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EP-4735481-A2 - TRBC TARGETING ANTIBODY-DRUG CONJUGATES

EP4735481A2EP 4735481 A2EP4735481 A2EP 4735481A2EP-4735481-A2

Abstract

Provided herein are antibody-drug conjugates comprising (a) an antibody or antigen-binding fragment thereof that specifically binds to a T cell receptor β chain constant region (TRBC) polypeptide; and (b) a therapeutic agent conjugated to the antibody or antigen-binding fragment thereof.

Inventors

  • VOGELSTEIN, BERT
  • KINZLER, KENNETH W.
  • PAPADOPOULOS, NICKOLAS
  • ZHOU, SHIBIN
  • PAUL, Suman
  • NICHAKAWADE, Tushar
  • GE, JIAXIN

Assignees

  • The Johns Hopkins University

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. An antibody-drug conjugate comprising: (a) an antibody or antigen-binding fragment thereof that specifically binds to a T cell receptor p chain constant region (TRBC) polypeptide; and (b) a therapeutic agent conjugated to the antibody or antigen-binding fragment thereof.
  2. 2. The antibody-drug conjugate of claim 1, wherein the TRBC polypeptide comprises a TRBC1 polypeptide.
  3. 3. The antibody-drug conjugate of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises: (a) a light chain variable region sequence having at least 90% sequence identity to SEQ ID NO: 1; and (b) a heavy chain variable region sequence having at least 90% sequence identity to SEQ ID NO: 2.
  4. 4. The antibody-drug conjugate of claim 3, wherein the antibody or antigen-binding fragment thereof comprises: (a) a light chain variable region sequence comprising SEQ ID NO: 1; and (b) a heavy chain variable region sequence comprising SEQ ID NO: 2.
  5. 5. The antibody-drug conjugate of claim 1, wherein the TRBC polypeptide comprises a TRBC2 polypeptide.
  6. 6. The antibody-drug conjugate of claim 1 or 5, wherein the antibody or antigen-binding fragment thereof comprises: (a) a light chain variable region sequence having at least 90% sequence identity 7 to SEQ ID NO: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37; and (b) a heavy chain variable region sequence having at least 90% sequence identity to SEQ ID NO: 8. 10. 12. 14. 16. 18. 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38, respectively.
  7. 7. The antibody-drug conjugate of claim 6, wherein the antibody or antigen-binding fragment thereof comprises: (a) a light chain variable region sequence comprising SEQ ID NO: 7, 9, 1 1, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, or 37; and (b) a heavy chain variable region sequence comprising SEQ ID NO: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, or 38, respectively.
  8. 8. The antibody-drug conjugate of any one of claims 1-7, wherein the antigen -bin ding fragment thereof comprises a Fab, Fab’, F(ab’)2, Fab^SH, Fv, diabody, linear antibody or single-chain variable fragment (scFv).
  9. 9. The antibody-drug conjugate of any one of claims 1 -8, wherein a heavy chain of the antigen-binding fragment thereof comprises a human immunoglobulin G1 (IgGl) heavy chain.
  10. 10. The antibody-drug conjugate of any one of claims 1-9, wherein a light chain of the antigen-binding fragment thereof comprises a human kappa light chain.
  11. 11. The antibody-drug conjugate of any one of claims 1-10, wherein the antibody or antigen-binding fragment thereof is a humanized or chimeric antibody.
  12. 12. The antibody-drug conjugate of any one of claims 1-11, w herein the therapeutic agent comprises an anti-cancer agent.
  13. 13. The antibody-drug conjugate of claim 12, wherein the therapeutic agent comprises SG3199, MMAE, DM1, SN38, or Exatecan.
  14. 14. The antibody-drug conjugate of claim 13, wherein the therapeutic agent comprises SG3199 or MMAE.
  15. 15. The antibody-drug conjugate of any one of claims 1-14, wherein the therapeutic agent is conjugated to the antibody or antigen-binding fragment thereof via a linker.
  16. 16. The antibody-drug conjugate of claim 15, wherein the linker is a cleavable linker.
  17. 17. The antibody-drug conjugate of claim 16, wherein the linker comprises a cathepsin cleavable linker comprising a VA or VC protease sensitive site and self-immolative para-amino benzyloxy carbonyl (PAB) group.
  18. 18. A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1-17.
  19. 19. A method for treating a T-cell cancer in a subject, the method comprising administering to the subject the antibody-drug conjugate of any one of claims 1-17 or the pharmaceutical composition of claim 18.
  20. 20. The method of claim 19, wherein the T-cell cancer is a clonal T-cell cancer.

Description

TRBC TARGETING ANTIBODY-DRUG CONJUGATES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority’ to U.S. Provisional Patent Application No. 63/523,813, filed on June 28, 2023, which is incorporated herein by reference in its entirety. FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant numbers CA006973 and CA270403, awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named “44807-0458WOl_ST26_SL.XML.” The XML file, created on June 26, 2024, is 57,154 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD Described herein are antibody-drug conjugates, pharmaceutical compositions, and methods for targeting TRBC-1 and treating T-cell cancer. BACKGROUND T-cell leukemias and lymphomas, collectively known as T-cell cancers, affect -100,000 patients each year. Patients with relapsed T-cell cancers have a 5-year survival of only 7% to 38%, which is considerably worse than patients with B-cell cancers. The increased survival in B-cell cancers is in part due to the availability of novel antibody and CAR T-cell mediated therapies targeting pan B-cell antigens. Developing analogous therapeutics targeting T-cell cancers has been challenging. Normal and neoplastic T or B cells express similar antigens on the cell surface. Pan-B cell targeting is feasible as the resulting normal B cell aplasia is well- tolerated. Targeting pan-T cell antigens, however, is infeasible, as it results in severe immunosuppression. Thus, T-cell cancers require more specific targeting of the cancerous T cells. SUMMARY Provided herein are antibody-drug conjugates comprising: (a) an antibody or antigenbinding fragment thereof that specifically binds to a T cell receptor 0 chain constant region (TRBC) polypeptide; and (b) a therapeutic agent conjugated to the antibody or antigen-binding fragment thereof. In some embodiments, the TRBC polypeptide comprises a TRBC1 polypeptide. In some embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a light chain variable region sequence having at least 90% sequence identity to SEQ ID NO: 1 ; and (b) a heavy chain variable region sequence having at least 90% sequence identity to SEQ ID NO: 2. In some embodiments, the antibody or antigen-binding fragment thereof comprises: (a) a light chain variable region sequence comprising SEQ ID NO: 1; and (b) a heavy chain variable region sequence comprising SEQ ID NO: 2. In some embodiments, the antigenbinding fragment thereof comprises a Fab, Fab’, F(ab’)2, Fabl-SH, Fv, diabody, linear antibody or single-chain variable fragment (scFv). In some embodiments, a heavy chain of the antigen-binding fragment thereof comprises a human immunoglobulin G1 (IgGl ) heavy chain. In some embodiments, a light chain of the antigen-binding fragment thereof comprises a human kappa light chain. In some embodiments, the antibody or antigen-binding fragment thereof is a humanized or chimeric antibody. In some embodiments, the therapeutic agent comprises an anti-cancer agent. In some embodiments, the therapeutic agent comprises SG3199, MMAE, DM1. SN38, or Exatecan. In some embodiments, the therapeutic agent comprises SG3199 or MMAE. In some embodiments, the therapeutic agent is conjugated to the antibody or antigenbinding fragment thereof via a linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a cathepsin cleavable linker comprising the VA or VC dipeptide and the para-amino benzyloxy carbonyl (PAB) self-immolative spacer. Also provided herein are pharmaceutical compositions comprising a therapeutically effective amount of any one of the antibody-drug conjugates described herein. Also provided herein are methods for treating a T-cell cancer in a subject, the method comprising administering to the subject any one of the antibody-drug conjugates or any one of the pharmaceutical compositions described herein. In some embodiments, the T-cell cancer is a clonal T-cell cancer. In some embodiments, the T-cell cancer is a T-cell leukemia or lymphoma. In some embodiments, the subject is a human. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and n