title: Anti-CD4 monoclonal antibody ibalizumab exhibits breadth and potency against HIV-1, with natural resistance mediated by the loss of a V5 glycan in envelope.
abstract: OBJECTIVE
  Passive immunization for the prevention of HIV-1 infection is currently being reenergized. The anti-CD4 monoclonal antibody ibalizumab has demonstrated safety and efficacy in phase 1 and 2 clinical trials for treatment of HIV-1 infection and is undergoing a phase 1 clinical trial in HIV-1 uninfected individuals for prevention. Here, we sought to assess ibalizumab antiviral breadth and potency and to identify determinants of natural preexisting resistance.
  
  
  METHODS
  Ibalizumab breadth and potency was assessed against a large clinically relevant panel of HIV-1 pseudoviruses (n = 116) commonly used to assess vaccine candidates. Determinants of resistance were assessed by sequence analysis.
  
  
  RESULTS
  Ibalizumab neutralized 92% and 66% of viruses as defined by 50% and 80% inhibition, respectively. Median in vitro neutralization potency by IC50 was 0.03 μg/mL, substantially lower than the broadly neutralizing mAbs, PG9, or VRC01. The dominant determinant of resistance was the absence of a potential N-linked glycosylation site (PNGS) at the V5 N-terminus (P < 0.001), with the V2 loop length possibly influencing the degree of resistance afforded by the absence of the V5 N-terminal PNGS (P = 0.001). Other significant independent correlates of resistance included PNGS at position 386 and the side chain length of residue 375. Ibalizumab exhibited complementary resistance to VRC01 (P = 0.006) and sCD4 (P < 0.001), in part mediated by the V5 PNGS.
  
  
  CONCLUSIONS
  Ibalizumab breadth and potency compared favorably with broadly neutralizing anti-HIV-1 monoclonal antibodies, supporting the clinical development of ibalizumab, alone or in combination, for HIV-1 prevention.
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA. cpace@adarc.org
authors.forename: Craig S
authors.initials: CS
authors.lastname: Pace
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Fordyce
authors.forename: David
authors.initials: D
authors.lastname: Franco
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Kao
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009500:Neutralization Tests
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C481504:ibalizumab