KUMAR, Anand; PLANCHAIS, Cyril; FRONZES, Rémi; MOUQUET, Hugo; REYES, Nicolas

doi:10.1126/science.abb8008

Mécanismes des Protéines Membranaires - Membrane Protein Mechanisms
Microbiologie Fondamentale et Pathogénicité [MFP]

PLANCHAIS, Cyril

FRONZES, Rémi

Microbiologie Fondamentale et Pathogénicité [MFP]

Langue

Article de revue

Ce document a été publié dans

Science. 2020-08-14, vol. 369, n° 6505, p. 793-799

Résumé en anglais

Monoclonal 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.< Réduire

URI

https://oskar-bordeaux.fr/handle/20.500.12278/182446

DOI

http://dx.doi.org/10.1126/science.abb8008

Projet Européen

Molecular bases of human excitatory neurotransmitter transport across the plasma membrane

Project ANR

GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - ANR-10-LABX-0069
Centre d'analyse de systèmes complexes dans les environnements complexes - ANR-11-EQPX-0008

Unités de recherche

MFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234

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Binding mechanisms of therapeutic antibodies to human CD20