Humanized monoclonal antibodies that target VE-PTP (HPTP-β)
The disclosure provides compositions and methods for the treatment of ocular conditions associated with angiogenesis comprising administering an antibody that targets a tyrosine phosphatase inhibitor in a subject.
1. An antibody comprising:
a heavy chain variable domain sequence that is any one of SEQ ID NOs: 9-12,
wherein the heavy chain variable domain sequence comprises complementarity-determining region (CDR) sequences that are SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56, wherein heavy chain CDR1 comprises SEQ ID NO: 54, heavy chain CDR2 comprises SEQ ID NO: 55, and heavy chain CDR3 comprises SEQ ID NO: 56,
wherein the heavy chain variable domain sequence is contained within a heavy chain sequence that is any one of SEQ ID NOs: 29-32; and
a light chain variable domain sequence that is any one of SEQ ID NOs: 20-23,
wherein the light chain variable domain sequence comprises CDR sequences that are SEQ ID NO: 57, SEQ ID NO: 58, and SEQ ID NO: 59, wherein light chain CDR1 comprises SEQ ID NO: 57, light chain CDR2 comprises SEQ ID NO: 58, and light chain CDR3 comprises SEQ ID NO: 59,
wherein the light chain variable domain sequence is contained within a light chain sequence that is any one of SEQ ID NOs: 34-37,
wherein the antibody binds to human protein tyrosine phosphatase-beta (HPTP-β).
2. The antibody of claim 1 , wherein the antibody binds an extracellular domain of HPTPβ.
3. The antibody of claim 1 , wherein a binding affinity (K D ) of the antibody to the extracellular domain of HPTP-β is about 70 pM to about 70 nM.
4. The antibody of claim 1 , wherein the antibody binds a first FN3 repeat of an extracellular domain of HPTP-β.
5. The antibody of claim 1 , wherein the antibody inhibits HPTP-β.
6. The antibody of claim 1 , wherein the antibody activates tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie-2).
7. The antibody of claim 1 , wherein the antibody activates Protein kinase B (Akt).
8. The antibody of claim 1 , wherein the antibody is humanized.
9. The antibody of claim 1 , wherein the heavy chain variable domain sequence is SEQ ID NO: 9.
10. The antibody of claim 1 , wherein the heavy chain variable domain sequence is SEQ ID NO: 10.
11. The antibody of claim 1 , wherein the heavy chain variable domain sequence is SEQ ID NO: 11.
12. The antibody of claim 1 , wherein the heavy chain variable domain sequence is SEQ ID NO: 12.
13. The antibody of claim 1 , wherein the light chain variable domain sequence is SEQ ID NO: 20.
14. The antibody of claim 1 , wherein the light chain variable domain sequence is SEQ ID NO: 21.
15. The antibody of claim 1 , wherein the light chain variable domain sequence is SEQ ID NO: 22.
16. The antibody of claim 1 , wherein the light chain variable domain sequence is SEQ ID NO: 23.
17. A pharmaceutical composition comprising a therapeutically effective amount of an antibody comprising:
a heavy chain variable domain sequence that is any one of SEQ ID NOs: 9-12,
wherein the heavy chain variable domain sequence comprises complementarity-determining region (CDR) sequences that are SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56, wherein heavy chain CDR1 comprises SEQ ID NO: 54, heavy chain CDR2 comprises SEQ ID NO: 55, and heavy chain CDR3 comprises SEQ ID NO: 56,
wherein the heavy chain variable domain sequence is contained within a heavy chain sequence that is any one of SEQ ID NOs: 29-32;
a light chain variable domain sequence that is any one of SEQ ID NOs: 20-23,
wherein the light chain variable domain sequence comprises CDR sequences that are SEQ ID NO: 57, SEQ ID NO: 58, and SEQ ID NO: 59, wherein light chain CDR1 comprises SEQ ID NO: 57, light chain CDR2 comprises SEQ ID NO: 58, and light chain CDR3 comprises SEQ ID NO: 59,
wherein the light chain variable domain sequence is contained within a light chain sequence that is any one of SEQ ID NOs: 34-37; and
a pharmaceutically acceptable carrier.
18. The composition of claim 17 , wherein the therapeutically effective amount of the antibody is from about 0.25 mg to about 200 mg.
19. The composition of claim 17 , wherein the therapeutically effective amount of the antibody is from about 1 mg/kg to about 10 mg/kg.
20. The composition of claim 17 , wherein the therapeutically effective amount of the antibody is from about 1 mg to about 50 mg.
21. The composition of claim 17 , wherein the therapeutically effective amount of the antibody is from about 50 mg to about 200 mg.
22. The composition of claim 17 , wherein the composition is formulated for intravitreal administration.
23. The composition of claim 17 , wherein the composition is formulated for intravenous administration.
24. The composition of claim 17 , wherein the composition is formulated for subcutaneous administration.
25. The composition of claim 17 , wherein the composition is formulated for topical administration.
26. The composition of claim 17 , wherein the heavy chain variable domain sequence is SEQ ID NO: 9.
27. The composition of claim 17 , wherein the heavy chain variable domain sequence is SEQ ID NO: 10.
28. The composition of claim 17 , wherein the heavy chain variable domain sequence is SEQ ID NO: 11.
29. The composition of claim 17 , wherein the heavy chain variable domain sequence is SEQ ID NO: 12.
30. The composition of claim 17 , wherein the light chain variable domain sequence is SEQ ID NO: 20.
31. The composition of claim 17 , wherein the light chain variable domain sequence is SEQ ID NO: 21.
32. The composition of claim 17 , wherein the light chain variable domain sequence is SEQ ID NO: 22.
33. The composition of claim 17 , wherein the light chain variable domain sequence is SEQ ID NO: 23.