In Vitro Binding Affinity Specificity Internalization and Expression Levels Related to In Vivo Efficacy

While Ab selection has a definitive impact on efficacy, high affinity does not always translate into superior efficacy. For example, mucin 16 (MUC16) is a cell surface marker for epithelial ovarian adenocarcinoma (139), and ADCs recognizing this antigen have been evaluated for ovarian cancer therapy. Chen and colleagues compared two Abs with monovalent (11D10 binds a unique epitope on the target antigen) or multivalent (3A5 binds to multiple epitopes per target antigen) binding to the extracellular domain (ECD) of MUC16, and the efficacies of their respective conjugates to auristatin were assessed (140). The higher-affinity unique epitope-binding ADC (11D10) actually bound to fewer sites per cell than 3A5 by flow cytometric analysis (Fig. 3A) and was a less potent inhibitor of in vitro ovarian carcinoma (OVCAR)-3 cell growth than its multiple epitope-binding counterpart (3A5) (Fig. 3B). Better in vivo efficacy was also observed for 3A5 in vivo in the OVCAR-3 intraperitoneal xenograft tumor model (Fig. 3C). In this case, increased ADC binding per cell may have resulted in an increased overall delivery of drug into the cells both in vitro and in vivo. Importantly, multivalent Ab-antigen interactions seem to have ultimately overcome any advantage of increased binding affinity.

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