Anti-CTLA-4 antibodies and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12246066-B2
Application number	US-202318187367-A
Country	US
Kind code	B2
Filing date	Mar 21, 2023
Priority date	Dec 7, 2016
Publication date	Mar 11, 2025
Grant date	Mar 11, 2025

Abstract

The instant disclosure provides antibodies that specifically bind to CTLA-4 (e.g., human CTLA-4) and antagonize CTLA-4 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

First claim

What is claimed is:

1. An isolated antibody that specifically binds to human CTLA-4, the antibody comprising:
a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 20; and
a VL comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 9,
wherein the CDRH1, CDRH2, and CDRH3 sequences of the antibody are not SEQ ID NOs: 10, 11, and 13, respectively.

2. The isolated antibody of claim 1 , wherein: the VH comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 2; and the VL comprises the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 9.

3. The isolated antibody of claim 1 , wherein: the VH comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 4; and the VL comprises the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 9.

4. The isolated antibody of claim 1 , wherein: the VH comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 6; and the VL comprises the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 9.

5. The isolated antibody of claim 1 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the antibody comprise the amino acid sequences set forth in SEQ ID NOs: 10, 18, 19, 15, 16, and 17, respectively.

6. The isolated antibody of claim 1 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the antibody comprise the amino acid sequences set forth in SEQ ID NOs: 10, 11, 14, 15, 16, and 17, respectively.

7. The isolated antibody of claim 1 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the antibody comprise the amino acid sequences set forth in SEQ ID NOs: 10, 12, 13, 15, 16, and 17, respectively.

8. The isolated antibody of claim 1 , wherein the antibody comprises:
a VH comprising an amino acid sequence which is at least 75% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2-8 and 20; and/or
a VL comprising an amino acid sequence which is at least 75% identical to the amino acid sequence of SEQ ID NO: 9.

9. The isolated antibody of claim 1 , wherein the VH and the VL comprise the amino acid sequences set forth in SEQ ID NOs: 2 and 9; 3 and 9; 4 and 9; 5 and 9; 6 and 9; or 7 and 9, respectively.

10. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain constant region selected from the group consisting of human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 .

11. The isolated antibody of claim 1 , wherein:
the antibody comprises an IgG 1 heavy chain constant region, optionally wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 28;
the antibody comprises an IgG 1 heavy chain constant region comprising S239D/1332E mutations, numbered according to the EU numbering system, optionally wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 29;
the antibody comprises an IgG 1 heavy chain constant region comprising S239D/A330L/1332E mutations, numbered according to the EU numbering system, optionally wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 30; or
the antibody comprises an IgG 1 heavy chain constant region comprising L235V/F243L/R292P/Y300L/P396L mutations, numbered according to the EU numbering system, optionally wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 31.

12. The isolated antibody of claim 11 , wherein the IgG 1 heavy chain constant region is afucosylated IgG 1 .

13. The isolated antibody of claim 1 , wherein the antibody comprises a human IgG heavy chain constant region that is a variant of a wild type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to FcγRIIIA with a higher affinity than the wild type human IgG heavy chain constant region binds to FcγRIIIA, optionally wherein the variant human IgG heavy chain constant region is a variant human IgG 1 heavy chain constant region.

14. The isolated antibody of claim 1 , wherein the antibody comprises a light chain constant region selected from the group consisting of human Igk and Ig), optionally wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 32.

15. The isolated antibody of claim 1 , wherein:
the antibody binds to the same epitope of human CTLA-4 as an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9; and/or
the antibody binds to an epitope located within a region of human CTLA-4 consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 34-39.

16. The isolated antibody of claim 1 conjugated to a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label.

17. An isolated antibody that specifically binds to human CTLA-4, the antibody comprising:
a heavy chain comprising the amino acid sequence of SEQ ID NO: 23, and a light chain comprising the amino acid sequence of SEQ ID NO: 27;
a heavy chain comprising the amino acid sequence of SEQ ID NO: 24, and a light chain comprising the amino acid sequence of SEQ ID NO: 27;
a heavy chain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain comprising the amino acid sequence of SEQ ID NO: 27;
a heavy chain comprising the amino acid sequence of SEQ ID NO: 47, and a light chain comprising the amino acid sequence of SEQ ID NO: 27; or
a heavy chain comprising the amino acid sequence of SEQ ID NO: 48, and a light chain comprising the amino acid sequence of SEQ ID NO: 27.

18. A polypeptide comprising a VH comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 2, 4, 5, 6, 7, or 8.

19. A polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 23, 24, 25, 26, 47, or 48.

Assignees

• Agenus Inc
• Ludwig Inst For Cancer Res Ltd
• Memorial Sloan Kettering Cancer Center

Inventors

• Van Dijk Marc
• Mundt Cornelia Anne
• Ritter Gerd
• Schaer David
• Wolchok Jedd David
• Merghoub Taha
• Wilson Nicholas Stuart
• Savitsky David Adam
• Findeis Mark Arthur
• Underwood Dennis John
• Cuillerot Jean-Marie
• Proscurshim Igor
• Shebanova Olga

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• C07K2317/515

  Complete light chain, i.e. VL + CL · CPC title

• C07K2317/51

  Complete heavy chain or Fd fragment, i.e. VH + CH1 · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title