MONOCLORAL ANTIBODY KILLS HUMAN PLURIPOTENT STEM CELLS BY ONCOSIS VIA EXCESS REACTIVE OXYGEN SPECIES PRODUCTION

Abstract

THE RISK OF TERATOMA FORMATION BY RESIDUAL UNDIFFERENTIATED HUMAN PLURIPOTENT STEM CELLS (HPSC) REMAINS A SAFETY CONCERN FOR THE APPLICATION OF HPSC-DERIVED CELLS. HERE, A MONOCLONAL ANTIBODY (MAB), TAG-A1 (A1), WAS GENERATED TO SELECTIVELY BIND TO AND KILL UNDIFFERENTIATED HPSC VIA ONCOSIS. IN SEVERE COMBINED IMMUNODEFICIENT (SCID) MOUSE MODELS, IN VITRO A1 TREATMENT PREVENTED TERATOMA FORMATION. MECHANISTIC STUDIES DEMONSTRATED THAT EXCESS REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, MEDIATED BY THE NOX2 ISOFORM OF NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (NADPH) OXIDASE, IS CRITICAL FOR A1-INDUCED HPSC DEATH. ROS PRODUCTION OCCURS DOWNSTREAM OF MICROVILLI DEGRADATION AND HOMOTYPIC ADHESION, BUT UPSTREAM OF ACTIN RE-ORGANIZATION, PLASMA MEMBRANE DAMAGE AND MITOCHONDRIAL MEMBRANE PERMEABILIZATION. TAKEN TOGETHER, A1 IS DEMONSTRATED AS AN EFFECTIVE TOOL TO INCREASE THE SAFETY OF HPSC-BASED THERAPY AND PROPOSED FOR THE FIRST TIME, A MECHANISTIC MODEL OF ANTIBODY-INDUCED ONCOSIS ON HPSC