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A TCR mimic monoclonal antibody reactive with the "public" phospho-neoantigen pIRS2/HLA-A*02:01 complex

Tao Dao1, Sung Soo Mun1, Zaki Molvi2

  • 1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.

JCI Insight
|March 9, 2022
PubMed

Insights

Researchers developed a novel antibody targeting cancer-specific phosphopeptides presented by HLA-A*02:01. This antibody shows potential for developing new cancer immunotherapies by targeting a broad range of tumor neoantigens.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Tumor-specific antigens are crucial for cancer immunotherapy.
  • Phosphopeptides from dysregulated protein phosphorylation represent a promising source of cancer neoantigens.
  • Current therapeutic strategies often target single neoantigens, limiting efficacy.

Purpose of the Study:

  • To develop a T-cell receptor mimic (TCRm) monoclonal antibody (mAb) targeting a specific phosphopeptide-MHC complex.
  • To investigate the potential of TCRm mAbs for targeting a broad range of cancer neoantigens.
  • To explore novel immunotherapeutic strategies for cancer treatment.

Main Methods:

  • Generation of a TCR mimic (TCRm) mAb (6B1) specific for a phosphopeptide derived from insulin receptor substrate 2 (pIRS2) presented by HLA-A*02:01.
  • Mass spectrometry to confirm pIRS2 epitope presentation.
  • Binding assays to assess TCRm 6B1 specificity for pIRS2/HLA-A2 complex on tumor cells.
  • Bispecific antibody-mediated T-cell killing assays.
  • Structure modeling to predict binding prerequisites.

Main Results:

  • The TCRm mAb 6B1 specifically bound to the pIRS2/HLA-A2 complex on relevant tumor cell lines.
  • Bispecific antibodies demonstrated tumor cell killing in a pIRS2- and HLA-A*02:01-restricted manner.
  • Structure modeling indicated that the antibody could recognize various phosphopeptides with similar amino acid compositions, suggesting broader applicability.

Conclusions:

  • This study presents the first TCRm mAb targeting a phosphopeptide/MHC class I complex.
  • The developed TCRm mAb shows potential for targeting a range of phosphopeptides presented by HLA-A*02:01 in various tumors.
  • This class of agents holds promise for future clinical applications in cancer immunotherapy.
Keywords:
Antigen presentationCancer immunotherapyImmunologyOncologyT cell receptor

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