title: Distinct HIV-1 Neutralization Potency Profiles of Ibalizumab-Based Bispecific Antibodies.
abstract: BACKGROUND
  Preexposure prophylaxis using antiretroviral agents has been shown to effectively prevent human immunodeficiency virus type 1 (HIV-1) acquisition in high-risk populations. However, the efficacy of these regimens is highly variable, which is thought to be largely due to the varying degrees of adherence to a daily intervention in the populations. Passive immunization using broadly neutralizing antibodies (bNAbs) against HIV-1, with their relatively long half-life and favorable safety profile, could provide an alternative to daily preexposure prophylaxis. However, most bNAbs have a limited breadth, only neutralizing 70%-90% of all HIV-1 strains.
  
  
  METHODS
  To overcome the problem of limited antiviral breadth, we proposed that targeting human CD4 and HIV-1 envelope proteins simultaneously may improve virus-neutralization breadth and potency. Therefore, we constructed bispecific antibodies (biAbs) using single-chain variable fragments of anti-gp120 bNAbs fused to ibalizumab (iMab), a humanized monoclonal antibody that binds human CD4, the primary receptor for HIV-1.
  
  
  RESULTS
  Some of our biAbs neutralized 100% of HIV-1 strains tested in vitro at clinically achievable concentrations. Distinct neutralization patterns were observed in this panel of biAbs. Those biAbs with specificity for the CD4-binding site on gp120 demonstrated 100% breadth, as well as slightly improved potency compared with iMab. In contrast, biAbs with specificity for the V1-V2 apex epitope or the V3-glycan epitope on gp120 demonstrated dramatically improved potency; some showed limited gain in neutralization breadth, whereas others (eg, PGT128-LM52 and 123-iMab) improved to 100% breadth.
  
  
  CONCLUSIONS
  Our data suggest that this panel of iMab-based biAbs could be used to probe the parameters for potent HIV-1 neutralization. Moreover, a few of these biAbs warrant further studies and possibly clinical development.
authors: *Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY; and†Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors: Ruijiang
authors: R
authors: Song
authors: Craig
authors: C
authors: Pace
authors: Michael S
authors: MS
authors: Seaman
authors: Qing
authors: Q
authors: Fang
authors: Ming
authors: M
authors: Sun
authors: Chasity D
authors: CD
authors: Andrews
authors: Amos
authors: A
authors: Wu
authors: Neal N
authors: NN
authors: Padte
authors: David D
authors: DD
authors: Ho
mesh_terms: D018033:Antibodies, Bispecific / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology; D000918:Antibody Specificity; D016207:Cytokines / Q000378:metabolism; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D009500:Neutralization Tests
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D016207:Cytokines; D015483:HIV Antibodies; C481504:ibalizumab