A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention. Issue 1 (1st January 2021)

• Record Type: Journal Article
• Authors: Kwon, Young D.; Asokan, Mangaiarkarasi; Gorman, Jason; Zhang, Baoshan; Liu, Qingbo; Louder, Mark K.; Lin, Bob C.; McKee, Krisha; Pegu, Amarendra; Verardi, Raffaello; Yang, Eun Sung; Program, VRC Production; Carlton, Kevin; Doria-Rose, Nicole A.; Lusso, Paolo; Mascola, John R.; Kwong, Peter D.
• Is Part Of: MAbs. Volume 13:Issue 1(2021)
• Publication Date: 2021-01-01
• Subjects: Antibody VRC01 -- broadly neutralizing antibody -- HIV-1 envelope trimer -- matrix-based design -- polyreactivity -- prophylaxis -- treatment; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2021.1946918
• Languages: English
• ISSNs: 1942-0862

Abstract

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.