2. Academic Validation
  3. Binding mechanisms of therapeutic antibodies to human CD20

Binding mechanisms of therapeutic antibodies to human CD20

  • Science. 2020 Aug 14;369(6505):793-799. doi: 10.1126/science.abb8008.
Anand Kumar 1 2 3,  Cyril Planchais 4 5,  Rémi Fronzes 3 6,  Hugo Mouquet 4 5,  Nicolas Reyes 7 2 3
Affiliations

Affiliations

  • 1 Membrane Protein Mechanisms Unit, Institut Pasteur, 75015 Paris, France.
  • 2 Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, 33607 Pessac, France.
  • 3 CNRS UMR 5234 Fundamental Microbiology and Pathogenicity, Bordeaux, France.
  • 4 Laboratory of Humoral Immunology, Department of Immunology, Institut Pasteur, Paris, France.
  • 5 INSERM U1222, Paris, France.
  • 6 Structure and Function of Bacterial Nanomachines Group, European Institute of Chemistry and Biology, University of Bordeaux, 33607 Pessac, France.
  • 7 Membrane Protein Mechanisms Unit, Institut Pasteur, 75015 Paris, France. [email protected].
PMID: 32792392 DOI: 10.1126/science.abb8008
Abstract

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.

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