A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced Fcγriiia-Mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques

Brian Moldt, Mami Shibata-Koyama, Eva G. Rakasz, Niccole Schultz, Yutaka Kand, D. Cameron Dunlop, Samantha L. Finstad, Chenggang Jin, Gary Landucci, Michael D. Alpert, Anne Sophie Dugast, Paul W H I Parren, Falk Nimmerjahn, David T. Evans, Galit Alter, Donald N. Forthal, Jörn E. Schmitz, Shigeru Iida, Pascal Poignard, David I. WatkinsAnn Hessell, Dennis R. Burton

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    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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    ASJC Scopus subject areas

    • Immunology
    • Virology

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