L to A) or positions 235 (for example, from L to A), for example, as shown in table. 3. In certain embodiments, the anti-PD-L1 antibody molecules comprise human IgG1 that is mutated at one or more of the above positions, for example, as shown in Table 1. 3; and a kappa light chain constant region, for example, as shown in Table 1. 3.

In one embodiment, the anti-PD-L1 antibody molecule is isolated or recombinant.

In one embodiment, the anti-PD-L1 antibody molecule is a humanized antibody molecule.

The invention also relates to a nucleic acid molecule that contains one or both nucleotide sequences that encode variable regions, CDRs, hypervariable loops, framework regions of heavy and light chain anti-PD-L1 antibody molecules as described herein. In certain embodiments, the nucleotide sequence that encodes an anti-PD-L1 antibody molecule is codon-optimized. For example, the invention relates to first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an anti-PD-L1 antibody molecule selected from one or more, for example, any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11,

BAP058-hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17,

BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O, as summarized in Table 1, or a sequence substantially identical to them. For example, the nucleic acid may include the nucleotide sequence as listed in Table. 1 and 2, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99%, or more identical to it, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables 1 and 2).

In other embodiments, the nucleic acid molecule comprises a nucleotide sequence that encodes a heavy chain variable domain and/or a heavy chain constant region comprising the amino acid sequence BAP058-Clone-K, BAP058-Clone-L, BAP058Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table. 1; or the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, a sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the aforementioned 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 BAP058-Clone-K, BAP058-Clone-L, BAP058Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table. 1; or the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, a sequence at least about 85%, 90%, 95%, 99% or more identical) to any of the above sequences.

The aforementioned nucleotide sequences encoding the anti-PD-L1 antibody heavy and light chain variable domain and constant regions may be present in a single nucleic acid molecule or in the same nucleic acid molecule. In certain embodiments, the nucleic acid molecules comprise a nucleotide sequence encoding a leader sequence.

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

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

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

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In another embodiment, the nucleic acid molecule comprises one or more heavy chain framework regions (e.g., any of VHFW1 (type a), VHFW1 (type b), VHFW1 (type c), VHFW1 (type d), VHFW2 (type a), VHFW2 (type a'), VHFW2 (type b), VHFW2 (type c), VHFW2 (type d), VHFW2 (type e), VHFW3 (type a), VHFW3 (type b), VHFW3 (type c), VHFW3 (type d), VHFW3 (type e) or VHFW4, or any combination thereof, such as a combination of framework regions as described herein) of any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058hum05, BAP058-hum06 BAP058-hum07 BAP058-hum08 BAP058-hum09 BAP058-hum10 BAP058hum11 BAP058-hum12 BAP058-hum13 BAP058-hum14 BAP058-hum15 BAP058-hum16 BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N or BAP058-Clone-O, as summarized in Table 1 and 2, or a sequence substantially identical to them. For example, a nucleic acid molecule may contain a nucleotide sequence, as indicated in table. 1 and 2, or a sequence substantially identical to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences presented in Tables 1 and 2).

In another embodiment, the nucleic acid molecule comprises 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), VLFW1 (type f), VLFW2 (type a), VLFW2 (type c), VLFW3 (type a), VLFW3 (type b), VLFW3 (type c), VLFW3 (type d), VLFW3 (type e), VLFW3 ( type f), VLFW3 (type g), or VLFW4, or any combination thereof, such as a combination of framework regions as described herein) of any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05 . -Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O, as summarized in Table 1 and 2, or a sequence substantially identical to them. For example, a nucleic acid molecule may contain a nucleotide sequence, as indicated in table. 1 and 2, or a sequence substantially identical to it (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it, or that differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences presented in Tables 1 and 2).

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

In another aspect, the application relates to host cells and vectors containing the nucleic acids described in the present description. Nucleic acids can be in the same vector or in different vectors in the same host cell or in separate host cells. The host cell may be a eukaryotic cell, eg a mammalian cell, an insect cell, a yeast cell, or a prokaryotic cell, eg E. coll. For example, the mammalian cell may be a cultured cell or cell line. Exemplary mammalian cells include lymphocytic cell lines (eg, NSO), Chinese hamster ovary (CHO) cells, COS cells, oocytes, and transgenic animal cells, eg, mammary epithelial cells.

In one aspect, the invention relates to a method for providing an antibody molecule as described herein. The method includes providing a PD-L1 antigen (eg, an antigen containing at least a portion of a PD-L1 epitope); obtaining an antibody molecule that specifically binds to the PD-L1 polypeptide; and evaluating whether the antibody molecule specifically binds to the PD-L1 polypeptide, or evaluating the effectiveness of the antibody molecule in modulating, eg inhibiting, PD-L1 activity. In addition, the method may include administering the antibody molecule to an individual, such as a human or non-human animal.

In another aspect, the invention relates to compositions, such as pharmaceutical compositions, which include a pharmaceutically acceptable carrier, excipient or stabilizer, and at least one of the anti-PD-L1 antibody molecules described herein. In one embodiment, a composition, eg, a pharmaceutical composition, comprises a combination of an antibody molecule and one or more agents, eg, a drug or other antibody molecule, as described herein. In one embodiment, the antibody molecule is conjugated to a label or drug.

The anti-PD-L1 antibody molecules described herein can inhibit, reduce, or neutralize one or more PD-L1 activities, resulting in blockade or reduction of immune checkpoint activity. In one embodiment, the antibody molecule results in one or more of: an increase in the level of tumor-infiltrating lymphocytes, an increase in T-cell receptor-mediated proliferation, a decrease in immune escape of malignant cells, a restoration of effector cell function (e.g., one or more of T-cell proliferation, secretion IFN-γ or cytolytic function), inhibition of regulatory T cell function or effect on the activity of multiple cell types such as regulatory T cells, effector T cells and NK cells). Thus, such antibody molecules can be used to treat or prevent disorders in which it is desirable to enhance the immune response in an individual.

Use of Anti-PD-L1 Antibody Molecules.

Thus, in another aspect, a method for modulating an immune response in an individual is provided. The method includes administering to an individual an anti-PD-L1 antibody molecule as described herein (e.g., a therapeutically effective amount of an anti-PD-L1 antibody molecule), alone or in combination with one or more agents or procedures, such that the individual's immune response is modulated. In one embodiment, the antibody molecule enhances, stimulates or enhances the immune response in an individual. The subject may be a mammal, eg a primate, preferably a higher primate, eg a human (eg, a patient having or at risk of having a disorder described herein). In one embodiment, the individual needs to enhance the immune response. In one embodiment, the individual has or is at risk of having a disorder described herein, such as a cancer or infectious disorder, as described herein. In certain embodiments, the individual is an immunodeficient individual or is at risk of being immunodeficient. For example, the subject is or has been subjected to chemotherapy treatment and/or radiation therapy. Alternatively, or in combination, the individual is immunodeficient as a result of the infection or is at risk of having it.

In one aspect, a method is provided for treating (eg, one or more of reducing, inhibiting, or slowing the progression) of a cancer or neoplasm in an individual. The method includes administering to an individual an anti-PD-L1 antibody molecule as described herein, for example, a therapeutically effective amount of an anti-PDL1 antibody molecule, alone or in combination with one or more agents or techniques. In certain embodiments, the anti-PD-L1 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), for example, as described herein.

In certain embodiments, the cancer being treated with the anti-PD-L1 antibody molecule includes, but is not limited to, solid tumor, hematologic cancer (eg, leukemia, lymphoma, myeloma, eg, multiple myeloma), and metastatic lesion. In one embodiment, the cancer is a solid tumor. Examples of solid tumors include malignant neoplasms such as sarcomas and carcinomas such as adenocarcinomas and carcinomas of various organ systems such as adenocarcinomas and carcinomas of the lung, breast, ovary, lymphoid system, gastrointestinal tract (eg colon), anal area, genitals, and genitourinary tract (eg, kidney, urothelium, bladder cells, prostate), pharynx, CNS (eg, brain, neuronal or glial cells), head and neck, skin (eg, melanoma), nasopharyngeal cancer, eg, differentiated or undifferentiated metastasizing or locally recurrent carcinoma of the nasopharynx), and pancreas, as well as adenocarcinomas, which include malignancies such as colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, cancer of the small intestine, and cancer of the esophagus . The cancer may be an early, intermediate or late stage cancer, or a metastatic cancer.

In one embodiment, the cancer is selected from lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC with squamous and/or non-squamous histology, or NSCLC adenocarcinoma)), melanoma (e.g., advanced melanoma), kidney cancer (e.g., renal cell carcinoma), liver cancer, myeloma (eg, multiple myeloma), prostate cancer, breast cancer (eg, breast cancer that does not express one, two, or all of the estrogen receptor, progesterone receptor, or Her2/neu, for example, triple-negative breast cancer), colorectal cancer, pancreatic cancer, head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC)), anal cancer, gastric and esophageal cancer, thyroid cancer, cervical cancer , lymphoproliferative disease (eg, post-transplant lymphoproliferative disease), or hematologic malignancy, T -cell lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, or leukemia (eg, myeloid leukemia or lymphoid 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 lymphoma, eg, diffuse large B cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma.

In one embodiment, the cancer is breast cancer, such as metastatic breast cancer.

In one embodiment, the cancer is a leukemia, such as chronic myelogenous leukemia.

In one embodiment, the cancer is a head and neck cancer, such as head and neck squamous cell carcinoma (HNSCC).

In one embodiment, the cancer is a myelodysplastic syndrome.

In one embodiment, the cancer is bladder cancer (eg, transitional cell carcinoma).

In one embodiment, the cancer is colon cancer.

In one embodiment, the cancer is a lung cancer, such as non-small cell lung cancer (NSCLC), such as stage IV NSCLC or recurrent NSCLC, NSCLC adenocarcinoma or NSCLC squamous cell carcinoma, or small cell lung cancer.

In one embodiment, the cancer is a skin cancer, such as melanoma (eg, stage III or IV melanoma) or Merkel cell carcinoma. In one embodiment, the cancer is a melanoma, such as advanced melanoma. In one embodiment, the cancer is an advanced or unresectable melanoma that has not responded to other therapies. In other embodiments, the cancer is a BRAF-mutated melanoma (eg, BRAF V600 mutation). In other embodiments, the anti-PD-L1 antibody molecule is administered following treatment with an anti-CTLA-4 antibody (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib).

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

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

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

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

In one embodiment, the cancer microenvironment has an increased level of PD-L1 expression. Alternatively, or in combination, the cancer microenvironment may have increased expression of IFNy and/or CD8. In one embodiment, alternatively or in combination, the individual has an increased level of Bim expression (eg, in PD-1+ CD8+ T cells compared to PD-1 ^- CD8+ T cells).

In some embodiments, the individual has or is identified as having a tumor that has one or more of a high level or expression of PD-L1, or as being positive for tumor-infiltrating lymphocytes (TIL+) (e.g., as having an increased amount of TIL), or having both of these signs. In certain embodiments, the individual has or is identified as having a tumor that has a high level or expression of PD-L1 and that is TIL ⁺ . In some embodiments, the methods described herein further include identifying an individual based on the presence of a tumor that has one or more of a high level or expression of PD-L1, or is TIL ⁺ , or has both of these features. In certain embodiments, the methods described herein further comprise identifying an individual based on the presence of a tumor that has a high level or expression of PD-L1 and is TIL ⁺ . In some embodiments, tumors that are TIL ⁺ are positive for CD8 and IFNy. In some embodiments, the individual has or is identified as having a high percentage of cells that are positive for one, two, or more of PD-L1, CD8, and/or IFNy. In certain embodiments, the individual has or is identified as having a high percentage of cells that are positive for all of PD-L1, CD8, and IFNy. The subject may be identified before, during, or after the administration of therapy, eg, therapy with an anti-PD-L1 antibody molecule and/or other therapy, as described herein. In one variant

- 20 040861 implementation of the individual is identified prior to treatment, such as therapy, as described in the present description (eg, before therapy or between treatments).

In some embodiments, the methods described herein further include identifying an individual based on the presence of a high percentage of cells that are positive for one, two, or more of PD-L1, CD8, and/or IFNy. In certain embodiments, the methods described herein further include identifying an individual based on the presence of a high percentage of cells that are positive for all of PD-L1, CD8, and IFNy. In some embodiments, the individual has or is identified as having one, two, or more of PD-L1, CD8, and/or IFNy, and one or more of lung cancer, eg, squamous cell lung cancer or lung adenocarcinoma; head and neck cancer; squamous cell carcinoma of the cervix; stomach cancer; esophageal cancer; thyroid cancer; melanoma and/or nasopharyngeal cancer (NPC). In certain embodiments, the methods described herein further include identifying an individual based on the presence of one, two, or more of PD-L1, CD8, and/or IFNy, and one or more of a lung cancer, e.g., 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. The subject may be identified before, during, or after the administration of therapy, eg, therapy with an anti-PD-L1 antibody molecule and/or other therapy, as described herein. In one embodiment, the individual is identified prior to the administration of therapy, eg, therapy, as described herein (eg, before the start of therapy or between treatments).

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

In a further aspect, the invention relates to a method of treating an infectious disease in a subject, comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody molecule described herein, alone or in combination with one or more agents or techniques. In one embodiment, the infectious disease is selected from hepatitis (eg, hepatitis C infection) or sepsis.

In addition, the invention relates to a method of enhancing the immune response to an antigen in an individual, comprising administering to the individual: (i) the antigen; and (ii) an anti-PD-L1 antibody molecule such that there is an enhancement of the immune response to the antigen in the individual. The antigen may be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen from a pathogen.

The anti-PD-L1 antibody molecule can be administered to an individual systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary infusion), topically, or by application to mucous membranes, such as mucous membranes. membranes of the nose, throat and bronchial tubes.

Dosages and therapeutic regimens for an anti-PD-L1 antibody molecule can be determined by those skilled in the art. In certain embodiments, the anti-PD-L1 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 dosing regimen may vary from, for example, once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-PD-L1 antibody molecule is administered at a dose of about 10 to 20 mg/kg biweekly. In one embodiment, the anti-PD-L1 antibody molecule is administered, alone or in combination (eg, in combination with an anti-LAG-3 antibody molecule), at a dose of less than or about 5 mg/kg; less than or about 4 mg/kg; less than or about 3 mg/kg; less than or about 2 mg/kg; less than or approximately 1 mg/kg every other week. In one embodiment, the anti-PD-L1 antibody molecule is administered at a dose of 1 to 5 mg/kg biweekly; 1 to 4 mg/kg every other week, 1 to 3 mg/kg every other week, or 1 to 2 mg/kg every other week. In one embodiment, the anti-LAG-3 antibody molecule is administered, alone or in combination (eg, in combination with an anti-PD-L1 antibody molecule) at a dose of 1 to 5 mg/kg biweekly; 1 to 4 mg/kg every other week, 1 to 3 mg/kg every other week, or 1 to 2 mg/kg every other week.

The antibody molecules described herein may be used in the methods described herein, although other anti-PD-L1 antibodies may be used instead of or in combination with an anti-PD-L1 antibody molecule of the invention.

Combined therapy.

The methods and compositions described herein may be used in combination with other agents or therapies. In one embodiment, the methods described herein comprise administering to an individual an anti-PD-L1 antibody molecule, as described herein, in combination with an agent or therapeutic procedure or method of therapy, in an amount effective to treat or warning of a violation. Administration of the anti-PD-L1 antibody molecule and administration of therapeutic agents or administration of therapeutic procedures or therapies may be performed simultaneously or sequentially in any order. Any combination and sequence of anti-PD-L1 antibody molecules and other agents, procedures, or treatments (eg, as described herein) may be used. The administration of the anti-PD-L1 antibody molecule and/or the administration of other therapeutic agents or the administration of therapeutic procedures or therapies can be performed during periods of active disorder or during periods of remission or less active disease. The anti-PD-L1 antibody molecule can be administered prior to another treatment, concurrently with treatment, after treatment, or during remission of the disorder.

In certain embodiments, the methods and compositions described herein are administered in combination with one or more other antibody molecules, chemotherapy, another anti-cancer agent (e.g., targeted anti-cancer therapy, gene therapy, viral therapy, RNA therapy, bone marrow transplantation, nanotherapy, or oncolytic drugs), cytotoxic agents, immune therapies (eg, cytokines or cellular immune therapy), surgical procedures (eg, lumpectomy or mastectomy), or radiation procedures, or a combination of any of the above. Additional therapy may be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the complementary therapy is an enzymatic inhibitor (eg, a small molecule enzymatic inhibitor) or a metastatic inhibitor. Exemplary cytotoxic agents that can be administered in combination include antimicrotubulin agents, topoisomerase inhibitors, antimetabolites, mitosis inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents that can interfere with the signaling cascade, agents that stimulate apoptosis, proteasome inhibitors, and radiation therapy (for example, local irradiation or irradiation of the whole body (for example, gamma irradiation)). In other embodiments, the complementary therapy is surgery or radiation therapy, or a combination thereof. In other embodiments, the adjunctive therapy is a therapy that targets one or more of the PI3K/AKT/mTOR cascades, an HSP90 inhibitor, or a tubulin inhibitor.

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

Illustrative non-limiting combinations and uses of anti-PD-L1 antibody molecules include the following.

In certain embodiments, an anti-PD-L1 antibody molecule is administered in combination with a modulator of a co-stimulatory molecule or an inhibitory molecule, such as a co-inhibitory ligand or receptor.

In one embodiment, an anti-PD-L1 antibody molecule is administered in combination with a modulator, such as an agonist, of a costimulatory molecule. In one embodiment, the costimulatory molecule agonist is selected from an agonist (e.g., an antibody agonist or antigen-binding fragment thereof, or a soluble fusion construct) 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.

In one embodiment, an anti-PD-L1 antibody molecule is administered in combination with an inhibitor of an inhibitory molecule (or immune response checkpoint inhibitor) selected from PD-1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM ( eg CEACAM-1, CEACAM-3 and/or CEACAM-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) can be used to inhibit the expression of an inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, such as a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to an inhibitory molecule. In one embodiment, the inhibitor is a soluble ligand (eg, CTLA-4Ig), or an antibody or antibody fragment that binds to PD-1, PD-L2, or CTLA-4. For example, an anti-PD-L1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, such as ipilimumab, for example, for the treatment of a cancer (for example, a cancer selected from: melanoma, for example, metastatic melanoma; lung cancer, for example, 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 (eg, ipilimumab) with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib).

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In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof.

In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or antigen-binding fragment thereof.

In other embodiments, an anti-PD-L1 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 PD-L1 antibody molecule is administered in combination with a CEACAM inhibitor (eg, CEACAM-1, CEACAM-3 and/or CEACAM-5), eg, an anti-CEACAM antibody molecule. In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with a CEACAM-1 inhibitor, eg, an anti-CEACAM-1 antibody molecule. In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with a CEACAM-5 inhibitor, eg, an anti-CEACAM-5 antibody molecule.

The combination of antibodies described herein can be administered alone, eg as single antibodies or antigen-binding fragments thereof, or in a bound state, eg as a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody is administered that comprises an anti-PD-L1 antibody molecule and an anti-TIM-3 antibody, anti-CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5) or anti-LAG-3, or its antigen binding fragment. In certain embodiments, a combination of the antibodies described herein is used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor or a hematologic cancer).

In some embodiments, an antibody molecule (e.g., a mono-, bi-, or trispecific antibody) for TIM-3, LAG-3, and/or PD-1 used in any of the methods and compositions described herein comprises an amino acid sequence, or it is encoded by a nucleotide sequence as described herein (for example, as described in the section titled Inhibitors of Immune Checkpoint Molecules starting on page 218 of this specification below (including all publications cited therein).

In other embodiments, the anti-PD-L1 antibody molecule is administered in combination with a cytokine. The cytokine can be administered as a fusion with an anti-PD-L1 antibody molecule or as separate compositions. In one embodiment, the anti-PD-L1 antibody is administered in combination with one, two, three or more cytokines, eg, as a fusion molecule or as separate compositions. In one embodiment, the cytokine is an interleukin (IL) selected from one, two, three or more of IL-1, IL-2, IL-15, or IL-21. In certain embodiments, a combination of an anti-PD-L1 antibody molecule and a cytokine of the present invention is used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor).

In certain embodiments, an anti-PD-L1 antibody molecule is administered in combination with an antibody specific for HLA C, eg, an antibody specific for killer cell immunoglobulin-like receptors (also referred to as an anti-KIR antibody). In certain embodiments, a combination of an anti-PD-L1 antibody molecule and an anti-KIR antibody is used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor, eg, an advanced solid tumor).

In one embodiment, the anti-PD-L1 antibody molecule is administered in combination with cellular immunotherapy (eg, Provenge® (eg, Sipuleucel-T)) and optionally in combination with cyclophosphamide. In certain embodiments, a combination of an anti-PD-L1 antibody molecule, Provenge®, and/or cyclophosphamide is used to treat a cancer, eg, a cancer as described herein (eg, prostate cancer, eg, advanced prostate cancer).

In another embodiment, the PD-L1 antibody molecule is administered in combination with a vaccine, eg, a cancer vaccine (eg, dendritic cell-based renal carcinoma (DC-RCC) vaccine). In one embodiment, the vaccine is peptide-based, DNA-based, RNA-based, or antigen-based, or a combination thereof. In embodiments, the vaccine contains one or more peptides, nucleic acids (eg, DNA or RNA), antigens, or a combination thereof. In certain embodiments, the combination of an anti-PD-L1 antibody molecule and a DC-RCC vaccine is used to treat a cancer, e.g., a cancer as described herein (e.g., renal cell carcinoma, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).

In another embodiment, the anti-PD-L1 antibody molecule is administered in combination with an adjuvant.

In another embodiment, the anti-PD-L1 antibody molecule is administered in combination with chemotherapy and/or immunotherapy. For example, an anti-PD-L1 antibody molecule can be used to treat myeloma, alone or in combination with one or more of: chemotherapeutic or other anti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), anti-TIM-3 antibodies treated with a tumor dendritic cell antigen, fusion (eg, electrofusion) of tumor cells and dendritic cells, or vaccination with an immunoglobulin idiotype produced by malignant plasma cells. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with an anti-TIM-3 antibody for the treatment of myeloma, eg, multiple myeloma.

In one embodiment, an anti-PD-L1 antibody molecule is used in combination with chemotherapy to treat lung cancer, eg, non-small cell lung cancer. In one embodiment, an anti-PD-L1 antibody molecule is used with standard lung cancer chemotherapy, eg, NSCLC, eg, platinum doublet therapy, to treat lung cancer. In other embodiments, an anti-PD-L1 antibody molecule is used in combination with an indolamine-pyrrole-2,3-dioxygenase (IDO) inhibitor (e.g., (4E)-4-[(3-chloro-4fluoroanilino)nitrosomethylidene]-1,2 ,5-oxadiazol-3-amine (also known as INCB24360), indoxymod (1-methyl-D-tryptophan), a-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919 ), etc.)) in an individual with advanced or metastatic cancer (eg, a patient with metastatic and recurrent NSCL cancer).

In other embodiments, an anti-PD-L1 antibody molecule is used in combination with one or more of: an immune-based strategy (eg, interleukin-2 or interferon-alpha), 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; a RNA-i inhibitor; or an inhibitor of a downstream mediator of VEGF signaling, eg, the mammalian target of rapamycin (mTOR) inhibitor, eg, everolimus and temsirolimus. Any of these combinations can be used to treat kidney cancer, eg, renal cell carcinoma (RCC) (eg, clear cell renal cell carcinoma (CCRCC)) or metastatic RCC.

In some embodiments, an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule described herein, is used in combination with a MEK inhibitor (eg, a MEK inhibitor as described herein). In some embodiments, a combination of an anti-PD-L1 antibody and a MEK inhibitor is used to treat a cancer (eg, the cancer described herein). In some embodiments, the cancer being treated with the combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell carcinoma. In certain embodiments, the cancer comprises a BRAF mutation (eg, BRAF V600E mutation), wild-type BRAF, wild-type KRAS, or an activating KRAS mutation. The cancer may be an early, intermediate or late stage cancer.

In another embodiment, an anti-PD-L1 antibody molecule is used in combination with one, two, or all of oxaliplatin, leucovorin, or 5-FU (eg, FOLFOX concomitant treatment). Alternatively, or in combination, the combination further comprises a VEGF inhibitor (eg, a VEGF inhibitor as described herein). In some embodiments, a combination of an anti-PD-L1 antibody, FOLFOX concomitant treatment, and a VEGF inhibitor is used to treat a cancer (eg, the cancer described herein). In some embodiments, the cancer being treated with the combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell carcinoma. The cancer may be an early, intermediate or late stage cancer.

In other embodiments, the anti-PD-L1 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-L1 antibody molecule is administered with an agent that targets the 4-1BB receptor (eg, an antibody that stimulates signaling through 4-1BB (CD-137), eg, PF-2566). In one embodiment, an anti-PD-L1 antibody molecule is administered in combination with a tyrosine kinase inhibitor (eg, axitinib) and an agent that targets the 41BB receptor.

An anti-PD-L1 antibody molecule may be associated with a substance, such as a cytotoxic agent or a moiety (eg, a therapeutic drug; a radiation-emitting compound; molecules of plant, fungal, or bacterial origin; or a biological protein (eg, a protein toxin) or particle (for example, a recombinant viral particle, for example, through a viral envelope protein)). For example, an antibody can be associated with a radio

- 24 040861 active isotope, such as α-, β- or γ-emitter or β- and γ-emitter.

You can use any combination and sequence of molecules of antibodies against PD-L1 and other drugs, techniques or treatments (for example, as described in the present description). Administration of the antibody molecule and/or other drugs, treatments or therapies can be done during periods of active disorder or during periods of remission or less active disease. The antibody molecule can be administered prior to another treatment, concurrently with treatment, after treatment, or during remission of the disorder.

Additional combined therapies.

The methods and compositions described herein (for example, anti-PD-L1 antibodies and methods using them) can be used in combination with other agents or therapeutic regimens, for example, a second drug selected from one or more of the agents shown in Table. 6. In one embodiment, the methods described herein comprise administering to an individual an anti-PD-L1 antibody molecule as described herein (optionally in combination with one or more inhibitors of PD-1, PD-L2, LAG-3, TIM -3, CEACAM (for example, CEACAM-1, CEACAM-3 and/or CEACAM-5), or CTLA-4) also include the introduction of a second drug selected from one or more of the funds listed in table. 6 in an amount effective to treat or prevent a disorder, such as a disorder as described herein, such as cancer. When administered in combination, an anti-PD-L1 antibody molecule, an additional agent (e.g., a second or third agent), or all of them, may be administered in an amount or dose that is greater than, lower, or the same as the amount or dosage each agent separately, for example, as monotherapy. In certain embodiments, the administered amount or dosage of the anti-PD-L1 antibody, the additional agent (e.g., the second or third agent), or all of them, is lower (e.g., at least 20%, at least 30%, at least 40% or at least 50%) than the amount or dosage of each agent used alone, for example, as monotherapy. In other embodiments, the amount or dosage of the anti-PD-L1 antibody, additional agent (e.g., second or third agent), or all of them that results in the desired effect (e.g., cancer treatment) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower).

In other embodiments, the implementation of the second drug is selected from one or more of the funds listed in table. 6. In one embodiment, the cancer is selected from lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC with squamous and/or non-squamous histology or NSCLC adenocarcinoma)) or described in the publication shown in Table. 6. In some embodiments, the second drug is selected from one or more of:

1) protein kinase C (PKC) inhibitor;

2) inhibitor of heat shock protein 90 (HSP90);

3) a phosphoinositide 3-kinase inhibitor (PI3K) and/or a rapamycin target (mTOR);

4) a cytochrome P450 inhibitor (eg a CYP17 inhibitor or a 17-alpha-hydroxylase/C17-20-lyase inhibitor);

5) an iron chelating agent;

6) an aromatase inhibitor;

7) a p53 inhibitor, eg an inhibitor of the p53/Mdm2 interaction;

8) apoptosis inducer;

9) an angiogenesis inhibitor;

10) an aldosterone synthase inhibitor;

11) a smoothened receptor inhibitor (SMO);

12) a prolactin receptor (PRLR) inhibitor;

13) Wnt signal transduction inhibitor;

14) a CDK4/6 inhibitor;

15) fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor;

16) an inhibitor of macrophage colony stimulating factor (M-CSF);

17) an inhibitor of one or more of c-KIT, histamine release, Flt3 (eg FLK2/STK1) or PKC;

18) an inhibitor of one or more of VEGFR-2 (eg, FLK-1/KDR), PDGFR-beta, c-KIT, or Raf kinase C;

19) a somatostatin agonist and/or a growth hormone releasing inhibitor;

20) an anaplastic lymphoma kinase (ALK) inhibitor;

21) inhibitor of insulin-like growth factor receptor 1 (IGF-1R);

22) P-glycoprotein 1 inhibitor;

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23) vascular endothelial growth factor receptor (VEGFR) inhibitor;

24) BCR-ABL kinase inhibitor;

25) an FGFR inhibitor;

26) CYP11B2 inhibitor;

27) an HDM2 inhibitor, eg an HDM2-p53 interaction inhibitor;

28) a tyrosine kinase inhibitor;

29) c-MET inhibitor;

30) a JAK inhibitor;

31) DAC inhibitor;

32) Πβ-hydroxylase inhibitor;

33) an IAP inhibitor;

34) a PIM kinase inhibitor;

35) porcupine inhibitor;

36) a BRAF inhibitor, eg V600E BRAF or wild-type BRAF;

37) HER3 inhibitor;

38) MEK inhibitor; or

39) a lipid kinase inhibitor, for example, as described in the present description and in table. 6.

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

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

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

In some embodiments, the implementation of the second drug is administered at a therapeutic dose or at a dose below the therapeutic dose. In certain embodiments, the concentration of the second drug that is required to achieve inhibition, such as growth inhibition, is lower when the second drug is administered in combination with an anti-PD-L1 antibody molecule than when the second drug is administered alone. In certain embodiments, the concentration of the anti-PD-L1 antibody molecule that is required to achieve inhibition, e.g., growth inhibition, is lower when the anti-PD-L1 antibody molecule is administered in combination with a second drug than when the anti-PD-L1 antibody molecule is administered. individually. In certain combination therapy embodiments, the concentration of the second drug that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second drug as monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower. In certain embodiments, in combination therapy, the concentration of the anti-PD-L1 antibody molecule that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the anti-PD-L1 antibody molecule as monotherapy, for example, by 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower.

Additional Features and Embodiments Alternatively, or in combination with the methods described herein, the invention relates to a method of treating (e.g., inhibiting, reducing, mitigating, or preventing) a disorder, e.g., a hyperproliferative condition or disorder (e.g., cancer) in an individual. The method includes administering to an individual a combination of two, three or more drugs selected from one, two or all of the following categories (i)-(iii):

(i) an agent that enhances the presentation of an antigen (eg, tumor antigen);

(ii) an agent that enhances an effector cell response (eg, activation and/or mobilization of B cells and/or T cells); or (iii) an agent that reduces tumor immunosuppression, thereby treating a disorder, eg, a hyperproliferative condition or disorder (eg, cancer).

In some embodiments, the combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein). The cancer to be treated may be, for example, the cancer described herein, such as lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), gastric cancer, thyroid cancer , melanoma, oropharyngeal cancer, or breast cancer.

In another aspect, the invention relates to a method for reducing the activity (eg, growth, survival, or viability, or all of them) of a hyperproliferative (eg, malignant) cell. The method includes contacting a cell with a combination of two, three or more drugs selected from one, two or all of the following categories (i)-(iii):

(i) an agent that enhances the presentation of an antigen (eg, tumor antigen);

(ii) an agent that enhances an effector cell response (eg, activation and/or mobilization of B cells and/or T cells); or (iii) an agent that reduces tumor immunosuppression, thereby reducing the activity of a hyperproliferative cell.

In some embodiments, the combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein). The method can be performed on an individual, for example, as part of a therapeutic protocol. The cancer cell can be, for example, a cancer cell as described herein, such as lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), gastric cancer, thyroid cancer, melanoma, nasopharyngeal cancer, or breast cancer.

In certain embodiments of the methods described herein, the method further comprises determining the level and/or distribution of immune cell (e.g., T-cell) infiltrate (e.g., the level and/or distribution of tumor-infiltrating lymphocytes (TIL)) in an individual. . In one embodiment, the level and/or distribution of immune cell infiltrate is determined in vivo, e.g., in a non-invasive manner (e.g., by detecting an antibody to a T-cell marker labeled with a detectable label using a suitable imaging technique, e.g., scanning with a positron emission tomography (PET)). In other embodiments, the level of immune cell infiltrate is determined in a sample (eg, tumor biopsy) obtained from an individual (eg, using immunohistochemical methods). In some embodiments, an increased level and/or a wider distribution of TIL in a cancer, eg, a neoplasm (eg, relative to a reference or control) indicates a better prognosis for the individual, eg, a better therapeutic outcome. In some embodiments, a reduced level and/or less widespread TIL in a cancer, eg, neoplasm (eg, relative to a reference or control) indicates a poorer prognosis for the individual, eg, a more negative therapeutic outcome. In some embodiments, the reference is an individual at a different time period, such as prior to therapy or at an earlier stage of therapy). In embodiments corresponding to a low level or undetectable tumor infiltrate in an individual, one or more agents of categories (i) or (ii), or both (i) and (ii) are administered. In other embodiments, corresponding to a detectable level or elevated level of tumor infiltrate in an individual, one or more agents of category (iii) are administered. The discovery steps can also be used, for example, to monitor the effectiveness of a drug described in the present invention. For example, the discovery step can be used to monitor the efficacy of category (i), (ii) and/or (iii) drugs.

In another aspect, the invention relates to a composition (for example, one or more compositions or dosage forms), which includes a combination of two, three or more drugs selected from one, two or all of the following categories (i)-(iii):

(i) an agent that enhances the presentation of an antigen (eg, tumor antigen);

(ii) an agent that enhances an effector cell response (eg, activation and/or mobilization of B cells and/or T cells); or (iii) an agent that reduces tumor immunosuppression.

In some embodiments, the combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein).

In another aspect, the invention provides a composition (eg, one or more compositions or dosage forms as described herein) for use in the treatment of a disorder, eg, cancer. In some embodiments, the composition for use includes a combination of two, three or more drugs selected from one, two or all of the following categories (i)-(iii):

(i) an agent that enhances the presentation of an antigen (eg, tumor antigen);

(ii) an agent that enhances an effector cell response (eg, activation and/or mobilization of B cells and/or T cells); or (iii) an agent that reduces tumor immunosuppression.

In some embodiments, the combination used includes a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein). The malignant tumor may be, for example, a malignant tumor described herein, such as lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), gastric cancer, thyroid cancer, melanoma , nasopharyngeal cancer, or breast cancer.

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Also contemplated are formulations, such as dosage formulations, and kits, such as therapeutic kits, that include a combination of two, three, or more drugs selected from one, two, or all of the following categories (i)-(iii):

(i) an agent that enhances the presentation of an antigen (eg, tumor antigen);

(ii) an agent that enhances an effector cell response (eg, activation and/or mobilization of B cells and/or T cells); or (iii) an agent that reduces the immunosuppression of the tumor, thereby reducing its activity in the cell, and (optionally) instructions for use.

In some embodiments, the combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein).

Combinations of drugs described in the present description, include two or more drugs described in the present description. Drugs in combination may belong to the same category, for example, two or more drugs of category (i), or may include at least one drug from two or more categories (for example, a drug of category (i) in combination with category (ii)) as described below. Certain medicines may belong to two or more categories from categories (i)-(iii). For example, a drug (eg, GITR agonist, IDO antagonist, TGF-b inhibitor, among others) can serve as a drug in several categories.

In certain embodiments, the combination described herein includes one, two, three or more drugs that enhance the presentation of an antigen (eg, tumor antigen) (referred to herein as an antigen-presenting combination). In certain embodiments, the antigen-presenting combination comprises one or more of: an agent that enhances antigen presentation (eg, a vaccine, eg, a cell- or antigen-based vaccine); an agent that enhances the lysis of tumor cells (eg, oncolytic virus); an agent that stimulates (e.g., disinhibits) a phagocyte, e.g., an interferon type I (IFN) activator (e.g., a TLR agonist, a RIG-I-like receptor (RLR) agonist), and/or an agent that activates and/or recruits dendritic a cell or a macrophage (eg, macrophage I), for example, a bispecific or trispecific cell-binding agent.

In some embodiments, the antigen presenting combination comprises one, two, three, four, five or more drugs selected from:

(i) an interferon gene stimulator agonist (STING agonist), (ii) a Toll-like receptor (TLR) agonist (e.g., a TLR-3, -4, -5, -7, -8, or -9 agonist), (iii) a TIM-3 modulator (e.g., an anti-TIM-3 antibody molecule), (iv) a vascular endothelial growth factor receptor (VEGFR) inhibitor, (v) a c-Met inhibitor, (vi) a TGFb inhibitor (e.g., an anti-TGFb antibody), (vii) an IDO/TDO inhibitor, (viii) an A2AR antagonist, (ix) an oncolytic virus, (x) a vaccine (eg, a scaffold vaccine), or (xi) a bispecific or trispecific cell-binding agent.

Any of the above means (i)-(xi) can be used in combination for antigen presentation. In one exemplary embodiment, the antigen presenting combination comprises a STING agonist. In another exemplary embodiment, the antigen presenting combination comprises a TLR agonist (eg, a TLR7 agonist). In another exemplary embodiment, the antigen presenting combination comprises a STING agonist and a TLR agonist (eg, a TLR7 agonist). In some embodiments, the antigen presenting combination is selected from a STING agonist, a TLR agonist, an A2AR antagonist, or an oncolytic virus, or a combination thereof, and optionally one or more of (iii)-(vii) or (x)-(xi). In some embodiments, the antigen presenting combination is selected from a STING agonist or a TLR agonist, or a combination of both and optionally one or more of (iii)-(xi). In another embodiment, the antigen-presenting combination comprises a STING agonist, a TLR agonist (eg, a TLR7 agonist), and a TIM-3 modulator (eg, a TIM-3 inhibitor). In another embodiment, the antigen presenting combination comprises a STING agonist, a TLR agonist (eg, a TLR7 agonist), and a VEGFR inhibitor. In another embodiment, the antigen presenting combination comprises a STING agonist, a TLR agonist (eg, a TLR7 agonist), and a c-MET inhibitor. In other embodiments, the antigen-presenting combination comprises an oncolytic virus. In other embodiments, the antigen-presenting combination comprises an oncolytic virus and a cytokine, eg, an oncolytic virus expressing one or more of GM-CSF or CSF (eg, CSF1 or CSF2). In some embodiments, the antigen-presenting combination comprises a bispecific or trispecific cell-binding agent, for example, a bispecific or trispecific anti-CD47 and CD19 antibody molecule, with or without an Fc domain. In some embodiments, the antigen presenting combination comprises a TGFb inhibitor (eg, an anti-TGFb antibody). In other embodiments, the antigen presenting combination comprises an IDO/TDO inhibitor. In other embodiments, the antigen presenting combination comprises an A2AR antagonist. In other embodiments, the antigen-presenting combination comprises a vaccine (eg IL-2 in combination with MUC1 or a dendritic cell based vaccine (eg Provenge®)). In other embodiments, the antigen-presenting combination comprises a vaccine and a TLR agonist (eg, a TLR agonist as described herein). In a certain embodiment, the antigen presenting combination comprises a vaccine and a STING agonist. In a particular embodiment, the antigen presenting combination comprises a vaccine, a STING agonist, and a TLR agonist.

In certain embodiments, the combination includes one, two, three, four, five, or more drugs that enhance the effector cell response (referred to herein as an effector cell-targeted combination). In some embodiments, the combination directed to effector cells includes a lymphocyte activator, such as an NK cell activator and/or a T cell activator. In some embodiments, the effector cell-targeted combination activates (eg, disinhibits) tumor infiltrating lymphocytes (TILs), such as NK cells or T cells. In some embodiments, the effector cell-targeting combination comprises an NK cell modulator selected from an NK receptor modulator (eg, an antibody molecule) (eg, a modulator of one or more of NKG2A, KIR3DL, NKp46, MICA, or CEACAM1); an interleukin or interleukin variant (eg, cytokine IL-2, IL-15, IL-21, IL-13R, or IL-12, or a variant or combination thereof); a bispecific or trispecific cell-binding agent (eg, an anti-NKG2A and CD138 bispecific antibody molecule, or an anti-CD3 and TCR bispecific antibody molecule); NK cell therapy; or a vaccine that includes NK cells and an antigen/immune stimulant. In some embodiments, the effector cell-targeting combination comprises an immunomodulator (eg, one or more of: a costimulatory molecule activator or an immune checkpoint molecule inhibitor, as described herein). In some embodiments, the effector cell-targeted combination comprises a T cell modulator selected from a checkpoint inhibitor inhibitor (e.g., an inhibitor of one or more of: PD-1, PD-L1, TIM-3, LAG3, VISTA, DKG- α, B7-H3, B7-H4, TIGIT, CTLA-4, BTLA, CD160, TIM1, IDO, LAIR1, IL-12, or combinations thereof, e.g. a PD-1 and TIM-3 inhibitor, or a PD-1 inhibitor and LAG-3). In one embodiment, the checkpoint inhibitor inhibitor is an antibody molecule (eg, a monospecific or bispecific antibody, or fragment thereof, as described herein). For example, a checkpoint inhibitor inhibitor is an anti-PD-1, PD-L1, TIM-3, LAG-3, VISTA, B7-H4, CTLA-4, or TIGIT antibody molecule, or any combination thereof (e.g., a combination as described in this description). In some embodiments, the effector cell-targeting combination comprises a T cell modulator selected from an agonist or an activator of a costimulatory molecule. In one embodiment, the co-stimulatory molecule agonist is selected from an agonist (e.g., agonist antibody or antigen-binding or soluble fusion construct) GITR, OX40, ICOS, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM -1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or CD83 ligand. In other embodiments, the effector cell-targeting combination comprises a bispecific T cell binding agent (e.g., a bispecific antibody molecule that binds to CD3 and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2, among others).

In some embodiments, the effector cell-targeted combination comprises one, two, three, four, five or more drugs selected from:

(i) a GITR modulator (e.g., a GITR agonist), (ii) a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule as described herein), (iii) a PD-1 inhibitor, (iv) an IAP inhibitor ( apoptotic protein inhibitor), (v) EGFR (epidermal growth factor receptor) inhibitor, (vi) rapamycin target (mTOR) inhibitor, (vii) IL-15 or a variant thereof, (viii) CTLA-4 inhibitor, (ix) bispecific binder agent T cells (eg, a bispecific antibody molecule that binds to CD3 and a tumor antigen (eg, EGFR, PSCA, PSMA, EpCAM, HER2, among others), (x) a CD40 agonist (eg, an anti-CD40 antibody molecule), ( xi) an OX40 agonist (eg, an anti-OX40 antibody molecule); or (xii) a CD27 agonist (eg, an anti-CD27 antibody molecule).

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Any combination of the above agents can be used in combination directed to effector cells. In one exemplary embodiment, the effector cell combination comprises a GITR agonist. In another embodiment, the effector cell-targeted combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein). In another embodiment, the effector cell combination comprises a PD-1 inhibitor. In other embodiments, the effector cell-targeting combination comprises a GITR agonist and a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein). In other embodiments, the effector cell combination comprises a GITR agonist and a PD-1 inhibitor. In other embodiments, the effector cell-targeted combination comprises a GITR agonist, a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein), and a PD-1 inhibitor. In other embodiments, the effector cell-targeting combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein) and a PD-1 inhibitor. In one embodiment, the effector cell combination comprises a GITR agonist and an IAP inhibitor. In another embodiment, the effector cell combination comprises a GITR agonist and an EGFR inhibitor inhibitor. In another embodiment, the effector cell combination comprises a GITR agonist and an mTOR inhibitor inhibitor. In one embodiment, the effector cell-targeting combination comprises IL-15 or a variant thereof. In one embodiment, the effector cell combination comprises a CTLA-4 inhibitor. In one embodiment, the effector cell-targeting combination comprises a bispecific T cell binding agent (e.g., a bispecific antibody molecule that binds to CD3 and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2, among others). B In one embodiment, the combination directed to effector cells comprises a CD40 agonist (e.g., an anti-CD40 antibody molecule.) In one embodiment, the combination directed to effector cells comprises an OX40 agonist (e.g., an anti-OX40 antibody molecule).In one embodiment, the combination directed to effector cells includes a CD27 agonist (eg, an anti-CD27 antibody molecule).

In certain embodiments, the combination includes one, two, three, four, five, or more drugs that reduce tumor immunosuppression (referred to herein as an anti-tumor immunosuppression combination). In some embodiments, the combination modulates the activity or level of one or more of T _reg , macrophage 2, or MDSC. In some embodiments, the combination increases one or more of M2 polarization, T _reg depletion, or T cell recruitment. In some embodiments, the antitumor immunosuppression combination comprises one, two, three, four, five or more drugs selected from:

(i) an immunomodulator (eg, one or more of a co-stimulatory molecule activator (eg, a GITR agonist) or an inhibitor of an immune checkpoint molecule (eg, one or more of PD-L1, PD-1, LAG-3, TIM-3, or CTLA -4) as described herein), (ii) a CSF-1/1R inhibitor (e.g., a macrophage colony stimulating factor (M-CSF) inhibitor), (iii) an IL-17 inhibitor, (iv) an IL-1- beta, (v) CXCR2 inhibitor, (vi) phosphoinositide 3-kinase (PI3K, e.g. PI3K-delta or PI3K-gamma) inhibitor, (vii) BAFF-R inhibitor, (viii) MALT-1/BTK inhibitor, ( ix) JAK inhibitor, (x) CRTH2 inhibitor, (xi) VEGFR inhibitor, (xiii) IL-15 or variant thereof, (xiv) CTLA-4 inhibitor, (xv) IDO/TDO inhibitor, (xvi) A2AR antagonist, ( xvii) a TGFb inhibitor; or (xviii) a PFKFB3 inhibitor.

In certain embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule (e.g., a PD-L1, PD-1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3, and/or -5) inhibitor, or CTLA-4, or any combination thereof). Any combination of the above agents can be used in combination against tumor immunosuppression. In an aqueous exemplary embodiment, the anti-tumor immunosuppression combination comprises one, two, three, four, five or more drugs selected from a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule as described herein), a PD-1 inhibitor , inhibitor

- 30 040861

LAG-3, TIM-3 modulator (eg, TIM-3 inhibitor), GITR agonist, CSF-1/1R inhibitor (eg, M-CSF inhibitor), IL-17 inhibitor, IL-1beta inhibitor, or CXCR2 inhibitor. In one embodiment, the anti-tumor immunosuppression combination comprises one, two, or all of a CSF-1/1R inhibitor (eg, an M-CSF inhibitor), an IL-17 inhibitor, an IL-1beta inhibitor. In one embodiment, the antitumor immunosuppression combination comprises an IL-17 inhibitor, a CXCR2 inhibitor, a CRTH2 inhibitor, an A2AR antagonist, or a PFKFB3 inhibitor, or a combination thereof.

In some embodiments, the combination includes one or more antigen-presenting combination drugs. In other embodiments, the combination includes one or more combination drugs directed to effector cells. In other embodiments, the combination comprises one or more antitumor immunosuppression combination drugs. In other embodiments, the combination includes one or more antigen-presenting combination drugs and one or more effector cell-targeting combination drugs. In other embodiments, the combination comprises one or more antigen presenting combination drugs and one or more tumor immunosuppression combination drugs. In other embodiments, the combination includes one or more antigen-presenting combination drugs, one or more effector cell-targeting combination drugs, and one or more tumor immunosuppression combination drugs. In other embodiments, the combination includes one or more antigen-presenting combination drugs, one or more effector cell-targeting combination drugs, and one or more tumor immunosuppression combination drugs.

In certain embodiments, the combination includes:

(i) one or more antigen-presenting combination drugs selected from one, two, or all of a STING agonist, a TLR agonist (eg, a TLR7 agonist), or a TIM-3 modulator (eg, a TIM-3 inhibitor);

(ii) one or more combination drugs directed to effector cells selected from one, two, or all of a GITR modulator (e.g., a GITR agonist), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule as described herein) description) or a PD-1 inhibitor;

(iii) one or more tumor immunosuppression combination drugs selected from one, two, or all of a CSF-1/1R inhibitor (e.g., an M-CSF inhibitor), an IL-17 inhibitor, or an IL-1-beta inhibitor:

(iv) a combination of (i) and (ii);

(v) a combination of (i) and (iii);

(vi) a combination of (ii) and (iii); or (vii) a combination of (i), (ii) and (iii).

The combination can be used to treat cancer as described herein such as lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), gastric cancer, thyroid cancer, melanoma (e.g. , advanced melanoma), nasopharyngeal cancer, or breast cancer.

In other embodiments, the combination comprises a drug from an antigen presenting combination (e.g., one or more of a STING agonist, a TLR agonist, a vaccine, or an oncolytic virus) in combination with a therapeutic agent from an effector cell combination and/or an antitumor immunosuppression combination ( e.g. check point inhibitor, e.g. PD-L1, PD-1, LAG-3, TIM-3, CEACAM (e.g. CEACAM-1, -3 and/or -5) inhibitor, or CTLA-4, or any their combination). In one embodiment, one or more of a STING agonist, a TLR agonist, a vaccine, or an oncolytic virus is administered in combination with an anti-PD-L1 antibody molecule as described herein. In one embodiment, the STING agonist and/or vaccine is administered in combination with an anti-PD-L1 antibody molecule as described herein. In one embodiment, the oncolytic virus is administered in combination with an anti-PD-L1 antibody molecule as described herein. The combination can be used to treat cancer as described herein, such as lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), gastric cancer, thyroid cancer, melanoma (e.g. , advanced melanoma), nasopharyngeal cancer, or breast cancer.

In certain embodiments, the combination includes a combination of drugs as described in the section titled Exemplary Combinations of Antigen Presenting Combinations, Effector Cell Targeting Combinations, and Anti-Tumor Immunosuppression Combinations of the Detailed Description.

The combinations described herein may be administered together in one composition, or may be administered separately in two or more different compositions, eg compositions or dosage forms as described herein. The administration of drugs can be

- 31 040861 drive in any order. The first agent and additional agents (eg, second, third agents) may be administered by the same route of administration or by different routes of administration. For example, the first drug may be administered simultaneously, before or after the additional agent. In certain embodiments, the first agent is administered topically, e.g., a drug of any of categories (i)-(iii) may be coupled to a tumor-targeting agent, e.g., a tumor-targeting antibody (e.g., to form an antibody drug conjugate), or any other delivery vehicle (eg, a formulation, such as a targeted formulation), such that administration of the first agent is localized to the desired area, eg, a tumor site (eg, a dendritic cell rich area). In one embodiment, the drug is an antigen (eg, a vaccine, eg, an in situ cancer vaccine) that targets the tumor environment, thereby causing dendritic cell activation. The drug can also be administered locally, eg by injection, to the site of the tumor (eg intratumoral or peritumoral administration). Localized delivery or administration of a drug may reduce one or more of the side effects or toxicity otherwise associated with systemic drug administration. In one exemplary embodiment, a drug (eg, STING or TLR) can be conjugated to a tumor-binding antibody (eg, an antibody that binds to HER2), thereby delivering the drug to a HER-2 expressing cell.

Detection/Theranostics.

In another aspect, the present invention relates to methods for detecting the presence of PD-L1 in a sample, for example, in vitro or in vivo (for example, in a biological sample, for example, in serum, semen or urine, or in a tissue biopsy, for example, from a hyperproliferative or malignant hearth). The method of the invention can be used to evaluate (eg, monitor treatment or progression, diagnose and/or staging a disorder described herein, eg, a hyperproliferative or malignant disorder in an individual). The method includes:

(i) contacting a sample (and optionally a reference, such as a control sample), or administering to an individual, with an antibody molecule as described herein under conditions that allow interaction, and (ii) detecting the formation of a complex between the antibody molecule and sample (and, optionally, a reference, for example, a control sample).

The formation of the complex indicates the presence of PD-L1 and may indicate the suitability or necessity of the treatment described in the present invention. In some embodiments, PD-L1 is detected prior to treatment, such as prior to initial treatment, or prior to treatment after a treatment interval. Detection may involve immunohistochemistry, immunocytochemistry, FACS, antibody molecule complexed with magnetic beads, ELISA assays, PCR methods (eg, RT-PCR), or in vivo imaging techniques. Typically, the antibody molecule used in in vivo and in vitro detection methods is directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound binding compound. Suitable detectable substances include various biologically active enzymes, prosthetic groups, fluorescent materials, luminescent materials, paramagnetic (eg, nuclear magnetic resonance active) materials, and radioactive materials. In other embodiments, the antibody molecule is detected in vivo, e.g., using an in vivo imaging method as described herein (e.g., PET imaging)

Additional embodiments relate to a method for treating cancer, comprising: identifying in an individual, for example, in a sample (for example, a sample from an individual containing cancer cells and optionally immune cells, such as TIL) the presence of one, two or all of PD-L1, CD8 or IFN-γ, thereby providing a value for one, two or all of PD-L1, CD8 and IFN-γ. In addition, the method may include comparing the values for PD-L1, CD8 and/or IFN-γ with a reference value, for example, a control value. If the values for PD-L1, CD8, and/or IFN-γ are greater than a reference value, e.g., control values, a therapeutically effective amount of an anti-PD-L1 antibody (e.g., an anti-PD-L1 antibody described herein) is administered to the subject, optionally in combination with one or more other agents, thereby treating cancer. In some embodiments, the individual is identified prior to treatment, such as prior to initial treatment or prior to treatment after a treatment interval. The malignant tumor may be, for example, a malignant tumor described herein, such as lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer (squamous cell), gastric cancer, thyroid cancer, melanoma , nasopharyngeal cancer, or breast cancer, such as cancer

- 32 040861 breast TN, for example breast cancer IM-TN. In some embodiments, the cancer is ER+ breast cancer or pancreatic cancer.

Also provided is a method for treating cancer, comprising: examining an individual, e.g., a sample (e.g., a sample of an individual containing malignant cells) for the presence of PD-L1, thereby identifying a value for PD-L1, comparing the value for PD-L1 with a control value and, if the value for PD-L1 is greater than the control value, administering a therapeutically effective amount of an anti-PD-L1 antibody (e.g., an anti-PD-L1 antibody described herein) to the subject, optionally in combination with one or more other agents, thereby effecting cancer treatment. The cancer may be, for example, a cancer as described herein, such as non-small cell lung adenocarcinoma (NSCLC) (ASA), NSCLC squamous cell carcinoma (SCC), or hepatocellular carcinoma (HCC).

Without wishing to be bound by theory, it is believed that an individual who demonstrates a preexisting immune response to cancer, such as an immune response to immunomodulator therapy (eg, checkpoint molecule inhibitor therapy), may have a prolonged and/or more sustained response to therapy compared to an individual who does not have the same immune response. Thus, in some embodiments, assessing the activation status of immune cells (eg, T cells) in an individual prior to immunomodulator therapy may serve as a means of assessing and/or monitoring the individual's ability to respond to immunomodulator therapy. In embodiments, such an assessment can be used to identify, select, and/or stratify individuals (eg, a patient or population of patients) as more or less likely to respond to immunomodulator therapy.

Thus, alternatively or in combination with the methods described herein, a method is provided for assessing the activation status of immune cells (eg, T cells) of an individual (eg, assessing the likelihood of an individual responding to immunomodulator therapy). The method includes determining the level and/or distribution of T cell activation in an individual. In one embodiment, the level and/or distribution of T cell activation includes a measure of the level and/or distribution of one or more of: CD8, PD-L1, or other checkpoint inhibitor (e.g., one or more of PD-1, LAG-3, TIM-3, CEACAM (eg CEACAM-1, -3 and/or -5) or CTLA-4), or any combination thereof. For example, the level and/or distribution of CD8-expressing cells can be assessed as a marker of activated T cells. In other embodiments, the level and/or distribution of cells expressing PD-L1 or another checkpoint inhibitor can be assessed. The subject may be assessed before, during or after immunomodulator therapy. In one embodiment, the subject is evaluated prior to immunomodulator therapy (eg, checkpoint molecule inhibitor therapy), eg, prior to initial treatment or prior to treatment after a treatment interval. In one embodiment, an elevated level of one or more of CD8, PD-L1, or other checkpoint inhibitor in an individual (e.g., relative to a reference, e.g., control) is indicative of an increased ability of the individual to respond to therapy (also referred to herein as a positive immune activation status). ). In another embodiment, a reduced level of one or more of CD8, PD-L1, or other checkpoint inhibitor in an individual (e.g., relative to a reference, e.g., control) is indicative of the individual's reduced ability to respond to therapy (also referred to herein as immune activation status negative). ). Optionally, the method may include administering therapy with an immunomodulator as described herein (eg, a checkpoint molecule inhibitor as described herein) if the subject is determined to have a positive immune activation status.

In one embodiment, immunomodulator therapy comprises a co-stimulatory molecule activator, eg one or more activators as described herein (eg, a GITR molecule agonist as described herein). In other embodiments, the immunomodulator therapy comprises an immune checkpoint molecule inhibitor, e.g., one or more checkpoint inhibitor inhibitors as described herein (e.g., an inhibitor of one or more of PD-L1, PD-1, TIM-3, or CTLA- 4 as described herein). In one embodiment, the immunomodulator therapy comprises an anti-PD-L1 antibody molecule as described herein. In other embodiments, immunomodulator therapy comprises a combination of a costimulatory molecule activator and a checkpoint inhibitor.

In some embodiments, the level and/or distribution of CD8, PD-L1, or other checkpoint inhibitor is determined in vivo, e.g., non-invasively (e.g., by detecting an antibody to a T-cell marker labeled with a detectable label using an appropriate imaging method, for example, positron emission tomography (PET) scanning For example, PET with a target antibody or immune PET (for example, PET with anti-CD8 antibody or PET with anti-PD-L1 antibody) can be used to detect the level

- 33 040861 and/or distribution (eg tumor localization) expressing CD8 or PD-L1 cells in vivo. Antibody imaging techniques (eg, antibody PET imaging) are known in the art, eg, as described by Lamberts, L. E. et al. (2015) J. Clin. oncol. 33 (DOI: 1o, 1200/JCO.2014, 57, 8278); Tavare, R. et al. (2014) PNAS 111(3):1108-1113; and Boerman and Oyen (2011) The Journal of Nuclear Medicine 52(8):1171-72, incorporated herein by reference. In other embodiments, the level of CD8, PD-L1, or other checkpoint inhibitor is determined in a sample (eg, tumor biopsy) obtained from an individual (eg, using immunohistochemical methods).

As an exemplary embodiment, an increased number or repositioning of CD8-expressing cells from the tumor margin into the tumor may indicate an improved outcome, such as an increased ability to respond to immunomodulator therapy in an individual. In certain embodiments, a positive immune activation status (e.g., increased levels of activated T cells) occurs in response to prior cancer treatment, e.g., in response to one or more of radiation therapy, chemotherapy, an oncolytic virus, a bispecific T cell binding agent , biological, or targeted therapy (eg, cancer therapy as described herein). In some embodiments, an individual who demonstrates a positive immune activation status in response to prior treatment becomes a better candidate for immunomodulator therapy. In one embodiment, an individual that has a B-Raf mutation (eg, a B-Raf mutation, as described herein) is treated with a B-Raf inhibitor (eg, a B-Raf inhibitor, as described herein). The individual may have an increase in CD8-expressing T cells following treatment with a B-Raf inhibitor and thus may be a better candidate for immunomodulator therapy.

In another exemplary embodiment, expression of PD-L1 or other checkpoint inhibitors (eg, relative to a reference) can be used to determine or analyze an individual's ability to respond to cancer therapy. In one embodiment, the PET imaging tool can demonstrate that the individual has pre-existing expression of PD-L1 or other checkpoint molecules. Expression of these molecules on tumors may help stratify patients for additional diagnostic purposes. If an individual did not have a detectable pre-existing immune response to immunomodulator therapy and did not have detectable control point molecule expression, then such an individual is likely to be a poor candidate for therapy. PET imaging can also demonstrate expression heterogeneity and show those tumors (PET positive) that are the actual tumors/lesions most likely to respond. This would be useful because sampling a small number of given lesions can be misleading; for example, to determine if an individual is responding or if an error has occurred in sampling by a biopsy method or due to a low number of samples. With the use of PET imaging, it is possible to detect most tumors and thus make a more accurate determination of the effectiveness of tumor loading and a better understanding of how the therapy works.

In another aspect, the invention relates to diagnostic or therapeutic kits that include the antibody molecules described in the present description, and instructions for use.

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

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

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

Brief description of the figures

In FIG. 1 shows the amino acid sequences of the light (SEQ ID NO: 8) and heavy (SEQ ID NO: 6) variable regions of the mouse anti-PD-L1 mAb BAP058. Light and heavy chain CDR sequences based on Kabat numbering are underlined. Heavy chain CDR sequences based on Chothia numbering are shown in bold and italics.

In FIG. 2 shows the amino acid sequences of the variable regions of the light (SEQ ID NOS: 8 and 249, respectively, in order of presentation) and heavy (SEQ ID NOS: 6 and 248, respectively, in order of presentation) of the mouse anti-PD-L1 mAb BAP058 chains aligned with germline sequences. The top and bottom sequences are the germline (GL) and BAP058 (Mu mAb) sequences, respectively. Light and heavy chain CDR sequences based on Kabat numbering are underlined. Light and heavy chain CDR sequences based on Chothia numbering are shown in bold and italics. - means an identical amino acid residue.

In FIG. 3 is a bar graph showing the results of a FACS binding assay for seventeen humanized BAP058 clones (BAP058-hum01 to BAP058-hum17). Antibody concentrations are 200, 100, 50, 25 and 12.5 ng/mL from leftmost bar to rightmost bar for each mAb tested.

In FIG. 4 shows a structural analysis of humanized BAP0058 clones (a, b, c, d, e, f and g correspond to different types of framework sequences). The mAb concentrations in the samples are also shown.

In FIG. 5 shows the binding affinity and specificity of the humanized BAP058 mAb measured in a competitive binding assay using a constant concentration of Alexa 488 labeled mouse BAP058 mAb, serial dilutions of test antibodies, and 300.19 PD-L1 expressing cells.

In FIG. 6 shows the ranking of humanized BAP058 clones based on FACS data, competitive binding and structural analysis. The mAb concentrations in the samples are also shown.

In FIG. 7 shows blockage of PD-1 ligand binding by selected humanized BAP058 clones. Blocking of PD-1-Ig binding to PD-L1 expressing cells is presented. BAP058-hum01, BAP058-hum03, BAP058-hum04, BAP058-hum06, BAP058-hum07, BAP058-hum11 and BAP058-hum13 were evaluated. The mouse BAP058 mAb and the chimeric mAb were also included in the analysis.

In FIG. 8A-8B show sequence alignments of the heavy chain variable domains for seventeen humanized clones of BAP058 and BAP058-chi. In FIG. 8A, all sequences are shown. In FIG. 8A shows SEQ ID NOs: 250, 251, 251, 251, 252, 252, 252, 253, 253, 254, 254, 255, 255, 256, 256, 257, 258, 259, respectively, in order of presentation. In FIG. 8B, only amino acid sequences are shown that differ from the mouse sequence. In FIG. 8B shows SEQ ID NOs: 250, 251, 251, 251, 252, 252, 252, 253, 253, 254, 254, 255, 255, 256, 256, 257, 258, 259, respectively, in order of presentation.

In FIG. 9A-9B show the sequence alignment of the light chain variable domains for seventeen BAP058 and BAP058-chi clones. In FIG. 9A shows all sequences. In FIG. 9A shows SEQ ID NOs: 17, 86, 86, 86, 86, 42, 42, 42, 66, 66, 66, 22, 22, 26, 34, 58, 82, 74, respectively, in order of presentation. In FIG. 9B shows only amino acid sequences that differ from the mouse sequence. In FIG. 9B shows SEQ ID NOs: 17, 86, 86, 86, 86, 42, 42, 42, 66, 66, 66, 22, 22, 26, 34, 58, 82, 74, respectively, in order of appearance.

In FIG. 10 shows exemplary cancers in which relatively high proportions of patients are triple positive for PD-L1/CD8/IFN-Y.

In FIG. 11 shows exemplary ER+ breast and pancreatic cancers in which relatively low proportions of patients are triple positive for PDL1/CD8/IFN-y.

In FIG. 12 shows the proportion of exemplary breast cancer patients who are triple positive for PD-L1/CD8/IFN-y.

In FIG. 13 shows the proportion of exemplary colon cancer patients who are triple positive for PD-L1/CD8/IFN-y.

In FIG. 14 shows a graphical representation of flow cytometry for surface expression of PD-L1 in EBC-1 cells in vitro with or without compound A17 treatment. EBC-1 cells are non-small cell lung cancer cells with cMET amplification.

In FIG. 15 shows a graphical representation of PD-L1 mRNA expression in HS.746.T cells in a tumor xenograft model with or without compound A17 treatment. Hs.746.T cells are c-MET amplification and c-MET mutation gastric cancer cells.

In FIG. 16 shows a graphical representation of PD-L1 mRNA expression in H3122 cells in vitro with or without A23 compound. H3122 cells are non-small cell lung cancer (NSCLC) cells with an ALK translocation.

In FIG. 17 shows a graphical representation of PD-L1 mRNA expression in LOXIMV1 cells (BRAF mutant melanoma cells) in a tumor xenograft model with or without compound A29 treatment.

In FIG. 18 shows a graphical representation of PD-L1 mRNA expression in HEYA8 cells (KRAS mutated ovarian cancer cells) in a tumor xenograft model with or without compound A34 treatment.

In FIG. 19 shows a graphical representation of PD-L1 mRNA expression in UKE-1 cells (myeloproliferative neoplasm cells with V617F JAK2 mutation) in a tumor xenograft model with or without compound A18 treatment.

In FIG. 20 is a schematic diagram showing antigen processing and presentation, effector cell responses, and immunosuppression cascades targeted by the combination therapies described herein.

In FIG. 21 shows the effect of exemplary anti-PD-L1 antibodies on promoting IFN-γ release from co-cultures of dendritic cells and CD4+ T cells.

In FIG. 22 shows the effect of exemplary anti-PD-L1 antibodies on SEB-induced IL-2 secretion by T cells.

Brief description of the tables

Tab. 1 is a summary representation of the amino acid and nucleotide sequences of mouse anti-PD-L1 antibody molecules, chimeric and humanized anti-PD-L1 antibody molecules. Antibody molecules include the mouse BAP058 mAb, the BAP058-chi chimeric mAb, and the humanized BAP058-hum01 to BAP058-hum17 and BAP058-Clone-K to BAP058-Clone-O mAbs. This table lists the amino acid and nucleotide sequences of the heavy and light chain CDRs, the amino acid and nucleotide sequences of the heavy and light chain variable regions, and the amino acid and nucleotide sequences of the heavy and light chains.

In table. 2 shows the amino acid and nucleotide sequences of the heavy and light chain framework regions of the humanized BAP058-hum01 to BAP058-hum17 and BAP058-CloneK to BAP058-Clone-O mAbs.

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

Tab. 4 is a summary representation of yield, titer, monomer content, and endotoxin levels for selected humanized BAP058 mAbs expressed in CHO cells.

In table. 5 shows the charge isoforms identified by Novex IEF analysis for selected humanized BAP058 mAbs expressed in CHO cells.

Tab. 6 is a generalized representation of individual drugs that can be administered in combination with anti-PD-1 antibody molecules and other immunomodulators (e.g., one or more of a co-stimulatory molecule activator and/or immune checkpoint molecule inhibitor) described herein. In table. 6, from left to right, is the following: the compound designation for the second drug, the structure of the compound, and the patent publication(s) describing the compound.

In table. 7 is an illustrative drug list of antigen-presenting combinations (category A), effector cell-targeting combinations (category B), and anti-tumor immunosuppression combinations (category C).

In table. 8 shows cross-species binding of exemplary PD-L1 antibodies as assessed by the Biacore method.

Detailed description

The immune system has the ability to recognize and destroy tumor cells; however, tumors can use many strategies to evade the immune system. Blockade of immune checkpoints is one approach to activate or reactivate therapeutic antitumor immunity. Programmed death protein ligand 1 (PD-L1) has been described as a ligand for the immunoinhibitory programmed death receptor protein 1 (PD-1). Binding of PD-L1 to PD-1 results in inhibition of T-cell receptor-mediated lymphocyte proliferation and cytokine secretion (Freeman et al. (2000) J Exp Med 192:1027-34). Thus, blocking PD-L1 can lead to increased antitumor immunity.

Several cell types express PD-L1. For example, PD-L1 is expressed on activated T cells, dendritic cells (DC), natural killer (NK), macrophages, B cells, monocytes, and vascular endothelial cells. PD-L1 is expressed in many cancers, including human lung, ovarian, and colon carcinomas and various myelomas (Iwai et al. (2002) PNAS 99:12293-7; Ohigashi et al. (2005) Clin Cancer Res 11:2947- 53 Okazaki et al (2007) Intern Immun 19:813-24 Thompson et al (2006) Cancer Res 66:3381-5). Expression of PD-L1 is strongly correlated with poor prognosis in various types of cancer, including cancer of the kidney, ovary, bladder, breast, stomach, and pancreas.

Many tumor-infiltrating T-lymphocytes have a predominant expression of PD-1 compared to T-lymphocytes in normal tissues and T-lymphocytes in peripheral blood. This indicates that activation of PD-1 on tumor-reactive T cells can lead to disruption of the antitumor immune response (Ahmadzadeh et al. (2009) Blood 114:1537-44). Thus, PD-L1 signaling mediated by PD-L1-expressing tumor cells interacting with PD-1-expressing T cells may result in attenuated T cell activation and escape from immune surveillance (Sharpe et al. (2002) Nat Rev Immunol. 2:116-26; Keir et al. (2008) Annu Rev Immunol. 26:677-704). Blockade of PD-1 can inhibit the hematogenous spread of low immunogenic tumor cells through increased recruitment of effector T cells (Iwai et al. (2005) Int. Immunol. 17:133-144).

An anti-PD-L1 antibody can enhance T-cell immunity, for example, by blocking its inhibitory interactions with both PD-1 and B7-1. An anti-PD-1 antibody can mediate immune regulation via PD-L2/PD-1. Both PD-1 and B7-1 are expressed on T cells, B cells, DCs, and macrophages, providing the potential for bidirectional interactions between B71 and PD-L1 on these cell types. PD-L1 on non-hematopoietic cells can interact with B7-1, and

- 36 040861 also with PD-1, on T cells.

Thus, the present invention relates, at least in part, to antibody molecules (eg, humanized antibody molecules) that bind to programmed death protein ligand 1 (PD-L1) with high affinity and specificity. In one embodiment, humanized anti-PD-L1 antibodies are provided that exhibit surprisingly low immunogenicity. For example, humanized anti-PD-L1 antibodies may have a risk score of less than 650, 600, 550, or less than 500 as measured by T-cell epitope analysis. In other embodiments, it has been shown that individual combinations of framework regions, such as those shown in FIG. 5 and 7 have certain production efficiency and binding properties.

Additional aspects of the invention include nucleic acid molecules encoding antibody molecules, expression vectors, host cells, and methods for producing antibody molecules. Also contemplated are immunoconjugates, multispecific or bispecific molecules, and pharmaceutical compositions containing antibody molecules. The anti-PD-L1 antibody molecules described herein can be used to treat, prevent, and/or diagnose malignant or neoplastic disorders (e.g., solid and soft tissue tumors; melanoma, e.g., advanced melanoma; hepatocellular carcinoma; pancreatic cancer). glands; renal cell carcinoma (RCC), such as metastatic RCC or clear cell RCC; gliomas or glioblastomas; multiple myeloma; colon and rectal and lung cancers, such as non-small cell carcinoma), and infectious diseases (eg, infectious disorders such as hepatitis, eg hepatitis C (eg, chronic viral hepatitis); sepsis). Thus, methods for detecting PD-L1 as well as methods for treating various disorders, including cancer and infectious diseases, are described herein using anti-PD-L1 antibody molecules.

Also described herein are methods and compositions comprising a combination of two, three or more drugs selected from one, two or all of the following categories (i)-(iii):

(i) an agent that enhances antigen presentation (eg, tumor antigen presentation) (eg, by enhancing one or more of dendritic cell activity or maturation, antigen uptake, or antigen processing);

(ii) an agent that enhances an effector cell response (eg, an immune effector cell response, eg, activation and/or mobilization of B cells and/or T cells, eg, in a lymph node); or (iii) an agent that reduces tumor immunosuppression (eg, by increasing T cell infiltration and tumor cell killing).

In some embodiments, the combination comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule as described herein). Without being bound by theory, it is believed that therapeutic approaches that enhance antitumor immunity operate more effectively when the immune response is optimized across multiple targets at different stages of the immune response. Each of these steps is shown in schematic form in FIG. 20. For example, approaches that result in dendritic cell activation, in combination with approaches that enhance cellular humoral immunity, may result in a more effective and/or prolonged therapeutic response.

The terms programmed death protein ligand 1 or PD-L1 include isoforms of PD-L1, mammalian, eg, human, species homologues of human PD-1, and analogues sharing at least one epitope with PD-L1. The amino acid sequence of PD-L1, eg human PD-1, is known in the art, eg Dong et al. (1999) Nat Med. 5(12):1365-9; Freeman et al. (2000) J Exp Med. 192(7):1027-34).

Additional terms are defined below and throughout the application.

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

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

Approximately and approximately generally means an acceptable degree of error for the quantity measured, given the nature or accuracy of the measurements. Exemplary error rates are within 20 percent (%), typically within 10%, and more specifically within 5% of a given value or range of values.

By combination or in combination with does not mean that the therapy or drugs must be administered simultaneously and/or formulated for delivery together, although these methods of delivery are included in the scope described in the present description. The combination drugs may be administered simultaneously, before or after one or more additional therapies or drugs. Drug administration or therapeutic protocols can be

- 37 040861 to carry out in any order. Typically, each agent is administered at a dose and/or schedule determined for that agent. In addition, it will be understood that the additional drug used in this combination may be administered together in a single composition or may be administered separately in different compositions. Generally, additional drugs used in combination are expected to be used at levels that do not exceed the levels at which they are used alone. In some embodiments, levels used in combination will be lower than levels used alone.

In embodiments, the additional drug is administered at a therapeutic dose or at a dose below the therapeutic dose. In certain embodiments, the concentration of the second drug that is required to provide inhibition, such as growth inhibition, is lower when the second drug is administered in combination with the first drug, such as an anti-PD-L1 antibody molecule, than when the second drug is administered. separately. In certain embodiments, the concentration of the first drug that is required to achieve inhibition, such as growth inhibition, is lower when the first drug is administered in combination with the second drug than when the first drug is administered alone. In certain embodiments, in combination therapy, the concentration of the second drug that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second drug as monotherapy, e.g., 10-20%, 20-30%, 3040 %, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower. In certain embodiments, in combination therapy, the concentration of the first drug that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the first drug as monotherapy, e.g., 10-20%, 20-30%, 3040 %, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower.

The term inhibition, inhibitor or antagonist includes the reduction of a particular parameter, eg activity, of a given molecule, eg an immune checkpoint inhibitor. For example, the term includes inhibition of an activity, eg, PD-1 or PD-L1 activity, by at least 5%, 10%, 20%, 30%, 40% or more. Thus, inhibition should not be 100%.

The term activation, activator or agonist includes an increase in a particular parameter, eg activity, of a given molecule, eg, a co-stimulatory molecule. For example, this term includes an increase in activity, such as costimulatory activity, at least 5%, 10%, 25%, 50%, 75% or more.

The term anti-cancer effect refers to a biological effect that can be manifested in various ways, including, but not limited to, for example, reduction in tumor volume, reduction in the number of malignant cells, reduction in the number of metastases, increase in life expectancy, reduction in the proliferation of malignant cells, reduction in the survival of malignant cells or alleviate various physiological symptoms associated with the malignant condition. The anti-cancer effect can also be manifested by the ability of peptides, polynucleotides, cells and antibodies to initially prevent the occurrence of a recurrence of a malignant tumor.

The term antitumor effect refers to a biological effect that can be manifested in various ways, including, but not limited to, for example, reduction in tumor volume, reduction in the number of tumor cells, reduction in tumor cell proliferation, or reduction in tumor cell survival.

The term malignant tumor refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Malignant cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, and the like. The terms neoplasm and malignant tumor are used interchangeably herein, for example, both terms encompass solid and liquid, eg, diffuse or circulating tumors. As used herein, the term malignant tumor or tumor includes premalignant as well as malignant neoplasms and tumors.

The term antigen presenting cell or APC refers to a cell of the immune system, such as a helper cell (eg, B cell, dendritic cell, etc.), which displays a foreign antigen in complex with a major histocompatibility complex (MHC) on its surface. T cells can recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

The term co-stimulatory molecule refers to a recognizable binding partner at T

- 38 040861 cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Co-stimulatory molecules are cell surface molecules, other than antigen receptors or ligands thereof, that are required for an effective immune response. Costimulatory molecules include, but are not limited to, MHC class I, TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, lymphocyte activation signaling molecules (SLAM proteins), activating NK cell receptors, BTLA, Toll ligand receptor, OX40 , CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8-alpha, CD8-beta, IL2R-beta, IL2R-gamma, IL7R-alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55) , PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GA DS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds to CD83.

An immune effector cell, as the term is used herein, refers to a cell that is involved in an immune response, for example, in stimulating an immune effector cell response. Examples of immune effector cells include T cells, such as alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK), natural killer T (NKT) cells, mast cells, and phagocytes of myeloid origin. .

Immune effector or effector function or response, as these terms are used herein, refers to a function or response, for example, of an immune effector cell that enhances or stimulates an immune attack on a target cell. For example, immune effector function or response refers to a property of T cells or NK cells that stimulates the destruction or inhibition of the growth or proliferation of a target cell. In the case of a T cell, primary stimulation and costimulation are examples of an immune effector function or response.

The term effector function refers to a specialized function of a cell. The effector function of a T cell, for example, may be a cytolytic activity or a helper activity, including the secretion of cytokines.

The term immune activation status refers to the likelihood that an individual will respond to therapy, such as immunomodulator therapy. In some embodiments, the immune activation status may be a positive status or a negative status. In embodiments, a positive immune activation status means that there is a greater than 50% chance (eg, greater than 50%, 60%, 70%, 80%, 90%, or more likely) that the individual will respond to therapy, eg, immunomodulator therapy. In embodiments, a negative immune activation status means that there is a greater than 50% chance (e.g., greater than 50%, 60%, 70%, 80%, 90%, or more chance) that the individual will not respond to therapy, such as immunomodulator therapy.

As used herein, the terms treat, treat, and administer treatment refer to reducing or alleviating the progression, severity, and/or duration of a disorder, such as a proliferative disorder, or alleviating one or more symptoms (preferably one or more noticeable symptoms) of a disorder due to one or more therapies. In specific embodiments, the terms treat, treat, and administer treatment refer to alleviating at least one measurable physical parameter of a proliferative disorder, such as tumor growth, not necessarily noticeable to the patient. In other embodiments, the terms treat, treat, and administer treatment refer to inhibiting the progression of a proliferative disorder, either physically, eg, by stabilizing a noticeable symptom, or physiologically, eg, by stabilizing a physical parameter, or both. In other embodiments, the terms treat, treat, and administer treatment refer to reducing or stabilizing the size of a tumor or the number of malignant cells.

The compositions and methods of the present invention encompass polypeptides and nucleic acids having said sequences, or sequences substantially identical or similar thereto, for example sequences that are at least 85%, 90%, 95% or greater identical to said sequence. In the context of amino acid sequence, the term substantially identical is used herein to refer to the first amino acid that contains a sufficient or minimum number of amino acid residues that i) are identical or ii) are conservative substitutions for aligned amino acid residues in the second amino acid sequence such that the first and second amino acid sequences may share a common structural domain and/or a common functional activity. Examples are amino acid sequences that contain a common structural domain having

- 39 040861 at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, for example, the sequence described herein.

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

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

The calculation of homology or sequence identity (these terms are used interchangeably herein) is carried out as follows.

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

Percent identity between two sequences is a function of the number of identical positions between sequences, taking into account the number of gaps and the length of each gap that must be made for optimal alignment of the two sequences.

Sequence comparison and determination of percent identity between two sequences can be performed using a mathematical algorithm. In a preferred embodiment, percent identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) which was included in the GAP program of the GCG software package (available at http:// www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a gap extension weight of 1, 2, 3, 4, 5, or 6. In another preferred embodiment, percent 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 template. CMP and skip weights of 40, 50, 60, 70, or 80 and skip continuation weights of 1, 2, 3, 4, 5, or 6. An especially preferred parameter set (and the parameter set to be used unless otherwise indicated) is the scoring matrix Blossum 62 with gap penalty of 12, gap extension penalty of 4, and frameshift gap penalty of 5.

Percent 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 weight table, gap continuation penalty 12 and gap penalty 4.

The nucleic acid and protein sequences described herein can be used as a query sequence to search against public databases, for example, to identify other members of a family or related sequences.

Such searches can be performed using the NBLAST and XBLAST (version 2.0) programs from Altschul, et al. (1990) J. Mol. Biol. 215:403-10. Nucleotide BLAST searches can be performed using the NBLAST program, weight=100, wordlength=12, to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed using the XBLAST program, weight=50, wordlength=3, to obtain amino acid sequences homologous to protein molecules of the invention. To perform gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al. (1997)

- 40 040861

Nucleic Acids Res. 25:3389-3402. When using the BLAST and Gapped BLAST programs, you can use the default settings of the respective programs (eg XBLAST and NBLAST). Cm.

http://www.nebi.nlm.nih.gov.

As used herein, the term hybridize under low stringency, moderate stringency, high stringency, or very high stringency describes the conditions for hybridization and washing. Guidelines for conducting 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 by reference. This reference describes aqueous and non-aqueous methods, and any of them can be used. Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6x sodium chloride/sodium citrate (SSC) at approximately 45°C followed by two washes in 0.2x SSC, 0.1% SDS at least 50°C (washing temperature can be increased up to 55°C for low stringency conditions); 2) moderate stringency hybridization conditions in 6x SSC at approximately 45°C followed by one or more washes in 0.2x SSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions in 6x SSC at approximately 45°C followed by one or more washes in 0.2x SSC, 0.1% SDS at 65°C; and preferably 4) very stringent hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65°C followed by one or more washes in 0.2x SSC, 1% SDS at 65°C. Very high stringency conditions (4) are the preferred conditions and the conditions to be used unless otherwise indicated.

It is understood that the molecules of the present invention may have additional conservative amino acid substitutions or non-essential amino acid substitutions that do not have a significant effect on their function.

The term amino acid encompasses all molecules, both natural and synthetic, that include both an amino functionality and an acid functionality, and are capable of being incorporated into a polymer from naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; analogues, derivatives and their congeners; amino acid analogs having variant side chains; and all stereoisomers of any of the above. As used herein, the term amino acid includes both D- and L-optical isomers and peptidomimetics.

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

The terms polypeptide, peptide and protein (when single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids. Also, the terms cover a polymer of amino acids that is modified; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation such as conjugation with a labeling moiety. The polypeptide may be isolated from natural sources, may be produced by recombinant methods from a eukaryotic or prokaryotic host, or may be the product of synthetic procedures.

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

The term isolated, as used herein, refers to material that is removed from its original or natural environment (eg, the natural environment if it is naturally occurring). 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 its coexisting 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 still be isolated because such vector or composition is not part of the environment in which it occurs naturally.

Various aspects of the invention are described in more detail below. Throughout the description, additional definitions are provided.

Antibody molecules.

In one embodiment, the antibody molecule binds to PD-L1 of a mammal, such as a human. For example, an antibody molecule binds specifically to an epitope, eg, a linear or conformational epitope (eg, an epitope as described herein) on PD-L1.

As used herein, the term antibody molecule refers to a protein, such as 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 one embodiment, the antibody molecule comprises a full length antibody or a full length immunoglobulin chain. In one embodiment, the antibody molecule comprises an antigen-binding or functional fragment of a full-length antibody or a full-length immunoglobulin chain.

In one embodiment, the antibody molecule is a monospecific antibody molecule and binds a single epitope. An example is a monospecific antibody molecule having multiple immunoglobulin variable domain sequences, each of which binds the same epitope.

In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain 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 second epitope. In one embodiment, the first and second epitopes are on the same antigen, eg, on the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, eg on different proteins (or different subunits of a multimeric protein). In one embodiment, the multispecific antibody molecule contains a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody molecule has specificity for no more than two antigens. The bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence that has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In one embodiment, the first and second epitopes are on the same antigen, eg, on the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, such as different proteins (or different subunits of a multimeric protein). In one embodiment, the bispecific antibody molecule comprises a light 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, the 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 an scFv or fragment thereof that has a binding specificity for a first epitope and an scFv or fragment thereof

- 42 040861 which have binding specificity for the second epitope. In one embodiment, the first epitope is located on PD-L1 and the second epitope is located on TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), PD-L1 or PD-L2 .

In one embodiment, the antibody molecule includes a diantibody, a single chain molecule, as well as an antigen-binding fragment of an 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 (L) variable domain sequence (abbreviated herein as VL). In one embodiment, the antibody molecule contains or consists of a heavy chain or a light chain (abbreviated herein as a half antibody). In another example, an antibody molecule comprises two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen binding sites, such as Fab, Fab', F(ab') ₂ , Fc, Fd, Fd', Fv, single chain antibodies (e.g., scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which can be obtained by modifying whole antibodies or antibodies synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind to their respective antigen or receptor. Antibodies and antibody fragments can be from any class of antibodies, including but not limited to IgG, IgA, IgM, IgD, and IgE, and from any subclass (eg, IgG1, IgG2, IgG3, and IgG4) of antibodies. The preparation of antibody molecules can be monoclonal or polyclonal. The antibody molecule can also be a human antibody, a humanized antibody, a CDR-grafted antibody, or an 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 have a light chain selected from, for example, kappa or lambda. The term immunoglobulin (Ig) is used herein interchangeably with the term antibody.

Examples of antigen-binding fragments of an antibody molecule include:

(i) Fab fragment, univalent fragment consisting of VL, VH, CL and CH1 domains;

(ii) F(ab') ₂ fragment, divalent fragment containing two Fab-fragment connected by a disulfide bridge in the hinge region;

(iii) an Fd fragment consisting of VH and CH1 domains;

(iv) an Fv fragment consisting of the VL and VH domains of one arm of an antibody, (v) a diaantibody fragment (dAb) which consists of a VH domain;

(vi) a camelid variable domain or camelized variable domain;

(vii) single chain Fv (scFv), see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. sci. USA 85:5879-5883);

(viii) single domain antibody.

These antibody fragments are prepared using conventional methods known to those skilled in the art and the fragments are screened for utility in the same manner as intact antibodies.

The term antibody includes intact molecules as well as their functional fragments. The constant regions of an antibody can be altered, eg, by mutation, to modify the properties of the antibody (eg, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, cysteine residue count, cellular effector function, or complement function).

The antibody molecules can also be single domain antibodies. Single domain antibodies may include antibodies whose complementarity determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally lacking light chains, single domain antibodies derived from conventional 4 chain antibodies, engineered antibodies, and single domain scaffolds other than those derived from antibodies. Single domain antibodies can be any prior art single domain antibody or any future single domain antibody. Single domain antibodies can be derived from any species, including, but not limited to, mouse, human, camel, llama, fish, goat, rabbit, and ruminants. According to another aspect of the 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, this heavy chain antibody derived variable domain naturally lacking a light chain is known herein as VHH or nanoantibody to distinguish it from the conventional VH of heavy chain immunoglobulins. . Such a VHH molecule may be derived from antibodies induced in Camelidae species such as camel, llama, dromedary, alpaca and guanaco. Species other than the Camelidae can produce heavy chain antibodies naturally lacking a light chain; such vhh

- 43 040861 are included in the scope of the present invention.

The VH and VL regions can be subdivided into regions of hypervariability called complementarity determining regions (CDRs) located between regions that are more conserved regions called framework regions (FRs or FWs).

The extent of the framework region and CDR has been accurately determined in a number of ways (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 196:901-917 and the AbM definition used by Oxford Molecular's AbM antibody modulation software See mainly for example Protein Sequence and Structure Analysis of Antibody Variable Domains 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 in the variable regions of an antibody that confer antigen specificity and binding affinity to it. Typically, there are three CDRs in each heavy chain variable region (HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, LCDR3).

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

For example, according to Kabat, the amino acid residues of the heavy chain variable domain (VH) CDRs are numbered 31-35 (HCDR1), 50-66 (HCDR2), and 99-109 (HCDR3); and amino acid residues of the CDRs in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1), 52-57 (HCDR2), and 99-109 (HCDR3); and amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2) and 9196 (LCDR3). When combining the CDR definitions from both Kabat and Chothia, CDRs consist of amino acid residues 26-35 (HCDR1), 50-66 (HCDR2) and 99-109 (HCDR3) in the human VH and amino acid residues 24-34 (LCDR1) , 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.

Generally, unless otherwise specified, PD-L1 antibody molecules may include any combination of one or more Kabat CDRs and/or Chothia hypervariable loops, such as those described in Table 1. 1. In one embodiment, for the anti-PD-L1 antibody molecules described in Table. 1 use the following definitions: HCDR1 according to the combined CDR definitions of both Kabat and Chothia, and HCCDR 2-3 and LCCDR 1-3 according to the Kabat CDR definition. In accordance with all definitions, each VH and VL, as a rule, includes three CDRs and four FRs, located from the N-terminus to the C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

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

The term antigen binding site refers to the portion of an antibody molecule that contains determinants that form a contact surface that binds to a PD-L1 polypeptide or epitope thereof. With respect to proteins (or protein mimetics), the antigen binding site typically includes one or more loops (of at least four amino acids or amino acid mimetics) that form a contact surface that binds to the PD-L1 polypeptide. Typically, the antigen-binding center of an antibody molecule comprises at least one or two CDRs and/or hypervariable loops, or more particularly at least three, four, five or six CDRs and/or hypervariable loops.

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

An effective human protein is one that does not induce a neutralizing antibody response, such as a human anti-mouse (HAMA) response. HAMA can be a problem in some cases, for example if the antibody molecule is administered multiple times, such as in the treatment of a chronic or relapsing disease. The HAMA response may render repeated administration of antibodies ineffective due to increased serum clearance of antibodies (see e.g. Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)) and also due to potency 44 040861 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 recombinantly produced, for example, produced by phage display methods or combinatorial methods.

Phage display methods and combinatorial methods for producing antibodies are known in the art (as described, for example, in Ladner et al., US Pat. No. 5,223,409; Kang et al., International Publication No. WO 91/17271 Winter et al. International Publication WO 92/20791 Markland et al. International Publication No. WO 92/15679 Breitling et al. International Publication No. WO 93/01288 McCafferty et al. WO 92/01047; Garrard et al., International Publication No. WO 92/09690; Ladner et al., International Publication No. WO 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum Antibod Hybridomas 3:81-85 Huse et al (1989) Science 246:1275-1281 Griffths et al (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 19:41 33-4137; and Barbas et al. (1991) PNAS 88:7978-7982, all of which are incorporated herein by reference).

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

Human monoclonal antibodies can be generated using transgenic mice containing human immunoglobulin genes instead of the mouse system. Splenocytes from these transgenic mice immunized with an antigen of interest are used to generate hybridomas that secrete human mAb with specific affinity for epitopes from human protein (see, e.g., Wood et al., WO 91/00906, Kucherlapati et al. ., PCT Publication 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 portion thereof, such as the CDR, is produced in a non-human body, such as a rat or mouse. Included within the scope of the invention are chimeric antibodies, CDR-grafted antibodies, and humanized antibodies. Included within the scope of the invention are antibodies produced in a non-human, eg rat or mouse, and then modified, eg in a variable framework region or constant region, to reduce antigenicity in humans.

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

In a humanized or CDR-grafted antibody, at least one or two, but typically all three, of the recipient CDRs (heavy and/or light chain immunoglobulins) are replaced by a donor CDR. In an antibody, at least a portion of the non-human CDR may be replaced, or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to change the number of CDRs required to bind the humanized antibody to PDL1. Preferably, the donor is a rodent antibody, such as a rat or mouse antibody, and the recipient is a human framework or human consensus framework. Typically, an immunoglobulin providing a CDR is referred to as a donor and an immunoglobulin providing a framework region is referred to as an acceptor. In one embodiment, the donor immunoglobulin is not human (eg, rodent). An acceptor framework is a naturally occurring (eg, human) framework or consensus framework, or a sequence about 85% or more, preferably 90%, 95%, 99% or more identical thereto.

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

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

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

Also included within the scope of the invention are humanized antibodies in which specific amino acids are substituted, deleted, or inserted. Donor amino acid selection criteria are described in US Pat. No. 5,585,089, for example, columns 12-16 of US Pat. Other methods for humanizing antibodies are described in Padlan et al., EP 519596 A1 published December 23, 1992.

The antibody molecule may be a single chain antibody. A single chain antibody (scFV) can be engineered (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 be dimerized or multimerized to produce polyvalent antibodies having specificity for different epitopes on the same target protein.

In other embodiments, the antibody molecule has a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE heavy chain constant regions; in particular selected from, for example, heavy chain (eg human) constant regions of IgG1, IgG2, IgG3 and IgG4. In another embodiment, the antibody molecule has a light chain constant region selected, for example, from kappa and lambda (eg, human) light chain constant regions. The constant region can be changed, for example, by mutation, to modify the properties of the antibody (for example, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, and/or complement function). In one embodiment, the antibody has an effector function and can fix complement. In other embodiments, the antibody does not attract effector cells or does not fix complement. In another embodiment, the antibody has reduced or no ability to bind the Fc receptor. For example, it is an isotype or subtype, fragment, or other mutant that does not support binding to the Fc receptor, for example, it has a mutated or deleted Fc receptor binding region.

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

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

One type of derivatized antibody molecule is obtained by cross-linking two or more antibodies (of the same type or different types, for example, to obtain bispecific antibodies). Suitable

- 46 040861 crosslinkers include crosslinkers that are heterobifunctional, having two separate reactive groups separated by an appropriate spacer (eg mmalimidobenzoyl-M-hydroxysuccinimide ester) or homobifunctional (eg disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, 111.

Suitable detectable means by which an antibody molecule of the invention can be derivatized (or labeled) include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, fluorescent metal atoms, e.g. europium (Eu) and other lanthanides, and radioactive materials (described below). Illustrative fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl chloride, phycoerythrin, and the like.

The antibody can also be derivatized with detectable enzymes such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, and the like. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that is detectable. The antibody molecule can also be derivatized with a prosthetic group (eg, streptavidin/biotin and avidin/biotin). For example, an antibody can be derivatized with biotin and can be detected by indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, 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 diagnostic purposes and/or experimentally in a number of contexts, including (i) to isolate a given antigen by standard methods such as affinity chromatography or immunoprecipitation;

(ii) to detect a given antigen (eg, in a cell lysate or cell supernatant) to assess the magnitude and profile of protein expression;

(iii) to monitor tissue protein levels as part of a clinical testing procedure, for example to determine the effectiveness of a given treatment regimen.

Antibody molecules may be conjugated to another molecular entity, typically a label or therapeutic (eg, cytotoxic or cytostatic) agent or moiety. In diagnostic or therapeutic applications, radioactive isotopes can be used. Radioactive isotopes that may be associated with anti-PSMA antibodies include, but are not limited to, α-, β-, or γ-emitters, or β- and γ-emitters. Such radioactive isotopes include, but are not limited to, iodine ( ¹³¹ I or ¹²⁵ I), yttrium ( ⁹⁰ Y), lutetium ( ¹⁷⁷ Lu), actinium ( ²²⁵ As), praseodymium, astatine ( ²¹¹ At), rhenium ( ¹⁸⁶ Re) , bismuth ( ²¹² Bi or ²¹³ Bi), indium ( ^1u In), 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). Radioisotopes useful as drugs 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). Radioisotopes useful as labels, for example for diagnostic applications, include iodine ( ¹³¹ I or ¹²⁵ I), indium ( ⁿ¹ In), technetium ( ⁹⁹ mTc), phosphorus ( ³² P), carbon ( ¹⁴ C) and tritium ( ³ H), or one or more of the therapeutic isotopes listed above.

The invention relates to radioactively labeled antibody molecules and methods for labeling them. In one embodiment, a method for labeling an antibody molecule is disclosed. The method includes bringing the antibody molecule into contact with a chelating agent, thereby obtaining a conjugated antibody. The conjugated antibody is radioactively labeled with a radioisotope such as ^1P indium, ⁹⁰ yttrium, and ¹⁷⁷ lutetium, thereby producing a labeled antibody molecule.

As discussed above, an antibody molecule may be conjugated to a drug. Therapeutically active radioisotopes have already been mentioned. Examples of other drugs include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxy anthracine dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids , procaine, tatracaine, lidocaine, propranolol, puromycin, maytansinoids, such as maytansinol (see US patent No. 5208020), CC-1065 (see US patent No. 5475092, 5585499, 5846545) and their analogues or homologues. Drugs include, but are not limited to, antimetabolites (eg, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (eg, mechlorethamine, thiotepa, chlorambucil, CC-1065, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannite, streptozotocin, mitomycin C, and cis-dichlorodiamineplatinum(II)

- 47 040861 ((DDP) cisplatin), anthracyclines (eg daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (eg dactinomycin (formerly actinomycin), bleomycin, mithramycin and anthramycin (AMC)) and antimitotics (eg vincristine, vinblastine, taxol and maytansinoids).

In one aspect, the invention relates to a method of providing a target-binding molecule that specifically binds to the PD-L1 receptor. For example, the target-binding molecule is an antibody molecule. The method includes: providing a target protein that contains at least a portion of a non-human protein, the portion being homologous (at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96, 97, 98% identical) to the corresponding human target protein, but differs by at least one amino acid (eg, at least one, two, three, four, five, six, seven, eight, or nine amino acids); obtaining an antibody molecule that specifically binds to the antigen; and evaluating the effectiveness of the binding compound in modulating the activity of the target protein. In addition, the method may include administering a binding compound (eg, an antibody molecule) or derivative (eg, a humanized antibody molecule) to a human.

In certain embodiments, the antibody molecule is a multispecific (eg, bispecific or trispecific) antibody molecule. Protocols for obtaining bispecific or heterodimeric antibody molecules are known in the art; including, but not limited to, for example, the ledge-in-cavity approach described, for example, in US 5,731,168; Fc pairing via electrostatic directional interaction as described, for example, in WO 09/089004, WO 06/106905 and WO 2010/129304; the formation of heterodimers of engineered chain exchange domains (SEEDs), as described, for example, in WO 07/110205; exchange of Fab arms as described, for example, in WO 08/119353, WO 2011/131746 and wO 2013/060867; a dual antibody conjugate, for example, by cross-linking to form a bispecific structure using a heterobifunctional reagent having an amine reactive group and a sulfhydryl reactive group, as described, for example, in US 4433059; bispecific antibody determinants obtained by recombination of half antibodies (heavy-light chain or Fab pairs) from different antibodies through a cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described, for example, in US 4444878; trifunctional antibodies, eg three Fab' fragments cross-linked via sulfhydryl reactive groups, as described, eg, in US5273743; biosynthetic binding proteins, for example, a pair of scFvs linked via C-terminal tails, preferably via disulfide or amine reactive chemical crosslinking, as described, for example, in US5534254; bifunctional antibodies, eg, Fab fragments with different binding specificities, dimerized through leucine zippers (eg, c-fos and c-jun), which have a changed constant domain, as described, for example, in US5582996; bispecific and oligospecific mono- and oligovalent receptors, e.g., the VH-CH1 regions of two antibodies (two Fab fragments) linked through a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody, usually with associated light chains, such as described, for example, in US5591828; bispecific DNA-antibody conjugates, eg cross-linking of antibodies or Fab fragments through a double-stranded DNA fragment, as described, for example, in US5635602; bispecific fusion proteins, for example, an expression construct containing two scFvs with a hydrophilic helical peptide linker between them and a complete constant region, as described, for example, in US5637481; multivalent or multispecific binding proteins, e.g., 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, commonly referred to as diabodies (higher-order structures are also contemplated, creating bispecific, trispecific, or tetraspecific molecules as described in, for example, US5837242; mini-antibody constructs with cross-linked VL and VH chains further linked via peptide spacers to the hinge and CH3 regions of the antibody, which can dimerize to form bispecific/polyvalent molecules, as described in, for example, US5837821 ; VH and VL domains linked by a short peptide linker (e.g. 5 or 10 amino acids) or no linker at all in any orientation, which can form dimers to form bispecific diabodies; trimers and tetramers as described in, for example, US5844094; strand VH domains (or VL domains in family members) linked by peptide bonds with crosslinkable groups at the C-terminus, further linked to VL domains to form a series of FVs (or scFvs), as described, for example, in US5864019; and single chain binding polypeptides with both a VH and a VL domain linked via a peptide linker, which are combined into multivalent structures via non-covalent or chemical crosslinking to form, for example, homobivalent, heterobivalent, trivalent and tetravalent structures using a format such as scFV, and a diabody as described, for example, in US5869620. Additional exemplary multispecific and bispecific molecules and methods for their preparation are provided, for example, in

- 48 040861

US5959083, US5989830, US6005079,

US6333396, US6476198, US6511663,

US6809185, US6833441, US7129330,

US5910573, US5932448,

US6239259, US6294353,

US6670453, US6743896,

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US7527787, US7f US2002103345A1, US2004220388A1, US2005069552A1, US2О05136051A1, US2ОО 612 О960А1, US2007087381А1, US2007274985A1, US2008171855A1, US2О09130106А1, US2О09162360А1, US2О09234105А1,

4866, US7612181, US2003207346A1, US2004242847A1, US2005079170A1, US2005163782А1, US2006204493A1, US2007128150А1, US2008050370A1, US2008241884A1, US2О09148905А1, US2О09175851А1,

US2009263392A1,

US2002004587A1,

US2003211078A1,

US2005003403A1,

US2005100543A1,

US2005266425A1,

US2006263367A1,

US2007141049A1,

US2008069820A1,

US2008254512A1,

US2O09155275A1,

US2O09175867A1,

US2 O 0 92 7 4 64 97

US2002076406A1, US200421964ЗА1, US2005004352A1, US2005136049A1, US2006083747A1, US2007004909A1, US2007154901А1, US2О 08152645А1, US2008260738A1, US2О 09162359А1, US2О 09232811А1, ., ЕР346087А2,

WO0006605A2, WO02072635A2, WO04081051A1, WOO 6020258A2,

WO2007044887A2, W02007095338A2, W02007137760A2, W02O 08119353A1,

WO2009021754A2, WO2O09068630A1, WO9103493A1, WO9323537A1,

WO9409131A1, WO9412625A2, WO9509917A1, WO9637621A2, WO9964460A1.

The content of the above applications is incorporated into the present description by reference in its entirety.

In other embodiments, an anti-PD-L1 antibody molecule (e.g., a monospecific, bispecific, or multispecific antibody molecule) is covalently linked, such as fused, to another partner, such as a protein, such as one, two, or more cytokines, such as a fusion molecule , for example, a fusion protein. In other embodiments, the implementation of the fused 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 of IL-1, IL-2, IL-12, IL-15, or IL-21. In one embodiment, the bispecific antibody molecule has a first binding specificity for a first target (e.g., PD-L1), a second binding specificity for a second target (e.g., LAG-3 or TIM-3), and optionally associated with an interleukin domain (e.g., IL -12), for example, full-length IL-12 or part of it.

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

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

Exemplary Anti-PD-L1 Antibody Molecules.

In certain embodiments, an anti-PD-L1 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 195; the amino acid sequence of VHCDR2 SEQ ID NO: 2 and the amino acid sequence of VHCDR3 SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 9, the VLCDR2 amino acid sequence of SEQ ID NO: 10, and the VLCDR3 amino acid sequence of SEQ ID NO: 11.

In other embodiments, the anti-PD-L1 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 195; the amino acid sequence of VHCDR2 SEQ ID NO: 5 and the amino acid sequence of VHCDR3 SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 12, the VLCDR2 amino acid sequence of SEQ ID NO: 13, and the VLCDR3 amino acid sequence of SEQ ID NO: 14.

In embodiments of the above antibody molecules, VHCDR1 contains the amino acid sequence of SEQ ID NO: 1. In other embodiments, VHCDR1 contains the amino acid sequence of SEQ ID NO: 4. In other embodiments, VHCDR1 contains the amino acid sequence of SEQ ID NO: 195.

In embodiments, the aforementioned antibody molecules have a heavy chain variable region comprising at least one framework region (FW) comprising any of the amino acid sequences of SEQ ID NOs: 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152 or 154, or an amino acid sequence at least 90% identical to them, or having no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences of SEQ ID NO: 124 , 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152 or 154.

In other embodiments, the aforementioned antibody molecules have a heavy chain variable region comprising at least one framework region comprising any of the amino acid sequences of SEQ ID NOs: 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152 or 154.

In other embodiments, the aforementioned antibody molecules have a heavy chain variable region comprising at least two, three, or four framework regions comprising any of the amino acid sequences of SEQ ID NOs: 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152 or 154.

In other embodiments, the aforementioned antibody molecules comprise the amino acid sequence of VHFW1 SEQ ID NO: 124, 126, 128, or 130, the amino acid sequence of VHFW2 SEQ ID NO: 132, 134, 136, 138, 140, or 142, and the amino acid sequence of VHFW3 SEQ ID NO: 144, 146, 148, 150 or 152, and optionally additionally contain the amino acid sequence of VHFW4 SEQ ID NO: 154.

In other embodiments, the aforementioned antibody molecules have a light chain variable region comprising at least one framework region comprising any of the amino acid sequences of SEQ ID NOs: 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184 or 186, or an amino acid sequence at least 90% identical to them, or having no more than two amino acid substitutions, insertions or deletions compared to any of the amino acid sequences 156, 158, 160, 162 , 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184 or 186.

In other embodiments, the aforementioned antibody molecules have a light chain variable region comprising at least one framework region comprising any of the amino acid sequences of SEQ ID NOs: 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184 or 186.

In other embodiments, the aforementioned antibody molecules have a light chain variable region comprising at least two, three, or four framework regions comprising any of the amino acid sequences of SEQ ID NOs: 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184 or 186.

In other embodiments, the aforementioned antibody molecules comprise the amino acid sequence of VLFW1 SEQ ID NO: 156, 158, 160, 162, 164, or 166, the amino acid sequence of VLFW2 SEQ ID NO: 168 or 170, and the amino acid sequence of VLFW3 SEQ ID NO: 172, 174, 176 , 178, 180, 182 or 184, and optionally additionally contain the amino acid sequence of VLFW4 SEQ ID NO: 186.

In other embodiments, the aforementioned antibodies comprise a heavy chain variable domain comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 18, 30, 38, 46, 50, 54, 62, 70, or 78.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 18, 30, 38, 46, 50, 54, 62, 70, or 78.

In other embodiments, the aforementioned antibody molecules comprise a light chain variable domain comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 22, 26, 34, 42, 58, 66, 74, 82, or 86.

In other embodiments, the aforementioned antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 22, 26, 34, 42, 58, 66, 74, 82, or 86.

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

In other embodiments, the aforementioned antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 20.

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

In other embodiments, the aforementioned antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 32.

- 50 040861

In other embodiments, the aforementioned antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 96.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 197.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In other embodiments, the aforementioned antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 247.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 260.

In other embodiments, said antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 22. In other embodiments, said antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 24.

In other embodiments, the aforementioned antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 26.

In other embodiments, the aforementioned antibody molecules comprise a light chain comprising the amino acid sequence of SEQ ID NO: 28.

In other embodiments, the aforementioned antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 34.

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

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

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

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

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

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

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

- 51 040861

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

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

In other embodiments, the aforementioned antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 82.

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

In other embodiments, the aforementioned antibody molecules comprise a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 86.

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

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 22.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 26.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 86.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 34.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66.

In other embodiments, the aforementioned 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: 42.

In other embodiments, the aforementioned 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 aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 42.

In other embodiments, the aforementioned 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: 42.

In other embodiments, the aforementioned 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: 22.

In other embodiments, the aforementioned 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: 86.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 86.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 62 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 62 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 86.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 70 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 66.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 78 and the variable

- 52 040861 light chain domain containing the amino acid sequence of SEQ ID NO: 82.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 20 and a light chain containing the amino acid sequence of SEQ ID NO: 24.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 20 and a light chain containing the amino acid sequence of SEQ ID NO: 28.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 20 and a light chain containing the amino acid sequence of SEQ ID NO: 88.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 32 and a light chain containing the amino acid sequence of SEQ ID NO: 36.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 32 and a light chain containing the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforementioned antibody molecules comprise 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.

In other embodiments, the aforementioned antibody molecules comprise 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.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 48 and a light chain containing the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the aforementioned antibody molecules comprise 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: 44.

In other embodiments, the aforementioned antibody molecules comprise 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: 24.

In other embodiments, the aforementioned antibodies comprise 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: 88.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 260 and a light chain containing the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 56 and a light chain containing the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 56 and a light chain containing the amino acid sequence of SEQ ID NO: 88.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 64 and a light chain containing the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 64 and a light chain containing the amino acid sequence of SEQ ID NO: 88.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 72 and a light chain containing the amino acid sequence of SEQ ID NO: 68.

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

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 247 and a light chain containing the amino acid sequence of SEQ ID NO: 84.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 197 and a light chain containing the amino acid sequence of SEQ ID NO: 36.

In other embodiments, the aforementioned antibody molecules comprise a heavy chain,

- 53 040861 containing 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 aforementioned antibodies comprise a heavy chain containing the amino acid sequence of SEQ ID NO: 96 and a light chain containing the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforementioned antibody molecules are selected from Fab, F(ab')2, Fv, or a single chain Fv fragment (scFv).

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

In other embodiments, the aforementioned antibody molecules comprise a light chain constant region selected from kappa or lambda light chain constant regions.

In other embodiments, the aforementioned antibody molecules comprise a human IgG4 heavy chain constant region with a mutation at position 228 of SEQ ID NO: 188 or 190 and a kappa light chain constant region.

In other embodiments, the aforementioned antibody molecules comprise a human IgG4 heavy chain constant region with a serine to proline mutation at position 228 of SEQ ID NO: 188 or 190 and a kappa light chain constant region.

In other embodiments, the aforementioned antibody molecules comprise a human IgG1 heavy chain constant region with an asparagine to alanine mutation at position 297 of SEQ ID NO: 192 and a kappa light chain constant region.

In other embodiments, the aforementioned antibody molecules comprise a human IgG1 heavy chain constant region with an aspartate to alanine mutation at position 265, and a proline to alanine mutation at position 329 of SEQ ID NO: 193, and a kappa light chain constant region.

In other embodiments, the aforementioned antibody molecules comprise a human IgG1 heavy chain constant region with a leucine to alanine mutation at position 234 and a leucine to alanine mutation at position 235 of SEQ ID NO: 194 and a kappa light chain constant region.

In other embodiments, the aforementioned antibody molecules are capable of binding to human PD-L1 with a dissociation constant (K _D ) of less than about 0.2 nM.

In some embodiments, the aforementioned antibody molecules bind to human PD-L1 with a KD of less than about 2.5, 2, 1.5, 1, 0.5, 0.2, 0.15, 0.1, 0.05, or 0.02 nM, e.g., about 0.2 to 0.1 nM, e.g., about 0.166 to 0.176 nM, e.g., about 0.171 nM, or, e.g., about 0.1 to 1.5 nM, e.g., about 0.25 up to 0.46 nM, eg about 0.137, 0.931 or 2.14 nM, eg as measured by the Biacore method.

In other embodiments, the aforementioned antibody molecules bind to cynomolgus monkey PD-L1 with a KD of less than about 1, 0.8, 0.6, 0.4, 0.2, 0.15, 0.1, 0.05, or 0 .02 nM e.g. about 0.1 to 1 nM e.g. about 0.2 to 0.8 nM e.g. about 0.13 to 0.11 nM e.g. about 0.124, 0.369, 0.431, 0.735 nM e.g. , when measured by the Biacore method.

In other embodiments, the above antibody molecules bind to mouse PD-L1 with a K _D of less than about 100, 60, 10, 1, 0.5, 0.2, 0.15, 0.1, 0.05, or 0.02 nM, eg about 0.13 to 0.11 nM, eg about 0.124, 0.04, 0.075 or 77.4 nM, eg as measured by the Biacore method.

In other embodiments, the above antibody molecules bind to rat PD-L1 with a KD of less than about 15, 10, 5, 1, 0.5, 0.2, 0.15, 0.1, 0.05, or 0.02 nM , for example about 0.1 to 3.5 nM, for example about 0.13 to 0.11 nM, for example about 0.124, 0.04, 0.075, 0.431, 1.36, 6.14 or 77.4 nM, for example, when measuring with the Biacore method. In certain embodiments, the aforementioned antibody molecules bind to both human PD-L1 and cynomolgus monkey PD-L1, with a similar KD, eg in the nM range, eg as measured by the Biacore method.

In some embodiments, the aforementioned antibody molecules bind to 300.19 cells that express human PD-L1 (e.g., 300.19 cells transfected with human PD-L1) with a KD of less than about 0.5, 0.4, 0.3, 0.2 , 0.1, 0.075, 0.05, 0.025 or 0.01 nM, eg about 0.285 nM, eg as measured by FACS analysis.

In some embodiments, the aforementioned antibody molecules bind to cells that express cynomolgus monkey PD-L1 (e.g., cells transfected with cynomolgus monkey PD-L1) with a KD of less than about 1, 0.75, 0.5, 0.25, or 0. .01 nM, eg approximately 0.129 nM, eg as measured by FACS analysis.

In certain embodiments, the aforementioned antibody molecules are not cross-reactive with mouse or rat PD-L1. In other embodiments, the aforementioned antibodies are cross-reactive with rhesus monkey PD-L1. For example, cross-reactivity can be measured by the Biacore method or by a binding assay using cells that express PD-L1 (eg, 300.19 cells expressing human PD-L1). In others

- 54 040861 embodiments, the aforementioned antibody molecules bind the extracellular Ig-like domain of PD-L1.

In other embodiments, the aforementioned antibody molecules are capable of reducing the binding of PD-1 or B7-1 to PD-L1 or a cell that expresses PD-L1. In some embodiments, the aforementioned antibody molecules reduce (e.g., block) the binding of PD-L1 to a cell that expresses PD-L1 (e.g., 300.19 cells expressing human PD-L1) with an IC ₅₀ of less than about 1.5, 1, 0 .8, 0.6, 0.4, 0.2, or 0.1 nM, such as about 0.2 to about 0.1 nM, such as about 0.15 nM or less, such as about 0.145 nM. In some embodiments, the aforementioned antibodies reduce (e.g., block) B7-1 binding to a cell that expresses PD-L1 (e.g., 300.19 cells expressing human PD-L1) with an IC ₅₀ of less than about 2, 1.5, 1, 0.5 or 0.2 nM, eg about 0.5 to about 0.01 nM, or about 0.2 nM or less, eg about 0.1 nM.

In other embodiments, the aforementioned antibody molecules are capable of enhancing the response of antigen-specific T cells.

In some embodiments, the aforementioned 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, 3, 4, 5, 6, 7, or 8 times, for example, about 2-3 times, for example, about 2-2.6 times, for example, about 2.39 times, or, for example, about 2.4 to 6.4 times, compared with the expression IL-2 when an isotype control (eg IgG4) is used, eg when measured in an SEB T cell activation assay, eg using peripheral blood mononuclear cells (PBMC) or an ex vivo human whole blood assay.

In some embodiments, the aforementioned antibody molecules increase expression of IFN-γ from SEB-activated T cells (e.g., at a concentration of 3 pg/mL) by at least about 2, 3, 4, 5, 6, 7, or 8-fold, e.g. , about 0.5-4.5 times, for example, about 2.72 times, or, for example, about 4-7 times compared to the expression of IFN-γ when an isotype control (for example, IgG4) is used, for example , when measured in an IFN-γ activity assay.

In some embodiments, the aforementioned antibody molecules bind PD-L1 to a Kd slower than 5x10' ⁴ , 1x10' ⁴ , 5x10'5 , or 1x10' ⁵ s ^-1 , e.g., approximately 6.33x10'5 s ^-1 , e.g. Biacore method. In some embodiments, the above antibody molecules bind to PD-L1 with Ka faster than 1x10 ⁴ , 5x10 ⁴ , 1x10 ⁵ , or 5x105 M' ¹ s' ¹ , e.g., approximately 3.07x10 ⁴ M' ¹ s' ¹ , e.g. measurement by the Biacore method.

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

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

An isolated nucleic acid encoding a heavy chain variable region or a light chain variable region, or both, from any of the aforementioned antibody molecules is provided.

In one embodiment, an isolated nucleic acid encoding heavy chain CDRs 1-3 is provided, wherein said nucleic acid comprises the nucleotide sequence of SEQ ID NOs: 104-108, 113-117, or 205-208.

In another embodiment, an isolated nucleic acid encoding light chain CDRs 1-3 is provided, wherein said nucleic acid comprises the nucleotide sequence of SEQ ID NOs: 109-112, 118-123, 209-214, and 245-246.

In other embodiments, the aforementioned 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 NOs: 19, 31, 39, 47, 51, 55, 63, 71, 79, 90, 95, 100, 196 or 201.

In other embodiments, said nucleic acid further comprises a nucleotide sequence encoding a heavy chain variable domain, wherein said nucleotide sequence comprises any of SEQ ID NOs: 19, 31, 39, 47, 51, 55, 63, 71, 79, 90, 95, 100, 196 or 201.

In other embodiments, the aforementioned 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 NOs: 21, 33, 41, 49, 53, 57, 65, 73, 81, 92,

- 55 040861

97, 101, 198 or 202.

In other embodiments, the aforementioned nucleic acid further comprises a nucleotide sequence encoding a heavy chain, wherein said nucleotide sequence comprises any of SEQ ID NOs: 21, 33, 41, 49, 53, 57, 65, 73, 81, 92, 97, 101, 198 or 202.

In other embodiments, said 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 NOs: 23, 27, 35, 43, 59, 67, 75, 83, 87, 93, 98, 102, 199 or 203.

In other embodiments, the aforementioned nucleic acid further comprises a nucleotide sequence encoding a light chain variable domain, wherein said nucleotide sequence comprises any of SEQ ID NOs: 23, 27, 35, 43, 59, 67, 75, 83, 87, 93, 98, 102, 199 or 203.

In other embodiments, the aforementioned 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 NOs: 25, 29, 37, 45, 61, 69, 77, 85, 89, 94, 99, 103, 200 or 204.

In other embodiments, the aforementioned nucleic acid further comprises a nucleotide sequence encoding a light chain, wherein said nucleotide sequence comprises any of SEQ ID NOs: 25, 29, 37, 45, 61, 69, 77, 85, 89, 94, 99, 103, 200 or 204.

In certain embodiments, one or more expression vectors and host cells containing the aforementioned nucleic acids are provided.

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

Pharmaceutical compositions and kits.

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

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

The terms parenteral administration and parenterally administered, as used herein, mean routes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intravertebral, epidural and intrasternal injection and infusion.

Therapeutic compositions 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 antibody concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (ie, antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of the ingredients listed above, if necessary, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains the basic dispersion medium and the other required ingredients from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred manufacturing methods are vacuum drying and freeze drying, which provide a powder of the active ingredient with any additional required ingredient from its previously filter-sterilized solution. Proper fluidity of the solution can be maintained, for example, using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. Prolonged absorption of an injectable composition can be achieved by including in the composition an agent that delays absorption, such as monostearates and gelatin.

Antibody molecules can be administered by various routes known in the art, although for many therapeutic applications the preferred route/method 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 20-40 mg/min, and typically greater than or equal to 40 mg/min to achieve a dose of about 35 to 440 mg/m ² typically from about 70 to 310 mg/m ² , and more often from about 110 to 130 mg/m ² . For example, antibody molecules can be administered by intravenous infusion at a rate of less than 10 mg/min; typically less than or equal to 5 mg/min to achieve a dose of about 1 to 100 mg/m ² , typically about 5 to 50 mg/m ² , about 7 to 25 mg/m ² , and more often about 10 mg/ ^m2 . As will be appreciated by one of skill in the art, the route and/or route of administration will vary depending on the desired results. In certain embodiments, the active compound can be formulated with a carrier that protects the compound from rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Many methods for preparing such formulations are patented or well known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

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

Dosing regimens are adjusted to provide the optimal desired response (eg, therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as necessary for the therapeutic case. It is particularly advantageous to formulate parenteral compositions in unit dosage form for ease of administration and dosage uniformity. Unit dosage form, as used in the present invention, refers to physically discrete units suitable as single dosages for individuals to be treated; wherein each unit contains a predetermined amount of the active compound, calculated to achieve the desired therapeutic effect, together with the desired pharmaceutical carrier. The characteristics of the unit dosage forms of the present invention are determined by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in this field in relation to the formulation of the active compound for the treatment of sensitivity of individuals.

An exemplary non-limiting range for a therapeutically or prophylactically effective amount of an antibody molecule is 0.1-30 mg/kg, more preferably 1-25 mg/kg. Dosages and therapeutic regimens of the anti-PD-L1 antibody molecule can be determined by the skilled artisan. In certain embodiments, the anti-PD-L1 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg. 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 dosing schedule may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-PD-L1 antibody molecule is administered at a dose of about 10 to 20 mg/kg biweekly. The antibody molecule can be administered by intravenous infusion at a rate greater than 20 mg/min, such as 20-40 mg/min, and typically greater than or equal to 40 mg/min to achieve a dose of about 35 to 440 mg/m ² as typically from about 70 to 310 mg/m ² , and more often from about 110 to 130 mg/m ² . In embodiments, an infusion rate of about 110 to 130 mg/m ² provides a level of about 3 mg/kg. In other embodiments, the antibody molecule may be administered by intravenous infusion at a rate of less than 10 mg/min, such as less than or equal to 5 mg/min, to achieve a dose of about 1 to 100 mg/m ² , such as about 5 to 50 mg /m ² , about 7 to 25 mg/m ² or about 10 mg/m ² . In some embodiments, the antibody is infused over a period of approximately 30 minutes. The antibody molecule can be administered via

- 57 040861 intravenous infusion at a rate of less than 10 mg/min, preferably less than or equal to 5 mg/min, to achieve a dose of about 1 to 100 mg/m ² , preferably about 5 to 50 mg/m ² , about 7 up to 25 mg/m ² , or more preferably about 10 mg/m ² . It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated. In addition, it should be understood that for any particular individual, specific dosage regimens should be adjusted over time in accordance with the needs of the individual and the professional opinion of the person who administers or supervises the administration of the compositions, and that the dosage ranges described herein are only illustrative and are not intended to limit the scope or practice of the claimed composition.

Pharmaceutical compositions of the present invention comprise a therapeutically effective amount or a prophylactically effective amount of an antibody or antibody portion of the invention. A therapeutically effective amount refers to an amount effective, at the required dosages and for the required periods of time, to achieve the desired therapeutic result. The therapeutically effective amount of the modified antibody or antibody fragment may vary depending on such factors as the disease, age, sex and body weight of the individual, and the ability of the antibody or antibody portion to induce the desired response in the individual. A therapeutically effective amount is also one in which any toxic or deleterious effects of the modified antibody or antibody fragment are outweighed by the therapeutically beneficial effects. A therapeutically effective dosage preferably inhibits the measurable parameter by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% relative to no treated individuals. The ability of a compound to inhibit a measurable parameter, eg, cancer, can be assessed in an animal model system predictive of efficacy in human tumors. Alternatively, this property of the composition can be assessed by testing the ability of the compound to inhibit, such as in vitro inhibition, using assays known to the skilled artisan.

A prophylactic effective amount refers to an amount effective, at the required dosages and for the required periods of time, to achieve the desired prophylactic result. Generally, since a prophylactic dose is used in individuals before or at an early stage of the disease, the prophylactically effective amount is less than the therapeutically effective amount.

Also within the scope of the present invention is a kit containing the antibody molecule described herein. The kit may include one or more elements, including: instructions for use; other reagents, for example, a label, a drug, or an agent suitable for chelating or otherwise binding the antibody to the label, or drug, or radioprotective composition; devices or other materials for preparing the antibody for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to an individual.

Use of Anti-PD-L1 Antibody Molecules.

The anti-PD-L1 antibody molecules described herein are useful for in vitro and in vivo diagnostics, as well as therapy and prophylaxis. For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to an individual, eg, a human, for the treatment, prevention and/or diagnosis of various disorders such as cancers and infectious disorders.

Thus, in one aspect, the invention relates to a method for modifying an immune response in an individual, comprising administering to the individual an antibody molecule described herein to modify the immune response in the individual. In one embodiment, the immune response is enhanced, stimulated or activated. In one embodiment, the antibody molecules enhance the immune response in the individual through the blockade of PD-L1.

As used herein, the term individual includes human and non-human animals. In one embodiment, the subject is a human, eg, a human patient, having a disorder or condition characterized by abnormal PD-L1 functioning. The term non-human animals includes mammals and non-mammals such as non-human primates. In one embodiment, the individual is a human. In one embodiment, the subject is a human patient in need of enhanced immune response. In one embodiment, the individual is immunocompromised, for example, the individual is or has been undergoing chemotherapy or radiation therapy. Alternatively, or in combination, the individual is immunodeficient or at risk of being immunodeficient as a result of infection. The methods and compositions described herein are useful in the treatment of human patients having a disorder that can be treated by enhancing a T-cell mediated immune response. For example, methods and compositions

- 58 040861 described in the present description, can enhance a number of immune activities. In one embodiment, the individual has an increased number or activity of tumor-infiltrating

T-lymphocytes (TIL). In another embodiment, the individual has increased interferon-gamma (IFN-γ) expression or activity. In another embodiment, the individual has reduced expression or activity of PD-L1.

Therapeutic applications.

Blockade of PD-L1 by antibodies can enhance the immune response to malignant cells in a patient. PD-L1 is generally not expressed in normal human cells, but is common in various human cancers (Dong et al. (2002) Nat Med 8:787-9). The interaction between PD-1 and PD-L1 leads to a decrease in the level of tumor-infiltrating lymphocytes, a decrease in T-cell receptor-mediated proliferation, and immune escape of malignant cells (Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2005) Cancer Immunol Immunother 54:307-14); Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can be reversed by inhibiting the local interaction of PD-L1 with PD-1, and this effect is additive when the interaction of PD-L2 with PD-1 is also blocked (Iwai et al. (2002) PNAS 99:12293-7; Brown et al (2003) J Immunol 170:1257-66). Anti-PD-L1 antibody can be used alone to inhibit the growth of malignant tumors. Alternatively, an anti-PD-L1 antibody can be used in conjunction with other immunogenic agents, standard cancer treatments, or other antibodies as described herein. Thus, inhibition of PDL1 may enhance the immune response.

In one aspect, the present invention relates to in vivo treatment of a subject with an anti-PD-L1 antibody molecule such that the growth of malignant tumors is inhibited or reduced. Anti-PD-L1 antibody can be used alone to inhibit the growth of malignant tumors. Alternatively, an anti-PD-L1 antibody may be used in combination with one or more of: a standard cancer treatment (e.g., for malignant or infectious disorders), another antibody or antigen-binding fragment thereof, an immunomodulator (e.g., an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule) ; vaccines, for example a therapeutic cancer vaccine; or other forms of cellular immunotherapy as described below.

Thus, in one embodiment, the invention relates to a method of inhibiting tumor cell growth in an individual, comprising administering to the individual a therapeutically effective amount of an anti-PD-L1 antibody molecule described herein.

In one embodiment, the methods are suitable for treating cancer in vivo. To achieve antigen-specific enhancement of immunity, the anti-PD-L1 antibody molecule can be administered together with the antigen of interest. When anti-PD-L1 antibodies are administered in combination with one or more agents, the combination may be administered in any order or simultaneously.

Types of malignant tumor; teragnostic ways

In another aspect, a method is provided for treating, eg, reducing or alleviating, a hyperproliferative condition or disorder (eg, cancer), eg, a solid tumor, soft tissue tumor, or metastatic lesion, in a subject in an individual. The method includes administering to an individual one or more of the anti-PD-L1 antibody molecules described herein, alone or in combination with other agents or therapeutic moieties.

As used herein, the term cancer is intended to include all types of malignant growth or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, regardless of histopathological type or degree of invasiveness. Examples of malignant disorders include, but are not limited to, solid tumors, hematologic malignancies, soft tissue tumors, and metastatic lesions.

Examples of solid tumors include malignant tumors such as sarcomas and carcinomas (including adenocarcinomas and squamous cell carcinomas) of various organ systems such as tumors affecting the liver, lung, breast, lymphoid organs, gastrointestinal tract (eg colon), urogenital pathways (eg, kidneys, urothelial cells), prostate, and pharynx. Adenocarcinomas include malignancies such as most types of colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung carcinoma, small intestine cancer, and esophageal cancer. Squamous cell carcinoma includes malignant tumors, for example, in the lung, esophagus, skin, head and neck, oral cavity, anus, and cervix. In one embodiment, the cancer is a melanoma, such as advanced stage melanoma. Metastatic lesions of the aforementioned cancers can also be treated or prevented using the methods and compositions of the present invention.

Exemplary cancers whose growth can be inhibited using the antibody molecules described herein include cancers that typically respond to immunotherapy. Non-limiting examples of preferred cancers for treatment include lymphoma (e.g., diffuse large B cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma), breast cancer (e.g., metastatic breast cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), eg, stage IV non-small cell lung cancer or recurrent non-small cell lung cancer, NSCLC adenocarcinoma or NSCLC squamous cell carcinoma), myeloma (eg, multiple myeloma), leukemia (eg, chronic myelogenous leukemia), skin cancer (eg, melanoma (eg, stage III melanoma or IV) or Merkel cell carcinoma), head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC)), myelodysplastic syndrome, bladder cancer (eg, transitional cell carcinoma), kidney cancer (eg, renal cell carcinoma eg, clear cell renal cell carcinoma, eg, advanced or metastatic clear cell carcinoma renal cell carcinoma) and colon cancer. In addition, refractory or recurrent cancers can be treated using the antibody molecules described herein.

Examples of other cancers that can be treated include bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, endometrial cancer, ovarian cancer, rectal cancer, anal cancer, gastric and esophageal cancer. , gastric cancer, testicular cancer, uterine body cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Merkel cell carcinoma, 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, childhood solid tumors , lymphocytic lymphoma, bladder cancer, multiple myeloma, myelodysplastic syndromes, kidney or urethral cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced malignant tumors including asbestos-induced cancers (eg, mesothelioma) and combinations of these cancers.

Using the antibody molecules described herein, it is possible to treat metastatic tumors, for example, metastatic tumors that express PD-L1 (Iwai et al. (2005) Int. Immunol. 17:133-144). In one embodiment, the cancer expresses elevated levels of PD-L1, IFNy, and/or CD8.

PD-L1 signaling may provide increased expression of Bim in CD8+ T cells. Treatment of malignancies, such as advanced melanomas, in patients who express high levels of Bim (eg, increased levels of Bim in PD-1+CD8+ T cells compared to PD-1-CD8+ T cells) can be achieved using molecules antibodies described in the present description.

Animal models that can be used to investigate the efficacy of an anti-PD-L1 antibody in monotherapy or combination therapy for cancer include, for example, the CT26 colon carcinoma model (Sakuishi et al. (2010) J Exp Med. 207(10): 21872194 ) and the 5T33 sheloma model (Manning et al. (1992) Br J Cancer. 66(6): 1088-1093).

In one embodiment, the cancer expresses elevated levels of PD-L1, IFNy, and/or CD8.

Without wishing to be bound by theory, in some embodiments, a patient is more likely to respond to treatment with an immunomodulator (optionally in combination with one or more agents as described herein) if the patient has a cancer that highly expresses PD-L1, and /or if the cancer is infiltrated with antitumor immune cells, eg TIL. Antitumor immune cells may be positive for CD8, PD-L1 and/or IFN-y; thus, CD8, PD-L1 and/or IFN-y levels can serve as an indicator of TIL levels in the microenvironment. In certain embodiments, the cancer microenvironment is referred to as triple positive for PD-L1/CD8/IFN-y.

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

In the following indications, a high proportion of patients are triple positive for PDL1/CD8/IFN-y: lung cancer (squamous cell); lung cancer (adenocarcinoma); head and neck cancer; cancer

- 60 040861 boat; NSCLC; HNSCC; gastric cancer (eg, MSIhi and/or EBV+); CRC (for example, MSIhi); nasopharyngeal cancer (NPC); cervical cancer (eg, squamous cell); thyroid cancer, eg papillary thyroid cancer; melanoma; breast cancer TN; and DLBCL (diffuse large B-cell lymphoma). In breast cancer in general and colon cancer in general, a moderate proportion of patients are triple positive for PD-L1/CD8/IFN-y. In the following indications, a small proportion of patients are triple positive for PDL1/CD8/IFN-y: ER ⁺ breast cancer and pancreatic cancer. These data are discussed further in Example 4. Regardless of whether a large or small proportion of patients are triple positive for these markers, patient screening for these markers identifies the proportion of patients who are particularly likely to respond favorably to anti-PD-L1 antibody therapy ( e.g., anti-PD-L1 blocking antibody), optionally in combination with one or more other immunomodulators (e.g., anti-TIM-3 antibody molecule, anti-LAG-3 antibody molecule, or anti-PD-L1 antibody molecule) and/or anti-cancer agents , for example, the means given in table. 6 and described in the publications given in table. 6.

In some embodiments, the sample is classified as triple positive for PD-L1/CD8/IFN-y. This indicator can be roughly reduced to two thresholds: whether an individual cell is classified as positive and whether the sample as a whole is classified as positive. First, the level of PD-L1, CD8 and/or IFN-y can be measured in an individual cell. 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 than a control cell or reference value. For example, in some embodiments, a high level of PD-L1 in a given cell is a level greater than the level of PD-L1 in a corresponding non-cancerous tissue in a patient. As another example, in some embodiments, the high level of CD8 or IFN-y in a given cell is the level of that protein normally seen in TIL. Second, it is also possible to measure the percentage of cells in a sample that are positive for PD-L1, CD8, and/or IFN-y (it is not necessary that one cell expresses all three markers). In some embodiments, a triple positive sample is a sample that has a high percentage of cells that are positive for these markers, such as higher than a reference value or higher than a control sample.

In other embodiments, the levels of PD-L1, CD8 and/or IFN-y in general in the sample can be measured. In this case, a high level of CD8 or IFN-y in the sample may represent the level of this protein normally seen in a TIL-infiltrated tumor. Likewise, a high level of PD-L1 may represent the level of this protein commonly seen in a tumor sample, eg, in the tumor microenvironment.

The identification of patient subgroups that are triple positive for PDL1/CD8/IFN-y, as shown in Example 4 of the present disclosure, has identified certain patient subpopulations that are likely to respond particularly well to anti-PD-1 antibody therapy. For example, many IM-TN (immunomodulatory, triple negative) breast cancer patients are triple positive for PD-L1/CD8/IFN-y. IM-TN breast cancer is described, for example, in Brian D. Lehmann et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies, J Clin Invest. Jul 1, 2011; 121(7): 2750-2767. Triple negative breast cancer is a breast cancer that does not express the estrogen receptor (ER), progesterone receptor (PR), and Her2/neu. These cancers are difficult to treat because they usually do not respond to agents that target ER, PR, and Her2/neu. Triple negative breast cancer can be further subdivided into different classes, one of which is immunomodulatory. As described in Lehmann et al., IM-TN breast cancer is enriched in factors involved in immune cell processes, e.g., one or more of immune cell signaling (e.g., TH1/TH2 cascade, NK cell cascade, B signaling cascade α-cell receptor, DC cascade and T cell receptor signaling), cytokine signaling (eg, cytokine cascade, IL-12 cascade, and IL-7 cascade), antigen processing and presentation, signaling through central immune signaling cascades (eg , NFKB, TNF and JAK/STAT signaling), genes involved in T-cell function, immune transcription, interferon response (IFN) and antigen processing. Thus, in some embodiments, the cancer being treated is a cancer that is or has been determined to be positive for one or more IM-TN breast cancer markers, e.g., a factor that stimulates one or more from immune cell signaling (eg, TH1/TH2 cascade, NK cell cascade, B cell receptor signaling cascade, DC cascade, and T cell receptor signaling), cytokine signaling (eg, cytokine cascade, IL-12 cascade, and IL-7),

- 61 040861 antigen processing and presentation, signaling through the central immune signaling cascades (for example, signaling through NFKB, TNF and JAK/STAT), genes involved in T-cell function, immune transcription, interferon response (IFN) and antigen processing.

As another example, within the scope of the present invention, it has been shown that a subgroup of colon cancer patients with high MSI (microsatellite instability) is also triple positive for PD-L1/CD8/IFN-y. Thus, in some embodiments, an anti-PD-L1 antibody, such as an anti-PD-L1 antibody described herein (optionally in combination with one or more immunomodulators, such as an anti-LAG3 antibody, an anti-TIM-3 antibody, or an anti-PD antibody). -1, and one or more anti-cancer agents, for example, the anti-cancer agent described in Table 6 or the publication in Table 6) is administered to a patient who has or is identified as having high MSI colon cancer, thereby in the treatment of malignant tumors. In some embodiments, a high MSI cell is a cell having an MSI level greater than a reference value or a value in a control cell, such as a non-cancerous cell of the same tissue type as the cancer.

As another example, the present invention shows that a subset of gastric cancer patients who have high MSI and/or who are EBV+ are also triple positive for PD-L1/CD8/IFN-y. Thus, in some embodiments, an anti-PD-L1 antibody, such as an anti-PD-L1 antibody described herein (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 against PD-1, and one or more anti-cancer agents, for example, the anti-cancer agent described in Table 6 or in the publication in Table 6) is administered to a patient who has or is identified as having gastric cancer with high MSI and /or EBV+, thereby carrying out the treatment of a malignant tumor. In some embodiments, a high MSI cell is a cell having an MSI level greater than a reference value or a value in a control cell, such as a non-cancerous cell of the same tissue type as the cancer.

Also described herein are methods for assaying a cancer for PD-L1 and then treating the cancer with an anti-PD-L1 antibody. As described in Example 5 of the present disclosure, a cancer sample can be analyzed for protein levels or mRNA levels of PD-L1. A sample having levels of PD-L1 (protein or mRNA) greater than a reference value or a value in a control cell (eg, a non-cancerous cell) can be classified as PD-L1 positive. Thus, in some embodiments, an anti-PD-L1 antibody, e.g., an anti-PD-L1 antibody described herein (optionally in combination with one or more anti-cancer agents) is administered to a patient who has or is identified as having cancer. , which is positive in PD-L1. The malignant tumor may be, for example, non-small cell lung adenocarcinoma (NSCLC) (ASA), NSCLC squamous cell carcinoma (SCC), or hepatocellular carcinoma (HCC).

In some embodiments, the methods described herein involve the use of an anti-PD-L1 antibody, e.g., an anti-PD-L1 antibody as described herein, e.g., as monotherapy, for the treatment of a cancer that is (or identified as being ) positive for PD-L1. In some embodiments, the cancer is colon cancer (e.g., high MSI), gastric cancer (e.g., high MSI and/or EBV+), NPC, cervical cancer, breast cancer (e.g., breast cancer TN) and ovarian cancer. In some embodiments, the cancer is NSCLC, melanoma, or HNSCC. In some embodiments, the anti-PD-L1 antibody is administered at a dose of, for example, 1, 3, 10, or 20 mg/kg.

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

Based on, for example, Example 4 of this disclosure, a CRC of, for example, a patient who has (or is identified as having) a high MSI CRC can be treated with an anti-PD-L1 antibody, optionally in combination with a therapeutic agent that targets one or more from

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LAG-3, RNF43 and BRAF. For example, these cancers can be treated with an anti-PDL1 antibody, optionally in combination with one or more therapeutic agents that target one or more of LAG-3, PD-1, RNF43, and BRAF. In embodiments, one or more therapeutic agents include immunomodulators, such as an anti-LAG-3 antibody molecule and an anti-cancer agent described in Table 1. 6 or in the publication given in table. 6. LAG-3 inhibitors, such as antibodies, are described herein. RNF43 can be inhibited, for example, by an antibody, a small molecular weight compound (for example, 2-(2',3-dimethyl-[2,4'bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin- 2-yl)acetamide (compound A28)), miRNA or Rspo ligand or its derivative. BRAF inhibitors (eg, vemurafenib or dabrafenib) are described herein.

Based on, for example, Example 4 of the present disclosure, a patient who has (or is identified as having) squamous cell lung cancer can be treated with an anti-PD-L1 antibody molecule in combination with a therapeutic agent that targets LAG-3, for example, an anti-LAG antibody molecule. -3, and optionally one or more anti-cancer agents, such as the anti-cancer agent described in Table 1. 6 or in the publication given in table. 6.

In some embodiments, an individual who has (or is identified as having) squamous cell lung cancer may be treated with an anti-PD-1 antibody, optionally in combination with a therapeutic agent that targets TIM-3, such as an anti-TIM-3 antibody. TIM-3 inhibitors, such as antibodies, are described herein.

Based on, for example, Example 4 of the present disclosure, a patient who has (or is identified as having) thyroid cancer can be treated with an anti-PD-1 antibody molecule, optionally in combination with a therapeutic agent that targets BRAF, and optionally in combination with one or more immunomodulators, for example, an anti-LAG-3 antibody molecule, an anti-TIM-3 antibody molecule, and an anti-PD-L1 antibody molecule. BRAF inhibitors (eg, vemurafenib or dabrafenib) are described herein, for example, in Table. 6 and in the publications given in table. 6.

In some embodiments, the methods of therapy described herein can be used to treat a patient who has (or is identified as having) a cancer associated with an infection, such as a viral or bacterial infection. Illustrative malignancies include cervical cancer, anal cancer, HPV-associated head and neck squamous cell carcinoma, HPV-associated esophageal papillomas, HHV6-associated lymphomas, EBV-associated lymphomas (including Burkitt's lymphoma), gastric MALT lymphoma, other associated with MALT lymphoma infection, HCC, Kaposi's sarcoma.

In other embodiments, the cancer is a hematological cancer or cancer, including but not limited to leukemia or lymphoma. For example, an anti-PD-L1 antibody molecule can be used to treat malignant tumors and neoplasms, including, but not limited to, for example, acute leukemias, including, but not limited to, for example, B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), acute lymphoid leukemia (ALL); one or more of chronic leukemias, including but not limited to, for example, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic malignancies or hematologic conditions including, but not limited to, e.g. lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone cell lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström's macroglobulinemia and preleukemia, which is a diverse set hematological conditions associated with ineffective production (or dysplasia) of myeloid blood cells, etc.

In one embodiment, the cancer is breast cancer, e.g., metastatic breast cancer, e.g., breast cancer that does not express one, two, or all of the estrogen receptor, progesterone receptor, or Her2/neu, e.g., triple negative breast cancer. glands.

In another embodiment, the cancer is lung cancer, e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer), e.g., locally advanced or metastatic non-small cell lung cancer, e.g., stage IV non-small cell lung cancer or recurrent non-small cell lung cancer.

In another embodiment, the cancer is a skin cancer, eg, Merkel cell carcinoma (MCC), eg, metastatic Merkel cell carcinoma.

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In one embodiment, the cancer is selected from lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC with squamous and/or non-squamous histology, NSCLC adenocarcinoma, or NSCLC squamous cell carcinoma)), 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 does not express one, two, or all of the estrogen receptor, progesterone receptor or Her2/neu, such as triple-negative breast cancer), colorectal cancer, pancreatic cancer, head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC), anal cancer, gastric and esophageal cancer , thyroid cancer, cervical cancer, lymphoproliferative disease (eg, post-transplant lymphoproliferative disease) or hematologic malignancy, T-cell lymphoma, non-Hodgkin's lymphoma, or leukemia (eg, myeloid 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 lung cancer, such as non-small cell lung cancer.

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

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

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

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

In one embodiment, the cancer is a melanoma, such as advanced melanoma. In one embodiment, the cancer is an advanced or unresectable melanoma that has not responded to other therapies. In other embodiments, the cancer is a melanoma with a BRAF mutation (eg, a BRAF V600 mutation). In other embodiments, the anti-PD-L1 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 described herein are useful in the treatment of metastatic lesions associated with the aforementioned cancers.

Combining anti-PD-L1 antibodies with cancer vaccines Anti-PD-L1 antibody molecules can be combined with an immunogenic agent 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 tumor vaccines that can be used include melanoma antigen peptides such as gp100 peptides, MAGE, Trp2, MART1 and/or tyrosinase antigens, or tumor cells transfected to express the GMCSF cytokine, DNA-based vaccines, RNA-based vaccines and vaccines based on viral transduction. A cancer vaccine may be prophylactic or therapeutic.

PD-L1 blockade can be combined with a vaccination protocol. Many experimental strategies have been developed for vaccination against tumors (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C, 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428 Foon, K. 2000, ASCO Educational Book Spring: 730-738, see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al (eds.), 1997, Cancer: Principles and Practice of Oncology Fifth Edition). In one of these strategies, the vaccine is produced using autologous or allogeneic tumor cells. These cell vaccines have been shown to be most effective when tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent antigen presentation activator for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43).

Blockade of PD-L1 can be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor to induce an immune response to these proteins. These proteins are normally considered by the immune system as self antigens and thus are tolerant to them. The tumor antigen may also include the protein telomerase, which is required for the synthesis of chromosome telomeres and which is expressed in more than 85% of malignant tumors and only in a limited

- 64 040861 number of somatic tissues (Kim, N et al. (1994) Science 266: 2011-2013) (these somatic tissues can be protected from immune attack in various ways). The tumor antigen can also be neoantigens expressed in malignant cells due to somatic mutations that change the protein sequence or form fusion proteins between two unrelated sequences (i.e. bcr-abl on the Philadelphia chromosome), or an idiotype in the case of B cell tumors.

Other tumor vaccines may include proteins from viruses involved in human cancers such as human papillomaviruses (HPV), hepatitis viruses (HBV and HCV) and Kaposi's sarcoma herpes virus (KHSV) and Epstein-Barr virus (EBV). Another form of specific tumor antigen that can be used in conjunction with PD-1 blockade are purified heat shock proteins (HSPs) isolated directly from tumor tissue. These heat shock proteins contain fragments of proteins from tumor cells and these HSPs are highly effective in delivering to antigen presenting cells to induce tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al (1997) Science 278:117-120).

Dendritic cells (DC) are efficient antigen-presenting cells that can be used to induce antigen-specific responses. DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs can also be transduced by genetic means to express these tumor antigens. DCs have been fused directly to tumor cells for immunization purposes (Kugler, A. et al. (2000) Nature Medicine 6:332336). As a vaccination method, DC immunization can be effectively combined with PD-1 blockade to activate more potent antitumor responses.

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

PD-L1 blockade can also be combined with standard cancer treatment. Blockade of PD-L1 can be effectively combined with chemotherapy regimens. In these cases, it may be possible to reduce the dose of the chemotherapeutic agent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304). In certain embodiments, the methods and administration of the compositions described herein are carried out in combination with one or more other antibody molecules, chemotherapy, other cancer therapy (e.g., targeted cancer therapy or oncolytic drugs), cytotoxic agents, immune therapies (eg, cytokines), surgical and/or radiation procedures. Exemplary cytotoxic agents that can be administered in combination include antimicrotubulin agents, topoisomerase inhibitors, antimetabolites, mitosis inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents that can interfere with the signaling cascade, agents that stimulate apoptosis, proteasome inhibitors, and radiation therapy (for example, local radiation or radiation of the whole body).

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

Illustrative non-limiting combinations and uses of anti-PD-L1 antibody molecules include the following combinations.

In certain embodiments, an anti-PD-L1 antibody molecule is administered in combination with a modulator of a co-stimulatory molecule or an inhibitory molecule, such as a co-inhibitory ligand or receptor.

In one embodiment, an anti-PD-L1 antibody molecule is administered in combination with a modulator, eg, an agonist, of a costimulatory molecule. In one embodiment, the co-stimulatory molecule agonist is selected from an agonist (e.g., antibody agonist or antigen binding fragment thereof or soluble fusion construct) 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.

In another embodiment, an anti-PD-L1 antibody molecule is used in combination with a co-stimulatory molecule, eg, a positive signal-associated agonist, which includes the co-stimulatory domain of CD28, CD27, ICOS, and GITR.

Exemplary GITR agonists include, for example, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion protein described in the patent.

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US Pat. No. 6,111,090, EP No. 090505B1, US Pat. No. 8,586,023, PCT Publication Nos. WO 2010/003118 and 2011/090754, or an anti-GITR antibody as described, for example, in US Pat. , US Patent No. 8388967, US Patent No. 8591886, European Patent No. EP 1866339, PCT Publication No. WO 2011/028683, PCT Publication No. WO 2013/039954, PCT Publication No. WO 2005/007190, PCT Publication No. WO 2007/133822, PCT Publication No. WO 2005/055808, PCT Publication No. WO 99/40196, PCT Publication No. WO 2001/03720, PCT Publication No. WO 99/20758, PCT Publication No. WO 2006/083289, PCT Publication No. WO 2005/115451, U.S. Patent No. 7618632 and PCT Publication No. WO 2011/051726. In one embodiment, an anti-PD-L1 antibody molecule is administered in combination with an inhibitor of a molecule that inhibits an immune checkpoint molecule. One skilled in the art will understand that the term immune checkpoints means a group of molecules on the surface of CD4 and CD8 T cells. These molecules can effectively serve as brakes to suppress or inhibit the antitumor immune response. Immune checkpoint molecules include, but are not limited to, programmed death protein 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and LAG-3, which directly inhibit immune cells. Immunotherapeutic agents that may act as immune checkpoint inhibitors useful in the methods of the present invention include, but are not limited to, inhibitors of PD-1, PD-L2, CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CEACAM (eg CEACAM-1, CEACAM-3 and/or CEACAM-5) and/or TGFR-beta.

Inhibition of an inhibitory molecule can be carried out by inhibition at the level of DNA, RNA or protein. In embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA, or shRNA) can be used to inhibit the expression of an inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, such as a soluble ligand, or an antibody or 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 an antibody or antibody fragment that binds to PD-1, PD-L2, or CTLA-4. For example, an anti-PD-L1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, such as ipilimumab, for example, to treat a cancer (for example, a cancer selected from: melanoma, for example, metastatic melanoma; lung cancer, for example, non-small cell lung carcinoma; or prostate cancer). Exemplary anti-CTLA-4 antibodies include tremelimumab (an IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675.206); and ipilimumab (an anti-CTLA-4 antibody also known as MDX-010, CAS no. 477202-00-9). In one embodiment, the anti-PD-L1 antibody molecule is administered post-treatment, such as after treatment of melanoma, with an anti-CTLA-4 antibody (eg, ipilimumab), with or without a BRAF inhibitor (eg, vemurafenib or dabrafenib). Illustrative doses that may be used include an anti-PD-L1 antibody dose of about 1 to 10 mg/kg, eg 3 mg/kg, and an anti-CTLA-4 antibody dose, eg ipilimumab, of about 3 mg/kg.

Immune inhibitory molecules, eg, PD-L1 and LAG-3, can regulate, eg, synergistically regulate, T cell function to promote immune escape of the tumor. In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or antigen-binding fragment thereof. In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or antigen-binding fragment thereof. In other embodiments, an anti-PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody, or antigen-binding fragments thereof. The combination of antibodies described herein can be administered individually, eg, as single antibodies, or in linked form, eg, as a bispecific or trispecific antibody molecule.

In some embodiments, an antibody molecule (e.g., a monospecific, bispecific, or trispecific antibody) for TIM-3, LAG-3, and/or PD-1 used in any of the methods described herein comprises an amino acid sequence or is encoded by a nucleotide sequence, as described herein (for example, as described in the section titled Immune Checkpoint Molecule Inhibitors beginning on page 218 of the present specification below (including all publications cited therein).

In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with a CEACAM inhibitor (eg, a CEACAM-1, CEACAM-3 and/or CEACAM-5 inhibitor), eg an anti-CEACAM antibody molecule. In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with a CEACAM-1 inhibitor, eg, an anti-CEACAM-1 antibody molecule. In another embodiment, an anti-PD-L1 antibody molecule is administered in combination with a CEACAM-5 inhibitor, eg, an anti-CEACAM-5 antibody molecule. In one embodiment, a bispecific antibody is administered that includes an anti-PD-L1 antibody molecule and an anti-PD-L1 antibody.

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TIM-3 or against LAG-3, or an antigen-binding fragment thereof. In certain embodiments, a combination of antibodies described herein is used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor). The efficacy of the above combinations can be tested in animal models known in the art.

In one embodiment, the CEACAM inhibitor (eg, CEACAM-1 and/or CEACAM-5) is an anti-CEACAM antibody molecule. Without being bound by theory, CEACAM-1 has been described as a ligand and partner of TIM-3 (see, for example, WO 2014/022332). A synergistic in vivo effect of a combination of anti-TIM-3 and anti-CEACAM-1 antibodies has been found in cancer xenograft models (see, for example, WO 2014/022332). Tumors are believed to use CEACAM-1 or CEACAM-5 to inhibit the immune system, as described, for example, in Markel et al., J Immunol. 2002 Mar 15; 168(6): 2803-10; Markel et al., J Immunol. 2006 Nov 1;177(9):6062-71; Markel et al., Immunology. February 2009; 126(2):186-200; Markel et al., Cancer Immunol Immunother. 2010 Feb;59(2):21530; Ortenberg et al., Mol Cancer Ther. Jun 2012; 11(6): 1300-10; Stern et al., J Immunol. 2005 Jun 1;174(11):6692-701; Zheng et al., PIOS One. 2010 Sep 2;5(9). pii:e12529. Thus, CEACAM inhibitors can be used with other immunomodulators described herein (eg, PD-1 or TIM-3 inhibitors) to enhance the immune response against cancer, eg, melanoma, lung cancer (eg, NSCLC), bladder cancer , colon cancer or ovarian cancer, or other malignancies as described herein. In one embodiment, the CEACAM inhibitor is an anti-CEACAM-1 antibody as described in WO 2010/125571, WO 2013/82366 and WO 2014/022332, e.g., a 34B1, 26H7, and 5F4 monoclonal antibody, or a recombinant form thereof, as described, for example , in US 2004/0047858, US 7132255 and WO 99/52552. In other embodiments, the anti-CEACAM antibody is an anti-CEACAM-1 and/or anti-CEACAM-5 antibody molecule as described, for example, in WO 2010/125571, WO 2013/054331 and US 2014/0271618.

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

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

In other embodiments, the anti-PD-L1 antibody molecule is administered in combination with a cytokine, such as interleukin-2, -15, -12, or -21. In certain embodiments, the combination of an anti-PD-L1 antibody molecule and a cytokine described herein is used to treat a cancer, eg, a cancer as described herein (eg, a solid tumor or melanoma).

Illustrative immunomodulators that can be used in combination with anti-PD-L1 antibody molecules include, but are not limited to, for example, afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimide (CC4047); and cytokines, eg IL-21 or IRX-2 (a mixture of human cytokines including interleukin 1, interleukin 2 and interferon γ, CAS 951209-71-5, available from IRX Therapeutics).

In other embodiments, an anti-PD-L1 antibody molecule is used in combination with an indolamine-pyrrole-2,3-dioxygenase (IDO) inhibitor (e.g., INCB24360) in an individual with advanced or metastatic cancer (e.g., in a patient with metastatic or recurrent cancer). NSCL tumor).

In other embodiments, anti-PD-L1 antibody molecules are co-administered to an individual with (e.g., before, concurrently, or after) one or more of: bone marrow transplantation, T-cell depleting therapy using chemotherapeutic agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide and/or antibodies such as OKT3 or CAMPATH. In one embodiment, anti-PD-L1 antibody molecules are administered following B cell depleting therapy, such as agents that react with CD20, such as Rituxan. For example, in

- 67 040861 in one embodiment, individuals may be treated with standard high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, after transplantation, individuals are administered antibody molecules against

PD-L1. In a further embodiment, anti-PD-L1 antibody molecules are administered before or after surgery.

Another example of a combination is an anti-PD-L1 antibody in combination with decarbazine for the treatment of melanoma. Without being bound by theory, it is believed that the combined use of PD-L1 blockade and chemotherapy is promoted by cell death, which is a consequence of the cytotoxic effect of most chemotherapeutic compounds, which can lead to increased levels of tumor antigen in the antigen presentation cascade. Other combination therapies that may result in synergy with PD-L1 blockade through cell death are radiotherapy, surgery, and hormone deficiency. Each of these protocols creates a source of tumor antigen in the host. Angiogenesis inhibitors can also be combined with PD-L1 blockade. Inhibition of angiogenesis results in the death of tumor cells, which can provide tumor antigen to host antigen presentation cascades.

PD-L1 blocking antibodies can also be used in combination with bispecific antibodies. Bispecific antibodies can be used to target two separate antigens. For example, anti-Fc receptor/anti-tumor antigen bispecific antibodies (eg, Her-2/neu) are used to target macrophages to the tumor site. This targeting may more effectively activate tumor-specific responses. The T-cell link of these responses can be enhanced using PD-L1 blockade. Alternatively, the antigen can be delivered directly to the DC using bispecific antibodies that bind to the tumor antigen and a specific dendritic cell surface marker.

Tumors elude the host's immune surveillance through a wide variety of mechanisms. Many of these mechanisms can be overcome by inactivating proteins that are expressed by tumors and that are immunosuppressive. These include, among others, 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: 1363-1365).

Antibodies or antigen-binding fragments thereof to each of these structures can be used in combination with an anti-PD-L1 antibody to counteract the effects of an immunosuppressive agent and promote host immune responses.

Other antibodies that can be used to activate the immune response capability of the host can be used in combination with an anti-PD-L1 antibody. They include molecules on the surface of dendritic cells that activate DC function and antigen presentation. Anti-CD40 antibodies are able to effectively replace T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in conjunction with anti-PD-1 antibodies (Ito, N. et al. ( 2000) Immunobiology 201 (5) 527-40). Antibodies to T-cell co-stimulatory molecules such as CTLA-4 (e.g. US Pat. No. 5,811,097), OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997) and ICOS (Hutloff, A. et al. (1999) Nature 397: 262-266) can also provide increased levels of T cell activation.

Additional exemplary standard treatments are described in the section entitled Combination Therapies below.

In all of the methods described herein, PD-L1 blockade can be combined with other forms of immunotherapy, such as cytokine treatment (eg, interferons, GM-CSF, G-CSF, IL-2, IL-21) or bispecific antibody therapy. that provide enhanced presentation of tumor antigens (see, for example, Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123).

Methods for introducing antibody molecules are known in the art and are described below. Suitable dosages of the molecules used depend on the age and body weight of the individual and the particular drug used. Dosages and therapeutic regimens of the anti-PD-L1 antibody molecule can be determined by the skilled artisan. In certain embodiments, the anti-PD-L1 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-L1 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-L1 antibody molecule is administered at a dose of about 1-3 mg/kg, or about 3-10 mg/kg. In some embodiments, the anti-PD-L1 antibody molecule is administered at a dose of about 0.5-2, 2-4, 2-5, 5-15, or 5-20 mg/kg. The dosing schedule may vary, for example, from once a week to once every 2, 3 or 4 weeks. In one embodiment, the anti-PD-L1 antibody molecule is administered at a dose of about 10 to 20 mg/kg biweekly.

Antibody molecules can be used unconjugated or in conjugated form with

- 68 040861 a second agent, eg a cytotoxic drug, a radioactive isotope or a protein, eg a protein toxin or a viral protein. This method includes: administering an antibody molecule, alone or conjugated to a cytotoxic drug, to an individual in need of such treatment. Antibody molecules can be used to deliver various drugs, e.g., a cytotoxic moiety, e.g., a therapeutic drug, a radioactive isotope, 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 mixtures thereof.

Immunosuppression

Immunosuppression involves an action that reduces the activation or effectiveness of the immune system. Certain parts of the immune system themselves have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse response to treatment for other conditions.

Deliberately induced immunosuppression (eg, by an immunosuppressant (eg, an immunosuppressive drug or an environmental toxin), surgery (splenectomy), plasmapheresis, or radiation) can be done to prevent the body from rejecting an organ transplant, treat graft-versus-host disease after bone marrow transplantation, or treat autoimmune diseases such as rheumatoid arthritis or Crohn's disease.

Unintentional immunosuppression can occur, for example, in malnutrition, aging, many types of cancer (eg, leukemia, lymphoma, multiple myeloma), and certain chronic infections, such as human immunodeficiency virus (HIV). An undesirable effect of inadvertent immunosuppression is immunodeficiency, which leads to increased susceptibility to pathogens such as bacteria and viruses. Immunodeficiency may be a potential adverse effect of certain immunosuppressive drugs. As used herein, in some embodiments, the terms immunosuppressed, immunodeficient, or immunocompromised may be used interchangeably.

Immunosuppression is one of the leading causes of death in patients with sepsis. Neutrophils are classical components of innate immunity, however, neutrophils can exhibit antigen presentation function and inhibit proliferation through PD-L1 expression.

Thus, in one embodiment, the invention provides a method for inhibiting immunosuppression in a subject, comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody molecule described herein. In one embodiment, the methods are suitable for the treatment of sepsis.

In one aspect, a method is provided for treating, for example, reducing or alleviating, immunosuppression in an individual. In one embodiment, the subject is septic or at risk of developing sepsis. In another embodiment, the Subject has or is at risk of developing a chronic infection (eg, HIV) or cancer. In another embodiment, the subject is or has been treated for cancer, such as chemotherapy or radiation therapy. The method includes administering to an individual one or more of the anti-PD-L1 antibody molecules described herein, alone or in combination with other therapies or therapies.

Additional Combination Therapies The anti-PD-L1 antibody molecule can be used in combination with other therapies. For example, combination therapy may include a composition of the present invention co-formulated and/or co-administered with one or more additional drugs, e.g., one or more anti-cancer agents, cytotoxic or cytostatic agents, hormonal treatments, vaccines, and/or other means. immunotherapy. In other embodiments, the antibody molecules are administered in combination with other therapeutic modalities, including surgery, radiation therapy, cryosurgery, and/or thermotherapy. Such combination therapies can advantageously use lower dosages of administered drugs, thus avoiding the potential toxicity or complications associated with various monotherapies.

The term in combination with means that the administration of therapy or administration of drugs must be carried out at the same time and / or be combined for delivery, although these methods of delivery are included in the scope described in the present description. Molecules of antibodies against PDL1 can be administered simultaneously, before or after one or more other additional therapies or drugs. Administration of the anti-PD-L1 antibody molecule and the other agent, or administration of the therapeutic protocol, can be done in any order. Typically, each agent is administered at a dose and/or schedule determined for that agent. In addition, it will be understood that the additional drug used in this combination may be administered together in the same composition or administered separately in different compositions. In general, it is expected that additional drugs used in combination can be used at levels that do not exceed the levels at which they are used separately. In some embodiments, levels used in combination will be lower than levels used alone.

Immunomodulators.

In certain embodiments, the immunomodulator used in combination with an anti-PD-L1 antibody molecule or in the combinations described herein (eg, in combination with a drug selected from an antigen-presenting combination) is an inhibitor of the immune checkpoint molecule. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g. CEACAM-1, -3 and/or -5), VISTA , BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR-beta. In one embodiment, the immune control point molecule inhibitor inhibits PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3 and/or -5), CTLA-4, or any combination thereof. .

Inhibition of an inhibitory molecule can be carried out at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA, or shRNA) can be used to inhibit the expression of an inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, such as a soluble ligand (eg, PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, that binds to an inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as an antibody molecule) that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and/or -5), CTLA -4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR-beta, or a combination thereof.

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

In certain embodiments, the immunomodulator is an inhibitor of PD-1, eg, human PD-1 (eg, an antibody molecule as described herein).

In another embodiment, the immunomodulator is a PD-L1 inhibitor, eg, human PD-L1. In one embodiment, the PD-1 or PD-L1 inhibitor is an anti-PD-1 or PD-L1 antibody molecule. A PD-1 or PD-L1 inhibitor can be administered alone or in combination with other immunomodulators, e.g. in combination with a LAG-3, TIM-3, CEACAM (e.g. CEACAM-1, -3 and/or -5) or CTLA inhibitor -4. In an exemplary embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a LAG-3 inhibitor, eg, an anti-LAG-3 antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a TIM-3 inhibitor, eg, an anti-TIM-3 antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, e.g., an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a CEACAM inhibitor (e.g., a CEACAM-1, -3 and/or -5 inhibitor), e.g. , an anti-CEACAM antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a CEACAM-1 inhibitor, eg, an anti-CEACAM-1 antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor, eg, an anti-PD-1 or PD-L1 antibody molecule, is administered in combination with a CEACAM-5 inhibitor, eg, an anti-CEACAM-5 antibody molecule. In other embodiments, the PD-1 inhibitor

- 70 040861 or PD-L1, eg an anti-PD-1 antibody molecule, is administered in combination with a LAG-3 inhibitor, eg an anti-LAG-3 antibody molecule, and a TIM-3 inhibitor, eg an anti-TIM-3 antibody molecule. Also within the scope of the invention are combinations of immunomodulators with a PD-1 inhibitor (e.g., one or more of PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or -5 ), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR). Any of the antibody molecules known in the art or described herein can be used in the above combinations of checkpoint molecule inhibitors.

In other embodiments, the immunomodulator is an inhibitor of CEACAM (eg CEACAM-1, -3 and/or -5), eg human CEACAM (eg CEACAM-1, -3 and/or -5). In one embodiment, the immunomodulator is a CEACAM-1 inhibitor, such as human CEACAM-1. In another embodiment, the immunomodulator is a CEACAM-3 inhibitor, such as human CEACAM-3. In another embodiment, the immunomodulator is a CEACAM-5 inhibitor, such as human CEACAM-5. In one embodiment, the CEACAM inhibitor (eg CEACAM-1, -3 and/or -5) is an anti-CEACAM antibody molecule (eg CEACAM-1, -3 and/or -5). A CEACAM inhibitor (eg CEACAM-1, -3 and/or -5) can be administered alone or in combination with other immunomodulators, for example in combination with a LAG-3, TIM-3, PD-1, PD-L1 or CTLA inhibitor -4.

In other embodiments, the immunomodulator is a LAG-3 inhibitor, such as human LAG-3. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. The LAG-3 inhibitor can be administered alone or in combination with other immunomodulators, for example in combination with a CEACAM inhibitor (eg CEACAM-1, -3 and/or -5), TIM-3, PD-1, PD-L1 or CTLA -4.

In other embodiments, the immunomodulator is an inhibitor of TIM-3, such as human TIM-3. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. The TIM-3 inhibitor can be administered alone or in combination with other immunomodulators, for example in combination with a CEACAM inhibitor (eg CEACAM-1, -3 and/or -5), LAG-3, PD-1, PD-L1 or CTLA -4.

In certain embodiments, the immunomodulator used in the combinations described herein (eg, in combination with a drug selected from an antigen-presenting combination) is an activator or agonist of a costimulatory molecule. In one embodiment, the co-stimulatory molecule agonist is selected from an agonist (eg, an agonist antibody or antigen-binding fragment thereof, or a soluble fusion construct).

OX40, CD2, CD27, CD28, 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.

In other embodiments, the immunomodulator is a GITR agonist. In one embodiment, the GITR agonist is an anti-GITR antibody molecule. The GITR agonist may be administered alone or in combination with other immunomodulators, e.g., in combination with a PD-1 inhibitor, PD-L1, CTLA-4, CEACAM (e.g. CEACAM-1, -3 and/or -5), TIM-3 or LAG-3. In some embodiments, the anti-GITR antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and/or -5), TIM-3 or LAG-3. In one exemplary embodiment, the antibody molecule is administered in combination with an anti-PD-1 antibody molecule (eg, an anti-PD-1 antibody molecule as described herein). The anti-GITR antibody molecule and the anti-PD-1 antibody molecule may be in the form of separate antibody formulations or in the form of a bispecific antibody molecule. In other embodiments, a GITR agonist may be administered in combination with another costimulatory molecule, e.g., an OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB agonist ( CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.

In other embodiments, the immunomodulator is a costimulatory molecule activator (eg, an OX40 agonist). In one embodiment, the OX40 agonist is an anti-OX40 antibody molecule. The OX40 agonist can be administered alone or in combination with other immunomodulators, e.g. in combination with a PD-1 inhibitor, PD-L1, CTLA-4, CEACAM (e.g. CEACAM-1, -3 and/or -5), TIM-3 or LAG-3. In some embodiments, the OX40 antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and/or -5), TIM-3 or LAG-3. In one exemplary embodiment, an anti-OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (eg, an anti-PD-1 antibody molecule as described herein). The anti-OX40 antibody molecule and the anti-PD-1 antibody molecule may be in the form of separate antibody compositions or in the form of a bispecific antibody molecule. In other embodiments, the OX40 agonist may be administered in combination with another costimulatory molecule, such as a GITR agonist,

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CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40,

BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.

It should be noted that only exemplary combinations of checkpoint inhibitors or costimulatory molecule agonists are described herein. Additional combinations of these agents are within the scope of the present invention.

In certain embodiments, the anti-PD-L1 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., the Fc region of an immunoglobulin sequence). In some embodiments, implementation the PD-1 inhibitor is AMP-224 In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody In some embodiments, the PD-L1 binding antagonist is selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB -OO1O718C or MDX-1105 MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874 Antibody YW243.55.S70 (heavy and light chain variable region sequences shown in SEQ ID NOs: 20 and 21 respectively) is an anti-PD-L1 antibody described in WO 2010/077634.

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, also known as MK-3475 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-PD-1 monoclonal antibodies are described in WO2009/101611. In other embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (trade name Keytruda, formerly lambrolizumab, also known as MK-3475), described, for example, in Hamid, O. et al. (2013) New England Journal of Medicine 369(2): 134-44. AMP-224 (B7-DCIg; Amplimmune; eg, described in WO2010/027827 and WO2011/066342) is a soluble PD-L2 receptor Fc fusion construct 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 described in US 8609089, US 2010028330 and/or US 20120114649.

In some embodiments, the other anti-PD-1 antibody is MDX1106. 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 accession number: 946414-94-4). Nivolumab (also referred to as BMS-936558 or MDX1106; Bristol-Myers Squibb) is a fully 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 8008449 and WO 2006/121168. Pembrolizumab or labrolizumab (also known as MK-3475; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies are described in US 8354509 and WO 09/114335. MDPL3280A (Genentech/Roche) is a human Fc optimized monoclonal IgG1 antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PDL1 are described in US Pat. No. 7,943,743 and US Publication No. 20120039906. Other PD-L1 binding compounds include YW243.55.S70 (heavy and light chain variable regions shown in SEQ ID NOs: 20 and 21 in WO 2010/077634) and MDX-1105 (also referred to as BMS936559, and for example the PD-L1 binding compounds described in WO2007/005874).

In some embodiments, an antibody molecule (e.g., a mono-, bi-, or trispecific antibody) against TIM-3, LAG-3, and/or PD-1 used in any of the methods and combinations described herein comprises the amino acid sequence or encoded by a nucleotide sequence as described herein (eg, as described in the section titled Inhibitors of Immune Checkpoint Molecules beginning on page 218 of this specification below (including all publications cited therein).

Methods for the treatment of malignant tumors.

Exemplary combinations of anti-PD-L1 antibody molecules (alone or in combination with other stimulants) and standard of care for cancer include at least the following.

In certain embodiments, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule described herein, is used in combination with a standard cancer treatment that is a chemotherapeutic agent,

- 72 040861 including, but not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injectable (Busulfex®), capecitabine (Xeloda®), no. 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 liposomal injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposomal injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®) , L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinthol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (yttrium 90 /MX-DTPA), pentostatin, polyfeprosan 20 implant with carmustine (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®) and vinorelbine (Navelbine®), ibrutinib, idelicib, and brentuximab vedotin.

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

Illustrative anthracyclines include, for example, doxorubicin (Adriamycin® and Rubex®); bleomycin (lenoxane®); daunorubicin (daunorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, Cerubidine®); liposomal daunorubicin (daunorubicin citrate liposomes, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin; ravidomycin and deacetylravidomycin.

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

Illustrative proteasome inhibitors that can be used in combination with anti-PD-L1 antibody molecules, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule) include, but are not limited to , bortezomib (Velcade®); carfilzomib (PX-171-007, (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran2-yl)-1 -oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4phenylbutanamido)pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770); and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2oxiranyl]-2 -oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX-0912).

In some embodiments, an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein, is used alone or in combination with another

- 73 040861 an immunomodulator (eg, an anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule) in combination with a tyrosine kinase inhibitor (eg, a receptor tyrosine kinase (RTK) inhibitor). An exemplary tyrosine kinase inhibitor includes, but is not limited to, an inhibitor of the epidermal growth factor (EGF) cascade (e.g., an inhibitor of the epidermal growth factor receptor (EGFR)), an inhibitor of the vascular endothelial growth factor (VEGF) cascade (e.g., an inhibitor of the vascular endothelial factor receptor (VEGFR) (eg, VEGFR-1 inhibitor, VEGFR-2 inhibitor, VEGFR-3 inhibitor)), platelet-derived growth factor cascade (PDGF) inhibitor (eg, platelet-derived growth factor receptor (PDGFR) inhibitor (eg, PDGFRB inhibitor)) , RAF-1 inhibitor, KIT inhibitor, and RET inhibitor. In some embodiments, the cancer agent used in combination with the hedgehog inhibitor is selected from the group consisting of: axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS- 354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP701), neratinib (HKI-272), nilotinib ( TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab ( AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), alemtuzumab (CAMPATH®), gemtuzumab ozagomycin (MYLOTARG ®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-29980 4, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozaniba (AV-951), OSI-930, MM-121, XL-184, XL-647, XL228, AEE788, AG-490, AST-6, BMS-599626, CUDC-101, PD153035, Pelitinib (EKV-569), Vandetanib (Zaktima), WZ3146, WZ4002, WZ8040, ABT-869 (linifanib), AEE788, AP24534 (ponatinib), AV-951 (tivozanib), axitinib, BAY 73-4506 (regorafenib), bivanib alaninate (BMS-582664), brivanib (BMS-540215), cediranib ( AZD2171), CHIR-258 (dovitinib), CP 673451, CYC116, E7080, Ki8751, masitinib (AB1010), MGCD-265, motesanib diphosphate (AMG-706), MP-470, OSI-930, pazopanib hydrochloride, PD173074, sorafenib tosylate (Bay 43-9006), Su 5402, TSU-68 (SU6668), vatalanib, XL880 (GSK1363089, EXEL-2880). Individual tyrosine kinase inhibitors are selected from sunitinib, erlotinib, gefitinib, or sorafenib.

In certain embodiments, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule described herein, is used alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti- TIM-3), in combination with vascular endothelial growth factor (VEGF) receptor inhibitors. Exemplary VEGF/VEGFR inhibitors are described herein below, for example, in the section titled Exemplary Agents Used in Combinations.

In some embodiments, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule described herein, is used alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti-TIM3 antibody molecule). ), in combination with a PI3K inhibitor. In one embodiment, the PI3K inhibitor is an inhibitor of the delta and gamma isoforms of PI3K. Exemplary PI3K inhibitors that can be used in combination are described herein below, for example, in the section titled Exemplary Agents Used in Combinations.

In some embodiments, the anti-PD-L1 antibody molecules described herein are used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), in combination with an inhibitor mTOR, for example, one or more of the mTOR inhibitors described herein below, for example, in the section titled Exemplary Agents Used in Combinations.

In some embodiments, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule described herein, is used alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti- TIM-3), in combination with a BRAF inhibitor such as GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720 and sorafenib tosylate (Bay 43-9006). In some embodiments, the combination includes a RAF inhibitor, such as debrafinib or N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4yl]-2-fluorophenyl} -2,6-difluorobenzenesulfonamide.

In some embodiments, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule described herein, is used alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti- TIM-3), in combination with a MEK inhibitor. In some embodiments, a combination of an anti-PD-L1 antibody and a MEK inhibitor is used to treat a cancer (eg, the cancer described herein). In some embodiments, the cancer being treated with the combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell cancer. . In certain embodiments, the cancer comprises a BRAF mutation (eg, BRAF V600E mutation), wild-type BRAF, wild-type KRAS, or an activating KRAS mutation. A malignant tumor may be at an early, intermediate or late stage.

Any MEK inhibitor can be used in combination, including but not limited to ARRY-142886, G02442104 (also known as GSK1120212), RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (also known as AZD-6244 or selumetinib), BIX 02188 , BIX 02189, CI-1040 (PD-184352), 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 known as AS703206) or a pharmaceutically acceptable salt or solvate thereof. Additional examples of MEK inhibitors are described in WO 2013/019906, WO 03/077914, WO 2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, the contents of which are incorporated herein by reference. In some embodiments, the MEK inhibitor is trametinib or N(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3, 4,6,7tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide.

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

In some embodiments, the pharmaceutical composition described herein is used, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1, or anti-TIM-3 antibody molecule), in combination with paclitaxel or an agent based on paclitaxel, eg TAXOL®, protein-bound paclitaxel (eg ABRAXANE®). Exemplary paclitaxel-based agents include, but are not limited to, nanoparticulate 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, marketed by Cell Therapeutic), tumor-activated prodrug (TAP), ANG105 (Angiopep-2 linked to three molecules of paclitaxel, marketed by ImmunoGen), paclitaxel-EC -1 (paclitaxel linked to erbB2 recognition peptide EC1; see Li et al., Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl-2-glucopyranosyl succinate, see Liu et al., Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620).

Radiation therapy can be delivered by one of several methods or a combination of methods, including, but not limited to, external beam therapy, internal radiation therapy, implant-assisted radiation, stereotactic radiosurgery, systemic radiation therapy, radiation therapy, and permanent or temporary interstitial brachytherapy. The term brachytherapy refers to radiation therapy delivered by spatially confined radioactive material placed in or near a tumor or other area of tissue proliferative disease. The term is intended to include, but is not limited to, 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 isotopes Lu). Suitable radiation sources for use as the cell treatment agent of the present invention include both solids and liquids. As a non-limiting example, the radiation source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation and other therapeutic beams. The radioactive material can also be a liquid made from any solution of the radionuclide(s), such as a solution of I-125 or I-131, or the radioactive liquid can be produced using a slurry of a suitable liquid containing small particles of solid radionuclides, such as Au-198 , Y-90. Moreover, the radionuclide(s) may be in the form of a gel or radioactive microspheres.

Anti-PD-L1 antibody molecules, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), may be administered in combination with one or more of the existing cancer treatments, including but not limited to: surgery; radiation therapy (eg, external beam therapy, which involves three-dimensional conformal radiation therapy, where the irradiation field is a calculated local irradiation (eg, irradiation directed to 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 exposure can

- 75 040861 have a radiation source selected from the group consisting of a particle beam (proton), cobalt-60 (photon) and a linear accelerator (X-ray), for example, as described in WO 2012/177624.

In certain embodiments, an anti-PD-L1 antibody molecule, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), is administered in combination with an antibody against immunoglobulin-like killer cell receptors. cells (also referred to herein as an anti-KIR antibody), a general anti-KIR antibody or an anti-NKG2D antibody, and/or an anti-MICA antibody. In certain embodiments, the combination of an anti-PD-L1 antibody molecule and an anti-KIR antibody, a generic anti-KIR antibody, or an anti-NKG2D antibody described herein is used to treat a cancer, e.g., a cancer as described herein (e.g. , solid tumor, e.g. advanced solid tumor).

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

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

In another embodiment, an anti-PD-L1 antibody molecule, alone or in combination with another immunomodulator (eg, an anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), is administered in combination with chemotherapy and/or immunotherapy. For example, an anti-PD-L1 antibody molecule can be used to treat myeloma, alone or in combination with one or more of: chemotherapy or other anti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), anti-TIM-3 antibodies treated with a tumorigenic dendritic cell antigen, fusion (eg, electrofusion) of tumor cells and dendritic cells, or vaccination with an immunoglobulin idiotype produced by malignant plasma cells. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with an anti-TIM-3 antibody for the treatment of myeloma, eg, multiple myeloma.

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

In another embodiment, an anti-PD-L1 antibody molecule, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), is used to treat kidney cancer, e.g., renal cell carcinoma ( RCC) (e.g., clear cell renal cell carcinoma (CCRCC) or metastatic RCC. The anti-PD-L1 antibody molecule can be administered in combination with one or more of: an immune-based strategy (e.g., interleukin-2 or interferon-α), a targeted agent ( for example, a VEGF inhibitor such as an anti-VEGF monoclonal antibody; a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib, and pazopanib; a RNA-i inhibitor) or an inhibitor of a downstream VEGF signaling mediator, such as a target inhibitor of rapamycin (mTOR) mammals such as everolimus and temsirolimus).

An example of suitable therapeutic agents for use in combination with the anti-PD-L1 antibody molecules described herein, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), for treatment of pancreatic cancer includes, but is not limited to, a chemotherapeutic agent such as paclitaxel or a paclitaxel-based agent (eg, a paclitaxel formulation such as TAXOL, an albumin-stabilized formulation of paclitaxel in the form of nanoparticles (eg, ABRAXANE) or a liposomal formulation of paclitaxel); gemcitabine (eg, gemcitabine alone or in combination with AChP107-11); other chemotherapeutic agents such as oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicin hydrochloride, NC-6004, cisplatin, docetaxel (eg TAXOTERE), mitomycin C, ifosfamide; interferon; a tyrosine kinase inhibitor (eg, an EGFR inhibitor (eg, erlotinib, panitumumab, cetuximab, nimotuzumab); an HER2/neu receptor inhibitor (eg, trastuzumab); a dual kinase inhibitor (eg, bosutinib, saracatinib, lapatinib, vandetanib);

- 76 040861 multikinase inhibitor (eg sorafenib, sunitinib, XL184, pazopanib); a VEGF inhibitor (eg, bevacizumab, AV-951, brivanib); radioimmunotherapy (eg XR303); cancer vaccine (eg GVAX, survivin peptide); a COX-2 inhibitor (eg, celecoxib); an IGF-1 receptor inhibitor (eg AMG 479, MK-0646); an mTOR inhibitor (eg, everolimus, temsirolimus); an IL-6 inhibitor (eg CNTO 328); cyclin-dependent kinase inhibitor (eg P276-00, UCN-01); targeting altered energy metabolism (AEMD) compound (eg, CPI-613); an HDAC inhibitor (eg, vorinostat); TRAIL receptor 2 (TR-2) agonist (eg, conatumumab); a MEK inhibitor (eg, AS703026, selumetinib, GSK1120212); dual kinase inhibitor Raf/MEK (eg RO5126766); a Notch signaling inhibitor (eg, MK0752); fusion protein monoclonal antibody-antibody (for example, L19IL2); curcumin; an HSP90 inhibitor (eg tanespimycin, STA-9090); rIL-2;, denileukin diftitox; a topoisomerase 1 inhibitor (eg, irinotecan, PEP02); a statin (eg simvastatin); a factor VIIa inhibitor (eg, PCI27483); an AKT inhibitor (eg RX-0201); hypoxia-activated prodrug (eg, TH302); metformin hydrochloride, gamma secretase inhibitor (eg RO4929097); a ribonucleotide reductase inhibitor (eg, 3-AR); immunotoxin (eg HuC242-DM4); a PARP inhibitor (eg KU-0059436, veliparib); a CTLA-4 inhibitor (eg, CP-675, 206, ipilimumab); AdV-tk therapy; a proteasome inhibitor (eg, bortezomib (Velcade), NPI-0052); thiazolidinedione (eg pioglitazone); NPC-1C; Aurora kinase inhibitor (eg R763/AS703569), CTGF inhibitor (eg FG-3019); siG12D LODER; and radiation therapy (eg, tomotherapy, seterotactic radiation, proton therapy), surgery, and a combination thereof. In certain embodiments, a combination of paclitaxel or a paclitaxel and gemcitabine agent can be used with the anti-PD-L1 antibody molecules described herein.

An example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules, alone or in combination with another immunomodulator (e.g. anti-LAG-3, anti-PD-1 or anti-TIM-3 antibody molecule) for the treatment of small cell lung cancer includes, but not limited to, a chemotherapeutic agent, e.g., etoposide, carboplatin, cisplatin, oxaliplatin, irinotecan, topotecan, gemcitabine, SN-38 liposomal, bendamustine, temozolomide, belotecan, NK012, FR901228, flavopiridol); tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor (eg, sorafenib, sunitinib); VEGF inhibitor (eg, bevacizumab, vandetanib); cancer vaccine (eg, GVAX); inhibitor Bcl-2 (eg, oblimersen sodium, ABT-263), proteasome inhibitor (eg, bortezomib (Velcade), NPI-0052), paclitaxel or paclitaxel-based agent, docetaxel, IGF-1 receptor inhibitor (eg, AMG 479); HGF/SF inhibitor (eg, AMG 102, MK-0646); chloroquine; Aurora kinase inhibitor (eg, MLN8237); radioimmunotherapy (eg, TF2); HSP90 inhibitor (eg, tanespimycin, STA-9090); mTOR inhibitor (eg. , everolimus); anti-Ep-CAM/CD3 bispecific antibody (eg, MT110); CK-2 inhibitor (eg, CX-4945); HDAC inhibitor (eg, belinostat); SMO antagonist (eg, BMS 833923); peptide vaccine against malignant tumor and radiation therapy (for example, radiation therapy intensity-modulated apia (IMRT), hypofractionated radiotherapy, hypoxia-guided radiotherapy), surgery, and combinations thereof.

An example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules, alone or in combination with another immunomodulator (e.g. anti-LAG-3, anti-PD-1 or anti-TIM-3 antibody molecule), for the treatment of non-small cell lung cancer includes but not limited to, a chemotherapeutic agent, e.g., vinorelbine, cisplatin, docetaxel, pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine, irinotecan, tegafur-gimeracil-oteracil potassium , 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 inhibitor of Raf/MEK kinases (eg, RO5126766), dual inhibitor of PI3K/mTOR kinases (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), cancer vaccine (eg, BLP25 liposomal vaccine, GVAX, recombinant DNA and adenovirus expressing L523S protein), Bcl-2 inhibitor (eg, oblimersen sodium), proteasome inhibitor (eg, bortezomib, carcilzomib, N PI-0052, MLN9708), paclitaxel or paclitaxel-based agent, docetaxel, IGF-1 receptor inhibitor (eg, cixutumumab, MK-0646, OSI 906, CP-751,871, BIIB022), hydroxychloroquine, HSP90 inhibitor (eg, tanespimycin, STA -9090, AUY922, XL888), mTOR inhibitor (eg, everolimus, temsirolimus, ridaphorolimus), anti-Ep-CAM-/CD3 bispecific antibody (eg, MT110), CK-2 inhibitor (eg, CX-4945), HDAC inhibitor ( e.g. MS 275, LBH589, vorinostat, valproic acid

- 77 040861 slot, FR901228), DHFR inhibitor (eg pralatrexate), retinoid (eg bexarotene, tretinoin), antibody drug conjugate (eg SGN-15), bisphosphonate (eg zoledronic acid), cancer vaccine (eg, belagenpumatucel-L), low molecular weight heparin (LMWH) (eg, tinzaparin, enoxaparin), GSK1572932A, melatonin, talactoferrin, dimesna, topoisomerase inhibitor (eg, amrubicin, etoposide, carenitecin), nelfinavir, cilengitide, ErbB3 inhibitor (eg, MM-121, U3-1287), survivin inhibitor (eg, YM155, LY2181308), eribulin mesylate, COX-2 inhibitor (eg, celecoxib), pegfilgrastim, Polo-like kinase 1 inhibitor (eg, BI 6727), receptor 2 agonist TRAIL (TR-2) (e.g., CS1008), CNGRC peptide conjugate (SEQ ID NO: 225)-TNF-alpha, dichloroacetate (DCA), HGF inhibitor (e.g., SCH 900105), SAR240550, PPAR-gamma agonist (e.g., CS-7017), gammasecretase inhibitor (e.g. RO4929097), epigenetic therapy (eg, 5-azacytidine), nitroglycerin, MEK inhibitor (eg, AZD6244), cyclin-dependent kinase inhibitor (eg, UCN-01), cholesterol-Fus1, antitubulin agent (eg, E7389), farnesyl-OH- inhibitor transferase (eg, lonafarnib), immunotoxin (eg, BB-10901, SS1 (dsFv) PE38), fondaparinux, vasoconstrictor (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), cascade inhibitor P70 (eg, LY2584702), an AKT inhibitor (eg, MK-2206), an angiogenesis inhibitor (eg, lenalidomide), a Notch signaling inhibitor (eg, OMP-21M18), radiation therapy, surgery, and combinations thereof.

An example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules, alone or in combination with another immunomodulator (e.g. anti-LAG-3, anti-PD-1 or anti-TIM-3 antibody molecule), for the treatment of ovarian cancer includes, but not limited to, a chemotherapeutic agent (e.g., paclitaxel or paclitaxel-based agent; docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin; irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, melphalan, pemetrexed disodium, SJG-136, cyclophosphamide, etoposide, decitabine); ghrelin antagonist (eg, AEZS-130), immunotherapy (eg, APC8024, oregovomab, ORT-821), tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, erlotinib), dual inhibitor (eg, E7080), multikinase inhibitor (eg, AZD0530 , JI-101, sorafenib, sunitinib, pazopanib), ON 01910.Na), VEGF inhibitor (eg, bevacizumab, BIBF 1120, cediranib, AZD2171), PDGFR inhibitor (eg, IMC-3G3), paclitaxel, topoisomerase inhibitor (eg, carenitecin, irinotecan), HDAC inhibitor (eg, valproate, vorinostat), folate receptor inhibitor (eg, farletuzumab), angiopoietin inhibitor (eg, AMG 386), epothilone analogue (eg, ixabepilone), proteasome inhibitor (eg, carfilzomib), inhibitor IGF-1 receptor (eg, OSI 906, AMG 479), PARP inhibitor (eg, veliparib, AGO14699, iniparib, MK-4827), Aurora kinase inhibitor (eg, MLN8237, ENMD-2076), angiogenesis inhibitor (eg, lenalidomide ), DHFR inhibitor (e.g. pralatrexate), RFID an unotherapeutic agent (eg Hu3S193), a statin (eg lovastatin), a topoisomerase 1 inhibitor (eg NKTR-102), a cancer vaccine (eg p53 synthetic long peptide vaccine, autologous OS-DC vaccine), mTOR inhibitor (eg, temsirolimus, everolimus), BCR/ABL inhibitor (eg, imatinib), ET-A receptor antagonist (eg, ZD4054), TRAIL receptor 2 (TR-2) agonist (eg, CS-1008), HGF inhibitor /SF (eg AMG 102), EGEN-001, Polo-like kinase 1 inhibitor (eg BI 6727), gamma secretase inhibitor (eg RO4929097), Wee-1 inhibitor (eg MK-1775), antitubulin agent (e.g. vinorelbine, E7389), immunotoxin (e.g., denileukin diftitox), SB-485232, vascular disruptor (e.g., AVE8062), integrin inhibitor (e.g., EMD 525797), kinesin spindle inhibitor (e.g., 4SC-205), revlimid, HER2 inhibitor (eg MGAH22), ErrB3 inhibitor (eg MM-121), radiation therapy; and their combinations.

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

In another embodiment, an anti-PD-L1 antibody molecule, alone or in combination with another immunomodulator (e.g., an anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule) is used to treat kidney cancer, e.g., renal cell carcinoma (RCC). ) or metastatic RCC. The anti-PD-L1 antibody molecule can be administered in combination with one or more of: an immune-based strategy (eg, interleukin-2 or interferon-α), targeted

- 78 040861 agents (for example, an inhibitor of VEGF, such as a monoclonal antibody to VEGF, for example, 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):90-99)); RNA-i inhibitor) or an inhibitor of a downstream mediator of VEGF signaling, e.g., the mammalian target of rapamycin (mTOR) inhibitor, e.g., everolimus and temsirolimus (Hudes, G. et al. (2007) N. Engl. J. Med. 356 ( 22): 2271-2281, Motzer, R. J. et al (2008) Lancet 372: 449-456).

An example of suitable therapeutic agents for use in combination with the anti-PD-L1 antibody molecules described herein, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), for treatment of chronic myelogenous leukemia (AML) according to the invention includes, but is not limited to, a chemotherapeutic agent (e.g., cytarabine, hydroxyurea, clofarabine, melphalan, thiotepa, fludarabine, busulfan, etoposide, cordycepin, pentostatin, capecitabine, azacitidine, cyclophosphamide, cladribine, topotecan ), tyrosine kinase inhibitor (eg, BCR/ABL inhibitor (eg, imatinib, nilotinib), ON 01910.Na, dual inhibitor (eg, dasatinib, bosutinib), multikinase inhibitor (eg, DCC-2036, ponatinib, sorafenib, sunitinib, RGB -286638)), interferon-alpha, steroids, apoptotic agent (eg, omacetaxin mepesuccinate), immunotherapy (eg, allogeneic CD4+ Th1-like memory T cells /microparticle-bound anti-CD3/anti-CD28 antibody, autologous cytokine-inducible killer cells (CIK), AHN-12), CD52-targeting agent (e.g., alemtuzumab), HSP90 inhibitor (e.g., tanespimycin, STA9090, AUY922, XL888), inhibitor mTOR (eg, everolimus), SMO antagonist (eg, BMS 833923), ribonucleotide reductase inhibitor (eg, 3-AP), JAK-2 inhibitor (eg, INCB018424), hydroxychloroquine, retinoid (eg, fenretinide), cyclin-dependent kinase inhibitor (e.g. UCN-01), HDAC inhibitor (e.g. belinostat, vorinostat, JNJ-26481585), PARP inhibitor (e.g. veliparib), MDM2 antagonist (e.g. RO5045337), Aurora B kinase inhibitor (e.g. TAK-901), radioimmunotherapy (eg, actinium 225-labeled anti-CD33 antibody HuM195), Hedgehog inhibitor (eg, PF-04449913), STAT3 inhibitor (eg, OPB-31121), KB004, cancer vaccine (eg, AG858), bone marrow transplant, transplant stem cells, radiation therapy, and combinations thereof.

An example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), for the treatment of chronic lymphocytic leukemia ( CLL) includes, but is not limited to, a chemotherapeutic agent (e.g., fludarabine, cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, 5-azacytidine, pemetrexed disodium), a tyrosine kinase inhibitor (e.g. , EGFR inhibitor (eg, erlotinib), BTK inhibitor (eg, PCI-32765), multikinase inhibitor (eg, MGCD265, RGB-286638), CD-20 targeting agent (eg, rituximab, ofatumumab, RO5072759, LFB-R603) CD52-targeting agent (eg, alemtuzumab), prednisolone, darbepoetin alfa, lenalidomide, Bcl-2 inhibitor (eg, ABT-263), immunotherapy (eg, allogeneic CD4+ Th1-like T cells memory tags/microparticle-bound anti-CD3/anti-CD28 antibody, autologous cytokine inducible killer cells (CIK)), 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(Fv)-PE38 (LMB2)) targeting CD37 agent (eg, TRU-016), radioimmunotherapy (eg, 131tositumomab), hydroxychloroquine, perifosine, SRC inhibitor (eg, dasatinib), thalidomide, PI3K delta inhibitor (eg, CAL-101), retinoid (eg, fenretinide), antagonist MDM2 (eg, RO5045337), plerixaphor, Aurora kinase inhibitor (eg, MLN8237, TAK-901), proteasome inhibitor (eg, bortezomib), CD-19 targeting agent (eg, MEDI-551, MOR208), MEK inhibitor ( e.g. ABT-348), JAK-2 inhibitor (e.g. INCB018424), hypoxia-activated prodrug (e.g. p, TH-302), paclitaxel or paclitaxel-based agent, HSP90 inhibitor, AKT inhibitor (eg, MK2206), HMG-CoA inhibitor (eg, simvastatin), GNKG186, radiotherapy, bone marrow transplantation, stem cell transplantation, and combinations thereof .

An example of suitable therapeutic agents for use in combination with the anti-PD-L1 antibody molecules described herein, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule) for treatment acute lymphocytic leukemia (ALL) includes, but is not limited to, a chemotherapeutic agent (eg, 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) targeting CD52

- 79 040861 agent (eg alemtuzumab), HSP90 inhibitor (eg STA-9090), mTOR 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, inotuzumab), immunotherapy (eg, autologous cytokine-inducible killer cells (CIK), AHN-12), bilanatumomab, cyclin- dependent kinase (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-based agent, STAT3 inhibitor (eg ORV-31121), PARP inhibitor (eg veliparib), EZN-2285, radiotherapy, steroid, bone marrow transplant, stem cell transplant, or a combination thereof.

An example of suitable therapeutic agents for use in combination with the anti-PD-L1 antibody molecules described herein, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), for treatment of acute myeloid leukemia (AML) includes, but is not limited to, a chemotherapeutic agent (eg, cytarabine, daunorubicin, idarubicin, clofarabine, decitabine, vosaroxin, azacitidine, clofarabine, ribavirin, CPX-351, treosulfan, elacytarabine, azacitidine), tyrosine kinase inhibitor (eg, BCR/ABL inhibitor (eg, imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (eg, midostaurin, SU 11248, quisartinib, sorafinib)), immunotoxin (eg, gemtuzumab ozagomycin), DT388IL3 fusion protein, HDAC inhibitor (eg, vorinostat, LBH589), plerixafor, mTOR inhibitor (eg, everolimus), SRC inhibitor (eg, dasatinib), HSP90 inhibitor (eg, STA-9090), retinoid (eg, bexar oten, Aurora kinase inhibitor (eg, BI 811283), JAK-2 inhibitor (eg, INCB018424), Polo-like kinase inhibitor (eg, BI 6727), cenersen, CD45 targeting agent (eg, BC8), cyclin- dependent kinase (eg, UCN-01), MDM2 antagonist (eg, RO5045337), mTOR inhibitor (eg, everolimus), LY57363b-sodium, ZRx-101, MLN4924, lenalidomide, immunotherapy (eg, AHN-12), histamine dihydrochloride, radiation therapy, bone marrow transplantation, stem cell transplantation, and a combination thereof.

An example of suitable therapeutic agents for use in combination with the anti-PD-L1 antibody molecules described herein, alone or in combination with another immunomodulator (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 antibody molecule), for treatment of multiple myeloma (MM) includes, but is not limited to, a chemotherapeutic agent (e.g., melphalan, amifostine, cyclophosphamide, doxorubicin, clofarabine, bendamustine, fludarabine, adriamycin, SyB L-0501), thalidomide, lenalidomide, dexamethasone, prednisone, pomalidomide, proteasome inhibitor (eg, bortezomib, carfilzomib, MLN9708), cancer vaccine (eg, GVAX), CD-40 targeting agent (eg, SGN-40, CHIR-12.12), perifosine, zoledronic acid, immunotherapy (eg, MAGE -A3, NY-ESO-1, HuMax-CD38), HDAC inhibitor (eg, vorinostat, LBH589, AR-42), aplidine, cyclin-dependent kinase inhibitor (eg, PD0332991, dinaciclib), arsenic trioxide, CB3304, HS inhibitor P90 (eg, KW-2478), tyrosine kinase inhibitor (eg, EGFR inhibitor (eg, cetuximab), multikinase inhibitor (eg, AT9283)), VEGF inhibitor (eg, bevacizumab), plerixaphor, MEK inhibitor (eg, AZD6244), IPH2101 , atorvastatin, immunotoxin (eg, BB-10901), NPI-0052, radioimmunotherapy (eg, yttrium Y 90 ibritutomab tiuxetan), STAT3 inhibitor (eg, ORV-31121), MLN4924, Aurora kinase inhibitor (eg, ENMD-2076 ), IMGN901, ACE-041, a CK-2 inhibitor (eg, CX-4945), radiation therapy, bone marrow transplantation, stem cell transplantation, and a combination thereof.

An example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules, alone or in combination with another immunomodulator (e.g. anti-LAG-3, anti-PD-1 or anti-TIM-3 antibody molecule), for the treatment of prostate cancer includes but not limited to, chemotherapy (eg, docetaxel, carboplatin, fludarabine), abiraterone, hormonal t (eg, 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, cancer vaccine (eg, BRX-101, PEP223 ), lenalidomide, TOK-001, IGF-1 receptor inhibitor (eg, cixutumumab), TRC105, Aurora A kinase inhibitor (eg, MLN8237), proteasome inhibitor (eg, boron ezomib), OGX-011, radioimmunotherapy (eg, HuJ591-GS), HDAC inhibitor (eg, valproic acid, SB939, LBH589), hydroxychloroquine, mTOR inhibitor (eg, everolimus), dovininib lactate, diindolylmethane, efavirenz, OGX-427, genistein, IMC-3G3, bafetinib, CP-675.206, radiotherapy, surgery, or a combination thereof.

An example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules alone or in combination with another immunomodulator (e.g., antibody molecule

- 80 040861 against LAG-3, against PD-1, or against TIM-3) for the treatment of HNSCC includes, but is not limited to, one or both of Compound A8 as described herein (or the compound described in PCT Publication No. WO 2010/029082) and cetuximab (eg Erbitux, marketed by BMS). In some embodiments, the therapeutic agent (eg, an A8 compound or an A8 related compound) is a PI3K modulator, eg, a PI3K inhibitor. In some embodiments, the therapeutic agent (eg, cetuximab) modulates, eg, inhibits, EGFR. In some embodiments, the cancer has or is identified as having elevated levels or activity of PI3K or EGFR compared to a control cell or reference value.

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

Example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules alone or in combination with another immunomodulator (e.g. anti-LAG-3, anti-PD-1 or anti-TIM-3 antibody molecule) for the treatment of gastric cancer, e.g. stomach with high MSI and/or inactivated RNF43 includes, but is not limited to, Compound A28 as described herein (or the compound described in PCT Publication No. WO 2010/101849). In some embodiments, the therapeutic agent (eg, compound A28 or an A28-related compound) is a modulator, eg, inhibitor, of porcupine. In some embodiments, the cancer has or is identified as having elevated levels or activity of porcupin compared to a control cell or reference value.

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

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

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

- 81 040861

Example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules alone or in combination with another immunomodulator (e.g. anti-LAG-3, anti-PD-1 or anti-TIM-3 antibody molecule) for the treatment of melanoma (e.g. NRAS melanoma ) includes, but is not limited to, one or both of compound A29 as described herein (or compound described in PCT Publication No. WO2011/025927) and compound A34 as described herein (or compound described in PCT Publication No. WO2011/025927) No. WO2003/077914). In some embodiments, a compound (eg, an A29 compound or an A29-related compound) modulates, eg, inhibits, BRAF. In some embodiments, a compound (eg, an A34 compound or an A34-related compound) modulates, eg, inhibits, MEK. In some embodiments, the cancer has, or is identified as having, elevated levels or activity of one or both of BRAF and MEK compared to a control cell or reference value.

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

An example of suitable therapeutic agents for use in combination with anti-PD-L1 antibody molecules alone or in combination with another immunomodulator (e.g. anti-LAG-3, anti-PD-1 or anti-TIM-3 antibody molecule) for the treatment of colorectal cancer includes , but not limited to, one or both of Compound A29 as described herein (or a compound as per PCT Publication No. WO2011/025927) and cetuximab (eg Erbitux, marketed by BMS). In some embodiments, the therapeutic agent (eg, compound A29 or an A29 related compound) modulates, eg, inhibits, BRAF. In some embodiments, the therapeutic agent (eg, cetuximab) modulates, eg, inhibits EGFR. In some embodiments, the cancer has or is identified as having elevated levels or activity of BRAF or EGFR compared to a control cell or reference value.

The present invention also relates to a method of treating cancer with Compound A8, cetuximab and an anti-PD-L1 antibody molecule (optionally in combination with an anti-PD-1 antibody or an anti-TIM-3 antibody molecule). In some embodiments, the patient is first treated with Compound A8 and cetuximab. This treatment is continued for a certain amount of time, for example, for a given amount of time, for example, for about 1, 2, 4, 6, 8, 10 or 12 months. An anti-PD-L1 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-L1 antibody may optionally be administered in combination with cetuximab.

In some embodiments, the patient is first treated with all three of compound A8, cetuximab, and an anti-PD-L1 antibody molecule (optionally in combination with an anti-TIM-3 antibody or an anti-LAG-3 antibody molecule). This treatment is continued for an amount of time, eg a predetermined amount of time, eg about 6, 8, 10 or 12 months. Further, Compound A8 and/or cetuximab can be waived such that the maintenance phase involves treatment with an anti-PD-L1 antibody molecule (e.g., as monotherapy or in combination with an anti-TIM-3 antibody or an anti-LAG-3 antibody molecule), but not compound A8 or cetuximab.

In other embodiments, the three compounds (compound A8, cetuximab, and an anti-PD-L1 antibody molecule, optionally in combination with an anti-TIM-3 antibody or an anti-LAG-3 antibody molecule) are administered sequentially at the start of treatment. For example, Compound A8 and cetuximab may be administered first as described above. An anti-PDL1 antibody molecule is then added to the regimen (optionally in combination with an anti-TIM-3 antibody molecule or an anti-LAG-3 antibody molecule). Further connection A8 and/or cetuximab can be canceled as described above.

Exemplary dosage regimens with three (or more) agents are as follows. The anti-PD-L1 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 200-300, 300-400, or 200-400 mg. In some embodiments, cetuximab is administered at an initial dose of 400 mg/m ² as an intravenous infusion over 120 minutes, followed by a 250 mg/m ² infusion every week for 60 minutes. In embodiments, one or more of Compounds A8, cetuximab, and an anti-PD-L1 antibody molecule is administered at a dose that is lower than the dose at which the agent would normally be administered alone.

- 82 040861 rapies, for example, approximately 0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or -90% lower than the dose at which the agent is usually administered as monotherapy. In embodiments, one or more of compound A8, cetuximab, and an anti-PD-L1 antibody molecule is administered at a dose that is lower than the dose of that agent specified in this paragraph, e.g., about 0-10%, 10-20% , 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower than the dose of this remedy indicated in this paragraph. In certain 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-L1 antibody molecule than when Compound A8 is administered alone. In certain 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-L1 antibody molecule than when cetuximab is administered alone. In certain embodiments, the concentration of an anti-PD-L1 antibody molecule that is required to achieve inhibition, e.g., growth inhibition, is lower when the anti-PD-L1 antibody molecule is administered in combination with one or both of cetuximab and Compound A8 than when the antibody molecule is against PD-L1 is administered individually.

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

Infectious diseases.

Other methods of the invention are used to treat patients who have been exposed to specific toxins or pathogens. Thus, another aspect of the invention relates to a method of treating an infectious disease in a subject, comprising administering to the subject an anti-PD-L1 antibody molecule such that the subject is treated for the infectious disease.

In the treatment of infection (eg, acute and/or chronic), the administration of anti-PD-L1 antibody molecules can be combined with conventional treatments in addition to or instead of stimulating the host's natural immune defense against infection. The host's natural immune defense against infection includes, but is not limited to, inflammation, fever, antibody-mediated host defense, T-lymphocyte-mediated host defense, including lymphokine secretion and cytotoxic T-cells (especially during viral infection), complement-mediated lysis, and opsonization. (facilitated by phagocytosis) and phagocytosis. The ability of anti-PD-L1 antibody molecules to reactivate dysfunctional T cells may be useful in the treatment of chronic infections, in particular infections in which cell-mediated immunity is essential for complete recovery.

Similar to use against tumors as described above, antibody-mediated blockade of PD-L1 can be used alone or as an adjuvant, in combination with vaccines, to stimulate an immune response to pathogens, toxins, or self antigens. 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 less than fully effective. These include, but are not limited to, HIV, hepatitis (A, B, and C), influenza virus, herpes virus, giardia, malaria, leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa. Blockade of PD-L1 is particularly useful against common infections with agents such as HIV that present altered antigens during infections. These new epitopes are recognized as foreign at the time of administration of the anti-PD-L1 antibody, thus inducing a pronounced T cell response that is not inhibited by negative signals through PD-L1.

Viruses.

For infections resulting from viruses, anti-PD-L1 antibody molecules can be combined through use simultaneously, before or after standard therapies for treating viral infections. These standard therapies vary depending on the type of virus, although in almost all cases administration of human sera can be effective.

- 83 040861 loveca containing antibodies (eg IgA, IgG) specific to the virus.

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

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

Most conventional therapies are palliatives against symptoms resulting from infection, while in reality the disease is cleared by the host's immune response. However, certain strains (such as the influenza A virus) can cause more severe illness and death. Influenza A virus can be treated both clinically and prophylactically by administering the cyclic amine inhibitors amantadine and rimantidine, which inhibit viral replication. However, the clinical utility of these drugs is limited due to the relatively high incidence of adverse reactions that narrow the antiviral spectrum (influenza A virus only) and the tendency of the virus to become resistant. The introduction of serum IgG antibodies to the main surface proteins of the influenza virus: hemagglutinin and neuraminidase, can prevent pulmonary infection, while mucosal IgA is required to prevent infection of the upper respiratory tract and trachea. The most effective modern method of treating influenza is vaccination by introducing a virus inactivated with formalin or β-propiolactone.

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

Hepatitis B virus (HB-V) is the most infectious blood-borne pathogen. It is the main cause of acute and chronic hepatitis and liver carcinoma, as well as lifelong chronic infection. After infection, the virus replicates in hepatocytes, from which the surface antigen HBsAg is also separated. The detection of excessive serum HBsAg levels is used as a standard diagnostic tool for hepatitis B infection. An acute infection may resolve or may develop into a chronic persistent infection. Current treatments for chronic HBV include α-interferon, which increases the expression of human leukocyte antigen class I (HLA) on the surface of hepatocytes, thereby facilitating their recognition by cytotoxic T lymphocytes. In addition, the nucleoside analogues ganciclovir, famiciclovir and lamivudine have also shown some efficacy in treating HBV infection in clinical trials. Additional treatments for HBV include pegylated interferon-alpha, adenfovir, entecavir, and telbuvidin. Although passive immunity can be conferred through parenteral administration of serum antibodies against HBsAg, vaccination with inactivated or recombinant HBsAg also confers resistance to infection. Anti-PD-L1 antibody molecules can be combined with conventional treatments for hepatitis B infections to provide a therapeutic benefit.

Infection with hepatitis C virus (HC-V) can lead to chronic hepatitis leading to cirrhosis. Although symptoms are similar to those of hepatitis B virus infection, unlike HB-V, infected hosts may be asymptomatic for 10 to 20 years. An anti-PD-L1 antibody molecule can be administered as monotherapy or in combination with a standard treatment for hepatitis C infection. For example, an anti-PD-L1 antibody molecule can be administered with one or more of Sovaldi (sofosbuvir), Olisio (simeprevir), together with ribavirin or pegylated interferon. Although regimens that include Incivec (telaprevir) are also approved

- 84 040861 or Victrelis (boceprevir) plus ribavirin and pegylated interferon, these are associated with increased side effects and longer duration of treatment and thus are not considered preferred regimens.

The conventional method of treating HC-V infection involves administering a combination of interferon α and ribavirin. A promising potential therapy for HC-V infection is the protease inhibitor telaprevir (VX-960). Additional treatments include: anti-PD-1 antibody (MDX-1106, Medarex), bavituximab (an antibody that binds to the anionic phosphatidylserine phosphatidylserine in a B2-glycoprotein I dependent manner, Peregrine Pharmaceuticals), antibody(s) against HPV viral envelope E2 protein (eg ATL 6865-Ab68+Ab65, XTL Pharmaceuticals) and Civacir® (human anti-HCV polyclonal immunoglobulin). Anti-PD-L1 antibodies of the invention can be combined with one or more of these treatments for hepatitis C infections to provide a therapeutic benefit. Protease, polymerase and NS5A inhibitors that can be used in combination with anti-PD-L1 antibody molecules to specifically treat hepatitis C infection include those described in US 2013/0045202, incorporated herein by reference.

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

Treatment of measles involves passive administration of pooled human IgG, which can prevent infection in non-immune individuals, even when administered up to one week after exposure. However, prior immunization with live attenuated virus is the most effective treatment and prevents disease in more than 95% of immunized individuals. Since there is one serotype of the virus, one immunization or infection usually results in lifelong protection against subsequent infection.

In a small proportion of infected hosts, measles can develop into SSPE, which is a chronic, progressive neurological disorder resulting from persistent infection of the central nervous system. SSPE is caused by clonal variants of the measles virus with defects that prevent assembly and budding of the virus. For these patients, it may be desirable to reactivate the T cells with anti-PD-L1 antibody molecules to help clear the virus.

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

An HIV-infected host may be asymptomatic, or may develop an acute illness that resembles mononucleosis—fever, headache, sore throat, malaise, and rash. Symptoms may progress to progressive immune dysfunction, including persistent fever, night sweats, weight loss, unexplained diarrhea, eczema, psoriasis, seborrheic dermatitis, herpes zoster, oral candidiasis, and oral hairy leukoplakia. In patients whose infections develop into AIDS, there are frequent opportunistic host infections with parasites.

HIV treatment includes antiviral therapy, including nucleoside analogues, zidovudine (AST), either alone or in combination with 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-L1 antibody molecules can be combined with conventional treatments for HIV infections to provide a therapeutic benefit.

In another embodiment, the infection is a cytomegalovirus (CMV) infection. CMV infection is often associated with persistent, latent, and recurrent infection. CMV infects monocytes and monocyte granulocyte progenitors and remains latent in them. Clinical symptoms of CMV include mononucleosis-like symptoms (ie, fever, enlarged tonsils, malaise) and a tendency to develop an allergic skin rash to antibiotics. The virus is spread through direct contact. The virus is excreted in urine, saliva, semen and, to a lesser extent, other body fluids. Transmission can also occur from an infected mother to her fetus or newborn child and through blood transfusion and organ transplantation. CMV infection typically results in reduced cellular immunity characterized by reduced blastogenic responses to nonspecific mitogens and specific antigens.

CMV, decrease in cytotoxic capacity and increase in the number of CD8-lymphocytes or CD4+ lymphocytes.

Treatment for CMV infection includes the antiviral drugs ganciclovir, foscarnet, and sidovir, but these drugs are generally reserved for immunocompromised patients. Anti-PD-L1 antibody molecules can be combined with conventional treatments for cytomegalovirus infections to provide a therapeutic benefit.

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

While palliative treatment of symptoms is the typical treatment for EBV infections, EBV has been associated with the development of certain malignancies such as Burkitt's lymphoma and nasopharyngeal cancer. Thus, clearing the viral infection before these complications occur would be of significant benefit. Anti-PD-L1 antibody molecules can be combined with conventional treatments for Epstein-Barr virus infections to provide a therapeutic benefit.

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

Treatments for herpes virus infections are primarily aimed at resolving symptomatic exacerbations and include systemic antiviral drugs such as: acyclovir (eg Zovirax®), valaciclovir, famiciclovir, penciclovir and topical drugs such as provenol (Abreva®), tromantidin and zilactin. The elimination of latent infections with the herpes virus would be of significant clinical benefit. Anti-PD-L1 antibody molecules can be combined with conventional treatments for herpes virus infections to provide a therapeutic benefit.

In another embodiment, the infection is a human T-lymphotropic virus (HTLV-1, HTLV-2) infection. HTLV is transmitted through sexual contact, breastfeeding, or exposure to contaminated blood. The virus activates a subset of TH cells called Th1 cells, resulting in overproliferation and overproduction of Th1 cytokines (eg, IFN-γ and TNFα). This in turn leads to suppression of Th2 lymphocytes and reduced production of Th2 cytokines (eg, IL-4, IL-5, IL-10 and IL-13), causing a decrease in the ability of the infected host to induce an adequate immune response to invading organisms, for elimination of which a Th2-dependent response is required (eg, parasitic infections, production of mucosal and humoral antibodies).

HTLV infections lead to opportunistic infections causing bronchiectasis, dermatitis, and superinfections with Staphylococcus spp. and Strongyloides spp., resulting in death from polymicrobial sepsis. HTLV infection can also lead directly to adult T-cell leukemia/lymphoma and progressive upper motor neuron demyelinating disease known as KAM/TSP. Clearing latent HTLV infections may have significant clinical benefit. Anti-PD-L1 antibody molecules can be combined with conventional treatments for HTLV infections to provide a therapeutic benefit.

In another embodiment, the infection is a human papillomavirus (HPV) infection. HPV mainly affects keratinocytes and occurs in two forms: cutaneous and genital. Transmission is believed to occur through direct contact and/or sexual activity. Both skin and genital HPV infection can lead to warts and latent infections, and sometimes recurrent infections, which are controlled by the host's immune system, which controls symptoms and blocks the appearance of warts, but leaves the host able to transmit the infection to others.

HPV infection can also lead to certain cancers such as cancer of the cervix, anal canal, vulva, penis, and oropharynx. There are currently no known treatments for HPV infection, however, the current treatment is topical imiquimod, which stimulates the immune system to attack the affected area. Clearing latent HPV infections can be of significant clinical benefit. Anti-PD-L1 antibodies of the invention can be combined with conventional treatments for HPV infections to provide a therapeutic benefit.

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bacterial infections.

Some examples of pathogenic bacteria that cause infections treatable by the methods of the invention include syphilis, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and gonococci, Klebsiella, Proteus, serratia, Pseudomonas, Legionella, diphtheria, salmonella, bacilli, cholera pathogens, tetanus pathogens, botulism pathogens, anthrax pathogens, plague pathogens, leptospirosis pathogens and Lyme disease pathogens. Anti-PD-L1 antibody molecules can be used in combination with existing treatments for the above infections. For example, treatments for syphilis include penicillin (eg, penicillin G), tetracycline, doxycillin, ceftriaxone, and azithromycin.

Lyme disease, caused by Borrelia burgdorferi, is transmitted to humans through tick bites. The disease initially presents as a localized rash followed by flu-like symptoms including malaise, fever, headache, neck stiffness, and joint pain. Later manifestations may include migratory and polyarticular arthritis, nervous system and cardiac involvement with cranial nerve palsies and radiculopathy, myocarditis, and arrhythmias. Some cases of Lyme disease become persistent, causing permanent damage similar to tertiary syphilis. Current treatments for Lyme disease mainly involve the administration of antibiotics. Antibiotic-resistant strains can be treated with hydroxychloroquine or methotrexate. Antibiotic-refractory patients with neuropathic pain can be treated with gabapentin. Minocycline may be useful in late/chronic Lyme disease with neurological or other inflammatory manifestations.

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

fungi and parasites.

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

Some examples of pathogenic parasites that cause infections amenable to treatment by the methods described herein include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Nippostrongylus brasiliensis.

Additional combined therapies.

Combinations of anti-PD-L1 antibody molecules with one or more second therapeutic agents are contemplated within the scope of the present invention. Many of the combinations in this section are useful in the treatment of cancer, but other indications are also described. This section focuses on combinations of anti-PD-L1 antibody molecules, optionally with one or more immunomodulators (e.g., anti-TIM-3 antibody molecule, anti-LAG-3 antibody molecule, or anti-PD-L1 antibody molecule), with one or more of the agents described in table. 6. In the combinations described below, in one embodiment, the anti-PD-1 antibody molecule comprises (i) a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 195; the amino acid sequence of VHCDR2 SEQ ID NO: 2 or SEQ ID NO: 5; and the amino acid sequence of VHCDR3 SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 9 or SEQ ID NO: 12, the amino acid sequence of VLCDR2 SEQ ID NO: 10 or SEQ ID NO: 13, and the amino acid sequence of VLCDR3 SEQ ID NO: 11 or SEQ ID NO: 14.

In one embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the PKC inhibitor sotrastaurine (compound A1) or compound described in PCT Publication No. WO 2005/039549 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the PKC inhibitor is sotrastaurine (compound A1) or the compound described in PCT Publication No. WO 2005/039549. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with sotrastaurine (Compound A1) or a compound as described in PCT Publication No. WO 2005/039549 to treat a disorder such as cancer, melanoma, non-Hodgkin's lymphoma, inflammatory bowel disease , transplant rejection, ophthalmic disorder, or psoriasis.

In certain embodiments, sotrastaurine (Compound A1) is administered at a dose of about 20 to 600 mg, such as about 200 to about 600 mg, about mg to about 450 mg, about 100 to 400 mg, about 150 to 350 mg or about 200 to 300 mg, such as about 50, 100, 150, 200, 300, 400, 500 or 600 mg.

The dosing regimen may vary, for example, from administration every other day to administration every day, twice or three times a day.

In one embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the BCR-ABL inhibitor TASIGNA (compound A2 or the compound described in PCT Publication No. WO 2004/005281), for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the BCR-ABL inhibitor is TASIGNA or a compound described in PCT Publication No. WO 2004/005281. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with TASIGNA (compound A2) or a compound as described in PCT Publication No. WO 2004/005281 for the treatment of a disorder such as lymphocytic leukemia, Parkinson's disease, neurological malignancy, melanoma , gastrointestinal/gastrointestinal cancer, colorectal cancer, myeloid leukemia, chronic myelogenous leukemia (CML), head and neck cancer, or pulmonary hypertension.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an HSP90 inhibitor such as 5-(2 ,4dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (compound A3) or the compound described in PCT Publication No. WO 2010/060937 or WO 2004/072051, for treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the HSP90 inhibitor is 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4(morpholinomethyl)phenyl)isoxazole-3-carboxamide (compound A3) or a compound described in the publication PCT No. WO 2010/060937 or WO 2004/072051. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4(morpholinomethyl)phenyl)isoxazole-3-carboxamide (compound A3) or a compound as described in PCT Publication No. WO 2010/060937 or WO 2004/072051 for the treatment of a disorder such as cancer, multiple myeloma, non-small cell lung cancer, lymphoma, gastric cancer, breast cancer, gastrointestinal/gastrointestinal cancer. intestinal cancer, pancreatic cancer, colorectal cancer, solid tumor or hematopoietic disorder.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the PI3K inhibitor and/or mTOR dactolisib (compound A4) or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3trifluoromethylphenyl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one (Compound A41) or a compound described in PCT Publication No. WO 2006/122806 for the treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the PI3K and/or mTOR inhibitor is dactolisib (compound A4), 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3trifluoromethylphenyl)-1, 3-dihydroimidazo[4,5-c]quinolin-2-one (Compound A41) or the compound described in PCT Publication No. WO 2006/122806. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with dactolisib (compound A4), 8-(6-methoxypyridin-3-yl)-3methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)- 1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Compound A41) or the compound described in PCT Publication No. WO 2006/122806 for the treatment of a disorder such as cancer, prostate cancer, leukemia (eg, lymphocytic leukemia), breast cancer, brain cancer, bladder cancer, pancreatic cancer, kidney cancer, solid tumor, gastrointestinal/gastrointestinal cancer, or liver cancer.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR 3-(2,6- dichloro-3,5dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea (compound A5) or the compound described in the US patent 8552002, for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the FGFR inhibitor is 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1 yl)phenyl)amino)pyrimidin-4-yl )-1-methylurea (Compound A5) or the compound described in US Pat. No. 8,552,002. In one embodiment, an anti-PD-L1 antibody molecule is used in

- 88 040861 combinations with Compound A5 or a compound as described in US 8,552,002 for the treatment of a disorder such as gastrointestinal/gastrointestinal cancer, hematological malignancy, or solid tumor.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the PI3K inhibitor buparlisib (compound A6) or compound described in PCT Publication No. WO 2007/084786 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the PI3K inhibitor is buparlisib (Compound A6) or the compound described in PCT Publication No. WO 2007/084786. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with buparlisib (Compound A6) or a compound described in PCT Publication No. WO 2007/084786 to treat a disorder such as prostate cancer, lung cancer (e.g., non-small cell lung cancer). (NSCLC)), prostate cancer, gastric cancer, pancreatic cancer, endocrine malignancy, leukemia, ovarian cancer, melanoma, bladder cancer, breast cancer, female reproductive system cancer, digestive tract/gastrointestinal cancer, colon and rectum, glioblastoma multiforme (GBM), solid tumor, leukemia, 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 about 100 mg (eg, per day).

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR 8-(2,6- difluoro-3,5dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxalin-5-carboxamide (compound A7) or the compound described in PCT Publication No. WO 2009/141386, for treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the FGFR inhibitor is 8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1nimidazol-2-yl)quinoxalin-5-carboxamide (Compound A7 ) or a compound described in PCT Publication No. WO 2009/141386. In one embodiment, the FGFR inhibitor is 8-(2,6difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxalin-5carboxamide (compound A7). In one embodiment, an anti-PD-L1 antibody molecule is used in combination with 8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1nimidazol-2-yl)quinoxalin- 5-carboxamide (Compound A7) or the compound described in PCT Publication No. WO 2009/141386 for the treatment of a disorder such as cancer characterized by angiogenesis, cancer of the digestive tract/gastrointestinal cancer or hematological cancer.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PI3K inhibitor (S)-N1-( 4-methyl-5-(2(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidin-1,2-dicarboxamide (compound A8) or compound described in PCT Publication No. WO 2010/029082 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the PI3K inhibitor is (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4yl)thiazol-2-yl )pyrrolidine-1,2-dicarboxamide (Compound A8) or the compound described in PCT Publication No. WO 2010/029082. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4 -yl)thiazol2-yl)pyrrolidine-1,2-dicarboxamide (Compound A8) or the compound described in PCT Publication No. WO 2010/029082 for the treatment of a disorder such as lung cancer (e.g. non-small cell lung cancer (NSCLC)), prostate cancer, endocrine malignancy, ovarian cancer, melanoma, bladder cancer, female reproductive tract cancer, colorectal cancer, glioblastoma multiforme (GBM), gastric cancer, breast cancer, pancreatic cancer, gastrointestinal/gastrointestinal cancer - intestinal cancer, solid tumor, leukemia, non-Hodgkin's lymphoma; or impaired hematopoiesis, and head and neck cancer.

In one embodiment, the PI3K inhibitor or (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-89 040861 methylpropan-2-yl)pyridin-4-yl)thiazol- 2-yl)pyrrolidin-1,2-dicarboxamide (compound A8) is administered at a dose of about 150-300, 200-300, 200-400 or 300-400 mg (e.g. per day), e.g. about 200, 300 or 400 mg.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a cytochrome P450 inhibitor (e.g., a CYP17 inhibitor) or a compound described in PCT Publication No. WO 2010/149755 for the treatment of a disorder, eg, a disorder described in the present invention. In one embodiment, the cytochrome P450 inhibitor (eg, CYP17 inhibitor) is a compound described in PCT Publication No. WO 2010/149755. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with a compound described in PCT Publication No. WO 2010/149755 for the treatment of prostate cancer.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an HDM2 (S)-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 PCT Publication No. WO 2011/076786 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the HDM2 inhibitor is (S)-l-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl- 3oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (Compound A10) or the compound described in PCT Publication No. WO 2011/076786. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with (S)-1-(4-chlorophenyl)-7-isopropoxy-6methoxy-2-(4-(methyl(((1r,4S)-4-( 4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2dihydroisoquinolin-3(4H)-one (Compound A10) or the compound described in PCT Publication No. WO 2011/076786 for treatment a disorder such as a solid tumor.

In one embodiment, an HDM2 inhibitor or (S)-l-(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, two 2 weeks from administration and one week without administration. In some embodiments, the dose is about 400, 500, 600, or 700 mg; about 400-500, 500-600 or 600-700 mg, for example, administered three times a week.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the iron chelating agent deferasirox (also known as EXJADE ; Compound A11) or a compound described in PCT Publication No. WO 1997/049395 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the iron chelating agent is deferasirox or the compound described in PCT Publication No. WO 1997/049395. In one embodiment, the iron chelating agent is deferasirox (compound A11). In one embodiment, an anti-PD-L1 antibody molecule is used in combination with deferasirox (Compound A11) or a compound described in PCT Publication No. WO 1997/049395 to treat iron overload, hemochromatosis, or myelodysplasia.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the aromatase inhibitor lectrozole (also known as FEMARA; connection A12) or a compound described in US 4978672, for the treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the aromatase inhibitor is a lecturer (Compound A12) or a compound described in US Pat. No. 4,978,672. for the treatment of a disorder such as cancer, leiomyosarcoma, endometrial cancer, breast cancer, cancer of the female reproductive system, or hormone deficiency.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PI3K inhibitor, e.g., a common PI3K inhibitor ( 4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl)-4(hydroxymethyl)-5-methyloxazolidin-2-one (Compound A13) or a compound described in PCT Publication No. WO 2013/124826 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the PI3K inhibitor is (4S,5R)-3-(2'-amino2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl)-4-(hydroxymethyl) -5-methyloxazolidin-2-one (compound A13) or the compound described in PCT Publication No. WO 2013/124826. In one variant

- 90 040861 an anti-PD-L1 antibody molecule is used in combination with (4S,5R)-3-(2'-amino-2morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl) -4-(hydroxymethyl)-5-methyloxazolidin-2-one (Compound A13) or the compound described in PCT Publication No. WO 2013/124826 for the treatment of a disorder such as a malignant tumor or an advanced solid tumor.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an inhibitor of p53 and/or p53/Mdm2 interaction. (8)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4dimethoxypyrimidin-5-yl)- 1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (compound A14) or a compound described in PCT Publication No. WO 2013/111105 for the treatment of a disorder, e.g., the disorder described in the present invention. In one embodiment, the p53 and/or p53/Mdm2 interaction inhibitor is (S)-5-(5-chloro-1-methyl-2-oxo-1,2dihydropyridin-3-yl)-6-(4-chlorophenyl) -2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6dihydropyrrolo[3,4-d]imidazol-4(1H)-one (compound A14) or the compound described in PCT Publication No. WO 2013/111105. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl )-2-(2,4dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one (compound A14) or the compound described in PCT Publication No. WO 2013/111105 for the treatment of a disorder such as cancer or soft tissue sarcoma.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a CSF-1R tyrosine kinase inhibitor 4-(( 2(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide (Compound A15) or the compound described in PCT Publication No. WO 2005/073224 for treatment violations, for example, the violations described in the present invention. In one embodiment, the CSF-1R tyrosine kinase inhibitor is 4-((2-(((1R,2R)-2hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide (Compound A15) or the compound described in PCT Publication No. WO 2005/073224. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with 4-((2-(((1R,2R)-2hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide (compound A15) or a compound described in PCT Publication No. WO 2005/073224 for the treatment of a disorder such as cancer.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an apoptosis inducer and/or angiogenesis inhibitor, such as imatinib mesylate (also known as GLEEVEC; Compound A16), or the compound described in PCT Publication No. WO 1999/003854, for the treatment of a disorder, for example the disorder described. In one embodiment, the apoptosis inducer and/or angiogenesis inhibitor is imatinib mesylate (Compound A16) or the compound described in PCT Publication No. WO1999/003854. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with imatinib mesylate (Compound A16) or a compound described in PCT Publication No. WO1999/003854 to treat a disorder such as cancer, multiple myeloma, prostate cancer, non-small cell cancer. lung, lymphoma, gastric cancer, melanoma, breast cancer, pancreatic cancer, digestive tract/gastrointestinal cancer, colorectal cancer, glioblastoma multiforme, liver cancer, head and neck cancer, asthma, multiple sclerosis, allergies, dementia of the Alzheimer's type, amyotrophic lateral sclerosis or rheumatoid arthritis.

In certain embodiments, imatinib mesylate (Compound A16) is administered at a dose of about 100 to 1000 mg, such as about 200 to 800 mg, about 300 to 700 mg, or about 400 to 600 mg, such as about 200, 300, 400, 500, 600 or 700 mg. The dosing regimen may vary from, for example, once every two days to once a day, two or three times a day. In one embodiment, imatinib mesylate is administered at an oral dose of about 100 to 600 mg every day, such as about 100, 200, 260, 300, 400, or 600 mg every day.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule, an antibody as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a JAK inhibitor 2-fluoro-Kmethyl- 4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide (compound A17) or its dihydrochloride or with the compound described in PCT Publication No. WO 2007/070514, for the treatment of a disorder, such as the disorder described in the present invention. In one embodiment, the JAK inhibitor is 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)umidazo[1,2b][1,2,4]triazin-2-yl)benzamide (compound A17) or its dihydrochloride, or a compound described in

- 91 040861 PCT Publication No. WO 2007/070514. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazine -2yl)benzamide (compound A17) or its dihydrochloride, or the compound described in PCT Publication No. WO 2007/070514, for the treatment of a disorder such as a solid tumor, e.g. lung cancer (e.g. non-small cell lung cancer (NSCLC))), glioblastoma multiphore (GBM), kidney cancer, liver cancer, gastric cancer, colorectal cancer, myeloid leukemia, hematologic malignancy, autoimmune disease, non-Hodgkin's lymphoma, or thrombocythemia. In some embodiments, the cancer has or is identified as having a c-MET mutation (eg, c-MET mutation or c-MET amplification).

In certain embodiments, Compound A17 is administered at an oral dose of about 100 to 1000 mg, such as about 200 to 900 mg, about 300 to 800 mg, or about 400 to 700 mg, such as about 400, 500, or 600 mg. The dosing regimen may vary from, for example, every two days to once a day, two or three times a day. In one embodiment, Compound A17 is administered at an oral dose of about 400 to 600 mg twice daily.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the JAK inhibitor ruxolitinib phosphate (also known as JAKAFI ; Compound A18) or a compound described in PCT Publication No. WO 2007/070514 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the JAK inhibitor is ruxolitinib phosphate (Compound A18) or the compound described in PCT Publication No. WO 2007/070514. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with ruxolitinib phosphate (Compound A18) or a compound described in PCT Publication No. WO 2007/070514 to treat a disorder such as prostate cancer, lymphocytic leukemia, multiple myeloma, lymphoma (eg, non-Hodgkin's lymphoma), lung cancer, leukemia (eg, myeloid leukemia, lymphocytic leukemia), cachexia, breast cancer, pancreatic cancer, rheumatoid arthritis, psoriasis, colorectal cancer, myeloid leukemia, hematologic malignancy, autoimmune disease, non-Hodgkin's lymphoma, or thrombocythemia. In some embodiments, the cancer has or is identified as having a JAK mutation. In some embodiments, the JAK mutation is a V617F JAK2 mutation.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the deacetylase (DAC) inhibitor panobinostat (compound A19 ) or a compound described in PCT Publication No. WO 2014/072493 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the DAC inhibitor is a panobinostat (compound A19) or a compound described in PCT Publication No. WO 2014/072493. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with panobinostat (Compound A19), a compound described in PCT Publication No. WO 2014/072493, to treat a disorder such as small cell lung cancer, respiratory tract/chest cancer, prostate cancer, multiple myeloma, myelodysplastic syndrome, bone cancer, non-small cell lung cancer, endocrine malignancy, lymphoma, neurological malignancy, leukemia, HIV/AIDS, immune disorder, transplant rejection, gastric cancer, melanoma, breast cancer, pancreatic cancer gland, colon cancer, glioblastoma multiforme, myeloid leukemia, hematologic malignancy, kidney cancer, non-Hodgkin's lymphoma, head and neck cancer, multiple myeloma, myelodysplastic syndrome, lymphoma (eg, non-Hodgkin's lymphoma), or leukemia (eg, myeloid leukemia) , hematopoietic disorders, or liver cancer.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an inhibitor of one or more of the cytochrome P450 (e.g. , 11B2), aldosterone or angiogenesis, osilodrostat (compound A20), or a compound described in PCT Publication No. WO 2007/024945, for the treatment of a disorder, for example, on

- 92 040861 destruction described in the present invention. In one embodiment, the inhibitor of one or more of cytochrome P450 (eg, 11B2), aldosterone, or angiogenesis is osilodrostat (Compound A20) or the compound described in PCT Publication No. WO 2007/024945. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with osilodrostat (compound A20) or a compound described in PCT Publication No. WO 2007/024945 for the treatment of a disorder such as Cushing's syndrome, hypertension, or for the treatment of heart failure.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an IAP inhibitor, (S)-N- ((S)-1-cyclohexyl2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide (compound A21) or a compound described in US 8,552,003 for the treatment of a disorder, eg, a disorder described in the present invention. In one embodiment, the IAP inhibitor is (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1- yl)-2oxoethyl)-2-(methylamino)propanamide (Compound A21) or the compound described in US Pat. No. 8,552,003. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with (S)-N-((S)- 1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2(methylamino)propanamide (compound A21) or compound described in US Pat. No. 8,552,003 for the treatment of a disorder such as multiple myeloma, breast cancer, ovarian cancer, pancreatic cancer, or a hematopoietic disorder.

In one embodiment, an IAP inhibitor or (S)-N-((S)-1-cyclohexyl-2-((S)-2-(4-(4fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)- 2-oxoethyl)-2-(methylamino)propanamide (compound A21) or the compound described in US 8552003 is administered at a dose of approximately 1800 mg, for example once a week. In one embodiment, Compound A21 is administered at a dose (e.g., oral dose) of about 10-3000 mg, e.g., about 20-2400 mg, about 50-1800 mg, about 100-1500 mg, about 200-1200 mg, about 300- 900 mg, such as about 600 mg, about 900 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg. In one embodiment, compound A21 is administered once a week or once every two weeks.

In one embodiment, in combination therapy, Compound A21 is administered orally. In one embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, is administered, for example, intravenously, at least one, two, three, four, five, six, or seven days apart. , for example, three days after administration of the compound A21, for example, orally. In one embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, is administered, for example, intravenously, at least one, two, three, four, five, six, or seven days apart. , for example, three days before the administration of compound A21, for example, orally. In another embodiment, an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule as described herein, is administered, eg, intravenously, on the same day as Compound A21, eg, administered orally.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the Smoothened (SMO) inhibitor, sonidegib phosphate ( compound A22), (R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1yl)pyrazin-2-yl)propan-2-ol ( compound A25) or a compound described in PCT Publication No. WO 2007/131201 or WO 2010/007120 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the SMO inhibitor is sonidegiba phosphate (compound A22), (R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1yl)pyrazine -2-yl)propan-2-ol (compound A25) or the compound described in PCT Publication No. WO 2007/131201 or WO 2010/007120. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with sonidegiba phosphate (compound A22), (R)-2-(5-(4-(6-benzyl-4,5dimethylpyridazin-3-yl)-2-methylpiperazine -1-yl)pyrazin-2-yl)propan-2-ol (Compound A25) or the compound described in PCT Publication No. WO 2007/131201 or WO 2010/007120 for the treatment of a disorder such as cancer, medulloblastoma, small cell lung cancer, prostate cancer, basal cell carcinoma, pancreatic cancer, or inflammation.

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

In another embodiment, an anti-TIM-3 antibody molecule, e.g., an anti-TIM-3 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the Alk inhibitor ceritinib (also from

- 93 040861 known as ZYKADIA; compound A23) or a compound described in PCT Publication No. WO 2007/131201 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the Alk inhibitor is ceritinib (compound A23) or the compound described in PCT Publication No. WO 2007/131201. In one embodiment, an anti-TIM-3 antibody molecule is used in combination with ceritinib (compound A23) or a compound described in PCT Publication No. WO 2007/131201 to treat a disorder such as non-small cell lung cancer or solid tumors, e.g., lung cancer ( eg, non-small cell lung cancer (NSCLC)), lymphoma (eg, anaplastic large cell lymphoma or non-Hodgkin's lymphoma), inflammatory myofibroblastic tumor (IMT), or neuroblastoma. In some embodiments, the NSCLC is stage IIIB or IV NSCLC, or recurrent locally advanced or metastatic NSCLC. In some embodiments, the cancer (eg, lung cancer, lymphoma, inflammatory myofibroblastic tumor, or neuroblastoma) has or is identified as having an ALK rearrangement or translocation, eg, ALK fusion. In one embodiment, the ALK fusion is an EML4-ALK fusion, such as the EML4-ALK fusion described herein. In another embodiment, the ALK fusion is an ALK-ROS1 fusion. In certain embodiments, the cancer has progressed to or is resistant or tolerant to a ROS1 inhibitor or an ALK inhibitor, eg, an ALK inhibitor other than Compound A23. In some embodiments, the cancer has progressed to or is resistant or tolerant to crizotinib. In one embodiment, the individual is an ALK naive patient, eg, a human patient. In another embodiment, the subject is a patient, eg a human patient, previously treated with an ALK inhibitor. In another embodiment, the subject is a patient, eg, a human patient, previously treated with Compound A23.

In one embodiment, Compound A23 and an anti-PD-L1 antibody molecule, for example an anti-PD-L1 antibody molecule as described herein, are administered to an ALK-naive patient. In another embodiment, Compound A23 and an anti-PD-L1 antibody molecule, for example an anti-PD-L1 antibody molecule as described herein, are administered to a patient who has previously been treated with an ALK inhibitor. In another embodiment, Compound A23 and an anti-PD-L1 antibody molecule, eg, an anti-PD-L1 antibody molecule as described herein, are administered to a patient previously treated with Compound A23.

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

In certain embodiments, Compound A23 is administered at an oral dose of about 100 to 1000 mg, such as about 150 to 900 mg, about 200 to 800 mg, about 300 to 700 mg, or about 400 to 600 mg, such as about 150 , 300, 450, 600 or 750 mg. In a particular embodiment, Compound A23 is administered at an oral dose of about 750 mg or less, eg, about 600 mg or less, eg, about 450 mg or less. In certain embodiments, Compound A23 is administered with food. In other embodiments, the dose is administered on an empty stomach. The dosing schedule may vary, for example, from every two days to once a day, two or three times a day. In one embodiment, compound A23 is administered every day. In one embodiment, Compound A23 is administered at an oral dose of about 150 to 750 mg per day, either with meals or on an empty stomach. In one embodiment, Compound A23 is administered at an oral dose of approximately 750 mg per day on an empty stomach. In one embodiment, Compound A23 is administered at an oral dose of approximately 750 mg per day via capsule or tablet. In another embodiment, Compound A23 is administered at an oral dose of approximately 600 mg per day via capsule or tablet. In one embodiment, Compound A23 is administered at an oral dose of approximately 450 mg per day via a capsule or tablet.

In one embodiment, compound A23 is administered at a dose of approximately 450 mg and nivolumab is administered at a dose of approximately 3 mg/kg. In another embodiment, the dose of compound A23 is 600 mg and the dose of nivolumab is 3 mg/kg. In one embodiment, Compound A23 is administered with a low fat meal.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a JAK inhibitor and/or CDK4/67 cyclopentyl- N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6carboxamide (compound A24) or the compound described in US Pat. No. 8,415,355 or US Pat. No. 8,685,980 for the treatment of a disorder, such as the disorder described in the present invention. In one embodiment, the JAK and/or CDK4/6 inhibitor is 7-cyclopentyl-N,Ndimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxamide (Compound A24) or the compound described in US Pat. No. 8,415,355 or US Pat. No. 8,685,980. In one

- 94 040861 An anti-PD-L1 antibody molecule is used in combination with 7-cyclopentylN,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2 ,3-d]pyrimidine-6carboxamide (compound A24) or a compound described in US 8,415,355 or US 8,685,980 for the treatment of a disorder such as lymphoma, neurological malignancy, melanoma, breast cancer, or a solid tumor such as lung cancer (e.g. , non-small cell lung cancer (NSCLC)).

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

In another embodiment, an antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a prolactin receptor (PRLR) inhibitor, a human monoclonal antibody molecule (compound A26), as described in US Pat. No. 7,867,493, for the treatment of a disorder, such as the disorder described in the present invention. In one embodiment, the PRLR inhibitor is a human monoclonal antibody (Compound A26) described in US Pat. No. 7,867,493. , for the treatment of a disorder such as cancer, prostate cancer, or breast cancer. Exemplary anti-PRLR antibodies described in US 7,867,493 include

chXHA.06.642 , chXHA. 06.275, , he.06,642-1, he.06,642-2, , he.06,275- 1,he.06, 275-2, he.06,275-3, he.06,275-4, XRA.06,128, XRA.06, 129, XRA.06,130, XRA.06.131, XRA.06.141, XRA.06, 147, XRA.06, 148, XRA.06,158, XRA.06.159, XRA.06.163, XRA.06, 167, XRA.06, 171, XRA.06.178, CHRA.06,181, CHRA.06, 192, XRA.06,202, XRA.06, 203, XRA.06,206, XRA.06, 207, XRA.06,210, XRA.06, 212, XRA.06, 217, XRA.06,219, XPA.06, 229, XPA.06, 233, XRA.06.235, XRA.06, 239, XNA.06.275, XRA.06,145, XHA.06.189 or XHA.06.567, XHA.06.642, XNA.06.907. XNA.06.983,

In some embodiments, compound A26 is an isolated antibody that binds to the extracellular domain of PRLR and contains (a) complementarity determining regions (CDRs) located at positions 24-38, positions 54-60, and positions 93-101 of the amino acid sequence of SEQ ID NO: 88 as described in US 7,867,493; and (b) CDRs located at positions 31-35, positions 50-66, and 99-113 of SEQ ID NO: 90 as described in US 7,867,493.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a PIM kinase N-(4- ((1R,3S,5S)3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (Compound A27) or the compound described in PCT Publication No. WO 2010 /026124, for the treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the PIM kinase inhibitor is N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6difluorophenyl)-5-fluoropicolinamide (compound A27) or the compound described in PCT Publication No. WO 2010/026124. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6- difluorophenyl)-5fluoropicolinamide (compound A27) or the compound described in PCT Publication No. WO 2010/026124 for the treatment of a disorder such as multiple myeloma, myelodysplastic syndrome, myeloid leukemia or non-Hodgkin's lymphoma.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a Wnt 2-(2' ,3dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide (compound A28) or the compound described in PCT Publication No. WO 2010 /101849, for the treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the Wnt signaling inhibitor is 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2yl) acetamide (compound A28) or the compound described in PCT Publication No. WO 2010/101849. In one embodiment, the Wnt signaling 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, a PD-L1 antibody molecule is used in combination with 2-(2',3-dimethyl-[2,4'-bipyridine]-5-95 040861 yl)-N-(5-(pyrazin-2- yl)pyridin-2-yl)acetamide (Compound A28) or a compound described in PCT Publication No. WO 2010/101849 for the treatment of a disorder such as a solid tumor (e.g. head and neck cancer, squamous cell carcinoma, breast cancer, cancer pancreatic or colon cancer).

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the BRAF inhibitor encorafenib (compound A29) or compound described in PCT Publication No. WO 2011/025927 for the treatment of a disorder, such as the disorder described in the present invention. In one embodiment, the BRAF inhibitor is encorafenib (Compound A29) or the compound described in PCT Publication No. WO 2011/025927. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with encorafenib (Compound A29) or a compound described in PCT Publication No. WO 2011/025927 to treat a disorder such as lung cancer (e.g., non-small cell lung cancer (NSCLC)) , melanoma (such as widespread melanoma), thyroid cancer (such as papillary thyroid cancer), or colon and rectal cancer.

In some embodiments, the cancer has or is identified as having a BRAF mutation (eg, a BRAF V600E mutation), wild-type BRAF, wild-type KRAS, or an activating KRAS mutation. A malignant tumor may be at an early, intermediate or late stage.

In one embodiment, the BRAF inhibitor or encorafenib (compound A29) is administered at a dose of about 200-300, 200-400, or 300-400 mg, 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-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the CDK4/6 inhibitor 7-cyclopentyl-N ,Ndimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4,2,1]nonan-3-yl)pyridin-2-yl)amino) -7Hpyrrolo[2,3-d]pyrimidine-6-carboxamide (compound A30) or the compound described in PCT Publication No. WO 2011/101409 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the CDK4/6 inhibitor is 7-cyclopentylN,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4,2,1 ]nonan-3-yl)pyridin-2-yl)amino)-7Hpyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound A30) or the compound described in PCT Publication No. WO 2011/101409. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with 7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9diazabicyclo[4 ,2,1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound A30) or the compound described in PCT Publication No. WO 2011/ 101409 for the treatment of a disorder such as cancer, mantle cell lymphoma, liposarcoma, non-small cell lung cancer, melanoma, squamous cell carcinoma of the esophagus, or breast cancer.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a HER3 inhibitor, Compound A31, or a compound described in PCT Publication No. WO 2012/022814, for the treatment of a disorder, such as the disorder described in the present invention. In one embodiment, the HER3 inhibitor is compound A31 or the compound described in PCT publication WO 2012/022814. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with Compound A31 or a compound described in PCT Publication WO 2012/022814 to treat a disorder such as gastric cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, gastric cancer. , breast cancer (eg, metastatic breast cancer), or gastrointestinal/gastrointestinal cancer.

In some embodiments, Compound A31 is a human monoclonal antibody molecule. In some embodiments, Compound A31 is an anti-HER3 monoclonal antibody, or antigen-binding fragment thereof, that contains 1, 2, 3, 4, 5, or 6 CDRs according to Kabat or Chothia, VH and/or VL, of any of the antibodies shown in Table 1. 1 U.S. 8,735,551. In one embodiment, the anti-HER3 monoclonal antibody, or antigen-binding fragment thereof, comprises VH SEQ ID NO: 141 and VL SEQ ID NO: 140 as described in U.S. 8735551.

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

- 96 040861

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an FGFR2 and/or FGFR4 inhibitor, Compound A32 or a compound described in PCT Publication No. WO 2014/160160 (e.g., anti-FGFR2 and/or FGFR4 antibody-drug conjugate, e.g., mAb 12425) for the treatment of a disorder, e.g., a disorder described in the present invention. In one embodiment, the FGFR2 and/or FGFR4 inhibitor is an A32 compound or a compound described in PCT Publication No. WO 2014/160160. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with Compound A32 or a compound as described in Table 1. 6 for treating a disorder such as cancer, gastric cancer, breast cancer, rhabdomyosarcoma, liver cancer, adrenal cancer, lung cancer, esophageal cancer, colon cancer, or endometrial cancer.

In some embodiments, compound A32 is an antibody-drug conjugate directed against FGFR2 and/or FGFR4, e.g., mAb 12425. In some embodiments, compound A32 is an antibody-drug conjugate directed against FGFR2 and/or FGFR4, which contains 1, 2, 3, 4, 5 or 6 CDR according to Kabat or Chothia, VH and/or VL of any of the antibodies presented in table. 1 WO 2014/160160. In some embodiments, Compound A32 is an anti-FGFR2 and/or FGFR4 antibody-drug conjugate that contains a Nsuccinimidyl-4-(maleimidomethyl)cyclohexanecarboxylate (SMCC) linker and an N ² '-deacetyl-N ² '- (3-mercapto-1-oxopropyl) maytansine (DM1). In some embodiments, Compound A32 is an antibody-drug conjugate having the following formula:

where Ab is an antibody or antigen-binding fragment containing a heavy chain CDR1 of SEQ ID NO: 1, 21, 41, 61, 81, or 101, a heavy chain CDR2 of SEQ ID NO: 2, 22, 42, 62, 82, or 102, a CDR3 heavy chain SEQ ID NO: 3, 23, 43, 63, 83, or 103, and light chain CDR1 SEQ ID NO: 11, 31, 51, 71, 91, or 111, light chain CDR2 SEQ ID NO: 12, 32, 52 , 72, 92 or 112, light chain CDR3 SEQ ID NO: 13, 33, 53, 73, 93 or 113, where CDR is determined in accordance with the definition of Kabat; and n is 1-10, for example, as described in claim 29 of the claims of WO 2014/160160.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an M-CSF inhibitor, Compound A33, or Compound described in PCT Publication No. WO 2004/045532 (for example, an antibody molecule or Fab fragment against M-CSF), for the treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the M-CSF inhibitor is Compound A33 or the compound described in PCT Publication No. WO 2004/045532. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with Compound A33 or a compound as described in PCT Publication No. WO 2004/045532 to treat a disorder such as cancer, prostate cancer, breast cancer, or pigmented villousonodular synovitis. (PVNS).

In some embodiments, compound A33 is an anti-M-CSF monoclonal antibody molecule or a fragment (eg, a Fab fragment) thereof. In some embodiments, Compound A33 is a monoclonal antibody or Fab fragment that binds to the same epitope as the 5H4 monoclonal antibody (ATCC Accession No. HB10027), for example, as described in WO 2004/045532. In other embodiments, Compound A33 is a monoclonal antibody or Fab fragment thereof that competes with monoclonal antibody 5H4 (ATCC accession number HB10027) for binding to M-CSF, for example, as described in WO 2004/045532. In some embodiments, Compound A33 is a monoclonal antibody or Fab fragment that contains 1, 2, 3, 4, 5, or 6 CDRs of a 5H4 monoclonal antibody (ATCC Accession No. HB10027), for example, as described in WO 2004/045532. In some embodiments, the M-CSF inhibitor or Compound A33 is administered at an average dose of about 10 mg/kg.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a MEK inhibitor, binimetinib (compound A34), or a compound described in PCT Publication No. WO 2003/077914 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the MEK inhibitor is binmetinib (Compound A34) or the compound described in PCT Publication No. WO 2003/077914. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with binmetinib (compound A34) or a compound described in PCT Publication No. WO 2003/077914 to treat a disorder such as non-small cell lung cancer, multisystem genetic disorder, melanoma, ovarian cancer , breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy or renal cell carcinoma, multisystem genetic disorder, gastric cancer, colorectal cancer, alimentary tract/gastrointestinal cancer, rheumatoid arthritis or colon and rectum. In some embodiments, the cancer has or is identified as having a KRAS mutation.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an inhibitor of one or more of cKIT, histamine release , Flt3 (eg, FLK2/STK1) or PKC with midostaurin (compound A35) or a compound described in PCT Publication No. WO 2003/037347 for the treatment of a disorder, eg, the disorder described in the present invention. In one embodiment, the inhibitor is midostaurin (Compound A35) or a compound described in PCT Publication No. WO 2003/037347. In one embodiment, the inhibitor of one or more of c-KIT, histamine release, Flt3 (eg, FLK2/STK1), or PKC is midostaurin. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with midostaurin (Compound A35) or a compound described in PCT Publication No. WO 2003/037347 to treat a disorder such as cancer, colorectal cancer, myeloid leukemia, myelodysplastic syndrome, age-related macular degeneration, diabetic complication, or dermatological disorder.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a TOR inhibitor (e.g., an mTOR inhibitor) everolimus (also known as AFINITOR; compound A36) or a compound described in PCT Publication No. WO 2014/085318 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the TOR inhibitor is everolimus (compound A36) or the compound described in PCT Publication No. WO 2014/085318. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with everolimus (compound A36) to treat a disorder such as interstitial lung disease, small cell lung cancer, respiratory/chest cancer, prostate cancer, multiple myeloma, sarcoma, age-related macular degeneration, bone cancer, tuberous sclerosis, lung cancer (eg, non-small cell lung cancer (NSCLC with squamous and/or non-squamous histology)), melanoma (eg, advanced melanoma), gastrointestinal/gastrointestinal cancer, prostate cancer, hematologic malignancy such as lymphoma or leukemia, endocrine malignancy, lymphoma, neurological disorders, astrocytoma, cervical cancer, neurological malignancy, leukemia, immune disorders, transplant rejection, gastric cancer, melanoma, epilepsy, breast cancer gland or bladder cancer.

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

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an inhibitor of one or more of VEGFR-2, PDGFR-beta, KIT or Raf-kinase C 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl) phenyl)-1H-benzo[d]imidazol-2-amine (compound A37) or the compound described in PCT Publication No. WO 2007/030377 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the inhibitor of one or more of VEGFR-2, PDGFR-beta, KIT, or Raf-kinase C is 1-methyl-5-((2-(5-98040861(trifluoromethyl)-1H-imidαzol-2- yl)niridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1Hbenzo[d]imidazol-2-amine (compound A37) or the compound described in PCT Publication No. WO

2007/030377. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with 1-methyl-5-((2-(5-(trifluoromethyl)-III-imidazol-2-yl)pyridin-4-yl)oxy)-H( 4(trifluoromethyl)phenyl)-III-benzo[d]imidazol-2-amine (Compound A37) or the compound described in PCT Publication No. WO 2007/030377 for the treatment of a disorder such as cancer, melanoma or solid tumor.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a somatostatin agonist and/or a growth hormone releasing inhibitor. , pasireotide diaspartate (also known as SIGNIFOR; compound A38), or a compound described in PCT Publication No. WO 2002/010192 or US Pat. No. 7,473,761 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the somatostatin agonist and/or growth hormone releasing inhibitor is pasireotide diaspartate (compound A38) or a compound described in PCT Publication No. WO 2002/010192 or US Pat. No. 7,473,761. In one embodiment, an anti-PD-L1 antibody molecule is used. in combination with pasireotide diaspartate (compound A38) or a compound described in PCT Publication No. WO 2002/010192 or US Pat. No. 7,473,761 for the treatment of a disorder such as prostate cancer, endocrine cancer, neurological cancer, skin cancer melanoma), pancreatic cancer, liver cancer, Cushing's syndrome, gastrointestinal disorder, acromegaly, liver and biliary tract disorder, or cirrhosis.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a signal transduction modulator and/or an angiogenesis inhibitor, dovitinib (compound A39) or a compound described in PCT Publication No. WO 2009/115562 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the signal transduction modulator and/or angiogenesis inhibitor is dovitinib (Compound A39) or the compound described in PCT Publication No. WO 2009/115562. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with dovitinib (compound A39) or a compound described in PCT Publication No. WO 2009/115562 to treat a disorder such as cancer, respiratory tract cancer/thoracic cancer , multiple myeloma, prostate cancer, non-small cell lung cancer, endocrine malignancy, or neurological genetic disorder.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an EGFR (R,E)-N inhibitor. -(7-chloro-1-(1-(4(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (compound A40) or a compound described in PCT Publication No. WO 2013/184757 for the treatment of a disorder, for example the disorder described in the present invention. In one embodiment, the EGFR inhibitor is (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1Hbenzo[d]imidazole -2-yl)-2-methylisonicotinamide (compound A40) or the compound described in PCT Publication No. WO 2013/184757. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl) -1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (compound A40) or a compound described in PCT Publication No. WO 2013/184757 for the treatment of a disorder such as a malignant tumor, e.g. a solid tumor, e.g. lung cancer (eg, non-small cell lung cancer (NSCLC)).

In one embodiment, an EGFR inhibitor or (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but2-enoyl)azepan-3-yl)-1H-benzo[d]imidazole- 2-yl)-2-methylisonicotinamide (compound A40) is administered at a dose of 150-250 mg, for example per day. In one embodiment, the compound is administered at a dose of about 150, 200, or 250 mg, or about 150-200 or 200-250 mg. In certain embodiments, Compound A40 is administered at an oral dose of about 50-500 mg, such as about 100 to 400 mg, about 150 to 350 mg, or about 200 to 300 mg, such as about 100, 150, or 200 mg. The dosing regimen may vary, for example, from every other day to once a day, two times or three times a day. In one embodiment, Compound A40 is administered at an oral dose of about 100 to 200 mg, such as about 150 mg, once a day.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an ALK inhibitor N ⁶ -(2-isopropoxy -5methyl-4-(1-methylpiperidin-4-yl)phenyl)-N ⁴ -(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3.4-99 040861

d]nupuMuguH-4,6-guaMUHOM (compound A42) or the compound described in PCT Publication No. WO 2008/073687 for the treatment of a disorder, for example, the disorder described in the present invention. In one embodiment, the ALK inhibitor is N ⁶ -(2-isopropoxy-5-methyl-4-(1methylpiperidin-4-yl)phenyl)-N ⁴ -(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3, 4-d]pyrimidine-4,6diamine (Compound A42) or the compound described in PCT Publication No. WO 2008/073687. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with N ⁶ -(2isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-^-(2-(isopropylsulfonyl)phenyl)-1Hpyrazolo [3,4-d]pyrimidine-4,6-diamine (compound A42) or the compound described in PCT Publication No. WO 2008/073687 for the treatment of a disorder such as cancer, anaplastic large cell lymphoma (ALCL), non-small cell lung carcinoma (NSCLC) or neuroblastoma.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an IGF-1R 3-(4- (4-((5-Chloro-4-((5methyl-1H-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 - (2-fluoro-5-methyl-4- (1- (tetrahydro-2H-pyran-4-yl) piperidin4-yl) phenyl) -N ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A44) or 5-χλορ-Ν ² -(4(1-ethylpiperidin-4-yl)-2-fluoro-5 -methylphenyl)-N ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or a compound described in PCT Publication No. WO 2010/002655 for the treatment of a disorder, for example, described violation. In one embodiment, the IGF-1R inhibitor is 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino) -5-fluoro-2methylphenyl)piperidin-1-yl)thiethane 1,1-dioxide (compound A43), 5-chloro-N ² -(2-fluoro-5-methyl-4-(1(tetrahydro-2H-pyran -4-yl)piperidin-4-yl)phenyl)-N ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4diamine (compound A44), 5-chloro-N ² -(4- (1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N ⁴ -(5-methyl-1Hpyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or the compound described in the publication PCT No. WO 2010/002655. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with 3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2- yl)amino)-5-fluoro-2methylphenyl)piperidin-1-yl)thiethane 1,1-dioxide (compound A43), 5-chloro-N ² -(2-fluoro-5-methyl-4-(1(tetrahydro -2H-pyran-4-yl)piperidin-4-yl)phenyl)-N ⁴ -(5-methyl-1H-pyrazol-3-yl)pyrimidin-2,4diamine (compound A44), 5-chloro-N ² -(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N ⁴ -(5-methyl1H-pyrazol-3-yl)pyrimidin-2,4-diamine (compound A45) or compound described in PCT Publication No. WO 2010/002655 for the treatment of a disorder such as cancer or sarcoma.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with the P-glycoprotein 1 inhibitor valspodar (also known as AMDRAY; compound A46) or a compound described in EP 296122 for the treatment of a disorder, eg the disorder described in the present invention. In one embodiment, the P-glycoprotein 1 inhibitor is valspodar (compound A46) or a compound described in EP 296122. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with valspodar (compound A46) or a compound described in EP 296122 , for the treatment of a disorder such as cancer or a drug-resistant tumor.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with one or more of the VEGFR inhibitor, vatalanib succinate (compound A47) or a compound described in EP 296122 for the treatment of a disorder, eg the disorder described in the present invention. In one embodiment, the VEGFR inhibitor is vatalanib succinate (compound A47) or a compound described in EP 296122. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with vatalanib succinate (compound A47) or a compound described in EP 296122, for the treatment of malignant tumors.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with an IDH inhibitor or a compound described in WO 2014 /141104, for the treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the IDH inhibitor is Compound A48 or the compound described in PCT Publication No. WO2014/141104. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with Compound A48 or a compound described in WO 2014/141104 to treat a disorder such as cancer.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a BCL-ABL inhibitor, (R)- N-(4(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (co

- 100 040861 unity A49), or a compound described in PCT Publication No. WO 2013/171639, WO 2013/171640, WO 2013/171641 or WO 2013/171642, for the treatment of a disorder, for example, a disorder described in the present invention. In one embodiment, the BCL-ABL inhibitor is a compound described in PCT Publication No. WO 2013/171639, WO 2013/171640, WO 2013/171641, or WO 2013/171642. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5yl) nicotinamide (Compound A49) or a compound described in PCT Publication No. WO 2013/171639, WO 2013/171640, WO 2013/171641 or WO 2013/171642 for the treatment of a disorder such as cancer.

In another embodiment, an anti-PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a c-RAF inhibitor or a compound described in PCT Publication No. WO 2014/151616, for the treatment of a disorder, such as the disorder described in the present invention. In one embodiment, the c-RAF inhibitor is an A50 compound or a compound described in PCT Publication No. WO 2014/151616. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with Compound A50 or a compound described in PCT Publication No. WO 2014/151616 to treat a disorder such as cancer.

In another embodiment, a PD-L1 antibody molecule, e.g., an anti-PD-L1 antibody molecule as described herein, alone or in combination with one or more other immunomodulators, is used in combination with a competitive ERK1/2 ATP inhibitor or a compound described in International Patent Application No. PCT/US2014/062913, for the treatment of a disorder, such as the disorder described in the present invention. In one embodiment, the competitive ERK1/2 ATP inhibitor is Compound A51 or the compound described in International Patent Application No. PCT/US2014/062913 or PCT Publication No. WO 2015/066188. In one embodiment, an anti-PD-L1 antibody molecule is used in combination with Compound A51 or a compound described in International Patent Application No. PCT/US2014/062913 or PCT Publication No. WO2015/066188 to treat a disorder such as cancer.

In some embodiments, the anti-PD-L1 antibody molecule is administered in combination with one or more of Compound A8, Compound A17, Compound A23, Compound A24, Compound A27, Compound A29, and Compound A33.

In some embodiments, an anti-PD-L1 antibody molecule is administered in combination with an anti-cancer agent having known activity in an immune cell assay, e.g., in one or more of a huMLR assay, a T cell proliferation assay, and a B cell proliferation assay. Exemplary analysis methods are described below. From this analysis, an IC ₅₀ can be calculated for each test agent. In embodiments, the anti-cancer agent has an IC ₅₀ , eg, 0-1 μM, 1-4 μM, or greater than 4 μM, eg, 4-10 μM or 4-20 μM. In embodiments, the second drug is selected from one or more of: Compound A9, Compound A16, Compound A17, Compound A21, Compound A22, Compound A25, Compound A28, Compound A48, and Compound 49.

In some embodiments, Compound A28 (or a related compound to Compound A28) is administered at a dose of about 5-10 or 10-30 mg. In some embodiments, Compound A22 (or a related compound to Compound A22) is administered at a dose of approximately 200 mg. In some embodiments, compound A17 (or a compound related to compound A17) is administered at a dose of about 400-600 mg. In some embodiments, Compound A16 (or a related compound to Compound A16) is administered at a dose of about 400-600 mg p/o per day. In some embodiments, Compound A29 (or a related compound to Compound A29) is administered at a dose of about 200-400 or 300-400 mg. In some embodiments, Compound A24 (or a related compound to Compound A24) is administered at a dose of about 200-600 mg. In some embodiments, compound A23 (ceritinib) (or a ceritinib-related compound) is administered at a dose of approximately 750 mg once daily. In some embodiments, compound A8 (or a compound related to compound A8) is administered at a dose of about 200-400 or 300-400 mg. In some embodiments, Compound A5 (or a related compound to Compound A5) is administered at a dose of about 100-125 mg. In some embodiments, Compound A6 (or a related compound to Compound A6) is administered at a dose of approximately 100 mg. In some embodiments, compound A1 (or a compound related to compound A1) is administered at a dose of about 200-300 or 200-600 mg. In some embodiments, Compound A40 (or a compound related to Compound A40) is administered at a dose of about 150-250 mg. In embodiments, Compound A10 (or a compound related to Compound A10) is administered at a dose of about 400 to 700 mg, eg, administered three times per week, with administration for 2 weeks and one week without administration. In embodiments of the BCR-ABL inhibitor, the inhibitor is administered at a dose of about 20 mg bid-80 mg bid.

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Below is an exemplary huMLR assay and B or T cell proliferation assay.

The reaction of mixed human lymphocytes.

The mixed lymphocyte response (MLR) is a functional assay that measures the proliferative response of one individual's lymphocytes (responder) to another individual's lymphocytes (stimulator). For allogeneic MLR, peripheral blood mononuclear cells (PBMCs) from three donors were isolated from buffy coats of unknown HLA type (Kantonspital Blutspendezentrum from Bern and Aarau, Switzerland). Cells were prepared at 2105 in 0.2 ml culture medium containing RPMI 1640 GlutaMAX™ with 10% fetal calf serum (FCS), 100 U penicillin/100 μg streptomycin, 50 μg 2-mercaptoethanol. Individual 2-targeted reactions were performed by mixing PBMCs from two different donors at a 1:1 ratio and cocultivation was performed in triplicate in 96-well flat-bottomed tissue culture plates for 6 days at 37°C, 5% CO2, in the presence or in lack of a range of concentrations of the studied compounds from 8 points. Cells were treated with 3H-TdR (1 mCi/0.2 ml) during the last 16 h of culture and the radioactivity incorporated therein was used as a measure of cell proliferation. For each compound, the concentration that inhibited 50% of the maximum huMLR response (IC ₅₀ ) was calculated. Cyclosporine was used as a positive control for huMLR inhibition.

Human B cell proliferation assay.

PBMCs were isolated immediately prior to analysis using a FicollPaque density gradient from human blood 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, 1x ITS (insulin, transferrin and sodium selenite), 1x non-essential amino acids) at a concentration of 9.104 per well in 96-well flat bottom culture plate. B cell stimulation was performed with a human anti-IgM antibody molecule (30 μg/ml) and IL-4 (75 ng/ml) or with a CD40 ligand (3 μg/ml) and IL-4 (75 ng/ml) in the presence of or in the absence of a range of studied concentrations of 7 points. After culture for 72 hours at 37° C., 10% CO2, cells were treated with 3H-TdR (1 μCi/well) for the last 6 hours of culture. B cells were then harvested and thymidine incorporation was measured using a scintillation counter. An average value was calculated for each duplicated treatment and these data were plotted in XLfit 4 to determine the corresponding IC ₅₀ values.

Human T cell proliferation assay.

PBMCs were isolated immediately prior to analysis using a FicollPaque density gradient from human blood 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, 1x ITS (insulin, transferrin and sodium selenite), 1x non-essential amino acids) at a concentration of 8.104 per well in 96-well flat bottom culture plate. T cell stimulation was performed with a human anti-CD3 antibody molecule (10 μg/mL) or with an anti-human CD3 antibody molecule (5 μg/mL) and an anti-CD28 antibody molecule (1 μg/mL) in the presence or absence of a range of test concentrations from 7 points. After culture for 72 hours at 37° C., 10% CO2, cells were treated with 3H-TdR (1 μCi/well) for the last 6 hours of culture. Cell proliferation was measured by thymidine incorporation allowing determination of the IC ₅₀ for each test compound.

Exemplary combinations for antigen-presenting combinations, combinations directed to effector cells, and combinations against tumor immunosuppression.

Exemplary drug combinations of two or more of the antigen-presenting category (A), the effector cell category (B), and the antitumor immunosuppression category (C) are provided in this section.

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Table 7

List of medicines of categories (A)-(C)

A = Antigen presentation B = effector cells C = antitumor immunosuppression 1 STING agonist GITR agonist PD-1 inhibitor 2 TLR agonist PD-1 inhibitor PD-L1 inhibitor 3 TIM-3 modulator PD-L1 inhibitor LAG-3 inhibitor 4 VEGFR inhibitor TAP inhibitor TIM-3 inhibitor 5 c-MET inhibitor EGFR inhibitor GITR inhibitor 6 TGFb inhibitor mTOR inhibitor CSF-1/1R inhibitor 7 Inhibitor IDO/TDO IL-15 agonist IL-17 inhibitor 8 A2AR antagonist CTLA-4 inhibitor IL-Ιβ inhibitor 9 Oncolytic viruses Bispecific binding T- cell means CXCR2 inhibitor 10 Frame vaccines CD40 agonist ΡΙ3Κ-γ, -δ inhibitor eleven Bispecific binding T- cell means Agonist 0X40 BAFF-R inhibitor 12 CD27 agonist MALT-1/BTK inhibitor 13 JAK inhibitor 14 CRTH2 inhibitor 15 VEGFR inhibitor 16 IL-15 agonist 17 TGFb inhibitor 18 IDO/TDO inhibitor 19 A2AR antagonist 20 CTLA-4 inhibitor 21 PFKFB3 inhibitor

In some embodiments, the combinations of the present invention include one or more of the following:

A1B1, A1B2, A1B3, A1B4, A1B5, A1B6, A1B7, A1B8, A1B9, A1B10, A1B11, A1B12, A2B1, A2B2, A2B3, A2B4, A2B5, A2B6, A2B7, A2B8,

A2B9, A2B10, A2B11, A2B12, AZV1, AZV2, AZVZ, AZV4, AZV5, AZV6,

AZV7, AZV8, AZV9, AZV10, AZV11, AZV12, А4В1, А4В2, А4ВЗ, А4В4,

A4B5, A4B6, A4B7, A4B8, A4B9, A4B10, A4B11, A4B12, A5B1, A5B2, A5B3, A5B4, A5B5, A5B6, A5B7, A5B8, A5B9, A5B10, A5B11, A5B12, A6B1, A6B2, A6B3, A6B5,4, A6B6, A6B7, A6B8, A6B9, A6B10, A6B11, A6B12, A7B1, A7B2, A7B3, A7B4, A7B5, A7B6, A7B7, A7B8,

A7B9, A7B10, A7B11, A7B12, A8B1, A8B2, A8BZ, A8B4, A8B5, A8B6,

A8B7, A8B8, A8B9, A8B10, A8B11, A8B12, A9B1, A9B2, A9BZ, A9B4,

A9B5, A9B6, A9B7, A9B8, A9B9, A9B10, A9B11, A9B12, A10B1, A10B2, A10B3, A10B4, A10B5, A10B6, A10B7, A10B8, A10B9, A10B10, A10B11, A10B12, A11, A11, A115 A11B6, A11B7, A11B8, A11B9, A11B10, A11B11, A11B12, A1C1, A1C2, A1C3, A1C4, A1C5, A1C6, A1C7, A1C8, A1C9, A1C10, A1C11, A1C12, A1C13, A1C14,

A1C15, A1C16, A1C17, A1C18, A1C19, A1C20, A1C21, A2C1, A2C2, A2C3, A2C4, A2C5, A2C6, A2C7, A2C8, A2C9, A2C10, A2C11, A2C12, A2C13, A2C14, A2C15, A2C18,2C18 A2S19, A2S20, A2S21,

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A3C1, A3C2, AZSZ, AZS4, AZS5, AZS6, AZS7, AZS8, AZS9, AZS10, AZS11, AZS12, A3C13, AZS14, AZS15, AZS16, AZS17, AZS18, AZS19, AZS20, AZS21, A4S1, AZS2 А4С5, А4С6, А4С7, А4С8, А4С9, А4С10, А4С11, А4С12, А4С13, А4С14, А4С15, А4С16, А4С17, А4С18, А4С19, А4С20, А4С21, А5С1, А5С2, А5СЗ, А5С4, А5С5, А5С6 A5C9, A5C10, A5C11, A5C12, A5C13, A5C14, A5C15,

A5C16, A5C17, A5C18, A5C19, A5C20, A5C21, A6C1, A6C2, A6C3, A6C4, A6C5, A6C6, A6C7, A6C8, A6C9, A6C10, A6C11, A6C12, A6C13,

A6C14, A6C15, A6C16, A6C17, A6C18, A6C19, A6C20, A6C21, A7C1, A7C2, A7C3, A7C4, A7C5, A7C6, A7C7, A7C8, A7C9, A7C10, A7C11,

A7S12, A7S13, A7S14, A7S15, A7S16, A7S17, A7S18, A7S19, A7S20,

A7C21, A8C1, A8C2, A8C3, A8C4, A8C5, A8C6, A8C7, A8C8, A8C9, A8C10, A8C11, A8C12, A8C13, A8C14, A8C15, A8C16, A8C17, A8C18,

A8C19, A8C20, A8C21, A9C1, A9C2, A9C3, A9C4, A9C5, A9C6, A9C7, A9C8, A9C9, A9C10, A9C11, A9C12, A9C13, A9C14, A9C15, A9C16, A9C17, A9C18, A9C19, A9C21 A10C2, A10C3, A10C4, A10C5, A10C6, A10C7, A10C8, A10C9, A10C10, A10C11, A10C12,

A10C13, A10C14, A10C15, A10C16, A10C17, A10C18, A10C19, A10C20, A10C21, A11C1, A11C2, A11C3, A11C4, A11C5, A11C6, A11C7, A11C8, A11C9, A11C10, A11C11, A11C12, A11C13, A11C14, A11C15, A11C16, A11C17, A11C18, A11C19, A11C20, A11C21, B1C1, B1C2, B1C3, B1C4, B1C5, B1C6, B1C7, B1C8, B1C9, B1C10, B1C11, B1C12, B1C13, B1C14, B1C15, B1C16, B1C18 B1C21, B2C1, B2C2, B2C3, B2C4, B2C5, B2C6, B2C7, B2C8, B2C9, B2C10, B2C11, B2C12, B2C13, B2C14, B2C15, B2C16, B2C17, B2C18, B2C19, B2C20, B2C21, B3C1 B3C4 B3C5 B3C6 B3C7 B3C8 B3C9 B3C10 B3C11 B3C12 B3C13 B3C14 B3C15 B3C16 B3C17 B3C18 B3C19 B3C20 B3C21 B4C1 B4C2 B4C3 B4C4 B4C5 B4C8, B4C9, B4C10, B4C11, B4C12, B4C13, B4C14, B4C15, B4C16, B4C17, B4C18, B4C19, B4C20, B4C21, B5C1, B5C2, B5C3, B5C4, B5C5, B5C6, B5C7, B5C8, B5C9 B5C12, B5C13, B5C14, B5C15,

B5C16, B5C17, B5C18, B5C19, B5C20, B5C21, B6C1, B6C2, B6C3,

B6C4, B6C5, B6C6, B6C7, B6C8, B6C9, B6C10, B6C11, B6C12, B6C13, B6C14, B6C15, B6C16, B6C17, B6C18, B6C19, B6C20, B6C21, B7C1, B7C2, B7C3, B7C4, B7C5 B7C8, B7C9, B7C10, B7C11, B7C12, B7C13, B7C14, B7C15, B7C16, B7C17, B7C18, B7C19, B7C20,

- 104 040861

B7C21, B8C1, B8C2, B8C3, B8C4, B8C5, B8C6, B8C7, B8C8, B8C9, B8C10, B8C11, B8C12, B8C13, B8C14, B8C15, B8C16, B8C17, B8C18, B8C19, B8C20, B8C21, B9, B9C1 B9C4, B9C5, B9C6, B9C7, B9C8, B9C9, B9C10, B9C11, B9C12, B9C13, B9C14, B9C15, B9C16, B9C17, B9C18, B9C19, B9C20, B9C21, B10C1, B10C2, B10C3, B10C4 B10C8, B10C9, B10C10, B10C11, B10C12, B10C13, B10C14, B10C15, B10C16, B10C17, B10C18, B10C19, B10C20, B10C21, B11C1, B11C2, B11C3, B11C4, B11C5, B11C6, B11C7, B11C8, B11C9, B11C10, ВИСИ, B11C12, B11C13, B11C14, B11C15, B11C16, B11C17, B11C18, B11C19, B11C20, B11C21, B12C1, B12C2, B12C3, B12C4, B12C5, B12C6, B12C7, B12C8, B12C9, B12C10, B12C11, B12C12, B12C13, B12C14, B12C15, B12C16, B12C17, B12C18, B12C19, B12C20, B12C21, A1B1C1, A1B1C2, A1B1C3, A1B1C4, A1B1C5, A1B1C6, A1B1C7, A1B1C8, A1B1C9, A1B1C10, A1B1C11, A1B1C12, A1B1C13, A1B1C14, A1B1C15, A1B1C16, A1B1C17, A1B1C18, A1B1C19, A1B1C20, A1B1C21, A1B2C1, A1B2C2, A1B2C3, A1B2C4, A1B2C5, A1B2C6, A1B2C7, A1B2C8 , A1B2C9, A1B2C10, A1B2C11, A1B2C12, A1B2C13, A1B2C14, A1B2C15, A1B2C16, A1B2C17, A1B2C18, A1B2C19, A1B2C20, A1B2C21, A1B3C1, A1B3C2, A1B3C3, A1B3C4, A1B3C5, A1B3C6, A1B3C7, A1B3C8, A1B3C9, A1B3C10, A1B3C11, A1B3C12 , A1B3C13, A1B3C14, A1B3C15, A1B3C16, A1B3C17, A1B3C18, A1B3C19, A1B3C20, A1B3C21, A1B4C1, A1B4C2, A1B4C3, A1B4C4, A1B4C5, A1B4C6, A1B4C7, A1B4C8, A1B4C9, A1B4C10, A1B4C11, A1B4C12, A1B4C13, A1B4C14, A1B4C15, A1B4C16 , A1B4C17, A1B4C18, A1B4C19, A1B4C20, A1B4C21, A1B5C1, A1B5C2, A1B5C3, A1B5C4, A1B5C5, A1B5C6, A1B5C7, A1B5C8, A1B5C9, A1B5C10, A1B5C11, A1B5C12, A1B5C13, A1B5C14, A1B5C15, A1B5C16, A1B5C17, A1B5C18, A1B5C19, A1B5C20 , A1B5C21, A1B6C1, A1B6C2, A1B6C3, A1B6C4, A1B6C5, A1B6C6, A1B6C7, A1B6C8, A1B6C9, A1B6C10, A1B6C11, A1B6C12, A1B6C13, A1B6C14, A1B6C15, A1B6C16, A1B6C17, A1B6C18, A1B6C19, A1B6C20, A1B6C21, A1B7C1, A1B7C2, A1B7C3 A1B7C12, A1B7C13, A1B7C14, A1B7C15, A1B7C16, A1B7C17, A1B7C18, A1B7C19, A1B7C20, A1B7C21, A1B8C1, A1B8C2, A1B8C3, A1B8C4, A1B8C5, A1B8C6, A1B8C7, A1B8C8, A1B8C9, A1B8C10, A1B8C11, A1B8C12, A1B8C13, A1B8C14, A1B8C15, A1B8C16, A1B8C17, A1B8C18, A1B8C19, A1B8C20, A1B8C21, A1B9C1, A1B9C2, A1B9C3,

- 105 040861

A1B9C4, A1B9C5, A1B9C6, A1B9C7, A1B9C8, A1B9C9, A1B9C10, A1B9C11, A1B9C12, A1B9C13, A1B9C14, A1B9C15, A1B9C16, A1B9C17, A1B9C18, A1B9C19, A1B9C20, A1B9C21, A1B10C1, A1B10C2, A1B10C3, A1B10C4, A1B10C5, A1B10C6, A1B10C7, A1B10C8, A1B10C9, A1B10C10, A1B10C11, A1B10C12, A1B10C13, A1B10C14, A1B10C15, A1B10C16, A1B10C17, A1B10C18, A1B10C19, A1B10C20, A1B10C21, A1B11C1, A1B11C2, A1B11C3, A1B11C4, A1B11C5, A1B11C6, A1B11C7, A1B11C8, A1B11C9, A1B11C10, A1B11C11, A1B11C12, A1B11C13, A1B11C14, A1B11C15, A1B11C16, A1B11C17, A1B11C18, A1B11C19, A1B11C20, A1B11C21, A1B12C1, A1B12C2, A1B12C3, A1B12C4, A1B12C5, A1B12C6, A1B12C7, A1B12C8, A1B12C9, A1B12C10, A1B12C11, A1B12C12, A1B12C13, A1B12C14, A1B12C15, A1B12C16, A1B12C17, A1B12C18, A1B12C19, A1B12C20, A1B12C21, A2B1C1, A2B1C2, A2B1C3, A2B1C4, A2B1C5, A2B1C6, A2B1C7, A2B1C8, A2B1C9, A2B1C10, A2B1C11, A2B1C12, A2B1C13, A2B1C14, A2B1C15, A2B1C16, A2B1C17, A2B1C18, A2B1C19, A2B1C20, A2B1C21, A2B2C1, A2B2C2, A2B2C3, A2B2C4, A2B2C5, A2B2C6, A2B2C7, A2B2C 8, A2B2C9, A2B2C10, A2B2C11, A2B2C12, A2B2C13, A2B2C14, A2B2C15, A2B2C16, A2B2C17, A2B2C18, A2B2C19, A2B2C20, A2B2C21, A2B3C1, A2B3C2, A2B3C3, A2B3C4, A2B3C5, A2B3C6, A2B3C7, A2B3C8, A2B3C9, A2B3C10, A2B3C11, A2B3C12, A2B3C13, A2B3C14, A2B3C15, A2B3C16, A2B3C17, A2B3C18, A2B3C19, A2B3C20, A2B3C21, A2B4C1, A2B4C2, A2B4C3, A2B4C4, A2B4C5, A2B4C6, A2B4C7, A2B4C8, A2B4C9, A2B4C10, A2B4C11, A2B4C12, A2B4C13, A2B4C14, A2B4C15, A2B4C16, A2B4C17, A2B4C18, A2B4C19, A2B4C20, A2B4C21, A2B5C1, A2B5C2, A2B5C3, A2B5C4, A2B5C5, A2B5C6, A2B5C7, A2B5C8, A2B5C9, A2B5C10, A2B5C11, A2B5C12, A2B5C13, A2B5C14, A2B5C15, A2B5C16, A2B5C17, A2B5C18, A2B5C19, A2B5C20, A2B5C21, A2B6C1, A2B6C2, A2B6C3, A2B6C4, A2B6C5, A2B6C6, A2B6C7, A2B6C8, A2B6C9, A2B6C10, A2B6C11, A2B6C12, A2B6C13, A2B6C14, A2B6C15, A2B6C16, A2B6C17, A2B6C18, A2B6C19, A2B6C20, A2B6C21, A2B7C1, A2B7C2, A2B7C3, A2B7C4, A2B7C5, A2B7C6, A2B7C7, A2B7C8, A2B7C9, A2B7C10, A2B7C11, A2B7C12, A2B7C13, A2B7C14, A2B7C15, A2B7C16, A2B7C17, A2B7C18, A2B7C19, A2B7C20, A2B7C21, A2B8C1, A2B8C2, A2B8C3, A2B8C4, A2B8C5, A2B8C6, A2B8C7, A2B8C8, A2B8C9, A2B8C10, A2B8C11, A2B8C12, A2B8C13, A2B8C14, A2B8C15, A2B8C16, A2B8C17, A2B8C18,

- 106 040861

A2B8C19, A2B8C20, A2B8C21, A2B9C1, A2B9C2, A2B9C3, A2B9C4, A2B9C5, A2B9C6, A2B9C7, A2B9C8, A2B9C9, A2B9C10, A2B9C11, A2B9C12, A2B9C13, A2B9C14, A2B9C15, A2B9C16, A2B9C17, A2B9C18, A2B9C19, A2B9C20, A2B9C21, A2B10C1, A2B10C2, A2B10C3, A2B10C4, A2B10C5, A2B10C6, A2B10C7, A2B10C8, A2B10C9, A2B10C10, A2B10C11, A2B10C12, A2B10C13, A2B10C14, A2B10C15, A2B10C16, A2B10C17, A2B10C18, A2B10C19, A2B10C20, A2B10C21, A2B11C1, A2B11C2, A2B11C3, A2B11C4, A2B11C5, A2B11C6, A2B11C7, A2B11C8, A2B11C9, A2B11C10, A2B11C11, A2B11C12, A2B11C13, A2B11C14, A2B11C15, A2B11C16, A2B11C17, A2B11C18, A2B11C19, A2B11C20, A2B11C21, A2B12C1, A2B12C2, A2B12C3, A2B12C4, A2B12C5, A2B12C6, A2B12C7, A2B12C8, A2B12C9, A2B12C10, A2B12C11, A2B12C12, A2B12C13, A2B12C14, A2B12C15, A2B12C16, A2B12C17, A2B12C18, A2B12C19, A2B12C20, A2B12C21, A3B1C1, A3B1C2, A3B1C3, A3B1C4, A3B1C5, A3B1C6, A3B1C7, A3B1C8, A3B1C9, A3B1C10, A3B1C11, A3B1C12, A3B1C13, A3B1C14, A3B1C15, A3B1C16, A3B1C17, A3B1C18, A3B1C19, A3B1C20, A3B1C21, A3B2C1, A3 B2C2, A3B2C3, A3B2C4, A3B2C5, A3B2C6, A3B2C7, A3B2C8, A3B2C9, A3B2C10, A3B2C11, A3B2C12, A3B2C13, A3B2C14, A3B2C15, A3B2C16, A3B2C17, A3B2C18, A3B2C19, A3B2C20, A3B2C21, A3B3C1, A3B3C2, АЗВЗСЗ, АЗВЗС4, АЗВЗС5, АЗВЗС6, АЗВЗС7, АЗВЗС8, АЗВЗС9, АЗВЗС10, АЗВЗС11, АЗВЗС12, A3B3C13, АЗВЗС14, АЗВЗС15, АЗВЗС16, АЗВЗС17, АЗВЗС18, АЗВЗС19, АЗВЗС20, АЗВЗС21, АЗВ4С1, АЗВ4С2, АЗВ4СЗ, АЗВ4С4, АЗВ4С5, АЗВ4С6, АЗВ4С7, АЗВ4С8, АЗВ4С9, АЗВ4С10, АЗВ4С11, АЗВ4С12, A3B4C13, АЗВ4С14, АЗВ4С15, АЗВ4С16, АЗВ4С17, АЗВ4С18, АЗВ4С19, АЗВ4С20, АЗВ4С21, АЗВ5С1, АЗВ5С2, АЗВ5СЗ, АЗВ5С4, АЗВ5С5, АЗВ5С6, АЗВ5С7, АЗВ5С8, АЗВ5С9, АЗВ5С10, АЗВ5С11, АЗВ5С12, A3B5C13, АЗВ5С14, АЗВ5С15, АЗВ5С16, АЗВ5С17, АЗВ5С18, АЗВ5С19, АЗВ5С20, АЗВ5С21, АЗВ6С1, АЗВ6С2, АЗВ6СЗ, АЗВ6С4, АЗВ6С5, АЗВ6С6, АЗВ6С7, АЗВ6С8, АЗВ6С9, АЗВ6С10, АЗВ6С11, АЗВ6С12, A3B6C13, АЗВ6С14, АЗВ6С15, АЗВ6С16, АЗВ6С17, AZV6S18, AZV6S19, AZV6S20, AZV6S21, AZV7S1, AZV7S2, AZV7SZ, AZV7S4, AZV7S5, AZV7S6, AZV7S7, AZV7S8, AZV7S9, AZV7S10, AZV7S11, AZV7S12, A3B7C13 B7S14, AZV7S15, AZV7S16, AZV7S17, AZV7S18, AZV7S19, AZV7C20, AZV7S21, AZV8S1, AZV8SZ, AZV8S4, AZV8S6, AZV8S7, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S8, AZV8S.

- 107 040861

A3B8C13, A3B8C14, A3B8C15, A3B8C16, A3B8C17, A3B8C18, A3B8C19 A3B8C20, A3B8C21, A3B9C1, A3B9C2 , A3B9C3, A3B9C4, A3B9C5 A3B9C6, A3B9C7, A3B9C8, A3B9C9, A3B9C10, A3B9C11, A3B9C12 A3B9C13, A3B9C14, A3B9C15, A3B9C16, A3B9C17, A3B9C18, A3B9C19 A3B9C20, A3B9C21, A3B10C1, A3B10C2, A3B10C3, A3B10C4, A3B10C5 A3B10C6, A3B10C7 , A3B10C8, A3B10C9, A3B10C10, A3B10C11 A3B10C12, , A3B10C13, A3B10C14, A3B10C15, A3B10C16, A3B10C17 A3B10C18, , A3B10C19, A3B10C20, A3B10C21, A3B11C1, A3B11C2 A3B11C3, A3B11C4, A3B11C5, A3B11C6, A3B11C7, A3B11C8, A3B11C9 A3B11C10, , A3B11C11, A3B11C12, A3B11C13, A3B11C14, A3B11C15 A3B11C16, , A3B11C17, A3B11C18, A3B11C19, A3B11C20, A3B11C21 A3B12C1, A3B12C2, A3B12C3, A3B12C4, A3B12C5, A3B12C6, A3B12C7 A3B12C8, A3B12C9 , A3B12C10, A3B12C11, A3B12C12, A3B12C13 A3B12C14, , A3B12C15, A3B12C16, A3B12C17, A3B12C18, A3B12C19 A3B12C20, , A3B12C2 1, A4B1C1, A4B1C2, A4B1C3 , A4B1C4, , A4B1C5 A4B1C6, A4B1C7, A4B1C8, A4B1C9, A4B1C10, A4B1C11, A4B1C12 A4B1C13, A4B1C14, A4B1C15, A4B1C16, A4B1C17, A4B1C18, A4B1C19 A4B1C20, A4B1C21, A4B2C1, A4B2C2 , A4B2C3, A4B2C4, A4B2C5 A4B2C6, A4B2C7, A4B2C8, A4B2C9, A4B2C10, A4B2C11, A4B2C12 A4B2C13, A4B2C14, A4B2C15, A4B2C16, A4B2C17, A4B2C18, A4B2C19 A4B2C20, A4B2C21, A4B3C1, A4B3C2 , A4B3C3, A4B3C4, A4B3C5 A4B3C6, A4B3C7, A4B3C8, A4B3C9, A4B3C10, A4B3C11, A4B3C12 A4B3C13, A4B3C14, A4B3C15, A4B3C16, A4B3C17, A4B3C18, A4B3C19 A4B3C20, A4B3C21, A4B4C1, A4B4C2 , A4B4C3, A4B4C4, A4B4C5 A4B4C6, A4B4C7, A4B4C8, A4B4C9, A4B4C10, A4B4C11, A4B4C12 A4B4C13, A4B4C14, A4B4C15, A4B4C16, A4B4C17, A4B4C18, A4B4C19 A4B4C20, A4B4C21, A4B5C1, A4B5C2 , A4B5C3, A4B5C4, A4B5C5 A4B5C6, A4B5C7, A4B5C8, A4B5C9, A4B5C10, A4B5C11, A4B5C12 A4B5C13, A4B5C14, A4B5C15, A4B5C16, A4B5C17, A4B5C18, A4B5C19 A4B5C20, A4B5C21, A4B6C1, A4B6C2 , A4B6C3, A4B6C4, A4B6C5 A4B6C6, A4B6C7, A4B6C8, A4B6C9, A4B6C10, A4B6C11, A4B6C12 A4B6C13, A4B6C14, A4B6C15, A4B6C16, A4B6C17, A4B6C18, A4B6C19 A4B6C20, A4B6C21, A4B7C1, A4B7C2 , A4B7C3, A4B7C4, A4B7C5 A4B7C6, A4B7C7, A4B7C8, A4B7C9, A4B7C10, A4B7C11, A4B7C12 A4B7C13, A4B7C14, A4B7C15, A4B7C16, A4B7C17, A4B7C18, A4B7C19 A4B7C20, A4B7C21, A4B8C1, A4B8C2 , A4B8C3, A4B8C4, A4B8C5

- 108 040861

A4B8C6, A4B8C7, A4B8C8, A4B8C9, A4B8C10, A4B8C11, A4B8C12, A4B8C13, A4B8C14, A4B8C15, A4B8C16, A4B8C17, A4B8C18, A4B8C19, A4B8C20, A4B8C21, A4B9C1, A4B9C2, A4B9C3, A4B9C4, A4B9C5, A4B9C6, A4B9C7, A4B9C8, A4B9C9, A4B9C10, A4B9C11, A4B9C12, A4B9C13, A4B9C14, A4B9C15, A4B9C16, A4B9C17, A4B9C18, A4B9C19, A4B9C20, A4B9C21, A4B10C1, A4B10C2, A4B10C3, A4B10C4, A4B10C5, A4B10C6, A4B10C7, A4B10C8, A4B10C9, A4B10C10, A4B10C11, A4B10C12, A4B10C13, A4B10C14, A4B10C15, A4B10C16, A4B10C17, A4B10C18, A4B10C19, A4B10C20, A4B10C21, A4B11C1, A4B11C2, A4B11C3, A4B11C4, A4B11C5, A4B11C6, A4B11C7, A4B11C8, A4B11C9, A4B11C10, A4B11C11, A4B11C12, A4B11C13, A4B11C14, A4B11C15, A4B11C16, A4B11C17, A4B11C18, A4B11C19, A4B11C20, A4B11C21, A4B12C1, A4B12C2, A4B12C3, A4B12C4, A4B12C5, A4B12C6, A4B12C7, A4B12C8, A4B12C9, A4B12C10, A4B12C11, A4B12C12, A4B12C13, A4B12C14, A4B12C15, A4B12C16, A4B12C17, A4B12C18, A4B12C19, A4B12C20, A4B12C21, A5B1C1, A5B1C2, A5B1C3, A5B1C4, A5B1C5, A5B1C6, A5B1C7, A5B1C8, A5B1C9, A5B1C 10, A5B1C11, A5B1C12, A5B1C13, A5B1C14, A5B1C15, A5B1C16, A5B1C17, A5B1C18, A5B1C19, A5B1C20, A5B1C21, A5B2C1, A5B2C2, A5B2C3, A5B2C4, A5B2C5, A5B2C6, A5B2C7, A5B2C8, A5B2C9, A5B2C10, A5B2C11, A5B2C12, A5B2C13, A5B2C14, A5B2C15, A5B2C16, A5B2C17, A5B2C18, A5B2C19, A5B2C20, A5B2C21, A5B3C1, A5B3C2, A5B3C3, A5B3C4, A5B3C5, A5B3C6, A5B3C7, A5B3C8, A5B3C9, A5B3C10, A5B3C11, A5B3C12, A5B3C13, A5B3C14, A5B3C15, A5B3C16, A5B3C17, A5B3C18, A5B3C19, A5B3C20, A5B3C21, A5B4C1, A5B4C2, A5B4C3, A5B4C4, A5B4C5, A5B4C6, A5B4C7, A5B4C8, A5B4C9, A5B4C10, A5B4C11, A5B4C12, A5B4C13, A5B4C14, A5B4C15, A5B4C16, A5B4C17, A5B4C18, A5B4C19, A5B4C20, A5B4C21, A5B5C1, A5B5C2, A5B5C3, A5B5C4, A5B5C5, A5B5C6, A5B5C7, A5B5C8, A5B5C9, A5B5C10, A5B5C11, A5B5C12, A5B5C13, A5B5C14, A5B5C15, A5B5C16, A5B5C17, A5B5C18, A5B5C19, A5B5C20, A5B5C21, A5B6C1, A5B6C2, A5B6C3, A5B6C4, A5B6C5, A5B6C6, A5B6C7, A5B6C8, A5B6C9, A5B6C10, A5B6C11, A5B6C12, A5B6C13, A5B6C14, A5B6C15, A5B6C16, A5B6C17, A5B6C18, A5B6C19, A5B6C20, A5B6C20 1, A5B7C1, A5B7C2, A5B7C3, A5B7C4, A5B7C5, A5B7C6, A5B7C7, A5B7C8, A5B7C9, A5B7C10, A5B7C11, A5B7C12, A5B7C13, A5B7C14, A5B7C15, A5B1C17, A5B7C17, A5B7C17, A5B7C17, A5B7C17

- 109 040861

A5B7C20, A5B7C21, A5B8C1, A5B8C2, A5B8C3, A5B8C4, A5B8C5, A5B8C6, A5B8C7, A5B8C8, A5B8C9, A5B8C10, A5B8C11, A5B8C12, A5B8C13, A5B8C14, A5B8C15, A5B8C16, A5B8C17, A5B8C18, A5B8C19, A5B8C20, A5B8C21, A5B9C1, A5B9C2, A5B9C3, A5B9C4, A5B9C5, A5B9C6, A5B9C7, A5B9C8, A5B9C9, A5B9C10, A5B9C11, A5B9C12, A5B9C13, A5B9C14, A5B9C15, A5B9C16, A5B9C17, A5B9C18, A5B9C19, A5B9C20, A5B9C21, A5B10C1, A5B10C2, A5B10C3, A5B10C4, A5B10C5, A5B10C6, A5B10C7, A5B10C8, A5B10C9, A5B10C10, A5B10C11, A5B10C12, A5B10C13, A5B10C14, A5B10C15, A5B10C16, A5B10C17, A5B10C18, A5B10C19, A5B10C20, A5B10C21, A5B11C1, A5B11C2, A5B11C3, A5B11C4, A5B11C5, A5B11C6, A5B11C7, A5B11C8, A5B11C9, A5B11C10, A5B11C11, A5B11C12, A5B11C13, A5B11C14, A5B11C15, A5B11C16, A5B11C17, A5B11C18, A5B11C19, A5B11C20, A5B11C21, A5B12C1, A5B12C2, A5B12C3, A5B12C4, A5B12C5, A5B12C6, A5B12C7, A5B12C8, A5B12C9, A5B12C10, A5B12C11, A5B12C12, A5B12C13, A5B12C14, A5B12C15, A5B12C16, A5B12C17, A5B12C18, A5B12C19, A5B12C20, A5B12C21, A6B1C1, A6B1C2, A6B 1C3, A6B1C4, A6B1C5, A6B1C6, A6B1C7, A6B1C8, A6B1C9, A6B1C10, A6B1C11, A6B1C12, A6B1C13, A6B1C14, A6B1C15, A6B1C16, A6B1C17, A6B1C18, A6B1C19, A6B1C20, A6B1C21, A6B2C1, A6B2C2, A6B2C3, A6B2C4, A6B2C5, A6B2C6, A6B2C7, A6B2C8, A6B2C9, A6B2C10, A6B2C11, A6B2C12, A6B2C13, A6B2C14, A6B2C15, A6B2C16, A6B2C17, A6B2C18, A6B2C19, A6B2C20, A6B2C21, A6B3C1, A6B3C2, A6B3C3, A6B3C4, A6B3C5, A6B3C6, A6B3C7, A6B3C8, A6B3C9, A6B3C10, A6B3C11, A6B3C12, A6B3C13, A6B3C14, A6B3C15, A6B3C16, A6B3C17, A6B3C18, A6B3C19, A6B3C20, A6B3C21, A6B4C1, A6B4C2, A6B4C3, A6B4C4, A6B4C5, A6B4C6, A6B4C7, A6B4C8, A6B4C9, A6B4C10, A6B4C11, A6B4C12, A6B4C13, A6B4C14, A6B4C15, A6B4C16, A6B4C17, A6B4C18, A6B4C19, A6B4C20, A6B4C21, A6B5C1, A6B5C2, A6B5C3, A6B5C4, A6B5C5, A6B5C6, A6B5C7, A6B5C8, A6B5C9, A6B5C10, A6B5C11, A6B5C12, A6B5C13, A6B5C14, A6B5C15, A6B5C16, A6B5C17, A6B5C18, A6B5C19, A6B5C20, A6B5C21, A6B6C1, A6B6C2, A6B6C3, A6B6C4, A6B6C5, A6B6C6, A6B6C7, A6B6C8, A6B6C9, A6B6C10, A6B6C11, A6B6C12, A6B6C13, A6B6C14 B6C15, A6B6C16, A6B6C17, A6B6C18, A6B6C19, A6B6C20, A6B6C21, A6B7C1, A6B7C2, A6B7C3, A6B7C4, A6B7C5, A6B7C6, A6B7C7, A6B7C8, A6B7C9, A6B7C10, A6B7C10, A6B7C10

- 110 040861

A6B7C13, A6B7C14, A6B7C15, A6B7C16, A6B7C17, A6B7C18, A6B7C19, A6B7C20, A6B7C21, A6B8C1, A6B8C2, A6B8C3, A6B8C4, A6B8C5, A6B8C6, A6B8C7, A6B8C8, A6B8C9, A6B8C10, A6B8C11, A6B8C12, A6B8C13, A6B8C14, A6B8C15, A6B8C16, A6B8C17, A6B8C18, A6B8C19, A6B8C20, A6B8C21, A6B9C1, A6B9C2, A6B9C3, A6B9C4, A6B9C5, A6B9C6, A6B9C7, A6B9C8, A6B9C9, A6B9C10, A6B9C11, A6B9C12, A6B9C13, A6B9C14, A6B9C15, A6B9C16, A6B9C17, A6B9C18, A6B9C19, A6B9C20, A6B9C21, A6B10C1, A6B10C2, A6B10C3, A6B10C4, A6B10C5, A6B10C6, A6B10C7, A6B10C8, A6B10C9, A6B10C10, A6B10C11, A6B10C12, A6B10C13, A6B10C14, A6B10C15, A6B10C16, A6B10C17, A6B10C18, A6B10C19, A6B10C20, A6B10C21, A6B11C1, A6B11C2, A6B11C3, A6B11C4, A6B11C5, A6B11C6, A6B11C7, A6B11C8, A6B11C9, A6B11C10, A6B11C11, A6B11C12, A6B11C13, A6B11C14, A6B11C15, A6B11C16, A6B11C17, A6B11C18, A6B11C19, A6B11C20, A6B11C21, A6B12C1, A6B12C2, A6B12C3, A6B12C4, A6B12C5, A6B12C6, A6B12C7, A6B12C8, A6B12C9, A6B12C10, A6B12C11, A6B12C12, A6B12C13, A6B12C14, A6B12C15, A6B12C16, A6B12C 17, A6B12C18, A6B12C19, A6B12C20, A6B12C21, A7B1C1, A7B1C2, A7B1C3, A7B1C4, A7B1C5, A7B1C6, A7B1C7, A7B1C8, A7B1C9, A7B1C10, A7B1C11, A7B1C12, A7B1C13, A7B1C14, A7B1C15, A7B1C16, A7B1C17, A7B1C18, A7B1C19, A7B1C20, A7B1C21, A7B2C1, A7B2C2, A7B2C3, A7B2C4, A7B2C5, A7B2C6, A7B2C7, A7B2C8, A7B2C9, A7B2C10, A7B2C11, A7B2C12, A7B2C13, A7B2C14, A7B2C15, A7B2C16, A7B2C17, A7B2C18, A7B2C19, A7B2C20, A7B2C21, A7B3C1, A7B3C2, A7B3C3, A7B3C4, A7B3C5, A7B3C6, A7B3C7, A7B3C8, A7B3C9, A7B3C10, A7B3C11, A7B3C12, A7B3C13, A7B3C14, A7B3C15, A7B3C16, A7B3C17, A7B3C18, A7B3C19, A7B3C20, A7B3C21, A7B4C1, A7B4C2, A7B4C3, A7B4C4, A7B4C5, A7B4C6, A7B4C7, A7B4C8, A7B4C9, A7B4C10, A7B4C11, A7B4C12, A7B4C13, A7B4C14, A7B4C15, A7B4C16, A7B4C17, A7B4C18, A7B4C19, A7B4C20, A7B4C21, A7B5C1, A7B5C2, A7B5C3, A7B5C4, A7B5C5, A7B5C6, A7B5C7, A7B5C8, A7B5C9, A7B5C10, A7B5C11, A7B5C12, A7B5C13, A7B5C14, A7B5C15, A7B5C16, A7B5C17, A7B5C18, A7B5C19, A7B5C20, A7B5C21, A7B6C1, A7B6C2, A7B6C3, A7B6C4, A7B6C5, A7B6C6, A7B6C7, A7B6C7 A7B6C8 A7B6C9 A7B6C10 A7B6C11 A7B6C12 A7B6C13 A7B6C14 A7B6C15 A7B6C16 A7B6C17 A7B6C18 A7B6C19 A7B6C20 A7B6C21 A7B7C1 A7B7C2

- 111 040861

A7B7C6, A7B7C7, A7B7C8, A7B7C9, A7B7C10, A7B7C11, A7B7C12, A7B7C13, A7B7C14, A7B7C15, A7B7C16, A7B7C17, A7B7C18, A7B7C19, A7B7C20, A7B7C21, A7B8C1, A7B8C2, A7B8C3, A7B8C4, A7B8C5, A7B8C6, A7B8C7, A7B8C8, A7B8C9, A7B8C10, A7B8C11, A7B8C12, A7B8C13, A7B8C14, A7B8C15, A7B8C16, A7B8C17, A7B8C18, A7B8C19, A7B8C20, A7B8C21, A7B9C1, A7B9C2, A7B9C3, A7B9C4, A7B9C5, A7B9C6, A7B9C7, A7B9C8, A7B9C9, A7B9C10, A7B9C11, A7B9C12, A7B9C13, A7B9C14, A7B9C15, A7B9C16, A7B9C17, A7B9C18, A7B9C19, A7B9C20, A7B9C21, A7B10C1, A7B10C2, A7B10C3, A7B10C4, A7B10C5, A7B10C6, A7B10C7, A7B10C8, A7B10C9, A7B10C10, A7B10C11, A7B10C12, A7B10C13, A7B10C14, A7B10C15, A7B10C16, A7B10C17, A7B10C18, A7B10C19, A7B10C20, A7B10C21, A7B11C1, A7B11C2, A7B11C3, A7B11C4, A7B11C5, A7B11C6, A7B11C7, A7B11C8, A7B11C9, A7B11C10, A7B11C11, A7B11C12, A7B11C13, A7B11C14, A7B11C15, A7B11C16, A7B11C17, A7B11C18, A7B11C19, A7B11C20, A7B11C21, A7B12C1, A7B12C2, A7B12C3, A7B12C4, A7B12C5, A7B12C6, A7B12C7, A7B12C8, A7B12C9, A7B12C10, A7B12C1 1, A7B12C12, A7B12C13, A7B12C14, A7B12C15, A7B12C16, A7B12C17, A7B12C18, A7B12C19, A7B12C20, A7B12C21, A8B1C1, A8B1C2, A8B1C3, A8B1C4, A8B1C5, A8B1C6, A8B1C7, A8B1C8, A8B1C9, A8B1C10, A8B1C11, A8B1C12, A8B1C13, A8B1C14, A8B1C15, A8B1C16, A8B1C17, A8B1C18, A8B1C19, A8B1C20, A8B1C21, A8B2C1, A8B2C2, A8B2C3, A8B2C4, A8B2C5, A8B2C6, A8B2C7, A8B2C8, A8B2C9, A8B2C10, A8B2C11, A8B2C12, A8B2C13, A8B2C14, A8B2C15, A8B2C16, A8B2C17, A8B2C18, A8B2C19, A8B2C20, A8B2C21, A8B3C1, A8B3C2, A8B3C3, A8B3C4, A8B3C5, A8B3C6, A8B3C7, A8B3C8, A8B3C9, A8B3C10, A8B3C11, A8B3C12, A8B3C13, A8B3C14, A8B3C15, A8B3C16, A8B3C17, A8B3C18, A8B3C19, A8B3C20, A8B3C21, A8B4C1, A8B4C2, A8B4C3, A8B4C4, A8B4C5, A8B4C6, A8B4C7, A8B4C8, A8B4C9, A8B4C10, A8B4C11, A8B4C12, A8B4C13, A8B4C14, A8B4C15, A8B4C16, A8B4C17, A8B4C18, A8B4C19, A8B4C20, A8B4C21, A8B5C1, A8B5C2, A8B5C3, A8B5C4, A8B5C5, A8B5C6, A8B5C7, A8B5C8, A8B5C9, A8B5C10, A8B5C11, A8B5C12, A8B5C13, A8B5C14, A8B5C15, A8B5C16, A8B5C17, A8B5C18, A8B5C19, A8B5C20, A8B5C2 1, A8B6C1, A8B6C2, A8B6C3, A8B6C4, A8B6C5, A8B6C6, A8B6C7, A8B6C8, A8B6C9, A8B6C10, A8B6C11, A8B6C12, A8B6C13, A8B6C14, A8B6C15, A8B6C16, A8B6C16, A8B6C16, A8B6C16, A8B6C16, A8B6C16, A8B6C16

- 112 040861

A8B6C20, A8B6C21, A8B7C1, A8B7C2, A8B7C3, A8B7C4, A8B7C5, A8B7C6, A8B7C7, A8B7C8, A8B7C9, A8B7C10, A8B7C11, A8B7C12, A8B7C13, A8B7C14, A8B7C15, A8B7C16, A8B7C17, A8B7C18, A8B7C19, A8B7C20, A8B7C21, A8B8C1, A8B8C2, A8B8C3, A8B8C4, A8B8C5, A8B8C6, A8B8C7, A8B8C8, A8B8C9, A8B8C10, A8B8C11, A8B8C12, A8B8C13, A8B8C14, A8B8C15, A8B8C16, A8B8C17, A8B8C18, A8B8C19, A8B8C20, A8B8C21, A8B9C1, A8B9C2, A8B9C3, A8B9C4, A8B9C5, A8B9C6, A8B9C7, A8B9C8, A8B9C9, A8B9C10, A8B9C11, A8B9C12, A8B9C13, A8B9C14, A8B9C15, A8B9C16, A8B9C17, A8B9C18, A8B9C19, A8B9C20, A8B9C21, A8B10C1, A8B10C2, A8B10C3, A8B10C4, A8B10C5, A8B10C6, A8B10C7, A8B10C8, A8B10C9, A8B10C10, A8B10C11, A8B10C12, A8B10C13, A8B10C14, A8B10C15, A8B10C16, A8B10C17, A8B10C18, A8B10C19, A8B10C20, A8B10C21, A8B11C1, A8B11C2, A8B11C3, A8B11C4, A8B11C5, A8B11C6, A8B11C7, A8B11C8, A8B11C9, A8B11C10, A8B11C11, A8B11C12, A8B11C13, A8B11C14, A8B11C15, A8B11C16, A8B11C17, A8B11C18, A8B11C19, A8B11C20, A8B11C21, A8B12C1, A8B12C2, A8B12C3, A8B12C4, A8B1 2C5, A8B12C6, A8B12C7, A8B12C8, A8B12C9, A8B12C10, A8B12C11, A8B12C12, A8B12C13, A8B12C14, A8B12C15, A8B12C16, A8B12C17, A8B12C18, A8B12C19, A8B12C20, A8B12C21, A9B1C1, A9B1C2, A9B1C3, A9B1C4, A9B1C5, A9B1C6, A9B1C7, A9B1C8, A9B1C9, A9B1C10, A9B1C11, A9B1C12, A9B1C13, A9B1C14, A9B1C15, A9B1C16, A9B1C17, A9B1C18, A9B1C19, A9B1C20, A9B1C21, A9B2C1, A9B2C2, A9B2C3, A9B2C4, A9B2C5, A9B2C6, A9B2C7, A9B2C8, A9B2C9, A9B2C10, A9B2C11, A9B2C12, A9B2C13, A9B2C14, A9B2C15, A9B2C16, A9B2C17, A9B2C18, A9B2C19, A9B2C20, A9B2C21, A9B3C1, A9B3C2, A9B3C3, A9B3C4, A9B3C5, A9B3C6, A9B3C7, A9B3C8, A9B3C9, A9B3C10, A9B3C11, A9B3C12, A9B3C13, A9B3C14, A9B3C15, A9B3C16, A9B3C17, A9B3C18, A9B3C19, A9B3C20, A9B3C21, A9B4C1, A9B4C2, A9B4C3, A9B4C4, A9B4C5, A9B4C6, A9B4C7, A9B4C8, A9B4C9, A9B4C10, A9B4C11, A9B4C12, A9B4C13, A9B4C14, A9B4C15, A9B4C16, A9B4C17, A9B4C18, A9B4C19, A9B4C20, A9B4C21, A9B5C1, A9B5C2, A9B5C3, A9B5C4, A9B5C5, A9B5C6, A9B5C7, A9B5C8, A9B5C9, A9B5C10, A9B5C11, A9B5C12, A9B5C13, A9B5C14, A9 B5C15, A9B5C16, A9B5C17, A9B5C18, A9B5C19, A9B5C20, A9B5C21, A9B6C1, A9B6C2, A9B6C3, A9B6C4, A9B6C5, A9B6C6, A9B6C7, A9B6C8, A9B6C9, A9B6C10, A9B6C10

- 113 040861

A9B6C13, A9B6C14, A9B6C15, A9B6C16, A9B6C17, A9B6C18, A9B6C19, A9B6C20, A9B6C21, A9B7C1, A9B7C2, A9B7C3, A9B7C4, A9B7C5, A9B7C6, A9B7C7, A9B7C8, A9B7C9, A9B7C10, A9B7C11, A9B7C12, A9B7C13, A9B7C14, A9B7C15, A9B7C16, A9B7C17, A9B7C18, A9B7C19, A9B7C20, A9B7C21, A9B8C1, A9B8C2, A9B8C3, A9B8C4, A9B8C5, A9B8C6, A9B8C7, A9B8C8, A9B8C9, A9B8C10, A9B8C11, A9B8C12, A9B8C13, A9B8C14, A9B8C15, A9B8C16, A9B8C17, A9B8C18, A9B8C19, A9B8C20, A9B8C21, A9B9C1, A9B9C2, A9B9C3, A9B9C4, A9B9C5, A9B9C6, A9B9C7, A9B9C8, A9B9C9, A9B9C10, A9B9C11, A9B9C12, A9B9C13, A9B9C14, A9B9C15, A9B9C16, A9B9C17, A9B9C18, A9B9C19, A9B9C20, A9B9C21, A9B10C1, A9B10C2, A9B10C3, A9B10C4, A9B10C5, A9B10C6, A9B10C7, A9B10C8, A9B10C9, A9B10C10, A9B10C11, A9B10C12, A9B10C13, A9B10C14, A9B10C15, A9B10C16, A9B10C17, A9B10C18, A9B10C19, A9B10C20, A9B10C21, A9B11C1, A9B11C2, A9B11C3, A9B11C4, A9B11C5, A9B11C6, A9B11C7, A9B11C8, A9B11C9, A9B11C10, A9B11C11, A9B11C12, A9B11C13, A9B11C14, A9B11C15, A9B11C16, A9B11C17, A9B11C18, A9B11C1 9, A9B11C20, A9B11C21, A9B12C1, A9B12C2, A9B12C3, A9B12C4, A9B12C5, A9B12C6, A9B12C7, A9B12C8, A9B12C9, A9B12C10, A9B12C11, A9B12C12, A9B12C13, A9B12C14, A9B12C15, A9B12C16, A9B12C17, A9B12C18, A9B12C19, A9B12C20, A9B12C21, A10B1C1, A10B1C2, A10B1C3, A10B1C4, A10B1C5, A10B1C6, A10B1C7, A10B1C8, A10B1C9, A10B1C10, A10B1C11, A10B1C12, A10B1C13, A10B1C14, A10B1C15, A10B1C16, A10B1C17, A10B1C18, A10B1C19, A10B1C20, A10B1C21, A10B2C1, A10B2C2, A10B2C3, A10B2C4, A10B2C5, A10B2C6, A10B2C7, A10B2C8, A10B2C9, A10B2C10, A10B2C11, A10B2C12, A10B2C13, A10B2C14, A10B2C15, A10B2C16, A10B2C17, A10B2C18, A10B2C19, A10B2C20, A10B2C21, A10B3C1, A10B3C2, A10B3C3, A10B3C4, A10B3C5, A10B3C6, A10B3C7, A10B3C8, A10B3C9, A10B3C10, A10B3C11, A10B3C12, A10B3C13, A10B3C14, A10B3C15, A10B3C16, A10B3C17, A10B3C18, A10B3C19, A10B3C20, A10B3C21, A10B4C1, A10B4C2, A10B4C3, A10B4C4, A10B4C5, A10B4C6, A10B4C7, A10B4C8, A10B4C9, A10B4C10, A10B4C11, A10B4C12, A10B4C13, A10B4C14, A10B4C15, A10B4C16, A10B4C17, A10B4C18, A1 0B4C19, A10B4C20, A10B4C21, A10B5C1, A10B5C2, A10B5C3, A10B5C4, A10B5C5, A10B5C6, A10B5C7, A10B5C8, A10B5C9, A10B5C10, A10B5C11, A10B5C12, A10B5C13, A10B5C14, A10B5C15,

- 114 040861

A10B5C16, A10B5C17, A10B5C18, A10B5C19, A10B5C20, A10B5C21, A10B6C1, A10B6C2, A10B6C3, A10B6C4, A10B6C5, A10B6C6, A10B6C7, A10B6C8, A10B6C9, A10B6C10, A10B6C11, A10B6C12, A10B6C13, A10B6C14, A10B6C15, A10B6C16, A10B6C17, A10B6C18, A10B6C19, A10B6C20, A10B6C21, A10B7C1, A10B7C2, A10B7C3, A10B7C4, A10B7C5, A10B7C6, A10B7C7, A10B7C8, A10B7C9, A10B7C10, A10B7C11, A10B7C12, A10B7C13, A10B7C14, A10B7C15, A10B7C16, A10B7C17, A10B7C18, A10B7C19, A10B7C20, A10B7C21, A10B8C1, A10B8C2, A10B8C3, A10B8C4, A10B8C5, A10B8C6, A10B8C7, A10B8C8, A10B8C9, A10B8C10, A10B8C11, A10B8C12, A10B8C13, A10B8C14, A10B8C15, A10B8C16, A10B8C17, A10B8C18, A10B8C19, A10B8C20, A10B8C21, A10B9C1, A10B9C2, A10B9C3, A10B9C4, A10B9C5, A10B9C6, A10B9C7, A10B9C8, A10B9C9, A10B9C10, A10B9C11, A10B9C12, A10B9C13, A10B9C14, A10B9C15, A10B9C16, A10B9C17, A10B9C18, A10B9C19, A10B9C20, A10B9C21, A10B10C1, A10B10C2, A10B10C3, A10B10C4, A10B10C5, A10B10C6, A10B10C7, A10B10C8, A10B10C9, A10B10C10, A10B10C11, A10B10C12, A10B10C13, A1 0B10C14, A10B10C15, A10B10C16, A10B10C17, A10B10C18, A10B10C19, A10B10C20, A10B10C21, A10B11C1, A10B11C2, A10B11C3, A10B11C4, A10B11C5, A10B11C6, A10B11C7, A10B11C8, A10B11C9, A10B11C10, A10B11C11, A10B11C12, A10B11C13, A10B11C14, A10B11C15, A10B11C16, A10B11C17, A10B11C18, A10B11C19, A10B11C20, A10B11C21, A10B12C1, A10B12C2, A10B12C3, A10B12C4, A10B12C5, A10B12C6, A10B12C7, A10B12C8, A10B12C9, A10B12C10, A10B12C11, A10B12C12, A10B12C13, A10B12C14, A10B12C15, A10B12C16, A10B12C17, A10B12C18, A10B12C19, A10B12C20, A10B12C21, A11B1C1, A11B1C2, A11B1C3, A11B1C4, A11B1C5, A11B1C6, A11B1C7, A11B1C8, A11B1C9, A11B1C10, A11B1C11, A11B1C12, A11B1C13, A11B1C14, A11B1C15, A11B1C16, A11B1C17, A11B1C18, A11B1C19, A11B1C20, A11B1C21, A11B2C1, A11B2C2, A11B2C3, A11B2C4, A11B2C5, A11B2C6, A11B2C7, A11B2C8, A11B2C9, A11B2C10, A11B2C11, A11B2C12, A11B2C13, A11B2C14, A11B2C15, A11B2C16, A11B2C17, A11B2C18, A11B2C19, A11B2C20, A11B2C21, A11B3C1, A11B3C2, A11B3C3, A11B3C4, A11B3C5, A11B3C6, A11B3C7, A11B3 C8 A11B3C9 A11B3C10 A11B3C11 A11B3C12 A11B3C13 A11B3C14 A11B3C15

- 115 040861

A11B4C4, A11B4C5, A11B4C6, A11B4C7, A11B4C8, A11B4C9, A11B4C10, A11B4C11, A11B4C12, A11B4C13, A11B4C14, A11B4C15, A11B4C16,

A11B4C17, A11B4C18, A11B4C19, A11B4C20, A11B4C21, A11B5C1,

A11B5C2, A11B5C3, A11B5C4, A11B5C5, A11B5C6, A11B5C7, A11B5C8, A11B5C9, A11B5C10, A11B5C11, A11B5C12, A11B5C13, A11B5C14,

A11B5C15, A11B5C16, A11B5C17, A11B5C18, A11B5C19, A11B5C20,

A11B5C21, A11B6C1, A11B6C2, A11B6C3, A11B6C4, A11B6C5, A11B6C6, A11B6C7, A11B6C8, A11B6C9, A11B6C10, A11B6C11, A11B6C12,

A11B6C13, A11B6C14, A11B6C15, A11B6C16, A11B6C17, A11B6C18,

A11B6C19, A11B6C20, A11B6C21, A11B7C1, A11B7C2, A11B7C3,

A11B7C4, A11B7C5, A11B7C6, A11B7C7, A11B7C8, A11B7C9, A11B7C10, A11B7C11, A11B7C12, A11B7C13, A11B7C14, A11B7C15, A11B7C16,

A11B7C17, A11B7C18, A11B7C19, A11B7C20, A11B7C21, A11B8C1,

A11B8C2, A11B8C3, A11B8C4, A11B8C5, A11B8C6, A11B8C7, A11B8C8, A11B8C9, A11B8C10, A11B8C11, A11B8C12, A11B8C13, A11B8C14,

A11B8C15, A11B8C16, A11B8C17, A11B8C18, A11B8C19, A11B8C20,

A11B8C21, A11B9C1, A11B9C2, A11B9C3, A11B9C4, A11B9C5, A11B9C6, A11B9C7, A11B9C8, A11B9C9, A11B9C10, A11B9C11, A11B9C12,

A11B9C13, A11B9C14, A11B9C15, A11B9C16, A11B9C17, A11B9C18,

A11B9C19, A11B9C20, A11B9C21, A11B10C1, A11B10C2, A11B10C3,

A11B10C4, A11B10C5, A11B10C6, A11B10C7, A11B10C8, A11B10C9,

A11B10C10, A11B10C11, A11B10C12, A11B10C13, A11B10C14, A11B10C15, A11B10C16, A11B10C17, A11B10C18, A11B10C19, A11B10C20, A11B10C21, A11B11C1, A11B11C2, A11B11C3, A11B11C4,

A11B11C5, A11B11C6, A11B11C7, A11B11C8, A11B11C9, A11B11C10,

A11B11C11, A11B11C12, A11B11C13, A11B11C14, A11B11C15, A11B11C16, A11B11C17, A11B11C18, A11B11C19, A11B11C20, A11B11C21, A11B12C1, A11B12C2, A11B12C3, A11B12C4, A11B12C5,

A11B12C6, A11B12C7, A11B12C8, A11B12C9, A11B12C10, A11B12C11,

A11B12C12, A11B12C13, A11B12C14, A11B12C15, A11B12C16,

A11B12C17, A11B12C18, A11B12C19, A11B12C20 or A11B12C21.

Illustrative means used in combinations.

Described herein are methods and compositions that include a combination of one, two, or more of:

(i) an agent that enhances the presentation of an antigen (eg, tumor antigen);

(ii) an agent that enhances an effector cell response (eg, activation and/or mobilization of B cells and/or T cells); or (iii) an agent that reduces tumor immunosuppression, thereby treating a disorder, eg, a hyperproliferative condition or disorder (eg, cancer).

In some embodiments, one or more of (i), (ii), and/or (iii) described herein may be used in combination with a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule as described in present description).

Illustrative means that can be used in these combinations are presented in the present description.

Exemplary STING agonists.

In one embodiment, the combination includes a STING agonist. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., breast cancer, squamous cell carcinoma, melanoma, ovarian cancer, fallopian tube carcinoma, peritoneal carcinoma, soft tissue sarcoma , melanoma, breast cancer, esophageal cancer, head and neck cancer, endometrial cancer, cervical cancer, or basal cell carcinoma), eg, hematologic malignancy (eg, leukemia (eg, chronic lymphocytic leukemia (CLL)), or lymphoma (eg, , B-cell marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma)).

In some embodiments, the STING agonist is a cyclic dinucleotide, e.g., a cyclic dinucleotide containing purine or pyrimidine nucleic acids.

- 116 040861 bases (for example, the nucleic bases adenosine, guanine, uracil, thymine or cytosine). In some embodiments, the cyclic dinucleotide nucleobases comprise the same nucleobase or different nucleobases.

In some embodiments, the STING agonist comprises the nucleobase adenosine or guanosine. In some embodiments, the STING agonist comprises one adenosine nucleobase and one guanosine nucleobase. In some embodiments, the STING agonist comprises two adenosine nucleobases or two guanosine nucleobases.

In some embodiments, the implementation of the STING agonist includes a modified cyclic dinucleotide, for example, containing a modified nucleobase, a modified ribose, or a modified phosphate bond. In some embodiments, the modified cyclic dinucleotide contains a modified phosphate bond, such as a thiophosphate.

In some embodiments, the STING agonist comprises a cyclic dinucleotide (eg, a modified cyclic dinucleotide) with 2',5'- or 3',5'-phosphate bonds. In some embodiments, the STING agonist comprises a cyclic dinucleotide (eg, a modified cyclic dinucleotide) with Rp or Sp stereochemistry around phosphate bonds.

In some embodiments, the STING agonist is Rp,Rp-dithio-2',3'c-diAMP (e.g., Rp,Rp-dithio-c-[A(2',5')pA(3',5') p]), or its cyclic dinucleotide analogue. In some embodiments, the STING agonist is a compound shown in US Patent Publication No. US2015/0056224 (eg, the compound in Figure 2c, eg, compound 21 or compound 22). In some embodiments, the STING agonist is c[G(2',5')pg(3',5')p], its O-substituted dithioribose derivative, or the compound shown in FIG. 4 PCT Publication Nos. WO 2014/189805 and WO 2014/189806. In some embodiments, the STING agonist is G-[A(2',5')pA(3',5')p] or an O-substituted dithioribose derivative thereof, or is the compound shown in FIG. 5 PCT Publications No. WO 2014/189805 and WO 2014/189806. In some embodiments, the STING agonist is c[G(2',5')pA(3',5')p] or an O-substituted dithiorebose derivative thereof, or is the compound shown in FIG. 5 PCT Publications No. WO 2014/189805 and WO 2014/189806. In some embodiments, the STING agonist is 2'-O-propargyl-cyclic[A(2',5')pA(3',5')p] (2'-O-propargyl-ML-CDA) or a compound shown in FIG. 7 of PCT Publication No. WO 2014/189806.

Other exemplary STING agonists are described in, for example, PCT Publication Nos. WO 2014/189805 and WO 2014/189806, and US Publication No. 2015/0056225.

Illustrative TLR agonists.

In one embodiment, the combination described herein comprises a Toll-like receptor (TLR) agonist. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., breast cancer, squamous cell carcinoma, melanoma, ovarian cancer, fallopian tube carcinoma, peritoneal carcinoma, soft tissue sarcoma , melanoma, breast cancer, esophageal cancer, head and neck cancer, endometrial cancer, cervical cancer, or basal cell carcinoma), eg, hematologic malignancy (eg, leukemia (eg, chronic lymphocytic leukemia (CLL), or lymphoma ( eg B-cell marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma)).

TLRs are a family of pattern recognition receptors that were originally identified as sensors in the innate immune system that recognize microbial pathogens. In humans, TLRs include TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, and TLR-10. TLR-1, -2, -4, -5 and -6 are expressed on the cell surface and TLR-3, -7/8 and -9 are expressed in the ER compartment. Subgroups of human dendritic cells can be identified based on different TLR expression patterns. The myeloid or traditional human dendritic cell subgroup expresses TLR 1-8 and the plasmacytoid dendritic cell subset expresses only TLR-7 and TLR-9. Binding of the ligand to TLR activates a cascade of intracellular signal transduction cascades that induce the production of factors involved in inflammation and immunity. Upon stimulation, the myeloid subset and the plasmacytoid subset of human dendritic cells result in the priming of antigen-specific CD4+ and CD8+ T cells and activation of NK cells and T cells, respectively.

In some embodiments, the TLR agonist is selected from one or more of a TLR-1 agonist, a TLR-2 agonist, a TLR-3 agonist, a TLR-4 agonist, a TLR-5 agonist, a TLR-6 agonist, a TLR-7 agonist, a TLR- 8, a TLR-9 agonist, a TLR-10 agonist, a TLR-1/2 agonist, a TLR-2/6 agonist, or a TLR-7/8 agonist. In one embodiment, the TLR agonist is a TLR7 agonist.

In some embodiments, the TLR agonist is imiquimod or 3-(2methylpropyl)-3,5,8-triazatricyclo[7.4.0.02.6]trideca-1(9),2(6),4,7,10,12- hexaene-7-amine. Imiquimod

- 117 040861 or 3-(2-methylpropyl)-3,5,8-triazatricyclo[7.4.0.02.6]trideca-1(9),2(6),4,7,10,12-hexaen-7- the amine can bind and activate TLR-7 and/or TLR-8.

In some embodiments, the TLR agonist is 852A. 852A is described, for example, in Inglefield et al., J Interferon Cytokine Res. 2008;28(4):253-63. 852A can bind and activate TLR-7 and/or TLR-8.

In some embodiments, the TLR agonist is Bacillus Calmette-Guérin (BCG). BCG can bind and activate TLR-9.

In some embodiments, the TLR agonist is EMD 120108. EMD 120108 is a synthetic oligonucleotide containing a phosphorothioate oligodeoxynucleotide. EMD 1201081 can bind and activate TLR-9, for example, in monocytes/macrophages, plasmacytoid dendritic cells (DCs), and B cells, initiating immune signaling cascades, activating B cells, and inducing cytokine production by T helper cells.

In some embodiments, the TLR agonist is IMO-2055. IMO-2055 is a synthetic oligonucleotide containing unmethylated CpG dinucleotides. By mimicking unmethylated CpG sequences in bacterial DNA, IMO-2055 can bind and activate TLR-9, for example, in monocytes/macrophages, plasmacytoid dendritic cells (DCs), and B cells, leading to the initiation of immune signaling cascades, and activation of B cells and DC, and induction of cytokine production by T-helper cells.

Other exemplary TLR agonists that may be used in combination include, for example, TLR-1/2 agonists (eg, Pam3Cys), TLR-2 agonists (eg, CFA, MALP2, Pam2Cys, FSL-1 or Hib-OMPC), agonists TLR-3 (e.g., polyribosine:polyribocytidylic acid (poly IiC), polyadenosine-polyuridic acid (poly AU), poly-inosine-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Hiltonol®)), TLR-4 agonists (e.g., monophosphoryl lipid A (MPL), LPS, sialyl-Tn (STn)), TLR-5 agonists (eg bacterial flagellin), TLR-7 agonists (eg imiquimod), TLR-7/8 agonists (eg resiquimod or loxoribin) and TLR-9 agonists (eg unmethylated CpG dinucleotide (CpG-ODN)).

In another embodiment, a TLR agonist is used in combination with a GITR agonist, for example as described in WO 2004060319 and International Publication No. WO 2014012479.

Exemplary VEGFR Inhibitors.

In one embodiment, the combination described herein comprises a vascular endothelial growth factor (VEGF) receptor inhibitor (eg, an inhibitor of one or more of the VEGFRs (eg, VEGFR-1, VEGFR-2, VEGFR-3) or VEGF). In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., melanoma, breast cancer, colon cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), kidney cancer (eg, renal cell carcinoma), liver cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, or gastric cancer), eg, hematological malignancy (eg, lymphoma).

In some embodiments, the VEGFR inhibitor is vatalanib succinate (compound A47) or a compound described in EP 296122.

In some embodiments, the VEGFR inhibitor is an inhibitor of one or more of VEGFR-2, PDGFR-beta, KIT, or Raf kinase C, 1-methyl-5-((2-(5-(trifluoromethyl)-1-nimidazol-2-yl )pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine (Compound A37) or the compound described in PCT Publication No. WO 2007/030377.

Other exemplary VEGFR cascade inhibitors that can be used in the combinations described herein include, for example, bevacizumab (AVASTIN®), axitinib (INLYTA®); brivaniba alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5methylpyrrolo[2,1-C[1,2 ,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (NEXAVAR®); pazopanib (VOTRIENT®); sunitinib malate (SUTENT®); cediranib (AZD2171, CAS 288383-20-1); vargatef (BIBF1120, CAS 928326-83-4); foretinib (GSK1363089); telatinib (BAY57-9352, CAS 332012-405); apatinib (YN968D1, CAS 811803-05-1); imatinib (GLEEVEC®); ponatinib (AP24534, CAS 94331970-8); tivozanib (AV951, CAS 475108-18-0); regorafenib (BAY73-4506, CAS 755037-03-7); vatalanib dihydrochloride (RTK787, CAS 212141-51-0); brivanib (BMS-540215, CAS 649735-46-6); vandetanib (CAPRELSA® or AZD6474); motesaniba diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide described in PCT Publication No. WO 02/066470); dovitinib dilactic acid (TKI258, CAS 852433-84-2); linfanib (ABT869, CAS 796967-16-3); cabozantinib (XL184, CAS 849217-68-1); lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(l,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5yl)methyl)piperidin-3-ol (BMS690514); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine ( XL647, CAS 781613-23-8); 4- 118 040861 methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3(trifluoromethyl)phenyl] benzamide (BHG712, CAS 940310-85-0); aflibercept (EYLEA®); and endostatin (ENDOSTAR®).

Exemplary anti-VEGF antibodies include, but are not limited to, a monoclonal antibody that binds to the same epitope as the anti-VEGF monoclonal antibody A4.6.1 produced by ATCC hybridoma HB 10709; recombinant humanized anti-VEGF monoclonal antibody prepared according to Presta et al. (1997) Cancer Res. 57:4593-4599. In one embodiment, the anti-VEGF antibody is bevacizumab (BV), also known as rhuMAb VEGF or AVASTIN®. It contains mutant human IgG1 framework regions and antigen-binding complementarity-determining regions from the mouse anti-hVEGF monoclonal antibody A.4.6.1, which blocks the binding of human VEGF to its receptors. Bevacizumab and other humanized anti-VEGF antibodies are further described in US Pat. No. 6,884,879 issued February 26, 2005. Additional antibodies include antibodies of the G6 or B20 series (e.g., G631, B20-4.1) as described in PCT Publication No. WO 2005/012359, PCT Publication No. WO 2005/044853, the contents of these patent applications are hereby incorporated by reference in their entirety. volume. For additional antibodies, see US Patents No. 7060269, 6582959, 6703020, 6054297, Wo 98/45332, Wo 96/30046, Wo 94/10202, EP 06668688V1, Publishing of US Patent Applications No. 200600360, 20050186208, 200302020899, 200399, 20020199, 20020199, 20020199, 20020, 20020, 2002020, 20020201, 20020199, 20020199, 20020199, 20020199, 20020199, 20020199, 20020199, 20020199, 20020199, 20020199, 20020199, 2002020 ; and Popkov et al, Journal of Immunological Methods 288: 149-164 (2004). Other antibodies include antibodies that bind to a functional epitope on human VEGF containing residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103 and C104 or alternatively containing residues F17, Y21, Q22, Y25, D63, 183 and Q89.

Exemplary c-MET inhibitors.

In one embodiment, the combination described herein includes a c-MET inhibitor. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., non-small cell lung cancer, pancreatic cancer, liver cancer, thyroid cancer, brain tumor (e.g., glioblastoma ), kidney cancer (eg, renal cell carcinoma), head and neck cancer (eg, squamous cell carcinoma of the head of the neck)).

In some embodiments, the c-MET inhibitor is Compound A17 or the compound described in US Pat. Nos. 7,767,675 and 8,420,645). c-MET, a receptor tyrosine kinase, overexpressed or mutated in many types of tumor cells, plays a key role in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. Inhibition of c-MET can induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-MET protein.

In some embodiments, the c-MET inhibitor is JNJ-38877605. JNJ38877605 is an orally available small molecule c-Met inhibitor. JNJ38877605 binds selectively to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signaling cascades.

In some embodiments, the c-Met inhibitor is AMG 208. AMG 208 is a selective small molecule c-MET inhibitor. AMG 208 inhibits ligand-dependent and ligand-independent activation of c-MET by inhibiting its tyrosine kinase activity, which can lead to inhibition of cell growth in tumors that overexpress c-Met.

In some embodiments, the c-Met inhibitor is AMG 337. AMG 337 is an orally bioavailable c-Met inhibitor. AMG 337 selectively binds to cMET, thereby disrupting the c-MET signaling cascades.

In some embodiments, the c-Met inhibitor is LY2801653. LY2801653 is an orally available small molecule c-Met inhibitor. LY2801653 binds selectively to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signaling cascades.

In some embodiments, the c-Met inhibitor is MSC2156119J. MSC2156119J is an orally bioavailable c-Met inhibitor. MSC2156119J binds selectively to c-MET, inhibits c-MET phosphorylation, and disrupts c-Met mediated signaling cascades.

In some embodiments, the c-MET inhibitor is capmatinib. Capmatinib is also known as INCB028060. Capmatinib is an orally bioavailable c-MET inhibitor. Capmatinib binds selectively to c-Met, thereby inhibiting cMet phosphorylation and disrupting c-Met signaling cascades.

In some embodiments, the c-MET inhibitor is crizotinib. Crizotinib is also known as PF-02341066. Crizotinib is an orally available aminopyridine tyrosine kinase receptor anaplastic lymphoma kinase (ALK) and c-Met/hepatocyte growth factor receptor (HGFR) inhibitor. Crizotinib binds to and inhibits ALK kinase and ALK fusion proteins in an ATP-competitive manner. In addition, crizotinib inhibits cMet kinase and disrupts the c-Met signaling cascade. In general, this agent inhibits the growth of tumor cells.

In some embodiments, the implementation of the c-MET inhibitor is a golvatinib. Golvatinib is an orally bioavailable dual c-MET and VEGFR-2 kinase inhibitor with potential antineoplastic activity. Golvatinib binds and inhibits both c-MET and VEGFR-2 activity, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases.

In some embodiments, the c-MET inhibitor is tivantinib. Tivantinib is also known as ARQ 197. Tivantinib is an orally bioavailable small molecule c-MET inhibitor. Tivantinib binds to c-MET protein and disrupts c-Met signaling cascades, which can induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-Met protein.

Exemplary TGFb inhibitors.

In one embodiment, the combination described herein comprises a transforming growth factor-beta (TGF-β) inhibitor. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., brain cancer (e.g., glioma), melanoma, kidney cancer (e.g., renal cell carcinoma), pleural malignant mesothelioma (eg, recurrent pleural malignant mesothelioma) or breast cancer (eg, metastatic breast cancer)).

In some embodiments, the TGF-β inhibitor is fresolimumab (CAS accession number: 948564-73-6). Fresolimumab is also known as GC1008. Fresolimumab is a human monoclonal antibody that binds and inhibits TGF-beta isoforms 1, 2, and 3.

The heavy chain of fresolimumab has the amino acid sequence (SEQ ID NO: 300):

QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPGQGLEWMGGVIPIVDIANYAQRF

KGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLLVLDAMDYWGQGTLVTVSSASTKGPSV

FPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRT

PEVTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYK

CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK.

The light chain of fresolimumab has the amino acid sequence (SEQ ID NO: 301):

ETVLTQSPGTLSLSPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPGIPDRFS

GSGSGTDFTLTISRLEPEDFAVYYCQQYADSPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKS

GTASWCLLNNFYPREAKVQWKVflHKLQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV

YACEVTHQGLSSPVTKSFNRGEC.

Fresolimumab is described, for example, in WO 2006/086469, US 8383780 and US 8591901.

In some embodiments, the TGF-β inhibitor is XOMA 089. XOMA 089 is also known as XPA.42.089. XOMA 089 is a fully human monoclonal antibody that specifically binds and neutralizes TGF-beta 1 and 2 ligands.

The XOMA 089 heavy chain variable region has the amino acid sequence (SEQ ID NO: 302):

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKF

QGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWGQGTLVTVSS (described as SEQ ID NO: 6 in WO 2012/167143). The light chain variable region of XOMA 089 has the amino acid sequence (SEQ ID NO: 303):

SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIPERISGS

NSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLG (described as SEQ ID NO: 8 in WO 2012/167143).

Exemplary IDO/TDO Inhibitors.

In one embodiment, the combination described herein includes an inhibitor of indolamine-2,3-dioxygenase (IDO) and/or tryptophan-2,3-dioxygenase (TDO). In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., melanoma, non-small cell lung cancer, colon cancer, head and neck squamous cell carcinoma, ovarian cancer, peritoneal cancer, fallopian tube cancer, breast cancer (eg, metastatic or HER2-negative breast cancer)), eg, hematologic malignancy (eg, lymphoma, eg, non-Hodgkin's lymphoma or Hodgkin's lymphoma (eg, diffuse large B-cell lymphoma ( DLBCL))).

In some embodiments, the IDO/TDO inhibitor is selected from (4E)-4-[(3-chloro-4fluoroanilino)nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB24360), indoxymod (1-methyl -D-tryptophan) or a-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as

NLG919).

In some embodiments, the IDO/TDO inhibitor is epacadostat (CAS accession number: 1204669-58-8). Epacadostat is also known as INCB24360 or INCB024360 (Incyte). Epacadostat is a potent and selective inhibitor of indolamine 2,3-dioxygenase (IDO1) with an IC ₅₀ of 10 nM, highly selective for other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO).

In some embodiments, the IDO/TDO inhibitor is indoxymod (New Link Genetics). Indoxymod, the D-isomer of 1-methyl-tryptophan, is an orally administered small molecule inhibitor of the indolamine-2,3-dioxygenase (IDO) cascade that disrupts the mechanisms by which tumors escape immune-mediated destruction.

In some embodiments, the IDO/TDO inhibitor is NLG919 (New Link Genetics). NLG919 is a potent inhibitor of the IDO (indolamine-(2,3)-dioxygenase) cascade with a Ki/EC ₅₀ of 7 nM/75 nM in cell-free assays.

In some embodiments, the IDO/TDO inhibitor is F001287 (Flexus/BMS). F001287 is a small molecule inhibitor of indolamine 2,3-dioxygenase 1 (IDO1).

Exemplary A2AR Antagonists.

In one embodiment, the combination described herein comprises an adenosine A2a receptor (A2aR) antagonist (eg, an inhibitor of the A2aR cascade, eg, an adenosine inhibitor, eg, an A2aR or CD-73 inhibitor). In some embodiments, the combination is used to treat a cancer, such as the cancer described herein.

In some embodiments, the A2aR antagonist is istradifillin (CAS accession number: 155270-99-8). Istradefillin is also known as KW-6002 or 8-[(E)-2-(3,4dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6- dione. Istradephyllin is described, for example, in LeWitt et al. (2008) Annals of Neurology 63(3): 295-302).

In some embodiments, the A2aR antagonist is tosadenant (Biotie). Tosadenant is also known as SYN115 or 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzothiazol2-yl)-4-methylpiperidine-1-carboxamide. Tosadenant blocks the effect of endogenous adenosine on A2a receptors, which leads to an increase in the effect of dopamine on the D2 receptor and inhibition of the effect of glutamate on the mGluR5 receptor. For example, in some embodiments, the A2aR antagonist is a preladenant (CAS accession number: 377727-87-2). The preladenant is also known as SCH 420814 or 2-(2-furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7Hpyrazolo[4,3-e][1 ,2,4]triazolo[1,5-c]pyrimidine-5-amine. Preladenant has been developed as a drug that acts as a potent and selective adenosine A2A receptor antagonist.

In some embodiments, the A2aR antagonist is vipadenan. Vipadenan is also known as BIIB014, V2006 or 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5d]pyrimidine-5-amine. For example, in some embodiments, the A2aR antagonist is PBF-509 (Palobiofarma). For example, in some embodiments, an A2aR antagonist, such as PBF-509, is administered at a daily dose of about 80 mg, 160 mg, or 240 mg.

Other exemplary A2aR antagonists include, for example, ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, or ZM-241.385.

In some embodiments, the A2aR antagonist is an A2aR cascade antagonist (eg, a CD-73 inhibitor, eg, an anti-CD73 antibody) MEDI9447. MEDI9447 is a monoclonal antibody specific for CD73. Targeting extracellular adenosine production via CD73 may reduce the immunosuppressive effects of adenosine. MEDI9447 has been reported to have a number of activities, such as inhibition of CD73 ectonucleotidase activity, mitigation of AMP-mediated lymphocyte suppression, and inhibition of syngeneic tumor growth. MEDI9447 can trigger changes in both myeloid and lymphoid infiltrating leukocyte populations in the tumor microenvironment. These changes include, for example, an increase in the level of CD8 effector cells and activated macrophages, as well as a decrease in the proportions of myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes.

Illustrative oncolytic viruses.

In some embodiments, the combination as described herein includes an oncolytic virus. In some embodiments, oncolytic viruses are capable of selectively replicating in malignant cells and triggering their death or growth retardation. In some cases, oncolytic viruses have no or minimal effect on non-cancerous cells. Oncolytic virus includes, but is not limited to, oncolytic adenovirus, oncolytic herpes simplex viruses, oncolytic retrovirus, oncolytic parvovirus, oncolytic vaccinia virus, oncolytic Sinbis virus, oncolytic influenza virus, or oncolytic RNA virus (e.g., oncolytic reovirus, oncolytic Newcastle disease virus). (NDV), measles oncolytic virus, or oncolytic vesicular stomatitis virus (VSV)).

In some embodiments, the oncolytic virus is a virus, such as the recombinant oncolytic virus described in US2010/0178684 A1, which is incorporated herein by reference in its entirety.

In some embodiments, the recombinant oncolytic virus contains a nucleic acid sequence (e.g., a heterologous nucleic acid sequence) encoding an inhibitor of an immune or inflammatory response, for example, as described in US2010/0178684 A1, incorporated herein by reference in its entirety. In some embodiments, the recombinant oncolytic virus, e.g., oncolytic NDV, contains a pro-apoptotic protein (e.g., apoptin), a cytokine (e.g., GM-CSF, CSF, interferon-gamma, interleukin-2 (IL-2), tumor necrosis factor-alpha ), an immunoglobulin (eg, an anti-fibronectin ED-B antibody), a tumor-associated antigen, a bispecific adapter protein (eg, a bispecific antibody or antibody fragment directed against the NDV HN protein and a costimulatory T-cell receptor such as CD3 or CD28; or a fusion protein between human IL-2 and a single chain antibody directed against NDV HN protein). See, for example, Zamarin et al., Future Microbiol. 7.3(2012):347-67, incorporated herein by reference in its entirety. In some embodiments, the oncolytic virus is a chimeric oncolytic NDV described in US 8591881 B2, US 2012/0122185 A1 or US 2014/0271677 A1, each of which is incorporated herein by reference in its entirety.

In some embodiments, the oncolytic virus includes a conditionally replicating adenovirus (CRAd) that is engineered to replicate exclusively in malignant cells. See, for example, Alemany et al., Nature Biotechnol. 18 (2000): 723-27. In some embodiments, the implementation of the oncolytic adenovirus includes the virus described in table. 1 on page 725 Alemany et al., incorporated herein by reference in its entirety.

Illustrative oncolytic viruses include, but are not limited to, the following:

oncolytic adenovirus group B (ColoAdl) (PsiOxus Therapeutics Ltd.) (see, for example, clinical trial identification number: NCT02053220);

ONCOS-102 (formerly called CGTG-102), which is an adenovirus containing granulocyte-macrophage colony-stimulating factor (GM-CSF) (Oncos Therapeutics) (see, for example, clinical trial identifier: NCT01598129);

VCN-01, which is a genetically modified human oncolytic adenovirus encoding human hyaluronidase PH20 (VCN Biosciences, S.L.) (see, for example, clinical trial identifiers: NCT02045602 and NCT02045589);

the conditionally replicative adenovirus ICOVIR-5, which is a virus derived from wild-type human adenovirus serotype 5 (Had5) modified to selectively replicate in malignant cells deregulated in the retinoblastoma/E2F cascade (Institut Catala d'Oncologia) (see e.g. , clinical trial identifier: NCT01864759);

celivir, which contains bone marrow-derived autologous mesenchymal stem cells (MSC) infected with ICOVIR5, an oncolytic adenovirus (Hospital Infantil Universitario Nino Jesus, Madrid, Spain/ Ramon Alemany) (see, for example, clinical trial identifier: NCT01844661);

CG0070, which is a conditionally replicating oncolytic adenovirus serotype 5 (Ad5) in which the human E2F-1 promoter controls the expression of essential E1a viral genes, thereby limiting viral replication and cytotoxicity against tumor cells with a defect in the Rb cascade (Cold Genesys, Inc. .) (see, for example, clinical trial identifier: NCT02143804); or

DNX-2401 (formerly Delta-24-RGD), which is an adenovirus engineered to replicate selectively in cells with a defect in the retinoblastoma (Rb) cascade and to infect cells that more efficiently express certain RGD-binding integrins (Clinica Universidad de Navarra , Universidad de Navarra/DNAtrix, Inc.) (see, for example, clinical trial identifier: NCT01956734).

In some embodiments, the oncolytic virus described herein is administered by injection, such as subcutaneous, intra-arterial, intravenous, intramuscular, intrathecal, or intraperitoneal injection. In some embodiments, the oncolytic virus described herein is administered intratumorally, transdermally, transmucosally, orally, intranasally, or via pulmonary administration.

Illustrative vaccines, for example, scaffold vaccines.

- 122 040861

In one embodiment, the combination described herein includes a vaccine, such as a scaffold vaccine. In some embodiments, the combination is used to treat a cancer, such as the cancer described herein.

Cancer vaccines are described, for example, in PCT Publication Nos. WO 2007/070660 and WO 2012/167230, EP 1960009 B1, US Patent Nos. US 8067237 and US 8932583, and US Publication No. US 2011/0020216. Components that can be used in cancer vaccines (eg, implantable scaffold materials) are described, for example, in PCT Publication Nos. WO 2009/102465 and WO 2013/106852. Methods that can be used to administer cancer vaccines are described, for example, in PCT Publication Nos. WO 2013/158673, WO 2012/048165 and WO 2012/149358.

In some embodiments, the cancer vaccine comprises a macroporous scaffold comprising (i) cells or composition to attract cells, and (ii) a dispersal signal capable of inducing or accelerating cell migration, and (iii) a bioactive composition applied or seeded to/into scaffold that causes modification of cells attracted to the scaffold. The migration of modified cells can be accelerated by open interconnected macropores and a dispersal signal.

In some embodiments, a cancer vaccine induces an endogenous immune response to a cancer target by introducing a porous scaffold containing a recruitment composition and a target antigen composition, wherein endogenous antigen-presenting cells are recruited to the scaffold to interact with the antigen, and where said cells remain until until the dispersal signal induces an outlet into the lymph node tissue outside the scaffold, thereby stimulating the endogenous immune response to said malignant target.

In some embodiments, a cancer vaccine is used to remove target cells from a mammal using a scaffold composition.

In some embodiments, an in situ cancer vaccine is produced by recruiting cancer cells to an implanted scaffold and killing the cells using a cytotoxic agent.

In some embodiments, the scaffold component uses a cytosing guanosine oligonucleotide (CpG-ODN) that can effectively reprogram and disperse dendritic cells attracted to the scaffold and induce an effective anti-tumor response.

In some embodiments, polyinosine-polycytidylic acid (poly T:C) and/or CpG ODN are used to exhibit a synergistic effect on tumor inhibition.

In some embodiments, porous rods are used containing an immune cell recruiting compound (e.g., GM-CSF) and an immune cell activating compound (e.g., CpG ODN), and optionally containing an antigen, such as a tumor lysate, e.g., to induce an immune response. to the vaccine antigen. In some embodiments, pores that promote cell recruitment or release are formed in situ in the hydrogels following injection of the hydrogel. In some embodiments, an injectable shape-memory porous hydrogel polymer is used for administration.

In other embodiments, the combinations described herein include a cancer or neoplasm vaccine. Non-limiting examples of cancer vaccines that can be used include melanoma antigen peptides such as gp100 peptides, MAGE, Trp-2, MART1 and/or tyrosinase antigens, tumor cells transfected to express the cytokine GM-CSF, DNA based vaccines, vaccines based on RNA and vaccines based on virus transduction. The cancer vaccine may be prophylactic or therapeutic.

Many experimental strategies for vaccination against tumors have been developed (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C, 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428 Foon, K. 2000, ASCO Educational Book Spring: 730-738, 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). In one of these strategies, the vaccine is produced using autologous or allogeneic tumor cells. These cell vaccines have been shown to be most effective when tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent antigen presentation activator for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:3539-43).

The combinations described herein, such as PD-1 blockade, can be used in conjunction with a collection of recombinant tumor-expressed proteins and/or peptides to achieve an immune response to these proteins. These proteins are usually considered by the immune system as self-antigens and are thus tolerant to them. The tumor antigen may also include the protein telomerase, which is required for the synthesis of chromosome telomeres and which is expressed in more than 85% of malignant tumors 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 various ways). The tumor antigen can also be neoantigens expressed in malignant cells due to somatic mutations that change the protein sequence or create fusion proteins between two unrelated sequences (i.e. bcr-abl on the Philadelphia chromosome), or an idiotype in the case of B cell tumors.

Other tumor vaccines may include proteins from viruses involved in human cancers such as human papillomaviruses (HPV), hepatitis viruses (HBV and HCV) and Kaposi's sarcoma herpes virus (KHSV) and Epstein-Barr virus (EBV). Another form of specific tumor antigen that can be used in conjunction with PD-1 blockade is purified heat shock proteins (HSPs) isolated directly from tumor tissue. These heat shock proteins contain fragments of proteins from tumor cells and these HSPs are highly effective in delivering to antigen presenting cells to induce tumor immunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura, Y. et al (1997) Science 278:117-120).

Dendritic cells (DC) are efficient antigen-presenting cells that can be used to induce antigen-specific responses. DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCs can also be transduced by genetic means to express these tumor antigens. DCs have been fused directly to tumor cells for immunization purposes (Kugler, A. et al. (2000) Nature Medicine 6:332336). As a vaccination method, DC immunization can be effectively combined with another agent, such as PD-1 blockade, to activate more potent antitumor responses.

Exemplary bispecific T cell binding agents.

In one embodiment, the combination described herein includes a bispecific T cell binding agent. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., gastrointestinal cancer, melanoma, or lung cancer) or a hematological cancer (e.g., lymphoma (e.g., non-Hodgkin's disease). lymphoma) or leukemia (eg, acute lymphoblastic leukemia)).

Bispecific T cell binding agents (BiTE®) are a class of artificial bispecific monoclonal antibodies that can target the host's immune system, eg T cell cytotoxic activity, against malignant cells. Bispecific T cell binding agents can form a bond between T cells and tumor cells that allows T cells to exhibit cytotoxic activity against tumor cells through the production of proteins such as perforin and granzymes, regardless of the presence of MHC I or co-stimulatory molecules. These proteins enter tumor cells and initiate cell apoptosis. This action mimics the physiological processes seen during T cell attacks against tumor cells.

In some embodiments, the bispecific T cell binding agent is a fusion protein containing two single chain variable fragments (scFv) from different antibodies. In some embodiments, one of the scFvs binds to T cells, eg, via the CD3 receptor, and the other to tumor cells, eg, via a tumor-specific molecule.

In some embodiments, the bispecific T cell binding agent is an anti-NKG2A and CD138 bispecific antibody molecule, or an anti-CD3 and TCR bispecific antibody molecule. In some embodiments, the bispecific T cell binding agent is a bispecific antibody molecule that binds to CD3 and a tumor antigen (eg, EGFR, PSCA, PSMA, EpCAM, HER2, among others).

In some embodiments, the bispecific T cell-binding agent is blinatumomab (CAS Accession Number: 853426-35-4).

Blinatumomab is also known as MT103. Blinatumomab specifically targets the CD3 region for T cells and the CD19 region for B cells.

In some embodiments, the bispecific T cell binding agent is MT110. MT110 is a single chain antibody that targets EpCAM and CD3. MT110 is described, for example, in Amann et al., J Immunother. 2009; 32(5):452-64.

In some embodiments, the bispecific T cell binding agent targets melanoma-associated chondroitin sulfate proteoglycan (MCSP). In some embodiments, the bispecific T cell binding agent targets CD33. IN

- 124 040861 In some embodiments, the bispecific T cell binding agent comprises trastuzumab (targeting HER2/neu), cetuximab, or panitumumab (both of which target the EGF receptor), and a functional fragment thereof. In some embodiments, the bispecific T cell binding agent targets CD66e and EphA2.

An exemplary GITR agonist.

In one embodiment, the combination described herein includes a GITR agonist. In some embodiments, the combination is used to treat a cancer, eg, the cancer described herein, eg, a solid tumor or a hematologic cancer.

Exemplary GITR agonists include, for example, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies) such as the GITR fusion protein described in US Pat. No. 6,111,090, EP No. 0920505B1, US Pat. 2010/003118 and 2011/090754, or an anti-GITR antibody as described, for example, in US Patent No. 7025962, EP No. 1947183B1, US Patent No. 7812135, US Patent No. 8388967, US Patent No. 8591886, EP Patent No. 1866339, publications PCT No. WO 2011/028683, U.S. Patent No. 8709424, PCT Publication No. WO 2013/039954, International Publication No. WO2013/039954, U.S. Publication No. US2014/0072566, International Publication No. WO 2015/026684, pCt Publication No. WO 2005/007190, PCT Publication No. WO 2007/133822, PCT Publication No. WO 2005/055808, PCT Publication No. WO 99/40196, PCT Publication No. WO 2001/03720, PCT Publication No. WO 99/20758, U.S. Patent No. 6689607, PCT Publication No. WO 2006 /083289, PCT Publication No. WO 2005/115451, US Patent No. 7618632, PCT Publication No. WO 2011/051726, International Publication No. WO 2004060319 and International Publication No. WO 2014012479.

In one embodiment, a GITR agonist is used in combination with a PD-1 inhibitor, for example as described in WO 2015/026684.

In another embodiment, a GITR agonist is used in combination with a TLR agonist, for example as described in WO 2004060319 and International Publication No. WO 2014012479.

Immune Checkpoint Molecule Inhibitors

In one embodiment, the combinations described herein include a PD-1 inhibitor, for example, an anti-PD-1 antibody as described herein. In one embodiment, the PD-1 inhibitor combination comprises a PD-L1 inhibitor, for example, an anti-PD-L1 antibody molecule as described herein. In embodiments, the combination of anti-PD-1 antibody and anti-PD-L1 antibody is present as separate antibodies. In other embodiments, the anti-PD-1 antibody and the anti-PD-L1 antibody are present in the same antibody molecule, eg, as a bispecific or multispecific antibody molecule.

In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in US 2015/0210769, published July 30, 2015, titled Antibody Molecules to PD-1 and Uses Thereof, incorporated by reference in the full volume. In one embodiment, an anti-PD-1 antibody molecule comprises at least one or two heavy chain variable domains (optionally including a constant region), at least one or two light chain variable domains (optionally including a constant region), or both of those containing the amino acid sequence BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D or BAP049-Clone-E; or as described in Table. 1 US 2015/0210769, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences. An anti-PD-1 antibody molecule optionally contains a leader sequence from a heavy chain, a light chain, or both, as shown in Table 1. 4 US 2015/0210769; or a sequence substantially identical to it.

In another embodiment, an anti-PD-1 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, 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, BAP049-hum14, BAP049-hum15, BAP049-hum16,

BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or as described in Table. 1, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the aforementioned sequences.

In another embodiment, an anti-PD-1 antibody molecule comprises at least one, two, or three CDRs (or, collectively, all CDRs) from a heavy chain variable region comprising the amino acid sequence shown in Table 1. 1 US 2015/0210769, or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more

- 125 040861 changes, for example, amino acid substitutions or deletions, relative to the amino acid sequence shown in table. 1 or encoded by the nucleotide sequence shown in table. 1.

In another embodiment, the PD-1 antibody molecule comprises at least one, two or three CDRs (or collectively all CDRs) from the light chain variable region containing the amino acid sequence shown in Table 1. 1 US 2015/0210769 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or, collectively, all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1. In certain embodiments, the anti-PD-1 antibody molecule comprises a light chain CDR substitution, for example, one or more light chain CDR1, CDR2 and/or CDR3 substitutions. In one embodiment, an anti-PD-1 antibody molecule comprises a change in the light chain CDR3 at position 102 of the light chain variable region, e.g., a change of a cysteine residue to a tyrosine, or a change of a cysteine residue to a serine, at position 102 of the light chain variable region according to Table 1 ( e.g., SEQ ID NO: 16 or 24 for a mouse or chimeric sequence, unmodified, 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 comprises at least one, two, three, four, five, or six CDRs (or, in the aggregate, all CDRs) of the heavy and light chain variable regions comprising the amino acid sequence shown in Table 1. . 1 US 2015/0210769 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table . 1 or encoded by the nucleotide sequence shown in table. 1.

In one embodiment, an anti-PD-1 antibody molecule comprises:

(a) a heavy chain variable region (VH) containing the amino acid sequence VHCDR1 GYTFTTY (SEQ ID NO: 261) (SEQ ID NO: 4 shown in Table 1 of US 2015/0210769), the amino acid sequence VHCDR2 YPGTGG (SEQ ID NO: 262) (SEQ ID NO: 5 shown in Table 1 US 2015/0210769) and the amino acid sequence of VHCDR3 WTTGTGAY (SEQ ID NO: 263) (SEQ ID NO: 3 shown in Table 1 US 2015/0210769); and a light chain variable region (VL) containing the VLCDR1 amino acid sequence SQSLLDSGNQKNF (SEQ ID NO: 264) (SEQ ID NO: 13 described in Table 1 US 2015/0210769), the VLCDR2 amino acid sequence WAS (SEQ ID NO: 265) (SEQ ID NO: 14 described in Table 1 US 2015/0210769) and the VLCDR3 DYSYPY amino acid sequence (SEQ ID NO: 266) (SEQ ID NO: 33 described in Table 1 US 2015/0210769);

(b) VH containing the VHCDR1 amino acid sequence selected from TYWMH (SEQ ID NO: 267) (SEQ ID NO: 1 described in Table 1 of US 2015/0210769); the amino acid sequence of VHCDR2 NIYPGTGGSNFDEKFKN (SEQ ID NO: 268) (SEQ ID NO: 2 described in Table 1 of US 2015/0210769); and the amino acid sequence of VHCDR3 SEQ ID NO: 263; And

VL containing the amino acid sequence of VLCDR1 KSSQSLLDSGNQKNFLT (SEQ ID NO: 269) (SEQ ID NO: 10 described in Table 1 US 2015/0210769), the amino acid sequence of VLCDR2 WASTRES (SEQ ID NO: 270) (SEQ ID NO: 11, described in Table 1 US 2015/0210769) and the amino acid sequence VLCDR3 QNDYSYPYT (SEQ ID NO: 271) (SEQ ID NO: 32 described in Table 1 US 2015/0210769);

(c) VH containing the amino acid sequence of VHCDR1 GYTFTTYWMH (SEQ ID NO: 272) (SEQ ID NO: 224 described in US 2015/0210769), the amino acid sequence of VHCDR2 SEQ ID NO: 262, and the amino acid sequence of VHCDR3 SEQ ID NO: 263 ; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 264, the amino acid sequence of VLCDR2 SEQ ID NO: 265 and the amino acid sequence of VLCDR3 SEQ ID NO: 266; or (d) a VH containing the amino acid sequence of VHCDR1 SEQ ID NO: 272; the amino acid sequence of VHCDR2 SEQ ID NO: 268; and the amino acid sequence of VHCDR3 SEQ ID NO: 263; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 269, the amino acid sequence of VLCDR2 SEQ ID NO: 270 and the amino acid sequence of VLCDR3 SEQ ID NO: 271.

In the combinations described herein below, in another embodiment, the anti-PD-1 antibody molecule comprises (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 267, SEQ ID NO: 261, or SEQ ID NO: 272; the amino acid sequence of VHCDR2 SEQ ID NO: 268 or SEQ ID NO: 262; and the amino acid sequence of VHCDR3 SEQ ID NO: 263; and (ii) a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 269 or SEQ ID NO: 264, the VLCDR2 amino acid sequence of SEQ ID NO: 270 or SEQ ID NO: 265, and the VLCDR3 amino acid sequence of SEQ ID NO: : 271 or SEQ ID NO: 266.

In one embodiment, the anti-PD-1 antibody molecule comprises the amino acid sequence of VHCDR1 SEQ ID NO: 267. In another embodiment, the anti-PD-1 antibody molecule comprises the amino acid sequence of VHCDR1 of SEQ ID NO: 261. In another embodiment, the anti-PD-1 antibody molecule contains the amino acid sequence VHCDR1 SEQ ID NO: 272.

In other embodiments, the PD-1 inhibitor is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, or pidilizumab.

In some embodiments, the anti-PD-1 antibody is nivolumab. Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. In some embodiments, the anti-PD-1 antibody is nivolumab (CAS accession number: 946414-94-4). Nivolumab is a fully 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 8008449 and WO 2006/121168. In one embodiment, the PD-1 inhibitor is nivolumab having the sequence described herein (or a sequence substantially identical or similar to, e.g., at least 85%, 90%, 95% or greater sequence identity to said sequence ).

The amino acid sequences of the heavy and light chains of nivolumab are as follows:

Heavy chain (SEQ ID NO: 304)

QVQLVESGGGWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRY

YADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPE VTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Light chain (SEQ ID NO: 305)

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIP

ARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGEC

In some embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (also called lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies are described in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8354509 and WO 2009/114335. The amino acid sequences of the heavy and light chains of pembrolizumab are as follows:

Heavy chain (SEQ ID NO: 306)

QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG50

INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD100

YRFDMGFDYW GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK150

DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTKT200

YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT250

LMISRTPEVT CVWDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY300

RWSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT350

LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS400

DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK447

Light chain (SEQ ID NO: 307)

EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRL50

LIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPL100

TFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKV150

QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV200

THQGLSSPVTKSFNRGEC218

In one embodiment, the PD-1 inhibitor is pembrolizumab as described,

- 127 040861 for example, in US 8354509 and WO 2009/114335 and having the sequence described in the present description (or a sequence essentially identical or similar to it, for example, a sequence at least 85, 90, 95% or higher identical specified sequence).

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

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

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., the Fc region of an immunoglobulin sequence). In some embodiments, implementation PD-1 inhibitor is AMP-224 (B7-DCIg; Amplimmune; e.g. described in WO 2010/027827 and WO 2011/066342), is a PD-L2-soluble Fc receptor fusion that blocks the interaction between PD- 1 and B7-H1.

Exemplary PD-L1 or PD-L2 inhibitors.

In some embodiments, the PD-L1 inhibitor is an antibody molecule, such as an anti-PD-L1 antibody, as described herein. In one embodiment, the PD-L1 antibody molecule is selected from the antibody molecule described in the Summary of the Invention and in the section titled Exemplary Anti-PD-L1 Antibody Molecules described herein.

In other embodiments, the PD-L1 inhibitor is selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1. Pembrolizumab and other humanized anti-PD-L1 antibodies are described in WO 2013/079174 and have the sequence described therein (or a sequence substantially identical or similar to it, e.g., a sequence of at least 85%, 90%, 95% or greater identical to the specified sequence).

The amino acid sequences of the heavy and light chains of MSB0010718C include at least the following:

Heavy chain (SEQ ID NO: 308) (SEQ ID NO: 24 as described in WO 2013/079174)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITF

YADKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS

Light chain (SEQ ID NO: 309) (SEQ ID NO: 25 as described in WO 2013/079174)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN

RPSGVSNRFSSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL

In one embodiment, the PD-L1 inhibitor is YW243.55.S70. Antibody YW243.55.S70 is an anti-PD-L1 antibody described in WO 2010/077634 (heavy and light chain variable region sequences shown in SEQ ID NOs: 20 and 21, respectively) and having the sequence described therein (or the sequence , essentially identical or similar to it, for example, the sequence is at least 85%, 90%, 95% or higher identical to the specified sequence).

In one embodiment, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874 and having the sequence described therein (or a sequence substantially identical or similar to it, e.g., a sequence at least at least 85%, 90%, 95% or greater identical to the specified sequence).

In one embodiment, the PD-L1 inhibitor is MDPL3280A (Genentech/Roche). MDPL3280A is a human IgG1 monoclonal antibody with an optimized Fc region that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are described in US Pat. No. 7,943,743 and US Publication No. 20120039906.

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

Exemplary LAG-3 Inhibitors

In one embodiment, the combinations described herein include a LAG-3 inhibitor, eg, an anti-LAG-3 antibody as described herein. In one embodiment, the LAG-3 inhibitor combination comprises a PD-L1 inhibitor, for example, an anti-PD-L1 antibody molecule as described herein. In some embodiments, the antibody

- 128 040861 anti-LAG-3 and anti-PD-L1 antibody in combination are present as separate antibodies. In other embodiments, the anti-LAG-3 antibody and the anti-PD-L1 antibody are in the same antibody molecule, eg, as a bispecific or multispecific antibody molecule.

In one embodiment, the combination described herein includes a LAG-3 inhibitor. In some embodiments, the combination is used to treat a cancer, such as the cancer described herein, such as a solid tumor or a hematologic cancer.

In one embodiment, the anti-LAG-3 antibody is an anti-LAG-3 antibody molecule described in US 2015/0259420, filed March 13, 2015, under the title "Antibody Molecules to LAG-3 and Uses Thereof", incorporated by reference in in full. In one embodiment, an anti-LAG-3 antibody molecule comprises at least one or two heavy chain variable domains (optionally including a constant region), at least one or two light chain variable domains (optionally including a constant region), or both, containing the amino acid sequence of any of BAP050-hum01, BAP050-hum02, BAP050hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050 hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050 -hum03-Ser BAP050-hum04-Ser BAP050hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050hum10-Ser BAP050-hum11-Ser BAP050 -hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050 hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Cl one-F, BAP050Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described in Table. 1 US 2015/0259420, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13 BAP050-hum14, BAP050-hum15, BAP050hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser , BAP050-hum04-Ser, BAP050-hum05-Ser,

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

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

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

BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J; or as described in Table. 1 US 2015/0259420, or encoded by the nucleotide sequence shown in table. 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, the anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs (or collectively all of the CDRs) from the heavy chain variable region containing the amino acid sequence shown in Table 1. 1 US 2015/0259420 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or, collectively, all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1.

In another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three CDRs (or, in the aggregate, all CDRs) from a light chain variable region containing the amino acid sequence shown in Table 1. 1 US 2015/0259420 or encoded by the nucleotide sequence shown in table. 1. In one embodiment, one or more CDRs (or, collectively, all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table. 1 or encoded by the nucleotide sequence shown in table. 1. In certain embodiments, the anti-PD-L1 antibody molecule comprises a light chain CDR substitution, eg, one or more substitutions in the light chain CDR1, CDR2 and/or CDR3.

In another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, three, four, five, or six CDRs (or, in the aggregate, all of the CDRs) from the heavy and light chain variable region, comprising the amino acid sequence shown in Table 1. . 1 or encoded by the nucleotide sequence shown in table. 1 US 2015/0259420. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in tab. 1 or encoded by the nucleotide sequence shown in table. 1.

In one embodiment, an anti-LAG-3 antibody molecule contains:

(a) a heavy chain variable region (VH) containing the amino acid sequence VHCDR1 GFTLTNY (SEQ ID NO: 274) (SEQ ID NO: 4 described in Table 1 US 2015/0259420), the amino acid sequence VHCDR2 NTDTGE (SEQ ID NO: 281) (SEQ ID NO: 5 described in Table 1 US 2015/0259420) and the VHCDR3 amino acid sequence NPPYYYGTNNAEAMDY (SEQ ID NO: 277) (SEQ ID NO: 3 described in Table 1 US 2015/0259420); and a light chain variable region (VL) containing the amino acid sequence VLCDR1 SQDISNY (SEQ ID NO: 282) (SEQ ID NO: 13 described in Table 1 US 2015/0259420), the amino acid sequence VLCDR2 YTS (SEQ ID NO: 283) (SEQ ID NO: 14 described in Table 1 US 2015/0259420) and VLCDR3 YYNLPW amino acid sequence (SEQ ID NO: 284) (SEQ ID NO: 15 described in Table 1 US 2015/0259420);

(b) VH containing the amino acid sequence VHCDR1 NYGMN (SEQ ID NO: 273) (SEQ ID NO: 1 described in Table 1 of US 2015/0259420); amino acid sequence VHCDR2 WINTDTGEPTYADDFKG (SEQ ID NO: 276) (SEQ ID NO: 2 described in Table 1 of US 2015/0259420); and the amino acid sequence of VHCDR3 SEQ ID NO: 277; And

VL containing the amino acid sequence of VLCDR1 SSSQDISNYLN (SEQ ID NO: 278) (SEQ ID NO: 10 described in Table 1 US 2015/0259420), the amino acid sequence of VLCDR2 YTSTLHL (SEQ ID NO: 279) (SEQ ID NO: 11, described in Table 1 of US 2015/0259420) and the amino acid sequence of VLCDR3 QQYYNLPWT (SEQ ID NO: 280) (SEQ ID NO: 12 described in Table 1 of US 2015/0259420);

(c) VH containing the amino acid sequence of VHCDR1 GFTLTNYGMN (SEQ ID NO: 275) (SEQ ID NO: 286 described in US 2015/0259420), the amino acid sequence of VHCDR2 SEQ ID NO: 281, and the amino acid sequence of VHCDR3 SEQ ID NO: 277; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 282, the amino acid sequence of VLCDR2 SEQ ID NO: 283, and the amino acid sequence of VLCDR3 SEQ ID NO: 284; or (d) a VH containing the amino acid sequence of VHCDR1 SEQ ID NO: 275; the amino acid sequence of VHCDR2 SEQ ID NO: 276; and the amino acid sequence of VHCDR3 SEQ ID NO: 277; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 278, the amino acid sequence of VLCDR2 SEQ ID NO: 279, and the amino acid sequence of VLCDR3 SEQ ID NO: 280.

In another embodiment, in the combinations described herein below, the anti-LAG-3 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 273, SEQ ID NO: 274, or SEQ ID NO: 275; the amino acid sequence of VHCDR2 SEQ ID NO: 276; and the amino acid sequence of VHCDR3 SEQ ID NO: 277; and (ii) a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 278, the VLCDR2 amino acid sequence of SEQ ID NO: 279, and the VLCDR3 amino acid sequence of SEQ ID NO: 280.

In another embodiment, in the combinations described herein below, the anti-LAG-3 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from SEQ ID NO: 273, SEQ ID NO: 274, or SEQ ID NO: 275; the amino acid sequence of VHCDR2 SEQ ID NO: 281 and the amino acid sequence of VHCDR3 SEQ ID NO: 277; and (ii) a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 282, the VLCDR2 amino acid sequence of SEQ ID NO: 283, and the VLCDR3 amino acid sequence of SEQ ID NO: 284.

In one embodiment, the anti-LAG-3 antibody molecule comprises the amino acid sequence of VHCDR1 SEQ ID NO: 273. In another embodiment, the anti-LAG-3 antibody molecule comprises the amino acid sequence of VHCDR1 of SEQ ID NO: 274. In another embodiment, the anti-LAG-3 antibody molecule contains the amino acid sequence VHCDR1 SEQ ID NO: 275.

In some embodiments, the anti-LAG-3 antibody is BMS-986016. BMS-986016 (also referred to as BMS986016; Bristol-Myers Squibb) is a monoclonal antibody that binds to LAG-3. BMS-986016 and other humanized anti-LAG-3 antibodies are described in US 2011/0150892, WO 2010/019570 and WO 2014/008218.

Exemplary TIM-3 Inhibitors.

In one embodiment, the combinations described herein include a TIM-3 inhibitor, such as an anti-TIM-3 antibody as described herein. In one embodiment, the TIM-3 inhibitor combination comprises a PD-L1 inhibitor, eg, an anti-PD-L1 antibody molecule as described herein. In some embodiments, the anti-TIM-3 antibody and the anti-PD-L1 antibody are present in combination as separate antibodies. In other embodiments, the anti-TIM-3 antibody and the anti-PD-L1 antibody are present in the same antibody molecule, for example, as a bispecific or multispecific antibody molecule.

In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule described in US 2015/0218274, published Aug. 6, 2015, titled "Antibody Molecules to TIM-3 and Uses Thereof", incorporated herein as links in full.

In one embodiment, an anti-TIM-3 antibody molecule comprises at least one or two heavy chain variable domains (optionally including a constant region), at least one or two light chain variable domains (optionally including a constant region), or both, containing the amino acid sequence ABTIM3, ABTIM3hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-hum10, ABTIM3-hum11, ABTIM3-hum12, ABTIM3hum13 , ABTIM3-hum14, ABTIM3-hum15, ABTIM3-hum16, ABTIM3-hum17, ABTIM3-hum18, ABTIM3hum19, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Table. 1-4

US 2015/0218274; or encoded by the nucleotide sequence shown in table. 1-4; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences. The TIM-3 antibody molecule optionally contains a leader sequence from the heavy chain, light chain, or both, as shown in US 2015/0218274; or a sequence substantially identical to it.

In another embodiment, an anti-TIM-3 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from the heavy chain variable region and/or the light chain variable region of an antibody described herein, e.g., an antibody selected from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-hum10, ABTIM3-hum11, ABTIM3-hum12, ABTIM3-hum13, ABTIM3-hum14, ABTIM3-hum15, ABTIM3-hum16, ABTIM3-hum17, ABTIM3-hum18, ABTIM3-hum19, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Table. 1-4 US 2015/0218274; or encoded by the nucleotide sequence shown in table. 1-4; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identical) to any of the above sequences.

In another embodiment, an anti-TIM-3 antibody molecule comprises at least one, two, or three CDRs (or, in the aggregate, all CDRs) from a heavy chain variable region comprising the amino acid sequence shown in Tables 1-4 of US 2015/0218274 or encoded by the nucleotide sequence shown in table. 1-4. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1. 1-4 or encoded by the nucleotide sequence shown in table. 1-4.

In another embodiment, the anti-TIM-3 antibody molecule comprises at least one, two, or three CDRs (or, collectively, all CDRs) from a light chain variable region containing the amino acid sequence shown in Table 1. 1-4 US 2015/0218274 or encoded by the nucleotide sequence shown in table. 1-4. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1. 1-4 or encoded by the nucleotide sequence shown in table. 1-4. In certain embodiments, the anti-TIM-3 antibody molecule comprises a substitution in the light chain CDR, e.g., one or more substitutions in the light chain CDR1, CDR2 and/or CDR3.

In another embodiment, the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five, or six CDRs (or, in the aggregate, all of the CDRs) from the heavy and light chain variable region, comprising the amino acid sequence shown in Table . 1-4 US 2015/0218274 or encoded by the nucleotide sequence shown in table. 1-4. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1. 1-4 or encoded nucleotide after

- 131 040861 with the accuracy presented in Table. 1-4.

In one embodiment, an anti-TIM-3 antibody molecule comprises:

(a) a heavy chain variable region (VH) containing the VHCDR1 amino acid sequence selected from GYTFTSY (SEQ ID NO: 285) (SEQ ID NO: 9 described in Tables 1-4 of US 2015/0218274); the amino acid sequence of VHCDR2 YPGNGD (SEQ ID NO: 286) (SEQ ID NO: 10 described in Tables 1-4 of US 2015/0218274); and the amino acid sequence of VHCDR3 VGGAFPMDY (SEQ ID NO: 287) (SEQ ID NO: 5 described in Tables 1-4 of US 2015/0218274); and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SESVEYYGTSL (SEQ ID NO: 288) (SEQ ID NO: 12 described in Tables 1-4 of US 2015/0218274), the amino acid sequence of VLCDR2 AAS (SEQ ID NO: 289) (SEQ ID NO: 13 described in US 2015/0218274 Tables 1-4) and VLCDR3 SRKDPS amino acid sequence (SEQ ID NO: 290) (SEQ ID NO: 14 described in US 2015 Tables 1-4 /0218274);

(b) VH containing the amino acid sequence of VHCDR1 selected from SYNMH (SEQ ID NO: 291) (SEQ ID NO: 3 described in tables 1-4 of US 2015/0218274); the amino acid sequence of VHCDR2 DIYPGNGDTSYNQKFKG (SEQ ID NO: 292) (SEQ ID NO: 4 described in Tables 14 of US 2015/0218274); and the amino acid sequence of VHCDR3 SEQ ID NO: 287; And

VL containing the amino acid sequence of VLCDR1 RASESVEYYGTSLMQ (SEQ ID NO: 293) (SEQ ID NO: 6, described in Table 1-4 of US 2015/0218274), the amino acid sequence of VLCDR2 AASNVES (SEQ ID NO: 294) (SEQ ID NO: 7 described in Tables 1-4 of US 2015/0218274) and the amino acid sequence of VLCDR3 QQSRKDPST (SEQ ID NO: 295) (SEQ ID NO: 8 described in Tables 1-4 of US 2015/0218274);

(c) VH containing the amino acid sequence of VHCDR1 selected from SEQ ID NO: 285; the amino acid sequence of VHCDR2 YPGSGD (SEQ ID NO: 296) (SEQ ID NO: 25 described in Tables 1-4 of US 2015/0218274); and the amino acid sequence of VHCDR3 SEQ ID NO: 287; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 288, the amino acid sequence of VLCDR2 SEQ ID NO: 289 and the amino acid sequence of VLCDR3 SEQ ID NO: 290;

(d) VH containing the amino acid sequence of VHCDR1 selected from SEQ ID NO: 291; amino acid sequence VHCDR2 DIYPGSGDTSYNQKFKG (SEQ ID NO: 297) (SEQ ID NO: 24 described in Tables 1-4 of US 2015/0218274); and the amino acid sequence of VHCDR3 SEQ ID NO: 287; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 293, the amino acid sequence of VLCDR2 SEQ ID NO: 294 and the amino acid sequence of VLCDR3 SEQ ID NO: 295;

(e) VH containing the amino acid sequence of VHCDR1 selected from SEQ ID NO: 285; the amino acid sequence of VHCDR2 YPGQGD (SEQ ID NO: 298) (SEQ ID NO: 31 described in Tables 1-4 of US 2015/0218274); and the amino acid sequence of VHCDR3 SEQ ID NO: 287; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 288, the amino acid sequence of VLCDR2 SEQ ID NO: 289 and the amino acid sequence of VLCDR3 SEQ ID NO: 290; or (f) VH containing the amino acid sequence of VHCDR1 selected from SEQ ID NO: 291; amino acid sequence VHCDR2 DIYPGQGDTSYNQKFKG (SEQ ID NO: 299) (SEQ ID NO: 30 described in Tables 1-4 of US 2015/0218274); and the amino acid sequence of VHCDR3 SEQ ID NO: 287; And

VL containing the amino acid sequence of VLCDR1 SEQ ID NO: 293, the amino acid sequence of VLCDR2 SEQ ID NO: 294 and the amino acid sequence of VLCDR3 SEQ ID NO: 295.

In one embodiment, the combination described herein includes a TIM-3 inhibitor. In some embodiments, the combination is used to treat a cancer, eg, the cancer described herein, eg, a solid tumor or a hematologic cancer.

Illustrative antibodies against TIM-3 are described in US Pat. No. 8,552,156, WO 2011/155607, EP 2581113 and US Publication No. 2014/044728.

Exemplary CTLA-4 Inhibitors.

In one embodiment, the combination described herein includes a CTLA-4 inhibitor. In some embodiments, the combination is used to treat a cancer, eg, the cancer described herein, eg, a solid tumor or a hematologic cancer.

Exemplary anti-CTLA-4 antibodies include tremelimumab (an IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206) and ipilimumab (antibody

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CTLA-4, also known as MDX-010, CAS No. 477202-00-9).

In one embodiment, the combination comprises an anti-PD-1 antibody molecule, eg, as described herein, and an anti-CTLA-4 antibody, eg, ipilimumab. Illustrative doses that may be used include 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-4 antibody, such as ipilimumab, of about 3 mg/kg.

Other exemplary anti-CTLA-4 antibodies are described, for example, in US Pat. No. 5,811,097.

Exemplary IAP Inhibitors.

In one embodiment, the combination described herein comprises an apoptosis protein (IAP) inhibitor. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., breast, ovarian, or pancreatic cancer), e.g., a hematological cancer (e.g., multiple myeloma ).

In some embodiments, the IAP inhibitor is (S)-N-((S)-1cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl) -2-oxoethyl)-2(methylamino)propanamide (compound A21) or the compound described in US patent No. 8552003.

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

Exemplary EGFR Inhibitors.

In one embodiment, the combination described herein comprises an epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, breast cancer, or colon cancer) .

In some embodiments, the EGFR inhibitor is (R,E)-N-(7-chloro-1-(1(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d] imidazol-2-yl)-2-methylisonicotinamide (compound A40) or the compound described in PCT Publication No. WO 2013/184757.

In some embodiments, an EGFR inhibitor, such as (R,E)-N-(7-chloro-1-(1-(4(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d ]imidazol-2-yl)-2-methylisonicotinamide (Compound A40) or the compound described in PCT Publication No. WO 2013/184757 is administered at a dose of 150-250 mg, for example per day. In some embodiments, an EGFR inhibitor such as (R,E)-N-(7-chloro1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d] imidazol-2-yl)-2-methylisonicotinamide (compound A40) or the compound described in PCT Publication No. WO 2013/184757 is administered at a dose of about 150, 200 or 250 mg, or about 150-200 or 200-250 mg.

In some embodiments, the EGFR inhibitor is selected from one or more of erlotinib, gefitinib, cetuximab, panitumumab, netcitumumab, PF-00299804, nimotuzumab, or RO5083945.

Exemplary mTOR inhibitors.

In one embodiment, the combination described herein includes an inhibitor of the target of rapamycin (mTOR). In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., prostate cancer, breast cancer, brain cancer, bladder cancer, pancreatic cancer, cancer kidney or liver cancer, lung cancer (eg, small cell lung cancer or non-small cell lung cancer), respiratory system/thoracic cancer, sarcoma, bone cancer, non-small cell lung cancer, endocrine cancer, astrocytoma, cervical cancer, neurological cancer, or gastric cancer melanoma), eg, hematological malignancy (eg, leukemia (eg, lymphocytic leukemia), eg, lymphoma, or, eg, multiple myeloma).

In some embodiments, the mTOR inhibitor is dactolisib (compound A4) or 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)- 1,3dihydro-imidazo[4,5-c]quinolin-2-one (Compound A41), or the compound described in PCT Publication No. WO 2006/122806.

In some embodiments, the mTOR inhibitor is everolimus (also known as AFINITOR®; compound A36) or the compound described in PCT Publication No. WO 2014/085318.

In some embodiments, an mTOR inhibitor, such as everolimus (compound A36) or a compound described in PCT Publication No. WO 2014/085318, is administered at a dose of about 2.5-20 mg/day. In one embodiment, a TOR inhibitor, e.g., everolimus (Compound A36) or a compound described in PCT Publication No. WO 2014/085318, is administered at a dose of approximately 2.5, 5, 10

- 133 040861 or 20 mg/day, for example about 2.5-5, 5-10 or 10-20 mg/day.

In some embodiments, the mTOR inhibitor is selected from one or more of rapamycin, temsirolimus (TORISEL®), AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE-354, palomide 529 (P529), PF-04691502 or PKI-587, ridaforolimus (formerly known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R ,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy15,17,21,23,29,35-hexamethyl-2,3,10, 14,20-pentaoxo-11,36-dioxa-4azatricyclo[30.3.1.04.9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03/064383); everolimus (AFINITOR® or RAD001); rapamycin (AY22989, SIROLIMUS®); simapimod (CAS registration number: 164301-51-3); (5-{2,4-6uc[(3S)-3methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin7(8H)-one (PF04691502 , CAS registration number: 1013101-36-4); N ² -[1,4-dioxo-4-[[4-(4-oxo-8phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L- α-aspartyl-L-serine, internal salt (SF1126, CAS Registry Number: 936487-67-1) or XL765 (SAR245409).

Other exemplary mTOR inhibitors include, but are not limited to, temsirolimus; ridaphorolimus (1R,2R,4S)-4-[^)-2-^1^,^,15^^,18^19^2^^^^^^^^^)1,18-dihydroxy-19.30 -dimethoxy-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]-2methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669; everolimus (RAD001); rapamycin (AY22989); simapimod; (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one ( PF04691502); and N ² -[1,4-dioxo-4-[[4(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl- L-αaspartyl-L-serine (SEQ ID NO: 360), internal salt (SF1126); and XL765.

Exemplary IL-15 agonists.

In one embodiment, the combination described herein comprises an interleukin-15 (IL-15) agonist. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., refractory solid tumor), (e.g., melanoma (e.g., metastatic or advanced melanoma), kidney cancer (e.g. , renal cell carcinoma), non-small cell lung cancer, head and neck squamous cell carcinoma, or bladder cancer (eg, non-muscle invasive bladder cancer)), eg, hematologic malignancy (eg, leukemia, eg, acute myelogenous leukemia (eg, refractory or relapsed acute myelogenous leukemia), eg lymphoma, eg non-Hodgkin's lymphoma (eg relapsed/refractory indolent B-cell non-Hodgkin's lymphoma), or eg multiple myeloma (eg relapsed or refractory multiple myeloma)).

IL-15, secreted by mononuclear phagocytes (and some other cell types) after a viral infection, regulates the activation and proliferation of T cells and natural killer cells. This cytokine induces the activation of the transcriptional activators STAT3, STAT5, and STAT6 through JAK kinase signaling cascades in mast cells, T cells, and dendritic epidermal T cells. IL-15 and interleukin-2 (IL-2) are structurally similar and have many biological activities; both of these can bind to common subunits of the hematopoietin receptor, inhibiting each other's activity. The number of CD8+ memory T cells can be regulated through the balance between IL-15 and IL-2.

In some embodiments, the IL-15 agonist is recombinant human IL-15 (rhIL-15), such as CYP0150 (Cytune). CYP0150 is a recombinant protein consisting of human IL-15 coupled to the Sushi ⁺ domain of the human alpha chain receptor (transpresentation).

CYP0150 is described, for example, in PCT Publication No. WO 2007/046006. CYP0150 has the amino acid sequence:

MAPRRARGCRTLGLPALLLLLLRPPATRGDYKDDDDKIEGRITCPPPMSVEHADIWVKSYSLY

SRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSGGSGGGGS GGGSGGGGSLQNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLE SGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS (SEQ ID NO: 310) (описанная в качестве SEQ ID NO: 60 в WO 2007/046006) или

- 134 040861

MDSKGSSQKAGSRLLLLLVVSNLLLCQGVVSTTRDYKDDDDKIEGRNWVNVISDLKKIEDLIQS

MHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTE

SGCKECEELEEKNIKEFLQSFVHIVQMFINTSSGGGSGGGGSGGGGSGGGGSGGGSLQITCPPP

MSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALV HQRPAPP (SEQ ID NO: 311) (described as SEQ ID NO: 62 in WO 2007/046006).

In some embodiments, the IL-15 agonist is ALT-803 (Altor BioScience). ALT-803 is a soluble IL-15N72D:IL-15Ra.Su/Fc complex produced from a high yield recombinant mammalian cell line that co-expresses IL-15N72D and the IL-15Ra.Su/Fc fusion protein. The IL-15 mutant (N72D) has enhanced IL-15 biological activity (Zhu et al., 2009, J Immunol. 183:3598). The IL-15N72D mutant and the IL-15Ra soluble domain can form stable heterodimeric complexes in solution, and this complex shows increased biological activity (approximately 25 times more active) than uncomplexed IL-15. ALT-803 is described, for example, in PCT Publication No. WO 2012/040323 and US Patent No. 8507222.

In some embodiments, the IL-15 agonist is hetIL-15 (Admune). HetIL15 is a heterodimeric human IL-15 (IL-15/sIL-15Ra). HetIL-15 is described, for example, in PCT Publication No. WO 2009/002562 and WO 2014/066527.

Illustrative CD40 agonists.

In one embodiment, the combination includes a CD40 agonist. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., lung cancer, esophageal carcinoma, melanoma, or renal cell carcinoma), e.g., a hematological malignancy (e.g., leukemia ( eg chronic lymphocytic leukemia (CLL)), eg lymphoma (eg non-Hodgkin's lymphoma), or eg multiple myeloma).

In one embodiment, the CD40 agonist is ADC-1013 (Alligator/Biolnvent). ADC-1013 is a fully human anti-human CD40 monoclonal IgG agonist. CD40, an integral membrane protein found on the surface of B lymphocytes, is a member of the tumor necrosis factor receptor superfamily and is highly expressed in a number of cancers such as B cell cancers. CD40 agonists, such as anti-CD40 antibodies, are able to effectively displace T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478).

ADC-1013 is described, for example, in PCT Publication No. WO 2015/091853. ADC-1013 clones include, for example, 1136/1137, 1132/1133, 1148/1149, 1140/1135, 1134/1135, 1107/1108, 1142/1135, 1146/1147 and 1150/1151.

The heavy chain variable region 1132/1133 has the amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGIGSYGGGTYYADSV

KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYVNFGMDYWGQGTLVTVSS (SEQ ID NO: 312) (described as SEQ ID NO: 65 in WO 2015/091853).

The light chain variable region 1132/1133 has the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG

SGSGTDFTLTISSLQPEDFATYYCQQYGRNPPTFGQGTKLEIK (SEQ ID NO: 313) (described as SEQ ID NO: 66 in WO 2015/091853). Heavy chain CDR1 1132/1133 has the amino acid sequence: GFTFSSYA (SEQ ID NO: 314) (described as SEQ ID NO: 13 in WO 2015/091853). Heavy chain CDR2 1132/1133 has the amino acid sequence: IGSYGGGT (SEQ ID NO: 315) (described as SEQ ID NO: 14 in WO 2015/091853). Heavy chain CDR3 1132/1133 has the amino acid sequence: ARYVNFGMDY (SEQ ID NO: 316) (described as SEQ ID NO: 15 in WO 2015/091853). Light chain CDR1 1132/1133 has the amino acid sequence: QSISSY (SEQ ID NO: 317) (described as SEQ ID NO: 16 in WO 2015/091853). Light chain CDR2 1132/1133 has the amino acid sequence: AAS (SEQ ID NO: 289) (described as SEQ ID NO: 17 in WO 2015/091853). Light chain CDR3 1132/1133 has the amino acid sequence: QQYGRNPPT (SEQ ID NO: 318) (described as SEQ ID NO: 18 in WO 2015/091853).

The heavy chain variable region 1107/1108 has the amino acid sequence:

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSV

KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRVWGFDYWGQGTLVTVSS (SEQ ID NO: 319) (described as SEQ ID NO: 79 in WO 2015/091853).

Light chain variable region 1107/1108 has the amino acid sequence (SEQ ID

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NO: 320):

DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG

SGSGT DFTLTISSLQPEDFATYYCQQYGVYPFTFGQGTKLEIK (described as SEQ ID NO: 80 in WO 2015/091853). Heavy chain CDR1 1107/1108 has the amino acid sequence: GFTFSSYA (SEQ ID NO: 314) (described as SEQ ID NO: 55 in WO 2015/091853). Heavy chain CDR2 1107/1108 has the amino acid sequence: ISGSGGST (SEQ ID NO: 321) (described as SEQ ID NO: 56 in WO 2015/091853). Heavy chain CDR3 1107/1108 has the amino acid sequence: ARRVWGFDY (SEQ ID NO: 322) (described as SEQ ID NO: 57 in WO 2015/091853). Light chain CDR1 1107/1108 has the amino acid sequence: QSISSY (SEQ ID NO: 317) (described as SEQ ID NO: 58 in WO 2015/091853). Light chain CDR2 1107/1108 has the amino acid sequence: AAS (SEQ ID NO: 289) (described as SEQ ID NO: 59 in WO 2015/091853). Light chain CDR3 1107/1108 has the amino acid sequence: QQYGVYPFT (SEQ ID NO: 323) (described as SEQ ID NO: 60 in WO 2015/091853).

In some embodiments, the CD40 agonist is ISF35. ISF35 is a chimeric CD154. ISF is described in PCT Publication Nos. WO 2003/099340 and WO 2008/070743.

In some embodiments, the CD40 agonist is dacetuzumab. Dacetuzumab is also known as SGN-40 or huS2C6. Dacetuzumab is a humanized monoclonal antibody that targets CD40. Dacetuzumab is described, for example, in Advani et al., J Clin Oncol. 2009; 27(26):4371-7; and Khubchandani et al., Curr Opin Investig Drugs. 2009; 10(6):579-87.

In some embodiments, the CD40 agonist is lucatumumab (CAS accession number: 903512-50-5). Lucatumumab is also known as CHIR-12.12 or HCD-122. Lucatumumab binds and inhibits CD40, thereby inhibiting CD40 ligand-induced cell proliferation and triggering cell lysis via antibody-dependent cellular cytotoxicity (ADCC) in CD40-overexpressing cells.

Lucatumumab is described, for example, in Tai et al., Cancer Res. 2005; 65(13):5898-906.

Anti-CD40 antibodies are able to effectively replace T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474-478) and can be used in conjunction with anti-PD-1 antibodies (Ito, N. et al. ( 2000) Immunobiology 201 (5) 527-40).

Exemplary OX40 agonists.

In one embodiment, the combination described herein includes an OX40 agonist. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., breast cancer, melanoma, head and neck cancer, or prostate cancer), e.g., a hematological malignancy ( eg, lymphoma (eg, B-cell lymphoma)).

OX40, also known as CD134, is a cell surface glycoprotein of the tumor necrosis factor (TNF) receptor superfamily, is expressed on T lymphocytes and provides a costimulatory signal for proliferation and survival of activated T cells. Activation of OX40 can induce the proliferation of effector T lymphocytes, which stimulates an immune response against tumor cells that express tumor-associated antigens (TAAs).

In some embodiments, the OX40 agonist is selected from mAb 106-222, humanized 106-222 (Hu106), mAb 119-122, or humanized 119-122 (Hu119).

MAb 106-222, humanized 106-222 (Hu106), mAb 119-122, and humanized 119-122 (Hu119) are described, for example, in PCT Publication No. WO 2012/027328 and US Pat. No. 9,006,399. 106-222 is described as SEQ ID NO: 4 in WO 2012/027328. The amino acid sequence of the light chain variable region of mAb 106-222 is described as SEQ ID NO: 10 in WO 2012/027328. The amino acid sequence of the heavy chain variable region of humanized 106-222 (Hu106) is described as SEQ ID NO: 5 in WO 2012/027328. The amino acid sequence of the light chain variable region of humanized 106-222 (Hu106) is described as SEQ ID NO: 11 in WO 2012/027328. The amino acid sequence of the heavy chain variable region of mAb 119-122 is described as SEQ ID NO: 16 in WO 2012/027328. The amino acid sequence of the light chain variable region of mAb 119-122 is described as SEQ ID NO: 22 in WO 2012/027328. The amino acid sequence of the heavy chain variable region of humanized 119-122 (Hu119) is described as SEQ ID NO: 17 in WO 2012/027328. The amino acid sequence of the light chain variable region of humanized 119-122 (Hu119) is described as SEQ ID NO: 23 in WO 2012/027328.

In some embodiments, the OX40 agonist is a humanized monoclonal antibody as described in US Pat. No. 7,959,925 and PCT Publication No. WO 2006/121810.

In some embodiments, the OX40 agonist is selected from MEDI6469, MEDI0562, or

- 136 040861

MEDI6383. MEDI6469 is a mouse monoclonal antibody against OX40. MEDI0562 is a humanized anti-OX40 monoclonal antibody. MEDI6383 is a monoclonal antibody against OX40.

In some embodiments, an OX40 agonist, such as MEDI6469, is administered intravenously at a dose of about 0.4 mg/kg, such as every other day.

Other illustrative anti-OX-40 antibodies are described, for example, in Weinberg, A. et al. (2000) Immunol 164: 2160-2169).

Exemplary CD27 agonists.

In one embodiment, the combination described herein comprises a CD27 agonist. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., melanoma, renal cell carcinoma, hormone-refractory adenocarcinoma of the prostate, ovarian cancer, breast cancer, adenocarcinoma of the colon and rectal or non-small cell lung cancer), such as a hematologic malignancy (eg, lymphoma (eg, Hodgkin's lymphoma, Burkitt's lymphoma, mantle cell lymphoma, primary central nervous system lymphoma, or marginal zone B-cell lymphoma), or leukemia (eg. , chronic lymphocytic leukemia (CLL)).

In one embodiment, the CD27 agonist is varlilumab (CAS accession number: 1393344-72-3). Varlilumab is also known as CDX-1127 (Celldex) or 1F5. Varlilumab is a fully human monoclonal antibody (mAb) that targets CD27, a molecule in the lymphocyte activation cascade. CDX-1127 is a CD27 agonist mAb that can activate human T cells in the context of T cell receptor stimulation and thus mediate antitumor effects. CDX-1127 may also provide direct therapeutic effects against tumors expressing CD27.

Varlilumab is described, for example, in Vitale et al., Clin Cancer Res. 2012; 18(14):3812-21, WO 2008/051424 and US 8481029.

In one embodiment, the CD27 agonist is BION-1402 (BioNovion). BION1402 is also known as hCD27.15. BION-1402 is a monoclonal antibody against human CD27. BION-1402 can stimulate the proliferation and/or survival of CD27+ cells. BION-1402 can activate human CD27 more efficiently than its CD70 ligand, resulting in a significantly increased effect on CD8+ and CD4+ T cell proliferation.

BION-1402 is described for example as hCD27.15 in WO 2012/004367. This antibody is produced by the hCD27.15 hybridoma, which was deposited with the ATCC on June 2, 2010 as PTA11008. The hCD27.15 heavy chain variable region has the amino acid sequence:

EVRLQQSGADLVKPGASVKLSCASGFIIKATYMHWVRQRPEQGLEWIGRIDPANGE KY

DPKFQVKAITADTSSSTAYLQLNSLTSDDTAVYYCARYAWYFDVWGAGTTVTVSSAKTTPPXVY

PXXPGS (SEQ ID NO: 324) (described as SEQ ID NO: 3 in WO 2012/004367). The hCD27.15 light chain variable region has the amino acid sequence:

DIQMTQSPASLSASVGDTVTITCRASENIYSFLAWYHQKQGRSPQLLVYHAKTLAEGVPSRFSG

SGSGTQFSLKINSLQAEDFGSYYCQHYYGSPLTFGAGTKLEVKRADAAPTVSIFPPSSEELSL (SEQ ID NO: 325) (described as SEQ ID NO: 4 in WO 2012/004367). The heavy chain CDR1 of hCD27.15 has the amino acid sequence: GFIIKATYMH (SEQ ID NO: 326) (described as SEQ ID NO: 5 in WO 2012/004367). The heavy chain CDR2 of hCD27.15 has the amino acid sequence:

RIDPANGETKYDPKFQV (SEQ ID NO: 327) (described as SEQ ID NO: 6 in WO 2012/004367). The heavy chain CDR3 of hCD27.15 has the amino acid sequence: YAWYFDV (SEQ ID NO: 328) (described as SEQ ID NO: 7 in WO 2012/004367). The light chain CDR1 of hCD27.15 has the amino acid sequence: RASENIYSFLA (SEQ ID NO: 329) (described as SEQ ID NO: 8 in WO 2012/004367). The light chain CDR2 of hCD27.15 has the amino acid sequence: HAKTLAE (SEQ ID NO: 330) (described as SEQ ID NO: 9 in WO 2012/004367). The light chain CDR3 of hCD27.15 has the amino acid sequence: QHYYGSPLT (SEQ ID NO: 331) (described as SEQ ID NO: 10 in WO 2012/004367).

Exemplary CSF-1/1R binding agents.

In one embodiment, the combination described herein includes a CSF-1/1R binding agent. In some embodiments, the combination is used to treat a cancer, eg, the cancer described herein, eg, a solid tumor (eg, prostate cancer, breast cancer, or pigmented villonodular synovitis (PVNS)).

In some embodiments, the CSF-1/1R binding agent is a macrophage colony stimulating factor (M-CSF) inhibitor.

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In another embodiment, the CSF-1/1R binding agent is a CSF-1R tyrosine kinase inhibitor, 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-ul)oxy )-Nmethylpicolinamide (Compound A15) or the compound described in PCT Publication No. WO 2005/073224.

In some embodiments, the CSF-1/1R binding agent is an M-CSF inhibitor, an A33 compound, or a CSF-1 binding agent as described in PCT Publication No. WO 2004/045532 or PCT Publication No. WO 2005/068503, including RX1 or 5H4 ( for example, an antibody molecule or a Fab fragment against M-CSF).

In some embodiments, a CSF-1/1R binding agent, e.g., an MCSF inhibitor, an A33 compound, or a compound described in PCT Publication No. WO 2004/045532 (e.g., an anti-M-CSF antibody molecule or Fab) is administered at a medium dose approximately 10 mg/kg. In some embodiments, the CSF-1/1R binding agent is a CSF1R inhibitor or 4-(2-(( 1 R,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide. 4(2-((1R,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide is described as Example 157 on p. 117 of PCT Publication No. WO 2007/121484.

In some embodiments, the CSF-1/1R binding agent is pexidartinib (CAS accession number 1029044-16-3). Pexidartinib is also known as PLX3397 or 5-((5-chloro-1H-pyrrolo[2,3-b]pyrudin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl) pyridine-2amine. Pexidartinib is a small molecule inhibitor of the receptor tyrosine kinase (RTK) KIT, CSF1R and FLT3. FLT3, CSF1R and FLT3 are overexpressed or mutated in many cancer cell types and play a significant role in tumor cell proliferation and metastasis. PLX3397 can bind and inhibit the phosphorylation of stem cell factor receptor (KIT), colony stimulating factor receptor 1 (CSF1R), and FMS-like tyrosine kinase 3 (FLT3), which can lead to inhibition of tumor cell proliferation and suppression of macrophages, osteoclasts, and mast cells involved in osteolytic metastatic disease. In some embodiments, a CSF-1/1R binding agent, eg, pexidartinib, is used in combination with a PD-1 inhibitor, eg, an anti-PD-1 antibody molecule described herein.

In some embodiments, the CSF-1/1R binding agent is emactuzumab. Emactuzumab is also known as RG7155 or RO5509554. Emactuzumab is a humanized IgG1 mAb that targets CSF1R. In some embodiments, a CSF-1/1R binding agent, eg, pexidartinib, is used in combination with a PD-L1 inhibitor, eg, an anti-PD-L1 antibody molecule described herein.

In some embodiments, the CSF-1/1R binding agent is FPA008. FPA008 is a humanized mAb that inhibits CSF1R. In some embodiments, a CSF-1/1R binding agent, such as FPA008, is used in combination with a PD-1 inhibitor, such as an anti-PD-1 antibody molecule described herein.

Illustrative Inhibitors of IL-17.

In one embodiment, the combination described herein includes an inhibitor of interleukin 17 (IL-17). In some embodiments, the combination is used to treat a cancer, eg, the cancer described herein, eg, a solid tumor, eg, breast cancer, lung cancer, or colon cancer.

In some embodiments, the IL-17 inhibitor is secukinumab (CAS accession numbers: 875356-43-7 (heavy chain) and 875356-44-8 (light chain)).

Secukinumab is also known as AIN457 and COSENTYX®. Secukinumab is a recombinant human IgG1/K monoclonal antibody that specifically binds to IL-17A. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line.

Secukinumab is described, for example, in WO 2006/013107, US 7807155, US 8119131, US 8617552 and EP 1776142. The secukinumab heavy chain variable region has the amino acid sequence (SEQ ID NO: 332):

EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVAAINQDGSEKYYVGSV

KGRFTISRDNAKNSLYLQMNSLRVEDTAVYYCVRDYYDILTDYYIHYWYFDLWGRGTLVTVSS (described as SEQ ID NO: 8 in WO 2006/013107). The light chain variable region of secukinumab has the amino acid sequence (SEQ ID NO: 333):

EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVAAINQDGSEKYYVGSV

KGRFTISRDNAKNSLYLQMNSLRVEDTAVYYCVRDYYDILTDYYIHYWYFDLWGRGTLVTVSS (described as SEQ ID NO: 10 in WO 2006/013107). The secukinumab heavy chain CDR1 has the amino acid sequence NYWMN (SEQ ID NO: 334) (described as SEQ ID NO: 1 in WO 2006/013107). The secukinumab heavy chain CDR2 has the amino acid sequence AINQDGSEKYYVGSVKG (SEQ ID NO: 335) (described as SEQ ID NO: 2 in WO 2006/013107). The CDR3 of the heavy chain of secukinumab has the amino acid sequence DYYDILTDYYIHYWYFDL

- 138 040861 (SEQ ID NO: 336) (described as SEQ ID NO: 3 in WO 2006/013107). The secukinumab light chain CDR1 has the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 337) (described as SEQ ID NO: 4 in WO 2006/013107). The secukinumab light chain CDR2 has the amino acid sequence GASSRAT (SEQ ID NO: 338) (described as SEQ ID NO: 5 in WO 2006/013107). The light chain CDR3 of secukinumab has the amino acid sequence QQYGSSPCT (SEQ ID NO: 361) (described as SEQ ID NO: 6 in WO 2006/013107).

In some embodiments, the IL-17 inhibitor is CJM112. CJM112 is also known as XAB4. CJM112 is a fully human human monoclonal antibody that targets IL-17A.

CJM112 is described, for example, in WO 2014/122613. The heavy chain of CJM112 has the amino acid sequence (SEQ ID NO: 339):

EVQLVESGGDLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSV

KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRGSLYYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (описанная в качестве SEQ ID NO: 14 в WO 2014/122613). The light chain of CJM112 has the amino acid sequence (SEQ ID NO: 340):

AIQLTQSPSSLSASVGDRVTITCRPSQGINWELAWYQQKPGKAPKLLIYDASSLEQGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC (описанная в качестве SEQ ID NO: 44 в WO 2014/122613).

In some embodiments, the IL-17 inhibitor is ixekizumab (CAS accession number: 1143503-69-8). Ixekizumab is also known as LY2439821. Ixekizumab is a humanized IgG4 monoclonal antibody that targets IL-17A.

Ixekizumab is described, for example, in WO 2007/070750, US 7838638 and US 8110191. The heavy chain variable region of ixekizumab has the amino acid sequence (SEQ ID NO: 341):

QVQLVQSGAEVKKPGSSVKVSCKASGYSFTDYHIHWVRQAPGQGLEWMGVINPMYGTTDYNQRF

KGRVTITADESTSTAYMELSSLRSEDTAVYYCARYDYFTGTGVYWGQGTLVTVSS (described as SEQ ID NO: 118 in WO 2007/070750). The light chain variable region of ixekizumab has the amino acid sequence (SEQ ID NO: 342):

DIVMTQTPLSLSVTPGQPASISCRSSRSLVHSRGNTYLHWYLQKPGQSPQLLIYKVSNRFIGVP

DRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHLPFTFGQGTKLEIK (described as SEQ ID NO: 241 in WO 2007/070750).

In some embodiments, the IL-17 inhibitor is brodalumab (CAS Accession Number: 1174395-19-7). Brodalumab is also known as AMG 827 or AM-14. Brodalumab binds to the interleukin-17 receptor A (IL-17RA) and prevents receptor activation by IL-17.

Brodalumab is described, for example, in WO 2008/054603, US 7767206, US 7786284, US 7833527, US 7939070, US 8435518, US 8545842, US 8790648 and US 9073999. Brodalumab heavy chain CDR1 has the amino acid sequence NO: GIS 343 (as described as SEQ ID NO: 146 in WO 2008/054603). The heavy chain CDR2 of brodalumab has the amino acid sequence WISTYSGNTNYAQKLQG (SEQ ID NO: 344) (as described as SEQ ID NO: 147 in WO 2008/054603). The heavy chain CDR3 of brodalumab has the amino acid sequence RQLYFDY (SEQ ID NO: 345) (as described as SEQ ID NO: 148 in WO 2008/054603). The light chain CDR1 of brodalumab has the amino acid sequence RASQSVSSNLA (SEQ ID NO: 346) (as described as SEQ ID NO: 224 in WO 2008/054603). The heavy chain CDR2 of brodalumab has the amino acid sequence DASTRAT (SEQ ID NO: 347) (as described as SEQ ID NO: 225 in WO 2008/054603). The heavy chain CDR3 of brodalumab has the amino acid sequence QQYDNWPLT (SEQ ID NO: 348) (as described as SEQ ID NO: 226 in WO 2008/054603).

Exemplary inhibitors of IL-1e.

In one embodiment, the combination described herein comprises an inhibitor of interleukin 1-beta (IL-1p). In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a hematologic cancer (e.g., lymphoma (e.g., Hodgkin's lymphoma), leukemia (e.g., acute or chronic leukemia), or multiple myeloma) .

In some embodiments, the IL-13 inhibitor is canakinumab. Kanaki-139 040861 numab is also known as ACZ885 or ILARIS®. Canakinumab is a human IgGl/κ monoclonal antibody that neutralizes the biological activity of human IL-1e.

Canakinumab is described, for example, in WO 2002/16436, US 7446175 and EP 1313769. The heavy chain variable region of canakinumab has the amino acid sequence (SEQ ID NO: 349):

MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSVYGMNWVRQAPGKGL

EWVAIIWYDGDNQYYADSVKGRFTISRDNSKNTLYLQMNGLRAEDTAVYYCARDLRTGPFDYWG QGTLVTVSS (described as SEQ ID NO: 1 in US 7446175).

The light chain variable region of canakinumab has the amino acid sequence (SEQ ID NO: 350):

MLPSQLIGFLLLWVPASRGEIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPK

LLIKYASQSFSGVPSRFSGSGSGTDFTLTINSLEAEDAAAYYCHQSSSLPFTFGPGTKVDIK (described as SEQ ID NO: 2 in US 7446175).

Exemplary inhibitors of CXCR2.

In one embodiment, the combination described herein comprises a chemokine receptor 2 (CXCR2) inhibitor (C-X-C motif). In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor, e.g., breast cancer, metastatic sarcoma, pancreatic cancer, melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) or a pediatric tumor (eg, rhabdomyosarcoma).

In some embodiments, the CXCR2 inhibitor is danirixin (CAS accession number: 954126-98-8). Danirixin is also known as GSK1325756 or 1-(4-chloro-2hydroxy-3-piperidin-3-ylsulfonylphenyl)-3-(3-fluoro-2-methylphenyl)urea. Danirixin is described, for example, in Miller et al., Eur J Drug Metab Pharmacokinet (2014) 39:173-181; and Miller et al., BMC Pharmacology and Toxicology (2015), 16:18.

In some embodiments, the CXCR2 inhibitor is reparixin (CAS accession number: 266359-83-5). Reparixin is also known as repertaxin or (2R)-2-[4-(2methylpropyl)phenyl]-N-methylsulfonylpropanamide. Reparixin is a noncompetitive allosteric inhibitor of CXCR1/2. Reparixin is described, for example, in Zarbock et al., British Journal of Pharmacology (2008), 1-8.

In some embodiments, the CXCR2 inhibitor is navarixin. Navarixin is also known as MK-7123, SCH 527123, PS291822 or 2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1(5-methylfuran-2-yl)propyl]amino]- 3,4-dioxocyclobuten-1-yl]amino]benzamide. Navarixin is described, for example, in Ning et al., Mol Cancer Ther. 2012;11(6):1353-64.

Exemplary PI3K-Y inhibitors, -δ.

In one embodiment, the combination described herein comprises a phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) inhibitor, e.g. ). In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., prostate cancer, breast cancer, brain cancer, bladder cancer, pancreatic cancer, cancer kidney, solid tumor, liver cancer, non-small cell lung cancer, endocrine cancer, ovarian cancer, melanoma, cancer of the female reproductive system, digestive tract/gastrointestinal cancer, glioblastoma multiforme, head and neck cancer, or colon cancer), eg, hematological malignancy (eg, leukemia (eg, lymphocytic leukemia, eg, chronic lymphocytic leukemia (CLL) (eg, recurrent CLL)), eg, lymphoma (eg, non-Hodgkin's lymphoma (eg, recurrent follicular B-cell non-Hodgkin's lymphoma (FL) or recurrent small lymphocytic lymphoma (SLL)) or, for example, multiple myeloma).

In some embodiments, the PI3K inhibitor is an inhibitor of the delta and gamma isoforms of PI3K. Exemplary PI3K inhibitors GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL-101, CAL 263, SF1126, PX-886 and PI3K Dual Inhibitor (e.g. Novartis BEZ235) which can be used in combination are described, for example, in WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556.

In some embodiments, the PI3K-γ,δ inhibitor is idelicib (CAS accession number: 870281-82-6). Idelalisib is also known as ZYDELIG®, GS-1101, CAL-101, or 5-fluoro-3-phenyl-2-[(1S)-1-(7H-n-urin-6-ylamino)propyl]-4(3H)-quinazolinone . Idelalisib blocks P1105, the delta isoform of PI3K. Idelalisib is described, for example, in Wu et al., Journal of Hematology & Oncology (2013) 6:36.

In some embodiments, the PI3K-γ,δ inhibitor is dactolisib (compound A4) or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)- 1,3-140 040861 dihydro-imidazo[4,5-c]quinolin-2-one (compound A41) or a compound described in PCT Publication No.

WO 2006/122806.

In some embodiments, the PI3K-γ,δ inhibitor is buparlisib (Compound A6) or the compound described in PCT Publication No. WO 2007/084786.

In one embodiment, a PI3K-γ,δ inhibitor such as buparlisib (compound A6) or a compound described in PCT Publication No. WO 2007/084786 is administered at a dose of approximately 100 mg (eg per day).

Other exemplary PI3K-γ,δ inhibitors that may be used in combination include, for example, pictilisib (GDC-0941), LY294002, pilaralisib (XL147), PI-3065, PI-103, VS-5584 (SB2343), CZC24832, duvelisib (IPI-145, INK1197), TG100-115, CAY10505, GSK1059615, PF-04691502, AS-605240, voxtalisib (SAR245409, XL765), IC-87114, omipalisib (GSK2126458, GSK4458), TG1007 , PKI-587), PKI-402, XL147 analog, PIK-90, PIK-293, PIK-294, 3-methyladenine (3-MA), AS-252424, AS-604850, or apitolisib (GDC-0980, RG7422) .

In some embodiments, the PI3K inhibitor is Compound A8 or the compound described in PCT Publication No. WO 2010/029082.

In some embodiments, the PI3K inhibitor is a general PI3K inhibitor (4S,5R)-3-(2'-amino-2-morpholino-4'-(trifluoromethyl)-[4,5'-bipyrimidin]-6-yl)- 4-(hydroxymethyl)-5methyloxazolidin-2-one (Compound A13) or the compound described in PCT Publication No. WO 2013/12482b.

Exemplary PI3K-γ,δ inhibitors include, but are not limited to, duvelisib and idelicib. Idelalisib (also called GS-1101 or CAL-101; Gilead) is a small molecule compound that blocks the delta isoform of PI3K. The structure of Idelalisib (5-fluoro-3-phenyl2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone) is shown below.

Duvelysib (also called IPI-145; Infinity Pharmaceuticals and Abbvie) is a small molecule compound that blocks PI3K-δ,γ. The structure of duvelysib (8-chloro-2-phenyl-3[(1S)-1-(9H-purin-6-ylamino)ethyl]-1 (2H)-isoquinolinone) is shown below.

In one embodiment, the inhibitor is a dual phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitor selected from

2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one ( PF-04691502);

N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5triazin-2-yl)phenyl ]urea (PF-05212384, PKI-587);

2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1 H-imidazo[4,5-c]quinolin-1 yl] phenyl}propanenitrile (BEZ-235);

apitolisib (GDC-0980, RG7422);

2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3pyridinyl}benzenesulfonamide (GSK2126458);

8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1Nimidazo[4,5-c]quinoline-2(3H )-one of maleic acid (NVP-BGT226);

3-[4-(4-morpholinylpyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol (PI-103);

5-(9-isopropyl-8-methyl-2-morpholino-9H-purin-6-yl)pyrimidin-2-amine (VS-5584, SB2343); or

N-[2-[(3,5-dimethoxyphenyl)amino]quinoxalin-3-yl]-4-[(4-methyl-3-methoxyphenyl)carbonyl]aminophenylsulfonamide (XL765).

Exemplary BAFF-R Inhibitors.

In one embodiment, the combination described herein comprises a B cell activating factor receptor (BAFF-R) inhibitor. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a hematologic cancer, e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), e.g., relapsed or refractory chronic lymphocytic leukemia).

In one embodiment, the BAFF-R inhibitor is VAY736. VAY736 is a fully human combinatorial antibody library (HuCAL) derived monoclonal antibody that targets BAFF-R. BAFF-R, also known as a member of the 13C tumor necrosis factor receptor superfamily, is overexpressed in certain tumor cell types and in autoimmune diseases. VAY736 has both anti-inflammatory and antineoplastic activity. In malignant cells, BAFF-R plays a key role in B cell proliferation and survival. VAY736 targets and binds BAFF-R, which inhibits both BAFF/BAFF-R interaction and BAFF-R mediated signaling. This may reduce the growth of tumor cells expressing BAFF-R.

VAY736 is described, for example, in US 8106163. The heavy chain CDR1 of VAY736 has the amino acid sequence GDSVSSNSAAWG (SEQ ID NO: 351) (described as SEQ ID NO: 3 in US 8106163). The heavy chain CDR2 of VAY736 has the amino acid sequence RIYYRSKWYNSYAVSVKS (SEQ ID NO: 352) (described as SEQ ID NO: 10 in US 8106163). The heavy chain CDR3 of VAY736 has the amino acid sequence YDWVPKIGVFDS (SEQ ID NO: 362) (described as SEQ ID NO: 17 in US 8106163). The VAY736 light chain CDR1 has the amino acid sequence RASQFISSSYLS (SEQ ID NO: 353) (described as SEQ ID NO: 24 in US 8,106,163). The VAY736 light chain CDR2 has the amino acid sequence LLIYGSSSRAT (SEQ ID NO: 354) (described as SEQ ID NO: 31 in US 8,106,163). The VAY736 light chain CDR3 has the amino acid sequence QQLYSSPM (SEQ ID NO: 355) (described as SEQ ID NO: 38 in US 8,106,163). The heavy chain variable region of VAY736 has the amino acid sequence (SEQ ID NO: 356):

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYA

VSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDSWGQGTLVTVSS (described as SEQ ID NO: 52 in US 8106163). The light chain variable region of VAY736 has the amino acid sequence (SEQ ID NO: 357):

DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFS

GSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRT (described as SEQ ID NO: 45 in US 8106163). The heavy chain of VAY736 has the amino acid sequence (SEQ ID NO: 358):

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYA VSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDSWGQGTLVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK (описанная в качестве SEQ ID NO: 75 в US 8106163).

The light chain variable region of VAY736 has the amino acid sequence (SEQ ID NO: 359):

DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFS GSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC (описанная в качестве SEQ ID NO: 71 в US 8106163).

Exemplary MALT-1/BTK Inhibitors.

In one embodiment, the combination described herein includes a MALT-1 inhibitor and/or BTK. In some embodiments, the combination is used to treat a cancer, such as the cancer described herein.

Exemplary MALT-1/BTK inhibitors include, but are not limited to:

(S)-1-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-3-(2-chloro-7-(1methoxyethyl)pyrazolo [1,5-a]pyrimidin-6-yl)urea, (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3- (2-(trifluoromethyl)pyridin-4yl)urea, (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(1- methyl-2-oxo-5- 142 040861 (trifluoromethyl)-1,2-dihydropyridin-3 -yl)urea, (R)-1-(6-(2H-1,2,3-triazol-2-yl) -5-(trifluoromethyl)pyridin-3-yl)-3-(2-chloro-7-(1-methoxy-2methylpropyl)pyrazolo[1,5-a]pyrimidin-6-yl)urea, (R)-1 -(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-3 -(2-chloro-7-(1-methoxy-2methylpropyl)pyrazolo[1, 5-a]pyrimidin-6-yl)urea, (S)-1-(7-(1-methoxyethyl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(2-( trifluoromethyl)pyridin-4yl)urea, (S)-1-(2-fluoro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(2-(trifluoromethyl)pyridine -4yl)urea, (S)-1-(2-chloro-7-(1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)-3-(5-cyanopyridin-3-yl)urea .

Exemplary BTK inhibitors include, but are not limited to, ibrutinib (PCI-32765); GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; SS-292; ONO-4059; CNX-774 or LFM-A13. In one embodiment, the BTK inhibitor does not reduce or inhibit the kinase activity of interleukin-2 inducible kinase (ITK), for example, it is selected from GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774 or LFM-A13.

In one embodiment, the kinase inhibitor is a BTK inhibitor, such as ibrutinib (PCI-32765). Structure of ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-b]pyrimidin-1-yl]piperidin-1-yl]prop-2-ene -1-he) is presented below.

In other embodiments, the BTK inhibitor is the BTK inhibitor described in WO 2015/079417, which is incorporated herein by reference in its entirety. For example, in some embodiments, the BTK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof;

where R1 represents hydrogen, C1-C ₆ -alkyl, optionally substituted with hydroxy;

R2 is hydrogen or halogen;

R3 is hydrogen or halogen;

R4 is hydrogen;

R5 is hydrogen or halogen;

or R4 and R5 are linked to each other and represent a bond, -CH ₂ -, -CH ₂ -CH ₂ -, -CH=CH-, -CH=CH-CH ₂ -; -CH ₂ -CH=CH- or -CH ₂ -CH ₂ -CH ₂ R6 and R7 are independently H, C ₁ -C ₆ alkyl optionally substituted with hydroxyl, C ₃ -C ₆ cycloalkyl optionally substituted with halogen, or hydroxy, or halogen;

R8, R9, R, R', R10 and R11 are independently H, or C1- _C6 alkyl optionally substituted with C1- _C6 alkoxy; or any two of R8, R9, R, R', R10 and R11, together with the carbon atom to which they are attached, may form a 3-6 membered saturated carbocyclic ring;

_R12 is hydrogen or C1- _C6 alkyl optionally substituted with halogen or _C1-6 alkoxy;

or R12 and any of R8, R9, R, R', R10 or R11 together with the atoms to which they are attached may form a 4, 5, 6 or 7 membered azacyclic ring which may be optionally substituted with halogen, cyano, hydroxyl , C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy;

n is 0 or 1; And

R13 is C ₂ -C ₆ alkenyl optionally substituted with C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy or N,N-di-C ₁ -C ₆ alkylamino; C ₂ -C ₆ alkynyl optionally substituted with C 1 -C ₆ alkyl or C 1 -C 6 alkoxy; or C2-C6 alkylenyl oxide optionally substituted with C1-C6 alkyl.

In some embodiments, the BTK inhibitor of Formula I is selected from:

- 143 040861

N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2fluorobenzamide; (E)-N-(3-(6-amino-5-((1-(but-2-enoyl)azetidin-3yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4 -cyclopropyl-2fluorobenzamide; N-(3-(6-amino-5-((1-propioylazetidine-Zyl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2fluorobenzamide; N-(3-(6-amino-5-((1-(but-2-inoyl)azetidin-3yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2fluorobenzamide ; N-(3-(5-((1-acryloylpiperidin-4-yl)oxy)-6aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (E)-N-(3-(6-amino-5-(2-(N-methylbut2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (E)-N-(3-(6-amino-5-(2-(4-methoxy N-methylbut-2-enamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2methylphenyl)-4- cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2·(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(2-((4-amino-6-(3 (4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5yl)oxy)ethyl)-N-methyloxirane-2-carboxamide ; N-(2-((4-amino-6 ) (3-(6-cyclopropyl-8-fluoro-1-oxoisoquinoline-2(1H)yl)phenyl)pyrimidin-5-yl)oxy)ethyl)-N- methylacrylamide; N-(3-(5·(2-acrylamidoethoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2·(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-(2 fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)4-cyclopropyl-2-fluorobenzamide; N-(3-(5-((1·acrylamidocyclopropyl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(5-(2·acrylamidopropoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2·inamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N· methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut 2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4cyclopropyl-2- fluorobenzamide; N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(5-((1-acryloylpyrrolidin 2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3 - (6-amino-5-((1-(but-2 inoyl)pyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro-2methylphenyl)-4 -cyclopropyl-2-fluorobenzamide; (S)-2- (3- (5- ( (1 acryloylpyrrolidin-2-yl) methoxy) -6-aminopyrimidin-4-yl) -5-fluoro 2- (hydroxymethyl) phenyl) - 6-cyclopropyl-3, 4-dihydroisoquinolin- 144 040861 (2H)-one; N-(2-((4-amino-6-(3-(6-cyclopropyl-1-oxo-3,4dihydroisoquinolin-2(1H)-yl)-5-fluoro-2(hydroxymethyl)phenyl)pyrimidin-5 -yl)oxy)ethyl)-N-methylacrylamide; N-(3-(5-(((2S,4R)-1-acryloyl-4methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2methylphenyl)-4-cyclopropyl-2 -fluorobenzamide; N-(3-(6-amino-5(((2S,4R)-1-(but-2-inoyl)-4-methoxypyrrolidin-2yl)methoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2fluorobenzamide; 2-(3-(5-(((2S,4R)-1-acryloyl-4-methoxypyrrolidin2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2(hydroxymethyl)phenyl)-6 -cyclopropyl-3,4-dihydroisoquinoline-1(2H)one; N-(3-(5-(((2S,4S)-1-acryloyl-4-methoxypyrrolidin-2yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4cyclopropyl-2 -fluorobenzamide; N-(3-(6-amino-5-(((2S,4S)-1-(but-2inoyl)-4-methoxypyrrolidin-2-yl)methoxy)pyrimidin-4-yl)-5-fluoro2-methylphenyl )-4-cyclopropyl-2-fluorobenzamide; N-(3-(5-(((2S,4R)1-acryloyl-4-fluoropyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-fluorobenzamide; N-(3-(6-amino-5-(((2S,4R)-1-(but-2-inoyl)-4-fluoropyrrolidin-2yl)methoxy)pyrimidin-4-yl)-5-fluoro-2 -methylphenyl)-4-cyclopropyl-2fluorobenzamide; (S)-N-(3-(5-((1-Acryloylazetidin-2-yl)methoxy)-6aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2fluorobenzamide; (S)-N-(3-(6-amino-5-((1-propioylazetidin-2yl)methoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2fluorobenzamide; (S)-2-(3-(5-((1-acryloylazetidin-2-yl)methoxy)-6aminopyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)-6cyclopropyl-3,4- dihydroisoquinolin-1(2H)-one; (R)-N-(3-(5-((1acryloylazetidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (R)-N-(3-(5-((1acryloylpiperidin-3-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(5-(((2R,3S)-1acryloyl-3-methoxypyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide; N-(3-(5(((2S,4R)-1-acryloyl-4-cyanopyrrolidin-2-yl)methoxy)-6aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2fluorobenzamide or N-(3-(5-(((2S,4S)-1-acryloyl-4cyanopyrrolidin-2-yl)methoxy)-6-aminopyrimidin-4-yl)-5-fluoro-2methylphenyl)-4-cyclopropyl -2-fluorobenzamide.

Unless otherwise indicated, the chemical terms used above in describing the BTK inhibitor of formula I are used in accordance with their meanings specified in international application WO/2015/079417, which is incorporated herein by reference in its entirety.

Exemplary JAK Inhibitors.

In one embodiment, the combination described herein comprises a Janus kinase (JAK) inhibitor. In some embodiments, the combination is used to treat a cancer, e.g., the cancer described herein, e.g., a solid tumor (e.g., colon cancer, prostate cancer, lung cancer, breast cancer, or pancreatic cancer), e.g., a hematological malignancy (eg, leukemia (eg, myeloid leukemia or lymphocytic leukemia), eg, lymphoma (eg, non-Hodgkin's lymphoma), or, eg, multiple myeloma.

In some embodiments, the JAK inhibitor is 2-fluoro-N-methyl-4-(7(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide ( compound A17) or its dihydrochloride, or the compound described in PCT Publication No. WO 2007/070514.

In some embodiments, a JAK inhibitor, e.g., 2-fluoro-N-methyl-4-(7-(quinolin-6ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide ( compound A17), or its dihydrochloride, or the compound described in PCT Publication No. WO 2007/070514, is administered at a dose of about 400-600 mg (e.g. per day), 500 or

- 145 040861

500-600 mg.

In some embodiments, the JAK inhibitor is ruxolitinib phosphate (also known as JAKAFI; Compound A18) or a compound described in PCT Publication No. WO

2007/070514.

In one embodiment, a JAK inhibitor, for example, ruxolitinib phosphate (also known as JAKAFI; Compound A18) or a compound described in PCT Publication No. WO 2007/070514, is administered at a dose of about 15-25 mg, for example, twice a day. In some embodiments, the dosage is about 15, 20, or 25 mg, or about 15-20 or 20-25 mg.

Exemplary CRTH2 Inhibitors.

In one embodiment, the combination described herein comprises an inhibitor of a chemoattractant receptor homologous to a molecule expressed on T helper 2 (CRTH2). In some embodiments, the combination is used to treat a cancer, such as the cancer described herein.

In some embodiments, the CRTH2 inhibitor is QAV680 (CAS accession number: 872365-16-7). QAV680 is also known as fevipiprant and 2-[2-methyl-1-[(4methylsulfonylphenyl)methyl]pyrrolo[2,3-b]pyridin-3-yl]acetic acid. QAV680 is described, for example, in Sandham et al., Bioorg Med Chem. 2013;21(21):6582-91. QAW039 is also known as [1-(4methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]acetic acid. QAW039 is described, for example, in Sykes et al., European Respiratory Journal September 1, 2014 vol. 44 no. Suppl 58 P4074.

In some embodiments, the CRTH2 inhibitor is QAW039 (CAS number: 872365-14-5).

Other CRTH2 inhibitors that can be used in combination include, for example, AZD1981, ARRY-502, setipiprant (ACT-453859) and ACT-129968.

Exemplary inhibitors of PFKFB3.

In one embodiment, the combination described herein comprises a 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) inhibitor. In some embodiments, the combination is used to treat a cancer, eg, the cancer described herein, eg, a solid tumor (eg, advanced solid tumor).

In some embodiments, the PFKFB3 inhibitor is PFK-158. PFK-158 is also known as ACT-PFK-158 or (E)-1-(pyridin-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)prop-2-en1-one. PFK-158 is a derivative of 3-(3-pyridinyl)-1-[4-pyridinyl]-2-propen-1-one (3PO). PFKFB3, which catalyzes the conversion of fructose-6-phosphate to fructose-2,6-bisphosphate, is highly expressed and active in human malignant cells and plays a key role in increasing both the glycolytic flux in malignant cells and malignant cell proliferation. Inhibitors of PFKFB3, such as PFK-158, can bind and inhibit the activity of PFKFB3, resulting in inhibition of both the glycolytic pathway in malignant cells and glucose uptake by malignant cells. This interferes with the production of macromolecules and energy production, which cause increased proliferation of malignant cells compared to normal healthy cells. Depriving malignant cells of nutrients and energy leads to inhibition of the growth of malignant cells.

PFK158 is described, for example, on page 5 of WO 2013/148228.

In some embodiments, the PFKFB3 inhibitor has the following structure:

Means that suppress the immune system.

In an alternative embodiment, the anti-TIM-3 antibody molecules described herein are used to generate 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) against B7-H1 or PD-1.

Suppression of the immune system is desirable in the treatment of inflammatory and autoimmune diseases, and graft-versus-host disease (GvHD). Examples of autoimmune disorders that can be treated by administering the antibodies of the present invention include, but

- 146 040861 are not limited to them, focal alopecia, ankylosing spondylitis, antiphospholipid syndrome, autoimmune disease of Addison, autoimmune adrenal diseases, autoimmune hemolytic anemia, autoimmune hepatitis, orchitis, auto-bombotenica, Bullet's disease, beules, beules of beules. dermatitis, chronic fatigue and immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, 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, lupus vulgaris, Meniere's disease, mixed connective tissue disease, disseminated clerosis, neuromyelitis optic (NMO), type 1 diabetes mellitus 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, orypsoriatic cirrhosis arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, muscle stiffness syndrome, systemic lupus erythematosus, lupus vulgaris, Takayasu's arteritis, temporal arteritis/giant cell arteritis, transverse myelitis, ulcerative colitis, uveitis, vasculitis such as dermatitis herpetiformis, vasculitis, vitiligo and Wegener's granulomatosis.

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

Thus, the antibodies and antigen-binding fragments of the present invention can be used to treat inflammatory and autoimmune diseases.

diagnostic application.

In one aspect, the present invention relates to a diagnostic method for detecting the presence of a PD-L1 protein in vitro (eg, in a biological sample, such as a tissue biopsy, eg, from malignant tissue) or in vivo (eg, imaging in an individual in vivo). The method includes:

(i) contacting a sample with an antibody molecule as described herein, or administering an antibody molecule to an individual; (optionally), (ii) bringing into contact with it a reference sample, for example, a control sample (eg, a control biological sample, such as plasma, tissue, biopsy) or a control individual; and (iii) detecting complex formation between the antibody molecule and the sample or individual or control sample or individual, wherein a change, e.g., a statistically significant change, in complex formation in the sample or individual relative to the control sample or individual indicates the presence of PD-L1 in the sample.

The antibody molecule can be directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, and radioactive materials, as described above and as described in more detail below.

The term sample, as used for samples used to detect polypeptides, includes, but is not limited to, cells, cell lysates, extracts of proteins or cell membranes, body fluids, or tissue samples.

Complex formation between an antibody molecule and PD-L1 can be detected by measuring or visualizing either the binding molecule bound to the PD-L1 antigen or the unbound binding molecule. You can use conventional methods of analysis for detection, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA) or tissue immunohistochemistry. As an alternative to labeling the antibody molecule, the presence of PD-L1 in a sample can be analyzed by a competitive immunoassay using detectably labeled standards and an unlabeled antibody molecule. In that assay, a biological sample, labeled standards, and an antibody molecule are combined and the amount of labeled standard bound to an unlabeled binding molecule is determined. The amount of PD-L1 in a sample is inversely proportional to the amount of labeled standard bound to the antibody molecule.

Alternatively, or in combination with the methods described herein, a method for assessing an individual's immune cell (eg, T-cell) activation status (eg, assessing the likelihood of an individual's response to immunomodulator therapy) is described. The method includes determining the level

- 147 040861 and/or T-cell activation distributions in an individual. In one embodiment, the level and/or distribution of T cell activation includes a measure of the level and/or distribution of one or more of: CD8, PD-L1, or other checkpoint inhibitor (e.g., one or more of PD-1, LAG-3, TIM-3, CEACAM (eg CEACAM-1, -3 and/or -5) or CTLA-4), or any combination thereof. For example, the level and/or distribution of CD8-expressing cells can be assessed as a marker of activated T cells. In other embodiments, the level and/or distribution of cells expressing PD-L1 or another checkpoint inhibitor can be assessed. The subject may be assessed before, during or after immunomodulator therapy. In one embodiment, the subject is evaluated prior to immunomodulator therapy (eg, checkpoint molecule inhibitor therapy), eg, prior to initial treatment or prior to treatment after a treatment interval. In one embodiment, an elevated level of one or more of CD8, PD-L1, or another checkpoint inhibitor in an individual (e.g., relative to a reference, e.g., control) is indicative of an increased ability of the individual to respond to therapy (also referred to herein as a positive immune activation status). ). In another embodiment, a reduced level of one or more of CD8, PD-L1, or other checkpoint inhibitor in an individual (e.g., relative to a reference, e.g., control) is indicative of the individual's reduced ability to respond to therapy (also referred to herein as immune activation status negative). ). Optionally, the method may include administering therapy with an immunomodulator as described herein (eg, a checkpoint molecule inhibitor as described herein) if the subject is determined to have a positive immune activation status.

In one embodiment, immunomodulator therapy comprises a co-stimulatory molecule activator, eg one or more activators as described herein (eg, a GITR molecule agonist as described herein). In other embodiments, the immunomodulator therapy comprises an immune checkpoint molecule inhibitor, e.g., one or more checkpoint inhibitors as described herein (e.g., an inhibitor of one or more of PD-L1, PD-1, TIM-3, or CTLA- 4 as described herein). In one embodiment, the immunomodulator therapy comprises an anti-PD-L1 antibody molecule as described herein. In other embodiments, the immunomodulator therapy comprises a combination of a costimulatory molecule activator and a checkpoint inhibitor inhibitor.

In some embodiments, the level and/or distribution of CD8, PD-L1, or other checkpoint inhibitor is determined in vivo, e.g., non-invasively (e.g., by detecting an antibody to a T-cell marker labeled with a detectable label using a suitable method). imaging, such as positron emission tomography (PET) scanning For example, target antibody PET or immune PET (eg, anti-CD8 antibody PET or anti-PD-L1 antibody PET) can be used to detect the level and/or distribution (e.g., tumor location) of CD8 or PD-L1 expressing cells in vivo Antibody imaging techniques (e.g., antibody PET imaging) are known in the art, for example, as described by Lamberts, L. E. et al (2015) J. Clin. Oncol 33 (DOI: 10, 1200/JCO.2014, 57, 8278); Tavare, R. et al. (2014) PNAS 111 (3): 1108-1113; Pampaloni et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 3084); and Boerman and Oyen (2011) The Journal of Nuclear Medicine 52(8):1171-72; in US Patent No.

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2006/074129, WO 2006/100562, WO 2006/147379, WO 2007/092115, WO

2008/023251, WO 2008/057166, WO 2008/115854, WO 2008/143706, WO

2009/121631, WO 2010/127054, WO 2011/153346, WO 2015/085179, WO

2015/100498, WO 2015/103039 and WO 92/06068; and European Patent Nos. EP 05514 34 Bl, EP 133 0 652 Bl and EP 18 61713 Bl;

all of which are incorporated herein by reference.

In one embodiment, the level and/or distribution of CD8 is determined in vivo, e.g., by detecting an anti-CD8 antibody labeled with a detectable PET reagent, e.g. 1,4,7-triacetic acid for radiolabeling ⁶⁴ Cu, for example, as described in Tavare, R. et al. (2014) PNAS 111(3):1108-1113. In another embodiment, the level and/or distribution of PD-1 or PD-L1 is determined in vivo, e.g., by detecting an anti-PD-1 antibody or an anti-PD-L1 antibody labeled with a detectable PET reagent, e.g., ¹⁸ F-fluorodeoxyglucose (FDG ), for example, as described in Pampaloni et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 3084). In another embodiment, the level and/or distribution of CTLA-4 is determined in vivo, for example by detecting an anti-CTLA-4 antibody labeled with a detectable PET reagent, for example as described in WO 2009/121631.

In other embodiments, the level of CD8, PD-L1, or other checkpoint inhibitor is determined in a sample (eg, tumor biopsy) obtained from an individual (eg, using immunohistochemical methods).

Also within the scope of the invention are detection reagents. An example is immuno-PET reagents that include an anti-PD-L1 antibody molecule as described herein. Exemplary labeling reagents include, but are not limited to, bromine-76 ( ⁷⁶ Br), calcium 47 ( ⁴⁷ Ca), carbon-11 ( ¹¹ C), carbon-14 ( ¹⁴ C), chromium-51 ( ⁵¹ Cr), cobalt -57 ( ⁵⁷ Co), cobalt-58 ( ⁵⁸ Co), copper-64 ( ⁶⁴ Cu), erbium-169 ( ¹⁶⁹ Er), fluorine-18 ( ¹⁸ F), fluorodeoxyglucose (18F-FDG), gallium-67 ( ⁶⁷ Ga), gallium-68 ( ⁶⁸ Ga), hydrogen-3 ( ³ H), indium-111 ( ¹¹¹ In), iodine-123 ( ¹²³ I), iodine-124 ( ¹²⁴ I), iodine-125 ( ¹²⁵ I ), iodine-131 ( ¹³¹ I), iron-59 ( ⁵⁹ Fe), krypton-Sim ( ^81m Kr), lutetium-177 ( ¹⁷⁷ Lu), nitrogen-13 ( ¹³ N), oxygen-15 ( ¹⁵ O), phosphorus-32 ( ³² P), samarium-153 ( ¹⁵³ Sm), selenium-75 (75Se), strontium-89 ( ⁸⁹ Sr), thallium-201 ( ²⁰¹ Tl), sodium-22 ( ²² Na), sodium-24 ( ²⁴ Na), technetium-99m ( ^99m Tc), xenon-133 ( ¹³³ Xe), yttrium-8b ( ⁸⁶ Y), yttrium-88 ( ⁸⁸ Y), yttrium-90 ( ⁹⁰ Y), and zirconium-89 ( ⁸⁹ Zr). Additional exemplary labeling reagents and their uses in immuno-PET are described, for example, in Lamberts, LE et al. (2015) J. Clin. oncol. 33 (DOI: 10,1200/JCO.2014,57,8278) and Boerman and Oyen (2011) The Journal of Nuclear Medicine 52(8):1171-72. Nucleic acids

The present invention also relates to nucleic acids containing nucleotide sequences that encode heavy and light chain variable regions and CDRs or hypervariable loops of anti-PD-L1 antibody molecules as described herein. For example, the present invention provides first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an anti-PD-L1 antibody molecule selected from one or more of the antibody molecules described herein. Nucleic acid may contain a nucleotide sequence, as indicated in table. of the present description, or a sequence essentially identical to it (for example, a sequence at least about 85%, 90%, 95%, 99% or more identical to it or differing by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in the table of the present description).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a heavy chain variable region having an amino acid sequence as set forth in the tables provided herein, or a sequence essentially homologous to it (eg, sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or having one or more substitutions, eg conservative substitutions). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a light chain variable region having an amino acid sequence as set forth in the tables provided herein, or a sequence essentially homologous to it (eg, a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or having one or more substitutions, eg conservative substitutions). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops from the heavy and light chain variable regions having the amino acid sequence as shown in Table 1. 149 040861 herein, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or having one or more substitutions, e.g., conservative substitutions) .

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a heavy chain variable region having a nucleotide sequence as set forth in the Table provided herein, a sequence substantially homologous to her (eg, a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridizing under the stringent conditions described herein). In another embodiment, the nucleic acid may comprise a nucleic acid sequence encoding at least one, two, or three CDRs or hypervariable loops from a light chain variable region having a nucleotide sequence as set forth in the tables provided herein, or a sequence according to substantially homologous to it (eg, a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridizing under the stringency conditions described herein). In another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops from the heavy and light chain variable regions, having a nucleotide sequence as indicated in the table presented in herein, or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridizing under the stringency conditions described herein).

In another aspect, the application relates to host cells and vectors containing the nucleic acids described in the present description. The nucleic acids may be present in a single vector or in separate vectors within the same host cell or in a separate host cell, as described in more detail below.

Vectors.

In addition, the present invention provides for vectors containing nucleotide sequences encoding the antibody molecule described in the present description. In one embodiment, the vectors contain nucleotides encoding the antibody molecule described in the present description. In one embodiment, the vectors contain the nucleotide sequences described in the present description. Vectors include, but are not limited to, 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 bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, vaculovirus, retroviruses (Rous sarcoma virus, MMTV or MOMLV), or SV40. Another class of vectors uses RNA elements derived from RNA viruses such as Semliki forest virus, eastern equine encephalitis virus, and flaviviruses.

In addition, the selection of cells that have stably integrated DNA into their chromosomes can be carried out by introducing one or more markers that allow the selection of transfected host cells. The marker may confer, for example, prototropy to an auxotrophic host, resistance to biocides (eg antibiotics), or resistance to heavy metals such as copper or similar. The selectable marker gene can either be directly linked to the DNA sequences to be expressed, or it can be introduced into the same cell by co-transformation. Additional elements may be required for optimal mRNA synthesis. These elements may include splicing signals as well as transcription promoters, enhancers, and termination signals.

Once an expression vector or DNA sequence containing constructs has been obtained for expression, the expression vectors can be transfected or introduced into an appropriate host cell. Various methods can be used to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid-based transfection, or other conventional methods. In the case of protoplast fusion, cells are grown in medium and screened for appropriate activity.

Methods and conditions for culturing the resulting transfected cells and isolating the produced antibody molecule are known to those skilled in the art and may be varied or optimized depending on the particular expression vector and mammalian host cell used, as described herein.

Cells.

The present invention also relates to host cells containing a nucleic acid encoding an antibody molecule as described herein.

- 150 040861

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

In one embodiment, host cells are modified by genetic engineering using an expression cassette. Expression cassette refers to nucleotide sequences that are capable of influencing gene expression in hosts compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. You can also use additional factors necessary or useful to achieve expression, such as, for example, an inducible promoter.

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

The cell may be, but is not limited to, 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.

Tab. 1: Amino acid and nucleotide sequences of mouse antibody molecules, chimeric and humanized antibody molecules. Antibody molecules include the mouse BAP058 mAb, the chimeric BAP058-chi mAb, and the humanized BAP058-hum01 to BAP058-hum17 and BAP058-Clone-K to BAP058-Clone-O mAbs. Shown are the amino acid and nucleotide sequences of the heavy and light chain CDRs, the heavy and light chain variable regions, and the heavy and light chains.

Table 1

VAR058 NS SEQ ID NO: 1 (Kabat) HCDR1 SYWMY SEQ ID NO: 2 (kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 3 (Kabat) HDDR3 DYRKGLYAMDY SEQID NO: 4(Chothia) HCDR1 GYTFTSY SEQID NO: 5(Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 6 vh QVHLQQPGAELVKPGASVKLSCKASGYTFTSYWMYWV KQGPGRGLEWIGRIDPNSGSTKYNEKFKNKATLTVDK S S S TAYMQLS S LT S EDSAVYYCARDYRKGLYAMDYWG QGTSVTVSS SEQ ID NO: 7 DNA VH caggtccacctgcagcagcctggggctgagcttgtga agcctggggcttcagtgaagctgtcctgcaaggcttc tggctacaccttcaccagttactggatgtactgggtg aaacaggggcctggacgaggccttgagtggattggaa ggattgatcctaatagtgggagtactaagtacaatga gaagttcaagaacaaggccacactgactgtagacaaa tcctccagcacagcctacatgcagctcagcagcctga catctgaggactctgcggtctattattgtgcaaggga ctatagaaaggggctctatgctatggactactggggt caaggaacctcagtcaccgtctcctca

- 151 040861

BAP058LC SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA SEQ ID NO: 10 (Rabat) LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 8 VL DIVMTQSHRFMSTSVGDRVSITCRASQDVGTAVAWYQ QRPGQSPRLLIYWASTRHTGVPDRFTGSGSGTDFTLT ISNVQSEDLADYFCQQYNSYPLTFGAGSRLELR SEQ ID NO: 15 DNA VL Gacattgtgatgacccagtctcacaaattcatgtcca catcagtaggagacagggtcagcatcacctgcaaggc cagtcaggatgtgggtactgctgtagcctggtatcaa cagaaaccagggcaatctcctaaactactgatttact gggcatccacccggcacactggagtccctgatcgctt cacaggcagtggatctgggacagatttcactctcacc attagcaatgtgcagtctgaagacttggcagattatt tctgtcagcagtataacagctatcctctcacgttcgg tgctgggtccaagctggagctgaaa BAP058-chi HC SEQ ID NO: 1 (Rabat) HCDR1 SYWMY SEQ ID NO: 2 (Rabat) HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO: 3 (Rabat) HDDR3 DYRRGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRRGLYAMDY SEQ ID NO: 16 vh EVQLQQSGAELVRPGASVRLSCRASGYTFTSYWMYWV RQGPGRGLEWIGRIDPNSGSTRYNERFRNRATLTVDR SSSTAYMQLSSLTSEDSAVYYCARDYRKGLYAMDYWG QGTTVTVSS BAP058-chi LC SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA

- 152 040861

SEQID NO: (kabat) 10 LCDR2 WASTRHT SEQ ID 11(Kabat) NO: LCDR3 QQYNSYPLT SEQ ID NO: (Chothia) 12 LCDR1 SQDVGTA SEQ ID NO: (Chothia) 13 LCDR2 WAS SEQ ID NO: (Chothia) 14 LCDR3 YNSYPL SEQID NO: 17 VL DIMMTQSHKFMSTSVGDRVSITCKASQDVGTAVAWYQ QKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLT ISNVQSEDLADYFCQQYNSYPLTFGQGTKVEIK BAP058-hum01-HC SEQ ID NO (Kabat) 1 HCDR1 SYWMY SEQ ID NO (Kabat) 2 HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO (Kabat) 3 HDDR3 DYRKGLYAMDY SEQ ID NO (Chothia) 4 HCDR1 GYTFTSY SEQ ID NO (Chothia) 5 HCDR2 DPNSGS SEQ ID NO (Chothia) 3 HDDR3 DYRKGLYAMDY SEQID NO: 18 vh QVQLVQ S GAEVKKPGASVKVS CKAS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQID NO: 19 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA

- 153 040861

G GAT T GAT C C TAATAG T G GGAG TAC TAAG TACAAT GA GAAG Τ T CAAGAACAGAT T CAC SAT C T C CAGAGAT GAT TCAAAGAACACGGCGTATCTGCAAAATGAACAGCCTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTGGGCCTTGGACTACTGGGC CAGGCACCCCC SEQ ID NO: 20 heavy chain QVQLVQ S GAEVKKPGASVKVS CKAS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 21 DNA, heavy chain CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA G GAT T GAT С С ΤAATAG T G GGAG ТАС TAAG TACAATGA GAAG Τ T CAAGAACAGAT T СAC CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA

- 154040861

C GAAGAC С ТАС AC С T G С AAC G T AGAT C AC AAG С С C AG СAACAC CAAG G T G GACAAGAGAG T T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA VARO58-humOΙ- ΣΟ SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL

- 155 040861

SEQ ID NO: 22 VL DIVMTQTPLSLPVTPGEPASISCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 23 DNA VL GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCG TCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG СAGAAG С СAG G G СAG Т С Т С СACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACC AT CAGCAGCC Т GCAGT С Т GAAGAT Т Т Т GCAGT Т ТАТ Т ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 24 Light chain DIVMTQTPLSLPVTPGEPASISCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKAD YEKHKVYACEVTHQ SEQ ID NO: 25 DNA, light chain GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCG TCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG СAGAAG С СAG G G СAG Т С Т С СACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACC AT CAGCAGCC Т GCAGT С Т GAAGAT Т Т Т GCAGT Т ТАТ Т ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATААС ТТСТАТСС СAGAGAG G С СAAAG ТАСAG Т G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G Т CACAGAGCAGGACAGCAAGGACAGCACC ТА CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAC GAGAAAASACAAAG TCTACGCCTGC GAAG T CAC C C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA

- 156 040861

CAGGGGAGAGTGT BAP058-hum02-HC SEQ ID NO: 1 (kabat) HCDR1 SYWMY SEQ ID NO: 2 (kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 3 (kabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 18 vh QVQLVQ S GAEVKKPGASVKVS OKAS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO: 19 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAT T СAC CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 20 heavy chain QVQLVQ S GAEVKKPGASVKVS CKAS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV

- 157 040861

TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQID NO: 21 DNA, heavy chain CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAT T САС CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAGС С CAG СAACACCAAGGT GGACAAGAGAGT T GAGT СCAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGA ACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT

- 158 040861

GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G СACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-hum02- LC SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA SEQ ID NO: 10 (Rabat) LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 26 VL DIQMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYL QRPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQYNSYPLTFGQGTRVEIR SEQ ID NO: 27 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTG CAT С T G TAGGAGACAGAGT CACCAT САС T T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAT T T САС T С T CACC ATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 28 Light DIQMTQSPSSLSASVGDRVTITCRASQDVGTAVAWYL

- 159 040861

chain QRPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLRSGTASWCLLNNFYPREARVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTRSFNRGEC SEQ ID NO: 29 DNA, light chain GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTG CAT С T G TAGGAGACAGAGT CACCAT САС T T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAT T T САС T С T CACC ATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T СAC С C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-hum03-HC SEQID NO: (Rabat) : 1 HCDR1 SYWMY SEQID NO: (Rabat) : 2 HCDR2 RIDPNSGSTRYNERFRN SEQID NO: (Rabat) : 3 HDDR3 DYRRGLYAMDY SEQ ID NO: (Chothia) : 4 HCDR1 GYTFTSY SEQ ID NO: (Chothia) : 5 HCDR2 DPNSGS SEQ ID NO: : 3 HDDR3 DYRRGLYAMDY

- 160 040861

(Chothia) SEQ ID NO: 30 vh EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO: 31 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС ТAAG ТACААТ GA GAAG Т Т СAAGAACAGAG Т САС GAT ТАС С G С G GAGААА TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 32 heavy chain ЕVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 33 DNA, heavy chain GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAG T GAG GAT TAC C G C G GACAAA TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA

- 161 040861

GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAG С С CAG СAACAC CAAG G T G GACAAGAGAG T T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGA CGGCTCCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058- LC hum03- SEQID (Rabat) NO: 9 LCDR1 KASQDVGTAVA SEQ ID NO: 10 LCDR2 WASTRHT

- 162 040861

(kabat) SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 34 VL ΕIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPDRFSGSGSGTDFTLK ISRVEAEDVGVYYCQQYNSYPLT FGQGTKVEIK SEQ ID NO: 35 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCAGACAGGTT CAGT GGCAGT GGGT CAGGCAC T GAT T T CACAC T GAAA ATCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 36 Light chain ΕIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPDRFSGSGSGTDFTLK ISRVEAEDVGVYYCQQYNSYPLT FGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESTKVTEQDSKDSTYVSLSSTLECSSKAD YEKHSLSSTLECTSKATHPV SEQ ID NO: 37 DNA, light chain GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCAGACAGGTT CAGT GGCAGT GGGT CAGGCAC T GAT T T CACAC T GAAA ATCAGCAGGGTGGAGGCTGAGGATGTTGGAGTTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG

- 163 040861

CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAG TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAAGACAAAG TCTACGCCTGC GAAG T САС С C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-hum04-HC SEQ ID NO (Rabat) 1 HCDR1 SYWMY SEQ ID NO (Rabat) 2 HCDR2 RIDPNSGSTRYNERFRN SEQID NO: (Rabat) : 3 HDDR3 DYRRGLYAMDY SEQ ID NO: (Chothia) : 4 HCDR1 GYTFTSY SEQ ID NO: (Chothia) : 5 HCDR2 DPNSGS SEQ ID NO: (Chothia) : 3 HDDR3 DYRRGLYAMDY SEQID NO: 38 vh EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWV RQAPGQGLEWMGRIDPNS GS TRYNERFRNRVTISVDT SRNQFSLRLSSVTAADTAVYYCARDYRRGLYAMDYWG QGTTVTVSS SEQID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAG T CAC CATAT CAG TAGACAC G TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGA CCGCCGCGGACACGGCTGTGTATTACTGTGCAAGGGA

- 164 040861

CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQID NO: 40 heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTSYWMYWV RQAPGQGLEWMGRIDPNS GS TKYNEKFKNRVTISVDT SKNQFSLKLSSVTAADTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQID NO: 41 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAG T CAC CATAT CAG TAGACAC G TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGA CCGCCGCGGACACGGCTGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАС AC С T G С AAC G T AGAT C AC AAG С С C AG СAACAC CAAG G T G GACAAGAGAG T T GAG T WITH СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC

- 165 040861

CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G СACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-hum04- LC SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA SEQ ID NO: 10 (Rabat) LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 42 VL EIVLTQS PDFQSVTPRERVTITCRASQDVGTAVAWYL QRPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTRVEIR SEQ ID NO: 43 DNA VL GAAATTGTGCTGACTCAGTCTCAGACTTTCAGTCTG

- 166 040861

Т GAC Т С CAAAGGAGAAAGT САССАТ САСС Т GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG СAGAAG С СAG G G СAG Т С Т С СACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С Т GGGACAGAT Т Т ТАС Т Т Т САСС AT CAGCAGCC Т GCAGCC Т GAAGATAT Т GCAACATAT Т ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 44 Light chain ЕIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSECTYSLSSTLTLSKAD YEKHKVYACESF SEQ ID NO: 45 DNA, light chain GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG Т GAC Т С CAAAGGAGAAAGT САССАТ САСС Т GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG СAGAAG С СAG G G СAG Т С Т С СACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С T GGGACAGAT Т Т ТАС Т Т Т САСС AT CAGCAGCC Т GCAGCC Т GAAGATAT Т GCAACATAT Т ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATААС TTSTATCSS CAGAGAG G C CAAAG TACAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAC GAGAAAASACAAAG TCTACGCCTGC GAAG T CAC C C ATCAGGGCCTGAGCTCCCGTCACAAAG BAP058-hum05-HC SEQ ID NO: 1 (kabat) HCDR1 SYWMY

- 167 040861

SEQID NO 2 HCDR2 RIDPNSGSTKYNEKFKN (kabat) SEQ ID NO (Kabat) 3 HDDR3 DYRKGLYAMDY SEQ ID NO (Chothia) 4 HCDR1 GYTFTSY SEQ ID NO (Chothia) 5 HCDR2 DPNSGS SEQ ID NO (Chothia) 3 HDDR3 DYRKGLYAMDY SEQID NO: 46 vh EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWI RQSPSRGLEWLGRIDPNSGSTKYNEKFKNRLTISKDT SKNQWLTMTNMDPVDPVDTATYYCARDYRKGLYAMDYWG QGTTVTVSS SEQID NO: 47 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC T GGC TACAC С T T CAC CAG T ТАС T GGAT G ТАС T GGAT C AGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAC T САС CAT С T С CAAG GACAC C T С СAAAAAC CAG GTGGTCCT TAGAAT GAC СAACAT G G ACCCTGTGGACACAGCCACGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQID NO: 48 heavy chain EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWI RQSPSRGLEWLGRIDPNSGSTKYNEKFKNRLTISKDT SKNQWLTMTNMDPVDTATYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY

- 168040861

SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQID NO: 49 DNA, heavy chain GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC T GGC TACAC C Τ T GAG GAG T ТАС T GGAT G ТАС T GGAT C AGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG Τ T CAAGAACAGAC T САС CAT С T С CAAG GAGAC C T С СAAAAAC CAG GTGGTCCT TAGAAT GAC СAACAT G G ACCCTGTGGACACAGCCACGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G CAAC G TAGAT CACAAG С С CAG CAACAC CAAG G T G GACAAGAGAG Τ T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC

- 169 040861

AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-hum05- LC SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA SEQ ID NO: 10 (Rabat) LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 42 VL EIVLTQS PDFQSVTPRERVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIR SEQ ID NO: 43 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С T GGGACAGAT Τ T ТАС T T T CACC AT CAGCAGCC T GCAGCC T GAAGATAT T GCAACATAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 44 Light chain EIVLTQS PDFQSVTPRERVTITCRASQDVGTAVAWYL QRPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTRVEIRRTVA APSVFIFPPSDEQLRSGTASWCLLNNFYPREARVQW RVDNALQSGNSQESVTEQDSRDSTYSLSSTLTLSRAD

- 170 040861

YEKHKVYACEVTHQGLSSPVTRSFNRGEC SEQ ID NO: 45 DNA, light chain GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С T GGGACAGAT T T ТАС T T T CACC AT CAGCAGCC T GCAGCC T GAAGATAT T GCAACATAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T СAC С C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-hum06- HC SEQID NO: (Rabat) : 1 HCDR1 SYWMY SEQID NO: (Rabat) : 2 HCDR2 RIDPNSGSTKYNERFRN SEQID NO: (Rabat) : 3 HDDR3 DYRRGLYAMDY SEQ ID NO: (Chothia) : 4 HCDR1 GYTFTSY SEQ ID NO: (Chothia) : 5 HCDR2 DPNSGS SEQ ID NO: (Chothia) : 3 HDDR3 DYRRGLYAMDY SEQ ID NO: 50 vh EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWI RQPPGRGLEWIGRIDPNS GS TRYNERFRNRVTITADR

- 171 040861

STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO: 51 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC Т GGC ТАСАС С Т Т САС CAG Т ТАС Т GGAT G ТАС Т GGAT С CGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGTA GGATTGATCCTAATAGTGG GAG ТАС ТAAG ТАСААТ GA GAAG Т Т СAAGAACAGAG Т САС GAT ТАС С G С G GACААА TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 heavy chain ЕVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWI RQPPGKGLEWIGRIDPNS GS TKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 53 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC Т GGC ТАСАС С Т Т САС CAG Т ТАС Т GGAT G ТАС Т GGAT С CGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGTA GGATTGATCCTAATAGTGG GAG ТАС ТAAG ТACААТ GA GAAG Т Т СAAGAACAGAG Т САС GAT ТАС С G С G GACААА TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA

- 172 040861

AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAG С С CAG СAACAC CAAG G T G GACAAGAGAG T T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC CAC TACAC ACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-hum06- LC SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA SEQ ID NO: 10 (Rabat) LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT

- 173 040861

SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID (Chothi NO:13 -a) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO:42 VL EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 4 3 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С T GGGACAGAT T T ТАС T T T CACC AT CAGCAGCC T GCAGCC T GAAGATAT T GCAACATAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO:44 Light chain Eivltqs SEQ ID NO:45 DNA, light chain GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG С CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С T GGGACAGAT T T ТАС T T T CACC AT CAGCAGCC T GCAGCC T GAAGATAT T GCAACATAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT

- 174 040861

GAATAACTTCTATCCCAGAGAGGCCAAAGTAGAGT GG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T BAP058-hum07- HC SEQ ID NO (Rabat) 1 HCDR1 SYWMY SEQ ID NO (Rabat) 2 HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO (Rabat) 3 HDDR3 DYRRGLYAMDY SEQ ID NO: (Chothia) : 4 HCDR1 GYTFTSY SEQ ID NO: (Chothia) : 5 HCDR2 DPNSGS SEQ ID NO: (Chothia) : 3 HDDR3 DYRRGLYAMDY SEQID NO: 54 vh QVQLVQ S GAEVRRPGASVRVS CRAS GYT FT S YWMYWI RQSPSRGLEWLGRIDPNSGSTRYNERFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQID NO: 55 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC T GGC TACAC С T T CAC CAG T ТАС T GGAT G ТАС T GGAT C AGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAT T САС CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC

- 175 040861

SEQ ID NO: 56 heavy chain QVQLVQS GAEVKKPGASVKVS СKASGYT FT S YWMYWI RQSPSRGLEWLGRIDPNSGSTKYNEKFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 57 DNA, heavy chain CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC T GGC TACAC С T T GAG GAG T ТАС T GGAT G ТАС T GGAT C AGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAT T СAC CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC C T G CAAC G TAGAT CACAAGC CAG CAACAC CAAG G T G GACAAGAGAG T T GAG T C CAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG

- 176 040861

AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G СACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA VARO58-humOΊ- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 58 VL EIVLTQSPATLSLSPGERATLSCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGIPPRFSGSGYGTDFTLT INNIESEDAAYYFCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 59 DNA VL GAAATTGTGTTGACACAAGTCTCCAGCCACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG

- 177 040861

CAGAAG C CAG G G CAG T C T C CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGATCCCACCTCGATT CAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACA AT TAATAAACATAGAAT C T GAGGAT GC T GCATAT TAC T TCTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCA SEQ ID NO: 60 Light chain EIVLTQSPATLSLSPGERATLSCRASQDVGTAVAWYL QRPGQSPQLLIYWASTRHTGIPPRFSGSGYGTDFTLT INNIESEDAAYYFCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHNSF SEQ ID NO: 61 DNA, light chain GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG СAGAAG С СAG G G СAG Т С Т С СACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGATCCCACCTCGATT CAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACA АТ ТААТAACATAGAAT С Т GAGGAT GC Т GCATAT ТАС Т TCTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATААС ТТСТАТСС СAGAGAG G С СAAAG ТАСAG Т G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G Т CACAGAGCAGGACAGCAAGGACAGCACC ТА CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC ТАС GAGАААСACAAAG TCTACGCCTGC GAAG T CAC C C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058- HC hum08- SEQID (Rabat) NO 1 HCDR1 SYWMY SEQ ID NO 2 HCDR2 RIDPNSGSTRYNERFRN

- 178 040861

(Rabat) SEQ ID NO: 3 (Rabat) HDDR3 DYRRGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRRGLYAMDY SEQ ID NO: 62 vh EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWV RQARGQRLEWIGRIDPNSGSTRYNERFRNRLTISRDT SRNQWLTMTNMDPVDTATYYCARDYRRGLYAMDYWG QGTTVTVSS SEQ ID NO: 63 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTA G GAT T GAT С С TAATAG T G GGAG ТАС TAAG TACAATGA GAAG T T CAAGAACAGAC T СAC CAT С T С CAAG GACAC C T С СAAAAAC CAG GTGGTCCT TAGAAT GAC СAACAT G G ACCCTGTGGACACAGCCACGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 64 heavy chain EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWV RQARGQRLEWIGRIDPNSGSTRYNERFRNRLTISRDT SRNQWLTMTNMDPVDTATYYCARDYRRGLYAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSESTAALGCL VRDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTRTYTCNVDHRPSNTRVDRRVESRY GPPCPPCPAPEFLGGPSVFLFPPRPRDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNARTRPREEQF NSTYRWSVLTVLHQDWLNGREYRCRVSNRGLPSS IE RTISRARGQPREPQVYTLPPSQEEMTRNQVSLTCLVR GFYPSDIAVEWESNGQPENNYRTTPPVLDSDGSFFLY SRLTVDRSRWQEGNVFSCSVMHEALHNHYTQRSLSLS

- 179040861

LGK SEQID NO: 65 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAC T САС CAT С T С CAAG GAGAC C T С СAAAAAC GAG GTGGTCCT TAGAAT GAG CAAGAT G G ACCCTGTGGACACAGCCACGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G CAAG G TAGAT GAGAAG С C GAG CAAGAC GAAG G T G GAGAAGAGAG T T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC GAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG

- 180 040861

GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC CAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-hum08- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 66 VL DWMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 67 DNA VL GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCG TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 68 Light chain DWMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKNSVYACEVY

- 181 040861

SEQ ID NO: 69 DNA, light chain GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCG TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAAGACAAAG TCTACGCCTGC GAAG T СAC С C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-hum09- HC SEQ ID NO: 1 (Rabat) HCDR1 SYWMY SEQ ID NO: 2 (Rabat) HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO: 3 (Rabat) HDDR3 DYRRGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRRGLYAMDY SEQ ID NO: 50 vh EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWI RQPPGRGLEWIGRIDPNS GS TRYNERFRNRVTITADR STSTAYMELSSLRSEDTAVYYCARDYRRGLYAMDYWG

- 182 040861

QGTTVTVSS SEQ ID NO: 51 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC Т GGC ТАСАС С Т Т САС CAG Т ТАС Т GGAT G ТАС Т GGAT С CGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGTA GGATTGATCCTAATAGTGG GAG ТАС ТAAG ТАСААТ GA GAAG Т Т СAAGAACAGAG Т САС GAT ТАС С G С G GACААА TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 heavy chain ЕVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWI RQPPGKGLEWIGRIDPNS GS TKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 53 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC Т GGC ТАСАС С Т Т САС CAG Т ТАС Т GGAT G ТАС Т GGAT С CGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGTA GGATTGATCCTAATAGTGG GAG ТАС ТAAG ТАСААТ GA GAAG Т Т СAAGAACAGAG Т САС GAT ТАС С G С G GACААА TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG

- 183 040861

GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G CAAC G TAGAT CACAAG С С CAG CAACAC CAAG G T G GACAAGAGAG T T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058- LC hum09- SEQ ID (Rabat) NO: 9 LCDR1 RASQDVGTAVA SEQID (Rabat) NO: 10 LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT SEQ ID NO:12 LCDR1 SQDVGTA

- 184 040861

(Chothia) SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 22 VL DIVMTQTPLSLPVTPGEPASISCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 23 DNA VL GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCG TCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG C CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACC AT CAGCAGCC T GCAGT С T GAAGAT T T T GCAGT T TAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 24 Light chain DIVMTQTPLSLPVTPGEPASISCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKAD YEKHKVYACEVTHQ SEQ ID NO: 25 DNA, light chain GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCG TCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG C CAG G G CAG T С T С CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACC AT CAGCAGCC T GCAGT С T GAAGAT T T T GCAGT T TAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G

- 185 040861

AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T CAC C C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGAGAGTGT BAP058-huml0- HC SEQ ID NO (Kabat) 1 HCDR1 SYWMY SEQ ID NO (Kabat) 2 HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO (Kabat) 3 HDDR3 DYRKGLYAMDY SEQ ID NO (Chothia) 4 HCDR1 GYTFTSY SEQ ID NO (Chothia) : 5 HCDR2 DPNSGS SEQ ID NO (Chothia) : 3 HDDR3 DYRKGLYAMDY SEQID NO: 70 vh QITLKESGPTLVKPTQTLTLTCTFSGYTFTSYWMYWV RQAPGKGLEWVSRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQID NO: 71 DNA VH CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGA AAC С CACACAGAC С С T CAC G С T GAC С T G СAC С T T С T C TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCAGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAG T CAC GAT TAC C G C G GACAAA TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQID NO: 72 heavy QITLKESGPTLVKPTQTLTLTCTFSGYTFTSYWMYWV

- 186 040861

chain RQAPGKGLEWVSRIDPNS GS TKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 73 DNA, heavy chain CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGA AACCCACACAGACCCTCACGCTGACCTGCACCTTCTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTC CGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCAGTA G GAT T GAT С С TAATAG T G GGAG ТАС TAAG TACAATGA GAAG T T CAAGAACAGAG T CAC GAT TAC C G C G GACAAA TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAG С С CAG СAACAC CAAG G T G GACAAGAGAGT T GAGT CCAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC

- 187 040861

GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAPO58-humlΟ- ΣΟ SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 66 VL DWMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 67 DNA VL GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCG TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT

- 188 040861

GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT C T GGGACAGAAT T CAC T C T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 68 Light chain DWMTQSPLSLPVTLGQPASISCRASQDVGTAVAWYQ QRPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLRSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLRGTRSFTHQGL SEQ ID NO: 69 DNA, light chain GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCG TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С Т GGGACAGAAT Т САС Т С Т САСС ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC ТТСТАТСС СAGAGAG G С СAAAG ТАСAG Т G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G Т CACAGAGCAGGACAGCAAGGACAGCACC ТА CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC ТАС GAGАААСACAAAG TCTACGCCTGC GAAG Т САС С С ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-humll- HC SEQ ID NO (Rabat) 1 HCDR1 SYWMY SEQ ID NO (Rabat) 2 HCDR2 RIDPNSGSTKYNERFRN

- 189 040861

SEQ ID NO: 3 (Rabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 30 vh EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO: 31 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA G GAT T GAT С С TAATAG T G GGAG ТАС TAAG TACAATGA GAAG T T CAAGAACAGAG T CAC GAT TAC C G C G GACAAA TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 32 heavy chain EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK

- 190 040861

SEQID NO: 33 DNA, GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA heavy AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC chain TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATTCCTAATAGTGG GAG TAC TAAG TACAAT GA GAAG T T CAAGAACAGAG T CAC GAT TAC C G C G GACAAA TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC C TACAC C T G CAAC G TAGAT CACAAG C CAG CAACAC CAAG G T G GACAAGAGAG T T GAG T WITH CAAATAT GGTCCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCCTGACCTGCCTGGTCAAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACCGCC TCCCGTGCTGGACTCCGACGGCCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT

- 191 040861

G CACAACСАС TACACACAGAAGAGCCTCTCCCTGTCT CTGGGTAAA BAPO58-humlΙ- ΣΟ SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA SEQ ID NO: 10 (Rabat) LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 66 VL DWMTQSPLSLPVTLGQPASISCRASQDVGTAVAWYQ QRPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 67 DNA VL GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCG TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 68 Light chain DWMTQSPLSLPVTLGQPASISCRASQDVGTAVAWYQ QRPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTRVEIRRTVA APSVFIFPPSDEQLRSGTASWCLLNNFYPREARVQW RVDNALQSGNSQESVTEQDSRDSTYSLSSTLTLSRAD YERHRVYACEVTHQGLSS SEQ ID NO: 69 DNA, GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCG

- 192 040861

light chain TCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T СAC С C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-huml2- HC SEQ ID NO: 1 (kabat) HCDR1 SYWMY SEQ ID NO: 2 (kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 3 (kabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 38 vh EVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWV RQAPGQGLEWMGRIDPNS GS TKYNEKFKNRVTISVDT SKNQFSLKLSSVTAADTAVYYCARDYRKGLYAMDYWG QGTTVTVSS

- 193 040861

SEQ ID NO: 39 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TAGAAT GA GAAG T T CAAGAACAGAG T GAG CATAT GAG TAGACAC G TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGA CCGCCGCGGACACGGCTGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 heavy chain EVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWV RQAPGQGLEWMGRIDPNS GS TKYNEKFKNRVTISVDT SKNQFSLKLSSVTAADTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 41 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TAGAAT GA GAAG T T CAAGAACAGAG T GAG CATAT GAG TAGACAC G TCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGA CCGCCGCGGACACGGCTGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG

- 194040861

GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАС AC С T G C AAC G T AGAT C AC AAG С C CAG CAACAC CAAG G T G GACAAGAGAG T T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-huml2- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA

- 195 040861

SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 74 VL DIQMTQSPSSLSASVGDRVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 75 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTG CAT С T G TAGGAGACAGAGT CACCAT САС T T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С T GGGACAGAT T T ТАС T T T CACC AT CAGCAGCC T GCAGCC T GAAGATAT T GCAACATAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 76 Light chain DIQMTQSPSSLSASVGDRVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKAD YEKHKNSTKPVACEVACEVACEV SEQ ID NO: 77 DNA, light chain GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTG CAT С T G TAGGAGACAGAGT CACCAT САС T T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGT GGAAGT GGAT С T GGGACAGAT T T ТАС T T T CACC AT CAGCAGCC T GCAGCC T GAAGATAT T GCAACATAT T ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG

- 196 040861

AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T CAC C C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-huml3- HC SEQ ID NO (Rabat) 1 HCDR1 SYWMY SEQ ID NO (Rabat) 2 HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO (Rabat) 3 HDDR3 DYRRGLYAMDY SEQ ID NO (Chothia) 4 HCDR1 GYTFTSY SEQ ID NO (Chothia) : 5 HCDR2 DPNSGS SEQ ID NO (Chothia) : 3 HDDR3 DYRRGLYAMDY SEQID NO: 78 vh EVQLVQ S GAEVRRPGATVRIS CRVS GYT FT S YWMYWV RQARGQRLEWIGRIDPNS GS TRYNERFRNRFTISRDN SRNTLYLQMNSLRAEDTAVYYCARDYRRGLYAMDYWG QGTTVTVSS SEQID NO: 79 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAT T СAC CAT С T С CAGAGACAAT T С CAAGAACAC GCTGTATCTT СAAAT GAACAG С С T GA GAGCCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID 247 NO: heavy chain EVQLVQ S GAEVRRPGATVRIS CRVS GYT FT S YWMYWV RQARGQRLEWIGRIDPNS GS TRYNERFRNRFTISRDN

- 197 040861

SKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 81 DNA, heavy chain GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGA AGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TAGAAT GA GAAG T T CAAGAACAGAT T САС CAT С T С CAGAGACAAT T С CAAGAACAC GCTGTATCTT СAAAT GAACAGС С T GA GAGCCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAG С С CAG СAACAC CAAG G T G GACAAGAGAG T T GAG T С CAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC

- 198 040861

AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-huml3- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 82 VL AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 83 DNA VL GCCATCCAGTTGACCAGTCTCCATCCTCCCTGTCTG CAT C T G TAGGAGACAGAGT CACCAT CAC T T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG CAGAAG CAG G G CAG T C T CACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGTCCCCTCGAGGTT

- 199 040861

CAG T G G CAG TGGATCTGG GACAGAT T T CAC C T T TAC C ATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 84 Light chain AIQLTQSPSSLSASVGDRVTITCRASQDVGTAVAWYL QRPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLEAEDAATYYCQQYNSYPLTFGQGTRVEIRRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW RVDNALQSGNSQESVTEQDSRDSTYSLSSTLTGPVTRSFTHQ SEQ ID NO: 85 DNA, light chain GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTG CAT С Т G TAGGAGACAGAGT САССАТ САС Т Т GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTG СAGAAG С СAG G G СAG Т С Т С СACAG CTCCTGATCTATT GGGCATCCACCCGGCACACTGGGGTCCCCTCGAGGTT СAG Т G G СAG TGGATCTGG GACAGAT Т Т САС С Т Т ТАС С ATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATААС ТТСТАТСС СAGAGAG G С СAAAG ТАСAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAC GAGAAAASACAAAG TCTACGCCTGC GAAG T CAC C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058- HC hum!4- SEQID (Rabat) NO 1 HCDR1 SYWMY SEQID (Rabat) NO 2 HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO 3 HDDR3 DYRRGLYAMDY

- 200 040861

(kabat) SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 18 vh QVQLVQ S GAEVKKPGASVKVS CKAS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO: 19 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TAGAAT GA GAAG Τ T CAAGAACAGAT T СAC CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 20 heavy chain QVQLVQ S GAEVKKPGASVKVS CKAS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRFTISRDD SKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 21 DNA, CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA

-201 040861 heavy AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC chain TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG

CGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TAGAAT GA GAAG T T CAAGAACAGAT T САС CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAG С C CAG СAACAC CAAG G T G GACAAGAGAG T T GAG T С CAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT

- 202 040861

CTGGGTAAA BAP058-huml4- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 86 VL EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 87 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 88 Light chain EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKAD YEKHKSSVYACEVACEV SEQ ID NO: 89 DNA, light GAAATTGTGCTGACTCAGTCTCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT CACC T GCAAGGC

- 203 040861

chain CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T СAC С C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-huml5- HC SEQ ID NO: 1 (kabat) HCDR1 SYWMY SEQ ID NO: 2 (kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 3 (kabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 50 vh EVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWI RQPPGKGLEWIGRIDPNS GS TKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO: 51 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA

- 204 040861

AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC Т GGG ТАСАС С Т Т САС CAG Т ТАС Т GGAT G ТАС Т GGAT С CGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGTA GGATTGATCCTAATAGTGG GAG ТАС ТAAG ТACAAT GA GAAG Т Т СAAGAACAGAG Т САС GAT ТАС С G С G GACААА TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 heavy chain ЕVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWI RQPPGKGLEWIGRIDPNS GS TKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 53 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC Т GGC ТАСАС С Т Т САС CAG Т ТАС Т GGAT G ТАС Т GGAT С CGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGTA GGATTGATCCTAATAGTGG GAG ТАС ТAAG ТАСAAT GA GAAG Т Т СAAGAACAGAG Т САС GAT ТАС С G С G GACААА TCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGA GATCTGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT

-205 040861

GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAG С С CAG СAACAC CAAG G T G GACAAGAGAG T T GAG T С СAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-huml5- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 LCDR2 WAS

- 206 040861

(Chothia) SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 86 VL EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 87 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG Т GAG Т С CAAAGGAGAAAGT САССАТ САСС Т GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С Т GGGACAGAAT Т САС Т С Т САСС ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 88 Light chain ЕIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTKTLSKAD YEKHKNSVYACEVACEV SEQ ID NO: 89 DNA, light chain GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA

- 207 040861

CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAC GAGAAACACAAAG TCTACGCCTGC GAAG T CAC C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-huml6- HC SEQ ID NO (Rabat) 1 HCDR1 SYWMY SEQ ID NO (Rabat) 2 HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO (Rabat) 3 HDDR3 DYRRGLYAMDY SEQ ID NO (Chothia) 4 HCDR1 GYTFTSY SEQ ID NO (Chothia) 5 HCDR2 DPNSGS SEQ ID NO (Chothia) : 3 HDDR3 DYRRGLYAMDY SEQID NO: 54 vh QVQLVQ S GAEVRRPGASVRVS CRAS GYT FT S YWMYWI RQSPSRGLEWLGRIDPNSGSTRYNERFRNRFTISRDD SRNTAYLQMNSLRTEDTAVYYCARDYRRGLYAMDYWG QGTTVTVSS SEQID NO: 55 DNA VH CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC T GGC TACAC С Τ T CAC CAG T ТАС T GGAT G ТАС T GGAT C AGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TAGAAT GA GAAG Τ T CAAGAACAGAT T САС CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQID NO: 56 heavy chain QVQLVQ S GAEVRRPGASVRVS CRAS GYT FT S YWMYWI RQSPSRGLEWLGRIDPNSGSTRYNERFRNRFTISRDD SRNTAYLQMNSLRTEDTAVYYCARDYRRGLYAMDYWG

- 208 040861

QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 57 DNA, heavy chain CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGA AGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTC T GGC TACAC С T T GAG GAG T ТАС T GGAT G ТАС T GGAT C AGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAT T СAC CAT С T С CAGAGAT GAT TCAAAGAACACGGCGTATСTGСAAATGAACAGССTGA AAACCGAGGACACGGCCGTGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G СAAC G TAGAT CACAAG С С CAG СAACAC CAAG G T G GACAAGAGAG T T GAG T С CAAATAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCAC CGTCC

- 209 040861

TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGC GAGAG G T G TAGAC CCTGCCCCCATCC GAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G GAGAAG САС TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA BAP058-huml6- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 86 VL EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 87 DNA VL gaaattgtgctgactcagtctccagactttcagtctg T GAG T C CAAAGGAGAAAGT CACCAT CACC T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACGAACTGGGTCCCATCAAGGTT CAGCGGCAGT GGAT C T GGGACA TCA C T

- 210 040861

ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 8 8 Light chain EIVLTQS PDFQSVTPRERVTITCRASQDVGTAVAWYQ QRPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW RVDNALQSGNSQESVTEQDSRDSTYSLSSTLTLSRAD YEKHKVYACEVTHQ SEQ ID NO: 8 9 DNA, light chain GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG Т GAG Т С CAAAGGAGAAAGT САССАТ САСС Т GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С Т GGGACAGAAT Т САС Т С Т САСС ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC ТТСТАТСС СAGAGAG G С СAAAG ТАСAG Т G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G Т CACAGAGCAGGACAGCAAGGACAGCACC ТА CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC ТАС GAGАААСACAAAG TCTACGCCTGC GAAG Т CAC C C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058- HC huml7- SEQID (Rabat) NO: 1 HCDR1 SYWMY SEQID (Rabat) NO: 2 HCDR2 RIDPNSGSTRYNERFRN SEQID (Rabat) NO: 3 HDDR3 DYRRGLYAMDY

- 211 040861

SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 62 vh EVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWV RQARGQRLEWIGRIDPNSGSTKYNEKFKNRLTISKDT SKNQWLTMTNMDPVDTATYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO: 63 DNA VH GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TACAAT GA GAAG T T CAAGAACAGAC T СAC CAT С T С CAAG GACAC C T С СAAAAAC CAG GTGGTCCT TACAATGACCAACATGG ACCCTGTGGACACAGCCACGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 64 heavy chain EVQLVQ S GAEVKKPGE SLRISCKGSGYTFTS YWMYWV RQARGQRLEWIGRIDPNSGSTKYNEKFKNRLTISKDT SKNQWLTMTNMDPVDTATYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LGK SEQ ID NO: 65 DNA, heavy GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAA AGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTC

- 212 040861 chain

TGGCTACACCTTCACCAGTTACTGGATGTACTGGGTG CGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTA GGATTGATCCTAATAGTGG GAG ТАС TAAG TAGAAT GA GAAG T T CAAGAACAGAC T СAC CAT С T С CAAG GACAC C T С СAAAAAC CAG GTGGTCCT TAGAATGACCAACAT GG ACCCTGTGGACACAGCCACGTATTACTGTGCAAGGGA CTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGC CAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAG GAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA C GAAGAC С ТАСAC С T G CAACGTAGAT CACAAGСCCAG CAACAC CAAG G T G GACAAGAGAG T T GAG T С СΑΆΑΤAT GGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACC CAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCG AGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTC AACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTG CAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAGC CACAG G T G TAGAC CCTGCCCCCATCC CAG GAG GAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA GGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGG GGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCT G CACAAC СAC TACACACAGAAGAG CCTCTCCCTGTCT CTGGGTAAA

- 213 040861

BAPO58-humlΊ- LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 86 VL ΕIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 87 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT САСС T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 88 Light chain ΕIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQRGDSKDSTYSLSSTLTLECSSTYSLSSTLTLECSSTYSLSSTLTLECSSTYSLSSTLTLECSSVGLEKHKVY SEQ ID NO: 89 DNA, light chain GAAATTGTGCTGACTCAGTCTCAGACTTTCAGTCTG T GAC T C CAAAGGAGAAAGT CACCAT CACC T GCAAGGC CAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCAG

- 214 040861

CAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATT GGGCATCCACCCGGCACACTGGGGTCCCATCAAGGTT CAGCGGCAGT GGAT С T GGGACAGAAT T САС T С T CACC ATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATT ACTGTCAGCAGTATAACAGCTATCCTCTCACGTTCGG CCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCT GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGC AGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAAC TTCTATCC CAGAGAG G С CAAAG TAGAG T G G AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGG AGAGT G T CACAGAGCAGGACAGCAAGGACAGCACC TA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TAG GAGAAACACAAAG TCTACGCCTGC GAAG T СAC С C ATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAA CAGGGGAGAGTGT BAP058-Clone To NS SEQ ID NO: 1 (kabat) HCDR1 SYWMY SEQ ID NO: 2 (kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 3 (kabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 30 vh EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS SEQ ID NO:196 DNA VH GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGA AACCCGGCGCTACCGTGAAGATCTCCTGCAAGGTGTC

- 215 040861

CGGCTACACCTTCACCAGCTACTGGATGTACTGGGTG CGACAGGCTACCGGCCAGGGCCTGGAATGGATGGGCA GAAT С GАС С С СAAC TCCGGCTC САС СAAG ТACAAC GA GAAG Т Т СAAGAAC С G С G Т GAC CAT САС С G С С GACAAG TCCACCTCCACCGCCTACATGGAACTGTCCTCCCTGC GGAGCGAGGACACCGCCGTGTACTACTGCGCCAGAGA CTACCGGAAGGGCCTGTACGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO:197 heavy chain ЕVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSS IE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG SEQ ID NO:198 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGA AACCCGGCGCTACCGTGAAGATCTCCTGCAAGGTGTC CGGCTACACCTTCACCAGCTACTGGATGTACTGGGTG CGACAGGCTACCGGCCAGGGCCTGGAATGGATGGGCA GAAT C GAC С С CAAC TCCGGCTC СAC CAAG TAGAAC GA GAAG T T CAAGAAC C G C G T GAC CAT СAC C G С C GACAAG TCCACCTCCACCGCCTACATGGAACTGTCCTCCCTGC GGAGCGAGGACACCGCCGTGTACTACTGCGCCAGAGA CTACCGGAAGGGCCTGTACGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCTGCTTCCACCA AGGGCCCAAGCGTGTTCCCCCTGGCCCCCTGCTCCAG AAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTG GTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCT GGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTT

-216040861

CCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTG AGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCA С CAAGAC С ТАСAC С T G TAAC G T G GAC CACAAG С С CAG CAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTAC GGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCC TGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCC CAAG GACAC С С T GAT GAT CAG CAGAAC С С С C GAG G T G ACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCG AGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGT GCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTT AACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGC TGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTG TAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAA AAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGC С С CAG G T С ТАСAC С С T G С СAC С CAG С CAAGAG GAGAT GACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAG GGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGA G CAAC G G С CAG С С C GAGAACAAC TAGAAGAC СAC С С C CCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTAC AGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGG GCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCT G CACAAC СAC ТАСAC С CAGAAGAG С С T GAG С С T G T С C CTGGGCTGATGAATTC BAP058-Clone To LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS

- 217 040861

SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO:34 VL EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPDRFSGSGSGTDFTLK ISRVEAEDVGVYYCQQYNSYPLT FGQGTKVEIK SEQ ID NO:199 DNA VL GAGATCGTGCTGACCCAGTCCCCCGACTTCCAGTCCG Т GAC С С С СAAAGAAAAAG Т GAC CAT СACAT G СAAG G С CTCCCAGGACGTGGGCACCGCCGTGGCTTGGTATCTG CAGAAGCCTGGCCAGTCCCCTCAGCTGCTGATCTACT GGGCCTCTACCAGACACACCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAG ATCTCCCGGGTGGAAGCCGAGGATGTGGGCGTGTACT ACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGG CCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO:36 Light chain ЕIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPDRFSGSGSGTDFTLK ISRVEAEDVGVYYCQQYNSYPLT FGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQRGSSKDSSFTKPVTKACEVGL SEQ ID NO:200 DNA, light chain GAGATCGTGCTGACCCAGTCCCCCGACTTCCAGTCCG T GAC С С С CAAAGAAAAAG T GAC CAT CACAT G CAAG G C CTCCCAGGACGTGGGCACCGCCGTGGCTTGGTATCTG CAGAAGCCTGGCCAGTCCCCTCAGCTGCTGATCTACT GGGCCTCTACCAGACACACCGGCGTGCCCGACAGATT CTCCGGCTCTGGCTCTGGCACCGACTTCACCCTGAAG ATCTCCCGGGTGGAAGCCGAGGATGTGGGCGTGTACT ACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGG CCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCC GCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGC AGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCT GAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGG AAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTA

- 218 040861

CAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGAC TAC GAGAAG CACAAG GTGTACGCCTGT GAG G T GAC C C ACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAA CAGGGGCGAGTGCTGATGAATTC BAP058-Clone L NS SEQ ID NO (Rabat) 1 HCDR1 SYWMY SEQ ID NO (Rabat) 2 HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO (Rabat) 3 HDDR3 DYRRGLYAMDY SEQ ID NO (Chothia) 4 HCDR1 GYTFTSY SEQ ID NO (Chothia) 5 HCDR2 DPNSGS SEQ ID NO (Chothia) : 3 HDDR3 DYRRGLYAMDY SEQID NO: 38 vh EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWV RQAPGQGLEWMGRIDPNS GS TRYNERFRNRVTISVDT SRNQFSLRLSSVTAADTAVYYCARDYRRGLYAMDYWG QGTTVTVSS SEQID NO: 90 DNA VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGA AGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTC AGGCTACACCTTCACTAGCTACTGGATGTACTGGGTC CGACAGGCCCCAGGGCAAGGCCTGGAGTGGATGGGTA GAAT C GAC CCTAATAGCGGCTCTAC TAAG TATAAC GA GAAG T T TAAGAATAGAG T GAC TATTAGCGTG GACAC C TCTAAGAATCAGTTTAGCCTGAAGCTGTCTAGCGTGA CCGCCGCTGACACCGCCGTCTACTACTGCGCTAGAGA CTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGT CAAGGCACTACCGTGACCGTGTCTTCA SEQID NO: 91 heavy chain EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWV RQAPGQGLEWMGRIDPNS GS TRYNERFRNRVTISVDT SRNQFSLRLSSVTAADTAVYYCARDYRRGLYAMDYWG

- 219 040861

QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG SEQ ID NO: 92 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGA AGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTC AGGCTACACCTTCACTAGCTACTGGATGTACTGGGTC CGACAGGCCCCAGGGCAAGGCCTGGAGTGGATGGGTA GAAT C GAG CCTAATAGCGGCTCTAC TAAG TATAAC GA GAAG T T TAAGAATAGAG T GAC TATTAGCGTG GACAC C TCTAAGAATCAGTTTAGCCTGAAGCTGTCTAGCGTGA CCGCCGCTGACACCGCCGTCTACTACTGCGCTAGAGA CTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGT CAAG G СAC TAC C G T GAC CGTGTCTT CAG С TAG CAC TA AGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCG GAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTG GTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCT GGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTT CCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTG TCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTA С CAAGAC С ТАСAC T T G CAAC G T G GAC CACAAG С С T T C CAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTAG GGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCC TCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCC CAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTG ACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGG AGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGT GCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTC AACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGC

- 220 040861

TGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTG CAAAG T G T С CAACAAG G GAC TTCCTAGCT СAAT C GAA AAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAAC С С CAAG TGTATACCCTGC СAC C GAG С CAG GAAGAAAT GACTAAGAACCAAGTСTCATTGACTTGССTTGTGAAG GGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGT С CAAC G G С CAG С C G GAAAACAAC TACAAGAC СAC С С C TCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTAC TCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGG GAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCT GCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCC CTGGGA BAP058-Clone LLC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 42 VL EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 93 DNA VL GAGATCGTCCTGACTCAGTCACCCGACTTTCAGTCAG T GAC C C C TAAAGAGAAAG T CAC TAT CAC C T G TAAAG C CTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTG CAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACT GGGCCTCTACTAGACACACCGGTGCCCTCTAGGTT TAGCGGTAGCGGTAGTGGCACCGACTTCACCTTC

- 221 040861

ATCTCTTCACTGCAGCCCGAGGATATCGCTACCTACT ACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGG TSAAGGCASTAAGGTCGAGATTAAG SEQ ID NO: 4 4 Light chain EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADVEKHQPVACE SEQ ID NO: 94 DNA, light chain GAGATCGTCCTGACTCAGTCACCCGACTTTCAGTCAG T GAC С С С TAAAGAGAAAG T СAC TAT СAC С T G TAAAG C CTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTG CAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACT GGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTT TAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACT ATCTCTTCACTGCAGCCCGAGGATATCGCTACCTACT ACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGG TCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCC GCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGC AGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCT GAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGG AAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTA CAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGAC TACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCC ACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAA CAGGGGCGAGTGC BAP058- MHC clone SEQID (Rabat) NO: 1 HCDR1 SYWMY SEQID (Rabat) NO: 2 HCDR2 RIDPNSGSTKYNEKFKN SEQID (Rabat) NO: 3 HDDR3 DYRKGLYAMDY

- 222 040861

SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRRGLYAMDY SEQ ID NO: 50 vh EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWI RQPPGRGLEWIGRIDPNS GS TRYNERFRNRVTITADR STSTAYMELSSLRSEDTAVYYCARDYRRGLYAMDYWG QGTTVTVSS SEQ ID NO:201 DNA VH GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGA AGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGGGCTC CGGCTACACCTTCACCAGCTACTGGATGTACTGGATC CGGCAGCCCCCTGGCAAGGGCCTGGAATGGATCGGCA GAAT C GAC С С CAAC TCCGGCTC СAC CAAG TAGAAC GA GAAG T T CAAGAAC C G C G T GAC CAT СAC C G С C GACAAG TCCACCTCCACCGCCTACATGGAACTGTCCTCCCTGA GATCCGAGGACACCGCCGTGTACTACTGCGCCAGAGA CTACCGGAAGGGCCTGTACGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO:260 heavy chain EVQLVQ S GAEVRRPGE SLRISCRGSGYTFTS YWMYWI RQPPGRGLEWIGRIDPNS GS TRYNERFRNRVTITADR STSTAYMELSSLRSEDTAVYYCARDYRRGLYAMDYWG QGTTVTVSSASTRGPSVFPLAPCSRSTSESTAALGCL VRDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTRTYTCNVDHRPSNTRVDRRVESRY GPPCPPCPAPEFLGGPSVFLFPPRPRDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNARTRPREEQF NSTYRWSVLTVLHQDWLNGREYRCRVSNRGLPSSIE RTISRARGQPREPQVYTLPPSQEEMTRNQVSLTCLVR GFYPSDIAVEWESNGQPENNYRTTPPVLDSDGSFFLY SRLTVDRSRWQEGNVFSCSVMHEALHNHYTQRSLSLS LG SEQ ID NO:202 DNA, heavy GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGA AGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGGGCTC

- 223 040861

chain CGGCTACACCTTCACCAGCTACTGGATGTACTGGATC CGGCAGCCCCCTGGCAAGGGCCTGGAATGGATCGGCA GAATCGACСCGAAGTСCGGСTССACCAAGTAGAAGGA GAAG Т Т СAAGAAC С G С G Т GAC CAT САС С G С С GACAAG TCCACCTCCACCGCCTACATGGAACTGTCCTCCCTGA GATCCGAGGACACCGCCGTGTACTACTGCGCCAGAGA CTACCGGAAGGGCCTGTACGCCATGGACTATTGGGGC CAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCA AGGGCCCAAGCGTGTTCCCCCTGGCCCCCTGCTCCAG AAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTG GTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCT GGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTT CCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTG AGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCA С СAAGAC С ТАСАС С Т G ТAAC G Т G GAC СACAAG С С СAG CAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTAC GGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCC TGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCC СAAG GACАС С С Т GAT GAT СAG СAGAAC С С С С GAG G Т G ACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCG AGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGT GCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTT AACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGC TGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTG TAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAA AAG ACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGC С С CAG G Т С ТАСАС С С Т G С САС С CAG С СAAGAG GAGAT GACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAG GGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGA G СAACGGССAGСССGAGAACAAC ТACAAGACСАСССС CCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTAC AGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGG GCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCT G САСААС САС ТАСАС С СAGAAGAG С С Т GAG С С Т G Т С С CTGGGCTGATGAATTC

- 224 040861

BAP058-Clone MLC SEQ ID NC (Kabat) ): 9 LCDR1 KASQDVGTAVA SEQ ID NO (Kabat) : 10 LCDR2 WASTRHT SEQ ID 11(Kabat) NO: LCDR3 QQYNSYPLT SEQ ID NO (Chothia) : 12 LCDR1 SQDVGTA SEQ ID NO (Chothia) : 13 LCDR2 WAS SEQ ID NO (Chothia) : 14 LCDR3 YNSYPL SEQ ID NO: 42 VL EIVLTQS PDFQSVTPKEKVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 203 DNA VL GAGATCGTGCTGACCCAGTCCCCCGACTTCCAGTCCG T GAC С С С CAAAGAAAAAG T GAC CAT CACAT G CAAG G C CTCCCAGGACGTGGGCACCGCCGTGGCTTGGTATCTG CAGAAGCCTGGCCAGTCCCCTCAGCTGCTGATCTACT GGGCCTCTACCAGACACACCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTTACCTTCACC ATCTCCAGCCTGCAGCCCGAGGATATCGCCACCTACT ACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGG CCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 44 Light chain Eivltqs SEQ ID NO: 204 DNA, light GAGATCGTGCTGACCCAGTCCCCCGACTTCCAGTCCG T GAC C C C CAAAGAAAAAG T GAC CAT CACAT G CAAG G C

- 225 040861

chain CTCCCAGGACGTGGGCACCGCCGTGGCTTGGTATCTG CAGAAGCCTGGCCAGTCCCCTCAGCTGCTGATCTACT GGGCCTCTACCAGACACACCGGCGTGCCCTCCAGATT CTCCGGCTCTGGCTCTGGCACCGACTTTACCTTCACC ATCTCCAGCCTGCAGCCCGAGGATATCGCCACCTACT ACTGCCAGCAGTACAACTCCTACCCCCTGACCTTCGG CCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCC GCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGC AGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCT GAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGG AAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTA CAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGAC TAG GAGAAG CACAAG GTGTACGCCTGT GAG G T GAC С C ACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAA CAGGGGCGAGTGCTGATGAATTC BAP058-Clone N NS SEQ ID NO: 1 (kabat) HCDR1 SYWMY SEQ ID NO: 2 (kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 3 (kabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 5 (Chothia) HCDR2 DPNSGS SEQ ID NO: 3 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 30 vh EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSS

- 226 040861

SEQ ID NO: 95 DNA VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGA AACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTC AGGCTACACCTTCACTAGCTACTGGATGTACTGGGTC CGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTA GAAT C GAG CCTAATAGCGGCTCTAC TAAG TATAAC GA GAAG T T TAAGAATAGAG T GAC TAT СAC C G С C GATAAG TCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGA GAT CAGAG GACAC CGCCGTCTACTACTGCGC TAGAGA CTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGT CAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 96 heavy chain EVQLVQ S GAEVKKPGATVKIS CKVS GYT FT S YWMYWV RQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADK STSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG SEQ ID NO: 97 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGA AACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTC AGGCTACACCTTCACTAGCTACTGGATGTACTGGGTC CGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTA GAAT C GAC CCTAATAGCGGCTCTAC TAAG TATAAC GA GAAG T T TAAGAATAGAG T GAC TAT СAC C G С C GATAAG TCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGA GAT CAGAG GACAC CGCCGTCTACTACTGCGC TAGAGA CTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGT CAAGGCACTACCGTGACCGTGTCTTCAGCTAGCACTA AGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCG GAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTG

-227040861

GTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCT GGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTT CCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTG TCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTA С CAAGAC C TAGAC Τ T G CAAC G T G GAC CACAAG С C Τ T C CAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTAC GGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCC TCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCC CAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTG ACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGG AGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGT GCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTC AACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGC TGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTG CAAAG T G T С CAACAAG G GAC TTCCTAGCT СAAT C GAA AAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAAC С С CAAG TGTATACCCTGC СAC C GAG С CAG GAAGAAAT GACTAAGAACCAAGTСTCATTGACΤTGСCΤTGTGAAG GGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGT C CAAC G G C CAG C C G GAAAACAAC TAGAAGAC CAC C C C TCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTAC TCGCGGCTGACCGTGGATAAGCAGATGGCAGGAGG GAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCT GCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCC CTGGGA BAP058-Clone NLC SEQ ID NO: 9 (Rabat) LCDR1 RASQDVGTAVA SEQ ID NO: 10 (Rabat) LCDR2 WASTRHT SEQID NO: 11(Rabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA

- 228 040861

SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 66 VL DWMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 98 DNA VL GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCG TGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGC CTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAG CAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACT GGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTT TAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACT ATCTCTTCACTGCAGCCCGACGACTTCGCTACCTACT ACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGG TGAAGGСАСTAAGGTCGAGATTAAG SEQ ID NO: 68 Light chain DWMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQ QKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLT ISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKNSVYACEVACEV SEQ ID NO: 99 DNA, light chain GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCG TGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGC CTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAG CAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACT GGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTT TAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACT ATCTCTTCACTGCAGCCCGACGACTTCGCTACCTACT ACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGG TCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCC GCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGC AGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCT GAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGG AAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG

- 229 040861

AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTA CAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGAC TACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCC ACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAA CAGGGGCGAGTGC BAP058-Clone 0 NS SEQ ID NO (Rabat) 1 HCDR1 SYWMY SEQ ID NO (Rabat) 2 HCDR2 RIDPNSGSTRYNERFRN SEQ ID NO (Rabat) 3 HDDR3 DYRRGLYAMDY SEQ ID NO (Chothia) 4 HCDR1 GYTFTSY SEQ ID NO (Chothia) : 5 HCDR2 DPNSGS SEQ ID NO (Chothia) : 3 HDDR3 DYRRGLYAMDY SEQID NO: 78 vh EVQLVQ S GAEVRRPGATVRIS CRVS GYT FT S YWMYWV RQARGQRLEWIGRIDPNS GS TRYNERFRNRFTISRDN SRNTLYLQMNSLRAEDTAVYYCARDYRRGLYAMDYWG QGTTVTVSS SEQ ID 100 NO: DNA VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGA AACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTC AGGCTACACCTTCACTAGCTACTGGATGTACTGGGTC CGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTA GAAT C GAC CCTAATAGCGGCTCTAC TAAG TATAAC GA GAAGTTTAAGAATAGGTTCACTATTAGTAGGGATAAC T С TAAGAACAC CCTGTACCTG CAGAT GAATAG С С T GA GAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGA CTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGT CAAGGCACTACCGTGACCGTGTCTTCA SEQID NO: 80 heavy chain EVQLVQ S GAEVRRPGATVRIS CRVS GYT FT S YWMYWV RQARGQRLEWIGRIDPNS GS TRYNERFRNRFTISRDN

- 230 040861

SKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY GPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF NSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLS LG SEQID NO: 101 DNA, heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGA AACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTC AGGCTACACCTTCACTAGCTACTGGATGTACTGGGTC CGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTA GAAT C GAC CCTAATAGCGGCTCTAC TAAG TATAAC GA GAAG T T TAAGAATAGG T T CAC TAT TAG TAGGGATAAC T С TAAGAACAC CCTGTACCTG CAGAT GAATAG С С T GA GAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGA CTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGT CAAG G САС TAC C G T GAC CGTGTCTT CAG С TAG CAC TA AGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCG GAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTG GTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCT GGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTT CCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTG TCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTA С CAAGAC С ТАСAC T T G CAAC G T G GAC CACAAG С С T T C CAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTAG GGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCC TCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCC CAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTG ACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGG AGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGT GCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTC

- 231 040861

AACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGC TGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTG CAAAG T G T С CAACAAG G GAC TTCCTAGCT CAAT C GAA AAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAAC С С CAAG TGTATACCCTGC СAC C GAG С CAG GAAGAAAT GACTAAGAACCAAGTСTCATTGACΤTGССΤTGTGAAG GGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGT С CAAC G G С CAG С C G GAAAACAAC TAGAAGAC СAC С С C TCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTAC TCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGG GAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCT GCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCC CTGGGA BAP058-Clone 0LC SEQ ID NO: 9 (kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 10 (kabat) LCDR2 WASTRHT SEQID NO: 11(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 12 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 13 (Chothia) LCDR2 WAS SEQ ID NO: 14 (Chothia) LCDR3 YNSYPL SEQ ID NO: 82 VL AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYL QKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK SEQ 102 ID NO: DNA VL G C TAT T CAG C T GAC T CAG T CAC C TAG TAG C C T GAG C G CTAGTGTGGGCGATAGAGTGACTATCACCTGTAAAGC CTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTG CAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACT GGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTT

- 232 040861

TAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACT ATCTCTTCACTGGAAGCCGAGGACGCCGCTACCTACT ACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGG TSAAGGCASTAAGGTCGAGATTAAG SEQ ID NO: 84 Light chain AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYL QRPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFT ISSLEAEDAATYYCQQYNSYPLTFGQGTRVEIRRTVA APSVFIFPPSDEQLRSGTASWCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHRVYACEVTHNSS SEQID NO: 103 DNA, light chain G С ТАТ Т СAG С Т GAC Т СAG Т САС С TAG TAG С С Т GAG С G CTAGTGTGGGCGATAGAGTGACTATCACCTGTAAAGC CTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTG CAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACT GGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTT TAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACT ATCTCTTCACTGGAAGCCGAGGACGCCGCTACCTACT ACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGG TCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCC GCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGC AGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCT GAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGG AAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGG AGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTA CAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGAC TACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCC ACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAA CAGGGGCGAGTGC BAP058HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac

- 233 040861

SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-chi HC SEQID NO: (kabat) HCDR1 SEQID NO: (kabat) HCDR2 SEQID NO: (kabat) HDDR3 SEQ ID NO: (Chothia) HCDR1 SEQ ID NO: (Chothia) HCDR2 SEQ ID NO: (Chothia) HDDR3 BAP058-chi LC SEQID NO: (kabat) LCDR1

- 234 040861

SEQID NO: (kabat) LCDR2 SEQID NO: (kabat) LCDR3 SEQ ID NO: (Chothia) LCDR1 SEQID NO: (Chothia) LCDR2 SEQ ID NO: (Chothia) LCDR3 BAP058-hum01- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum01- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: LCDR2 tgggcatcc

-235 040861

111 (Chothia) SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum02- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum02- LC SEQID NO: 245 (Rabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Rabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Rabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum03- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac

-236 040861

SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum03- LC SEQID NO: 245 (Rabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Rabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Rabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum04- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: HCDR2 gatcctaatagtgggagt

-237 040861

108 (Chothia) SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum04- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum05- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum05- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc

-238 040861

SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum06- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum06- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: LCDR2 tgggcatcc

-239 040861

111 (Chothia) SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum07- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum07- LC SEQID NO: 245 (Rabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Rabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Rabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum08- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac

-240040861

SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum08- LC SEQID NO: 245 (Rabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Rabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Rabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-hum09- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: HCDR2 gatcctaatagtgggagt

-241 040861

108 (Chothia) SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-hum09- LC SEQID NO: 245 (Rabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Rabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Rabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-huml0- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-huml0- LC SEQID NO: 245 (Rabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc

-242040861

SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-humll- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAPO58-humlΙ- ΣΟ SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: LCDR2 tgggcatcc

-243 040861

111 (Chothia) SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-huml2- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-huml2- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-huml3- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac

-244040861

SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-huml3- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-huml4- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: HCDR2 gatcctaatagtgggagt

-245 040861

108 (Chothia) SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-huml4- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-huml5- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-huml5- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc

-246040861

SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-huml6- HC SEQID NO: 104 (Kabat) HCDR1 agttactggatgtac SEQID NO: 105 (Kabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Kabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-huml6- LC SEQID NO: 245 (Kabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Kabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Kabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: LCDR2 tgggcatcc

-247040861

111 (Chothia) SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-huml7- HC SEQID NO: 104 (Rabat) HCDR1 agttactggatgtac SEQID NO: 105 (Rabat) HCDR2 aggattgatcctaatagtgggagtactaagtacaatg agaagttcaagaac SEQID NO: 106 (Rabat) HDDR3 gactatagaaaggggctctatgctatggactac SEQID NO: 107 (Chothia) HCDR1 ggctacaccttcaccagttac SEQID NO: 108 (Chothia) HCDR2 gatcctaatagtgggagt SEQID NO: 106 (Chothia) HDDR3 gactatagaaaggggctctatgctatggactac BAP058-huml7- LC SEQID NO: 245 (Rabat) LCDR1 aaggccagtcaggatgtgggtactgctgtagcc SEQID NO: 246 (Rabat) LCDR2 tgggcatccacccggcacact SEQID NO: 109 (Rabat) LCDR3 cagcagtataacagctatcctctcacg SEQID NO: 110(Chothia) LCDR1 agtcaggatgtgggtactgct SEQID NO: 111 (Chothia) LCDR2 tgggcatcc SEQID NO: 112 (Chothia) LCDR3 tataacagctatcctctc BAP058-Clone to HC SEQID NO: 113 (Rabat) HCDR1 agctactggatgtac

-248 040861

SEQID NO: 205(Rabat) HCDR2 agaatcgaccccaactccggctccaccaagtacaacg agaagttcaagaac SEQID NO: 206 (Rabat) HDDR3 gactaccggaagggcctgtacgccatggactat SEQID NO: 207 (Chothia) HCDR1 ggctacaccttcaccagctac SEQID NO: 208 (Chothia) HCDR2 gaccccaactccggctcc SEQID NO: 206 (Chothia) HDDR3 gactaccggaagggcctgtacgccatggactat BAP058-Clone To LC SEQID NO: 209 (Rabat) LCDR1 aaggcctcccaggacgtgggcaccgccgtggct SEQID NO: 210 (Rabat) LCDR2 tgggcctctctaccagacacacc SEQID NO: 211 (Rabat) LCDR3 cagcagtacaactcctaccccctgacc SEQID NO: 212 (Chothia) LCDR1 tcccaggacgtgggcaccgcc SEQID NO: 213 (Chothia) LCDR2 tgggcctct SEQID NO: 214 (Chothia) LCDR3 tacaactcctaccccctg BAP058-Clone LHC SEQID NO: 113 (Rabat) HCDR1 agctactggatgtac SEQID NO: 114 (Rabat) HCDR2 agaatcgaccctaatagcggctctactaagtataacg agaagtttaagaat SEQID NO: 115 (Rabat) HDDR3 gactatagaaagggcctgtacgctatggactac SEQID NO: 116 (Chothia) HCDR1 ggctacaccttcactagctac SEQID NO: HCDR2 gaccctaatagcggctct

-249040861

117 (Chothia) SEQID NO: 115 (Chothia) HDDR3 gactatagaaagggcctgtacgctatggactac BAP058-Clone LLC SEQID NO: 118 (Kabat) LCDR1 aaagcctctcaggacgtggggcaccgccgtggcc SEQID NO: 119 (Kabat) LCDR2 tgggcctctactagacacacc SEQID NO: 120 (Kabat) LCDR3 cagcagtataatagctaccccctgacc SEQID NO: 121 (Chothia) LCDR1 tctcaggacgtgggcaccgcc SEQID NO: 122 (Chothia) LCDR2 tgggcctct SEQID NO: 123 (Chothia) LCDR3 tataatagctaccccctg BAP058-Clone MHC SEQID NO: 113 (Kabat) HCDR1 agctactggatgtac SEQID NO: 205 (Kabat) HCDR2 agaatcgaccccaactccggctccaccaagtacaacg agaagttcaagaac SEQID NO: 206 (Kabat) HDDR3 gactaccggaagggcctgtacgccatggactat SEQID NO: 207 (Chothia) HCDR1 ggctacaccttcaccagctac SEQID NO: 208 (Chothia) HCDR2 gaccccaactccggctcc SEQID NO: 206 (Chothia) HDDR3 gactaccggaagggcctgtacgccatggactat BAP058-Clone MLC SEQID NO: 209 (Kabat) LCDR1 aaggcctcccaggacgtggggcaccgccgtggct

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SEQID NO: 210 (Rabat) LCDR2 tgggcctctctaccagacacacc SEQID NO: 211 (Rabat) LCDR3 cagcagtacaactcctaccccctgacc SEQID NO: 212 (Chothia) LCDR1 tcccaggacgtgggcaccgcc SEQID NO: 213 (Chothia) LCDR2 tgggcctct SEQID NO: 214 (Chothia) LCDR3 tacaactcctaccccctg BAP058-Clone NHC SEQID NO: 113 (Rabat) HCDR1 agctactggatgtac SEQID NO: 114 (Rabat) HCDR2 agaatcgaccctaatagcggctctactaagtataacg agaagtttaagaat SEQID NO: 115 (Rabat) HDDR3 gactatagaaagggcctgtacgctatggactac SEQID NO: 116 (Chothia) HCDR1 ggctacaccttcactagctac SEQID NO: 117 (Chothia) HCDR2 gaccctaatagcggctct SEQID NO: 115 (Chothia) HDDR3 gactatagaaagggcctgtacgctatggactac BAP058-Clone NLC SEQID NO: 118 (Rabat) LCDR1 aaagcctctcaggacgtggggcaccgccgtggcc SEQID NO: 119 (Rabat) LCDR2 tgggcctctactagacacacc SEQID NO: 120 (Rabat) LCDR3 cagcagtataatagctaccccctgacc SEQID NO: 121 (Chothia) LCDR1 tctcaggacgtgggcaccgcc SEQID NO: LCDR2 tgggcctct

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122 (Chothia) SEQID NO: 123 (Chothia) LCDR3 tataatagctaccccctg BAP058-Clone 0HC SEQID NO: 113 (Rabat) HCDR1 agctactggatgtac SEQID NO: 114 (Rabat) HCDR2 agaatcgaccctaatagcggctctactaagtataacg agaagtttaagaat SEQID NO: 115 (Rabat) HDDR3 gactatagaaagggcctgtacgctatggactac SEQID NO: 116 (Chothia) HCDR1 ggctacaccttcactagctac SEQID NO: 117 (Chothia) HCDR2 gaccctaatagcggctct SEQID NO: 115 (Chothia) HDDR3 gactatagaaagggcctgtacgctatggactac BAP058-Clone 0LC SEQID NO: 118 (Rabat) LCDR1 aaagcctctcaggacgtggggcaccgccgtggcc SEQID NO: 119 (Rabat) LCDR2 tgggcctctactagacacacc SEQID NO: 120 (Rabat) LCDR3 cagcagtataatagctaccccctgacc SEQID NO: 121 (Chothia) LCDR1 tctcaggacgtgggcaccgcc SEQID NO: 122 (Chothia) LCDR2 tgggcctct SEQID NO: 123 (Chothia) LCDR3 tataatagctaccccctg

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table 2

Amino acid and nucleotide sequences of heavy and light chain framework regions of humanized mAbs BAP058-hum01 to BAP058-hum17 and BAP058-C1one-K to BAP058-C1one-O

Amino acid subsequence Nucleotide subsequence VHFW1 (type a) QVQLVQSGAEVKKPGASVKVS CKAS (SEQ ID NO: 124) CAGGTTCAGCTGGTGCAGTCTGGAGCTGAG GTGAAGAAGCCTGGGGCCTCAGTGAAGGTC TCCTGCAAGGCTTCT (SEQ ID NO: 125) VHFW1 (type b) EVQLVQSGAEVKKPGESLRIS CKGS (SEQ ID NO: 126) GAAGTGCAGCTGGTGCAGTCTGGAGCAGAG GTGAAAAAGCCCGGGGAGTCTCTGAGGATC TCCTGTAAGGGTTCT (SEQ ID NO: 127) GAAGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAGCCCGGCGAGTCACTGAGAATT AGCTGTAAAGGTTCA (SEQ ID NO: 215) GAAGTGCAGCTGGTGCAGTCTGGCGCCGAA GTGAAGAAGCCTGGCGAGTCCCTGCGGATC TCCTGCAAGGGCTCC (SEQ ID NO: 216) VHFW1 (type c) EVQLVQSGAEVKKPGATVKIS CKVS (SEQ ID NO: 128) GAGGTCCAGCTGGTACAGTCTGGGGCTGAG GTGAAGAAGCCTGGGGCTACAGTGAAAATC TCCTGCAAGGTTTCT (SEQ ID NO: 129) GAAGTGCAGCTGGTGCAGTCTGGCGCCGAA GTGAAGAAACCCGGCGCTACCGTGAAGATC TCCTGCAAGGTGTCC (SEQ ID NO: 217) GAAGTGCAGCTGGTGCAGTCAGGCGCCGAA GTGAAGAAACCCGGCGCTACCGTGAAGATT AGTGTAAAGTCTCA (SEQ ID NO: 218) VHFW1 (type d) QITLKESGPTLVKPTQTLTLT CTFS (SEQ ID NO: 130) CAGATCACCTTGAAGGAGTCTGGTCCTACG C T G G T GAAAC C CACACAGAC C C T CAC G C T G ACCTGCACCTTCTCT (SEQ ID NO: 131) VHFW2 WVRQATGQGLEWMG TGGGTGCGACAGGCCACTGGACAAGGGCTT

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(type a) (SEQ ID NO: 132) GAGTGGATGGGT (SEQ ID NO: 133) TGGGTGCGACAGGCTACCGGCCAGGGCCTG GAATGGATGGGC (SEQ ID NO: 219) TGGGTCCGACAGGCTACCGGTCAAGGCCTG GAGTGGATGGGT (SEQ ID NO: 220) VHFW2 (type a') WVRQAPGQGLEWMG (SEQ ID NO: 134) TGGGTGCGACAGGCCCCTGGACAAGGGCTT GAGTGGATGGGT (SEQ ID NO: 135) TGGGTCCGACAGGCCCCAGGGCAAGGCCTG GAGTGGATGGGT (SEQ ID NO: 221) VHFW2 (type b) WIRQPPGKGLEWIG (SEQ ID NO: 136) TGGATCCGCCAGCCCCCAGGGAAGGGGCTG GAGTGGATTGGT (SEQ ID NO: 137) TGGATCCGGCAGCCCCCTGGCAAGGGCCTG GAATGGATGGGC (SEQ ID NO: 222) VHFW2 (type c) WIRQSPSRGLEWLG (SEQ ID NO: 138) TGGATCAGGCAGTCCCCATCGAGAGGCCTT GAGTGGCTGGGT (SEQ ID NO: 139) VHFW2 (type d) WVRQARGQRLEWIG (SEQ ID NO: 140) TGGGTGCGACAGGCTCGTGGACAACGCCTT GAGTGGATAGGT (SEQ ID NO: 141) TGGGTCCGACAGGCTAGAGGGCAAAGACTG GAGTGGATGGGT (SEQ ID NO: 223) VHFW2 (type e) WVRQAPGKGLEWVS (SEQ ID NO: 142) TGGGTCCGCCAGGCTCCAGGGAAGGGGCTG GAGTGGGTCAGT (SEQ ID NO: 143) VHFW3 (type a) RETISRDDSKNTAYLQMNSLK TEDTAVYYCAR (SEQ ID NO: 144) AGAT T CAC CAT C T C CAGAGAT GATT CAAAG AACACCGGCGTATCTGCAAATGAACAGCCTG AAAACCGAGGACACGGCCGTGTATTACTGT

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GCAAGG (SEQ ID NO: 145) VHFW3 (type b) RVTITADKSTSTAYMELSSLLR SEDTAVYYCAR (SEQ ID NO: 146) AGAG T CAO GAT TAC C G C G GACAAAT C CAC G AGCACAGCCTACATGGAGCTGAGCAGCCTG AGATTCTGAGGACACGGCCGTGTATTACTGT GCAAGG (SEQ ID NO: 147) CGCGTGACCATCACCGCCGACAAGTCCACC TCCACCGCCTACATGGAACTGTCCTCCCTG CGGAGCGAGGACACCGCCGTGTACTACTGC GCCAGA (SEQ ID NO: 224) CGCGTGACCATCACCGCCGACAAGTCCACC TCCACCGCCTACATGGAACTGTCCTCCCTG AGATCCGAGGACACCGCCGTGTACTACTGC GCCAGA (SEQ ID NO: 225) AGAG T GAC TAT CAC C G C C GATAAG T C TAC T AGCACCGCCTATATGGAACTGTCTAGCCTG AGAT CAGAG GACAC CGCCGTCTACTACTGC GCTAGA (SEQ ID NO: 226) VHFW3 (type c) RVTISVDTSKNQFSLKLSSVT AADTAVYYCAR (SEQ ID NO: 148) AGAG T CAC CATAT CAG TAGACAC G T C CAAG AACCAGTTCTCCCTGAAGCTGAGCTCTGTG ACCGCCGCGGACACGGCTGTGTATTACTGT GCAAGG (SEQ ID NO: 149) AGAG T GAC TATTAGCGTG GACAC C T C TAAG AATCAGTTTAGCCTGAAGCTGTCTAGCGTG ACCGCCGCTGACACCGCCGTCTACTACTGC GCTAGA (SEQ ID NO: 227) VHFW3 (type d) RLTISKDTSKNQWLTMTNMD PVDTATYYCAR (SEQ ID NO: 150) AGAC T CAC CAT C T C CAAG GACAC C T C CAAA AAC CAG GTGGTCCT TACAAT GAC CAACAT G GAC C C T G T G GACACAG C CAC GTATTACTGT

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GCAAGG (SEQ ID NO: 151) VHFW3 (type e) RFTISRDNSKNTLYLQMNSLR AEDTAVYYCAR (SEQ ID NO: 152) AGAT T CAC CAT C T C CAGAGACAAT T C CAAG AACACGCTGTATCTTCAAATGAACAGCCTG AGAGCCGAGGACACGGCCGTGTATTACTGT GCAAGG (SEQ ID NO: 153) AGGT T CAC TAT TAGTAGGGATAAC T C TAAG AACACCCTGTACCCTGCAGATGAATAGCCTG AGAGCCGAGGACACCGCCGTCTACTACTGC GCTAGA (SEQ ID NO: 228) VHFW4 WGQGTTVTVSS (SEQ ID NO: 154) TGGGGCCAGGGCACCACCGTGACCGTGTCC TCC (SEQ ID NO: 155) TGGGGCCAGGGCACCACCGTGACCGTGTCC TCT (SEQ ID NO: 229) TGGGGTCAAGGCACTACCGTGACCGTGTCT TCA (SEQ ID NO: 230) VLFW1 (type a) EIVLTQSPDFQSVTPKEKVTI TC (SEQ ID NO: 156) GAAATTGTGCTGACTCAGTCTCAGACTTT CAG T C T G T GAC T C CAAAG GAGAAAG T CAC C ATCACCTGC (SEQ ID NO: 157) GAGATCGTGCTGACCCAGTCCCCCGACTTC CAGTCCGTGACCCCCCAAAGAAAAAAGTGACC ATCACATGC (SEQ ID NO: 231) GAGATCGTCCTGACTCAGTCACCCGACTTT CAG T CAG T GAC C C C TAAAGAGAAAG T CAC T ATCACCTGT (SEQ ID NO: 232) VLFW1 (type b) DWMTQSPLSLPVTLGQPASI SC GATGTTGTGATGACTCAGTCTCCACTCTCC CTGCCCGTCACCCTTGGACAGCCGGCCTCC

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(SEQ ID NO: 158) ATCTCCTGC (SEQ ID NO: 159) GACGTCGTGATGACTCAGTCACCCCTGAGC CTGCCCGTGACCCTGGGGCAGCCCCGCCTCT ATTAGCTGT (SEQ ID NO: 233) VLFWl (type c) DIVMTQTPLSLPVTPGEPASI SC (SEQ ID NO: 160) GATATTGTGATGACCAGACTCCACTCTCC CTGCCCGTCACCCCTGGAGAGCCGGCCTCC ATCTCCTGC (SEQ ID NO: 161) VLFWl (type d) DIQMTQSPSSLSASVGDRVTI TO (SEQ ID NO: 162) GACATCCAGATGACCCAGTCTCCATCCTCC CTGTCTGCATCTGTAG GAGACAGAG T CAC C ATCACTTGC (SEQ ID NO: 163) VLFWl (type e) EIVLTQSPATLSLSPGERATL SC (SEQ ID NO: 164) GAAAT T G T G T T GAG AC AG T C T C C AG C C AC C CTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGC (SEQ ID NO: 165) VLFWl (type f) AIQLTQSPSSLSASVGDRVTI TC (SEQ ID NO: 166) GCCATCCAGTTGACCCAGTCTCCATCCTCC CTGTCTGCATCTGTAG GAGACAGAG T CAC C ATCACTTGC (SEQ ID NO: 167) GO TAT T CAGC T GAG T CAG T CAC C TAG TAGO CTGAGCGCTAGTGTGGGCGATAGAGTGACT ATCACCTGT (SEQ ID NO: 234) VLFW2 (type a) WYQQKPGQAPRLLIY (SEQ ID NO: 168) TGGTACCAGCAGAAACCTGGCCAGGCTCCC AGGCTCCTCATCTAT (SEQ ID NO: 169) TGGTATCAGCAGAAGCCAGGGCAAGCCCCT AGACTGOTGATOTAG (SEQ ID NO: 235) VLFW2 (type c) WYLQKPGQSPQLLIY (SEQ ID NO: 170) TGGTACCTGCAGAAGCCAGGGCAGTCTCCA CAGCTCCTGATCTAT

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(SEQ ID NO: 171) TGGTATCTGCAGAAGCCTGGCCAGTCCCCT CAGCTGCTGATCTAC (SEQ ID NO: 236) TGGTATCTGCAGAAGCCTGGTCAATCACCT CAGCTGCTGATCTAC (SEQ ID NO: 237) VLFW3 (type a) GVPSRFSGSGSGTEFTLTISS LQPDDFATYYC (SEQ ID NO: 172) GGGGTCCCATCAAGGTTCAGCGGCAGTGGA T C T GGGACAGAAT T CAC T C T SASSAT CAGC AGCCTGCAGCCTGATGATTTTGCAACTTAT TACTGT (SEQ ID NO: 173) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGT AGTGGCACCGAGTTCACCCTGACTATCTCT TCACTGCAGCCCGACGACTTCGCTACCTAC TACTGT (SEQ ID NO: 238) VLFW3 (type b) GVPSRFSGSGSGTDFTFTISS LQPEDIATYYC (SEQ ID NO: 174) GGGGTCCCATCAAGGTTCAGTGGAAGTGGA T C T GGGACAGAT T T TAC T T T SASSAT CAGC AGCCTGCAGCCTGAAGATATTGCAACATAT TACTGT (SEQ ID NO: 175) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGT AGTGGCACCGACTTCACCTTCACTATCTCT TCACTGCAGCCCGAGGATATCGCTACCTAC TACTGT (SEQ ID NO: 239) GGCGTGCCCTCCAGATTCTCCGGCTCTGGC TCTGGCACCGACTTTACCTTCACCATCTCC AGCCTGCAGCCCGAGGATATCGCCACCTAC TAGTGC (SEQ ID NO: 240) VLFW3 (type c) GIPARFSGSGSGTEFTLTISS LQSEDFAVYYC (SEQ ID NO: 176) GGGATCCCAGCCAGGTTCAGTGGCAGTGGG T C T GGGACAGAGT T CAC T C T SASSAT CAGC AGCCTGCAGTCTGAAGATTTTGCAGTTTAT

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TACTGT (SEQ ID NO: 177) VLFW3 (type d) GVPSRFSGSGSGTDFTLTISS LQPEDFATYYC (SEQ ID NO: 178) GGGGTCCCATCAAGGTTCAGCGGCAGTGGA T C T G G GACAGAT T T CAC T C T CAC CAT CAG C AGCCTGCAGCCTGAAGATTTTGCAACTTAT TACTGT (SEQ ID NO: 179) VLFW3 (type e) GVPDRFSGSGSGTDFTLKISR VEAEDVGVYYC (SEQ ID NO: 180) GGGGTCCCAGACAGGTTCAGTGGCAGTGGG T CAGGCAC T GAT T T CACAC T GAAAAT CAGC AGGGTGGAGGCTGAGGATGTTGGAGTTTAT TACTGT (SEQ ID NO: 181) GGCGTGCCCGACAGATTCTCCGGCTCTGGC TCTGGCACCGACTTCACCCCTGAAGATCTCC CGGTGGAAGCCGAGGATGTGGGCGTGTAC TACTGC (SEQ ID NO: 241) VLFW3 (type f) GIPPRFSGSGYGTDFTLTINN IESEDAAYYFC (SEQ ID NO: 182) GGGATCCCACCTCGATTCAGTGGCAGCGGG TAT G GAACAGATT T TACCC T CACAATTAAT AACATAGAAT C T GAGGAT GC T GCATAT TAG TTCTGT (SEQ ID NO: 183) VLFW3 (type d) GVPSRFSGSGSGTDFTFTISS LEAEDAATYYC (SEQ ID NO: 184) GGGGTCCCCTCGAGGTTCAGTGGCAGTGGA T C T G G GACAGAT T T CAC C T T TAC CAT CAG T AGCCTGGAAGCTGAAGATGCTGCAACATAT TACTGT (SEQ ID NO: 185) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGT AGTGGCACCGACTTCACCTTCACTATCTCT TCACTGGAAGCCGAGGACGCCGCTACCTAC TACTGT (SEQ ID NO: 242) VLFW4 FGQGTKVEIK (SEQ ID NO: 186) TTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 187) TTCGGCCAGGGCACCAAGGTGGAAATCAAG (SEQ ID NO: 243) TTCGGTCAAGGCACTAAGGTCGAGATTAAG (SEQ ID NO: 244)

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Table 3

Amino acid sequences of the human IgG heavy chain and human kappa light chain constant region

ns Amino acid sequence of the mutant constant region (S228P) of IgG4 (EU numbering) ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVWDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY RWSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK (SEQ ID NO: 188) LC Amino acid sequence of human kappa constant region RTVAAPSVFI FPPSDEQLKS GTASWCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC (SEQ ID NO: 189) NS Amino acid sequence of the mutant (S228P) IgG4 constant region spanning the C-terminal lysine (K) (EU numbering) ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVWDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY RWSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLG (SEQ ID NO: 190) NS wild-type IgGl ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS

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HEDPEVKFNW EYKCKVSNKA LVKGFYPSDI QQGNVFSCSV YVDGVEVHNA LPAPIEKTIS AVEWESNGQP MHEALHNHYT KTKPREEQYN STYRWSVLT KAKGQPREPQ VYTLPPSREE ENNYKTTPPV LDSDGSFFLY VLHQDWLNGK MTKNQVSLTC SKLTVDKSRW 191) QKSLSLSPGK (SEQID NO: ns Amino acid sequence of the mutant (N297A) IgGl constant region (EU numbering) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYA STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 192) NS Amino acid sequence of the mutant (D265A, P329A) IgGl constant region (EU numbering) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVWAVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LAAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 193) NS Amino acid sequence of the mutant (L234A, L235A) IgGl constant region (EU numbering) ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGG PSVFLFPPKP KDTLMISRTP EVTCVWDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 194)

Tab. 4: see examples.

Tab. 5: see examples.

Tab. 6: Selected drugs that can be administered in combination with anti-PD-L1 antibody molecules, for example as a single agent or in combination with other immunomodulators described herein. Each publication listed in this table is incorporated into this description by reference in its entirety, including all structural formulas given in it.

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Table 6

convoy Generic Connection structure on the- oh Cheney Name e Trade conn Name

inen

AND I

Nilotinib

HC1 monohydrate

TASIGNA®

Patents / publications of patent applications

EP 1682103 US

2007/142401 W0

2005/039549

WO2004/005281

US 7169791

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A29 Enkorafeni b n c'°Y^ γ γ ^χ _ΝΗ o cn _a Ϊ Ν^Ν / ^sn ' F H N Y o a XV O ^ CH ₃ D CI W02011/025927 AZO n _e with n. ^N -CH ₃ f δ & and / WO2011/101409 A31 monoclonal antibody human to HER3 W02012/022814 EP 2606070US 8735551 AZ 2 Antibody-conjugate medicinal product (ADC) WO 2014/160160 Ab : 12 42 5 (see table 1, paragraph [00191]) Linker: SMCC (see paragraph [00117] Cargo: DM1 (see paragraph [ 00111], also see item 2 9

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claims) AZZ Monoclonal antibody or Fab to M-CSF W0 2004/045532 AZ 4 Binimetini b Y IZ U. R " < h \ X about X WO2003/077914 AZ 5 midostauri n HN^ ^0: \u003d \ Jl \ L _n ^Z L-CH3 A / 'x UG ph ₃ WO2003/037347 EP 1441737US 2012/252785 AZ 6 Everolimus AFINITOR® ,—on 0—/ 2—/ ^n ₃ U-CH ₃ /n ₃ C o—ς 2—n P^o A U ^CH3 C ^N ^° °no4 0/ ^CH3 n3c but 2=0 ο=ς / ^SNz (o \ \ -/ y - cn ₃ o - ( / \u003d! ns ⁷ \ \u003d / H ₃ C 2 --- n ₃ s WO 2014/085318

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Examples

The examples below are provided to facilitate understanding of the invention, however they are not intended to be limiting and should not be construed as limiting its scope in any way.

Example 1: humanization of anti-PD-L1 antibody BAP058.

BAP058 mouse anti-PD-L1 monoclonal antibody was humanized. Sequences and test samples were prepared for seventeen humanized BAP058 clones with a unique variable region. These clones were further analyzed for their biological functions (eg, antigen binding and ligand blocking), structural features, and transient expression in CHO cells.

Example 1.1: technology and humanization process.

Humanization of BAP058 was performed using a combinatorial framework library (FW) of the human variable region. The technology encompasses the transfer of in-frame mouse CDRs into a human variable region (VR) library constructed by randomly combining human germline FW1, FW2 and FW3 sequences. Only one FW4 sequence was used, which is WGQGTTVTVSS (SEQ ID NO: 154) for the heavy chain (HC) (human HC subgroup I according to Kabat, #21) and FGQGTKVEIK (SEQ ID NO: 186) for the light chain (LC) ( subgroup I to a person according to Kabat, No. 5). The VR sequence library was fused with human IgG4(S228P) HC constant region (CR) and anti-human LC CR, and the resulting whole IgG-mAb library was expressed in CHO cells for screening. Screening was performed using tissue culture supernatants, measuring the avidity of binding on antigen-expressing cells by whole cell ELISA or FACS.

The humanization process was carried out in a stepwise manner, starting with the construction and expression of an appropriate chimeric mAb (murine VR, IgG4(S228P), to human) that can serve as a comparison when screening humanized clones. The amino acid sequences of the constant region for the IgG4(S228P) heavy chain and human kappa light chain are shown in Table 1. 3.

Humanization of VR LC and HC was carried out in two independent steps. The humanized LC (huLC) library was combined with chimeric HC (mouse VR, IgG4(S228P)) and the resulting semi-humanized mAbs were screened for binding activity by ELISA. huLC clones with sufficient binding activity (>binding of the chimeric mAb) were selected. Similarly, the humanized HC (huHC) library was combined with chimeric LC (VR mouse, to human) 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 then sequenced to identify huLCs and huHCs with unique sequences (some clones from the original selection process may have the same LC or HC). Then, unique huLCs and huHCs were randomly combined to form a small library of humanized mAbs (humAbs) that were expressed in CHO cells and screened on antigen-expressing cells by ELISA and FACS. Clones with binding activity equal to or better than the binding of the chimeric reference mAb are the end product of the humanization process.

Example 1.2: mouse mAb BAP058 sequence.

The LC variable regions and HC mouse anti-PD-L1 mAb sequences were determined. The sequences obtained from two independent assays were identical and are shown in FIG. 1.

Germline sequences were analyzed and a portion of the results are shown in FIG. 2 as an alignment of amino acid sequences. For the light chain, the V gene is 99.28% identical to mIGKV6-23*01F (277/279 nts) and the J gene is 97.06% identical to mIGKJ5*01F (33/34 nts). For the heavy chain, the V gene is 96.88% identical to mIGHVl-72*01F (279/288 nts), the J gene is 92.45% identical to mIGHJ4*01F, and the D gene is mIGHD25*01F.

Example 1.3: construction of a chimeric antibody.

The chimeric antibody was generated by cloning the HC and LC variable domains into a mammalian expression vector in frame with either a secretion signal and a human kappa constant region (LC) or a secretion signal and a human IgG4 constant domain (HC). The resulting antibody was inserted into an empty vector and transfected into CHO-S cells. The cell culture supernatant was collected 48 hours after transfection and the concentration of recombinant clones in the supernatant was determined by quantitative ELISA. IgG in the cell culture supernatant was captured on an anti-human IgG Fc antibody plate. Bound IgG was detected with an anti-human IgG antibody conjugated to HRP. The IgG concentration was calculated using commercially available human IgG4 as a standard.

Binding of the recombinant clone to human PD-L1 was investigated using cell line 300.19 expressing huPD-L1 on the cell surface and FACS analysis. The result showed

- 279 040861 that the chimera binds well to the antigen.

The amino acid sequences of the heavy and light chains for the BAP058-chi chimeric mAb are shown in Table 1. 1. Nucleotide sequences of the heavy and light chains of the chimeric mAb

BAP058-chi are presented in table. 1.

Example 1.4: clones of humanized antibodies.

As shown in FIG. 3, the humanization process provided seventeen clones with a binding affinity comparable to that of the chimeric antibody. In addition to binding data, for each clone, the VR sequences were provided with the mAb sample. Samples were obtained by transient transfection of CHO cells and were concentrated tissue culture supernatants.

The concentration of antibodies in solutions was determined using IgG4-specific ELISA.

As shown in FIG. 4, seventeen unique clones are combinations of nine unique HC sequences and nine unique LC sequences. For each of the HC and LC FW regions, four to seven different germline sequences were used in 17 humanized clones. The amino acid and nucleotide sequences of the heavy and light chain variable domains for the humanized BAP058 clones are shown in Table 1. 1. The amino acid and nucleotide sequences of the heavy and light chain CDRs of the humanized BAP058 clones are also shown in Table 1. 1.

In FIG. 4 shows that the mAb concentration ranged from 0.5 µg/mL to 47.6 µg/mL in the samples. These numbers were 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 mouse Alexa 488 BAP058 labeled, serial dilutions of test antibodies, and 300.19 PD-L1 expressing cells. Incubation with mAb mixtures having different concentration ratios of test mAb and labeled mAb was carried out at 4° C. for 30 min. The bound mouse mAb was then quantified using a FACS device. The experiment was carried out twice. The results are shown in FIG. 5. Fluorescence intensity is determined by plotting the concentrations of the test mAb against labeled mouse BAP058. In FIG. 6 shows the ratios of the IC ₅₀ values for each mAb. The ratio for the mouse parent mAb approached 1 (actual value is 1.34), indicating that the labeled mouse mAb BAP058 did not lose binding affinity.

The ratios for the mAbs tested ranged from 1.3 to 4.64, indicating that the binding strength may vary by approximately three times between different clones. These results correlated well with the semi-quantitative ranking performed on the FACS data presented in FIG. 3 and 5. Human BAP058 clones with high rank number (weaker binding compounds) had a high ratio in the competitive binding assay.

Example 1.5.2: sequence analysis.

Based on structural features, seventeen humanized mAbs were divided into six groups and ranked from 1-17. The results are shown in FIG. 6.

Example 1.5.3: selection of humanized clones.

In FIG. 6 summarizes the data that was taken into account in the selection of humanized clones. Expression data (2nd column), diversity in the composition of the variable regions (3rd column), relative score in binding studies (4th and 5th column) and structural analysis (6th column) were taken into account.

Selected clones were produced at higher levels (0.5 mg; transiently expressed in CHO cells) and purified by protein A affinity chromatography. Samples were shown to be free of endotoxins.

Example 1.5.4: blocking PD-1-Ig binding to 300.19 cells transfected with PD-L1.

Six preferred human BAP058 mAbs were tested for their ability to block PD-1-Ig binding to 300.19 cells expressing PD-L1. In a competition binding experiment, 300.19 cells expressing PD-L1 were incubated with mixtures of PE-labeled PD1-Ig at a constant concentration (0.7 μg/ml) and increasing concentrations of test mAbs at 4°C for 4 h. Then, fluorescence was measured when bound using FACS and IC ₅₀ values were determined using Prism software.

All human BAP058 mAbs and mouse BAP058 mAbs provided similar competitive binding curves. IC ₅₀ values varied within a narrow range from 0.29 nM to 0.33. The mouse parent mAb BAP058 shows an IC ₅₀ value of 0.30 nm. The results are shown in FIG. 7.

Generalization and conclusions.

The mouse anti-PD-L1 monoclonal antibody BAP058 was humanized. The technology encompasses cloning in-frame mouse CDRs into an ordered library of human germline variable framework regions, expression of the library of cloned variable regions as humanized mAbs with intact IgG4(S228P) in CHO cells, and selection of clones that bind to a comparable or higher affinity for the target as the parent mAb. Thus, mouse CDRs were used to select for appropriate human germline framework sequences that retain their conformation and thus the binding affinity and specificity of the mouse parent mAb. Seventeen humanized unique variable region mAbs were sequenced and tested and tested for binding to 300.19 cells transfected with PD-L1. These clones were further analyzed for their biological functions (eg, binding and blocking interaction with PD-1), structural features, and transient expression in CHO cells.

Example 2: Expression of the humanized anti-PD-L1 antibody BAP058.

The 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 Lonza's GS Xceed vectors (IgG4proAk for the heavy chain and kappa for the light chain). SGV was amplified and transiently co-transfected into CHOK1SV GS-KO cells for expression in a volume of 2.8 L.

Expression cultures were harvested 6 days after transfection and purified by centrifugation and filter sterilization. Purified cell culture supernatant was purified using one-step protein A chromatography. Product quality analysis in the form of size exclusion HPLC, SDS-PAGE, IEF and LAL was performed using purified material at 1 mg/mL containing antibody as a control.

Example 2.1: constructing a vector.

The sequences of the light and heavy chain variable domain coding regions were synthesized at GeneArt AG. The light chain variable domain coding regions were subcloned into the pXC-Karr vector and the heavy chain variable domain coding regions were subcloned into the pXCIgG4proAK vector, respectively, using the N-terminal Hind III restriction site and the C-terminal BsiWI (light chain ) and Apal (heavy chain). 5 μg of lyophilized shuttle vectors were resuspended in 50 μl of endotoxin-free sterile water. 1 μg of DNA was digested with the appropriate restriction enzymes in a total volume of 50 μl and the samples were incubated for 2 hours at 37°C. 8.3 μl of 6x DNA loading buffer was added and the samples were electrophoresed at 120 V for 40 min on a 1 w/v% agarose gel stained with ethidium bromide. 10 µl of Lonza SimplyLoad Tandem DNA ladder DNA marker was used as a reference marker.

Appropriate fragments were subjected to gel extraction using a QIAquick gel extraction kit (QIAGEN, 28704) according to the manufacturer's instructions. Ligation was performed using the Roche Quick Ligation Kit with a 1:12 ratio of vector backbone to DNA insert, 1 µl T4 quick ligase, 10 µl 2x T4 quick ligation buffer, the reaction volume was adjusted to 21 µl with endotoxin-free sterile water when was necessary, and the samples were incubated at room temperature for 10 min. 10 μl aliquots of ligation reactions were used to transform chemically competent Escherichia coli One Shot Top 10 cells (Invitrogen, C404003) using the heat shock method according to the manufacturer's instructions. Cells were distributed on ampicillin-containing (50 μg/ml) Luria-Bertani agar plates (Select APS LB Broth base, BD 292438, and Bactiological Agar, Sigma Aldrich A5306) and incubated overnight at 37°C until bacterial colonies did not become visible.

Single bacterial colonies were selected in 15 ml Luria-Bertani (LB) medium (Select APS LB Broth base, BD 292438) containing 50 μg/ml ampicillin and incubated at 37°C for 6 h with shaking. Vector DNA was isolated from 10 ml of these growth cultures using the QIAGEN miniprep system and eluted in 30 µl of EB buffer. Positive clones were identified by HindIII and EcoRIi digestion and confirmed by nucleotide sequencing of the gene of interest.

Example 2.2: DNA amplification.

A single bacterial colony was collected in 15 ml Luria-Bertani (LB) medium containing 50 μg/ml ampicillin and incubated at 37° C. overnight with shaking at 220 rpm. The resulting starter culture was used to inoculate 1 L of Luria-Bertani (LB) medium containing 50 μg/ml ampicillin and incubated at 37° C. overnight with shaking at 220 rpm. Vector DNA was isolated using the QIAGEN Plasmid Plus Gigaprep system (QIAGEN, 12991). In all cases, the DNA concentration was measured using a Nanodrop 1000 spectrophotometer (Thermo-Scientific) and adjusted to 1 mg/ml with EB buffer (10 mM Tris-Cl, pH 8.5). The DNA quality for single gene vectors was assessed by measuring the absorbance ratio of A260/A280 and found to be between 1.88 and 1.90. The DNA concentration was adjusted to 1 mg/ml with buffer EB.

Example 2.3: CHOK1SV GS-KO cell culture.

CHOK1SV GS-KO cells were cultured in CD-CHO medium (Invitrogen, 10743-029) supplemented with 6

- 281 040861 mM glutamine (Invitrogen, 25030-123). Cells were incubated in a rotating incubator 36.5°C, 5%

CO ₂ , 85% humidity, 140 rpm. Cells were subjected to standard subculturing every 3-4 days by seeding 2x105 cells/ml, and they were increased in number to have a sufficient number of cells available for transfection. Cells were discarded at passage 20.

Example 2.4: Transient transfections of CHOK1SV GS-KO cells.

Transient transfections were performed using CHOK1SV GS-KO cells that had been in culture for a minimum of two weeks. Cells were subcultured 24 h prior to transfection and cell viability at the time of transfection was >99%.

All transfections were performed by electroporation using the Gene Pulse MXCell (Bio-Rad), a plate-based electroporation system. For each transfection, live cells were resuspended in prewarmed medium to 2.86x107 cells/ml. 80 μg of DNA (1:1 ratio for SGV heavy and light chains) and 700 μl of cell suspension were aliquoted into each cuvette/well. Cells were electroporated at 300 V, 1300 mF. The transfected cells were transferred to prewarmed medium in Erlenmeyer flasks and the cuvette/wells were rinsed twice with prewarmed medium, which was also transferred to the flasks. The transfected cell cultures were incubated in a rotating incubator at 36.5°C, 5% CO2, 85% humidity, 140 rpm for 6 days. Cell viability and live cell concentrations were measured at the time of collection using a Vicell automated cell counter. Cell density and viability (>7.72x10 ⁶ cells/mL; >92.5% at day 6) were found to be within the typical observed range when harvesting the cell culture.

Example 2.5: Protein A affinity chromatography.

The cell culture supernatant was collected and purified by centrifugation at 2000 rpm for 10 minutes and then filtered through a 0.22 µm PES membrane filter. The purified supernatant was purified using a pre-filled 5 ml HiTrap MabSelect SuRE column (GE Healthcare, 11-0034-94) on an AKTA purifier (10 ml/min). The column was equilibrated with 5 column volumes (CV) of 50 mM sodium phosphate, 125 mM sodium chloride, pH 7.0 (equilibration buffer). After loading the sample, the column was washed with 2 CV of equilibration buffer followed by 3 CV of 50 mM sodium phosphate, 1 M sodium chloride, pH 7.0 and washed again with 2 CV of equilibration buffer. The product was then eluted with 10 mM sodium formate, pH 3.5, at 5-15 CV. The protein containing the eluted fractions was immediately adjusted to pH 7.2 and filtered through a 0.2 μm filter. After elution, the pH of the eluted fractions was adjusted to pH 7.4. The product was then concentrated using an Amicon Ultra-4 Centrifugal Filter Unit (MWCO 30 kDa) (UFC903024) to 5-10 mg/mL.

During the elution phase, a single protein-containing peak was observed. Through size exclusion HPLC and SDS-PAGE analysis, this peak was shown to contain mAb. The protein yield after concentration is presented in table. 4. The clones had transient expression ranging from 8.25 to 13.21 mg/l. The BAP058 antibody variants exhibited a slow elution profile (smeared peaks) under standard elution conditions (10 mM sodium formate, pH 3.5, in 5 column volumes), requiring an additional 5-10 colony volumes of elution buffer to reduce the UV signal to below 50mAU.

Table 4

Summary of Yield, Titer, Monomers, and Endotoxin Levels

Product Yield* (mg) Titer* (mg/l) Content monomer (%) Endotoxin Levels (EU/mg) Clone K 37.0 13.21 86, 23 0.191 Clone L 29.4 12.25 98.04 0.084 Clone M 25.0 8.92 84.57 0.193 Clone N 19, 8 8.25 91.48 0.122 Clone O 25.74 9, 19 93.70 <0.050 *After purification with protein A

Example 2.6: SEC HPLC analysis.

Duplicate protein A purified antibody samples were analyzed by SEHPLC on an Agilent 1200 series HPLC system using a Zorbax GF-250 column, 4 μm 9.4 mm ID x250 mm (Agilent). Sample aliquots at 1 mg/mL were filtered through a 0.2 µm filter prior to injection. Aliquots of 80 μl were injected, respectively, and run at 1 ml/min for 15 min. Soluble aggregate levels were analyzed using Chemstation software (Agilent).

Chromatography profiles with retention times showing the percentage of total peak areas detected were generated for test antibodies and control IgG4 antibody. Products demo

- 282 040861 a single protein peak was detected at approximately 9.05-9.07 minutes, comparable to a control human IgG4 antibody (approximately 9.03 minutes), and was consistent with a monomeric antibody. Varying amounts (up to 15.4%) of higher molecular weight impurities corresponding to soluble aggregates were found at retention times from 8.29 to 8.45 minutes. All products showed a similar retention profile but with varying levels of monomer found in the range of 84.6-98.0% of total protein. Clones K and M showed the highest amount of contaminants with a retention time corresponding to dimeric antibodies (soluble aggregates) of approximately 15%, while clone L showed the least amount (1.96%).

Example 2.7: SDS-PAGE analysis.

Reconstituted and non-reduced protein A purified antibody samples were prepared for analysis by mixing with 4x LDS NuPage Sample Buffer (Invitrogen, NP0007) and 10x NuPage Sample Reconstitution Agent (Invitrogen, NP0009) and incubated at 70°C, 10 min. For unrecovered samples, the reducing agent and heat incubation were not used. Samples were electrophoresed on 1.5 mm pre-embedded NuPage 4-12% Bis-Tris Novex gels (Invitrogen, NP0335PK2) with NuPage MES SDS running buffer under denaturing conditions. A 10 µl aliquot of SeeBlue Plus 2 pre-stained molecular weight standard (Invitrogen, LC5925) and control IgG4 antibody at a concentration of 1 mg/ml was included in the gel. 1 μl of each sample was applied to the gel at a concentration of 1 mg/ml. After electrophoresis, the gels were stained with InstantBlue (TripleRed, ISB01L) for 30 min at room temperature. Images of stained gels were analyzed on a BioSpectrum Imaging System (UVP).

The analysis confirms the presence of antibodies. Under non-reducing conditions, a predominant protein band above 98 kDa is observed, comparable to the control IgG4 antibody. The IgG4 control antibody shows an additional weaker band corresponding to a heavy chain plus light chain half antibody at approximately 70 kDa under non-reducing conditions. This is expected for a control antibody. Two bands were observed under reducing conditions corresponding to the size of the heavy chain (near the 49 kDa marker position) and light chain (near the 28 kDa marker position) and were comparable to the bands found for the control IgG4 antibody.

Example 2.8: analysis by isoelectric focusing (IEF).

Unreduced protein A purified antibody samples were subjected to electrophoresis as described below.

µg of protein A purified samples were electrophoresed on a 1.0 mm pH 3-10 Novex gradient gel (Invitrogen, EC66552BOX) using the manufacturer's recommended separation conditions. 10 µl aliquots of pH 3-10 IEF markers (Invitrogen, 39212-01) were included in the gel. After electrophoresis, the gels were fixed with 10% TCA for 30 min and then stained with InstantBlue (TripleRed, ISB01L) overnight at room temperature. Images of stained gels were analyzed on a BioSpectrum Imaging System (UVP).

As shown in Table. 5, the clones tested exhibited charge isoforms having greater than pH 7.8. The charge isoforms detected were somewhat more basic than the theoretically calculated isoelectric points (pI) for these antibodies, which were predicted to be between 7.72 and 8.21. This general shift to more basic isoforms indicates the presence of post-translational modifications such as glycosylation of the molecules. Clones K and M, L and N, show comparable charge isoforms, consistent with their theoretically calculated pI, which is the same for both pairs (7.72 for K and M, 7.87 for L and N). The pI for clone O could not be accurately determined because it did not exit the well into which it was applied. The predicted isoelectric point for clone O is 8.21, which is close to the limit of detection (8.3) in this assay. Since the general trend is for the measured pI to increase slightly over the predicted pI, this indicates that the actual pI is likely to be approximately 8.6, which is outside the detection limit. The IgG4 control antibody had the expected behavior.

- 283 040861

Table 5

Charge isoforms detected by Novex IEF analysis

Product R! dominant charge isoforms* Acidic charge isoforms* Main charge isoforms* Clone K 8.0 2x; 7.8-7.9 2x 8.2-8.3 Clone L 8.2 2x; 7.9-8.0 8.3 Clone M 8.0 2x 7.8-7.9 8.1 Clone N 8.3 2x 8.1-8.2 8.4 Clone 0 >8.3 N/D N/D *R data! evaluated from staining positions correlated against an IEF 3-10 marker.

Example 2.9 Endotoxin Assay.

Purified protein endotoxin levels (at 1 mg/mL) were measured using the Endosafe-PTS device, a cassette-based LAL assay method (Charles River).

As shown in Table. 4, the endotoxin content was found to be in the range of 0.05 to 0.191 IU/mg.

Conclusion.

Single gene GS expression vectors for selected humanized anti-PD-L1 mAbs were constructed and used to transiently transfect CHOK1SV GS-KO cells. From 2.4 to 2.8 liters of expression culture was incubated under standard conditions for 6 days and the resulting cell culture supernatant was purified using protein A chromatography. Titers after purification and concentration are shown in table. 4 and were found to be in the range of 8.25 to 13.21 mg/l. The final yield ranged from 19.8 to 37 mg.

SDS-PAGE analysis showed high levels of purity after initial purification with protein A and buffer exchange, while size exclusion HPLC analysis showed the presence of soluble aggregates (up to 15.43%) in the products, which is largely consistent with a dimeric antibody. Clones M and K showed increased amounts of these high molecular weight impurities (15.4% and 13.8%, respectively).

Isoelectric focusing revealed a number of charge isoforms of all mAbs. Clones K-N showed isoforms that were generally more basic than theoretically calculated pI values for these molecules, indicating some level of post-translational modifications, pI for clone O could not be accurately determined because the measured pI exceeded the detection range of the gel.

Endotoxin levels in all samples were measured prior to sample preparation and were found to be less than 0.191 EU/mg.

Example 3: Characterization of mouse anti-PD-L1 antibodies and humanized anti-PDL1 antibodies.

Example 3.1: Characterization of a humanized anti-PD-L1 antibody.

Binding affinity and specificity.

The binding of an exemplary humanized anti-PD-L1 antibody to human PD-L1 protein was measured using the Biacore method. The results are: K _a =3.07x10 ⁵ M- ¹ s- ¹ ; K _d \u003d 4.55x10 ⁵ s- ¹ ; KD=0.171 nM.

Binding of an exemplary humanized anti-PD-L1 antibody to cynomolgus monkey PD-L1 protein was determined using Biacore methods. The results are: K _a =9.51x10 ⁵ M' ¹ s'¹; Kd= ^4.55x10'5 s- ¹ ; Kd=0.124 nM.

Binding of an exemplary humanized anti-PD-L1 antibody to mouse PD-L1 protein was measured using the Biacore method. The results are: K _a =8.30x10 ⁶ M- ¹ s- ¹ ; K _d \u003d 1.67x10- ⁴ s- ¹ ; KD=0.0202 nM.

The binding of an exemplary humanized anti-PD-L1 antibody to the PD-L1 protein was measured using the Biacore method. The results are: K _a =9.45x10 ⁶ M- ¹ s- ¹ ; Kd= ^1.23x10-4 s ^-1 ; K _d =0.168 nM.

Binding of the same humanized anti-PD-L1 antibody to 300.19 cells expressing human PD-L1 was measured using FACS analysis. The result shows that the anti-PD-L1 antibody (human IgG4) binds to human PD-L1 with a KD of 0.285 nM.

Binding of the same humanized anti-PD-L1 antibody to 300.19 cells expressing cynomolgus monkey PD-L1 was measured using FACS analysis. The result shows that the anti-PD-L1 antibody (human IgG4) binds to human PD-L1 with a KD of 1.29 nM.

- 284 040861

These results show that an exemplary anti-PD-L1 antibody binds with high affinity to human, mouse, rat, and cynomolgus monkey PD-L1.

Blocking interactions between PD-L1 and its ligands.

The ability of an exemplary humanized anti-PD-L1 antibody to block interactions between PD-L1 and both of its known ligands, PD-1 and B7-1, was investigated. The results show that the anti-PD-L1 antibody blocks the binding of PD-1 and B7-1 to 300.19 cells expressing human PD-L1 compared to human IgG4 isotype control and control without antibody. Anti-PD-L1 antibody blocked PD-1 binding to 300.19 cells with an IC ₅₀ of 0.145 nM. The same antibody blocked B7-1 binding to 300.19 cells with an IC ₅₀ of 0.1 nM.

Cellular activity.

The ability of an exemplary humanized anti-PD-L1 antibody to enhance staphylococcal enterotoxin B (SEB) stimulated expression of IL-2 and IFNy was examined in an ex vivo human whole blood assay. Diluted whole blood was incubated with anti-PD-L1 antibody in the presence or absence of SEB at 37° C. for 48 hours prior to determination of IFNy and IL-2. The result shows that anti-PD-L1 antibody increases SEB-stimulated IFNy expression by 2.72±0.84-fold and increases IL-2 expression by 2.39±0.96-fold compared to isotype control human IgG4 (25 µg/mL SEB; n=5 donors).

Example 4 Selection of Patients Based on PD-L1/CD8/IFN-y Status.

For each of several types of cancer, samples from multiple patients were examined for PD-L1/CD8/IFN-y status. Each sample was classified as: triple negative for PD-L1/CD8/IFN-y, single or double positive for these markers, or triple positive for these markers. In FIG. 10 shows that in this experiment, in the patient population, the following types of cancer are often triple positive for PD-L1/CD8/IFN-y: lung cancer (squamous cell), lung cancer (adenocarcinoma), head and neck cancer, cervical cancer ( squamous cell), gastric cancer, thyroid cancer, melanoma and nasopharyngeal cancer. Patients having these types of cancers are good candidates for anti-PD-1 antibody therapy and combination therapies as described herein. The likelihood of successful treatment can be further enhanced by determining which patients are PD-L1/CD8/IFN-y triple positive and treating the triple positive patients with anti-PD-L1 antibodies and combination therapies as described herein.

In FIG. 11 shows that the following types of cancer are rarely triple positive for PD-L1/CD8/IFN-y in the patient population: ER+ breast cancer and pancreatic cancer. Notably, even in malignancies that are not normally PD-L1/CD8/IFN-y positive, it is possible to increase the likelihood of successful treatment by determining which patients are PD-L1/CD8/IFN-y triple positive and treating triple positive patients with anti-PD-L1 antibodies and combination therapies as described herein.

In FIG. 12 shows the proportion of breast cancer patients who are triple positive for PD-L1/CD8/IFN-y. Considering breast cancer in general, the proportion of triple positive patients is quite low. However, if one focuses only on IM-TN breast cancer, one can see that a significantly higher percentage of patients are triple positive for PDL1/CD8/IFN-y. IM-TN breast cancer is particularly difficult to treat with conventional therapies. The discovery that IM-TN breast cancer is often triple positive for PD-L1/CD8/IFN-y provides new avenues for therapy of this cancer with anti-PD-L1 antibodies and combination therapies as described herein.

In FIG. 13 shows the proportion of patients with colon cancer who are triple positive for PD-L1/CD8/IFN-y. Considering colon cancer as a whole, the proportion of triple positive patients is quite low. However, if one focuses only on breast cancers with high MSI (high microsatellite instability), it can be seen that a significantly higher percentage of patients are triple positive for PD-L1/CD8/IFN-y. MSI levels can be analyzed using, for example, commercially available PCR-based methods.

Gastric cancer samples were examined for PD-L1/CD8/IFN-y levels (data not shown). It was found that in high MSI gastric cancer or EBV+ gastric cancer, approximately 49% were positive for PDL1, and a high proportion of positive for PD-L1 cells were triple positive for PD-L1/CD8/IFN-y. It was also found that a proportion of PD-L1 positive cells and PD-L1/CD8/IFN-y positive cells were also positive for PIK3CA. These data indicate that these cancers can be treated with an anti-PD-L1 antibody, optionally in combination with a therapeutic agent directed at PIK3.

High MSI CRC samples were tested for a combination of markers (data not shown). In high MSI CRC samples, a high proportion of PDL1/CD8/IFN-y samples were also found to be positive for LAG-3, PD-1 (also referred to as PDCD1), RNF43 and BRAF.

These data indicate 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.

Squamous cell lung cancer was examined for a combination of markers (data not shown). In squamous cell lung cancer samples, a high proportion of PDL1/CD8/IFN-y positive samples were also found to be LAG-3 positive. These data indicate that these cancers can be treated with an anti-PD-1 antibody, optionally in combination with a therapeutic agent that targets LAG-3, such as an anti-LAG-3 antibody.

Papillary thyroid cancer was investigated for a combination of markers including the BRAF V600E mutation (data not shown). It has been found that a high proportion of thyroid cancer samples that are positive for PD-L1 are also positive for V600E BRAF. This data indicates that. That these cancers can be treated with an anti-PD-L1 antibody, optionally in combination with a therapeutic agent that targets BRAF.

Example 5 Selection of Patients Based on PD-L1 Status.

In order to provide extensive cancer research into PD-1/PD-L1 based therapies, the present inventors evaluated PD-L1 expression at both protein and mRNA levels in human cancers, including tumors of both lung, as well as the liver.

PD-L1 protein expression was assessed in a set of formalin-fixed paraffin-embedded lung non-small cell adenocarcinoma (ASA) (NSCLC), NSCLC squamous cell carcinoma (SCC) and hepatocellular carcinoma (HCC) tumors using immunohistochemistry (IHC). PD-L1 expression was assessed semi-quantitatively using a manual histo-score (H-score) methodology based on staining intensity and percentage of positive tumor cells. In the IHC assay conducted by the present inventors, PD-L1 positivity (PD-L1+) was defined as an H-score>20. In parallel, PD-L1 mRNA expression data from The Cancer Genome Atlas (TCGA) were examined in these indications (503 NSCLC ACA, 489 NSCLC SCC and 191 HCC) and analyzed by comparing expression in corresponding normal tissues from TCGA.

Using RNAseq analysis, data were calculated as log2 (RPKM+0.1) after RSEM normalization using the OmicSoft RNASeq system for oncology from TCGA. Expression of PD-L1 is elevated in ACA and SCC NSCLC relative to HCC. By overlaying distributions and comparing expression levels among all TCGA indications, the present inventors ranked the overexpression profiles for PD-L1 and found that the TCGA HCC group had significantly reduced levels of PD-L1 mRNA with a mean level of -0.8 compared to 1 .3 for ACA and 1.5 for SCC, which corresponds to a change from the average expression level by more than 2 times. Using RNAseq, the present inventors identified 50% of NSCLC adenocarcinoma cases, 54% of NSCLC squamous cell carcinoma cases, and 6% of HCC cases as highly expressing PD-L1.

Expression of PD-L1 protein in tumor cells was measured in 45 lung adenocarcinoma (ACA), 47 lung squamous cell carcinoma (SCC) and 36 hepatocellular carcinoma (HCC) samples. 16/45 (35.6%) cases of lung ACA, 21/47 (44.7%) cases of lung SCC were positive for PD-L1. In contrast, PD-L1 positivity was observed in only 2/36 (5.6%) HCC samples.

In general, using IHC and RNAseq analysis in large and independent sets of NSCLC and human HCC samples, the present inventors found that PD-L1 expression is more upregulated in NSCLC than in HCC. In the case of NSCLC, data between adenocarcinoma and squamous cell carcinoma were comparable. Importantly, among the large number of samples (128 for IHC and 1183 for RNAseq) for 3 diseases, there is a very high agreement between protein and mRNA based assays. Thus, the data obtained by the authors of the present invention establishes the basis for large-scale data collection based on mRNA in TCGA for diseases and patient segments in which responses to PD-1/PD-L1 based immune therapy can be enhanced.

Example 6: Effects of Directional Means on PD-L1 Modulation.

This example evaluates the effects of individual drugs (eg, cMET inhibitor, MEK inhibitor, bRAF inhibitor, and ALK inhibitor) on PD-L1 (CD274) modulation. Compound A17 can be prepared as described in Example 21 of US Pat. No. 8,420,645. Compound A18 (ruxolitinib phosphate), Compound A23 (ceritinib), Compound A34 (binimetinib), and Compound A29 (encorafinib) are available from Novartis AG, Basel, Switzerland. . Selected drugs were examined by real-time PCR and flow cytometry for PD-L1 levels. Significant inhibition of PD-L1 was observed by compound A17, compound

- 286 040861

A18, compound A34, compound A29 and compound A23 on tumor cells.

Inhibition of PD-L1 protein by junction A17 in non-small cell lung cancer cells

Expression of PD-L1 (CD274) was analyzed in malignant cell lines treated with compound A17. Cells were obtained from ATCC and cultured in vitro according to ATCC instructions. The cell lines used were previously characterized by the Cancer Cell Line Encyclopedia Project (http://www.broadinstitute.org/ccle/home).

Cells seeded in six well plates were treated with compound A17 at various concentrations (10, 100 and 1000 nM) for 24, 48 and 72 hours. An equal amount of vehicle (DMSO) was used as a control. Cells were washed with PBS and then harvested using a cell scraper.

For each reaction, 0.5-1x10 ⁶ cells were stained with 20 μl of anti-human PD-L1 monoclonal antibody with PE, clone M1H1 (BD), for 30-60 min at 4°C. Cells were washed twice and data was obtained 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 single cells. Unstained cells were used as a gating control.

Treatment of EBC-1 cells (non-small cell lung cancer (NSCLC) with cMET amplification) with compound A17 in vitro resulted in a significant suppression of surface expression of PD-L1, as observed by flow cytometry (Fig. 14). The results presented herein indicate that compound A17 functions as a PD-L1/PD-1 inhibitor.

Compound A17, compound A34, compound A18, compound A29 and compound A23 suppress PD-L1 mRNA.

TaqMan RT-PCR assays have been developed to detect changes in PDL1 (CD274) expression levels in cell lines and tumor xenografts. mRNA was isolated from frozen cell pellets and tumor fragments using the Qiagen RNeasy Mini kit. The isolated RNA was frozen at -80°C. RNA quality was checked and RNA was quantified using an Agilent 2100 Bioanalyzer device according to the Agilent RNA 6000 Nano Kit protocol. cDNA was obtained using the High Capacity RNA-to cDNA Kit (Applied Biosystems).

Real-time PCR reactions were performed in a total volume of 20 µl, including 10 µl Universal PCR master mix (Applied Biosystems), 1 µl human PD-L1 probe/primer kit (CD274) (Applied Biosystems) and 8 µl cDNA . Each sample was analyzed in triplicate. In each PCR reaction, the amount of cDNA produced from 25-50 ng of RNA in a reverse transcription reaction was used. Due to differences in mRNA levels between PD-L1 and GAPDH, two real-time PCR reactions were performed in separate tubes using the same amount of cDNA. The real-time PCR reaction was performed on a C1000 Thermal Cycle (BioRad) with the following cycle program: incubation for 10 min at 95°C, followed by 40 cycles at 95°C for 15 s and 60°C for 1 min. After completion of the PD-L1 reaction, the average Ct value was normalized to each Ct value from the GAPDH reference reaction. Each normalized log value was then converted to a linear value.

Inhibition of PD-L1 (mRNA) expression by Compound A17 was observed in Hs.746.T tumor xenograft (gastric cancer cells amplifying and mutating cMET) (FIG. 16). Inhibition of PD-L1 mRNA by compound A23 was observed in H3122 (non-small cell lung cancer (NSCLC) with ALK translocation) in vitro (FIG. 17). Suppression of PD-L1 mRNA by Compound A29 and Compound A34 was observed in tumor xenograft models including LOXIMV1 (BRAF mutant melanoma, Fig. 18) and HEYA8 (KRAF mutant ovarian cancer, Fig. 19) tumors, respectively. Suppression of PD-L1 mRNA by compound A18 was observed in tumor xenograft models including the UKE-1 lineage (myeloproliferative neoplasm (MPN) with JAK2V617F mutation, Fig. 19).

The results presented herein 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 agents indicates that these targeted agents may have immunomodulatory activity, in addition to their effects on signaling in cancer. Thus, the results presented in this example indicate that the administration of targeted agents with inhibitors of immune checkpoint inhibitors such as PD-1, PD-L1, LAG-3 and/or TIM-3 provides more effective reversal of the immune response. suppression mediated by immune control points.

Example 7: Reaction of mixed lymphocytes with monocyte-derived dendritic cells and allogeneic CD4+ T cells.

Peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats using standard techniques using a Ficoll gradient. The CD14+ monocyte fraction of PBMC was isolated by negative selection using StemCell's EasySep Monocyte Boosting Kit according to the supplier's instructions. To differentiate monocytes into dendritic cells (DC), medium was supplemented with 100 ng/ml human GM-CSF (BTP30538 manufactured by Novartis or commercially available from R&D) and 80 ng/ml human IL4 (BTP30884 manufactured by Novartis) and the cells were incubated for 7 days at 37°C and 5% CO2. On day 7 of culture, monocyte-derived DCs received increased concentration of fresh CD4+ T lymphocytes from PBMCs derived from a buffy coat obtained from another donor (ie, allogeneic). The CD4+ T cell fraction was isolated by negative selection using StemCell's Easysep CD4+ T Cell Boosting Kit according to the manufacturer's instructions. DC and allogeneic CD4+ T cells were then seeded at increased concentrations in 96-well U-bottomed plates at a ratio of 1:10 (10 ⁴ DC and 10 ⁵ CD4 T cells/well) in the presence of the indicated antibodies and in triplicate. Antibodies tested included control huIgG4 against chicken lysozyme (ACE14834). The cocultures were then incubated for 5 days at 37°C and 5% CO2. On day 5, 100 μl of the supernatant was collected and stored at -20°C for subsequent cytokine analysis. Stimulation indices (SI) for proliferation and release of IFNy in each experiment and for each antibody concentration tested were calculated by dividing the mean of each data measured for test antibodies by the mean measured for the control human IgG4 anti-chicken lysozyme antibody ACE14834. IFNy in coculture supernatants was determined by standard ELISA using commercially available ELISA kits.

Exemplary anti-PD-L1 antibodies showed a marked effect on detectable levels of IFNy in supernatants harvested on Day 5 of co-culture. As shown in FIG. 21, antibody treatment resulted in a dose-dependent increase in IFNy release, averaging ∼4-7 fold the levels observed with the isotype control antibody at doses ranging from 0.04 and 20 μg/mL.

Example 8: T cell stimulation assay with superantigen.

PBMCs were isolated from buffy coats by standard techniques using a Ficoll gradient and resuspended at 2x106 cells/ml in T cell culture medium. 200,000 cells/well were added to a 96-well round bottom plate. SEB (staphylococcal enterotoxin B) was then added at a final concentration of 1 ng/ml. Test antibodies or isotype control human IgG4 were added at a final concentration of 25 μg/ml and the plate was incubated at 37° C., 5% CO ₂ for 4 days. Supernatants were harvested for cytokine IL-2 measurement by MSD according to the manufacturer's protocol. Data are presented for 5 human donors.

As shown in FIG. 22, exemplary anti-PD-L1 antibodies enhanced SEB-induced IL-2 secretion from T cells compared to isotype control Ab in all donors, with a mean fold of stimulation of 4.4+2.0 (n=5). Anti-PD-1 antibodies were used as a positive control in this assay and showed a similar effect to anti-PD-L1 antibodies.

Example 9: Cross-species binding of anti-PD-L1 antibodies as assessed using Biacore.

A specific anti-human Fab antibody was immobilized on a CM5 chip (GE, catalog number: 28-9583-25). Immobilization was carried out at 25°C using a flow rate of 10 μl/min. IgG was diluted to 2.5 μg/ml and captured within 30 s at a flow rate of 10 μl/min. The antibody of interest was captured on the FC2, FC3 and FC4 flow cell. PD-L1 (rat, human, mouse or cynomolgus monkey) was skipped as follows: PD-L1 starting concentration is 100 nM, 2-fold dilutions: 100, 50, 25, 12.5, 6.25, 3.12, 1.56 and 0 nM. Kinetics/affinity of passage Biacore Wizards: association time 120 s, dissociation time 600 s (Running buffer HBS-EP+BSA 0.25 mg/ml, regenerating buffer: 10 mM glycine HCl, pH 2.1). Data analysis was performed using Biacore T-100 Evaluation software version 2 with a 1:1 approximation. The results are presented in table. 8.

Table 8

Binding affinity of exemplary anti-PD-L1 antibodies to PD-L1 measured using Biacore

View BAP058-huml3 BAP058-humll BAP058-hum04 Human PD-L1 0.137+0.035 nM 0.931+0.477 nM 2.14+0.289 nM PD-L1 macaque 0.431+0.289 nM 0.735+0.126 nM 0.369+0.175 nM PD-L1 mice 0.040+0.007 nM 0.075+0.031 nM 77.4+18.5 nM PD-L1 rat 0.431+0.451 nM 1.36+2.02 nM 6.14+8.12 nM

Inclusion as a link.

All publications, patents and access numbers mentioned in the present description are incorporated herein by reference in their entirety, as if it were specifically or individually indicated that each individual publication or patent is incorporated by reference.

Equivalents.

While specific embodiments of the present invention have been discussed, the above description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon reading this description and the claims below. The full scope of the invention is to be determined by the claims, their full scope of equivalents and the description, and such variations.

Claims (50)

1. An antibody molecule capable of binding to a human programmed death ligand-1 (PD-L1) protein, containing: (a) a heavy chain variable region (VH) containing VHCDR1 with amino acid sequence SEQ ID NO: 4, VHCDR2 with the amino acid sequence of SEQ ID NO: 5 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) containing VLCDR1 with amino acid sequence SEQ ID NO: 12, VLCDR2 with the amino acid sequence of SEQ ID NO: 13 and VLCDR3 with the amino acid sequence of SEQ ID NO: 14; (b) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 1, VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And VL containing VLCDR1 with amino acid sequence SEQ ID NO: 9, VLCDR2 with the amino acid sequence of SEQ ID NO: 10 and VLCDR3 with the amino acid sequence of SEQ ID NO: 11; (c) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 195, VHCDR2 with the amino acid sequence of SEQ ID NO: 5 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And VL containing VLCDR1 with amino acid sequence SEQ ID NO: 12, VLCDR2 with the amino acid sequence of SEQ ID NO: 13 and VLCDR3 with the amino acid sequence of SEQ ID NO: 14; or (d) a VH containing VHCDR1 with amino acid sequence SEQ ID NO: 195, VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And VL containing VLCDR1 with amino acid sequence SEQ ID NO: 9, VLCDR2 with the amino acid sequence of SEQ ID NO: 10 and VLCDR3 with amino acid sequence SEQ ID NO: 11. 2. An antibody molecule according to claim 1, which contains VH containing the amino acid sequence of SEQ ID NO: 18, 30, 38, 46, 50, 54, 62, 70 or 78, VL containing the amino acid sequence of SEQ ID NO: 22, 26, 34, 42, 58, 66, 74, 82 or 86, or both of these regions. 3. An antibody molecule according to claim 1, which contains: (a) VH containing the amino acid sequence of SEQ ID NO: 18 and VL containing the amino acid sequence of SEQ ID NO: 22; (b) VH containing the amino acid sequence of SEQ ID NO: 18 and VL containing the amino acid sequence of SEQ ID NO: 26; (c) VH containing the amino acid sequence of SEQ ID NO: 18 and VL containing the amino acid sequence of SEQ ID NO: 86; (d) VH containing the amino acid sequence of SEQ ID NO: 30 and VL containing the amino acid sequence of SEQ ID NO: 34; (e) VH containing the amino acid sequence of SEQ ID NO: 30 and VL containing the amino acid sequence of SEQ ID NO: 66; (f) VH containing the amino acid sequence of SEQ ID NO: 38 and VL containing the amino acid sequence of SEQ ID NO: 42; (g) VH containing the amino acid sequence of SEQ ID NO: 38 and VL containing the amino acid sequence of SEQ ID NO: 74; - 289 040861 (h) VH containing the amino acid sequence of SEQ ID NO: 46, and VL containing the amino acid sequence of SEQ ID NO: 42; (i) VH containing the amino acid sequence of SEQ ID NO: 50 and VL containing the amino acid sequence of SEQ ID NO: 42; (j) VH containing the amino acid sequence of SEQ ID NO: 50 and VL containing the amino acid sequence of SEQ ID NO: 22; (k) VH containing the amino acid sequence of SEQ ID NO: 50 and VL containing the amino acid sequence of SEQ ID NO: 86; (l) VH containing the amino acid sequence of SEQ ID NO: 54 and VL containing the amino acid sequence of SEQ ID NO: 58; (m) VH containing the amino acid sequence of SEQ ID NO: 54 and VL containing the amino acid sequence of SEQ ID NO: 86; (n) VH containing the amino acid sequence of SEQ ID NO: 62 and VL containing the amino acid sequence of SEQ ID NO: 66; (o) VH containing the amino acid sequence of SEQ ID NO: 62 and VL containing the amino acid sequence of SEQ ID NO: 86; (p) VH containing the amino acid sequence of SEQ ID NO: 70 and VL containing the amino acid sequence of SEQ ID NO: 66; or (q) VH containing the amino acid sequence of SEQ ID NO: 78 and VL containing the amino acid sequence of SEQ ID NO: 82. 4. An antibody molecule according to claim 1, which contains: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 20 and a light chain containing the amino acid sequence of SEQ ID NO: 24; (b) a heavy chain containing the amino acid sequence of SEQ ID NO: 20 and a light chain containing the amino acid sequence of SEQ ID NO: 28; (c) a heavy chain containing the amino acid sequence of SEQ ID NO: 20 and a light chain containing the amino acid sequence of SEQ ID NO: 88; (d) a heavy chain containing the amino acid sequence of SEQ ID NO: 32 and a light chain containing the amino acid sequence of SEQ ID NO: 36; (e) a heavy chain containing the amino acid sequence of SEQ ID NO: 32 and a light chain containing the amino acid sequence of SEQ ID NO: 68; (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: 76; (h) a heavy chain containing the amino acid sequence of SEQ ID NO: 48 and a light chain containing the amino acid sequence of SEQ ID NO: 44; (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: 44; (j) 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: 24; (k) 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: 88; (l) a heavy chain containing the amino acid sequence of SEQ ID NO: 56 and a light chain containing the amino acid sequence of SEQ ID NO: 60; (m) a heavy chain containing the amino acid sequence of SEQ ID NO: 56 and a light chain containing the amino acid sequence of SEQ ID NO: 88; (n) a heavy chain containing the amino acid sequence of SEQ ID NO: 64 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: 64 and a light chain containing the amino acid sequence of SEQ ID NO: 88; (p) a heavy chain containing the amino acid sequence of SEQ ID NO: 72 and a light chain containing the amino acid sequence of SEQ ID NO: 68; (q) a heavy chain containing the amino acid sequence of SEQ ID NO: 80 and a light chain containing the amino acid sequence of SEQ ID NO: 84; (r) a heavy chain containing the amino acid sequence of SEQ ID NO: 197 and a light chain containing the amino acid sequence of SEQ ID NO: 36; (s) 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; (t) a heavy chain containing the amino acid sequence of SEQ ID NO: 96 and a light chain containing the amino acid sequence of SEQ ID NO: 68; (u) a heavy chain containing the amino acid sequence of SEQ ID NO: 247 and a light - 290 040861 chain containing the amino acid sequence of SEQ ID NO: 84; or (v) a heavy chain containing the amino acid sequence of SEQ ID NO: 260 and a light chain containing the amino acid sequence of SEQ ID NO: 44. 5. The antibody molecule according to claim 1, where VH contains the amino acid sequence of SEQ ID NO: 30 and VL contains the amino acid sequence of SEQ ID NO: 66. 6. The antibody molecule according to claim 1, where VH contains the amino acid sequence of SEQ ID NO: 78 and VL contains the amino acid sequence of SEQ ID NO: 82. 7. An antibody molecule according to claim 1, wherein the heavy chain contains the amino acid sequence of SEQ ID NO: 96 and the light chain contains the amino acid sequence of SEQ ID NO: 68. 8. An antibody molecule according to claim 1, wherein the heavy chain contains the amino acid sequence of SEQ ID NO: 80 and the light chain contains the amino acid sequence of SEQ ID NO: 84. 9. A pharmaceutical composition containing an antibody molecule according to claim 1 and a pharmaceutically acceptable carrier, excipient or stabilizer. 10. A pharmaceutical composition containing an antibody molecule according to claim 5 and a pharmaceutically acceptable carrier, excipient or stabilizer. 11. A pharmaceutical composition containing an antibody molecule according to claim 6 and a pharmaceutically acceptable carrier, excipient or stabilizer. 12. A pharmaceutical composition containing an antibody molecule according to claim 7 and a pharmaceutically acceptable carrier, excipient or stabilizer. 13. A pharmaceutical composition containing an antibody molecule according to claim 8 and a pharmaceutically acceptable carrier, excipient or stabilizer. 14. An antibody molecule according to claim 1, which is a Fab, F(ab') ₂ , Fv or a single chain Fv fragment (scFv). 15. An antibody molecule according to claim 1, which contains an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region and/or a kappa or lambda light chain constant region. 16. An antibody molecule according to claim 15, which contains a kappa light chain constant region and: a) a human IgG4 heavy chain constant region comprising SEQ ID NO: 188 or 190, or a human IgG4 heavy chain constant region containing proline at the position corresponding to amino acid 108 in SEQ ID NO: 188; b) a human IgG1 heavy chain constant region comprising SEQ ID NO: 192 or a human IgG1 heavy chain constant region containing alanine at the position corresponding to amino acid 180 in SEQ ID NO: 191; c) a human IgG1 heavy chain constant region comprising SEQ ID NO: 193 or a human IgG1 heavy chain constant region containing alanine at the position corresponding to amino acids 148 and 212 in SEQ ID NO: 191; or d) a human IgG1 heavy chain constant region comprising SEQ ID NO: 194 or a human IgG1 heavy chain constant region containing alanine at the position corresponding to amino acids 117 and 118 in SEQ ID NO: 191. 17. An antibody molecule according to claim 1, which has one or more of the following properties: (a) capable of binding to human PD-L1 with a dissociation constant (K _D ) below about 0.2 nM; (b) binds to the extracellular domain of PD-L1; (c) is capable of reducing the binding of PD-1 to PD-L1; or (d) is capable of enhancing an antigen-specific T cell response. 18. An antibody molecule according to claim 1, wherein said antibody molecule is a humanized antibody molecule or a monospecific antibody molecule. 19. A bispecific antibody molecule with a first binding specificity for PD-L1 capable of binding to human programmed death ligand-1 (PD-L1) protein and a second binding specificity for TIM-3, LAG-3, CEACAM-1, CEACAM-5, PD-1 or PD-L2, where the first binding specificity contains: (a) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 4, VHCDR2 with the amino acid sequence of SEQ ID NO: 5 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And V L containing V LCDR1 with amino acid sequence SEQ ID NO: 12, VLCDR2 with the amino acid sequence of SEQ ID NO: 13 and V LCDR3 with the amino acid sequence of SEQ ID NO: 14; (b) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 1, VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And - 291 040861 VL containing VLCDR1 with amino acid sequence SEQ ID NO: 9, VLCDR2 with the amino acid sequence of SEQ ID NO: 10 and VLCDR3 with the amino acid sequence of SEQ ID NO: 11; (c) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 195, VHCDR2 with the amino acid sequence of SEQ ID NO: 5 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And VL containing VLCDR1 with amino acid sequence SEQ ID NO: 12, VLCDR2 with the amino acid sequence of SEQ ID NO: 13 and VLCDR3 with the amino acid sequence of SEQ ID NO: 14; or (d) a VH containing VHCDR1 with amino acid sequence SEQ ID NO: 195, VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And VL containing VLCDR1 with amino acid sequence SEQ ID NO: 9, VLCDR2 with the amino acid sequence of SEQ ID NO: 10 and VLCDR3 with amino acid sequence SEQ ID NO: 11. 20. A nucleic acid molecule comprising a first nucleotide sequence that encodes a heavy chain variable region (VH) and a second nucleotide sequence that encodes a light chain variable region (VL) of an antibody molecule capable of binding to human programmed death ligand-1 (PD -L1), where the antibody molecule contains: (a) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 4, VHCDR2 with the amino acid sequence of SEQ ID NO: 5 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And VL containing VLCDR1 with amino acid sequence SEQ ID NO: 12, VLCDR2 with the amino acid sequence of SEQ ID NO: 13 and VLCDR3 with the amino acid sequence of SEQ ID NO: 14; (b) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 1, VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And V L containing V LCDR1 with amino acid sequence SEQ ID NO: 9, VLCDR2 with the amino acid sequence of SEQ ID NO: 10 and V LCDR3 with the amino acid sequence of SEQ ID NO: 11; (c) VH containing VHCDR1 with amino acid sequence SEQ ID NO: 195, VHCDR2 with the amino acid sequence of SEQ ID NO: 5 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And VL containing VLCDR1 with amino acid sequence SEQ ID NO: 12, VLCDR2 with the amino acid sequence of SEQ ID NO: 13 and VLCDR3 with the amino acid sequence of SEQ ID NO: 14; or (d) a VH containing VHCDR1 with amino acid sequence SEQ ID NO: 195, VHCDR2 with the amino acid sequence of SEQ ID NO: 2 and VHCDR3 with the amino acid sequence of SEQ ID NO: 3; And V L containing V LCDR1 with amino acid sequence SEQ ID NO: 9, VLCDR2 with the amino acid sequence of SEQ ID NO: 10 and V LCDR3 with the amino acid sequence of SEQ ID NO: 11. 21. An expression vector containing the nucleic acid molecule according to claim 20. 22. An isolated host cell containing the nucleic acid of claim 20. 23. A method for producing an antibody molecule or an antigen-binding fragment thereof, comprising culturing the host cell of claim 22 under conditions suitable for gene expression, wherein said host cell contains said first nucleotide sequence that encodes VH and said second nucleotide sequence, which encodes VL. - 292 040861 24. The nucleic acid molecule according to claim 20, where the first nucleotide sequence encodes a VH containing the amino acid sequence of SEQ ID NO: 30, or contains the nucleotide sequence of SEQ ID NO: 95; and/or where the second nucleotide sequence encodes a VL containing the amino acid sequence of SEQ ID NO: 66, or contains the nucleotide sequence of SEQ ID NO: 98. 25. The nucleic acid molecule according to claim 20, where the first nucleotide sequence encodes a VH containing the amino acid sequence of SEQ ID NO: 78, or contains the nucleotide sequence of SEQ ID NO: 100; and/or where the second nucleotide sequence encodes a VL containing the amino acid sequence of SEQ ID NO: 82, or contains the nucleotide sequence of SEQ ID NO: 102. 26. The nucleic acid molecule according to claim 20, where the first nucleotide sequence encodes a heavy chain containing the amino acid sequence of SEQ ID NO: 80, or contains the nucleotide sequence of the heavy chain of SEQ ID NO: 101; and/or where the second nucleotide sequence encodes a light chain containing the amino acid sequence of SEQ ID NO: 84, or contains the light chain nucleotide sequence of SEQ ID NO: 103. 27. The nucleic acid molecule according to claim 20, where the first nucleotide sequence encodes a heavy chain containing the amino acid sequence of SEQ ID NO: 96, or contains the nucleotide sequence of the heavy chain of SEQ ID NO: 97; and/or where the second nucleotide sequence encodes a light chain containing the amino acid sequence of SEQ ID NO: 68, or contains the light chain nucleotide sequence of SEQ ID NO: 99. 28. A method for detecting PD-L1 in a biological sample or in an individual, comprising: (i) contacting the sample with an antibody molecule according to any one of claims 1-20, or administering to an individual an antibody according to any one of claims 1-20 under conditions that allow the interaction of the antibody molecule and the polypeptide, and (ii) detecting the formation of a complex between the molecule an antibody and a polypeptide in a sample or in an individual. 29. The use of an antibody molecule according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of a cancer expressing PD-L1. 30. Use according to claim 29, wherein the cancer is selected from solid tumor, lung cancer, skin cancer, kidney cancer, liver cancer, prostate cancer, breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, thyroid cancer, brain cancer, uterine cancer, nasopharyngeal cancer, head and neck cancer, ovarian cancer, endometrial cancer, endocrine cancer, bladder cancer, urothelial cancer or hematological malignancy, or metastasis of such cancer. 31. Application according to claim 29 or 30, 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; or (b) the skin cancer is melanoma or Merkel cell carcinoma; or (c) the kidney cancer is selected from renal cell carcinoma (RCC), metastatic renal cell carcinoma, or clear cell renal cell carcinoma (CCRCC); or (d) the hematologic neoplasm is selected from lymphoma, myeloma, or leukemia; or (e) the brain cancer is a glioblastoma; or (f) the breast cancer is triple negative breast cancer; or (g) the liver cancer is hepatocellular carcinoma; or (h) the cancer is a high MSI (high microsatellite instability) cancer. 32. Use according to claim 31, wherein the melanoma is selected from progressive melanoma, inoperable melanoma, metastatic melanoma, BRAF mutated melanoma, NRAS mutated melanoma, cutaneous melanoma, or intraocular melanoma. 33. The use of claim 32, wherein the NSCLC contains a KRAS mutation. 34. Use according to any one of claims 29-33, wherein the antibody molecule is used in combination with a second therapeutic agent or procedure, wherein the second therapeutic agent is selected from one or more of: an oncolytic drug, a cytotoxic agent, a cytokine, a costimulatory molecule activator, an inhibitor an inhibitory molecule or vaccine; and where the therapeutic procedure is selected from one or more of: chemotherapy, tumor targeting therapy, immunotherapy, surgical procedure, radiation therapy, or cellular immunotherapy. 35. Use according to any one of claims 29-33, wherein the antibody molecule is administered in combination with: - 293 040861 (a) a costimulatory molecule agonist selected from one or more of: GITR, 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 control point molecule inhibitor selected from one or more of: PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT , LAIR1, CD160, 2B4 or TGFR. 36. Use according to any one of claims 29-34, wherein the antibody molecule is used in combination with one or more of the following second additional agents: a PD-1 inhibitor; a LAG-3 inhibitor; a TIM-3 inhibitor; GITR agonist; interleukin; a MEK inhibitor; an FGFR inhibitor; an indolaminepyrrole-2,3-dioxygenase (IDO) inhibitor for the treatment of lung cancer; a CTLA-4 inhibitor for the treatment of lung cancer or melanoma; cancer vaccine; one or more of the following for the treatment of kidney cancer: a VEGF tyrosine kinase inhibitor, an RNA interference inhibitor, a targeting agent, or an inhibitor of a mediator downstream of the VEGF signaling pathway; one, two or all of: 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, hematologic cancer or renal cell carcinoma. 37. Use according to any one of claims 29-36, wherein the antibody molecule is used in combination with one or more of the following therapeutic procedures: chemotherapy for the treatment of lung cancer or immunotherapy for the treatment of kidney cancer. 38. Application according to claim 36, where: (a) the PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, AMP-224, or AMP 514; (b) the LAG-3 inhibitor is an anti-LAG-3 antibody molecule; (c) the TIM-3 inhibitor is an anti-TIM-3 antibody molecule; or (d) the GITR agonist is an anti-GITR antibody molecule or a GITR fusion protein; (e) the interleukin is IL-15; (f) MEK inhibitor selected from ARRY-142886, G02442104 (GSK1120212), RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (AZD-6244 or selumetinib), BIX 02188, BIX 029189, 92PD1040 (2PD18040) , U0126, GDC-0973 (methanone or [3,4-difluoro-2-[(2-fluoro-4iodophenyl)amino]phenyl] [3-hydroxy-3-(25)-2-piperidinyl-1-azetidinyl] - ), G-3 8963, G02443714 (AS703206) or a pharmaceutically acceptable salt or solvate thereof; (g) an FGFR inhibitor; (h) the IDO inhibitor is INCB24360; (i) the CTLA-4 inhibitor is an anti-CTLA-4 antibody or a soluble CTLA-4 ligand, or where the antibody molecule is further used in combination with a BRAF inhibitor; (j) the cancer vaccine is a renal carcinoma dendritic cell (DC-RCC) vaccine; (k) the targeting agent is a VEGF inhibitor; (l) the VEGF tyrosine kinase inhibitor is selected from sunitinib, sorafenib, axitinib, or pazopanib; and (m) the downstream VEGF signaling inhibitor is a mammalian target of rapamycin (mTOR) inhibitor. 39. Use according to claim 37, wherein the chemotherapy is platinum doublet therapy and the immunotherapy comprises interleukin-2 or interferon-γ. 40. Application according to claim 38, where: (a) a PD-1 inhibitor is used to treat thyroid cancer, non-small cell lung cancer, triple negative breast cancer, endometrial cancer, cervical cancer, or lymphoma; (b) a LAG-3 inhibitor is used to treat NSCLC, melanoma, RCC, or hematologic malignancy; (c) the targeting agent is an anti-VEGF antibody; (d) the CTLA-4 inhibitor is ipilimumab; (e) the VEGF tyrosine kinase inhibitor is selected from sunitinib, sorafenib, axitinib, or pazopanib; and (f) the downstream VEGF signaling inhibitor is temsirolimus. 41. Use according to any one of claims 29-40, wherein the individual has or is diagnosed as having one or more of the following: (a) cancer expressing PD-L1; - 294 040861 (b) cancer with a positive response to one, two or all of PD-L1, CD8, IFN-γ; (c) cancer that is triple positive for PD-L1, CD8 and IFN-γ; or (d) cancer with a positive response to tumor permeability to lymphocytes (TIL). 42. Use according to any one of claims 29-41, wherein the antibody molecule is administered at a dose of from about 1 to 30 mg/kg, for example, at a dose of about 1 to 5 mg/kg, where the antibody molecule is administered from once a week to once times every 2, 3 or 4 weeks. 43. The use of a combination of an anti-PD-L1 antibody molecule according to any one of claims 1 to 19 and one or more drugs for the manufacture of a medicament for the treatment of a PD-L1 expressing cancer in an individual, wherein the one or more drugs are selected from the following categories (i)-(iii): (i) an agent that enhances the presentation of a tumor antigen selected from one or more of: STING agonist, TLR agonist, A2AR antagonist, oncolytic virus, TIM-3 modulator, vascular endothelial growth factor receptor (VEGFR) inhibitor, c-Met inhibitor , a TGFb inhibitor, an IDO/TDO inhibitor, a vaccine, or a bi- or trispecific cell-binding agent, or combinations thereof; (ii) an agent that enhances the response of an effector cell selected from one or more of: GITR agonist, PD-1 inhibitor, PD-L1 inhibitor, IAP (apoptotic protein inhibitor), EGFR (epidermal growth factor receptor) inhibitor, target inhibitor rapamycin (mTOR), IL-15 or a variant thereof, a CTLA-4 inhibitor, a bispecific antibody molecule that binds to CD3 and tumor antigen, a CD40 agonist, an OX40 agonist, or a CD27 agonist, or combinations thereof; or (iii) an agent that reduces tumor immunosuppression, selected from one or more of: a GITR agonist, an inhibitor of an immune checkpoint molecule selected from one or more of PD-1, LAG-3, TIM-3, or CTLA-4, an inhibitor CSF-1/1R, IL-17 inhibitor, IL1β inhibitor, CXCR2 inhibitor, PI3Ky or PI3Kδ inhibitor, BAFF-R inhibitor, MALT-1/BTK inhibitor, JAK inhibitor, CRTH2 inhibitor, VEGFR inhibitor, IL-15 or a variant thereof, a CTLA-4 inhibitor, an IDO/TDO inhibitor, an A2AR antagonist, a TGFb inhibitor, or a PFKFB3 inhibitor, or a combination thereof. 44. A method for stimulating an immune response in an individual, comprising administering to the individual an antibody molecule according to any one of claims 1 to 19 in an amount effective to stimulate an immune response, further comprising administering a second drug to the individual or conducting an additional therapeutic procedure. 45. A method of treating a PD-L1 expressing cancer in an individual, comprising administering to the individual a combination of an anti-PD-L1 antibody molecule according to any one of claims 1 to 19 and one or more drugs selected from the following categories (i)-(iii ): (i) an agent that enhances the presentation of a tumor antigen selected from one or more of: STING agonist, TLR agonist, A2AR antagonist, oncolytic virus, TIM-3 modulator, vascular endothelial growth factor receptor (VEGFR) inhibitor, c-Met inhibitor , a TGFb inhibitor, an IDO/TDO inhibitor, a vaccine, or a bispecific or trispecific cell-binding agent, or combinations thereof; (ii) an agent that enhances the response of an effector cell selected from one or more of: GITR agonist, PD-1 inhibitor, PD-L1 inhibitor, IAP (apoptotic protein inhibitor), EGFR (epidermal growth factor receptor) inhibitor, target inhibitor rapamycin (mTOR), IL-15 or a variant thereof, a CTLA-4 inhibitor, a bispecific antibody molecule that binds to CD3 and tumor antigen, a CD40 agonist, an OX40 agonist, or a CD27 agonist, or combinations thereof; or (iii) an agent that reduces tumor immunosuppression, selected from one or more of: a GITR agonist, an inhibitor of an immune checkpoint molecule selected from one or more of PD-1, LAG-3, TIM-3, or CTLA-4, an inhibitor CSF-1/1R, IL-17 inhibitor, IL1β inhibitor, CXCR2 inhibitor, PI3Ky or PI3Kδ inhibitor, BAFF-R inhibitor, MALT-1/BTK inhibitor, JAK inhibitor, CRTH2 inhibitor, VEGFR inhibitor, IL-15 or a variant thereof, a CTLA-4 inhibitor, an IDO/TDO inhibitor, an A2AR antagonist, a TGFb inhibitor, or a PFKFB3 inhibitor, or a combination thereof. 46. A method of treating a PD-L1 expressing cancer in an individual, comprising administering to the individual an antibody molecule according to any one of claims 1 to 19 in an amount effective to treat the cancer, further comprising administering to the individual a second therapeutic agent or performing an additional therapeutic procedure . 47. A method of treating an infectious disease in an individual, comprising administering to the individual an antibody molecule according to any one of claims 1 to 19 in an amount effective to treat the infectious disease, further comprising administering to the individual a second therapeutic agent or performing a therapeutic procedure. - 295 040861 48. The method according to any one of claims 44, 46, or 47, wherein the therapeutic procedure is selected from one or more of: chemotherapy, targeted cancer therapy, immunotherapy, surgical procedure, radiation therapy, or cellular immunotherapy. 49. Use according to any one of claims 29-34 in combination with an AKT inhibitor to produce a medicament for the treatment of cancer in an individual. 50. The use of claim 49 wherein the AKT inhibitor is RX-0201 or MK-2206.