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Cell Rep. 2018 Jan 2;22(1):299-312. doi: 10.1016/j.celrep.2017.11.112.

Monoclonal Antibodies against Specific p53 Hotspot Mutants as Potential Tools for Precision Medicine.

Author information

1
p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A(∗)STAR), Singapore 138648, Singapore.
2
Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore.
3
Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Singapore 119228, Singapore.
4
Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore.
5
p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A(∗)STAR), Singapore 138648, Singapore. Electronic address: dplane@p53lab.a-star.edu.sg.
6
Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Institute of Molecular & Cellular Biology, Singapore 138673, Singapore. Electronic address: cmrksb@nccs.com.sg.

Abstract

The large number of mutations identified across all cancers represents an untapped reservoir of targets that can be useful for therapeutic targeting if highly selective, mutation-specific reagents are available. We report here our attempt to generate such reagents: monoclonal antibodies against the most common R175H, R248Q, and R273H hotspot mutants of the tumor suppressor p53. These antibodies recognize their intended specific alterations without any cross-reactivity against wild-type (WT) p53 or other p53 mutants, including at the same position (as exemplified by anti-R248Q antibody, which does not recognize the R248W mutation), evaluated by direct immunoblotting, immunoprecipitation, and immunofluorescence methods on transfected and endogenous proteins. Moreover, their clinical utility to diagnose the presence of specific p53 mutants in human tumor microarrays by immunohistochemistry is also shown. Together, the data demonstrate that antibodies against specific single-amino-acid alterations can be generated reproducibly and highlight their utility, which could potentially be extended to therapeutic settings.

KEYWORDS:

amino acid-specific antibody; diagnosis; hotspot mutations; mAbs; mutation specific; p53; precision medicine; therapeutic antibody; tumor suppressor

PMID:
29298430
DOI:
10.1016/j.celrep.2017.11.112
[Indexed for MEDLINE]
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