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US-20260125475-A1 - ANTI-CTLA4 ANTIBODIES AND METHODS OF USE THEREOF

US20260125475A1US 20260125475 A1US20260125475 A1US 20260125475A1US-20260125475-A1

Abstract

The invention provides anti-CTLA4 binding proteins (e.g., antibodies, bispecifc antibodies, and chimeric receptors) and their use in treating and preventing cancer, as well as compositions and kits comprising the anti-CTLA4 binding proteins.

Inventors

  • Margaret Karow

Assignees

  • Xilio Development, Inc.

Dates

Publication Date
20260507
Application Date
20250908

Claims (20)

  1. 1 - 54 . (canceled)
  2. 55 . A method of treating a cancer in a subject, the method comprising administering to the subject an effective amount of an anti-CTLA4 antibody, wherein the anti-CTLA4 antibody comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 21; and the VH domain comprises (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 24, and wherein the antibody comprises a heavy chain constant region (CH) comprising substitutions S239D and I332E, wherein the amino acid residues are numbered according to EU index as in Kabat.
  3. 56 . The method of claim 55 , wherein the VL domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 30 and the VH domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 31.
  4. 57 . The method of claim 55 , wherein the VL domain comprises an amino acid sequence identical to SEQ ID NO: 30 and the VH domain comprises an amino acid sequence to SEQ ID NO: 31.
  5. 58 . The method of claim 55 , wherein the anti-CTLA4 antibody comprises the CH sequence of SEQ ID NO: 38.
  6. 59 . The method of claim 55 , wherein the anti-CTLA4 antibody comprises a light chain constant region (CL) comprising an amino acid sequence of SEQ ID NO: 39.
  7. 60 . The method of claim 55 , wherein the light chain comprises the amino acid sequence of SEQ ID NO: 32, and the heavy chain comprises the amino acid sequence of SEQ ID NO: 34.
  8. 61 . The method of claim 55 , wherein the anti-CTLA4 antibody is afucosylated or fucose-deficient.
  9. 62 . The method of claim 55 , wherein the administration of the anti-CTLA4 antibody is subcutaneous administration, intraperitoneal administration, intramuscular administration, intravenous administration, intraarterial administration, intralesional administration, or intraarticular administration.
  10. 63 . The method of claim 62 , wherein the administration of the anti-CTLA4 antibody is intraperitoneal administration.
  11. 64 . The method of claim 55 , wherein the cancer is leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma, lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer or testicular cancer.
  12. 65 . The method of claim 55 , wherein the effective amount is 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg.
  13. 66 . The method of claim 65 , wherein the effective amount is 0.3 mg/kg.
  14. 67 . The method of claim 65 , wherein the effective amount is 3 mg/kg.
  15. 68 . A method of inhibiting tumor growth in a subject comprising administering to the subject an effective amount of an anti-CTLA4 antibody, wherein the anti-CTLA4 antibody comprises a light chain variable (VL) region and a heavy chain variable (VH) domain, wherein the VL domain comprises (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 21; and the VH domain comprises (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 24, and wherein the antibody comprises a heavy chain constant region (CH) comprising substitutions S239D and I332E, wherein the amino acid residues are numbered according to EU index as in Kabat.
  16. 69 . The method according to claim 68 , wherein the VL domain comprises an amino acid sequence identical to SEQ ID NO: 30 and the VH domain comprises an amino acid sequence to SEQ ID NO: 31.
  17. 70 . The method according to claim 68 , wherein the anti-CTLA4 antibody comprises a CH domain comprising the sequence of SEQ ID NO: 38 and a CL sequence comprising the sequence of SEQ ID NO: 39.
  18. 71 . The method according to claim 68 , wherein the effective amount is 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg.
  19. 72 . The method according to claim 71 , wherein the effective amount is 0.3 mg/kg.
  20. 73 . The method according to claim 71 , wherein the effective amount is 3 mg/kg.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. patent application Ser. No. 17/417,244, filed on Jun. 22, 2021, which is a 35 U.S.C. § 371 National Stage Application of International Patent Application No. PCT/US2019/068548, filed on Dec. 26, 2019, which claims priority from U.S. provisional application 62/785,111, filed Dec. 26, 2018, the content of which is incorporated by reference in their entireties. INCORPORATION OF SEQUENCE LISTING The instant application contains a Sequence Listing, which has been submitted electronically in XML file format and is incorporated by reference in its entirety. Said XML file, created on Sep. 3, 2025, is named XTX_CTLA4_03US2.xml and is 51,570 bytes in size. FIELD OF THE INVENTION This invention relates to anti-cytotoxic T-lymphocyte-associated protein 4(CTLA4) binding proteins (e.g., anti-CTLA4 antibodies) and methods related to use of the same. BACKGROUND OF THE INVENTION Cancer is the second leading cause of death in the United States, accounting for more deaths than the next five leading causes (chronic respiratory disease, stroke, accidents, Alzheimer's disease and diabetes). While great strides have been made especially with targeted therapies, there remains a great deal of work to do in this space. Immunotherapy and a branch of this field, immuno-oncology, is creating viable and exciting therapeutic options for treating malignancies. Specifically, it is now recognized that one hallmark of cancer is immune evasion and significant efforts have identified targets and developed therapies to these targets to reactivate the immune system to recognize and treat cancer. In fact, the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody, ipilimumab, has led to long-term survival of patients suffering from stage III/IV malignant melanoma. Ipilimumab is an immune checkpoint antagonist that interrupts the inhibition of T cells by blocking CTLA4, and may lead to the depletion of T Regulatory cells (Treg) (Korman, A., et al., 2005. Tumor immunotherapy: preclinical and clinical activity of anti-CTLA4 antibodies. Current Opinion in Investigational Drugs 6:582-591; Quezada et al., J. Exp. Med., 206(8):1717-1725, 2009; Selby et al. Cancer Immunol Res., 1(1); 32-42, 2013. Unfortunately, ipilimumab causes generalized (not tumor-specific) activation of T-cell dependent immune responses that leads to immune-related adverse effects which can be life-threatening and are often dose and treatment duration-limiting (Weber, J. S., et al., 2008. Phase I/II study of ipilimumab for patients with metastatic melanoma. Journal of Clinical Oncology 26:5950-5956). These include enterocolitis, dermatitis, hypophysitis, uveitis, hepatitis, nephritis and death. Enterocolitis is the most common major toxicity (affecting approximately 20% of patients). The severe safety risks related to immune-mediated adverse reactions prompted the FDA to approve ipilimumab with a Risk Evaluation and Mitigation Strategy (REMS). Recently, coadministration of ipilimumab and a second immune checkpoint modulator targeting PD1 (e.g., nivolumab) has been shown to significantly increase efficacy of immunotherapy of melanoma when compared to ipilimumab alone. This gain, however, was associated with increased frequencies of grade 3/4 adverse effects, which affected more than 50% of patients receiving combination treatment (Wolchok, J. D., et al. 2013. Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med). These findings illustrate the need for developing anti-CTLA4 protein therapeutics that effectively target tumors without the side effects associated with certain anti-CTLA4 antibodies such as ipilimumab. Provided herein are anti-CTLA binding proteins, compositions thereof and methods of use thereof for addressing this need. All references cited herein, including patent applications, patent publications, and scientific literature, are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference. SUMMARY OF THE INVENTION Provided herein are anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) binding proteins, compositions comprising thereof, and methods of using the same. Provided herein are anti-CTLA4 antibodies or antigen-binding fragment thereof comprising a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein: the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3; and/or the VH domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6; or the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L2 com