Design of Coltuximab Ravtansine, a CD19-Targeting Antibody–Drug Conjugate (ADC) for the Treatment of B-Cell Malignancies: Structure–Activity Relationships and Preclinical Evaluation

Coltuximab ravtansine (SAR3419) is an antibody–drug conjugate (ADC) targeting CD19 created by conjugating a derivative of the potent microtubule-acting cytotoxic agent, maytansine, to a version of the anti-CD19 antibody, anti-B4, that was humanized as an IgG1 by variable domain resurfacing. Four different linker-maytansinoid constructs were synthesized (average ∼3.5 maytansinoids/antibody for each) to evaluate the impact of linker-payload design on the activity of the maytansinoid-ADCs targeting CD19. The ADC composed of DM4 (N2′-deacetyl-N2′-[4-mercapto-4-methyl-1-oxopentyl]maytansine) conjugated to antibody via the N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB) linker was selected for development as SAR3419. A molar ratio for DM4/antibody of between 3 and 5 was selected for the final design of SAR3419. Evaluation of SAR3419 in Ramos tumor xenograft models showed that the minimal effective single dose was about 50 μg/kg conjugated DM4 (∼2.5 mg/kg conjugated antibody), while twice this dose gave comple...