T cell receptors targeting PIK3CA mutations and uses thereof
Inventors
Klebanoff, Christopher A. • Chandran, Smita S.
Assignees
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Publication Number
US-12371467-B2
Publication Date
2025-07-29
Expiration Date
Abstract
The presently disclosed subject matter provides for methods and compositions for treating cancer (e.g., breast cancer). It relates to mutant phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-targeted T cell receptors (TCRs) that specifically target a mutant PIK3CA peptide (e.g., a human mutant PIK3CA peptide), and immunoresponsive cells comprising such TCRs. The presently disclosed mutant PIK3CA peptide-specific TCRs have enhanced immune-activating properties, including anti-tumor activity.
Core Innovation
The invention relates to mutant PIK3CA peptide-specific recombinant T cell receptor (TCR) molecules. The TCR includes an alpha chain variable region comprising CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NO: 41, 42, and 43, respectively, and a beta chain variable region comprising CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NO: 44, 45, and 46, respectively. Binding is directed to mutant PIK3CA peptide(s), with specificity that distinguishes mutant from wildtype.
The disclosure further includes TCR polypeptides, analogs, nucleic acids, and vectors encoding the TCRs, including retroviral delivery, and functional TCR fragments. Optional modified constant regions are described, and the TCRs are epitope-restricted to HLA class I and/or HLA class II, including HLA-A/B/C and/or HLA-DP/DM/DO/DQ/DR.
The invention also describes expressing a TCR in immunoresponsive cells using non-viral gene transfer and genome-editing delivery options, including non-viral transfection/lipofection approaches and optional targeted nucleases such as CRISPR/Cas9, ZFN, and TALEN for genome integration. The description ties the TCR approach to producing immunoresponsive cells that bind a human mutant PIK3CA polypeptide.
Pharmaceutical compositions are provided for treating PIK3CA-mutated cancers.
Claims Coverage
The independent claim set centers on one TCR defined by alpha- and beta-chain variable region CDR1, CDR2, and CDR3 sequences. The dependent refinements add sequence identity and defined sequence elements, optional modified constant regions, and immunoresponsive-cell and nucleic-acid encoding concepts tied to binding a human mutant PIK3CA polypeptide.
CDR-defined mutant PIK3CA peptide-specific TCR
A T cell receptor comprising an alpha chain variable region with a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; and a beta chain variable region with a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46.
TCR variable regions with identity to specified sequences
The TCR has an alpha chain variable region that is at least 80% identical to SEQ ID NO: 47 and a beta chain variable region that is at least 80% identical to SEQ ID NO: 48.
Defined extracellular domain sequences via SEQ ID numbers
The TCR has an extracellular domain comprising an alpha chain containing the amino acid sequence of SEQ ID NO: 49 and a beta chain containing the amino acid sequence of SEQ ID NO: 50.
Modified constant region elements
The TCR includes either a modified alpha-chain constant region, a modified beta-chain constant region, or both the modified alpha-chain constant region and the modified beta-chain constant region.
Transduced immunoresponsive cells
An isolated immunoresponsive cell is transduced with a TCR.
Nucleic-acid introduction to produce PIK3CA mutant-binding immunoresponsive cells
A method for producing an immunoresponsive cell that binds to a human mutant PIK3CA polypeptide by introducing into the cell a nucleic acid molecule that encodes the TCR of claim 1.
Overall claim coverage centers on the defined alpha/beta variable-chain CDR1/CDR2/CDR3 sequence sets (SEQ ID NOs 41–46) for a TCR directed to mutant PIK3CA peptide(s), with dependent embodiments covering refined sequence and identity constraints, optional modified constant regions, and nucleic-acid encoding and immunoresponsive-cell embodiments.
Stated Advantages
Specificity that distinguishes mutant from wildtype.
Documented Applications
Treating PIK3CA-mutated cancers, including breast cancer.
Treating PIK3CA-mutated cancers including endometrial, cervical, anal, bladder, colorectal, head and neck squamous cell, nonmelanoma skin, and salivary gland cancers.
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