Process Development\nfor the First GMP Synthesis of\nSGD-9501-TFA, Part 2: Synthesis of the Payload, Linker, and Drug Linker

The discovery of novel auristatin-derived antibody drug\nconjugates\n(ADCs) with attenuated bystander activity is an area of intense research.\nRecently, drug-linker SGD-9501-TFA emerged as a promising clinical\ncandidate possessing a favorable off-target toxicity profile. To support\nthe clinical development of ADCs utilizing this drug linker, we set\nout to develop a first-in-human amenable Good Manufacturing Practice\nmanufacturing route. In this report, we describe the discovery and\ndevelopment of three of seven synthetic steps in convergent solution-phase\nsynthesis. The activation of the linker is achieved with SOCl<sub>2</sub> in NMP (step 6), and solutions to the challenges associated\nwith isolation and stability are described. Next, novel HTE platforms\nused to explore peptide coupling and crystallization for the synthesis\nof the payload, auristatin S, are unveiled (step 5). Finally, the\nsynthesis of the quaternary ammonium drug linker, SGD-9501-TFA, with\na NaI-mediated benzylic amination, is described (step 7). We also\ndiscuss solutions to a eutectic gelation risk to direct precipitation\nof the crude drug linker and a trifluoroacetate ester impurity forming\nduring lyophilization.