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EP-4737482-A1 - HUMANIZED ANTI-MYCT1 ANTIBODY AND USE THEREOF

EP4737482A1EP 4737482 A1EP4737482 A1EP 4737482A1EP-4737482-A1

Abstract

The present invention relates to a humanized anti-MYCT1 antibody and a use thereof.

Inventors

  • CHOE, Soheui
  • LEE, HYUN SOO

Assignees

  • Atheon Bio, Inc.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. An isolated humanized anti-MYCT1 antibody or antigen-binding fragment thereof comprising: at least one variable heavy chain region (VH) selected from the group consisting of SEQ ID NOs: 41 and 43 to 60; and at least one variable light chain region (VL) selected from the group consisting of SEQ ID NOs: 42 and 61 to 66; or at least one VH selected from the group consisting of SEQ ID NOs: 92 and 94 to 101; and at least one VL selected from the group consisting of SEQ ID NOs: 93 and 102 to 115.
  2. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH includes CDR1, CDR2, and CDR3 having amino acid sequences set forth in SEQ ID NOs: 3, 4, and 5, respectively, and the VL includes CDR1, CDR2, and CDR3 having amino acid sequences set forth in SEQ ID NOs: 6, 7, and 8, respectively.
  3. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH includes CDR1, CDR2, and CDR3 having amino acid sequences set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL includes CDR1, CDR2, and CDR3 having amino acid sequences set forth in SEQ ID NOs: 12, 13, and 14, respectively.
  4. The antibody or antigen-binding fragment thereof of claim 1, comprising a VH sequence of SEQ ID NO: 43 and a VL sequence of SEQ ID NO: 42; comprising a VH sequence of SEQ ID NO: 44 and a VL sequence of SEQ ID NO: 42; comprising a VH sequence of SEQ ID NO: 45 and a VL sequence of SEQ ID NO: 42; comprising a VH sequence of SEQ ID NO: 41 and a VL sequence of SEQ ID NO: 61; comprising a VH sequence of SEQ ID NO: 46 and a VL sequence of SEQ ID NO: 62; comprising a VH sequence of SEQ ID NO: 41 and a VL sequence of SEQ ID NO: 63; comprising a VH sequence of SEQ ID NO: 44 and a VL sequence of SEQ ID NO: 63; comprising a VH sequence of SEQ ID NO: 47 and a VL sequence of SEQ ID NO: 64; comprising a VH sequence of SEQ ID NO: 48 and a VL sequence of SEQ ID NO: 64; comprising a VH sequence of SEQ ID NO: 48 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 49 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 50 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 51 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 52 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 53 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 54 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 55 and a VL sequence of SEQ ID NO: 64; comprising a VH sequence of SEQ ID NO: 55 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 56 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 57 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 58 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 41 and a VL sequence of SEQ ID NO: 65; comprising a VH sequence of SEQ ID NO: 58 and a VL sequence of SEQ ID NO: 42; comprising a VH sequence of SEQ ID NO: 59 and a VL sequence of SEQ ID NO: 66; or comprising a VH sequence of SEQ ID NO: 60 and a VL sequence of SEQ ID NO: 66.
  5. A humanized anti-MYCT1 antibody or antigen-binding fragment thereof, comprising a VH sequence of SEQ ID NO: 92 and a VL sequence of SEQ ID NO: 102; comprising a VH sequence of SEQ ID NO: 92 and a VL sequence of SEQ ID NO: 103; comprising a VH sequence of SEQ ID NO: 92 and a VL sequence of SEQ ID NO: 104; comprising a VH sequence of SEQ ID NO: 94 and a VL sequence of SEQ ID NO: 105; comprising a VH sequence of SEQ ID NO: 95 and a VL sequence of SEQ ID NO: 105; comprising a VH sequence of SEQ ID NO: 96 and a VL sequence of SEQ ID NO: 105; comprising a VH sequence of SEQ ID NO: 97 and a VL sequence of SEQ ID NO: 105; comprising a VH sequence of SEQ ID NO: 98 and a VL sequence of SEQ ID NO: 105; comprising a VH sequence of SEQ ID NO: 99 and a VL sequence of SEQ ID NO: 106; comprising a VH sequence of SEQ ID NO: 99 and a VL sequence of SEQ ID NO: 107; comprising a VH sequence of SEQ ID NO: 99 and a VL sequence of SEQ ID NO: 108; comprising a VH sequence of SEQ ID NO: 99 and a VL sequence of SEQ ID NO: 109; comprising a VH sequence of SEQ ID NO: 99 and a VL sequence of SEQ ID NO: 110; comprising a VH sequence of SEQ ID NO: 95 and a VL sequence of SEQ ID NO: 110; comprising a VH sequence of SEQ ID NO: 100 and a VL sequence of SEQ ID NO: 110; comprising a VH sequence of SEQ ID NO: 100 and a VL sequence of SEQ ID NO: 111; comprising a VH sequence of SEQ ID NO: 101 and a VL sequence of SEQ ID NO: 111; comprising a VH sequence of SEQ ID NO: 92 and a VL sequence of SEQ ID NO: 111; comprising a VH sequence of SEQ ID NO: 101 and a VL sequence of SEQ ID NO: 112; comprising a VH sequence of SEQ ID NO: 95 and a VL sequence of SEQ ID NO: 113; comprising a VH sequence of SEQ ID NO: 100 and a VL sequence of SEQ ID NO: 114; or comprising a VH sequence of SEQ ID NO: 95 and a VL sequence of SEQ ID NO: 115.
  6. The humanized anti-MYCT1 antibody or antigen-binding fragment thereof of claim 1, wherein the antigen binding fragment includes Fd, Fab, Fab', F(ab')2, dsFv, scFv, and a single domain antibody (sdAb).
  7. A nucleic acid molecule encoding the antibody or antigen-binding fragment thereof of any one of claims 1 to 6.
  8. A recombinant expression vector comprising the nucleic acid molecule of claim 7.
  9. A host cell transfected with the expression vector of claim 8.
  10. An immunoconjugate comprising the antibody or antigen-binding fragment of any one of claims 1 to 6 and a cytotoxic agent.
  11. A pharmaceutical composition for preventing or treating an MYCT1-associated disease, comprising the antibody or antigen-binding fragment of any one of claims 1 to 6 as an active ingredient.
  12. The pharmaceutical composition of claim 11, wherein the MYCT1-associated disease is an angiogenesis-associated disease or cancer.
  13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is administered in combination with at least one additional therapeutic agent or therapeutic procedure.
  14. The pharmaceutical composition of claim 13, wherein the at least one additional therapeutic agent or therapeutic procedure is selected from one or more of chemotherapy, targeted anticancer therapy, an oncolytic drug, a cytotoxic agent, immune-based therapy, a cytokine, a surgical procedure, a radiation procedure, a vaccine, and cell therapy.
  15. A composition for diagnosing an MYCT1-associated disease, comprising the antibody or antigen-binding fragment of any one of claims 1 to 6 as an active ingredient.
  16. A pharmaceutical composition for enhancing sensitivity to an immunotherapy agent in cancer, comprising the antibody or antigen-binding fragment of any one of claims 1 to 6 as an active ingredient.
  17. A chimeric antigen receptor (CAR) comprising an antigen-binding domain that specifically binds to MYCT1, wherein the antigen-binding domain includes an antigen-binding fragment including: at least one variable heavy chain (VH) region selected from the group consisting of SEQ ID NOs: 41 and 43 to 60 and SEQ ID NOs: 92 and 94 to 101; and at least one variable light chain (VL) region selected from the group consisting of SEQ ID NOs: 42 and 61 to 66 and SEQ ID NOs: 93 and 102 to 115.
  18. An immune effector cell expressing the chimeric antigen receptor (CAR) of claim 17.
  19. A method of treating an MYCT1-associated disease, comprising a step of administering to a subject a composition including a therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1 to 6.
  20. A method of enhancing sensitivity of a subject to an immunotherapy agent, comprising a step of administering to the subject a composition including a therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1 to 6.

Description

[Technical Field] The present invention relates to a humanized anti-MYCT1 antibody and use thereof. The present invention claims priority from Korean Patent Application No. 2023-0082857, filed in the Republic of Korea on June 27, 2023, and Korean Patent Application No. 2023-0094413, filed in the Republic of Korea on July 20, 2023, the contents of which are incorporated herein by reference. [Background Art] Angiogenesis is a physiological process in which new blood vessels develop from pre-existing blood vessels. Angiogenesis is known to play a role in both normal and pathological processes. Angiogenesis is highly regulated by pro-angiogenic factors and anti-angiogenic factors, a process that is disrupted and dysregulated in cancer. Tumor-induced hypoxia increases the expression of angiogenic factors, which induce the formation of new blood vessels essential for tumor survival and proliferation. The vascular endothelial growth factor (VEGF) family, consisting of six growth factors (VEGFA-F), plays a key role in angiogenesis by binding to receptors VEGF receptors 1-3 (VEGFR1-3) and neuropilin. Angiogenesis may also be mediated independently of the VEGF pathway by the angiopoietin (Ang1-2)/Tie-2 pathway. Accordingly, over the past decade, drug development has focused on anti-angiogenesis as a strategy to deprive tumors of nutrients and inhibit tumor growth. However, despite the weak activity of these agents as single agents or in combination with chemotherapy, there still remains the problem that tumors overcome the effects and develop resistance. Cancer immunotherapy emerged as an effective treatment for various cancers following the discovery of immune checkpoints. Immune checkpoint inhibitors (ICIs) have demonstrated long-lasting clinical activity against malignant tumors. ICIs activate tumor-fighting effector immune cells by blocking another mechanism hijacked by tumor "immune exhaustion." Primary resistance to ICIs occurs in tumors lacking tumor-infiltrating lymphocytes. In addition, tumors that initially respond to ICIs may develop secondary resistance due to defects in antigen presentation mechanisms and overexpression of co-inhibitory molecules. Therefore, it is necessary to overcome the limitations of VEGF inhibitors and reprogram the tumor microenvironment (TME) by normalizing tumor blood vessels in order to facilitate immune cell migration into the TME. To achieve this, the development of drugs targeting MYCT1 (MYC Target 1) is essential. Currently, no anti-MYCT1 antibody has been approved as a treatment for human diseases. Therefore, the development of anti-MYCT1 antibodies with strong binding affinity for MYCT1, excellent specificity, potent antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities, and superior anti-tumor and anti-angiogenic activity through TME reprogramming is required. [Non-patent document] J. Cell. Mol. Med., 2016 Vol. 20, No. 3, pp. 471-481 [Disclosure] [Technical Problem] An object of the present invention is to provide a humanized antibody or antigen-binding fragment that binds to MYCT1. Another object of the present invention is to provide a nucleic acid molecule encoding the antibody or antigen-binding fragment, an expression vector including the same, and a host cell transfected with the vector. Still another object of the present invention is to provide an immunoconjugate including the antibody or antigen-binding fragment and a cytotoxic agent. Yet another object of the present invention is to provide the antibody or antigen-binding fragment for use in the diagnosis or treatment of an MYCT1-associated disease. Yet another object of the present invention is to provide the antibody or antigen-binding fragment for use in the diagnosis of sensitivity to immunotherapy. Yet another object of the present invention is to provide a chimeric antigen receptor (CAR) including the antigen-binding fragment and an immune effector cell expressing the same. However, the technical problems to be solved by the present invention are not limited to the above-mentioned problems, and other problems that are not mentioned may be clearly understood by those skilled in the art from the description below. [Technical Solution] In order to solve the above-described technical problems, one aspect of the present invention provides an isolated humanized anti-MYCT1 antibody or antigen-binding fragment thereof including: at least one variable heavy chain region (VH) selected from the group consisting of SEQ ID NOs: 41 and 43 to 60; and at least one variable light chain region (VL) selected from the group consisting of SEQ ID NOs: 42 and 61 to 66; orat least one VH selected from the group consisting of SEQ ID NOs: 92 and 94 to 101; and at least one VL selected from the group consisting of SEQ ID NOs: 93 and 102 to 115. In one embodiment, the VH may include CDR1, CDR2, and CDR3 having amino acid sequences set forth in SEQ ID NOs: 3, 4, and 5, respectively, and