Antagonists targeting the TGF-β pathway
Antitumor antagonists that bind specifically to immune checkpoint regulators, angiogenesis pathway regulators and/or TGF pathway regulators are disclosed. Also disclosed are methods for treating proliferative disorders, infections, and immunological disorders with the antitumor antagonists described herein.
1. An antitumor antagonist comprising:
a first targeting domain comprising a mutated TGF-β1 RII extracellular domain (mutated ECD); and
an immunoglobulin scaffold having an amino terminus and a carboxy terminus,
wherein the mutated ECD comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 114-123 and 251-270, and
wherein the antitumor antagonist comprises an immunoglobulin heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 124-133, 145, 147, 148, 150 and 271-303.
2. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 126.
3. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 129.
4. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 130.
5. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 131.
6. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 132.
7. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 133.
8. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 145.
9. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 148.
10. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 279.
11. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 283.
12. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 290.
13. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 291.
14. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 295.
15. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 302.
16. The antitumor antagonist of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 303.
17. The antitumor antagonist of claim 3 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 93.
18. The antitumor antagonist of claim 4 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 93.
19. The antitumor antagonist of claim 5 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 93.
20. The antitumor antagonist of claim 6 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 93.
21. The antitumor antagonist of claim 7 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 93.
22. The antitumor antagonist of claim 10 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 93.
23. The antitumor antagonist of claim 12 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 93.
24. The antitumor antagonist of claim 13 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 103.
25. The antitumor antagonist of claim 15 , wherein the antitumor antagonist further comprises an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 103.
26. A method of treating a cell proliferative disorder in a subject, comprising:
administering to a subject in need thereof an effective amount of the antitumor antagonist of claim 1 .
27. An antitumor antagonist comprising:
a first targeting domain comprising a mutated TGF-β1 RII extracellular domain (mutated ECD); and
an immunoglobulin scaffold having an amino terminus and a carboxy terminus, wherein the mutated ECD comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 114-123 and 251-270,
wherein the antitumor antagonist comprises an immunoglobulin heavy chain paired to an immunoglobulin light chain, and
wherein the antitumor antagonist comprises:
(1) a heavy chain comprising the amino acid sequence of SEQ ID NO: 126 or SEQ ID NO: 283 and a light chain comprising the amino acid sequence of SEQ ID NO: 93;
(2) a heavy chain comprising the amino acid sequence of SEQ ID NO: 145 or SEQ ID NO: 303 and a light chain comprising the amino acid sequence of SEQ ID NO: 95; or
(3) a heavy chain comprising the amino acid sequence of SEQ ID NO: 148 or SEQ ID NO: 295 and a light chain comprising the amino acid sequence of SEQ ID NO: 103.
28. The antitumor antagonist of claim 27 , wherein the antitumor antagonist comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 126 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.
29. The antitumor antagonist of claim 27 , wherein the antitumor antagonist comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 283 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.
30. The antitumor antagonist of claim 27 , wherein the antitumor antagonist comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 145 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.
31. The antitumor antagonist of claim 27 , wherein the antitumor antagonist comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 303 and a light chain comprising the amino acid sequence of SEQ ID NO: 95.
32. The antitumor antagonist of claim 27 , wherein the antitumor antagonist comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 148 and a light chain comprising the amino acid sequence of SEQ ID NO: 103.
33. The antitumor antagonist of claim 27 , wherein the antitumor antagonist comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 295 and a light chain comprising the amino acid sequence of SEQ ID NO: 103.
34. A method of treating a cell proliferative disorder in a subject, comprising:
administering to a subject in need thereof an effective amount of the antitumor antagonist of claim 27 .