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EP-4735005-A1 - RNA COMPOUNDS FOR TREATING PROLIFERATIVE DISORDERS

EP4735005A1EP 4735005 A1EP4735005 A1EP 4735005A1EP-4735005-A1

Abstract

The invention is based on in vitro transcribed or in vitro synthesized RNA compounds for a translation of tumor suppressor proteins in subjects suffering from a proliferative disease such as cancer. The invention provides the RNA compounds, as well as compositions for their delivery or administration to subjects.

Inventors

  • STREBHARDT, KLAUS
  • RAAB, MONIKA
  • KOSTOVA, Izabela
  • BECKER, SVEN

Assignees

  • Johann-Wolfgang-Goethe-Universität Frankfurt am Main

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. CLAIMS 1. A ribonucleic acid (RNA) compound for use in the treatment of High-grade serous ovarian cancer (HGSOC) in a subject, wherein the RNA compound encodes an amino acid sequence of a human p53 protein.
  2. 2. The RNA compound for use of claim 1, wherein the RNA compound encoding the amino acid sequence comprises the nucleotide sequence of SEQ ID NO: 1 (RNA sequence preferred), or a nucleotide sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the nucleotide sequence of SEQ ID NO: 1.
  3. 3. The RNA compound for use of claim 1 or 2, wherein the RNA compound is an in vitro transcribed (IVT) RNA or is a synthetically polymerized RNA.
  4. 4. The RNA compound for use of any one of claims 1 to 3, wherein at least one nucleotide is a modified nucleotide, such as pseudo uridine or 5-methylcytidine, for example wherein the modified nucleotide is a replacement of at least one uracil with pseudo uridine, preferably is a replacement of all uracil positions with pseudo uridine.
  5. 5. The RNA compound for use of any one of claims 1 to 4, wherein the RNA compound is administered to the subject by administering a pharmaceutically acceptable liposomal formulation comprising the RNA-compound.
  6. 6. The RNA compound for use of any one of claims 1 to 5, wherein the cancer is metastatic.
  7. 7. The RNA compound for use of any one of claims 1 to 6, wherein the cancer is relapsed.
  8. 8. The RNA compound for use of any one of claims 1 to 7, wherein the subject received a surgery.
  9. 9. The RNA compound for use of any one of claims 1 to 8, wherein the subject received tumor debulking therapy in the intra peritoneal cavity.
  10. 10. The RNA compound for use of any one of claims 1 to 9, wherein the RNA compound is administered to the subject intraperitoneal.
  11. 11. The RNA compound for use of any one of claims 1 to 10, wherein the subject received or receives at least one additional anticancer therapy.
  12. 12. The RNA compound for use of any one of claims 1 to 11, wherein the proliferative disease is HGSOC, the subject received debulking therapy, and wherein the RNA compound is administered into the intraperitoneal cavity.
  13. 13. A pharmaceutical composition, the composition comprising the RNA compound recited in any one of claims 1 to 12, and at least one pharmaceutically acceptable excipient.
  14. 14. The pharmaceutical composition of claim 13, which is a liposomal formulation of the RNA compound.
  15. 15. The pharmaceutical composition of claim 13 or 14, for a use in therapy as recited in any one of claims 1 to 11.

Description

RNA COMPOUNDS FOR TREATING PROLIFERATIVE DISORDERS FIELD OF THE INVENTION [1] The invention is based on in vitro transcribed or in vitro synthesized RNA compounds for a translation of tumor suppressor proteins in subjects suffering from a proliferative disease such as cancer. The invention provides the RNA compounds, as well as compositions for their delivery or administration to subjects. DESCRIPTION [2] High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy and the fifth most common cause of cancer-related death in women. The estimated annual incidence of this disease worldwide is over 200,000 individuals, with approximately 125,000 deaths. These cancers grow very fast, metastasize extensively, and show an aggressive course of the disease. Ovarian cancer (OC) cells stay within the peritoneal cavity and only disseminate to the mesothelium-lined surface1. The current standard of care encompasses cytoreductive surgery, chemotherapy (platinum compounds, paclitaxel, and cyclophosphamide), bevacizumab (Avastin), and PARP (poly-ADP-ribose polymerase) inhibitors. Still, around 70% of patients will suffer from a relapse within three years following surgery and platinum-based chemotherapy and succumb to disease progression. [3] The TP53 gene plays a key role in human cancer and is the most frequently mutated human tumor suppressor gene mostly through point mutations whereby amino acid substitutions lead to disruption of tumor protein p53 binding to DNA. p53 shields the human genome by counteracting cellular stress and DNA damage. Hence, cells with mutant TP53 can develop an unstable genome, evade apoptosis, and may finally develop into carcinogenesis. Multiple reports showed that tumor cells harboring functionally inactive p53 are resistant to chemotherapeutics since the mechanism of their efficacy is DNA damage leading to the activation of wild-type (wt) p53. The Cancer Genome Atlas Research Network revealed that HGSOC is characterized by TP53 mutations in up to 96% of all cases, leading to an inactive or truncated p53 protein10. Based on the TP53 database (http://www-p53.iarc.fr/) of the International Agency for Research on Cancer (IARC), most TP53 mutations in OC are missense mutations (>87.56%), which mainly cluster at hotspots (codons 175, 248, 273) within the DNA binding domain of p53. While a low prevalence (2–6%) of recurrently mutated genes such as BRCA1, BRCA2, RB1, and NF and a long list of infrequently mutated genes were found in this malignancy, TP53 is, in fact, the only gene that is frequently mutated at the somatic level in HGSOC10. Mutations in TP53 seem to be an early event in tumorigenesis, likely in precursor lesions of OC, supporting the importance of mutated TP53 as a driver of this malignancy. [4] Recently, RNA-based vaccines have emerged as valuable tools for immunotherapy. Novel strategies based on mRNA therapeutics came into view as efficacious and safe approaches to fighting infectious diseases and cancer based on their advantages such as relatively simple large- scale production, low side effects, and high efficacy. Unlike immune checkpoint blockade setting free immunosuppression and CAR-T cells eliminating cancer cells directly, recently developed cancer vaccines bring about the anticancer immune response via antigen-presenting cells, especially dendritic cells. Endeavors for replacing missing or faulty proteins by mRNA therapeutics have become an attractive strategy in different clinical areas like lung diseases and muscle atrophy, but approaches in cancer are still rare. Whether or not a p53 rescue has therapeutic value highly depends on the tumour indication and/or patient. [5] Thus, it is an object of the invention to provide novel treatment strategies to tackles proliferative disorders, in particular ovarian cancer. BRIEF DESCRIPTION OF THE INVENTION [6] Generally, and by way of brief description, the main aspects of the present invention can be described as follows: [7] In a first aspect, the invention pertains to a ribonucleic acid (RNA) compound for use in the treatment of a proliferative disease in a subject, wherein the RNA compound encodes an amino acid sequence of a human p53 protein. [8] In a second aspect, the invention pertains a pharmaceutical composition comprising the RNA compound which encodes an amino acid sequence of a human p53 protein. [9] In a third aspect, the invention pertains to a method of treating a proliferative disorder in a subject, the method comprising a step of administering to the subject an RNA compound which encodes an amino acid sequence of a human p53 protein. [10] In a fourth aspect, the invention pertains a method of manufacturing a medicament for use in the treatment of proliferative disorder in a subject, wherein the method comprises a step of formulating an RNA compound which encodes an amino acid sequence of a human p53 protein as a medicament. DETAILED DESCRIPTION OF THE INVENTION [11] In the following, the el