title: A cell-penetrating bispecific antibody for therapeutic regulation of intracellular targets.
abstract: The therapeutic use of antibodies is restricted by the limited access of antibodies to intracellular compartments. To overcome this limitation, we developed a cell-penetrating monoclonal antibody, mAb 3E10, as an intracellular delivery vehicle for the intracellular and intranuclear delivery of antibodies constructed as bispecific single-chain Fv fragments. Because MDM2 is an important target in cancer therapy, we selected monoclonal antibody (mAb) 3G5 for intracellular transport. mAb 3G5 binds MDM2 and blocks binding of MDM2 to p53. Here, we show that the resulting 3E10-3G5 bispecific antibody retains cell-penetrating and MDM2-binding activity, increases tumor p53 levels, and inhibits growth of MDM2-addicted tumors. The use of cell-penetrating bispecific antibodies in targeted molecular therapy will significantly broaden the spectrum of accessible intracellular targets and may have a profound impact in cancer therapy.
authors.affiliation: Veterans Affairs Greater Los Angeles Health Care System, 161111 Plummer St., Sepulveda, CA 91343, USA. rweisbar@ucla.edu
authors.forename: Richard H
authors.initials: RH
authors.lastname: Weisbart
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Gera
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: James E
authors.initials: JE
authors.lastname: Hansen
authors.forename: Erica
authors.initials: E
authors.lastname: Li
authors.forename: Cheri
authors.initials: C
authors.lastname: Cloninger
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Robert N
authors.initials: RN
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D057846:Cell-Penetrating Peptides; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2