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KR-20260068087-A - polypeptide for use in the treatment of glypican-3-expressing tumors

KR20260068087AKR 20260068087 AKR20260068087 AKR 20260068087AKR-20260068087-A

Abstract

The present invention relates to the field of cancer treatment. Specifically, the present invention relates to a polypeptide targeting glypican-3 (GPC3) and a T cell receptor (TCR) for use in the treatment of glypican-3-positive (GPC3+) solid tumors, such as hepatocellular carcinoma (HCC) or non-small cell lung cancer (NSCLC). Furthermore, the present invention relates to the dosage of said polypeptide when used as a treatment.

Inventors

  • 아바데사, 지오바니
  • 마시아리, 세레나
  • 멍, 완쥐

Assignees

  • 사노피

Dates

Publication Date
20260513
Application Date
20240904
Priority Date
20230904

Claims (20)

  1. A polypeptide for use in the treatment of glypican-3-positive (GPC3+) solid tumors, comprising or composed of at least three immunoglobulin monovariable domains (ISVDs), wherein each of the ISVDs comprises three complementarity determining regions (each CDR1 to CDR3), and wherein a) The first ISVD specifically binds to the constant domain of the T cell receptor (TCR) on T cells, and i. CDR1, the amino acid sequence of SEQ ID NO: 6; ii. CDR2, which is the amino acid sequence of SEQ ID NO: 10; and iii. Contains CDR3, the amino acid sequence of SEQ ID NO: 14; b) The second ISVD specifically binds to GPC3, and iv. CDR1, the amino acid sequence of SEQ ID NO: 7; v. CDR2, which is the amino acid sequence of SEQ ID NO: 11; and vi. Includes CDR3, the amino acid sequence of SEQ ID NO: 15; c) The third ISVD specifically binds to GPC3, and vii. CDR1, the amino acid sequence of SEQ ID NO: 8; viii. CDR2, the amino acid sequence of SEQ ID NO: 12; and ix. Includes CDR3, the amino acid sequence of SEQ ID NO: 16, and CDR is defined according to the AbM annotation, and A polypeptide in which the order of ISVDs indicates their relative positions to one another, considered from the N -terminus to the C -terminus of the polypeptide.
  2. In claim 1, the first ISVD is a polypeptide located at the N-terminus of the polypeptide.
  3. In paragraph 1 or 2, a) The amino acid sequence of the first ISVD contained in the polypeptide exhibits sequence identity of more than 90% with SEQ ID NO: 2; b) The amino acid sequence of the second ISVD contained in the polypeptide exhibits sequence identity of more than 90% with SEQ ID NO: 3; c) The amino acid sequence of the third ISVD contained in the polypeptide exhibits sequence identity of greater than 90% identity with SEQ ID NO: 4, and Here, CDR is a polypeptide defined according to the AbM annotation.
  4. In any one of paragraphs 1 through 3, a) The first ISVD included in the polypeptide consists of the amino acid sequence of SEQ ID NO: 2; b) The second ISVD included in the polypeptide consists of the amino acid sequence of SEQ ID NO: 3; c) The third ISVD included in the polypeptide consists of the amino acid sequence of SEQ ID NO: 4, and Here, CDR is a polypeptide defined according to the AbM annotation.
  5. A polypeptide according to any one of claims 1 to 4, wherein at least three ISVDs are connected through one or more peptide linkers.
  6. In claim 5, the first ISVD and the second ISVD included in the polypeptide are connected to each other through a linker consisting of fewer than 10 amino acids, preferably fewer than 6 amino acids, and the linker is most preferably a 5GS linker.
  7. A polypeptide according to any one of claims 1 to 6, wherein the polypeptide optionally further comprises one or more other groups, residues, moietyes, or bonding units connected via one or more peptide linkers, wherein the one or more other groups, residues, moietyes, or bonding units provide a polypeptide having an increased half-life compared to a corresponding polypeptide without the one or more other groups, residues, moietyes, or bonding units.
  8. In claim 7, the polypeptide having an increased half-life, wherein one or more other groups, residues, moiety, or binding units providing the polypeptide are selected from the group consisting of polyethylene glycol molecules, serum proteins or fragments thereof, binding units capable of binding to serum proteins, Fc portions, and small proteins or peptides capable of binding to serum proteins.
  9. In claim 7 or 8, the polypeptide having an increased half-life, wherein one or more other binding units providing the polypeptide are selected from the group consisting of binding units capable of binding to serum albumin or serum immunoglobulin.
  10. In claim 9, the binding unit providing the polypeptide having an increased half-life is a polypeptide that is an ISVD binding to human serum albumin.
  11. In paragraph 10, the ISVD that binds to human serum albumin i. CDR1, the amino acid sequence of SEQ ID NO: 9; ii. CDR2, the amino acid sequence of SEQ ID NO: 13; and iii. Contains CDR3, the amino acid sequence of SEQ ID NO: 17, and Here, CDR is a polypeptide defined according to the AbM annotation.
  12. A polypeptide according to claim 10 or 11, wherein the amino acid sequence of the ISVD binding to human serum albumin exhibits greater than 90% sequence identity with SEQ ID NO: 5.
  13. In any one of claims 10 to 12, the ISVD that binds to human serum albumin is a polypeptide consisting of the amino acid sequence of SEQ ID NO: 5.
  14. In any one of claims 1 to 13, the polypeptide comprises or consists of an amino acid sequence having more than 90% sequence identity with SEQ ID NO: 1.
  15. In any one of claims 1 to 14, the polypeptide is a polypeptide comprising or composed of the amino acid sequence of SEQ ID NO: 1.
  16. A composition for use in the treatment of GPC3+ solid tumors, comprising a polypeptide as defined in any one of claims 1 to 15.
  17. A composition comprising, in addition to pharmaceutically acceptable excipients, a component of Clause 16.
  18. In paragraph 16 or 17, the composition is provided as a liquid formulation.
  19. A polypeptide or composition according to any one of claims 1 to 18, wherein the polypeptide or composition is administered together with a PD-L1 inhibitor to a subject requiring the same.
  20. In paragraph 19, the PD-L1 inhibitor is a polypeptide or composition, preferably an anti-PD-L1 monoclonal antibody, which is atezolizumab.

Description

polypeptide for use in the treatment of glypican-3-expressing tumors The present invention relates to the field of cancer treatment. Specifically, the present invention relates to a polypeptide targeting glypican-3 (GPC3) and a T cell receptor (TCR) for use in the treatment of glypican-3-positive (GPC3+) solid tumors, such as hepatocellular carcinoma (HCC) or non-small cell lung cancer (NSCLC). Cancer causes immense loss of life worldwide. Today, cancer is the second leading cause of death globally, following heart disease and stroke. Cancer is one of the major causes of global morbidity and mortality, with approximately 19.3 million new cases and 10 million cancer-related deaths in 2020. The number of new cases is expected to increase further over the coming decades. Population growth, aging, and lifestyle changes have been cited as contributing factors to the rising burden of cancer. In 2013, the WHO projected that by 2030, cancer would surpass ischemic heart disease to become the most common cause of death globally (Source: WHO Cancer). Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the third leading cause of cancer-related deaths worldwide. Treatment for HCC depends on the stage of the disease, the patient's ability to tolerate surgery, and the availability of a liver transplant. If the cancer is in an early stage and confined to one or a few zones within the liver, surgically removing the tumor cells can be curative. However, if the cancer has spread beyond the liver or is too advanced within the liver, other treatment options must be explored. In 2007, sorafenib (marketed under the brand name Nexavar®), an oral multikinase inhibitor, was the first systemic agent approved for the first-line treatment of advanced HCC. In trials, only a modest improvement in overall survival of slightly over 2 to 3 months was observed. Additionally, undesirable side effects were observed very frequently. Therefore, additional treatment options were desired. Additionally, in a recent Phase III clinical trial, the combination of atezolizumab and bevacizumab was shown to improve overall survival as well as progression-free survival compared to sorafenib. Furthermore, in 2022, the FDA approved tremelimumab in combination with durvalumab for the treatment of unresectable HCC. However, overall, the prognosis for patients with HCC remains significantly poor. Although only about 10 to 20% of hepatocellular carcinomas can be completely removed surgically, if the cancer is not completely eliminated, HCC generally leads to patient death within 3 to 6 months. While the prognosis has improved slightly thanks to treatments such as sorafenib, there is still an urgent need for better treatment options for HCC patients. Non-small cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can arise from abnormal histological variants. NSCLC accounts for approximately 85% of all lung cancers. Overall, NSCLC is relatively insensitive to chemotherapy compared to small cell carcinoma. Standard care for selected patients with stage I and II non-small cell lung cancer (NSCLC), as well as stage IIIA, is surgical resection. After resection, systemic adjuvant therapy may be provided to the patient. Osimertinib, a third-generation oral EGFR-tyrosine kinase inhibitor (TKI), selectively binds to both EGFR driver mutations and EGFR T790M resistance mutations. It is approved for adjuvant therapy in completely resected stage II and III NSCLC (Mithoowani H, Febbraro M. Non-Small-Cell Lung Cancer in 2022: A Review for General Practitioners in Oncology. Curr Oncol. 2022 Mar 9;29(3):1828-1839). The prognosis for patients with NSCLC is also relatively poor. The 5-year relative survival rate for NSCLC in U.S. women is 33%, while for men it is 23%. Furthermore, there is still an urgent need for better treatment options for NSCLC patients. Glypican-3 (GPC3) is a GPI-fixed cell surface glycoprotein composed of a heparan sulfate GAG chain and a core protein. It is involved in embryonic development and early development, cell growth regulation, and differentiation. While GPC3 expression is high during development, it is almost absent in normal adult tissues and shows moderate to low levels in renal proximal tubules and bronchial cells. Consistent with its role in early development, high levels of GPC3 are also expressed in the placenta. GPC3 expression is predominant in tumor tissue, particularly from hepatocellular carcinoma. Soluble GPC3 can also be detected in the serum of HCC patients and has been used to differentiate it from liver diseases with other etiologies. Additionally, numerous studies have revealed that GPC3 is also involved in promoting cell proliferation and tumorigenesis in non-smal