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J Clin Invest. 2018 Jun 1;128(6):2239-2251. doi: 10.1172/JCI96764. Epub 2018 Apr 23.

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

Author information

1
AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
2
The University of Hong Kong AIDS Institute Shenzhen Research Laboratory, Guangdong Key Laboratory of Emerging Infectious Diseases and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen, Guangdong Province, People's Republic of China.
3
Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, People's Republic of China.
4
Unit of Antiviral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People's Republic of China.
5
Comprehensive AIDS Research Center and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing, People's Republic of China.

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.

KEYWORDS:

AIDS/HIV; Immunotherapy; Virology

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