Anti-EFNA4 antibody-drug conjugates
The present invention provides for anti-EFNA4 antibody-drug conjugates and methods for preparing and using the same.
1. A method of treating an EFNA-associated neoplastic disorder comprising administering a therapeutically effective amount of a composition comprising an antibody-drug conjugate of the formula Ab-(L-D) to a subject in need thereof, wherein:
(a) Ab is an antibody, or antigen-binding fragment thereof, that binds to EFNA4 and comprises a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 15, 19, and 23 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 29, 33, and 35; and
(b) L-D is a linker-drug moiety, wherein L is a linker and D is a drug, and wherein D is a calicheamicin or calicheamicin derivative.
2. The method of claim 1 , wherein the Ab comprises a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13 and a light chain variable having an amino acid sequence that is at least 90% identical to SEQ ID NO: 27.
3. The method of claim 2 , wherein the Ab comprises a heavy chain variable region set forth as SEQ ID NO: 13 and a light chain variable region set forth as SEQ ID NO: 27.
4. The method of claim 3 , wherein the Ab comprises a heavy chain set forth as SEQ ID NO: 25 and a light chain set forth as SEQ ID NO: 37.
5. The method of claim 1 , wherein the D is an N-acetyl derivative of calicheamicin.
6. The method of claim 5 , wherein the D is N-acetyl-γ-calicheamicin.
7. The method of claim 6 , wherein the D is N-acetyl-γ-calicheamicin dimethyl hydrazide (CM).
8. The method of claim 1 , wherein the linker L comprises 4-(4′acetylphenoxy)butanoic acid (AcBut).
9. The method of claim 1 , wherein the antibody-drug conjugate has a DAR from 1 to 12.
10. The method of claim 1 , wherein the neoplastic disorder comprises a solid tumor.
11. The method of claim 10 , wherein the neoplastic disorder is breast cancer, ovarian cancer, colorectal cancer, liver cancer, or lung cancer.
12. The method of claim 1 , wherein the neoplastic disorder comprises a hematologic malignancy.
13. The method of claim 12 , wherein the hematologic malignancy is leukemia.
14. A method of reducing the frequency of tumor initiating cells in a tumor cell population in vivo, the method comprising contacting a tumor cell population with an antibody-drug conjugate of the formula Ab-(L-D), wherein:
(a) Ab is an antibody, or antigen-binding fragment thereof, that binds to EFNA4 and comprises a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 15, 19, and 23 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 29, 33, and 35; and
(b) L-D is a linker-drug moiety, wherein L is a linker and D is a drug, and wherein D is a calicheamicin or calicheamicin derivative; and
whereby the frequency of tumor initiating cells in the tumor cell population is reduced.
15. The method of claim 14 , wherein the Ab comprises a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13 and a light chain variable having an amino acid sequence that is at least 90% identical to SEQ ID NO: 27.
16. The method of claim 15 , wherein the Ab comprises a heavy chain variable region set forth as SEQ ID NO: 13 and a light chain variable region set forth as SEQ ID NO: 27.
17. The method of claim 16 , wherein the Ab comprises a heavy chain set forth as SEQ ID NO: 25 and a light chain set forth as SEQ ID NO: 37.
18. The method of claim 14 , wherein the D is an N-acetyl derivative of calicheamicin.
19. The method of claim 18 , wherein the D is N-acetyl-γ-calicheamicin.
20. The method of claim 19 , wherein the D is N-acetyl-γ-calicheamicin dimethyl hydrazide (CM).
21. The method of claim 14 , wherein the linker L comprises 4-(4′acetylphenoxy)butanoic acid (AcBut).
22. The method of claim 14 , wherein the antibody-drug conjugate has a DAR from 1 to 12.
23. A method of treating an EFNA-associated ovarian cancer comprising administering a therapeutically effective amount of a composition comprising an antibody-drug conjugate of the formula Ab-(L-D) to a subject in need thereof, wherein: (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to EFNA4 and comprises a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 15, 19, and 23 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 29, 33, and 35; and (b) L-D is a linker-drug moiety, wherein L is a linker and D is a drug, and wherein D is a calicheamicin or calicheamicin derivative.
24. A method of treating an EFNA-associated breast cancer comprising administering a therapeutically effective amount of a composition comprising an antibody-drug conjugate of the formula Ab-(L-D) to a subject in need thereof, wherein: (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to EFNA4 and comprises a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 15, 19, and 23 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 29, 33, and 35; and (b) L-D is a linker-drug moiety, wherein L is a linker and D is a drug, and wherein D is a calicheamicin or calicheamicin derivative.
25. A method of treating an EFNA-associated lung cancer comprising administering a therapeutically effective amount of a composition comprising an antibody-drug conjugate of the formula Ab-(L-D) to a subject in need thereof, wherein: (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to EFNA4 and comprises a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 15, 19, and 23 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 29, 33, and 35; and (b) L-D is a linker-drug moiety, wherein L is a linker and D is a drug, and wherein D is a calicheamicin or calicheamicin derivative.