A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention

MAbs. 2021 Jan-Dec;13(1):1946918. doi: 10.1080/19420862.2021.1946918.

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.

Keywords: Antibody VRC01; HIV-1 envelope trimer; broadly neutralizing antibody; matrix-based design; polyreactivity; prophylaxis; treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal* / genetics
  • Antibodies, Monoclonal* / immunology
  • Antibodies, Monoclonal* / pharmacology
  • Antibodies, Neutralizing* / genetics
  • Antibodies, Neutralizing* / immunology
  • Antibodies, Neutralizing* / pharmacology
  • HIV Antibodies* / genetics
  • HIV Antibodies* / immunology
  • HIV Antibodies* / pharmacology
  • HIV Infections* / immunology
  • HIV Infections* / prevention & control
  • HIV-1 / immunology*
  • Humans
  • Mice, Knockout

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • HIV Antibodies