Linkers, Payloads, and Peptide Considerations in Antibody Drug Conjugate Chemistry

Sponsored by Waters Corporation

For several years, ADCs relied largely on maleimide-based, cysteine conjugation, an approach with known limitations including linker instability and premature payload release. Zhengqi Zhang, Associate Principal Scientist at Merck & Co., explains that recent progress in conjugation chemistry has introduced more stable linker-payload connections designed to address those constraints. Peptide-based linkers have emerged as one development that meaningfully improves linker stability. In parallel, the field has moved toward high-DAR conjugates, shifting from a typical drug-to-antibody ratio (DAR) of three to four toward DAR-8 species and, in some cases, DAR-10 or DAR-12 molecules produced through interchain cysteine conjugation and additional engineered cysteine sites. These combined advances position conjugation as a central technology for next-generation biologics, though higher DARs also introduce added analytical complexity.