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Cell. 2016 Jun 16;165(7):1609-1620. doi: 10.1016/j.cell.2016.04.050.

Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency.

Author information

1
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
2
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
3
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
4
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
5
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address: ravetch@rockefeller.edu.

Abstract

Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) suppress viremia in animal models of HIV-1 and humans. To achieve potent activity without the emergence of viral escape mutants, co-administration of different bNAbs is necessary to target distinct epitopes essential for viral fitness. Here, we report the development of bispecific anti-Env neutralizing antibodies (biNAbs) with potent activity. Synergistic activity of biNAbs was achieved by combining an engineered hinge domain of IgG3 to increase Fab domain flexibility necessary for hetero-bivalent binding to the Env trimer while retaining the functional properties of the IgG1-Fc. Compared to unmodified biNAbs, hinge domain variants exhibited substantially improved neutralization activity, with particular combinations showing evidence of synergistic neutralization potency in vitro and enhanced in vivo therapeutic activity in HIV-1-infected humanized mice. These findings suggest innovative strategies for generating biNAbs with enhanced neutralization breadth and potency, representing ideal candidate molecules for the control of HIV-1 infection.

PMID:
27315478
PMCID:
PMC4970321
DOI:
10.1016/j.cell.2016.04.050
[Indexed for MEDLINE]
Free PMC Article

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