Cancer immunotherapy by disrupting pd-1/pd-l1 signaling

Patent metadata

Field	Value
Publication number	US-2020308282-A1
Application number	US-202016827580-A
Country	US
Kind code	A1
Filing date	Mar 23, 2020
Priority date	May 15, 2012
Publication date	Oct 1, 2020
Grant date	—

Abstract

The disclosure provides a method for immunotherapy of a subject afflicted with cancer, comprises administering to the subject a composition comprising a therapeutically effective amount of an antibody that inhibits signaling from the PD-1/PD-L1 signaling pathway. This disclosure also provides a method for immunotherapy of a subject afflicted with cancer comprising selecting a subject that is a suitable candidate for immunotherapy based on an assessment that the proportion of cells in a test tissue sample from the subject that express PD-L1 on the cell surface exceeds a predetermined threshold level, and administering a therapeutically effective amount of an anti-PD-1 antibody to the selected subject. The invention additionally provides rabbit mAbs that bind specifically to a cell surface-expressed PD-L1 antigen in a FFPE tissue sample, and an automated IHC method for assessing cell surface expression in FFPE tissues using the provided anti-PD-L1 Abs.

First claim

1 - 17 . (canceled)

18 . A method of treating a tumor derived from a melanoma in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody and a BRAF inhibitor; wherein the anti-PD-1 antibody is administered by intravenous infusion.

19 . The method of claim 18 , wherein at least 10% of tumor cells in the tumor exhibit membrane PD-L1 expression.

20 . The method of claim 18 , wherein the therapeutically effective amount of the anti-PD-1 antibody is administered once every 4 weeks.

21 . The method of claim 18 , wherein the anti-PD-1 antibody is formulated in a pharmaceutical composition.

22 . The method of claim 21 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable salt, an anti-oxidant, an aqueous carrier, a non-aqueous carrier, or any combination thereof.

23 . The method of claim 22 , wherein the salt comprises a sodium salt.

24 . The method of claim 22 , wherein the salt comprises sodium chloride.

25 . The method of claim 18 , wherein the BRAF inhibitor inhibits mutated B-RAF protein.

26 . The method of claim 25 , wherein the mutated B-RAF protein comprises V600E-BRAF.

27 . The method of claim 19 , wherein the membranous PD-L1 expression on the tumor cells is measured prior to administering the anti-PD-1 antibody.

28 . The method of claim 27 , wherein the measuring comprises an immunohistochemistry.

29 . The method of claim 28 , wherein the immunohistochemistry is performed using an antibody comprising:
(a) a heavy chain (HC) complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in the HC-CDR1 of SEQ ID NO: 35; (b) an HC-CDR2 comprising the amino acid sequence set forth in the HC-CDR2 of SEQ ID NO: 35; (c) an HC-CDR3 comprising the amino acid sequence set forth in the HC-CDR3 of SEQ ID NO: 35; (d) a light chain (LC) CDR1 comprising the amino acid sequence set forth in the LC-CDR1 of SEQ ID NO: 36; (e) an LC-CDR2 comprising the amino acid sequence set forth in the LC-CDR2 of SEQ ID NO: 36; and (f) an LC-CDR3 comprising the amino acid sequence set forth in the LC-CDR3 of SEQ ID NO: 36.

30 . A method of treating a tumor derived from a melanoma in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody and a BRAF inhibitor;
wherein the anti-PD-1 antibody is administered by intravenous infusion once every 4 weeks; wherein at least 10% of tumor cells in the tumor exhibit membrane PD-L1 expression, as determined using an immunohistochemistry.

31 . The method of claim 30 , wherein the anti-PD-1 antibody is formulated in a pharmaceutical composition.

32 . The method of claim 31 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable salt, an anti-oxidant, an aqueous carrier, a non-aqueous carrier, or any combination thereof.

33 . The method of claim 32 , wherein the salt comprises a sodium salt.

34 . The method of claim 32 , wherein the salt comprises sodium chloride.

35 . The method of claim 18 , wherein the BRAF inhibitor inhibits mutated B-RAF protein.

36 . The method of claim 35 , wherein the mutated B-RAF protein comprises V600E-BRAF.

37 . The method of claim 30 , wherein the immunohistochemistry is performed using an antibody comprising:
(a) a heavy chain (HC) complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in the HC-CDR1 of SEQ ID NO: 35; (b) an HC-CDR2 comprising the amino acid sequence set forth in the HC-CDR2 of SEQ ID NO: 35; (c) an HC-CDR3 comprising the amino acid sequence set forth in the HC-CDR3 of SEQ ID NO: 35; (d) a light chain (LC) CDR1 comprising the amino acid sequence set forth in the LC-CDR1 of SEQ ID NO: 36; (e) an LC-CDR2 comprising the amino acid sequence set forth in the LC-CDR2 of SEQ ID NO: 36; and (f) an LC-CDR3 comprising the amino acid sequence set forth in the LC-CDR3 of SEQ ID NO: 36.

Assignees

• Bristol Myers Squibb Co

Inventors

• Cogswell John P
• Goldberg Stacie M
• Gupta Ashok K
• Jure-Kunkel Maria
• Wang xi-tao
• Wigginton Jon M

Classifications

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• C07K16/2818 Primary

  against CD28 or CD152 · CPC title

• A61K39/395 Primary

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title