Gram-Scale Antibody–Drug Conjugate Synthesis by Site-Specific Chemical Conjugation: AJICAP First Generation

Antibody–drug conjugates (ADCs) have become a major class of cancer biopharmaceuticals. Traditional ADCs have a stochastic distribution of cytotoxic drugs linked to an antibody at several different sites. The heterogeneous nature of stochastic ADCs diminishes their efficacy and results in a lower therapeutic index. To improve on traditional ADC technology, we have developed a chemical conjugation platform termed “AJICAP” for the site-specific modification of native antibodies through the use of a class of IgG Fc-affinity reagents. Here, we report the first gram-scale ADC synthesis using AJICAP first generation technology (Angew. Chem., Int. Ed. 2019, 58, 5592–5597) employing a scale-down manufacturing approach using tangential flow filtration. The minimum yield for each step was increased to 91% after optimization of the redox chemistry. The analytical data for the gram-scale synthesis of the ADC using AJICAP technology were identical to the results from a small-scale batch. Furthermore, biological evaluation using an in vitro cell-based assay indicated that this gram-scale AJICAP-ADC had sufficient efficacy for potential use as a cancer biopharmaceutical. The results reported herein for the gram-scale optimization indicate that AJICAP technology is amenable to relevant manufacturing production scales.