National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM103310
米国
引用
ジャーナル: MAbs / 年: 2021 タイトル: A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention. 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 ...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 / 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.