Nat Commun. 2018 Feb 28; 9(1):877.

PubMed ID: 29491415

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

Steinhardt JJ, Guenaga J, Turner HL, McKee K, Louder MK, O'Dell S, Chiang CI, Lei L, Galkin A, Andrianov AK, A Doria-Rose N, Bailer RT, Ward AB, Mascola JR, Li Y

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.