title: Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies.
abstract: A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90024, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Webb
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90024, USA.|Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
mesh_terms: D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D000918:Antibody Specificity; D016860:CD4 Immunoadhesins / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D016860:CD4 Immunoadhesins