Method for identifying an ovarian cancer in a subject likely to respond to anti-folate receptor 1 (FOLR1) antibody
The invention generally relates to antibodies that bind to human folate receptor and diagnostic assays for folate receptor 1-based therapies. Methods of using the antibodies to monitor therapy are further provided.
1. A method for identifying an ovarian cancer in a subject as likely to respond to an active agent comprising an anti-Folate Receptor 1 (FOLR1) antibody or antigen-binding fragment thereof, said method comprising:
(a) contacting a biological sample comprising cells from said cancer with a detection antibody or antigen-binding fragment thereof in an immunohistochemistry (IHC) assay,
wherein the detection antibody or antigen-binding fragment thereof is an anti-FOLR1 antibody or antigen-binding fragment thereof that specifically binds to an epitope of FOLR1 comprising an N-glycosylated amino acid, wherein said detection antibody or antigen-binding fragment thereof competitively inhibits binding to FOLR1 of an antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:28, and
(b) assigning a FOLR1 staining score to said biological sample
wherein a FOLR1 staining intensity score of 2 or greater in greater than 75% of the cells in the biological sample identifies said cancer as likely to respond to the active agent.
2. The method of claim 1 , further comprising administering the active agent to the subject if the FOLR1 staining score identifies said cancer as likely to respond to the active agent.
3. The method of claim 1 wherein said biological sample is a tissue sample.
4. The method of claim 1 , wherein the FOLR1 is membrane FOLR1.
5. The method of claim 1 , wherein the IHC is performed manually.
6. The method of claim 1 , wherein the IHC is performed using an automated system.
7. The method of claim 1 , wherein the detection antibody or antigen-binding fragment thereof further comprises a detection reagent selected from the group consisting of: an enzyme, a fluorophore, a radioactive label, and a luminophore.
8. The method of claim 7 , wherein said detection reagent is selected from the group consisting of: biotin, digoxigenin, fluorescein, tritium, and rhodamine.
9. The method of claim 1 , wherein the ovarian cancer is epithelial ovarian cancer.
10. The method of claim 9 , wherein the cancer is platinum resistant, relapsed, or refractory.
11. The method of claim 1 , wherein the active agent comprises an anti-FOLR1 antibody or antigen binding fragment thereof comprising: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:45; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 47.
12. The method of claim 11 , wherein the active agent is an antibody maytansinoid conjugate comprising the maytansinoid DM4, and the cleavable sulfo-SPDB linker.
13. The method of claim 1 , wherein the active agent is an anti-FOLR1 immunoconjugate having the formula (A)—(L)—(C), or (C)—(L)—(A) wherein:
(A) comprises an antibody or antigen binding fragment thereof comprising: the VH CDR1-3 polypeptide sequences of SEQ ID NOs:51, 52 and 54, respectively; and the VL CDR1-3 polypeptide sequences of SEQ ID NOs:48, 49, and 50, respectively;
(C) comprises a cytotoxic agent comprising a maytansinoid,
wherein the linker (L) links (A) to (C).
14. The method of claim 13 , wherein the maytansinoid is N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).
15. The method of claim 1 , wherein the detection antibody or antigen-binding fragment thereof comprises the VH CDR1-3 and VL CDR1-3 polypeptide sequences selected from the group consisting of:
(a) SEQ ID NOs:3-8, respectively;
(b) SEQ ID NOs:9-14, respectively;
(c) SEQ ID NOs:15-20, respectively;
(d) SEQ ID NOs:21-26, respectively;
(e) SEQ ID NOs: 3-5 and SEQ ID NOs: 59, 7, and 8, respectively;
(f) SEQ ID NOs: 3, 60, and 5 and SEQ ID NOs: 6-8, respectively;
(g) SEQ ID NOs: 3, 61, and 5 and SEQ ID NOs: 6-8, respectively;
(h) SEQ ID NOs: 3, 60, and 5 and SEQ ID NOs: 59, 7, and 8, respectively; and
(i) SEQ ID NOs: 3, 61, and 5 and SEQ ID NOs: 59, 7, and 8, respectively.
16. The method of claim 1 , wherein said detection antibody or antigen-binding fragment thereof comprises amino acid sequences selected from the group consisting of:
(a) SEQ ID NO:27 and SEQ ID NO:28;
(b) SEQ ID NO:29 and SEQ ID NO:30;
(c) SEQ ID NO:31 and SEQ ID NO:32
(d) SEQ ID NO:62 and SEQ ID NO:63 or SEQ ID NO:64; and
(e) SEQ ID NO:65 and SEQ ID NO:66 or SEQ ID NO:67.
17. The method of claim 1 , wherein said detection antibody or antigen-binding fragment thereof comprises amino acid sequences selected from the group consisting of:
(a) SEQ ID NO:33 and SEQ ID NO:34;
(b) SEQ ID NO:35 and SEQ ID NO:36; and
(c) SEQ ID NO:37 and SEQ ID NO:38.
18. The method of claim 1 , wherein the detection antibody or antigen-binding fragment thereof binds to a human folate receptor 1 with a Kd of about 0.5 to about 10 nM.
19. The method of claim 1 , wherein the detection antibody or antigen-binding fragment thereof binds to a human folate receptor 1 with a Kd of about 1.0 nM or better.
20. The method of claim 1 , wherein the detection antibody or antigen-binding fragment thereof comprises the VH CDR1-3 and VL CDR1-3 polypeptide sequences of SEQ ID NOs:3-8, respectively.
21. The method of claim 1 , wherein said detection antibody or antigen-binding fragment thereof comprises the amino acid sequences of SEQ ID NO:27 and SEQ ID NO:28.
22. The method of claim 1 , wherein said detection antibody or antigen-binding fragment thereof comprises the amino acid sequences of SEQ ID NO:33 and SEQ ID NO:34.
23. The method of claim 12 , wherein the detection antibody or antigen-binding fragment thereof comprises the VH CDR1-3 and VL CDR1-3 polypeptide sequences of SEQ ID NOs:3-8, respectively.
24. The method of claim 12 , wherein said detection antibody or antigen-binding fragment thereof comprises the amino acid sequences of SEQ ID NO:27 and SEQ ID NO:28.
25. The method of claim 12 , wherein said detection antibody or antigen-binding fragment thereof comprises the amino acid sequences of SEQ ID NO:33 and SEQ ID NO:34.
26. The method of claim 14 , wherein the detection antibody or antigen-binding fragment thereof comprises the VH CDR1-3 and VL CDR1-3 polypeptide sequences of SEQ ID NOs:3-8, respectively.
27. The method of claim 14 , wherein said detection antibody or antigen-binding fragment thereof comprises the amino acid sequences of SEQ ID NO:27 and SEQ ID NO:28.
28. The method of claim 14 , wherein said detection antibody or antigen-binding fragment thereof comprises the amino acid sequences of SEQ ID NO:33 and SEQ ID NO:34.