Discovery and Basic Research
Shawn Owen, PhD (he/him/his)
Associate Professor
University of Utah
Abhisheak Sharma, Ph.D.
Assistant Professor
University of Florida
Gainesville, Florida
Antibodies are important biological scaffolds used in biotherapeutics and diagnostics. The utility of antibodies can be expanded by coupling them with small-molecule drugs; however, these antibody drug conjugates (ADCs) often fail in the clinic due to the development of resistance and tumor heterogeneity. To address these issues, we have developed a modular synthetic strategy for the construction of ADCs with two distinct payloads. We synthesized a library of dual-drug ADCs where drugs are conjugated through unnatural cyclopentadiene-containing amino acids and through native cysteine residues on an anti-HER2 antibody scaffold. Because this strategy utilizes the same functional group on the linker-drug construct, the platform approach allows for the modular addition of drugs at either conjugation site which enables the evaluation of different drug-to-antibody ratios and combinations of drug pairs. We tested the library on high- and mid-HER2 expressing cell lines and observed increased toxicity in several dual-drug ADCs compared to single-drug constructs. Our results show the promise of simultaneous delivery of combinations of drugs with distinct mechanisms of action as the next generation of ADCs for targeted drug delivery.