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

Lionel Low, Angeline Goh, Joanna Koh, Samantha Lim and Cheng-I Wang ()
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Lionel Low: Agency for Science, Technology and Research
Angeline Goh: Agency for Science, Technology and Research
Joanna Koh: Ngee Ann Polytechnic
Samantha Lim: Ngee Ann Polytechnic
Cheng-I Wang: Agency for Science, Technology and Research

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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 p53125-134 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.

Date: 2019
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DOI: 10.1038/s41467-019-13305-z

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