Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice
File(s)
OA Location
Author(s)
Type
Journal Article
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.
Date Issued
2018-06-01
Date Acceptance
2018-02-16
Citation
Journal of Clinical Investigation, 2018, 128 (6), pp.2239-2251
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Start Page
2239
End Page
2251
Journal / Book Title
Journal of Clinical Investigation
Volume
128
Issue
6
Copyright Statement
© 2018 American Society for Clinical Investigation.
Subjects
11 Medical And Health Sciences
Immunology
Publication Status
Published
Date Publish Online
2018-02-20