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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.

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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    • Authors

    Moldt B, Shibata-Koyama M, Rakasz EG, Schultz N, Kanda Y, Dunlop DC, Finstad SL, Jin C, Landucci G, Alpert MD, Dugast AS, Parren PW, Nimmerjahn F, Evans DT, Alter G, Forthal DN, Schmitz JE, Iida S, Poignard P, Watkins DI, Hessell AJ, Burton DR

    Institution

    Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA.

    Source

    Journal of virology 86:11 2012 Jun pg 6189-96

    MeSH

    Animals
    Antibodies, Monoclonal
    Cells, Cultured
    Female
    HIV Antibodies
    HIV-1
    Humans
    Macaca mulatta
    Receptors, IgG
    Simian Acquired Immunodeficiency Syndrome
    Simian immunodeficiency virus
    Viral Load

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22457527