Comprehensive mutagenesis identifies the peptide repertoire of a p53 T-cell receptor mimic antibody that displays no toxicity in mice transgenic for human HLA-A*0201
Open Access
- 9 April 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 16 (4), e0249967
- https://doi.org/10.1371/journal.pone.0249967
Abstract
T-cell receptor mimic (TCRm) antibodies have expanded the repertoire of antigens targetable by monoclonal antibodies, to include peptides derived from intracellular proteins that are presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface. We have previously used this approach to target p53, which represents a valuable target for cancer immunotherapy because of the high frequency of its deregulation by mutation or other mechanisms. The T1-116C TCRm antibody targets the wild type p5365-73 peptide (RMPEAAPPV) presented by HLA-A*0201 (HLA-A2) and exhibited in vivo efficacy against triple receptor negative breast cancer xenografts. Here we report a comprehensive mutational analysis of the p53 RMPEAAPPV peptide to assess the T1-116C epitope and its peptide specificity. Antibody binding absolutely required the N-terminal arginine residue, while amino acids in the center of the peptide contributed little to specificity. Data mining the immune epitope database with the T1-116C binding consensus and validation of peptide recognition using the T2 stabilization assay identified additional tumor antigens targeted by T1-116C, including WT1, gp100, Tyrosinase and NY-ESO-1. Most peptides recognized by T1-116C were conserved in mice and human HLA-A2 transgenic mice showed no toxicity when treated with T1-116C in vivo. We conclude that comprehensive validation of TCRm antibody target specificity is critical for assessing their safety profile.Funding Information
- Medical Research Council scholarship
- Cancer Research UK Programme (A10702 and A21667)
- Cancer Research UK Programme (A10702 and A21667)
- Cancer Research UK Programme (A10702 and A21667)
- Cancer Research UK Programme (A10702 and A21667)
- Cancer Research UK Programme (A10702 and A21667)
- Cancer Research UK Programme (A10702 and A21667)
- Medical Research Council Confidence in Concept (BRR00080)
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