CANCER IMMUNOTHERAPY BY DISRUPTING PD-1/PD-L1 SIGNALING
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.
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.