Dual-mechanistic antibody-drug conjugate via site-specific selenocysteine/cysteine conjugation.

ABSTRACT:

Background

While all clinically translated antibody-drug conjugates (ADCs) contain a single-drug payload, most systemic cancer chemotherapies involve use of a combination of drugs. These regimens improve treatment outcomes and slow development of drug resistance. We here report the generation of an ADC with a dual-drug payload that combines two distinct mechanisms of action.

Methods

Virtual DNA crosslinking agent PNU-159682 and tubulin polymerization inhibitor monomethyl auristatin F (MMAF) were conjugated to a HER2-targeting antibody via site-specific conjugation at engineered selenocysteine and cysteine residues (thio-selenomab).

Results

The dual-drug ADC showed selective and potent cytotoxicity against HER2-expressing cell lines and exhibited dual mechanisms of action consistent with the attached drugs. While PNU-159682 caused S-phase cell cycle arrest due to its DNA-damaging activity, MMAF simultaneously inhibited tubulin polymerization and caused G2/M-phase cell cycle arrest.

Conclusion

The thio-selenomab platform enables the assembly of dual-drug ADCs with two distinct mechanisms of action.

SUBMITTER: Nilchan N 

PROVIDER: S-EPMC6953743 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature