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US-20260125474-A1 - Anti-CTLA-4 Binding Proteins and Methods of Use Thereof

US20260125474A1US 20260125474 A1US20260125474 A1US 20260125474A1US-20260125474-A1

Abstract

Provided herein are antigen-binding proteins (ABPs) that selectively bind to CTLA-4 and its isoforms and homologs, and compositions comprising the ABPs. Also provided are methods of using the ABPs, such as therapeutic and diagnostic methods.

Inventors

  • David Scott Johnson
  • Adam Shultz Adler
  • Rena Aviva Mizrahi
  • Yoong Wearn Lim
  • Michael Asensio
  • ERICA LYN STONE

Assignees

  • GIGAGEN, INC.

Dates

Publication Date
20260507
Application Date
20250827

Claims (20)

  1. 1 . An isolated antigen binding protein (ABP) that specifically binds a human cytotoxic T-lymphocyte associated protein 4 (CTLA-4), comprising a CDR1-L, a CDR2-L, a CDR3-L, a CDR1-H, a CDR2-H and a CDR3-H, wherein: the CDR1-L consists of SEQ ID NO: 1002, the CDR2-L consists of SEQ ID NO: 2002, the CDR3-L consists of SEQ ID NO: 3002, the CDR1-H consists of SEQ ID NO: 4002, the CDR2-H consists of SEQ ID NO: 5002, and the CDR3-H consists of SEQ ID NO: 6002.
  2. 2 . (canceled)
  3. 3 . (canceled)
  4. 4 . (canceled)
  5. 5 . The ABP of claim 1 , comprising a variable light chain (V L ) comprising a sequence at least 97% identical to a sequence of SEQ ID NO: 2 and a variable heavy chain (V H ) comprising a sequence at least 97% identical to a sequence of SEQ ID NO: 102.
  6. 6 . (canceled)
  7. 7 . The ABP of claim 1 , comprising a variable light chain (V L ) comprising a sequence of SEO ID NO: 2 and a variable heavy chain (V H ) comprising a sequence of SEO ID NO: 102.
  8. 8 . (canceled)
  9. 9 . The ABP of claim 1 , wherein the ABP comprises an scFv or a full length monoclonal antibody.
  10. 10 . The ABP of claim 1 , wherein the ABP comprises an immunoglobulin constant region.
  11. 11 . The ABP of claim 1 , wherein the ABP binds human CTLA-4 with a K D of less than 500 nM, or with a K D of less than 200 nM, or with a K D of less than 25 nM as measured by surface plasmon resonance or wherein the ABP binds to human CTLA-4 on a cell surface with a K D of less than 25 nM.
  12. 12 . (canceled)
  13. 13 . (canceled)
  14. 14 . (canceled)
  15. 15 . A pharmaceutical composition comprising the ABP of claim 1 and an excipient.
  16. 16 . A method of treating cancer in a subject, the method comprising: administering to the subject in need thereof an effective amount of the ABP of claim 1 .
  17. 17 . (canceled)
  18. 18 . The method of claim 16 , further comprising the step of administering one or more additional therapeutic agents to the subject.
  19. 19 . The method of claim 18 , wherein the additional therapeutic agent is selected from CTLA-4 inhibitor, TIGIT inhibitor, a chemotherapy agent, an immune-stimulatory agent, radiation, a cytokine, a polynucleotide encoding a cytokine and a combination thereof.
  20. 20 . An isolated polynucleotide encoding the ABP of claim 1 .

Description

1. CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. application Ser. No. 17/418,776, filed Jun. 25, 2021, which is the National Stage of International Application No PCT/US2019/068820, filed Dec. 27, 2019, which claims priority to and the benefit of U.S. Provisional Patent Application No. 62/785,659, filed on Dec. 27, 2018, the entire contents of which are incorporated by reference herein. 2. SEQUENCE LISTING The instant application contains a Sequence Listing with 11998 sequences which has been submitted via Patent Center and is hereby incorporated by reference in its entirety. Said XML copy, created on Aug. 27, 2025, is named64214US_CRF_sequencelisting.xml, and is 6,261,602 bytes in size. 3. FIELD Provided herein are antigen-binding proteins (ABPs) with binding specificity for CTLA-4 and compositions comprising such ABPs, including pharmaceutical compositions, diagnostic compositions, and kits. Also provided are methods of making CTLA-4 ABPs, and methods of using CTLA-4 ABPs, for example, for therapeutic purposes, diagnostic purposes, and research purposes. 4. BACKGROUND CTLA-4, also known as cytotoxic T-lymphocyte associated protein 4 and CD152 (cluster of differentiation 152), is a cell surface receptor that suppresses T cell inflammatory activity. CTLA-4 is constitutively expressed by regulatory T cells (Tregs) and upregulated in stimulated T cells. CD80 and CD86, also expressed in antigen presenting cells (APCs) such as dendritic cells (DCs), are the primary ligands of CTLA-4. The interaction between CTLA-4 and its ligands is vitally important for downregulating the immune responses and promoting self-tolerance by suppressing T cell inflammatory activity. This activity prevents autoimmune diseases, as well as prevents the immune system from killing cancer cells. CTLA-4 is a member of the immunoglobulin superfamily that is expressed by activated T cells and transmits an inhibitory signal to T cells. CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands. CTLA-4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. CTLA-4 is also found in regulatory T cells (Tregs) and contributes to their inhibitory function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4. The mechanism by which CTLA-4 acts in T cells remains somewhat controversial. Biochemical evidence suggested that CTLA-4 recruits a phosphatase to the T cell receptor (TCR), thus attenuating the signal. This work remains unconfirmed in the literature since its first publication. More recent work has suggested that CTLA-4 may function in vivo by capturing and removing B7-1 and B7-2 from the membranes of antigen-presenting cells, thus making these unavailable for triggering of CD28. Variants in CTLA-4 have been associated with insulin-dependent diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, primary biliary cirrhosis and other autoimmune diseases. The comparatively high binding affinity of CTLA-4 for CD80 and CD86 has made it a potential therapy for autoimmune diseases. Soluble fusion proteins of CTLA-4 and antibodies (CTLA-4-Ig) have been used in clinical trials for rheumatoid arthritis. Tumor cells suppress anti-tumor immune response through various mechanisms, including up-regulation of Tregs. Recently, CTLA-4 inhibitors have been shown to antagonize binding of CTLA-4 to its ligands, thereby activating the immune system to attack tumors. CTLA-4 antibodies have also been used to induce antibody-dependent cell-mediated cytotoxicity (ADCC) of Tregs specific to the tumor microenvironment, thus reducing immune tolerance to the tumor. CTLA-4 antibodies have been therefore used with varying success to treat some types of cancer. Thus, there is a need for developing CTLA-4 ABPs that can be used for treatment, diagnosis, and research of various diseases, including cancer and autoimmune disease. 5. SUMMARY Provided herein are novel ABPs with binding specificity for CTLA-4 and methods of using such ABPs. The CTLA-4 is a human CTLA-4 (SEQ ID: 7001) or a fragment of the human CTLA-4. The ABP can comprise an antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the ABP comprises an antibody fragment. In some embodiments, the ABP comprises an alternative scaffold. In some embodiments, the ABPs comprises a single-chain variable fragment (scFv). The ABPs provided herein can induce various biological effects associated with inhibition or activation of CTLA-4. In some embodiments, an ABP provided herein prevents binding between CTLA-4 and its ligands. In some embodiments, an ABP provided herein