Research Article

Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab

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Science  13 Mar 2020:
Vol. 367, Issue 6483, pp. 1224-1230
DOI: 10.1126/science.aaz9356

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Clustering for the kill

Cluster of differentiation 20 (CD20) is a membrane protein that defines most B cell populations and is the target of therapeutic antibodies to treat malignancies and autoimmune disorders. Rougé et al. present the structure of CD20 bound to the antibody rituximab that activates the complement system to kill B cells. CD20 forms a dimer and each monomer binds one rituximab antigen-binding fragment (Fab) to give 2:2 stoichiometry. The compact packing between Fab arms and CD20 gives rise to circular assemblies with a diameter similar to that of antibody hexamers known to recruit the first component of the complement cascade.

Science, this issue p. 1224

Abstract

Cluster of differentiation 20 (CD20) is a B cell membrane protein that is targeted by monoclonal antibodies for the treatment of malignancies and autoimmune disorders but whose structure and function are unknown. Rituximab (RTX) has been in clinical use for two decades, but how it activates complement to kill B cells remains poorly understood. We obtained a structure of CD20 in complex with RTX, revealing CD20 as a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope and an extensive homotypic Fab:Fab interface. Our data suggest that RTX cross-links CD20 into circular assemblies and lead to a structural model for complement recruitment. Our results further highlight the potential relevance of homotypic Fab:Fab interactions in targeting oligomeric cell-surface markers.

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