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

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TitleRational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity.
Publication TypeJournal Article
Year of Publication2018
AuthorsSteinhardt, JJ, Guenaga, J, Turner, HL, McKee, K, Louder, MK, O'Dell, S, Chiang, C-I, Lei, L, Galkin, A, Andrianov, AK, Doria-Rose, NA, Bailer, RT, Ward, AB, Mascola, JR, Li, Y
JournalNat Commun
Volume9
Issue1
Pagination877
Date Published2018 Feb 28
ISSN2041-1723
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.

DOI10.1038/s41467-018-03335-4
Alternate JournalNat Commun
PubMed ID29491415
PubMed Central IDPMC5830440
Grant ListT32 AI125186 / AI / NIAID NIH HHS / United States