A Structure-Based Matrix Approach Yields Improved VRC01-Class Antibodies for HIV-1 Therapy and Prevention

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, utilized diverse 3rd-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 had a breadth of 96% and an IC50 of 0.041 mg/ml; 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 days in humans. Another variant VRC07-523-F54-LS.v3 had 97% breadth at an IC50 of 0.027 mg/ml, though with slightly reduced half-life versus VRC01. Our structure-based matrix approach thus enables the engineering of VRC01 variants with improved potency, breadth, and pharmacokinetics.