title: Bispecific Antibodies Targeting Different Epitopes on the HIV-1 Envelope Exhibit Broad and Potent Neutralization.
abstract: The potency and breadth of the recently isolated neutralizing human monoclonal antibodies to HIV-1 have stimulated interest in their use to prevent or to treat HIV-1 infection. Due to the antigenically diverse nature of the HIV-1 envelope (Env), no single antibody is highly active against all viral strains. While the physical combination of two broadly neutralizing antibodies (bNAbs) can improve coverage against the majority of viruses, the clinical-grade manufacturing and testing of two independent antibody products are time and resource intensive. In this study, we constructed bispecific immunoglobulins (IgGs) composed of independent antigen-binding fragments with a common Fc region. We developed four different bispecific IgG variants that included antibodies targeting four major sites of HIV-1 neutralization. We show that these bispecific IgGs display features of both antibody specificities and, in some cases, display improved coverage over the individual parental antibodies. All four bispecific IgGs neutralized 94% to 97% of antigenically diverse viruses in a panel of 206 HIV-1 strains. Among the bispecific IgGs tested, VRC07 × PG9-16 displayed the most favorable neutralization profile. It was superior in breadth to either of the individual antibodies, neutralizing 97% of viruses with a median 50% inhibitory concentration (IC50) of 0.055 μg/ml. This bispecific IgG also demonstrated in vivo pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for the prevention and treatment of HIV-1 infection in humans.
  
  
  OBJECTIVE
  To prevent or treat HIV-1 infection, antibodies must potently neutralize nearly all strains of HIV-1. Thus, the physical combination of two or more antibodies may be needed to broaden neutralization coverage and diminish the possibility of viral resistance. A bispecific antibody that has two different antibody binding arms could potentially display neutralization characteristics better than those of any single parental antibody. Here we show that bispecific antibodies contain the binding specificities of the two parental antibodies and that a single bispecific antibody can neutralize 97% of viral strains with a high overall potency. These findings support the use of bispecific antibodies for the prevention or treatment of HIV-1 infection.
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: M
authors.initials: M
authors.lastname: Asokan
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Rudicell
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: M
authors.initials: M
authors.lastname: Louder
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: K
authors.initials: K
authors.lastname: McKee
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: S
authors.initials: S
authors.lastname: O'Dell
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: G
authors.initials: G
authors.lastname: Stewart-Jones
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: M
authors.initials: M
authors.lastname: Choe
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chuang
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: I S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Joyce
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kirys
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ko
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pegu
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Todd
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rao
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Nabel
authors.affiliation: Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA jmascola@nih.gov.
authors.forename: J R
authors.initials: JR
authors.lastname: Mascola
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D005260:Female; D015483:HIV Antibodies / Q000276:immunology / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male
chemical_list: D018033:Antibodies, Bispecific; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007074:Immunoglobulin G