Search

WO-2026096575-A1 - MRNA ENCODING CONCATEMERIC PRAME EPITOPE POLYPEPTIDE

WO2026096575A1WO 2026096575 A1WO2026096575 A1WO 2026096575A1WO-2026096575-A1

Abstract

Present disclosure provides engineered polynucleotides encoding concatemeric FRAME epitope polypeptides, including concatemeric FRAME epitope polypeptides capable of promoting an immune response to cancer cells expressing FRAME. The disclosure also provides pharmaceutical compositions and kits comprising the same, and methods of use and treatment of PRAME-positive cancers.

Inventors

  • BLASCO PATIÑO, Rafael Birilo
  • SUN, JING

Assignees

  • MODERNATX, INC.

Dates

Publication Date
20260507
Application Date
20251029
Priority Date
20241029

Claims (20)

  1. WHAT IS CLAIMED IS:
  2. 1. A pharmaceutical composition comprising an mRNA encoding a PRAME epitope concatemeric polypeptide, wherein the polypeptide comprises at least one PRAME epitope having the sequence of SLLQHLIGL (SEQ ID NO: 1),
  3. wherein the mRNA comprises one or more of the following: a 5’ UTR, a 3’ UTR, a nucleotide cap, and a poly A tail.
  4. 2. The pharmaceutical composition of claim 1, wherein the polypeptide comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 repeats, about 5-15 repeats, about 7-14 repeats, about 8-13 repeats, or about 9-12 repeats of the PRAME epitope.
  5. 3. The pharmaceutical composition of claim 2, wherein the polypeptide comprises no alanine linker residues.
  6. 4. The pharmaceutical composition of claim 2, wherein the polypeptide comprises an alanine linker linking adjacent repeats of the PRAME epitope.
  7. 5. The pharmaceutical composition of claim 4, wherein the alanine linker comprises a single alanine reside.
  8. 6. The pharmaceutical composition of claim 4, wherein the alanine linker comprises at least two alanine residues.
  9. 7. The pharmaceutical composition of claim 4, wherein the alanine linker comprises at least three alanine residues.
  10. 8. The pharmaceutical composition of claim 1, wherein the polypeptide comprises 12 repeats of the PRAME epitope.
  11. 9. The pharmaceutical composition of claim 8, wherein the polypeptide consists of 12 repeats of the PRAME epitope.
  12. 10. The pharmaceutical composition of claim 8, wherein the polypeptide comprises the amino acid sequence of
  13. MSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLL QHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGL (SEQ ID NO: 2).
  14. 11. The pharmaceutical composition of claim 1, wherein the polypeptide comprises 9 repeats of the PRAME epitope, wherein adjacent repeats are linked by two alanine residues. 12. The pharmaceutical composition of claim 11, wherein the polypeptide consists of the 9 repeats of the PRAME epitope and the alanine residues linking the adjacent repeats. 13. The pharmaceutical composition of claim 11, wherein the polypeptide comprises the amino acid sequence of MSLLQHLIGLAASLLQHLIGLAASLLQHLIGLAASLLQHLIGLAASLLQHLIGLAA SLLQHLIGLAASLLQHLIGLAASLLQHLIGLAASLLQHLIGL (SEQ ID NO: 3). 14. The pharmaceutical composition of claim 1, wherein the polypeptide comprises 9 repeats of the PRAME epitope, wherein adjacent repeats are linked by three alanine residues. 15. The pharmaceutical composition of claim 14, wherein the polypeptide consists of the 9 repeats of the PRAME epitope and the alanine residues linking the adjacent repeats. 16. The pharmaceutical composition of claim 14, wherein the polypeptide comprises the amino acid sequence of MSLLQHLIGLAAASLLQHLIGLAAASLLQHLIGLAAASLLQHLIGLAAASLLQHLI GLAAASLLQHLIGLAAASLLQHLIGLAAASLLQHLIGLAAASLLQHLIGL (SEQ ID NO: 4).
  15. 17. The pharmaceutical composition of claim 1, wherein the polypeptide comprises the amino acid sequence of MISALQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTH ISALQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTH (SEQ ID NO: 5).
  16. 18. The pharmaceutical composition of claim 1, wherein the polypeptide comprises the amino acid sequence of MTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLESYTLSFYGNSISISALQSLL QHLIGLSNLTHVLYPVPLESYTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLE SYTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLESY (SEQ ID NO: 6). 19. The pharmaceutical composition of claim 1, wherein the polypeptide comprises the amino acid sequence of MSLLQHLIGLSNLTHVLYPVPLESYTLSFYGNSISISALQSLLQHLIGLSNLTHVLY PVPLESYTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLESYSLSHCSQLTTLS FYGNSISISALQSLLQHLIGL (SEQ ID NO: 7).
  17. 20. The pharmaceutical composition of claim 1, wherein the polypeptide comprises the amino acid sequence of MISALQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTH ISALQSLLQHLIGLSNLTHGNSISISALQSLLQHLIGL (SEQ ID NO: 8).
  18. 21. The pharmaceutical composition of claim 1, wherein the polypeptide is about 50-150 amino acids in length, or about 80-120 amino acids in length, or about 90-110 amino acids in length.
  19. 22. The pharmaceutical composition of any of the preceding claims, wherein the mRNA comprises one or more of the following: a 5'-UTR comprising the sequence of any one of SEQ ID NOs: 19-49 and 118-120, and a 3' UTR comprising the sequence of any one of SEQ IDNOs: 50-58 and 121.
  20. 23. The pharmaceutical composition of claim 1, wherein the mRNA comprises the sequence of SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11.

Description

MRNA ENCODING CONCATEMERIC PRAME EPITOPE POLYPEPTIDE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U. S. C. § 119(e) of U. S. Provisional Patent Application No. 63/713,522, filed October 29, 2024, the entire contents of which are incorporated herein by reference in their entireties. BACKGROUND [0002 [ Preferentially Expressed Antigen of Melanoma (PRAME) is encoded by the PRAME gene, which is expressed at a high level in a large proportion of cancerous tumors, including melanomas, non-small-cell lung carcinomas, ovarian carcinoma renal cell carcinoma (RCC), breast carcinoma, cervix carcinoma, colon carcinoma, sarcoma, neuroblastoma, as well as several types of leukemia. PRAME is the best characterized member of the PRAME family of leucine-rich repeat (LRR) proteins. Mammalian genomes contain multiple members of the PRAME family whereas in other vertebrate genomes only one PRAME-like LRR protein was identified. PRAME is a cancer/testis antigen (CTA) that is expressed at very low levels in normal adult tissues except testis but at high levels in a variety of cancer cells. [0003] CTAs are attractive targets for cancer immunotherapy due to their restricted expression in germ cells and aberrant reactivation in various cancers, and their immunogenic properties. Many of these cancers still have a high unmet medical need, with patients needing improved, effective, and specific therapeutics. Accordingly, there exists a need to develop new anti-cancer agents that specifically target intracellular proteins highly specific to cancer cells. SUMMARY OF THE DISCLOSURE [0004] The present disclosure provides concatemeric PRAME epitope polypeptides and polynucleotides encoding the same, as well as pharmaceutical compositions comprising the same. The present disclosure also provides methods of treating cancer in a subject in need thereof comprising administering to a subject a pharmaceutical composition disclosed herein. [0OO5| In one aspect, the present disclosure provides a pharmaceutical composition comprising an mRNA encoding a PRAME epitope concatemeric polypeptide, wherein the polypeptide comprises at least one PRAME epitope having the sequence of SLLQHLIGL (SEQ ID NO: 1), wherein the mRNA comprises one or more of the following: a 5’ UTR, a 3’ UTR, a nucleotide cap, and a poly A tail. In some embodiments, the polypeptide comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 repeats, about 5-15 repeats, about 7-14 repeats, about 8-13 repeats, or about 9-12 repeats of the PRAME epitope. In some embodiments, the polypeptide comprises no alanine linker residues. In some embodiments, the polypeptide comprises an alanine linker linking adjacent repeats of the PRAME epitope. In some embodiments, the alanine linker comprises a single alanine reside. In some embodiments, the alanine linker comprises at least two alanine residues. In some embodiments, the alanine linker comprises at least three alanine residues. In some embodiments, the polypeptide comprises 12 repeats of the PRAME epitope. In some embodiments, the polypeptide consists of 12 repeats of the PRAME epitope. In some embodiments, the polypeptide comprises the amino acid sequence of MSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQHLIGLSLLQH LIGL SLLQHLIGL SLLQHLIGL SLLQHLIGL SLLQHLIGL SLLQHLIGL (SEQ ID NO: 2). In some embodiments, the polypeptide comprises 9 repeats of the PRAME epitope, wherein adjacent repeats are linked by two alanine residues. In some embodiments, the polypeptide consists of the 9 repeats of the PRAME epitope and the alanine residues linking the adjacent repeats. In some embodiments, the polypeptide comprises the amino acid sequence of MSLLQHLIGLAASLLQHLIGLAASLLQHLIGLAASLLQHLIGLAASLLQHLIGLAASLL QHLIGLAASLLQHLIGLAASLLQHLIGLAASLLQHLIGL (SEQ ID NO: 3). In some embodiments, the polypeptide comprises 9 repeats of the PRAME epitope, wherein adjacent repeats are linked by three alanine residues. In some embodiments, the polypeptide consists of the 9 repeats of the PRAME epitope and the alanine residues linking the adjacent repeats. In some embodiments, the polypeptide comprises the amino acid sequence of MSLLQHLIGLAAASLLQHLIGLAAASLLQHLIGLAAASLLQHLIGLAAASLLQHLIGL AAASLLQHLIGLAAASLLQHLIGLAAASLLQHLIGLAAASLLQHLIGL (SEQ ID NO: 4). In some embodiments, the polypeptide comprises the amino acid sequence of MISALQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTHISA LQSLLQHLIGLSNLTHISALQSLLQHLIGLSNLTH (SEQ ID NO: 5). In some embodiments, the polypeptide comprises the amino acid sequence of MTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLESYTLSFYGNSISISALQSLLQH LIGLSNLTHVLYPVPLESYTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLESYTL SFYGNSISISALQSLLQHLIGLSNLTHVLYPVPLESY (SEQ ID NO: 6). In some embodiments, the polypeptide comprises the amino acid sequence of MSLLQHLIGLSNLTHVLYPVPLESYTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPVP LESYTLSFYGNSISISALQSLLQHLIGLSNLTHVLYPV