A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention.
MAbs
; 13(1): 1946918, 2021.
Article
in En
| MEDLINE
| ID: mdl-34328065
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HIV Antibodies
/
HIV Infections
/
HIV-1
/
Antibodies, Neutralizing
/
Antibodies, Monoclonal
Limits:
Animals
/
Humans
Language:
En
Journal:
MAbs
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2021
Document type:
Article
Affiliation country: