Anti-AP2 antibodies and antigen binding agents to treat metabolic disorders
This invention is in the area of improved anti-aP2 antibodies and antigen binding agents, and compositions thereof, which target the lipid chaperone aP2/FABP4 (referred to as “aP2”) for use in treating disorders such as diabetes, obesity, cardiovascular disease, fatty liver disease, and/or cancer, among others. In one aspect, improved treatments for aP2 mediated disorders are disclosed in which serum aP2 is targeted and the biological activity of aP2 is neutralized or modulated using low-binding affinity aP2 monoclonal antibodies, providing lower fasting blood glucose levels, improved systemic glucose metabolism, increased systemic insulin sensitivity, reduced fat mass, reduced liver steatosis, reduced cardiovascular disease and/or a reduced risk of developing cardiovascular disease.
1. A method of attenuating an adipocyte protein 2 (aP2-mediated disorder in a human comprising administering an effective amount of a humanized anti-aP2 monoclonal antibody or antigen binding agent comprising:
(a) a light chain variable region comprising:
(i) a CDR-L1 complementarity determining region (CDR) comprising the amino acid sequence of Seq. ID No. 7;
(ii) a CDR-L2 CDR comprising the amino acid sequence of Seq. ID No. 8; and
(iii) a CDR-L3 CDR comprising an amino acid sequence selected from the group consisting of Seq. ID No. 9, Seq. ID No. 10, Seq. ID No. 11, and Seq. ID No. 12; and
(b) a heavy chain variable region comprising:
(i) a CDR-H1 CDR comprising the amino acid sequence of Seq. ID No. 14;
(ii) a CDR-H2 CDR comprising an amino acid sequence selected from the group consisting of Seq. ID No. 16 and Seq. ID No. 17; and
(iii) a CDR-H3 CDR comprising an amino acid sequence selected from the group consisting of Seq. ID No. 19 and Seq. ID No. 20;
wherein the aP2-mediated disorder is selected from the group consisting of Type I diabetes, Type II diabetes, hyperglycemia, obesity, fatty liver disease, dyslipidemia, and atherosclerosis.
2. The method of claim 1 , wherein the aP2-mediated disorder is Type I diabetes.
3. The method of claim 1 , wherein the aP2-mediated disorder is Type II diabetes.
4. The method of claim 1 , wherein the aP2-mediated disorder is hyperglycemia.
5. The method of claim 1 , wherein the aP2-mediated disorder is obesity.
6. The method of claim 1 , wherein the aP2-mediated disorder is fatty liver disease.
7. The method of claim 1 , wherein the aP2-mediated disorder is dyslipidemia.
8. The method of claim 1 , wherein the aP2-mediated disorder is atherosclerosis.
9. The method of claim 1 , wherein the CDR-L3 CDR comprises the amino acid sequence of Seq. ID No. 9.
10. The method of claim 1 , wherein the CDR-L3 CDR comprises the amino acid sequence of Seq. ID No. 10.
11. The method of claim 1 , wherein the CDR-L3 CDR comprises the amino acid sequence of Seq. ID. No. 11.
12. The method of claim 1 , herein the CDR-L3 CDR comprises the amino acid sequence of Seq. ID No. 12.
13. The method of claim 1 , wherein the CDR-H2 CDR comprises the amino acid sequence of Seq. ID No. 16.
14. The method of claim 1 , wherein the CDR-H2 CDR comprises the amino acid sequence of Seq. ID No. 17.
15. The method of claim 1 , wherein the CDR-H3 CDR comprises the amino acid sequence of Seq. ID No. 19.
16. The method of claim 1 , wherein the CDR-H3 CDR comprises the amino acid sequence of Seq. ID No. 20.
17. The method of claim 1 , wherein the CDR-H1 CDR comprises the amino acid sequence of Seq. ID No. 14, the CDR-H2 CDR comprises the amino acid sequence of Seq. ID No. 16, and the CDR-H3 CDR comprises the amino acid sequence of Seq. ID No. 19.
18. The method of claim 1 , wherein the CDR-H1 CDR comprises the amino acid sequence of Seq. ID No. 14, the CDR-H2 CDR comprises the amino acid sequence of Seq. ID No. 17, and the CDR-H3 CDR comprises the amino acid sequence of Seq. ID No. 19.
19. The method of claim 1 , wherein the CDR-H1 CDR comprises the amino acid sequence of Seq. ID No. 14, the CDR-H2 CDR comprises the amino acid sequence of Seq. ID No. 16, and the CDR-H3 CDR comprises the amino acid sequence of Seq. ID No. 20.
20. The method of claim 1 , wherein the CDR-H1 CDR comprises the amino acid sequence of Seq. ID No. 14, the CDR-H2 CDR comprises the amino acid sequence of Seq. ID No. 17, and the CDR-H3 CDR comprises the amino acid sequence of Seq. ID No. 20.
21. A method of attenuating an adipocyte protein 2 (aP2)-mediated disorder in a human comprising administering an effective amount of a humanized anti-aP2 monoclonal antibody or antigen binding agent comprising:
(a) a light chain variable region comprising an amino acid sequence selected from the group consisting of Seq. ID No. 446, Seq. ID No. 448, Seq. ID No. 487, Seq. ID No. 488, Seq. ID No. 450, and Seq. ID No. 452; and
(b) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of Seq. ID No. 455, Seq. ID No. 457, Seq. ID No. 459, Seq. ID No. 461, and Seq. ID No. 463;
wherein the aP2-mediated disorder is selected from the group consisting of Type I diabetes, Type II diabetes, hyperglycemia, obesity, fatty liver disease, dyslipidemia, and atherosclerosis.
22. The method of claim 21 , wherein the aP2-mediated disorder is Type I diabetes.
23. The method of claim 21 , wherein the aP2-mediated disorder is Type II diabetes.
24. The method of claim 21 , wherein the aP2-mediated disorder is hyperglycemia.
25. The method of claim 21 , wherein the aP2-mediated disorder is obesity.
26. The method of claim 21 , wherein the aP2-mediated disorder is fatty liver disease.
27. The method of claim 21 , wherein the aP2-mediated disorder is dyslipidemia.
28. The method of claim 21 , wherein the aP2-mediated disorder is atherosclerosis.
29. The method of claim 21 , wherein the light chain variable region comprises the amino acid sequence of Seq. ID No. 446.
30. The method of claim 21 , wherein the heavy chain variable region comprises the amino acid sequence of Seq. ID No. 455.
31. The method of claim 29 , wherein the heavy chain variable region comprises the amino acid sequence of Seq. ID No. 455.
32. The method of claim 21 , wherein the heavy chain variable region comprises the amino acid sequence of Seq. ID No. 461.
33. The method of claim 29 , wherein the heavy chain variable region comprises the amino acid sequence of Seq. ID No. 461.
34. The method of claim 21 , wherein the heavy chain variable region comprises the amino acid sequence of Seq. ID No. 463.
35. The method of claim 29 , wherein the heavy chain variable region comprises the amino acid sequence of Seq. ID No. 463.