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

• DOI: 10.1038/s41467-018-03335-4
• Publication Date: 2018-02-22T17:32:18Z
• Authors: James J. Steinhardt; Javier Guenaga; Hannah L. Turner; Krisha McKee; Mark K. Louder; Sijy O’Dell; Chi-I Chiang; Lin Lei; Andrey Galkin; Alexander K. Andr...; Nicole A. Doria-Rose; Robert T. Bailer; Andrew B. Ward; John R. Mascola; Yuxing Li
• Keywords: 0301 basic medicine; Science; Q; env Gene Products, Human Immunodeficiency Virus; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; Antiviral Agents; Article; 3. Good health; Drug Combinations; Epitopes; Microscopy, Electron; Protein Subunits; 03 medical and health sciences; Drug Design; Mutation; HIV-1; Humans; Single-Chain Antibodies

Abstract HIV-1 broadly neutralizing antibodies (bNAbs) are being explored as passively administered therapeutic and preventative agents. However, the extensively diversified envelope glycoproteins (Env) rapidly acquire mutations to evade individual bNAbs in monotherapy regimens. The use of a “single” agent simultaneously target distinct Env epitopes is desirable overcome viral diversity. Here, we report tandem single-chain variable fragment (ScFv) domains two bNAbs, specific for CD4-binding site V3 glycan patch, form anti-HIV-1 bispecific ScFvs (Bi-ScFvs). optimal Bi-ScFv crosslinks adjacent protomers within one spike has greater neutralization breadth than its parental bNAbs. Furthermore, combination this with third bNAb recognizing membrane proximal external region (MPER) results trispecific bNAb, which nearly pan-isolate high potency. Thus, multispecific combining functional moieties could achieve outstanding capacity augmented avidity.