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-Structure paper
タイトル | Binding mechanisms of therapeutic antibodies to human CD20. |
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ジャーナル・号・ページ | Science, Vol. 369, Issue 6505, Page 793-799, Year 2020 |
掲載日 | 2020年8月14日 |
著者 | Anand Kumar / Cyril Planchais / Rémi Fronzes / Hugo Mouquet / Nicolas Reyes / |
PubMed 要旨 | 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 ...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. |
リンク | Science / PubMed:32792392 |
手法 | EM (単粒子) |
解像度 | 3.69 - 4.73 Å |
構造データ | EMDB-10731, PDB-6y90: EMDB-10732, PDB-6y92: EMDB-10733, PDB-6y97: EMDB-10734, PDB-6y9a: |
化合物 | ChemComp-Y01: ChemComp-PC1: ChemComp-MYS: |
由来 |
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キーワード | MEMBRANE PROTEIN / cancer immunotherapy / therapeutic antibody |