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KR-20260067383-A - Composition and method for treating cancer with loss of HLA-A*03 expression

KR20260067383AKR 20260067383 AKR20260067383 AKR 20260067383AKR-20260067383-A

Abstract

The present disclosure provides an immune cell comprising a first activating factor receptor specific to a cancer antigen, such as a CAR, and a second inhibitory receptor specific to a ligand lost in cancer cells, particularly HLA-A*03, and a method for producing the same and using it for cancer treatment. The present disclosure also relates to an HLA-A*03 specific antibody, related products, and uses.

Inventors

  • 함부르거 아그네스
  • 워샤비악 도라 톨레도
  • 목 지영

Assignees

  • 에이투 바이오쎄라퓨틱스, 인크.

Dates

Publication Date
20260512
Application Date
20240802
Priority Date
20230802

Claims (20)

  1. As an immune cell, a. A first receptor comprising an extracellular ligand binding domain specific to a target antigen; and b. A second receptor comprising a humanized extracellular ligand binding domain specific to HLA-A*03, and Herein, the first receptor is an activating factor receptor that responds to a target antigen; and the second receptor is an inhibitory receptor that responds to HLA-A*03, an immune cell.
  2. In paragraph 1, Immune cells in which the above HLA-A*03 is lost through the loss of heterozygosity in target cells.
  3. In paragraph 1 or 2, An immune cell comprising an extracellular ligand binding domain of the second receptor as described above, comprising complementarity determining region (CDR) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3 as disclosed in Table 1A or Table 1B and Table 2A or Table 2B; or a CDR sequence having up to 1, 2, or 3 substitutions, deletions, or insertions compared to the CDRs of Table 1A or Table 1B and Table 2A or Table 2B.
  4. In paragraph 1 or 2, An immune cell comprising a humanized extracellular ligand binding domain of the second receptor, the complementarity determining region (CDR) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3 of the sequence disclosed in SEQ ID NO. 2-4 or 33-38 or Table 1A and Table 2A; or a CDR sequence having up to 1, 2, or 3 substitutions, deletions, or insertions compared to the CDR of the sequence disclosed in SEQ ID NO. 2-4 or 33-38 or Table 1A or Table 2A.
  5. In any one of paragraphs 1 through 4, An immune cell in which the humanized extracellular ligand binding domain of the second receptor comprises the complementarity determining region (CDR) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3 of SEQ ID NOs 2-4 or 33-38.
  6. In any one of paragraphs 1 through 5, An immune cell in which the humanized extracellular ligand binding domain of the second receptor comprises any one of SEQ ID NOs 83-94 or the sequence disclosed in Table 5A or a sequence having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity with respect thereto.
  7. In any one of paragraphs 1 through 5, An immune cell wherein the humanized extracellular ligand binding domain of the second receptor comprises a variable heavy chain (VH) portion comprising a sequence having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity with respect to SEQ ID NOs 51-57; and/or wherein the extracellular ligand binding domain of the second receptor comprises a variable light chain (VL) portion comprising a sequence having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity with respect to SEQ ID NOs 72-78; and/or wherein the humanized extracellular ligand binding domain of the second receptor comprises a sequence having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity with respect to SEQ ID NOs 83-94.
  8. In any one of paragraphs 1 through 7, An immune cell in which the above target antigen is a cancer cell-specific antigen.
  9. In paragraph 8, An immune cell in which the above-mentioned cancer cell-specific antigen is selected from the group consisting of EGFR, CEA, MSLN, and HER2.
  10. In Paragraph 9, An immune cell whose cancer cell-specific antigen is MSLN.
  11. In Paragraph 9, An immune cell whose cancer cell-specific antigen is EGFR.
  12. In Paragraph 9, An immune cell whose cancer cell-specific antigen is CEA.
  13. In Paragraph 9, An immune cell whose cancer cell-specific antigen is HER2.
  14. In any one of paragraphs 1 through 13, An immune cell in which the first receptor is a chimeric antigen receptor (CAR).
  15. In any one of paragraphs 1 through 9, paragraph 10, or paragraph 14, An immune cell in which the extracellular ligand binding domain of the first receptor comprises a complementarity determining region (CDR) as disclosed in Table 7, such as CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3; or a CDR sequence having up to 1, 2, or 3 substitutions, deletions, or insertions compared to the CDR of Table 7.
  16. In any one of paragraphs 1 through 9, paragraph 10, or paragraph 14, An immune cell comprising an extracellular ligand binding domain of the first receptor comprising a variable heavy chain (VH) portion having a sequence presented in Table 8; a variable light chain (VL) portion having a sequence presented in Table 9; or a sequence having at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% identity therewith.
  17. In any one of paragraphs 1 through 9, paragraph 10, or paragraph 14, An immune cell comprising an extracellular ligand binding domain of the first receptor comprising a variable heavy chain (VH) portion having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity with respect to SEQ ID NOs 917-978, and a variable light chain (VL) portion having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity with respect to SEQ ID NOs 979-982.
  18. In any one of paragraphs 1 through 9, paragraph 10, or paragraph 14, An immune cell comprising an extracellular ligand binding domain of the first receptor comprising a sequence selected from the group consisting of SEQ ID NOs 143-208 or a sequence having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity therewith.
  19. In any one of paragraphs 1 through 9, paragraph 10, or paragraph 14, An immune cell in which the extracellular ligand binding domain of the first receptor comprises the scFv sequence of SEQ ID NO. 164 or a sequence having at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% identity with respect thereto.
  20. In any one of paragraphs 1 through 9, paragraph 11, or paragraph 14, An immune cell in which the extracellular ligand binding domain of the first receptor comprises a complementarity determining region (CDR) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3 as disclosed in Table 13; or a CDR sequence having up to 1, 2, or 3 substitutions, deletions, or insertions compared to the CDR of Table 14.

Description

Composition and method for treating cancer with loss of HLA-A*03 expression Cross-reference regarding related applications This application claims priority to U.S. Provisional Application No. 63/517,255 filed on August 2, 2023, the contents of which are incorporated herein by reference in their entirety. Sequence list The present application was submitted electronically in XML format and includes a sequence list in which the full text is included by reference. The XML copy was created on July 19, 2024, the filename is 061250-556001WO.xml, and the size is 1010KB. The present disclosure relates to the field of adoptive cell therapy and cancer therapeutic agents. Human leukocyte antigens (HLA) are subunits of Major Histocompatibility Complex (MHC) Class I (MHC-I) and are encoded by a series of associated polymorphic genes. MHC is involved in the process of antigen binding and presentation on the cell surface for recognition by immune cells. MHC-I molecules, including HLA-A, are highly polymorphic. For example, there are at least 6,425 known HLA-A alleles in humans, which encode at least 3,929 HLA-A proteins. Human leukocyte antigen A*03 (HLA-A*03) is a human leukocyte antigen encoded by an HLA-A locus and has a serotype within the HLA-A serotype group. The present disclosure provides an antigen-binding domain capable of specifically targeting the A*03 allele of HLA-A. These antigen-binding domains can be used in cell therapy. Cell therapy is a powerful tool for treating various diseases, particularly cancer. In conventional adoptive cell therapy, immune cells are engineered to express specific receptors, such as chimeric antigen receptors (CARs) or T cell receptors (TCRs), which direct the immune cells' activity toward cellular targets through the interaction of the receptor with ligands expressed by the target cells. Identifying suitable target molecules remains difficult because many targets are expressed in normal tissues. This expression can cause toxicity when transplanted cells target normal tissues that express the target molecules. Therefore, there is a need in the industry for compositions and methods useful for treating diseases, particularly cancer, via adoptive cell therapy. Mesothelin (MSLN) was proposed as a cancer target in 1992 (Chang et al. Cancer Res 52:181-86), but there are still no viable therapies utilizing MSLN. It is expressed in most mesotheliomas, as well as in a significant subset of ovarian, cervical, uterine, gastric, pancreatic, and lung adenocarcinomas (Hassan et al. J Clin Oncol 34:4171-79). In healthy adults, MSLN is present only in the mesothelial tissue, and this tissue itself may be non-essential. Several investigational therapies targeting MSLN have been tested; examples include immunotoxin-conjugates, antibody-drug conjugates, bispecific antibodies, CAR-T, and hybrid TCR-scFv. All active systemic therapeutic agents were toxic. Therefore, compositions and methods related to the treatment of MSLN(+) cancer are needed in this field. In various embodiments, the present invention provides compositions and methods related to the treatment of MSLN(+) cancer. Advantageously, the compositions and methods disclosed herein can address MSLN(+) cancer by utilizing loss of heterozygosity (LOH). The compositions and methods disclosed herein may, in some cases, avoid systemic toxicity to normal tissues by combining an MSLN-targeted activator receptor with a blocker receptor. Without being bound by theory, the difference in blocker antigen expression between tumor tissue and normal tissue induced by LOH occurring at loci encoding the blocker antigen may confer high selectivity for tumor death. The present disclosure provides an immune cell comprising: a first receptor comprising an extracellular ligand binding domain specific to a target antigen; and a second receptor comprising a humanized extracellular ligand binding domain specific to HLA-A*03, wherein the first receptor is an activating factor receptor responding to a target antigen; and the second receptor is an inhibitory receptor responding to HLA-A*03. In some embodiments, HLA-A*03 is lost through heterozygosity loss. In some embodiments, the extracellular ligand binding domain of the second receptor comprises complementarity determining region (CDR) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3 as disclosed in Table 1A or Table 1B and Table 2A or Table 2B; or a CDR sequence having up to 1, 2, or 3 substitutions, deletions, or insertions compared to the CDRs of Table 1A or Table 1B and Table 2A or Table 2B. In some embodiments, the humanized extracellular ligand binding domain of the second receptor comprises complementary determining region (CDR) CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, CDR-H3 of the sequence disclosed in SEQ ID NO. 2-4 or 33-38 or Table 1A and 2A; or a CDR sequence having up to 1, 2, or 3 substitutions, deletions, or insertions compared to the CDR of the sequence disclosed in SEQ ID NO. 2-4 or 33-38 or Table 1A o