Process Development for the First GMP Synthesis of SGD-9501-TFA, Part 2: Synthesis of the Payload, Linker, and Drug Linker

The discovery of novel auristatin-derived antibody drug conjugates (ADCs) with attenuated bystander activity is an area of intense research. Recently, drug-linker SGD-9501-TFA emerged as a promising clinical candidate possessing a favorable off-target toxicity profile. To support the clinical development of ADCs utilizing this drug linker, we set out to develop a first-in-human amenable Good Manufacturing Practice manufacturing route. In this report, we describe the discovery and development of three of seven synthetic steps in convergent solution-phase synthesis. The activation of the linker is achieved with SOCl₂ in NMP (step 6), and solutions to the challenges associated with isolation and stability are described. Next, novel HTE platforms used to explore peptide coupling and crystallization for the synthesis of the payload, auristatin S, are unveiled (step 5). Finally, the synthesis of the quaternary ammonium drug linker, SGD-9501-TFA, with a NaI-mediated benzylic amination, is described (step 7). We also discuss solutions to a eutectic gelation risk to direct precipitation of the crude drug linker and a trifluoroacetate ester impurity forming during lyophilization.