Dual function antibodies specific to glycosylated PD-L1 and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11660352-B2
Application number	US-201716086582-A
Country	US
Kind code	B2
Filing date	Mar 24, 2017
Priority date	Mar 29, 2016
Publication date	May 30, 2023
Grant date	May 30, 2023

Abstract

Antibodies that bind specifically to glycosylated PD-L1 relative to unglycosylated PD-L1, block binding of PD-L1 to PD-1 and promote internalization and degradation of PD-L1 are provided. Antibodies that recognize specific epitopes on glycosylated PD-L1 protein and that exhibit the dual functions of both blocking the binding of PD-L1 to PD-1 and also facilitating the internalization of PD-L1 on cells are provided. In some aspects, PD-L1 polypeptides comprising glycosylated amino acid residues at amino and carboxy terminal positions of the PD-L1 extracellular domain are also provided. Methods for using such antibodies for the treatment of cancer, particularly PD-L1 positive cancer, are also provided.

First claim

What is claimed is:

1. An isolated antibody which binds to glycosylated PD-L1 comprising a V H domain comprising a CDR H1 with the amino acid sequence of SEQ ID NO: 4, a CDR H2 with the amino acid sequence of SEQ ID NO: 6, and a CDR H3 with the amino acid sequence of SEQ ID NO: 8 or a V H domain comprising a CDR H1 with the amino acid sequence of SEQ ID NO: 5, a CDR H2 with the amino acid sequence of SEQ ID NO: 7, and a CDR H3 with the amino acid sequence of SEQ ID NO: 9 and a V L domain comprising a CDR L1 with the amino acid sequence of SEQ ID NO: 12, a CDR L2 with the amino acid sequence of SEQ ID NO: 14, and a CDR L3 with the amino acid sequence of SEQ ID NO: 16.

2. The isolated antibody of claim 1 , wherein the V H domain has the amino acid sequence of SEQ ID NO: 3 and the V L has the amino acid sequence of SEQ ID NO: 11.

3. An isolated antibody which binds to glycosylated PD-L1 comprising
a V H domain comprising a CDR H1 with the amino acid sequence of SEQ ID NO: 20, a CDR H2 with the amino acid sequence of SEQ ID NO: 22, and a CDR H3 with the amino acid sequence of SEQ ID NO: 24, or a V H comprising a CDR H1 with the amino acid sequence of SEQ ID NO: 21 a CDR H2 with the amino acid sequence of SEQ ID NO: 23, and a CDR H3 with the amino acid sequence of SEQ ID NO: 25 and
wherein said antibody has a V L domain comprising a CDR L1 with the amino acid sequence of SEQ ID NO: 28, a CDR L2 with the amino acid sequence of SEQ ID NO: 30, and a CDR L3 with the amino acid sequence of SEQ ID NO: 32.

4. An isolated antibody of claim 1 comprising a V H domain encoded by a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 2, and/or a V L domain encoded by a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 10.

5. The isolated antibody of claim 3 , which has human antibody framework regions or a human constant domain.

6. The isolated antibody of claim 1 , wherein the antibody is at least one selected from the group consisting of a Fab′, a F(ab′)2, a F(ab′)3, a monovalent scFv, a bivalent scFv, a bispecific, and a biparatopic.

7. A composition comprising the antibody of claim 1 in a pharmaceutically acceptable carrier, diluent, excipient, or vehicle.

8. A method of treating a PD-L1 positive cancer in a subject in need, comprising administering to a subject having a PD-L1 positive cancer an effective amount of the isolated antibody of claim 1 .

9. The method of claim 8 , wherein the PD-L1 positive cancer is at least one cancer selected from the group consisting of a breast cancer, a lung cancer, a head & neck cancer, a prostate cancer, an esophageal cancer, a tracheal cancer, a skin cancer, a brain cancer, a liver cancer, a bladder cancer, a stomach cancer, a pancreatic cancer, an ovarian cancer, a uterine cancer, a cervical cancer, a testicular cancer, a colon cancer, a rectal cancer, and a skin cancer.

10. The isolated antibody of claim 1 , wherein the antibody is conjugated to an antineoplastic agent to produce an antibody-drug conjugate (ADC).

11. The isolated antibody of claim 10 , wherein the antibody is chemically conjugated to a maleimide and caproic acid (MC) attachment group, which is chemically conjugated to a cathepsin-cleavable linker, which is chemically conjugated to a paraminobenzoic acid (PAB) spacer, which is chemically conjugated to MMAE, thereby forming the ADC.

12. An ADC comprising a dual function anti-glycPD-L1 antibody chemically coupled to a cytotoxic drug, wherein the anti-glycPD-L1 antibody is that of claim 1 .

13. The isolated antibody of claim 1 , which has human antibody framework regions or a human constant domain.

14. The isolated antibody according to claim 3 , wherein the antibody is at least one selected from the group consisting of a Fab′, a F(ab′)2, a F(ab′)3, a monovalent scFv, a bivalent scFv, a bispecific, and a biparatopic.

15. An isolated antibody of claim 3 having a VH domain comprising the amino acid sequence of SEQ ID NO: 19 and VL domain comprising the amino acid sequence of SEQ ID NO: 27.

16. An isolated antibody of claim 3 comprising a V H domain encoded by a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 18, and a V L domain encoded by a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 26.

17. A composition comprising the antibody of claim 3 and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle.

18. A method of treating a PD-L1 positive cancer in a subject in need of said treatment, said method comprising administering to the subject an effective amount of the antibody according to claim 3 .

19. The method of claim 18 , wherein the cancer is at least one cancer selected from the group consisting of a hematological cancer, a breast cancer, a lung cancer, a head & neck cancer, a prostate cancer, an esophageal cancer, a tracheal cancer, a skin cancer, a brain cancer, a liver cancer, a bladder cancer, a stomach cancer, a pancreatic cancer, an ovarian cancer, a uterine cancer, a cervical cancer, a testicular cancer, a colon cancer, a rectal cancer, and a skin cancer.

20. A method of assessing PD-L1 glycosylation in a biological sample, said method comprising contacting a biological sample with an antibody according to claim 3 , wherein detection of binding of said antibody indicates that the sample comprises glycosylated PD-L1.

21. The method of claim 20 , wherein the sample is a cell sample from a cancer or tumor of a subject.

22. A method of assessing PD-L1 glycosylation in a biological sample, said method comprising contacting a biological sample with an antibody according to claim 1 , wherein detection of binding of said antibody indicates that the sample comprises glycosylated PD-L1.

23. The method of claim 22 , wherein the sample is a cell sample from a cancer or tumor of a subject.

24. The isolated antibody of claim 1 , wherein the antibody is an IgG antibody, an IgM antibody, or an IgA antibody.

25. The isolated antibody of claim 3 , wherein the antibody is an IgG antibody, an IgM antibody, or an IgA antibody.

26. The isolated antibody of claim 3 , wherein the antibody is conjugated to an antineoplastic agent to produce an antibody-drug conjugate (ADC).

27. The isolated antibody of claim 26 , wherein the antibody is chemically conjugated to a maleimide and caproic acid (MC) attachment group, which is chemically conjugated to a cathepsin-cleavable linker, which is chemically conjugated to a paraminobenzoic acid (PAB) spacer, which is chemically conjugated to MMAE, thereby forming the ADC.

28. An ADC comprising a dual function anti-glycPD-L1 antibody chemically coupled to a cytotoxic drug, wherein the anti-glycPD-L1 antibody is that of claim 3 .

Assignees

• Stcube Inc
• Univ Texas

Inventors

• Yoo Stephen S
• Chung Ezra M
• Kim Yong-Soo
• Han Kyu Lee
• Park Andrew H
• Hung Mien-Chie
• Li Chia-Wei
• Lim Seung-Oe

Classifications

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/77

  Internalization into the cell · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title