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

Nat Commun. 2018 Feb 28;9(1):877. doi: 10.1038/s41467-018-03335-4.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • Antibodies, Neutralizing / therapeutic use
  • Antiviral Agents / chemistry
  • Antiviral Agents / immunology
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Drug Combinations
  • Drug Design*
  • Epitopes / genetics
  • Epitopes / immunology
  • HIV Antibodies / chemistry
  • HIV Antibodies / immunology
  • HIV Antibodies / pharmacology*
  • HIV Antibodies / therapeutic use
  • HIV Infections / drug therapy*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / immunology
  • Humans
  • Microscopy, Electron
  • Mutation
  • Protein Subunits / immunology
  • Single-Chain Antibodies / chemistry
  • Single-Chain Antibodies / immunology
  • Single-Chain Antibodies / pharmacology
  • Single-Chain Antibodies / therapeutic use
  • env Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology


  • Antibodies, Neutralizing
  • Antiviral Agents
  • Drug Combinations
  • Epitopes
  • HIV Antibodies
  • Protein Subunits
  • Single-Chain Antibodies
  • env Gene Products, Human Immunodeficiency Virus