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EP-4525904-B1 - ENGINEERED SYNTHETIC PEPTIDES, COMPOSITIONS COMPRISING SAME, AND METHODS OF USE THEREOF FOR TREATING MALIGNANT GLIOMAS

EP4525904B1EP 4525904 B1EP4525904 B1EP 4525904B1EP-4525904-B1

Inventors

  • POLESZAK, Katarzyna
  • PASIERBINSKA, Maria
  • ELLERT-MIKLASZEWSKA, Aleksandra
  • PILANC-KUDLEK, Paulina
  • WISNIEWSKI, PAWEL
  • KAMINSKA-KACZMAREK, Bozena

Dates

Publication Date
20260506
Application Date
20230517

Claims (8)

  1. A synthetic peptide for use in inhibiting OPN activity, wherein said peptide comprises an amino acid sequence selected from the group consisting of: the amino acid sequence set forth in SEQ ID NO: 1, the amino acid sequence set forth in SEQ ID NO: 2; and the amino acid sequence set forth in SEQ ID NO: 3, or variants thereof having 70%, 80%, 90%, 95%, 97%, 98% or 99% sequence identity.
  2. The synthetic peptide according to claim 1, wherein said peptide is 14 amino acids in length.
  3. The synthetic peptide according to claim 1 or 2, wherein said peptide is a cyclic peptide.
  4. A pharmaceutical composition comprising a synthetic peptide according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
  5. The pharmaceutical composition according to claim 4, wherein said pharmaceutically acceptable carrier is selected from the group consisting of: an aqueous solution, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.
  6. The synthetic peptide according to any one of claims 1-3 or a pharmaceutical composition according to claims 4-5 for use in the treatment of glioma.
  7. The synthetic peptide or pharmaceutical composition for use according to claim 6, wherein said glioma is selected from the group consisting of: ependymoma, astrocytoma, oligodendroglioma, glioblastoma, or mixed glioblastoma.
  8. A kit for use in the treatment of glioma, said kit comprising the pharmaceutical composition according to one or more of claims 4 to 5 and instructions for use of said kit.

Description

Field of the invention The invention relates to engineered synthetic peptides, compositions comprising same, and methods of use thereof in the treatment of macrophage-infiltrated tumours, such as malignant gliomas. Prior art Gliomas are the most common tumours of the central nervous system (CNS) in adults. They account for 40% of all cancers and 78% of malignant tumours of the central nervous system. According to the classification made by the World Health Organization, gliomas are divided into 4 groups based on the degree of malignancy determined on the basis of various histological parameters and genetic changes in cancer cells. Stage IV of glioblastoma multiforme (GBM) is the most common glioma in adults and accounts for 69% of all cases of these tumours. Due to late diagnosis and lack of effective therapy, GBM regrows shortly after diagnosis and is incurable. The treatment recommended by the WHO and the National Health Fund includes the maximum acceptable surgical removal of the tumour, radiotherapy and chemotherapy, but due to the ineffective removal of the diffuse tumour and the resistance of cancer cells to treatment, the tumours recur after 6 months and are usually even more malignant. The average survival of patients is 14 months (Furnari et al., 2007). Many clinical trials are conducted on potential substances for the treatment of glioblastoma multiforme. So far, none of them has shown the expected effectiveness in extending or improving the patients' life. Even immunotherapy using checkpoint inhibitors, which have proven effective in the treatment of other cancers such as melanoma and lung cancer, has not brought benefits to patients in the treatment of glioma. This is related to the immunosuppressive microenvironment of glioma, referred to as "cold tumour microenvironment" characterized by low numbers of incoming cytotoxic T cells. In malignant gliomas, local and systemic immunosuppression is generated with myeloid cells recruited into the tumour. The glioblastoma-promoting phenotype of these cells is characterized by activation of pathways controlling microglial motility and phagocytosis, lack of inflammatory and anticancer responses, which promotes the influx of immunosuppressive myeloid cells (e.g. MDSC) and regulatory T cells, and blocks the activity of cytotoxic T or NK cells. Studies of the gene expression profile in microglia/macrophages in the tumour and in peripheral blood monocytes suggest that these cells acquire immunosuppressive and pro-invasive properties only in the presence of glioma (Gabrusiewicz et al., 2016; Sielska et al., 2021). Pharmacological (Sliwa et al., 2007; Gabrusiewicz et al., 2011, Markovic et al., 2011) or genetic (Zhai et al., 2011) elimination of microglia/macrophages in experimental gliomas significantly reduces tumour growth, indicating an important role of these cells in the pathogenesis of gliomas. Macrophage/microglia number in human gliomas correlate with the degree of malignancy of the tumour and shorter survival. The inventors of the present invention were among the first to show that glioblastoma cells attract myeloid cells, mainly microglia and peripheral monocytes/macrophages, to the tumour and transform them into cells that are immunosuppressive and support tumour invasiveness and progression (Sliwa et al. 2007, Wesolowska et al. 2008, Markovic et al. 2009; Gabrusiewicz et al. 2011, 2015; Ochocka, Segit et al. 2021). These cells referred to as GAMs (glioma-associated microglia/macrophages) often constitute up to 30% of the tumour mass. The inventors of the present invention have demonstrated that glioblastoma cells secrete proteins that reprogramme myeloid cells into cells that promote invasiveness, angiogenesis, and block the antitumour response. One of the key factors forming the pro-invasive GAM phenotype is osteopontin (SPP1, OPN) (Ellert-Miklaszewska et al., 2016). Silencing of Spp1 (a gene encoding osteopontin) expression in glioma cells inhibited the growth of glioma in rats and human glioma cells in an animal model using immunodeficient mice Crl:NU(Ico)-Foxn1nu. This was accompanied by a decrease in the number of amoeboid GAMs with a pro-cancer phenotype (Gieryng et al. unpublished). Increased SPP1 expression correlates with the degree of malignancy of the tumour, being the highest in GBM (Kijewska et al. 2017), and the concentration of protein in the tumour tissue and serum of patients with glioblastoma is a negative prognostic factor (Atai et al., 2011; Kijewska et al. 2017). Osteopontin stimulates the proliferation and invasiveness of cancer cells, as well as the process of angiogenesis, mediated by the alphavbeta3 and alphavbeta5 integrin receptors. The inventors of the present invention have previously shown that the short RGD peptide blocks the interaction between rat glioma and microglia in co-culture by blocking reprogramming towards pro-invasive microglia (Ellert-Miklaszewska et al., 2016). A new therapeutic strategy has been propose