Abstract
Therapeutic antibodies possess several clinically relevant mechanisms of action including cell death induction, perturbation of tumor cell signaling, activation of complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and induction of adaptive immunity. Obinutuzumab (GA101) is a novel humanized, glycoengineered Type II anti-CD20 monoclonal antibody engineered for displaying enhanced FcγRIIIa (CD16) binding affinity and characterized by stronger induction of ADCC and direct tumor cell death when compared to wild-type, Type I anti-CD20 antibodies rituximab and ofatumumab. In light of the important role of phagocytic lineage cells in the mechanism of action of therapeutic antibodies, we compared GA101, rituximab and ofatumumab for their ability to trigger FcγR-dependent monocyte and macrophage effector functions. We show that, due to glycoengineering, GA101 displays superior CD16-dependent binding to monocytes, M1 and M2c macrophages in presence of nonspecific, competing, human endogenous IgGs, a situation that more closely mimics physiological conditions. Subsequently, GA101 more strongly engages monocytes and macrophages and leads to significantly higher elimination of CD20-expressing tumor cells as shown by assays detecting total antibody activity (ADCP, ADCC and direct effects). In support of the stronger GA101 activity, higher nitric-oxide (NO) levels are also detected in supernatants of tumor/macrophage co-cultures treated with antibody. Taken together, our data show that in addition to stronger NK-cell mediated ADCC and direct cell death induction due to Type II CD20 binding, GA101 more potently engages phagocytic-lineage cells resulting in enhanced monocyte and macrophage activity under conditions that more closely resemble physiological settings. Disclosures:Herter:Roche: Employment. Klein:Roche Glycart AG: Employment. Umana:Roche: Employment, Equity Ownership. Bacac:Roche: Employment.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
