MULTISPECIFIC ANTIBODIES FOR IMMUNO-ONCOLOGY

1 . A multispecific antibody (e.g. bispecific antibody or a dual-binding antibody) which binds (and optionally has specificity for) ICOS (e.g. human ICOS) and another target antigen.

2 . A multispecific antibody according to claim 1 , wherein the ICOS is human ICOS.

3 . A multispecific antibody according to claim 2 , which comprises a VH domain comprising a CDRH1, a CDRH2 and a CDRH3 which VH domain binds (and optionally has specificity for) hICOS.

4 . A multispecific antibody according to claim 2 or claim 3 , which comprises a VL domain comprising a CDRL1, a CDRL2 and a CDRL3, which VL domain binds (and optionally has specificity for) hICOS.

5 . A multispecific antibody according to claim 3 or 4 , wherein the VH and/or VL domain is any of VH and/or VL domains:

a. of the antibody 7F12, 37A10, 35A9, 36E10, 16G10, 37A10S713, 37A10S714, 37A10S715, 37A10S716, 37A10S717, 37A10S718, 16G10S71, 16G10S72, 16G10S73, 16G10583, 35A9S79, 35A9S710, 35A9S89 or any other antibody described in WO2016/154177 and US2016/0304610;

b. of the antibody 422.2, H2L5, or any other antibody described in WO2016/120789 and US2016/0215059;

c. of the antibody 314-8, the antibody produced from hybridoma CNCM 1-4180, or any other antibody described in WO2014/033327 and US2015/0239978;

d. of the antibody Icos145-1, the antibody produced by hybridoma CNCM 1-4179, or any other antibody described in WO2012/131004, U.S. Pat. No. 9,376,493 and US2016/0264666;

e. of the antibody JMAb 136, “136”, or any other antibody described in WO2010/056804;

f. of the antibody MIC-944, 9F3 or any other antibody described in WO99/15553, U.S. Pat. Nos. 7,259,247, 7,132,099, 7,125,551, 7,306,800, 7,722,872, WO05/103086, US8.318.905 and U.S. Pat. No. 8,916,155;

g. of any JMAb antibody, e.g., any of JMAb-124, JMAb-126, JMAb-127, JMAb-128, JMAb-135, JMAb-136, JMAb-137, JMAb-138, JMAb-139, JMAb-140, JMAb-141, e.g., JMAb136, or any other antibodye described in WO98/3821, U.S. Pat. No. 7,932,358B2, US2002/156242, U.S. Pat. Nos. 7,030,225, 7,045,615, 7,279,560, 7,226,909, 7,196,175, 7,932,358, 8,389,690, WO02/070010, U.S. Pat. Nos. 7,438,905, 7,438,905, WO01/87981, U.S. Pat. Nos. 6,803,039, 7,166,283, 7,988,965, WO01/15732, U.S. Pat. Nos. 7,465,445 and 7,998,478;

h. of the antibody 17G9 or any other antibody described in WO2014/08911;

i. of any antibody described in WO2012/174338;

j. of any antibody described in US2016/0145344;

k. of any antibody described in WO2011/020024, US2016/002336, US2016/024211 and U.S. Pat. No. 8,840,889; or

l. of any antibody described in U.S. Pat. No. 8,497,244.

6 . A multispecific antibody according to claim 3 or 4 , wherein the VH and/or VL domain is any of VH and/or VL domains defined in sentences 1 to 102 or sentence 1a to 21a.

7 . A multispecific antibody according to any preceding claim, which has agonistic activity against ICOS.

8 . A multispecific antibody according to any preceding claim, which binds (and optionally has specificity for) mouse ICOS and/or cynomolgus ICOS.

9 . A multispecific antibody according to any preceding claim which is a bispecific antibody.

10 . A multispecific antibody according to claim 9 which is a dual binding antibody.

11 . A multispecific antibody according to claim 10 which is a FIT-Ig.

12 . A multispecific antibody according to any preceding claim, wherein the another target antigen is selected from immune checkpoint inhibitors, immune modulators and immune activators.

13 . A multispecific antibody according to claim 12 , wherein the another target antigen is selected from PD-1, PD-L1, CTLA-4, TIGIT, TIM-3, LAG-3, VISTA, BTLA, HVEM, CSF1R, CCR4, CD39, CD40, CD73, CD96, CXCR2, CXCR4, CD200, GARP, SIRPα, CXCL9, CXCL10, CD155, CD137, GITR, OX40, CXCR3 and CD3.

14 . A multispecific antibody according to claim 13 , wherein the another target antigen is selected from PD-L1, TIGIT, TIM-3, LAG-3, GARP, SIRPα, CXCR4, BTLA, HVEM, CSF1R, agonistic anti-CXCR3 antibodies), CD137, GITR and OX40.

15 . A multispecific antibody according to claim 14 , wherein the another target antigen is PD-L1 (e.g. human PD-L1).

16 . A multispecific according to claim 15 , wherein the binding (and optionally specificity for) PD-L1 is provided by any of the antibodies or fragments as defined in concepts 1 to 70.

17 . A multispecific antibody according to claim 15 or claim 16 , which comprises a VH domain comprising a CDRH1, a CDRH2 and a CDRH3 which VH domain has specificity for human PD-L1.

18 . A multispecific antibody according to any one of claims 15 to 17 , which comprises a VL domain comprising a CDRL1, a CDRL2 and a CDRL3, which VL domain as specificity for human PD-L1.

19 . A multispecific antibody according to claim 17 or claim 18 , wherein the VH and/or VL domain is any of VH and/or VL domains from 1D05, 416E01, atezolizumab (Roche), avelumab (Merck), BMS-936559 (BMS), durvalumab (Medimmune) or from any of the PD-L1 antibodies disclosed in WO2016/061142, WO2016/022630, WO2016/007235, WO2015/173267, WO2015/181342, WO2015/109124, WO2015/112805, WO2015/061668, WO2014/159562, WO2014/165082, WO2014/100079, WO2014/055897, WO2013/181634, WO2013/173223, WO2013/079174, WO2012/145493, WO2011/066389, WO2010/077634, WO2010/036959 or WO2007/005874.

20 . A multispecific antibody according to claim 17 or claim 18 , wherein the VH and/or VL domain is any of VH and/or VL domains described in concepts 1 to 70.

21 . A multispecific antibody according to any one of claims 15 to 20 , which binds (and optionally has specificity for) mouse PD-L1 and/or cynomolgus PD-L1.

22 . A composition comprising a multispecific antibody as defined in any preceding claim and a pharmaceutically acceptable excipient, diluent or carrier and optionally further comprising a further therapeutic agent independently selected from the group consisting of:

a) other immune checkpoint inhibitors (such as anti-TIM-3 antibodies, anti-PD-1 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies and anti-LAG-3 antibodies);

b) immune stimulators (such as anti-OX40 antibodies, anti-GITR antibodies, anti-CD137 antibodies, anti-ICOS antibodies and anti-CD40 antibodies);

c) chemokine receptor antagonists (such as CXCR4, CCR4 and CXCR2);

d) targeted kinase inhibitors (such as CSF-1R or VEGFR inhibitors);

e) angiogenesis inhibitors (such as anti-VEGF-A or Delta-like Ligand-4);

f) immune stimulating peptides or chemokines (such as CXCL9 or CXCL10);

g) cytokines (such as IL-15 and IL-21);

h) bispecific T-cell engagers (BiTEs) having at least one specificity against CD3 (e.g. CD3/CD19 BiTE);

i) other bi-specific molecules (for example IL-15-containing molecules targeted towards tumour associated antigens, for example Epidermal growth factor receptors such as EGFR, Her-2, New York Esophageal Cancer-1 (NY-ESO-1), GD2, EpCAM or Melanoma Associated Antigen-3 (MAGE-A3));

j) oncolytic viruses (such as HSV virus (optionally which secretes GMCSF), Newcastle disease virus and Vaccinia virus);

k) vaccination with tumour associated antigens (such as New York Esophageal Cancer-1 [NY-ESO-1], Melanoma Associated Antigen-3 [MAGE-3]);

l) cell-based therapies (such as chimeric Antigen Receptor-T-cells (CAR-T) for example expressing anti-CD19, anti-EpCam or anti-mesothelin); and

m) adoptive transfer of tumour specific T-cells or LAK cells.

23 . A multispecific antibody as defined in any one of claims 1 to 21 for use in treating or preventing a disease or condition, selected from neurological disease, neoplastic or non-neoplastic disease, chronic viral infections, and malignant tumours; such as melanoma, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, head and neck squamous cell carcinoma, mesothelioma, virally induced cancers (such as cervical cancer and nasopharyngeal cancer), soft tissue sarcomas, haematological malignancies such as Hodgkin's and non-Hodgkin's disease and diffuse large B-cell lymphoma (for example melanoma, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, head and neck squamous cell carcinoma and mesothelioma or for example virally induced cancers (such as cervical cancer and nasopharyngeal cancer) and soft tissue sarcomas).

24 . Use of a multispecific antibody as defined in any one of claims 1 to 21 in the manufacture of a medicament for administration to a human for treating or preventing a disease or condition in the human selected from neurological disease, neoplastic or non-neoplastic disease, chronic viral infections, and malignant tumours, such as melanoma, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, head and neck squamous cell carcinoma, mesothelioma, virally induced cancers (such as cervical cancer and nasopharyngeal cancer), soft tissue sarcomas, haematological malignancies such as Hodgkin's and non-Hodgkin's disease and diffuse large B-cell lymphoma (for example melanoma, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, head and neck squamous cell carcinoma and mesothelioma or for example virally induced cancers (such as cervical cancer and nasopharyngeal cancer) and soft tissue sarcomas).

25 . A method of treating or preventing a disease or condition selected from neurological disease, neoplastic or non-neoplastic disease, chronic viral infections, and malignant tumours, such as melanoma, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, head and neck squamous cell carcinoma, mesothelioma, virally induced cancers (such as cervical cancer and nasopharyngeal cancer), soft tissue sarcomas, haematological malignancies such as Hodgkin's and non-Hodgkin's disease and diffuse large B-cell lymphoma (for example melanoma, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, head and neck squamous cell carcinoma and mesothelioma or for example virally induced cancers (such as cervical cancer and nasopharyngeal cancer) and soft tissue sarcomas) in a human, comprising administering to said human a therapeutically effective amount of a multispecific antibody as defined in any one of claims 1 to 21 , wherein the disease or condition is thereby treated or prevented.

26 . The multispecific antibody according to claim 23 , the use according to claim 24 or the method according to claim 25 , wherein the neurological disease is a neurodegenerative disease, disorder or condition, optionally wherein the neurodegenerative disease, disorder or condition is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, corticobasal degeneration, Rett syndrome, a retinal degeneration disorder selected from age-related macular degeneration and retinitis pigmentosa; anterior ischemic optic neuropathy, glaucoma, uveitis, depression, trauma-associated stress or post-traumatic stress disorder, frontotemporal dementia, Lewy body dementias, mild cognitive impairments, posterior cortical atrophy, primary progressive aphasia and progressive supranuclear palsy or aged-related dementia, in particular Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease, and e.g. Alzheimer's disease.

27 . The multispecific antibody according to claim 23 , the use according to claim 24 or the method according to claim 25 , wherein the cancer is selected from melanoma, Merkel cell carcinoma, non-small cell lung cancer (squamous and non-squamous), renal cell cancer, bladder cancer, head and neck squamous cell carcinoma and mesothelioma or is selected from virally induced cancers (such as cervical cancer and nasopharyngeal cancer) and soft tissue sarcomas.

28 . The multispecific antibody, the use or the method according to any one of claims 23 to 27 , further comprising administering to the human a further therapy, for example a further therapeutic agent, optionally wherein the further therapeutic agent is independently selected from the group consisting of:

a. other immune checkpoint inhibitors (such as anti-TIM-3 antibodies, anti-PD-1 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies and anti-LAG-3 antibodies);

b. immune stimulators (such as anti-OX40 antibodies, anti-GITR antibodies, anti-CD137 antibodies and anti-CD40 antibodies);

c. chemokine receptor antagonists (such as CXCR4, CCR4 and CXCR2);

d. targeted kinase inhibitors (such as CSF-1R or VEGFR inhibitors);

e. angiogenesis inhibitors (such as anti-VEGF-A or Delta-like Ligand-4);

f. immune stimulating peptides or chemokines (such as CXCL9 or CXCL10);

g. cytokines (such as IL-15 and IL-21);

h. bispecific T-cell engagers (BiTEs) having at least one specificity against CD3 (e.g. CD3/CD19 BiTE);

i. other bi-specific molecules (for example IL-15-containing molecules targeted towards tumour associated antigens, for example Epidermal growth factor receptors such as EGFR, Her-2, New York Esophageal Cancer-1 (NY-ESO-1), GD2, EpCAM or Melanoma Associated Antigen-3 (MAGE-A3));

j. oncolytic viruses (such as HSV virus (optionally which secretes GMCSF), Newcastle disease virus and Vaccinia virus);

k. vaccination with tumour associated antigens (such as New York Esophageal Cancer-1 [NY-ESO-1], Melanoma Associated Antigen-3 [MAGE-3]);

l. cell-based therapies (such as chimeric Antigen Receptor-T-cells (CAR-T) for example expressing anti-CD19, anti-EpCam or anti-mesothelin); and

m. adoptive transfer of tumour specific T-cells or LAK cells,

or optionally wherein the further therapy is chemotherapy, radiotherapy and surgical removal of tumours.

29 . A nucleic acid that encodes a heavy chain and/or a light chain of a multispecific antibody as defined in any one of claims 1 to 21 .

30 . A vector comprising the nucleic acid as defined in claim 29 ; optionally wherein the vector is a CHO or HEK293 vector.

31 . A host comprising the nucleic acid as defined in claim 29 or the vector as defined in claim 30 .

32 . A multispecific antibody according to any of claims 15 to 21 , wherein

the anti-PD-L1 V H and V L domains are 1D05 V H and V L domains comprising a heavy chain amino acid sequence of Seq ID No:299 and a light chain amino acid sequence of Seq ID No:300 respectively, and wherein

the antibody is an immunocytokine comprising human wild type or variant IL-2.