title: Combining intracellular antibodies to restore function of mutated p53 in cancer.
abstract: TP53 is a tumor suppressor gene that is mutated in 50% of cancers, and its function is tightly regulated by the E3 ligase, Mdm2. Both p53 and Mdm2 are localized in the cell nucleus, a site that is impervious to therapeutic regulation by most antibodies. We identified a cell-penetrating lupus monoclonal anti-DNA antibody, mAb 3E10, that targets the nucleus, and we engineered mAb 3E10 to function as an intranuclear transport system to deliver therapeutic antibodies into the nucleus as bispecific single chain Fv (scFv) fragments. Bispecific scFvs composed of 3E10 include PAb421 (3E10-PAb421) that binds p53 and restores the function of mutated p53, and 3G5 (3E10-3G5) that binds Mdm2 and prevents destruction of p53 by Mdm2. We documented the therapeutic efficacy of these bispecific scFvs separately in previous studies. In this study, we show that combination therapy with 3E10-PAb421 and 3E10-3G5 augments growth inhibition of cells with p53 mutations compared to the effect of either antibody alone. By contrast, no enhanced response was observed in cells with wild-type p53 or in cells homozygous null for p53.
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angele Healthcare System, Sepulveda, CA.
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angele Healthcare System, Sepulveda, CA.
authors.forename: Gwen
authors.initials: G
authors.lastname: Jordaan
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angele Healthcare System, Sepulveda, CA.|Department of Neurology, University of California, Los Angeles, CA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Nishimura
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angele Healthcare System, Sepulveda, CA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Weisbart
mesh_terms: D018033:Antibodies, Bispecific / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D016159:Tumor Suppressor Protein p53
keywords: Mdm2; antibodies; cancer; oncogene; p53; tumor suppressor