Rational Design and Characterization of Trispecific Antibodies Targeting the HIV-1 Receptor and Envelope Glycoprotein

Abstract

Multitudinous broadly neutralizing antibodies (bNAbs) against HIV-1 have been developed as novel antiviral prophylactic and therapeutic agents. Combinations of bNAbs are generally even more effective than when they are applied individually, showing excellent neutralization coverage and limiting the emergence of escape mutants. In this study, we investigated the design and characterization of three trispecific antibodies that allow a single molecule to interact with independent HIV-1 envelope determinants—(1) the host receptor CD4, (2) the host co-receptor CCR5 and (3) distinct domains in the envelope glycoprotein of HIV-1—using an ELISA, an HIV-1 pseudovirus neutralization assay and in vivo antiviral experiments in humanized mice. We found that trispecific bNAbs and monovalent ones all had satisfactory binding activities against the corresponding antigens in the ELISA, exhibited higher potency and breadth than any previously described single bnAb in the HIV-1 pseudovirus neutralization assay and showed an excellent antiviral effect in vivo. The trispecific antibodies simultaneously recognize the host receptor CD4, host co-receptor CCR5 and HIV-1 envelope glycoprotein, which could mean they have promise as prophylactic and therapeutic agents against HIV-1.