DNA-targeting and cell-penetrating antibody-drug conjugate

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. ### Competing Interest Statement AE has equity interest in and receives consulting fees and equity options from Patrys Ltd. VD and JAC are employees of and have equity interest in Patrys Ltd. JEH has related intellectual property (IP) and equity interest in and receives grant support and consulting fees in the form of equity options from Patrys Ltd., a biotechnology company that has licensed IP that is the basis of this work. The remaining authors declare no conflicts of interest.