期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 22, 期 9, 页码 1241-1256出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.8b00205
关键词
Pyrrolobenzodiazepine; Antibody Drug Conjugate; High pressure chromatography; Loncastuximab tesirine; Camidanlumab tesirine
This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody-drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody-drug conjugates in multiple clinical trials, four of them pivotal.
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