Method for increasing the efficacy of cancer therapy by administering an anti-FOLR1 immunoconjugate
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 increasing the efficacy of cancer therapy with an active agent comprising an anti-FOLR1 immunoconjugate comprising an anti-FOLR1 antibody or antigen-binding fragment thereof, said method comprising administering the active agent to a subject having cancer, wherein increased expression of FOLR1 has been detected in a cancerous sample from said subject in an immunohistochemistry (IHC) assay using a detection antibody or antigen-binding fragment thereof
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 SEO ID NO:27 and a light chain variable region (VL) comprising the amino acid sequence of SEO ID NO:28.
2. The method of claim 1 , wherein greater than 25% of cells in the cancerous sample have a FOLR1 staining intensity score of 2 or greater.
3. The method of claim 1 , wherein the IHC is performed manually.
4. The method of claim 1 , wherein the IHC is performed using an automated system.
5. 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.
6. The method of claim 5 , wherein said detection reagent is selected from the group consisting of: biotin, digoxigenin, fluorescein, tritium, and rhodamine.
7. The method of claim 1 , wherein said cancer is selected from the group consisting of ovarian, brain, breast, uterine, endometrial, pancreatic, renal, and lung cancer.
8. The method of claim 7 , wherein the ovarian cancer is epithelial ovarian cancer.
9. The method of claim 8 , wherein the cancer is platinum resistant, relapsed, or refractory.
10. The method of claim 1 , wherein the anti-FOLR1 immunoconjugate comprises an anti-FOLR1 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.
11. The method of claim 1 , wherein the anti-FOLR1 immunoconjugate comprises an anti-FOLR1 antibody or antigen-binding fragment thereof comprising 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 1 , wherein the anti-FOLR1 immunoconjugate comprises an anti-FOLR1 antibody or antigen-binding fragment thereof, and a sulfo-SPDB linker conjugated to N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).
13. The method of claim 1 , wherein the anti-FOLR1 immunoconjugate has the formula (A)-(L)-(C), 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, and
(L) is a linker;
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 comprises the VH CDR1-3 and VL CDR1-3 polypeptide sequences of SEQ ID NOs:3-8, respectively.
19. The method of claim 1 , wherein the detection antibody or antigen-binding fragment thereof comprises the amino acid sequences of SEQ ID NO:27 and 28.