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
Date Published2018 Feb 28

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.

Alternate JournalNat Commun
PubMed ID29491415
PubMed Central IDPMC5830440
Grant ListT32 AI125186 / AI / NIAID NIH HHS / United States