Methods of treating PRLR positive breast cancer
Provided herein are methods of treating prolactin receptor positive breast cancer using an antibody drug conjugate (ADC) comprising an anti-PRLR antibody or antigen-binding fragment thereof conjugated to a cytotoxic agent. In certain embodiments, the anti-PRLR antibody or antigen-binding fragment thereof is conjugated to maytansinoid. In certain embodiments, the method of treating PRLR positive breast cancer includes administering the ADC in combination with one or more chemotherapeutic agents.
1. A method of treating PRLR positive breast cancer, the method comprising co-administering to a patient a therapeutically effective amount of:
(a) an antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof conjugated to a maytansinoid, wherein the antibody or antigen-binding fragment thereof binds to human prolactin receptor (PRLR); and wherein the antibody or antigen binding fragment comprises three heavy chain complementarity determining regions (CDRs) within the heavy chain variable region (HCVR) amino acid sequence and three light chain complementarity determining regions within light chain variable region (LCVR) amino acid sequence of the HCVR/LCVR pair SEQ ID NOs: 290/298, wherein between 2 to 3 mg/kg of the ADC is administered and
(b) fulvestrant, wherein the amount of fulvestrant is 150-250 mg/kg.
2. The method of claim 1 , wherein the antibody blocks prolactin mediated signaling in cells expressing PRLR with an IC50 of less than about 600 pM.
3. The method of claim 1 , wherein the antibody blocks prolactin mediated signaling in cells expressing PRLR with an IC50 of less than about 400 pM.
4. The method of claim 1 , wherein the antibody blocks prolactin mediated signaling in cells expressing PRLR with an IC50 of less than about 200 pM.
5. The method of claim 1 , wherein the antibody blocks prolactin mediated signaling in cells expressing PRLR with an IC50 of less than about 100 pM.
6. The method of claim 1 , wherein the antibody blocks prolactin mediated signaling in cells expressing PRLR with an IC50 of less than about 80 pM.
7. The method of claim 1 , wherein the antibody blocks prolactin mediated signaling in cells expressing PRLR with an IC50 of less than about 60 pM.
8. The method of claim 1 , wherein the antibody blocks prolactin mediated signaling in cells expressing PRLR with an IC50 of less than about 40 pM.
9. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof that binds prolactin receptor (PRLR) interacts with one or more amino acids contained within the first fibronectin-like type III domain of the extracellular domain of PRLR (amino acids 27-128 of SEQ ID NO:404), as determined by hydrogen/deuterium exchange.
10. The method of claim 9 , wherein the antibody or antigen-binding fragment thereof interacts with amino acids 72 to 95 of SEQ ID NO:404.
11. The method of claim 9 , wherein the antibody or antigen-binding fragment thereof interacts with one or more amino acids contained within SEQ ID NO:405, as determined by hydrogen/deuterium exchange.
12. The method of claim 11 , wherein the antibody or antigen-binding fragment thereof interacts with at least ten amino acids contained within SEQ ID NO: 405.
13. The method of claim 11 , wherein the antibody or antigen-binding fragment thereof interacts with at least twenty amino acids contained within SEQ ID NO: 405.
14. The method of claim 9 , wherein the antibody or antigen-binding fragment thereof interacts with the amino acid sequence of SEQ ID NO: 405.
15. The method of claim 1 , wherein the maytansinoid is DM4.
16. The method of claim 1 , wherein the maytansinoid is DM1.
17. The method of claim 1 , wherein the maytansinoid is conjugated to the antibody via a cleavable linker.
18. The method of claim 1 , wherein the maytansinoid is conjugated to the antibody via a non-cleavable linker.
19. The method of claim 1 , wherein the maytansinoid is conjugated to the antibody via a linker selected from the group consisting of 4-[-maleimidomethyl]cyclohexane-1-carboxylate), SPDB, mc-val-cit, and mc-val-cit-PAB.
20. The method of claim 1 , wherein the maytansinoid is conjugated to the antibody via a linker, and wherein the linker is 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (MCC).
21. The method of claim 1 , wherein the patient was previously treated with an estrogen receptor inhibitor.
22. The method of claim 1 , wherein the effective amount is sufficient to delay or inhibit progression of the cancer.
23. The method of claim 1 , wherein the ADC is administered intravenously.
24. The method of claim 1 , wherein the expression of PRLR in the breast cancer is not substantially reduced after treatment.
25. The method of claim 1 , wherein the fulvestrant is administered before the ADC at a predetermined time point.
26. The method of claim 1 , wherein the ADC is administered before the fulvestrant at a predetermined time point.
27. The method of claim 1 , wherein the ADC and the fulvestrant are administered at the same time point.
28. The method of claim 1 , wherein the ADC and the fulvestrant are administered at a different time point.
29. The method of claim 1 , wherein the ADC and the fulvestrant are administered on different days separated by a predetermined interval.
30. A method of treating PRLR positive breast cancer, the method comprising co-administering to a patient a therapeutically effective amount of:
(a) an antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof conjugated to a maytansinoid, wherein the antibody or antigen-binding fragment thereof binds to human prolactin receptor (PRLR); and wherein the antibody or antigen binding fragment comprises an HCDR1 comprising SEQ ID NO: 292; an HCDR2 comprising SEQ ID NO: 294; an HCDR3 comprising SEQ ID NO: 296; an LCDR1 comprising SEQ ID NO: 300; an LCDR2 comprising SEQ ID NO: 302; and an LCDR3 comprising SEQ ID NO: 304, wherein the antibody concentration is between 2 to 3 mg/kg and
(b) fulvestrant, wherein the amount of fulvestrant is 150-250 mg/kg.
31. The method of claim 30 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 290 and a LCVR comprising SEQ ID NO: 298.
32. A method of treating PRLR positive breast cancer in a patient, the method comprising co-administering to a patient a therapeutically effective amount of:
(a) an antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof conjugated to DM1 through an MCC linker, wherein the antibody or antigen-binding fragment thereof binds to human prolactin receptor (PRLR), wherein the antibody or antigen binding fragment comprises three heavy chain complementarity determining regions (CDRs) within the heavy chain variable region (HCVR) amino acid sequence and three light chain complementarity determining regions within light chain variable region (LCVR) amino acid sequence of the HCVR/LCVR pair SEQ ID NOs: 290/298, wherein between 2 to 3 mg/kg of the ADC is administered and
(b) fulvestrant wherein the amount of fulvestrant is 150-250 mg/kg.
33. A method of treating PRLR positive breast cancer, the method comprising co-administering to a patient a therapeutically effective amount of:
(a) an antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof conjugated to DM1 through an MCC linker, wherein the antibody or antigen-binding fragment thereof binds to human prolactin receptor (PRLR); and wherein the antibody or antigen binding fragment comprises an HCDR1 comprising SEQ ID NO: 292; an HCDR2 comprising SEQ ID NO: 294; an HCDR3 comprising SEQ ID NO: 296; an LCDR1 comprising SEQ ID NO: 300; an LCDR2 comprising SEQ ID NO: 302; and an LCDR3 comprising SEQ ID NO: 304, wherein the antibody concentration is between 2 to 3 mg/kg and
(b) fulvestrant, wherein the amount of fulvestrant is 150-250 mg/kg.
34. The method of claim 33 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 290/298.