Targeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen
Open accessAbstract
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.
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Wang's group developed a p53-specific TCR-like antibody, P1C1TM, that induces cellular cytotoxicity towards cancer cells bearing p53 mutations dependent on selective antibody.
“Later in 2019, Wang’s group developed another p53-specific TCR-like antibody, P1C1TM (260), that can induce cellular cytotoxicity towards cancer cells bearing p53 mutations dependent on selective antibody.608”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [608]
P1C1TM is a p53-specific TCR-like antibody that is suitable for promoting drug delivery into tumor cells with p53 mutation via ADCs.
“P1C1TM is a p53-specific TCR-like antibody, which has been verified by Wang’s group to be suitable for promoting drug delivery into tumor cells with p53 mutation via ADCs.608”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [608]
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References 72 · Cited by 48
- Authors
- Low, L., Goh, A., Koh, J., Lim, S., & Wang, C.-I.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Ngee Ann Polytechnic (SG)
- Corresponding author
- Wang, Cheng-I
- Venue
- Nature Communications
- Published
- 2019-11-26
- Volume
- 10
- Issue
- 1
- Pages
- 5382-5382
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6879612
- OpenAlex
- W2990193820
- Cited by
- 48
- References
- 72
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 5 · 2020: 5
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Agency for Science, Technology and Research (IAF311007, IAF311006, H16/99/b0/011)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- mutant p53, HLA-A24, T-cell receptor-like antibodies, affinity maturation, antibody-drug conjugates, antibody-dependent cellular cytotoxicity, cancer immunotherapy, tumor-specific antigens
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Antibodies, Antibody-Dependent Cell Cytotoxicity, Epitopes, Cross Reactions, Cytotoxicity, Immunologic, Humans, Mice, Transgenic, Mutation, Receptors, Antigen, T-Cell, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, Cell Line, Tumor, Molecular Targeted Therapy, HLA-A24 Antigen
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