Rational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity

James J. Steinhardt, Javier Guenaga, Hannah L. Turner, Krisha McKee, Mark K. Louder, Sijy O’Dell, Chi-I Chiang, Lin Lei, Andrey Galkin, Alexander K. Andrianov, Nicole Doria-Rose, Robert T. Bailer, Andrew B. Ward, John R. Mascola and Yuxing Li ()
Additional contact information
James J. Steinhardt: University of Maryland
Javier Guenaga: The Scripps Research Institute
Hannah L. Turner: The Scripps Research Institute
Krisha McKee: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Mark K. Louder: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Sijy O’Dell: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Chi-I Chiang: University of Maryland
Lin Lei: University of Maryland
Andrey Galkin: University of Maryland
Alexander K. Andrianov: University of Maryland
Nicole Doria-Rose: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Robert T. Bailer: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Andrew B. Ward: The Scripps Research Institute
John R. Mascola: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Yuxing Li: University of Maryland

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract HIV-1 broadly neutralizing antibodies (bNAbs) are being explored as passively administered therapeutic and preventative agents. However, the extensively diversified HIV-1 envelope glycoproteins (Env) rapidly acquire mutations to evade individual bNAbs in monotherapy regimens. The use of a “single” agent to simultaneously target distinct Env epitopes is desirable to overcome viral diversity. Here, we report the use of tandem single-chain variable fragment (ScFv) domains of two bNAbs, specific for the CD4-binding site and V3 glycan patch, to form anti-HIV-1 bispecific ScFvs (Bi-ScFvs). The optimal Bi-ScFv crosslinks adjacent protomers within one HIV-1 Env spike and has greater neutralization breadth than its parental bNAbs. Furthermore, the combination of this Bi-ScFv with a third bNAb recognizing the Env membrane proximal external region (MPER) results in a trispecific bNAb, which has nearly pan-isolate neutralization breadth and high potency. Thus, multispecific antibodies combining functional moieties of bNAbs could achieve outstanding neutralization capacity with augmented avidity.

Date: 2018
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DOI: 10.1038/s41467-018-03335-4

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