Research Article

Binding mechanisms of therapeutic antibodies to human CD20

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Science  14 Aug 2020:
Vol. 369, Issue 6505, pp. 793-799
DOI: 10.1126/science.abb8008

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Strength in numbers

Human cluster of differentiation 20 (CD20) is expressed on malignant B cells and is the target of therapeutic antibodies used in cancer immunotherapy. Kumar et al. now present structures that explain why so-called type I antibodies efficiently activate the complement pathway to kill cells, whereas type II antibodies do not. Type I antibodies each bind to two CD20 dimers and form clusters that facilitate binding to a component of the complement pathway. The second-generation type I antibody ofatumumab has molecular features that make it more efficient at clustering than first-generation rituximab. By contrast, the type II antibody obinutuzumab interacts with just one CD20 dimer and cannot form higher-order assemblies. Understanding these mechanisms will inform the design of next-generation immunotherapies.

Science, this issue p. 793

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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