title: Improving neutralization potency and breadth by combining broadly reactive HIV-1 antibodies targeting major neutralization epitopes.
abstract: The isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined the in vitro neutralizing activities of double-, triple-, and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 μg/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorable in vitro combinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment.
  
  
  OBJECTIVE
  Over the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1-infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy.
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kong
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Wagh
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: deCamp
authors.affiliation: Departments of Surgery and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Greene
authors.affiliation: Departments of Surgery and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gao
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Taft
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.
authors.forename: Cassie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.affiliation: Departments of Surgery and Immunology, Duke University Medical Center, Durham, North Carolina, USA monte@duke.edu jmascola@nih.gov.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA monte@duke.edu jmascola@nih.gov.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000494:pharmacology; D004347:Drug Interactions; D000939:Epitopes / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology* / Q000494:pharmacology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009500:Neutralization Tests
chemical_list: D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies