Humanized anti-tumor necrosis factor alpha receptor 2 (anti-TNFR2) antibodies and methods of use thereof to elicit an immune response against a tumor
The composition of anti-TNFR2 antibodies are provided, as well as methods of their preparation and use. This includes methods for treating disorders associated with TNF and/or TNFR2, such as cancer.
1. A pharmacological composition comprising a humanized anti-TNFα Receptor 2 (anti-TNFR2) antibody that blocks TNFα binding to TNFR2, and a pharmaceutically acceptable carrier, wherein the anti-TNFR2 antibody comprises a set of three heavy chain complementary determining regions (HCDRs) and three light chain complementary determining regions (LCDRs), wherein the set of three HCDRs and three LCDRs are selected from the group consisting of:
(a) SEQ ID NOs: 22-24 (HCDRs) and SEQ ID NOs: 25-27 (LCDRs); and
(b) SEQ ID NOs: 28-30 (HCDRs) and SEQ ID NOs: 31-33 (LCDRs).
2. The pharmacological composition of claim 1 , wherein said anti-TNFR2 antibody comprises a variable region heavy chain (V H ) comprising three heavy chain complementary determining regions (HCDRs) and a variable region light chain (V L ) comprising three light chain complementary determining regions (LCDRs), wherein the V H comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 66 or 68, and the three HCDRs have the amino acid sequences of SEQ ID NOs: 22-24 or SEQ ID NOs: 28-30; and the V L comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 67 or 69, and the three LCDRs have the amino acid sequences of SEQ ID NOs: 25-27 or SEQ ID NOs: 31-33.
3. The pharmacological composition of claim 1 , wherein said anti-TNFR2 antibody comprises a human IgG1 Fc domain.
4. The pharmacological composition of claim 3 , wherein said human IgG1 Fc domain is null for binding to an Fcγ receptor.
5. The pharmacological composition of claim 2 , wherein said anti-TNFR2 antibody comprises a variable region heavy chain (V H ) and a variable region light chain (V L ), wherein the V H comprises the amino acid sequence set forth in SEQ ID NO:66 and the V L comprises the amino acid sequence set forth in SEQ ID NO:67; the V H comprises the amino acid sequence set forth in SEQ ID NO:68 and the V L comprises the amino acid sequence set forth in SEQ ID NO:67; the V H comprises the amino acid sequence set forth in SEQ ID NO:66 and the V L comprises the amino acid sequence set forth in SEQ ID NO:69; or the V H comprises the amino acid sequence set forth in SEQ ID NO:68 and the V L comprises the amino acid sequence set forth in SEQ ID NO:69.
6. The pharmacological composition of claim 2 , wherein the V H comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 66 or 68.
7. The pharmacological composition of claim 2 , wherein the V H comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 66 or 68.
8. The pharmacological composition of claim 2 , wherein the V L comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 67 or 69.
9. The pharmacological composition of claim 2 , wherein the V L comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 67 or 69.
10. A humanized anti-TNFR2 antibody that blocks TNFα binding to TNFR2 and has a dissociation constant (Kd) for TNFR2 extracellular domain (ECD) ranging from 5 nM to 1.5 nM, wherein the anti-TNFR2 antibody comprises a set of three heavy chain complementary determining regions (HCDRs) and three light chain complementary determining regions (LCDRs), wherein the set of three HCDRs and three LCDRs are selected from the group consisting of:
(a) SEQ ID NOs: 22-24 (HCDRs) and SEQ ID NOs: 25-27 (LCDRs); and
(b) SEQ ID NOs: 28-30 (HCDRs) and SEQ ID NOs: 31-33 (LCDRs).
11. The humanized anti-TNFR2 antibody of claim 10 , wherein said anti-TNFR2 antibody comprises a variable region heavy chain (V H ) comprising three heavy chain complementary determining regions (HCDRs) and a variable region light chain (V L ) comprising three light chain complementary determining regions (LCDRs), wherein the V H comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 66 or 68, and the three HCDRs have the amino acid sequences of SEQ ID NOs: 22-24 or SEQ ID NOs: 28-30; and the V L comprises the amino acid sequence of at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 67 or 69, and the three LCDRs have the amino acid sequences of SEQ ID NOs: 25-27 or SEQ ID NOs: 31-33.
12. The humanized anti-TNFR2 antibody of claim 11 , wherein said anti-TNFR2 antibody comprises a variable region heavy chain (V H ) and a variable region light chain (V L ), wherein the V H comprises the amino acid sequence set forth in SEQ ID NO:66 and the V L comprises the amino acid sequence set forth in SEQ ID NO:67; the V H comprises the amino acid sequence set forth in SEQ ID NO:68 and the V L comprises the amino acid sequence set forth in SEQ ID NO:67; the V H comprises the amino acid sequence set forth in SEQ ID NO:66 and the V L comprises the amino acid sequence set forth in SEQ ID NO:69; or the V H comprises the amino acid sequence set forth in SEQ ID NO:68 and the V L comprises the amino acid sequence set forth in SEQ ID NO:69.
13. The humanized anti-TNFR2 antibody of claim 11 , wherein the V H comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 66 or 68.
14. The humanized anti-TNFR2 antibody of claim 11 , wherein the V H comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 66 or 68.
15. The humanized anti-TNFR2 antibody of claim 11 , wherein the V L comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 67 or 69.
16. The humanized anti-TNFR2 antibody of claim 11 , wherein the V L comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 67 or 69.
17. A method of eliciting an immune response against a tumor in a patient, comprising administering to the patient a pharmaceutical composition of claim 1 .