Binding mechanisms of therapeutic antibodies to human CD20

doi:10.1126/science.abb8008

GSTDTAP > 气候变化

DOI	10.1126/science.abb8008
	Binding mechanisms of therapeutic antibodies to human CD20
	Anand Kumar; Cyril Planchais; Rémi Fronzes; Hugo Mouquet; Nicolas Reyes
	2020-08-14
发表期刊	Science
出版年	2020
英文摘要	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][1] 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. [1]: /lookup/doi/10.1126/science.abb8008
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/288080
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Anand Kumar,Cyril Planchais,Rémi Fronzes,et al. Binding mechanisms of therapeutic antibodies to human CD20[J]. Science,2020.
APA	Anand Kumar,Cyril Planchais,Rémi Fronzes,Hugo Mouquet,&Nicolas Reyes.(2020).Binding mechanisms of therapeutic antibodies to human CD20.Science.
MLA	Anand Kumar,et al."Binding mechanisms of therapeutic antibodies to human CD20".Science (2020).