6y92
From Proteopedia
Structure of full-length CD20 in complex with Ofatumumab Fab
Structural highlights
DiseaseCD20_HUMAN Defects in MS4A1 are the cause of immunodeficiency common variable type 5 (CVID5) [MIM:613495; also called antibody deficiency due to CD20 defect. CVID5 is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.[1] FunctionCD20_HUMAN This protein may be involved in the regulation of B-cell activation and proliferation. Publication Abstract from PubMedMonoclonal antibodies (mAbs) targeting human antigen CD20 (cluster of differentiation 20) constitute important immunotherapies for the treatment of B cell malignancies and autoimmune diseases. Type I and II therapeutic mAbs differ in B cell binding properties and cytotoxic effects, reflecting differential interaction mechanisms with CD20. Here we present 3.7- to 4.7-angstrom cryo-electron microscopy structures of full-length CD20 in complexes with prototypical type I rituximab and ofatumumab and type II obinutuzumab. The structures and binding thermodynamics demonstrate that upon binding to CD20, type II mAbs form terminal complexes that preclude recruitment of additional mAbs and complement components, whereas type I complexes act as molecular seeds to increase mAb local concentration for efficient complement activation. Among type I mAbs, ofatumumab complexes display optimal geometry for complement recruitment. The uncovered mechanisms should aid rational design of next-generation immunotherapies targeting CD20. Binding mechanisms of therapeutic antibodies to human CD20.,Kumar A, Planchais C, Fronzes R, Mouquet H, Reyes N Science. 2020 Aug 14;369(6505):793-799. doi: 10.1126/science.abb8008. PMID:32792392[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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