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KR-20260065576-A - A combination therapy of IL-2 analog or conjugate thereof and CTLA-4 antagonist for preventing or treating cancer

KR20260065576AKR 20260065576 AKR20260065576 AKR 20260065576AKR-20260065576-A

Abstract

The present invention relates to the combined use of an interleukin 2 analog or a conjugate thereof and a CTLA-4 antagonist for the prevention or treatment of cancer, and to a pharmaceutical composition comprising the same.

Inventors

  • 김진영
  • 박상현
  • 신호철
  • 최재혁

Assignees

  • 한미약품 주식회사

Dates

Publication Date
20260508
Application Date
20251031
Priority Date
20241031

Claims (20)

  1. A pharmaceutical composition for the prevention or treatment of cancer containing an interleukin 2 analog comprising any one sequence selected from the amino acid sequences of SEQ ID NOs 3 to 106, wherein the pharmaceutical composition is characterized by being administered in combination with a CTLA-4 antagonist.
  2. In claim 1, the interleukin 2 analog is in the form of a sustained-release conjugate, and the sustained-release conjugate is a composition represented by the following chemical formula 1: [Chemical Formula 1] X - L - F In this case, X is an interleukin 2 analog comprising any one sequence selected from the amino acid sequences of SEQ ID NOs 3 to 106; L is a polyethylene glycol linker; F is the dimeric form of the immunoglobulin Fc region; - represents the covalent bond connection between X and L, and between L and F, and In the above sustained conjugate, one end of L is covalently connected to only one polypeptide chain of the dimeric Fc region, and X is covalently connected to the opposite end of this L.
  3. A composition according to claim 1 or 2, wherein the interleukin 2 analog comprises any one sequence selected from the group consisting of amino acid sequences of SEQ ID NOs 10, 13 to 15, 17, 20 to 22, 32, 35, 36, 42, 53, 54, 56, 58 to 60, 62, 71, 72, 74 to 78, 85, 87, 89, 91 to 94, and 97 to 106.
  4. A composition according to claim 1 or 2, wherein the interleukin 2 analog comprises any one sequence selected from the group consisting of amino acid sequences of SEQ ID NOs 17, 22, 42, 53, 56, 58 to 60, 62, 71, 72, 74 to 77, 87, 89, 91 to 93, 98 to 101, and 103 to 106.
  5. A composition according to claim 1 or 2, wherein the interleukin 2 analog comprises any one sequence selected from the group consisting of the amino acid sequences of SEQ ID NOs 22, 42, 53, 87, 105, and 106.
  6. A composition according to claim 1 or 2, wherein the interleukin 2 analog further comprises one or more amino acids at the C-terminus.
  7. A composition according to claim 1 or 2, wherein the interleukin 2 analog has increased binding affinity to interleukin 2 beta receptors compared to aldesleukin.
  8. In paragraph 2, the immunoglobulin Fc region is a composition derived from IgG, IgA, IgD, IgE, IgM, or a combination thereof or a hybrid thereof.
  9. A composition according to paragraph 2, wherein the immunoglobulin Fc region is an IgG4 Fc region.
  10. A composition according to paragraph 2, wherein the immunoglobulin Fc region is non-glycosylated.
  11. In paragraph 2, the sustained conjugate is a composition in which X is covalently connected to one of the Fc regions of the dimeric immunoglobulin through the polyethylene glycol linker.
  12. In paragraph 2, the composition wherein the polyethylene glycol linker is a linker with a molecular weight of 1 kDa to 100 kDa.
  13. A composition according to claim 1 or 2, wherein the composition further comprises a pharmaceutically acceptable excipient.
  14. In claim 1 or 2, the cancer is renal cell carcinoma, melanoma, colorectal cancer, liver cancer, uterine cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, skin cancer, breast cancer, bladder cancer, stomach cancer, head or neck cancer, esophageal cancer, laryngeal cancer, bone cancer, rectal cancer, proanal cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, renopelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brain tumor, glioma (astrocytoma, glioblastoma, oligodendroglioma) A composition selected from the group consisting of ependymoma, germ cell tumor, meningioma, brainstem glioma, pituitary adenoma, schwannoma, congenital tumor, craniopharyngioma, and brain tumor.
  15. A composition according to claim 1 or 2, wherein the cancer is a cancer with low responsiveness to a CTLA-4 antagonist.
  16. A composition according to claim 14, wherein the breast cancer is triple-negative breast cancer.
  17. A composition according to claim 1 or 2, wherein the composition is administered via a route of intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, local administration, nasal administration, pulmonary administration, or rectal administration.
  18. A composition according to claim 1 or 2, wherein the composition is administered at time intervals ranging from one week to one month.
  19. A composition according to claim 1 or 2, characterized in that the composition is administered in combination with a composition containing a CTLA-4 antagonist simultaneously, individually, sequentially, or in reverse order.
  20. A composition according to claim 1 or 2, wherein the CTLA-4 antagonist is one or more selected from an anti-CTLA-4 antibody or an antigen-binding fragment thereof.

Description

A combination therapy of IL-2 analog or conjugate thereof and CTLA-4 antagonist for preventing or treating cancer The present invention relates to a combination therapy for the prevention or treatment of cancer of an interleukin 2 analog or a conjugate thereof; and a CTLA-4 antagonist. Interleukin 2 is an important immunostimulant with a molecular weight of approximately 15 kDa, composed of a total of 133 amino acid residues, that activates various cells of the immune system, including T cells and B cells. The high efficacy of Interleukin 2 as an immunostimulant allows it to be used to treat various immune-related diseases, including cancer and AIDS (Korean Patent Publication No. 10-2017-0070091). Currently, Interleukin 2 (trademark Proleukin) is an FDA-approved drug for the treatment of metastatic renal cell carcinoma and metastatic melanoma. However, due to severe toxicity associated with high-dose Interleukin 2 therapy, the applicable patient population is limited, and in practice, this therapy is administered to only a small number of eligible patients. Toxicity associated with Interleukin 2 includes severe fever, nausea, vomiting, vascular leak, severe hypotension, pulmonary edema, and vascular leak syndrome, which causes liver damage. The Interleukin 2 receptor consists of three subunit receptors. These subunits are composed of the alpha chain (IL-2Rα, CD25), the beta chain (IL-2Rβ or CD122), and the gamma chain (IL-2Rγ or CD132), and Interleukin 2 can exert various functions by binding to various combinations of these receptor subunits. A single Interleukin 2 alpha receptor is referred to as a low-affinity Interleukin 2 receptor and does not participate in signal transduction. The complex of Interleukin 2 beta and gamma receptors binds to Interleukin 2 with moderate affinity. The complex of Interleukin 2 alpha, beta, and gamma receptors binds to Interleukin 2 with high affinity. The complex of Interleukin 2 beta and gamma receptors is required for effective signal transduction through the kinase activation of multiple signaling pathways. In particular, the Interleukin 2 beta and gamma coupled receptor is prominent in CD8+ cells and natural killer (NK) cells. Furthermore, complexes of high-affinity interleukin 2 alpha, beta, and gamma receptors are typically found in CD4 + T regulatory cells (Treg) as well as in recently activated T cells. Since interleukin 2 beta receptors are distributed in CD8 + T cells or natural killer (NK) cells and are involved in the body's immune response, research is being conducted to develop therapeutic agents by enhancing the activity of beta receptors to boost immunity. As an example of such research, interleukin 2 analogs and their sustained-release conjugates, which have enhanced therapeutic utility by modulating the binding affinity to interleukin 2 alpha, beta, and gamma receptors, have been studied (WO2021-201615 A1 and WO2022-211537 A1). Meanwhile, immune cells generally possess proteins called immune checkpoints on their cell membranes, which suppress unnecessary autoimmune responses while enabling them to eliminate cancer cells by detecting tumor-specific antigens expressed due to changes such as mutations occurring in the cells. However, to evade such immune mechanisms, cancer cells alter the function of these immune checkpoints, thereby suppressing T cell function and preventing the proper occurrence of an immune response. CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) is a representative immune checkpoint that induces immune cells to suppress the immune system. CTLA-4 is a protein expressed on T cells that functions to reduce the immune response by binding to CD80 (B7-1) and CD86 (B7-2) on the surface of antigen-presenting cells. Due to this action of CTLA-4 as an immune checkpoint, T cell function is blocked, ultimately preventing T cells from recognizing cancer cells and inducing their death. The possibility has been suggested that inhibiting CTLA-4 could treat cancer by preventing T cell inactivation and increasing T cell proliferation (e.g., ipilimumab or tremelimumab). As such, treatment methods that activate the body's immune system to enable immune cells to act on cancer cells and obtain an anticancer effect are being actively researched. However, when drugs that stimulate this immune system are used for anticancer treatment, side effects caused by the overactivation of immune cells become a problem. Therefore, it is necessary to discover safe and effective anticancer agents and treatment regimens. Figure 1 is the SDS-PAGE result of the interleukin 2 analog persistent couple (analogs 21, 41, and 52). Figures 2a to 2c show the results of purity analysis of interleukin 2 analog persistent conjugates (analogs 21, 41, and 52). Figure 3 shows the results of evaluating the antitumor efficacy of combination therapy in an animal model of triple-negative breast cancer (TNBC) using an interleukin 2 analog long-acting conjugate and an anti-CTLA-4 antibody. I