An alternative focus for route design for the synthesis of antibody−drug conjugate payloads

Arnaud C. Tiberghien, Philip W. Howard, William R. F. Goundry, Marc McCormick and Jeremy S. Parker. 
Recipharms Elfyn Jones and Mikael Hillgren supported with the upscale of intermediate that made this article possible.

ABSTRACT: An analysis of Antibody−Drug Conjugate Payload manufacturing has revealed that the majority of the cost is associated with the use of high-containment facilities for the latter stages of the synthesis. To make a significant reduction in the Cost of Goods (CoGs), a new approach to route design has been introduced which focuses on minimizing the number of steps that require high containment. This approach has been exemplified in a new synthesis of tesirine, including the first application of a ring-closing copper(I)/TEMPO aerobic oxidation to the pyrrolobenzodiazepine ring system, affording a 60% reduction in CoGs.

Antibody−Drug Conjugates (ADCs) are an important new class of oncology therapeutics, combining a tumor-targeting antibody with a cell-killing cytotoxic drug (payload).1
Significant activity in this new field has resulted in the approval of brentuximab vedotin (Adcetris)2 in 2011 and trastuzumab emtansine (Kadcyla)3 in 2013, followed by the
2017 approvals of inotuzumab ozogamicin (Besponsa) and gemtuzumab ozogamicin (Mylotarg). Extensive clinical programs continue to evaluate potential commercial candidates, with further launches expected in the next few years.

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