Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice

Abstract

The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral therapy (cART). Here, we investigate the potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving 2 single-chain variable fragment (scFv) binding domains of each parental bnAb, a single gene-encoded tandem bs-bnAb, BiIA-SG, displayed substantially improved breadth and potency. BiIA-SG neutralized all 124 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, transmitted/founder viruses, variants not susceptible to parental bnAbs and to many other bnAbs with an average IC50 value of 0.073 μg/ml (range < 0.001-1.03 μg/ml). In humanized mice, an injection of BiIA-SG conferred sterile protection when administered prior to challenges with diverse live HIV-1 stains. Moreover, whereas BiIA-SG delayed viral rebound in a short-term therapeutic setting when combined with cART, a single injection of adeno-associated virus-transferred (AAV-transferred) BiIA-SG gene resulted dose-dependently in prolonged in vivo expression of BiIA-SG, which was associated with complete viremia control and subsequent elimination of infected cells in humanized mice. These results warrant the clinical development of BiIA-SG as a promising bs-bnAb-based biomedical intervention for the prevention and treatment of HIV-1 infection.

Tandem bispecific broadly neutralizing antibody — a novel approach to HIV-1 treatment

“…As reported by Wu et al (25), the neutralizing breadth and potency of the new BiIA-SG molecule are definitely higher than those of the original neutralizing PGT128 mAb, or the BiIA-DG with a single scFv domain. The authors suggest that the improved activity of the BiIA-SG may be due to the ability of the anti-CD4 arm to bring the PGT121 arm in proximity to the HIV-1 Env.…”

“…Wu and collaborators (25) decided to take a different approach to circumvent the diversity of HIV-1 envelopes. They based their molecule on 1 single gene-encoded tandem bs-bnAb, namely BiIA-SG, where 2 single-chain variable fragment (scFv) binding domains against the V3 glycan epitope recognized by the PGT128 mAb infection and control virus rebound in the humanized mouse model for HIV-1 infection.…”

Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies

“…Major mechanisms appear to include a reduction of antibody binding to the contact residues and increased steric obstruction imposed by the bulky side-chains or glycansat the mutated residues.As the HIV-1 pandemic continues to evolve and particularly more CD4bs antibodies are entering clinical studies, more resistant strains are expected to arise. To overcome this resistance for optimal clinical outcomes, more potent and broadly effective antibodies are needed, either by isolating antibodies with exceptional neutralizing activity from patients,or engineering existing antibodies into bi-or tri-specific combinations [7,8,27,28,[65][66][67][68].A combination of VRC01 class and CDR H3-dominated antibodies, such as VRC13, may also be a beneficial alternative for developing therapeutic antibody cocktails due to their different sensitivity to resistance mutations at the CD4bs.…”

“…Treatment strategies based on the CD4bs bnAbs therefore must overcome such resistance to achieve optimal clinical outcomes.Recent scientific advances have identified a growing number of broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus type I (HIV-1), providing promising candidates for HIV-1 prevention and treatment [1][2][3][4][5]. Compared with bnAbs isolated in earlier studies, these bnAbs demonstrated broader and more potent activity against global HIV-1 panels and displayed impressive safety and efficacy profiles for therapeutic applications in a number of animal models and human clinical trials [1,[6][7][8][9][10][11]. These results also offer the opportunity to tailor these antibodies and maximize their prevention and treatment potential.…”

Clinical pharmacology in HIV cure research – what impact have we seen?

“…Moreover, BiIA-SG delayed HIV infection when compared to cART. A single injection of adeno-associated virus-transferred BiIA-SG gene resulted in prolonged in vivo A c c e p t e d M a n u s c r i p t 19 expression of BiIA-SG leading to HIV replication control and subsequently to the elimination of infected cells in humanized mice [110].…”