Anti-CD112R compositions and methods

1. An isolated antibody or antigen binding portion thereof, that binds to CD112R and comprises:

i) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 6; or

ii) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 101; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 102; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 103; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 104; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 105; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 106; or

iii) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 201; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 202; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 203; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 204; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 205; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 206; or

iv) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 301; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 302; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 303; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 304; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 305; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 306; or

v) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 401; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 402; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 403; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 404; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 405; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 406; or

vi) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 501; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 502; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 503; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 504; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 505; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 506; or

vii)(a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 601; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 602; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 603; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 604; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 605; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 606; or

viii) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 801; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 802; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 803; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 804; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 805; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 806; or

ix) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 901; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 902; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 903; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 904; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 905; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 906; or

x) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 1001; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 1002; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 1003; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 1004; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 1005; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 1006; or

xi) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 2001; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 2002; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 2003; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 2004; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 2005; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 2006; or

xii) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 3001; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 3002; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 3003; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 3004; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 3005; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 3006; or

xiii) (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 4001; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 4002; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 4003; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 4004; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 4005; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 4006.

2. The isolated antibody or antigen binding portion thereof, of claim 1 , wherein the isolated antibody or antigen binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

i) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 12 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 18; or

ii) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 112 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 118; or

iii) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 212 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 218; or

iv) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 312 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 318; or

v) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 412 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 418; or

vi) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 512 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 518; or

vii) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 612 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 618; or

viii) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 812 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 818; or

ix) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 912 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 918; or

x) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 1012 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 1018; or

xi) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 2012 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 2018; or

xii) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 3012 and the VL is at least 90% identical to the amino acid sequence of SEQ ID NO: 3018; or

xiii) the VH is at least 90% identical to the amino acid sequence of SEQ ID NO: 4012 and the VL is at least 90 identical to the amino acid sequence of SEQ ID NO: 4018.

3. The isolated antibody or antigen binding portion thereof, of claim 1 , wherein the antibody or antigen binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

i) the VH comprises the amino acid sequence of SEQ ID NO: 12 and the VL comprises the amino acid sequence of SEQ ID NO: 18; or

ii) the VH comprises the amino acid sequence of SEQ ID NO: 112 and the VL comprises the amino acid sequence of SEQ ID NO: 118; or

iii) the VH comprises the amino acid sequence of SEQ ID NO: 212 and the VL comprises the amino acid sequence of SEQ ID NO: 218; or

iv) the VH comprises the amino acid sequence of SEQ ID NO: 312 and the VL comprises the amino acid sequence of SEQ ID NO: 318; or

v) the VH comprises the amino acid sequence of SEQ ID NO: 412 and the VL comprises the amino acid sequence of SEQ ID NO: 418; or

vi) the VH comprises the amino acid sequence of SEQ ID NO: 512 and the VL comprises the amino acid sequence of SEQ ID NO: 518; or

vii) the VH comprises the amino acid sequence of SEQ ID NO: 612 and the VL comprises the amino acid sequence of SEQ ID NO: 618; or

viii) the VH comprises the amino acid sequence of SEQ ID NO: 812 and the VL comprises the amino acid sequence of SEQ ID NO: 818; or

ix) the VH comprises the amino acid sequence of SEQ ID NO: 912 and the VL comprises the amino acid sequence of SEQ ID NO: 918; or

x) the VH comprises the amino acid sequence of SEQ ID NO: 1012 and the VL comprises the amino acid sequence of SEQ ID NO: 1018; or

xi) the VH comprises the amino acid sequence of SEQ ID NO: 2012 and the VL comprises the amino acid sequence of SEQ ID NO: 2018; or

xii) the VH comprises the amino acid sequence of SEQ ID NO: 3012 and the VL comprises the amino acid sequence of SEQ ID NO: 3018; or

xiii) the VH comprises the amino acid sequence of SEQ ID NO: 4012 and the VL comprises the amino acid sequence of SEQ ID NO: 4018.

4. The isolated antibody or antigen binding portion thereof, of claim 1 , wherein the isolated antibody is a monoclonal antibody.

5. The isolated antibody or antigen binding portion thereof, of claim 1 , wherein the isolated antibody is an antibody fragment.

6. The isolated antibody or antigen binding portion thereof, of claim 1 , wherein the Fc region of the isolated antibody comprises IgG1, IgG2, IgG3, or IgG4.

7. The isolated antibody or antigen binding portion thereof, of claim 1 , wherein the isolated antibody comprises a human IgG1 heavy chain constant region, and wherein the isolated antibody

i) increases NK cell degranulation; and/or

ii) increases activation of NK cells; and/or

iii) increases activation of intra-tumoral NK cells when presented in combination with an anti-TIGIT antibody; and/or

iv) inhibits tumor growth in vivo; and/or

v) prevents tumor engraftment upon re-challenge with tumor.

8. A humanized or fully human version of the isolated antibody of claim 1 .

9. A composition comprising the isolated antibody or antigen binding portion thereof, of claim 1 , and a pharmaceutically acceptable carrier.

10. The composition of claim 9 , further comprising an antagonist of PD-1, PD-L1, CTLA-4, Lag-3 or TIM-3.

11. A method of enhancing, increasing and/or sustaining an anti-tumor immune response in a subject, the method comprising administering the isolated antibody or antigen binding portion thereof, of claim 1 , to a subject having a tumor.

12. A method of enhancing CD8 T cell activation and/or interferon gamma production in a subject, the method comprising administering the isolated antibody or antigen binding portion thereof, of claim 1 , to a subject in need of CD8 T cell activation.

13. A method of enhancing NK cell activation and/or NK cell mediated cytotoxicity in a subject, the method comprising administering the isolated antibody or antigen binding portion thereof, of claim 1 , to a subject in need of NK cell activation and/or in need of increasing NK cell mediated cytotoxicity.

14. A method of treating cancer in a subject, the method comprising administering the isolated antibody or antigen binding portion thereof, of claim 1 , to a subject having cancer.

15. The method of claim 14 , wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, renal cell carcinoma, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, or various types of head and neck cancer.

16. A method of enhancing CD226 interactions with CD112 in a subject, the method comprising administering the isolated antibody or antigen binding portion thereof, of claim 1 , to a subject.

17. The method of claim 11 , wherein the method further comprises administering a second therapy.

18. The method of claim 17 , wherein the second therapy comprises a chemotherapy, an opsonizing agent, or a regulatory T cell depleting agent.

19. The method of claim 17 , wherein the second therapy comprises:

i) an antagonist of PD-1, PD-L1, CTLA-4, Lag-3, TIM-3, TIGIT, CD96, PVRL1, PVRL2, PVRL3, PVRL4, CD155, CD47, CD39, or IL-27;

ii) a STING agonist; or

iii) a combination of (i) and (ii).

20. A nucleic acid encoding the isolated antibody or antigen binding portion thereof, of claim 1 .

21. A host cell comprising the nucleic acid of claim 20 .

22. A method of producing an antibody comprising culturing the host cell of claim 21 under conditions wherein the antibody is expressed.