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US-20260124314-A1 - ANTl-5T4 ANTIGEN BINDING DOMAINS, ANTIBODY-DRUG CONJUGATES AND METHODS OF USE THEREOF

US20260124314A1US 20260124314 A1US20260124314 A1US 20260124314A1US-20260124314-A1

Abstract

The disclosure provides anti-5T4 antigen binding domains, which can be incorporated into antibodies and receptors, including bispecific anti-5T4 antibodies, biparatopic anti-5T4 antibodies, and antibody-drug conjugates of same comprising a first antigen binding domain that specifically binds to a first 5T4 epitope, a second antibody antigen binding domain that specifically binds to a second 5T4 epitope that is not the same as the first 5T4 epitope, wherein the first antigen binding domain is operably linked to the second antigen binding domain, and a chemotherapeutic agent. The disclosure further provides methods of using same for the treatment of cancer.

Inventors

  • Samuel L. MURPHY
  • Jonathan P. MCNALLY
  • Binyam Z. BEZABEH
  • John Li

Assignees

  • SALUBRIS BIOTHERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20250919

Claims (20)

  1. 1 . An antibody-drug conjugate, comprising: a. a first antigen binding domain that specifically binds to a first 5T4 epitope; b. a second antigen binding domain that specifically binds to a second 5T4 epitope that is not the same as the first 5T4 epitope; and c. a chemotherapeutic agent; wherein the first antigen binding domain is operably linked to the second antigen binding domain.
  2. 2 . The antibody-drug conjugate of claim 1 , wherein the first and second antigen binding domains are independently selected from the group consisting of a Fab fragment, a F(ab′) 2 fragment, a scFv, a scab, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody.
  3. 3 . The antibody-drug conjugate of claim 1 , comprising a full-length IgG antibody comprising the first antigen binding domain, and wherein the second antigen binding domain comprises a scFv.
  4. 4 . (canceled)
  5. 5 . The antibody-drug conjugate of claim 3 , wherein the full-length IgG antibody comprises two heavy chains and two light chains.
  6. 6 . The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate comprises two second antigen binding domain scFv that both specifically bind the second 5T4 epitope.
  7. 7 .- 8 . (canceled)
  8. 9 . The antibody-drug conjugate of claim 6 , wherein: (i) the N-terminus of the second antigen binding domain is operably linked to the C-terminus of a heavy chain of the full length IgG antibody comprising the first antigen binding domain, (ii) the C-terminus of the second antigen binding domain is operably linked to the N-terminus of a heavy chain of the full length IgG antibody, or (iii) the second antigen binding domain is operably linked to the heavy chain of the full length IgG antibody using a linker.
  9. 10 .- 12 . (canceled)
  10. 13 . The antibody-drug conjugate of claim 5 , wherein the full length IgG antibody heavy chains comprise a heavy chain variable region domain and a heavy chain constant region domain, and/or wherein the full length IgG antibody light chains comprise a light chain variable region domain and a light chain constant region domain.
  11. 14 .- 16 . (canceled)
  12. 17 . The antibody-drug conjugate of claim 13 , wherein the heavy chain constant region domain comprises at least one mutation that reduces effector function, extends half-life, or a combination thereof.
  13. 18 . The antibody-drug conjugate of claim 17 , wherein: (i) at least one mutation comprises an F at position 237 relative to SEQ ID NO: 100 (L234F), a C or A at position 242 relative to SEQ ID NO: 100 (S239C/A), an A at position 437 relative to SEQ ID NO: 100 (N434A), or a combination thereof, or (ii) at least one mutation comprises an F at position 237 relative to SEQ ID NO: 100 (L234F), a C or A at position 242 relative to SEQ ID NO: 100 (S239C/A), and an A at position 437 relative to SEQ ID NO: 100 (N434A).
  14. 19 . (canceled)
  15. 20 . The antibody-drug conjugate of claim 1 , comprising a full-length IgG antibody comprising the first antigen binding domain, and wherein the second antigen binding domain comprises an scFv, and the antibody-drug conjugate comprises four polypeptides comprising: (a) two polypeptides comprising, from N to C terminus, (i) the full-length IgG antibody heavy chain, a linker, and the second antigen binding domain, or (ii) the second antigen binding domain, a linker, and the full-length IgG antibody; and (b) two polypeptides comprising the full-length IgG antibody light chain.
  16. 21 .- 24 . (canceled)
  17. 25 . The antibody-drug conjugate of claim 1 , wherein the first antigen binding domain comprises a heavy chain variable region domain comprising: a. a HC CDR1 sequence comprising an amino acid sequence of SEQ ID NO: 1, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; b. a HC CDR2 sequence comprising an amino acid sequence of SEQ ID NO: 2, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; c. a HC CDR3 sequence comprising an amino acid sequence of SEQ ID NO: 3, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; and wherein the first antigen binding domain comprises a light chain variable region domain comprising: a. a LC CDR1 sequence comprising an amino acid sequence of SEQ ID NO: 7 or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; b. a LC CDR2 sequence comprising an amino acid sequence of SEQ ID NO: 8 or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; and c. a LC CDR3 sequence comprising an amino acid sequence of SEQ ID NO: 9 or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto.
  18. 26 . The antibody-drug conjugate of claim 1 , wherein the second antigen binding domain comprises a heavy chain variable region domain comprising: a. a HC CDR1 sequence comprising an amino acid sequence of SEQ ID NO: 4, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; b. a HC CDR2 sequence comprising an amino acid sequence of SEQ ID NO: 5, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; c. a HC CDR3 sequence comprising an amino acid sequence of SEQ ID NO: 6, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; and wherein the second antigen binding domain comprises a light chain variable region domain comprising: a. a LC CDR1 sequence comprising an amino acid sequence of SEQ ID NO: 10, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; b. a LC CDR2 sequence comprising an amino acid sequence of SEQ ID NO: 11, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto; and c. a LC CDR3 sequence comprising an amino acid sequence of SEQ ID NO: 12, or a sequence having 1, 2 or 3 substitutions, insertions or deletions relative thereto.
  19. 27 . (canceled)
  20. 28 . The antibody-drug conjugate of claim 1 , wherein the first and/or second antigen binding domain comprises a heavy chain variable region domain comprising an amino acid sequence of SEQ ID NO: 96 or 97, and a light chain variable region domain comprising an amino acid sequence of SEQ ID NO: 98 or 99.

Description

RELATED APPLICATIONS This application is a continuation of International Patent Application No. PCT/US2024/020929, filed on Mar. 21, 2024, which claims priority to, and the benefit of, U.S. Provisional Application No. 63/453,929, filed on Mar. 22, 2023, the contents of each of which are incorporated herein by reference in their entireties. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (SBTI-005_C01US_SeqList_ST26.xml; Size: 163,185 bytes in size; and Date of Creation: Sep. 8, 2025) are herein incorporated by reference in its entirety. BACKGROUND Cancer is one of the leading causes of death in the developed world. In the United States alone, an estimated 1.8 million people were newly diagnosed, and over 600,000 cancer deaths occurred in 2020. In cancer, cells of the subject grow and divide abnormally, spreading into surrounding tissues. Each cancer is thought to have combination of genetic changes, which may vary between cancers that allow cancer cells to escape the body's natural controls on cellular proliferation and allow the cancer to spread. While some cancers are currently treatable, many cancers are not. There exists a need in the art for compositions and methods for the treatment of cancer. Human 5T4 is manifested in a variety of cancer types, including bladder cancer, breast cancer, cervical cancer, endometrial cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer, and testicular cancer. Human 5T4 is not generally found in normal tissues, and where found it is expressed at low levels, making it an ideal therapeutic target for the treatment of cancer. The present disclosure provides antibodies and antibody-drug conjugates comprising chemotherapeutic agents that specifically bind to a first and in some cases a second 5T4 epitope, compositions comprising the same, and methods of making and using the same for the treatment of diseases such as cancer. SUMMARY The disclosure provides 5T4 antigen binding domains, as well as antibodies, antibody-drug conjugates, and receptors comprising same. The disclosure provides 5T4 biparatopic antibody-drug conjugates, comprising: (a) a first antigen binding domain that specifically binds to a first 5T4 epitope; (b) an antigen binding domain that specifically binds to a second 5T4 epitope that is not the same as the first 5T4 epitope; and (c) a chemotherapeutic agent; wherein the first antigen binding domain is operably linked to the second antigen binding domain. In some embodiments of the 5T4 biparatopic antibodies and antibody-drug conjugates described herein, the biparatopic antibody or antibody-drug conjugate comprises a full length IgG antibody comprising the first antigen binding domain, and the second antigen binding domain comprises an scFv. In some embodiments of the antibody-drug conjugates of the disclosure, the N-terminus of the second antigen binding domain is operably linked to the C-terminus of a heavy chain of the first antigen binding domain. In some embodiments, the C-terminus of the second antigen binding domain is operably linked to the N-terminus of a heavy chain of the first antigen binding domain. In some embodiments, the second antigen binding domain is operably linked to the heavy chain of the first antigen binding domain using a linker. In some embodiments, the antibody or antibody-drug conjugate comprises a full-length IgG antibody comprising the first antigen binding domain, and the second antigen binding domain comprises an scFv, and the antibody or antibody-drug conjugate comprises four polypeptides comprising: (a) two polypeptides comprising, from N to C terminus, the first antigen binding domain heavy chain, a linker, and the second antigen binding domain; and (b) two polypeptides comprising the first antigen binding domain light chain. In some embodiments, antibody or antibody-drug conjugate comprises a full-length IgG antibody comprising the first antigen binding domain and the second antigen binding domain comprises an scFv, and the antibody-drug conjugate comprises four polypeptides comprising: (a) two polypeptides comprising, from N to C terminus, the second antigen binding domain, a linker, and the first antigen binding domain heavy chain; and (b) two polypeptides comprising the first antigen binding domain light chain. In some embodiments, the chemotherapeutic agent is an auristatin, for example an auristatin selected from the group consisting of auristatin E (AE), monomethyl auristatin D (MMAD), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and synthetic analogs of dolastatin. The disclosure provides nucleic acid systems and vectors encoding the antigen binding domains, antibodies and receptors of the disclosure. The disclosure provides pharmaceutical compositions comprising the antigen binding domains, antibodies, antibody-drug conjugates, and immune cells comprising receptors of the disclosure. The disclosure provides pharmaceut