IFN-γ-inducible regulatory T cell convertible anti-cancer (IRTCA) antibody and uses thereof
Provided are IFN-γ-Inducible Regulatory T Cell Convertible Anti-Cancer (IRTCA) antibodies and antigen-binding fragment thereof that bind to an activation-inducible TNFR (AITR) polypeptide. Various in vitro and in vivo methods and compositions related to IRTCA antibodies described herein are also provided. Methods include, for example, changing cytokine secretion from T cells in vivo or in vitro and prevention and/or therapeutic treatment of cancer using an IRTCA antibody or fragment thereof.
1. An IFN-γ-Inducible Regulatory T Cell Convertible Anti-Cancer (IRTCA) antibody or antigen-binding fragment thereof, comprising:
(a) a heavy chain CDR1 comprising a sequence of SEQ ID NO: 8 or 24, a heavy chain CDR2 comprising a sequence of SEQ ID NO: 9 or 25, and a heavy chain CDR3 comprising at least one sequence selected from SEQ ID NO: 14, 15, 16, and 17; and
(b) a light chain CDR1 comprising a sequence of SEQ ID NO: 11, a light chain CDR2 comprising a sequence of SEQ ID NO: 12 and a light chain CDR3 comprising a sequence of SEQ ID NO: 13 or 18,
wherein the IRTCA antibody or antigen-binding fragment thereof does not comprise each of: (i) a heavy chain CDR1 comprising a sequence of SEQ ID NO: 8; (ii) a heavy chain CDR2 comprising a sequence of SEQ ID NO: 9; (iii) a heavy chain CDR3 comprising a sequence of SEQ ID NO: 10; (iv) a light chain CDR1 comprising a sequence of SEQ ID NO: 11; (v) a light chain CDR2 comprising a sequence of SEQ ID NO: 12; and (vi) a light chain CDR3 comprising a sequence of SEQ ID NO: 13.
2. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises any one of the following:
(a) a heavy chain variable domain comprising a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 3, 4, 5, 6, 20, and 21;
(b) a light chain variable domain comprising a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 7, 22, and 23; or
(c) a heavy chain variable domain comprising a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 3, 4, 5, 6, 20, and 21 and a light chain variable domain comprising a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 7, 22, and 23.
3. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises any one of the following:
(a) a heavy chain variable domain comprising a sequence at least 98% identical to a sequence selected from SEQ ID NOs: 3, 4, 5, 6, 20, and 21;
(b) a light chain variable domain comprising a sequence at least 98% identical to a sequence selected from SEQ ID NOs: 7, 22, and 23; or
(c) a heavy chain variable domain comprising a sequence at least 98% identical to a sequence selected from SEQ ID NOs: 3, 4, 5, 6, 20, and 21 and a light chain variable domain comprising a sequence at least 98% identical to a sequence selected from SEQ ID NOs: 7, 22, and 23.
4. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises any one of the following:
(a) a heavy chain variable domain comprising a sequence selected from SEQ ID NOs: 3, 4, 5, 6, 20, and 21;
(b) a light chain variable domain comprising a sequence selected from SEQ ID NOs: 7, 22, and 23; or
(c) a heavy chain variable domain comprising a sequence selected from SEQ ID NOs: 3, 4, 5, 6, 20, and 21 and a light chain variable domain comprising a sequence selected from SEQ ID NOs: 7, 22, and 23.
5. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment has a binding affinity (K D ) for a human Activation-Inducible Tumor Necrosis Factor Receptor (AITR) molecule of 1×10 −7 to 1×10 −12 M.
6. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment binds to an epitope within the extracellular domain of human AITR polypeptide.
7. The IRTCA antibody or antigen-binding fragment of claim 6 , wherein epitope within the extracellular domain of human AITR polypeptide comprises SEQ ID NO: 19.
8. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody includes an immunoglobulin constant domain, wherein the constant domain is selected from an IgG1 or a variant thereof, an IgG2 or a variant thereof, an IgG4 or a variant thereof, an IgA or a variant thereof, an IgE or a variant thereof, an IgM or a variant thereof, and an IgD or a variant thereof.
9. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody is or comprises a human IgG1.
10. The IRTCA antibody or antigen-binding fragment of claim 9 , wherein the IgG1 is or comprises a sequence that is at least 95% identical to SEQ ID NO: 26.
11. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment is a monoclonal antibody.
12. The IRTCA antibody or antigen-binding fragment of claim 1 , wherein the antibody fragment is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a disulfide-bonded Fv fragment, a scFv fragment, a single domain antibody, humabody, nanobody, or a diabody.
13. A nucleic acid molecule encoding an IRTCA antibody or antigen-binding fragment of claim 1 .
14. A recombinant vector comprising the nucleic acid molecule of claim 13 .
15. A host cell comprising the nucleic acid molecule of claim 13 .
16. The host cell of claim 15 , wherein the host cell is selected from a bacterial, yeast, insect or mammalian cell.
17. The host cell of claim 16 , wherein the host cell is selected from the group consisting of E. coli, P. pastoris , Sf9, COS, HEK293, Expi293, CHO-S, CHO-DG44, CHO-K1, and a mammalian lymphocyte.
18. A pharmaceutical composition comprising:
(a) the IRTCA antibody or antigen-binding fragment of claim 1 ; and
(b) a pharmaceutically acceptable carrier.
19. A method of treating a subject in need thereof, the method comprising the steps of:
administering to the subject a composition that comprises or delivers the IRTCA antibody or antigen-binding fragment of claim 1 , wherein the IRTCA antibody or antigen-binding fragment comprises (a) a heavy chain CDR1 comprising a sequence of SEQ ID NO: 8, a heavy chain CDR2 comprising a sequence of SEQ ID NO: 9, and a heavy chain CDR3 comprising a sequence of SEQ ID NO: 16; and (b) a light chain CDR1 comprising a sequence of SEQ ID NO: 11, a light chain CDR2 comprising a sequence of SEQ ID NO: 12 and a light chain CDR3 comprising a sequence of SEQ ID NO: 13.
20. A method of inducing an immune response in a subject in need thereof, the method comprising the steps of:
administering to the subject a composition that comprises or delivers the IRTCA antibody or antigen-binding fragment of claim 1 .
21. A method of enhancing an immune response or increasing the activity of an immune cell in a subject in need thereof, the method comprising the steps of: administering to the subject a composition that comprises or delivers the IRTCA antibody or antigen-binding fragment of claim 1 .
22. The method of claim 19 , wherein the subject has, or is at risk for developing, cancer.
23. The method of claim 22 , wherein the cancer is selected from a colon cancer, melanoma, breast cancer and gastric cancer.
24. The method of claim 19 , wherein the subject has been administered or will be administered one or more additional anticancer therapies selected from ionizing radiation, a chemotherapeutic agent, an antibody agent, and a cell-based therapy, such that the subject receives treatment with both.
25. The method of claim 24 , wherein the one or more additional anticancer therapies comprise an immune checkpoint inhibitor, IL-12, GM-CSF, an anti-CD4 agent, cisplatin, fluorouracil, doxorubicin, irinotecan, paclitaxel, indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor, or cyclophosphamide.
26. A method for increasing secretion of IFN-γ by a T cell and/or decreasing secretion of TGF-β by a T cell in vivo or in vitro, the method comprising: contacting the cell with the IRTCA antibody or antigen-binding fragment of claim 1 .
27. A method of converting a T cell into a Type 1 helper T (T H 1) cell, the method comprising: contacting the cell with the IRTCA antibody or antigen-binding fragment of claim 1 .
28. The method of claim 26 , wherein the T cell expresses AITR protein.
29. The method of claim 26 , wherein the T cell is a regulatory T cell (T reg cell) or an effector T cell (T eff cell).
30. The IRTCA antibody or antigen-binding fragment of claim 1 , comprising:
(a) a heavy chain CDR1 comprising a sequence of SEQ ID NO: 24, a heavy chain CDR2 comprising a sequence of SEQ ID NO: 25, and a heavy chain CDR3 comprising a sequence of SEQ ID NO: 16; a light chain CDR1 comprising a sequence of SEQ ID NO: 11, a light chain CDR2 comprising a sequence of SEQ ID NO: 12 and a light chain CDR3 comprising a sequence of SEQ ID NO: 13; or
(b) a heavy chain CDR1 comprising a sequence of SEQ ID NO: 8, a heavy chain CDR2 comprising a sequence of SEQ ID NO: 25, and a heavy chain CDR3 comprising a sequence of SEQ ID NO: 16; a light chain CDR1 comprising a sequence of SEQ ID NO: 11, a light chain CDR2 comprising a sequence of SEQ ID NO: 12 and a light chain CDR3 comprising a sequence of SEQ ID NO: 18.