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.

CD4 binding site broadly neutralizing antibody selection of HIV-1 escape mutants

“…Also, the three BNMAbs, provided at the same time, never enabled the emergence of a resistant virus, cautiously suggesting that there is a limit to the amount of pressure the virus can withstand. Pre-exposure prophylaxis using modified BNMAb is considered as an option to prevent HIV-1 acquisition (Pace et al, 2013). Our findings would support such an approach and suggest that multiple BNMAbs targeting the CD4bs structure should be considered.…”

Towards HIV-1 remission: potential roles for broadly neutralizing antibodies

“…Finally, many potential modifications can enhance the antiviral functions of antibodies in vivo, such as mutations that enhance half-life, FcR binding, and potency (40,(91)(92)(93). Bispecific antibodies that express two different Fab regions have shown increased potency in vitro (94,95), and coupling antibodies to immunotoxins to enhance killing of infected cells is being explored in vivo (96). Both strategies remain active areas of investigation.…”

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

“…First, in addition to being able to encode combinations of bNAbs, which has been shown to prevent or delay viral escape, the larger carrying capacity of ADV vectors should support the delivery of the newly engineered bispecific and multivalent bNAbs, which have been reported to be 100-200 times more potent than conventional gp160-targeting bNAbs. 42,43 By encoding even more highly potent bNAbs, viremia may be fully suppressed for a longer period of time, reducing the chances of virological resistance or escape. Second, clinical safety is a major concern with any viral vector, and immunogenic effects have been observed, albeit rarely, for both ADV 44 and AAV.…”