EMD-21208
Cryo-EM structure of VRC01.23 in complex with HIV-1 Env BG505 DS.SOSIP
EMD-21208
Single-particle3.43 Å
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Map released: 13/01/2021
Last modified: 06/11/2024
Sample Organism:
Human immunodeficiency virus 1,
Homo sapiens
Sample: HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23
Fitted models: 6vi0 (Avg. Q-score: 0.502)
Deposition Authors: Gorman J
,
Kwong PD
Sample: HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23
Fitted models: 6vi0 (Avg. Q-score: 0.502)
Deposition Authors: Gorman J
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A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention.
Kwon YD,
Asokan M
,
Gorman J
,
Zhang B,
Liu Q,
Louder MK,
Lin BC,
McKee K,
Pegu A
,
Verardi R,
Yang ES,
Program VP,
Carlton K,
Doria-Rose NA,
Lusso P,
Mascola JR,
Kwong PD
MABs , 13 , 1946918 - 1946918
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MABs , 13 , 1946918 - 1946918
Abstract:
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 IC80 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 IC80 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.
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 IC80 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 IC80 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.