title: Optimizing a lupus autoantibody for targeted cancer therapy.
abstract: The specificity of binding by antibodies to target antigens is a compelling advantage to antibody-based cancer therapy, but most antibodies cannot penetrate cells to affect intracellular processes. Select lupus autoantibodies penetrate into cell nuclei, and the potential for application of these antibodies in cancer therapy is an emerging concept. Here, we show that a divalent lupus anti-DNA autoantibody fragment with enhancing mutations that increase its ability to penetrate cell nuclei and bind DNA causes accumulation of DNA double-strand breaks in and is highly and selectively toxic to cancer cells and tumors with defective homology-directed repair of DNA double-strand breaks. These findings provide proof of principle for the use of optimized lupus autoantibodies in targeted cancer therapy.
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Noble
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, California.
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Young
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, California.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Weisbart
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. james.e.hansen@yale.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Hansen
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology* / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded; D045325:HCT116 Cells; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000974:Antibodies, Antinuclear; D011994:Recombinant Proteins