Improved Manufacturing Process for Semi-Synthetic Calicheamicin Linker-Payload En Route to Antibody-Drug Conjugates

Calicheamicin is produced by fermentation of Micromonospora echinospora ssp. calichensis and isolated from the broth. The natural product is then synthetically modified to attach a linker, and the “linker-payload” product is reacted with antibodies to produce antibody-dug conjugates (ADCs) used in the treatment of cancer. We have developed an improved manufacturing process for the production of calicheamicin linker-payload and gained a better understanding of the chemistry at each step. Process improvements include fewer synthetic steps, fewer unit operations, reduced solvent usage, improved yield, and increased robustness. The improved process is now approved for commercial production of calicheamicin linker-payload as a drug substance intermediate for ADCs. Highlights of the process, learnings, development strategy, and benefits of implementation will be presented, along with selected aspects of the conjugation process to produce calicheamicin ADCs.