DNA-targeting and cell-penetrating antibody-drug conjugate

Abstract

DNA released by dying cancer cells offers a tumor targeting strategy that is independent of specific cell surface antigens. Anti-DNA antibodies preferentially localize to tumor microenvironments enriched in extracellular DNA and can penetrate live tumor cells through nucleoside salvage pathways. Nuclear-localizing variants of anti-DNA antibodies cause DNA damage and selectively kill cancer cells with defects in DNA repair. Here we show that an optimized full-length IgG1 anti-DNA antibody penetrates live cells and is synthetically lethal to BRCA2-deficient tumors but has minimal effect of DNA repair-proficient tumors. Linkage of the antibody to the anti-mitotic drug monomethyl auristatin E yields a DNA-targeting and cell-penetrating anti-DNA antibody-drug conjugate (ADC) that is well tolerated in mice and highly toxic to tumors with intact DNA repair. This work provides proof-of-concept for the novel use of an anti-DNA antibody as the backbone of a DNA-targeting, cell-penetrating ADC that can impact tumors that otherwise lack specifically targetable surface antigens. Statement of significanceA strategy for targeting tumors that lack specific surface antigens is revealed by an anti-DNA antibody-drug conjugate that localizes to tumor microenvironments enriched in DNA and penetrates cells through nucleoside salvage pathways.