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-Structure paper
タイトル | A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention. |
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ジャーナル・号・ページ | MAbs, Vol. 13, Issue 1, Page 1946918, Year 2021 |
掲載日 | 2022年1月21日 |
著者 | Young D Kwon / Mangaiarkarasi Asokan / Jason Gorman / Baoshan Zhang / Qingbo Liu / Mark K Louder / Bob C Lin / Krisha McKee / Amarendra Pegu / Raffaello Verardi / Eun Sung Yang / Vrc Production Program / Kevin Carlton / Nicole A Doria-Rose / Paolo Lusso / John R Mascola / Peter D Kwong / |
PubMed 要旨 | Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve ...Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC01-class variants that filled an interfacial cavity, used diverse third-complementarity-determining regions, reduced potential steric clashes, or exploited extended contacts to a neighboring protomer within the envelope trimer. On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. A cryo-electron microscopy structure of VRC01.23 Fab in complex with BG505 DS-SOSIP.664 Env trimer determined at 3.4-Å resolution confirmed the structural basis for its ~10-fold improved potency relative to VRC01. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics. |
リンク | MAbs / PubMed:34328065 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.43 Å |
構造データ | EMDB-21208, PDB-6vi0: |
化合物 | ChemComp-NAG: |
由来 |
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キーワード | IMMUNE SYSTEM / CD4 / HIV-1 / SOSIP / Vaccine |