title: Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1.
abstract: In the absence of an effective HIV-1 vaccine, passive immunization using broadly neutralizing Abs or Ab-like molecules could provide an alternative to the daily administration of oral antiretroviral agents that has recently shown promise as preexposure prophylaxis. Currently, no single broadly neutralizing Ab (bNAb) or combination of bNAbs neutralizes all HIV-1 strains at practically achievable concentrations in vivo. To address this problem, we created bispecific Abs that combine the HIV-1 inhibitory activity of ibalizumab (iMab), a humanized mAb directed to domain 2 of human CD4, with that of anti-gp120 bNAbs. These bispecific bNAbs (BibNAbs) exploit iMab's potent anti-HIV-1 activity and demonstrated clinical efficacy and safety to anchor and thereby concentrate a second broadly neutralizing agent at the site of viral entry. Two BibNabs, PG9-iMab and PG16-iMab, exhibit exceptional breadth and potency, neutralizing 100% of the 118 viruses tested at low picomolar concentrations, including viruses resistant to both parental mAbs. The enhanced potency of these BibNAbs was entirely dependent on CD4 anchoring, not on membrane anchoring per se, and required optimal Ab geometry and linker length. We propose that iMab-based BibNAbs, such as PG9-iMab and PG16-iMab, are promising candidates for passive immunization to prevent HIV-1 infection.
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Pace
authors.forename: Ruijiang
authors.initials: R
authors.lastname: Song
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.forename: Chasity D
authors.initials: CD
authors.lastname: Andrews
authors.forename: David
authors.initials: D
authors.lastname: Franco
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Deena A
authors.initials: DA
authors.lastname: Oren
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology; D002850:Chromatography, Gel; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000276:immunology* / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D020128:Inhibitory Concentration 50; D009500:Neutralization Tests; D020349:Surface Plasmon Resonance
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C481504:ibalizumab
keywords: antiviral; neutralization; synergy