Dual-mechanistic antibody-drug conjugate via site-specific selenocysteine/cysteine conjugation. (24th October 2019)

• Record Type: Journal Article
• Authors: Nilchan, Napon; Li, Xiuling; Pedzisa, Lee; Nanna, Alex R; Roush, William R; Rader, Christoph
• Is Part Of: Antibody therapeutics. Volume 2:Number 4(2019)
• Page Start: 71
• Page End: 78
• Publication Date: 2019-10-24
• Subjects: ADC -- dual-drug payload -- MMAF -- PNU-159682 -- cancer; Immunoglobulins -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Therapeutic use -- Periodicals; Immunotechnology -- Periodicals; 616.0798
• DOI: 10.1093/abt/tbz009
• Languages: English
• ISSNs: 2516-4236

Abstract

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.