Binding mechanisms of therapeutic antibodies to human CD20.
Language
EN
Article de revue
This item was published in
Science. 2020-08-14, vol. 369, n° 6505, p. 793-799
English 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 ...Read more >
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.Read less <
English Keywords
Antibodies
Monoclonal
Humanized
Antigen-Antibody Complex
Antigens
CD20
Antineoplastic Agents
B-Lymphocytes
Complement Activation
Cryoelectron Microscopy
Humans
Immunoglobulin Fab Fragments
Immunotherapy
Lymphoma
B-Cell
Protein Binding
Protein Conformation
Rituximab