Trispecific antagonists
Antitumor antagonists that bind specifically to immune checkpoint regulator and/or components of the angiogenesis pathways and/or components of the TGF pathway are disclosed. Also disclosed is a method of treating proliferative disorders with the antitumor antagonists.
1. A bispecific antibody, comprising:
a protein scaffold comprising an Fc fragment, wherein the Fc fragment comprises a CH3 domain;
a first targeting domain comprising a VEGFR component, wherein the first targeting domain comprises the amino acid sequence of SEQ ID NO:185 or 207; and
a second targeting domain comprising a peptide inhibitor of angiopoietin/Tie-2 signaling pathway, wherein the second targeting domain comprises the amino acid sequence selected from the group consisting of SEQ ID NOS:182, 184, 194, 195 and 196, and wherein the second targeting domain is inserted within the CH3 domain of the Fc fragment.
2. The bispecific antibody of claim 1 , wherein the Fe fragment comprises the amino acid sequence selected from the group consisting of SEQ ID NOS:210-217.
3. The bispecific antibody of claim 1 , wherein the first targeting domain comprises the amino acid sequence of SEQ ID NO:185.
4. The bispecific antitumor antagonist of claim 1 , wherein the first targeting domain comprises the amino acid sequence of SEQ ID NO:207.
5. The bispecific antibody of claim 1 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:182.
6. The bispecific antibody of claim 1 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:194.
7. The bispecific antibody of claim 1 , wherein the second targeting domain Currently Amended comprises the amino acid sequence of SEQ ID NO:184.
8. The bispecific antibody of claim 1 , wherein the Fe fragment comprises two CH3 domains and wherein the second targeting domain is incorporated within each of the two CH3 domains of the Fc fragment.
9. A bispecific antibody, comprising:
a protein scaffold comprising an Fc fragment, wherein the Fc fragment comprises a CH3 domain;
a first targeting domain comprising the amino acid sequence of SEQ ID NO:226 or 228; and
a second targeting domain comprising a peptide inhibitor of angiopoietin/Tie-2 signaling pathway, wherein the second targeting domain comprises the amino acid sequence selected from the group consisting of SEQ ID NOS:182, 184, 194, 195 and 196, and wherein the second targeting domain is inserted within the CH3 domain of the Fc fragment.
10. The bispecific antibody of claim 9 , wherein the Fc fragment comprises the amino acid sequence selected from the group consisting of SEQ ID NOS:210-217.
11. The bispecific antibody of claim 9 , wherein the first targeting domain comprises the amino acid sequence of SEQ ID NO:226.
12. The bispecific antibody of claim 9 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:182.
13. The bispecific antibody of claim 9 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:184.
14. The bispecific antibody of claim 9 , wherein the second targeting domain is incorporated within each of the two CH3 regions in the Fc fragment.
15. The bispecific antibody of claim 1 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:195.
16. The bispecific antibody of claim 1 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:196.
17. The bispecific antibody of claim 9 , wherein the first targeting domain comprises the amino acid sequence of SEQ ID NO:228.
18. The bispecific antibody of claim 9 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:194.
19. The bispecific antibody of claim 9 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:195.
20. The bispecific antibody of claim 9 , wherein the second targeting domain comprises the amino acid sequence of SEQ ID NO:196.