Camptothecin-based drug linkers for use in ADCs (antibody-drug conjugates) have shown great promise in the treatment of cancer. Approvals of Trodelvy and Enhertu have shown that such ADCs have a place in the fight against cancer, and the number of Topo-I inhibitory ADCs going to the clinic continues to grow. However, the physical and chemical properties of camptothecin-based drug linkers create novel problems in the development of a scaled-up final purification and isolation. Notably, the poor solubility of the drug linker, amorphous nature of the isolated solid, and chemical similarity of the impurities formed during the synthetic route necessitate a non-standard approach for the purification and isolation of the final drug linker product.
Herein we describe the development of a preparative chromatography process for the purification of our camptothecin drug linker and of a precipitation for the final isolation of our drug linker. Two stationary phases were investigated for the purification, with the one garnering the favorable impurity profile and more facile post-chromatography precipitation ultimately being selected. Using the drug linker solubility to guide options for the isolation post-chromatography, robust isolation conditions were identified. Solid form properties of the precipitate were studied to understand the impact of process parameters on filtration and handling, and the process was ultimately demonstrated on preparative scale to provide material of acceptable quality.
