Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency.
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.
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
Stylianos
S
Bournazos
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Anna
A
Gazumyan
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Michael S
MS
Seaman
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
Michel C
MC
Nussenzweig
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address: ravetch@rockefeller.edu.
Jeffrey V
JV
Ravetch
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology; D000939:Epitopes; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control / Q000628:therapy; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology; D051379:Mice
D018033:Antibodies, Bispecific; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G