VISTA ANTIGEN-BINDING MOLECULES

1 . An antigen-binding molecule, optionally isolated, which is capable of binding to VISTA and inhibiting VISTA-mediated signalling, independently of Fc-mediated function.

2 . The antigen-binding molecule according to claim 1 , wherein the antigen-binding molecule comprises:

(i) a heavy chain variable (VH) region incorporating the following CDRs:

HC-CDR1 having the amino acid sequence of SEQ ID NO:305

HC-CDR2 having the amino acid sequence of SEQ ID NO:306

HC-CDR3 having the amino acid sequence of SEQ ID NO:307; and

(ii) a light chain variable (VL) region incorporating the following CDRs:

LC-CDR1 having the amino acid sequence of SEQ ID NO:41

LC-CDR2 having the amino acid sequence of SEQ ID NO:308

LC-CDR3 having the amino acid sequence of SEQ ID NO:43.

3 . The antigen-binding molecule according to claim 1 or claim 2 , wherein the antigen-binding molecule comprises:

(i) a heavy chain variable (VH) region incorporating the following CDRs:

HC-CDR1 having the amino acid sequence of SEQ ID NO:290

HC-CDR2 having the amino acid sequence of SEQ ID NO:291

HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and

(ii) a light chain variable (VL) region incorporating the following CDRs:

LC-CDR1 having the amino acid sequence of SEQ ID NO:41

LC-CDR2 having the amino acid sequence of SEQ ID NO:309

LC-CDR3 having the amino acid sequence of SEQ ID NO:43.

4 . The antigen-binding molecule according to any one of claims 1 to 3 , wherein the antigen-binding molecule comprises:

(i) a heavy chain variable (VH) region incorporating the following CDRs:

HC-CDR1 having the amino acid sequence of SEQ ID NO:290

HC-CDR2 having the amino acid sequence of SEQ ID NO:291

HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and

(ii) a light chain variable (VL) region incorporating the following CDRs:

LC-CDR1 having the amino acid sequence of SEQ ID NO:41

LC-CDR2 having the amino acid sequence of SEQ ID NO:295

LC-CDR3 having the amino acid sequence of SEQ ID NO:43.

5 . The antigen-binding molecule according to any one of claims 1 to 3 , wherein the antigen-binding molecule comprises:

(i) a heavy chain variable (VH) region incorporating the following CDRs:

HC-CDR1 having the amino acid sequence of SEQ ID NO:290

HC-CDR2 having the amino acid sequence of SEQ ID NO:291

HC-CDR3 having the amino acid sequence of SEQ ID NO:278; and

(ii) a light chain variable (VL) region incorporating the following CDRs:

LC-CDR1 having the amino acid sequence of SEQ ID NO:41

LC-CDR2 having the amino acid sequence of SEQ ID NO:300

LC-CDR3 having the amino acid sequence of SEQ ID NO:43.

6 . The antigen-binding molecule according to any one of claims 1 to 5 , wherein the antigen-binding molecule comprises:

a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and

a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:310.

7 . The antigen-binding molecule according to any one of claims 1 to 6 , wherein the antigen-binding molecule comprises:

a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and

a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:294.

8 . The antigen-binding molecule according to any one of claims 1 to 6 , wherein the antigen-binding molecule comprises:

a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and

a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:297.

9 . The antigen-binding molecule according to any one of claims 1 to 6 , wherein the antigen-binding molecule comprises:

a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:289; and

a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:299.

10 . An antigen-binding molecule, optionally isolated, comprising (i) an antigen-binding molecule according to any one of claims 1 to 9 , and (ii) an antigen-binding molecule capable of binding to an antigen other than VISTA.

11 . A chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to any one of claims 1 to 10 .

12 . A nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule according to any one of claims 1 to 10 or a CAR according to claim 11 .

13 . An expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to claim 12 .

14 . A cell comprising an antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , or an expression vector or a plurality of expression vectors according to claim 13 .

15 . A method comprising culturing a cell comprising a nucleic acid or a plurality of nucleic acids according to claim 12 , or an expression vector or a plurality of expression vectors according to claim 13 , under conditions suitable for expression of the antigen-binding molecule or CAR from the nucleic acid(s) or expression vector(s).

16 . A composition comprising an antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , or a cell according to claim 14 .

17 . The composition according to claim 16 , additionally comprising an agent capable of inhibiting signalling mediated by an immune checkpoint molecule other than VISTA, optionally wherein the immune checkpoint molecule other than VISTA is selected from PD-1, CTLA-4, LAG-3, TIM-3, TIGIT and BTLA.

18 . An antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , a cell according to claim 14 , or a composition according to claim 16 or claim 17 for use in a method of medical treatment or prophylaxis.

19 . An antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , a cell according to claim 14 , or a composition according to claim 16 or claim 17 , for use in a method of treatment or prevention of a cancer or an infectious disease.

20 . Use of an antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , a cell according to claim 14 , or a composition according to claim 16 or claim 17 , in the manufacture of a medicament for use in a method of treatment or prevention of a cancer or an infectious disease.

21 . A method of treating or preventing a cancer or an infectious disease, comprising administering to a subject a therapeutically or prophylactically effective amount of an antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , a cell according to claim 14 , or a composition according to claim 16 or claim 17 .

22 . The antigen-binding molecule, CAR, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, cell or composition for use according to claim 19 , the use according to claim 20 or the method according to claim 21 , wherein the cancer is selected from: a cancer comprising cells expressing VISTA, a cancer comprising infiltration of cells expressing VISTA, a cancer comprising cancer cells expressing VISTA, a hematological cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, T cell lymphoma, multiple myeloma, mesothelioma, a solid tumor, lung cancer, non-small cell lung carcinoma, gastric cancer, gastric carcinoma, colorectal cancer, colorectal carcinoma, colorectal adenocarcinoma, uterine cancer, uterine corpus endometrial carcinoma, breast cancer, triple negative breast invasive carcinoma, liver cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, thyroid cancer, thymoma, skin cancer, melanoma, cutaneous melanoma, kidney cancer, renal cell carcinoma, renal papillary cell carcinoma, head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), ovarian cancer, ovarian carcinoma, ovarian serous cystadenocarcinoma, prostate cancer and/or prostate adenocarcinoma.

23 . An antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , a cell according to claim 14 , or a composition according to claim 16 or claim 17 , for use in a method of treatment or prevention of a disease in which myeloid-derived suppressor cells (MDSCs) are pathologically implicated.

24 . Use of an antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , a cell according to claim 14 , or a composition according to claim 16 or claim 17 , in the manufacture of a medicament for use in a method of treatment or prevention of a disease in which myeloid-derived suppressor cells (MDSCs) are pathologically implicated.

25 . A method of treating or preventing a disease in which myeloid-derived suppressor cells (MDSCs) are pathologically implicated, comprising administering to a subject a therapeutically or prophylactically effective amount of an antigen-binding molecule according to any one of claims 1 to 10 , a CAR according to claim 11 , a nucleic acid or a plurality of nucleic acids according to claim 12 , an expression vector or a plurality of expression vectors according to claim 13 , a cell according to claim 14 , or a composition according to claim 16 or claim 17 .

26 . The antigen-binding molecule, CAR, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, cell or composition for use, the use, or the method according to any one of claims 19 to 25 , wherein the method additionally comprises administration of an agent capable of inhibiting signalling mediated by an immune checkpoint inhibitor other than VISTA, optionally wherein the immune checkpoint inhibitor other than VISTA is selected from PD-1, CTLA-4, LAG-3, TIM-3, TIGIT or BTLA.

27 . A method of inhibiting VISTA-mediated signalling, comprising contacting VISTA-expressing cells with an antigen-binding molecule according to any one of claims 1 to 10 .

28 . A method for inhibiting the activity of myeloid-derived suppressor cells (MDSCs), the method comprising contacting MDSCs with an antigen-binding molecule according to any one of claims 1 to 10 .

29 . A method for increasing the number or activity of effector immune cells, the method comprising inhibiting the activity of VISTA-expressing cells with an antigen-binding molecule according to any one of claims 1 to 10 .

30 . An in vitro complex, optionally isolated, comprising an antigen-binding molecule according to any one of claims 1 to 10 bound to VISTA.

31 . A method comprising contacting a sample containing, or suspected to contain, VISTA with an antigen-binding molecule according to any one of claims 1 to 10 , and detecting the formation of a complex of the antigen-binding molecule with VISTA.

32 . A method of selecting or stratifying a subject for treatment with a VISTA-targeted agent, the method comprising contacting, in vitro, a sample from the subject with an antigen-binding molecule according to any one of claims 1 to 10 and detecting the formation of a complex of the antigen-binding molecule with VISTA.

33 . Use of an antigen-binding molecule according to any one of claims 1 to 10 as an in vitro or in vivo diagnostic or prognostic agent.

34 . Use of an antigen-binding molecule according to any one of claims 1 to 10 in a method for detecting, localizing or imaging a cancer, optionally wherein the cancer is selected from: a cancer comprising cells expressing VISTA, a cancer comprising infiltration of cells expressing VISTA, a cancer comprising cancer cells expressing VISTA, a hematological cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, T cell lymphoma, multiple myeloma, mesothelioma, a solid tumor, lung cancer, non-small cell lung carcinoma, gastric cancer, gastric carcinoma, colorectal cancer, colorectal carcinoma, colorectal adenocarcinoma, uterine cancer, uterine corpus endometrial carcinoma, breast cancer, triple negative breast invasive carcinoma, liver cancer, hepatocellular carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, thyroid cancer, thymoma, skin cancer, melanoma, cutaneous melanoma, kidney cancer, renal cell carcinoma, renal papillary cell carcinoma, head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), ovarian cancer, ovarian carcinoma, ovarian serous cystadenocarcinoma, prostate cancer and/or prostate adenocarcinoma.