Prolactin receptor binding proteins and uses thereof
The present invention encompasses PRLR binding proteins. Specifically, the invention relates to antibodies that are chimeric, CDR grafted and humanized antibodies. Preferred antibodies have high affinity for hPRLR and neutralize hPRLR activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Methods of making and methods of using the antibodies of the invention are also provided. The antibodies, or antibody portions, of the invention are useful for detecting hPRLR and for inhibiting hPRLR activity, e.g., in a human subject suffering from a disorder in which hPRLR activity is detrimental. Also included in the invention are anti-PRLR antibody drug conjugates (ADCs).
1. A method for reducing human prolactin receptor (PRLR) activity in a human subject suffering from a cancer in which PRLR activity is detrimental, comprising administering an anti-PRLR antibody, or an antigen-binding fragment thereof, to the human subject, such that human PRLR activity in the human subject is reduced, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable domain comprising the amino acid sequences of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42; and comprises a light chain variable domain comprising the amino acid sequences of SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 51.
2. A method for treating a human subject having a cancer in which PRLR activity is detrimental, said method comprising administering an anti-PRLR antibody, or an antigen-binding fragment thereof, to the human subject such that treatment is achieved, wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable domain comprising the amino acid sequences of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42; and comprises a light chain variable domain comprising the amino acid sequences of SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 51.
3. The method according to claim 2 , wherein said antibody, or an antigen-binding fragment thereof, is administered to the subject by a mode selected from the group consisting of parenteral, subcutaneous, intramuscular intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.
4. The method of claim 2 , wherein the cancer is selected from the group consisting of melanoma, lymphoma, ovarian cancer, renal carcinoma, gastrointestinal cancer, colon cancer, lung cancer, and pancreatic cancer.
5. The method of claim 2 , wherein the cancer is breast cancer.
6. The method of claim 2 , wherein the cancer is prostate cancer.
7. The method of claim 2 , wherein the cancer is endometrial cancer.
8. The method of claim 2 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 0.1-20 mg/kg.
9. The method of claim 2 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 1-10 mg/kg.
10. The method of claim 1 , wherein the antibody, or antigen binding fragment thereof, comprises a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 52, and a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 44.
11. The method according to claim 1 , wherein said antibody, or an antigen-binding fragment thereof, is administered to the subject by a mode selected from the group consisting of parenteral, subcutaneous, intramuscular, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.
12. The method of claim 1 , wherein the cancer is selected from the group consisting of melanoma, lymphoma, ovarian cancer, renal carcinoma, gastrointestinal cancer, colon cancer, lung cancer, and pancreatic cancer.
13. The method of claim 1 , wherein the cancer is breast cancer.
14. The method of claim 1 , wherein the cancer is prostate cancer.
15. The method of claim 1 , wherein the cancer is endometrial cancer.
16. The method of claim 1 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 0.1-20 mg/kg.
17. The method of claim 1 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 1-10 mg/kg.
18. A method for treating a human subject having a cancer in which PRLR activity is detrimental comprising administering an anti-PRLR antibody, or antigen binding fragment thereof, to the human subject, wherein the antibody, or antigen binding fragment thereof, comprises a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 52, and a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 44.
19. The method of claim 18 , wherein the antibody, or antigen binding fragment thereof, comprises a light chain comprising the amino acid sequence of SEQ ID NO:126.
20. The method of claim 18 , wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:129.
21. The method of claim 20 , wherein the antibody, or antigen binding fragment thereof, comprises a light chain comprising the amino acid sequence of SEQ ID NO:126.
22. The method according to claim 18 , wherein said antibody, or an antigen-binding fragment thereof, is administered to the subject by a mode selected from the group consisting of parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.
23. The method of claim 18 , wherein the cancer is selected from the group consisting of melanoma, lymphoma, ovarian cancer, renal carcinoma, gastrointestinal cancer, colon cancer, lung cancer, and pancreatic cancer.
24. The method of claim 18 , wherein the cancer is breast cancer.
25. The method of claim 18 , wherein the cancer is prostate cancer.
26. The method of claim 18 , wherein the cancer is endometrial cancer.
27. The method of claim 18 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 0.1-20 mg/kg.
28. The method of claim 18 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 1-10 mg/kg.
29. A method for treating a human subject having a cancer in which PRLR activity is detrimental, said method comprising administering an anti-PRLR antibody, or antigen binding fragment thereof, to the human subject, wherein the antibody, or antigen binding fragment thereof, is an IgG antibody, comprises a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 52, and comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 44.
30. The method of claim 29 , wherein the antibody, or antigen binding fragment thereof, comprises a light chain comprising the amino acid sequence of SEQ ID NO:126.
31. The method of claim 29 , wherein the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:129.
32. The method of claim 31 , wherein the antibody, or antigen binding fragment thereof, comprises a light chain comprising the amino acid sequence of SEQ ID NO:126.
33. The method according to claim 29 , wherein said antibody, or an antigen-binding fragment thereof, is administered to the subject by a mode selected from the group consisting of parenteral, subcutaneous, intramuscular, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.
34. The method of claim 29 , wherein the cancer is breast cancer.
35. The method of claim 29 , wherein the cancer is selected from the group consisting of melanoma, lymphoma, ovarian cancer, renal carcinoma, gastrointestinal cancer, colon cancer, lung cancer, and pancreatic cancer.
36. The method of claim 29 , wherein the cancer is prostate cancer.
37. The method of claim 29 , wherein the cancer is endometrial cancer.
38. The method of claim 29 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 0.1-20 mg/kg.
39. The method of claim 29 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 1-10 mg/kg.
40. A method of inhibiting tumor growth in a human subject having a tumor, comprising administering an anti-PRLR antibody, or an antigen-binding fragment thereof, to the human subject, such that tumor growth is inhibited,
wherein the tumor expresses PRLR, and
wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable domain comprising the amino acid sequences of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42; and comprises a light chain variable domain comprising the amino acid sequences of SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 51.
41. The method of claim 40 , wherein the antibody, or antigen binding fragment thereof, comprises a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 52, and a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 44.
42. The method of claim 40 , wherein antibody, or antigen binding fragment thereof, is administered intravenously.
43. The method of claim 40 , wherein the tumor is a breast tumor.
44. The method of claim 40 , wherein the tumor is a prostate tumor.
45. The method of claim 40 , wherein the tumor is an endometrial tumor.
46. The method of claim 40 , wherein the antibody, or antigen binding fragment thereof, is administered to the subject at a dose of 0.1-20 mg/kg.
47. The method of claim 40 , wherein said antibody, or an antigen-binding fragment thereof, is intravenously administered to the subject.
48. The method of claim 1 , wherein said antibody, or an antigen-binding fragment thereof, is intravenously administered to the subject.
49. The method of claim 2 , wherein said antibody, or an antigen-binding fragment thereof, is intravenously administered to the subject.
50. The method of claim 29 , wherein said antibody, or an antigen-binding fragment thereof, is intravenously administered to the subject.