Targeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen

• Published in: Nature communications Vol. 10; no. 1; pp. 5382 - 14
• Main Authors: Low, Lionel, Goh, Angeline, Koh, Joanna, Lim, Samantha, Wang, Cheng-I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.11.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/21; 13/31; 38/1; 631/154/51/1568; 631/154/556; 631/67/1059; 82/103; 82/80; 82/83; Animals; Antibodies; Antibodies - genetics; Antibodies - immunology; Antibodies - pharmacology; Antibody-Dependent Cell Cytotoxicity; Antigens; Antineoplastic Agents, Immunological - adverse effects; Antineoplastic Agents, Immunological - pharmacology; Biocompatibility; Cell differentiation; Cell Line, Tumor; Cell surface; Cross Reactions; Cytotoxicity; Cytotoxicity, Immunologic; Epitopes; Histocompatibility antigen HLA; HLA-A24 Antigen - genetics; HLA-A24 Antigen - immunology; HLA-A24 Antigen - metabolism; Humanities and Social Sciences; Humans; Immunotherapy; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mice, Transgenic; Molecular Targeted Therapy - methods; multidisciplinary; Mutants; Mutation; p53 Protein; Peptides; Proteins; Receptors, Antigen, T-Cell - immunology; Science; Science (multidisciplinary); T cell receptors; Toxicity; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13305-z

Accumulation of mutant p53 proteins is frequently found in a wide range of cancers. While conventional antibodies fail to target intracellular proteins, proteosomal degradation results in the presentation of p53-derived peptides on the tumour cell surface by class I molecules of the major histocompatibility complex (MHC). Elevated levels of such p53-derived peptide-MHCs on tumour cells potentially differentiate them from healthy tissues. Here, we report the engineering of an affinity-matured human antibody, P1C1TM, specific for the unmutated p53 125-134 peptide in complex with the HLA-A24 class I MHC molecule. We show that P1C1TM distinguishes between mutant and wild-type p53 expressing HLA-A24 + cells, and mediates antibody dependent cellular cytotoxicity of mutant p53 expressing cells in vitro. Furthermore, we show that cytotoxic PNU-159682-P1C1TM drug conjugates specifically inhibit growth of mutant p53 expressing cells in vitro and in vivo. Hence, p53-associated peptide-MHCs are attractive targets for the immunotherapy against mutant p53 expressing tumours. Several cancers harbour mutant p53 and express higher levels of p53-derived peptide-MHCs. Here, the authors report affinity matured human antibody, P1C1TM, specific for the p53 125-134 peptide in complex with the HLA-A24 class I MHC molecule and show its efficacy and specificity for mutant p53 expressing tumours.