Senior Principal Scientist Merck & Co., Inc. West Point, Pennsylvania
ADC is really gaining momentum by combing the best from mAb and chemotherapy worlds. We will present the case where a cell-based killing neutralizing antibody (NAb) assay for one of our ADC pipelines couldn’t be developed after multiple cell lines and NAb positive controls (PC) had been tested, due to either low sensitivity, or nonspecific killing through FcγRs internalization of drug. To overcome this obstacle, we developed and validated a cell-based binding assay utilizing the Meso Scale Discovery (MSD) platform. We also propose that among all in vivo MOAs of ADC-involved killing, an in vitro cell-based killing NAb assay cannot monitor bystander killing induced by pre-maturely released or dead-cell released payload, nor Ab-portion induced antibody-dependent cellular cytotoxicity (ADCC), and non-specific internalization through endocytosis or FcRs should be avoided, so the only MOA it can really monitor is the targe-binding induced internalization and killing, the same as a cell-based binding assay or competitive ligand binding NAb assay.
Learning Objectives:
Upon completion, participant will be able to learn that killing of the cells in an in vitro NAb assay could be non-specific due to FcgRs-involved internalization.
Upon completion, participant will be able to have a deeper understanding of the in vivo MOA of an ADC
Upon completion, participant will be able to understand why an in vitro cell-killing NAb assay for ADC may only monitor target-binding involved cell killing.
