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

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Title: Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice
Authors: Wu, X
Guo, J
Niu, M
An, M
Liu, L
Wang, H
Jin, X
Zhang, Q
Lam, KS
Wu, T
Wang, H
Wang, Q
Du, Y
Li, J
Cheng, L
Tang, HY
Shang, H
Zhang, L
Zhou, P
Chen, Z
Item 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.
Issue Date: 1-Jun-2018
Date of Acceptance: 16-Feb-2018
URI: http://hdl.handle.net/10044/1/64307
DOI: https://dx.doi.org/10.1172/JCI96764
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.
Keywords: 11 Medical And Health Sciences
Publication Status: Published
Open Access location: https://www.jci.org/articles/view/96764
Online Publication Date: 2018-02-20
Appears in Collections:Department of Medicine (up to 2019)