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A Nonfucosylated Variant of the anti-HIV-1 Monoclonal Antibody b12 Has Enhanced Fc?RIIIa-Mediated Antiviral Activity In Vitro but Does Not Improve Protection against Mucosal SHIV Challenge in Macaques

  • Author(s): Moldt, Brian;
  • Shibata-Koyama, Mami;
  • Rakasz, Eva G.;
  • Schultz, Niccole;
  • Kanda, Yutaka;
  • Dunlop, D. Cameron;
  • Finstad, Samantha L.;
  • Jin, Chenggang;
  • Landucci, Gary;
  • Alpert, Michael D.;
  • Dugast, Anne-Sophie;
  • Parren, Paul I.;
  • Nimmerjahn, Falk;
  • Evans, David T.;
  • Alter, Galit;
  • Forthal, Donald N.;
  • Schmitz, Jorn E.;
  • Iida, Shigeru;
  • Poignard, Pascal;
  • Watkins, David I.;
  • Hessell, Ann J.;
  • Burton, Dennis R.
  • et al.
Abstract

Eliciting neutralizing antibodies is thought to be a key activity of a vaccine against human immunodeficiency virus (HIV). However, a number of studies have suggested that in addition to neutralization, interaction of IgG with Fc gamma receptors (FcγR) may play an important role in antibody-mediated protection. We have previously obtained evidence that the protective activity of the broadly neutralizing human IgG1 anti-HIV monoclonal antibody (MAb) b12 in macaques is diminished in the absence of FcγR binding capacity. To investigate antibody-dependent cellular cytotoxicity (ADCC) as a contributor to FcγR-associated protection, we developed a nonfucosylated variant of b12 (NFb12). We showed that, compared to fully fucosylated (referred to as wild-type in the text) b12, NFb12 had higher affinity for human and rhesus macaque FcγRIIIa and was more efficient in inhibiting viral replication and more effective in killing HIV-infected cells in an ADCC assay. Despite these more potent in vitro antiviral activities, NFb12 did not enhance protection in vivo against repeated low-dose vaginal challenge in the simian-human immunodeficiency virus (SHIV)/macaque model compared to wild-type b12. No difference in protection, viral load, or infection susceptibility was observed between animals given NFb12 and those given fully fucosylated b12, indicating that FcγR-mediated activities distinct from FcγRIIIa-mediated ADCC may be important in the observed protection against SHIV challenge.

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