Antibodies specific for urokinase-type plasminogen activator and methods of treating cancer
View Patent ↗The present disclosure relates to antibodies specific for urokinase-type plasminogen activator (uPA). According to certain embodiments, the anti-uPA antibody specifically binds to the active form of uPA. In certain aspects, the anti-uPA antibody that specifically binds to active uPA binds specifically to the active form of human uPA (e.g., the antibody does not cross-react with active forms of uPA from non-human organisms). In certain aspects, an anti-uPA antibody of the present disclosure competes for specific binding to uPA with plasminogen activator inhibitor type 1 (PAI-1), where binding of the antibody to uPA results in internalization of a complex that includes the antibody, uPA, and urokinase-type plasminogen activator receptor (uPAR). Also provided are antibodies that specifically bind to uPA and compete for binding to uPA with a synthetic ligand of uPA. The disclosure also provides anti-uPA antibody conjugates and compositions (e.g., pharmaceutical formulations) comprising the antibodies and/or conjugates. Methods and kits related to the anti-uPA antibodies, conjugates, or formulations including the antibodies and/or conjugates are also provided.
1. A monoclonal antibody that competes for specific binding to urokinase-type plasminogen activator (uPA) with plasminogen activator inhibitor type 1 (PAI-1), wherein binding of the monoclonal antibody to uPA results in internalization of a complex comprising the antibody, uPA, and urokinase-type plasminogen activator receptor (uPAR).
2. The monoclonal antibody of claim 1 , wherein the monoclonal antibody competes for specific binding to uPA with an antibody comprising:
a heavy chain complementary determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO:1;
a heavy chain complementary determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO:2;
a heavy chain complementary determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO:3;
a light chain complementary determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO:4;
a light chain complementary determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO:5; and
a light chain complementary determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO:6.
3. The monoclonal antibody of claim 2 , wherein the monoclonal antibody comprises:
a heavy chain complementary determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO:1;
a heavy chain complementary determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO:2;
a heavy chain complementary determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO:3;
a light chain complementary determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO:4;
a light chain complementary determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO:5; and
a light chain complementary determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO:6.
4. The monoclonal antibody of claim 3 , wherein the monoclonal antibody comprises a heavy chain polypeptide comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO:7.
5. The monoclonal antibody of claim 3 , wherein the monoclonal antibody comprises a light chain polypeptide comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO:8.
6. The monoclonal antibody of claim 3 , wherein the monoclonal antibody comprises heavy and light chain polypeptides comprising variable regions comprising the amino acid sequences set forth in SEQ ID NO:7 and SEQ ID NO:8, respectively.
7. The monoclonal antibody of claim 1 , wherein the complex does not comprise PAI-1.
8. The monoclonal antibody of claim 1 , wherein the monoclonal antibody is selected from the group consisting of: an IgG, Fv, scFv, Fab, F(ab′)2, or Fab′.
9. A conjugate comprising:
a monoclonal antibody according to claim 1 ; and
an agent selected from the group consisting of: a therapeutic agent, and a labeling agent.
10. The conjugate of claim 9 , wherein the agent is a therapeutic agent.
11. The conjugate of claim 10 , wherein the therapeutic agent is a cytotoxic agent selected from the group consisting of: a radionuclide, a chemotherapeutic agent, and a toxin.
12. The conjugate of claim 9 , wherein the agent is a labeling agent.
13. The conjugate of claim 12 , wherein the labeling agent is an in vivo imaging agent.
14. A sterile pharmaceutical composition comprising:
a monoclonal antibody according to claim 1 ; and
a pharmaceutically acceptable carrier.
15. A method for treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a monoclonal antibody according to claim 1 .
16. The method of claim 15 , wherein the cancer is selected from the group consisting of: prostate cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, renal cancer, endometrial cancer, and ovarian cancer.
17. The method of claim 16 , wherein the cancer is castration-resistant prostate cancer (CRPC).
18. A monoclonal antibody that specifically binds to urokinase-type plasminogen activator (uPA) and competes for binding to uPA with a synthetic ligand of uPA.
19. The isolated antibody of claim 18 , wherein the synthetic ligand is a synthetic peptide ligand.
20. The monoclonal antibody of claim 18 , wherein the ligand is p-aminobenzamidine.
21. The monoclonal antibody of claim 18 , wherein the antibody competes for specific binding to urokinase-type plasminogen activator (uPA) with an antibody comprising:
a heavy chain complementary determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO:1;
a heavy chain complementary determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO:2;
a heavy chain complementary determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO:3;
a light chain complementary determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO:4;
a light chain complementary determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO:5; and
a light chain complementary determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO:6.
22. The monoclonal antibody of claim 21 , wherein the monoclonal antibody comprises:
a heavy chain complementary determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO:1;
a heavy chain complementary determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO:2;
a heavy chain complementary determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO:3;
a light chain complementary determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO:4;
a light chain complementary determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO:5; and
a light chain complementary determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO:6.
23. The monoclonal antibody of claim 22 , wherein the monoclonal antibody comprises a heavy chain polypeptide comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO:7.
24. The monoclonal antibody of claim 22 , wherein the monoclonal antibody comprises a light chain polypeptide comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO:8.
25. The monoclonal antibody of claim 22 , wherein the monoclonal antibody comprises heavy and light chain polypeptides comprising variable regions comprising the amino acid sequences set forth in SEQ ID NO:7 and SEQ ID NO:8, respectively.
26. The monoclonal antibody of claim 18 , wherein binding of the antibody to uPA results in internalization of a complex comprising the antibody, uPA, and urokinase-type plasminogen activator receptor (uPAR).
27. The monoclonal antibody of claim 18 , wherein the complex does not comprise PAI-1.
28. The monoclonal antibody of claim 18 , wherein the antibody is selected from the group consisting of: an IgG, Fv, scFv, Fab, F(ab′)2, or Fab′.
29. A conjugate comprising:
a monoclonal antibody according to claim 18 ; and
an agent selected from: a therapeutic agent, and a labeling agent.
30. The conjugate of claim 29 , wherein the agent is a therapeutic agent.
31. The conjugate of claim 30 , wherein the therapeutic agent is a cytotoxic agent selected from the group consisting of: a radionuclide, a chemotherapeutic agent, and a toxin.
32. The conjugate of claim 29 , wherein the agent is a labeling agent.
33. The conjugate of claim 32 , wherein the labeling agent is an in vivo imaging agent.
34. A sterile pharmaceutical composition comprising:
a monoclonal antibody according to claim 18 ; and
a pharmaceutically acceptable carrier.
35. A method for treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a monoclonal antibody according to claim 18 .
36. The method of claim 35 , wherein the cancer is selected from the group consisting of: prostate cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, renal cancer, endometrial cancer, and ovarian cancer.
37. The method of claim 36 , wherein the cancer is castration-resistant prostate cancer (CRPC).
38. A monoclonal antibody that specifically binds to urokinase-type plasminogen activator (uPA) and competes for binding to uPA with an antibody comprising:
a heavy chain complementary determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO:1;
a heavy chain complementary determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO:2;
a heavy chain complementary determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO:3;
a light chain complementary determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO:4;
a light chain complementary determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO:5; and
a light chain complementary determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO:6.
39. The monoclonal antibody of claim 38 , wherein the monoclonal antibody comprises:
a heavy chain complementary determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO:1;
a heavy chain complementary determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO:2;
a heavy chain complementary determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO:3;
a light chain complementary determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO:4;
a light chain complementary determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO:5; and
a light chain complementary determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO:6.
40. The monoclonal antibody of claim 38 , wherein the monoclonal antibody comprises a heavy chain polypeptide comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO:7.
41. The monoclonal antibody of claim 38 , wherein the monoclonal antibody comprises a light chain polypeptide comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO:8.
42. The monoclonal antibody of claim 38 , wherein the monoclonal antibody comprises heavy and light chain polypeptides comprising variable regions comprising the amino acid sequences set forth in SEQ ID NO:7 and SEQ ID NO:8, respectively.
43. The monoclonal antibody of claim 38 , wherein the antibody is selected from the group consisting of: an IgG, Fv, scFv, Fab, F(ab′)2, or Fab′.
44. A conjugate comprising:
a monoclonal antibody according to claim 38 ; and
an agent selected from the group consisting of: a therapeutic agent, and a labeling agent.
45. The conjugate of claim 44 , wherein the agent is a therapeutic agent.
46. The conjugate of claim 45 , wherein the therapeutic agent is a cytotoxic agent selected from the group consisting of: a radionuclide, a chemotherapeutic agent, and a toxin.
47. The conjugate of claim 44 , wherein the agent is a labeling agent.
48. The conjugate of claim 47 , wherein the labeling agent is an in vivo imaging agent.
49. A sterile pharmaceutical composition comprising:
a monoclonal antibody according to claim 38 ; and
a pharmaceutically acceptable carrier.
50. A method for treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a monoclonal antibody according to claim 38 .
51. The method of claim 50 , wherein the cancer is selected from the group consisting of: prostate cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, renal cancer, endometrial cancer, and ovarian cancer.
52. The method of claim 51 , wherein the cancer is castration-resistant prostate cancer (CRPC).