Self‐Assembled L–DNA Linkers for Rapid Construction of Multi‐Specific Antibody‐Drug Conjugates Library

Abstract One of the key challenges of improving clinical outcomes of antibody drug conjugates (ADCs) is overcoming cancer resistance to the antibody and/or drug components of ADCs, and hence the need for ADC platforms with high combinatory flexibility. Here, we introduce the use of self‐assembled left‐handed DNA (L–DNA) oligonucleotides to link combinatory single‐domain antibodies and toxin payloads for tunable and adaptive delivery of ADCs. We demonstrate that the method allows convenient construction of a library of ADCs with multi‐specific targeting, multi‐specific payloads, and exact drug‐antibody ratio. The newly constructed ADCs with L–DNA scaffold showed favorable properties of in vitro cell cytotoxicity and in vivo suppression and eradication of solid tumors. Collectively, our data suggest that the L–DNA based modular ADC (MADC) platform is a viable option for generating therapeutic ADCs and for potentially expanding ADC therapeutic window via multi‐specificity.