Engineering pan-HIV-1 neutralization potency through multispecific antibody avidity

Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2112887119. doi: 10.1073/pnas.2112887119.

Abstract

Deep mining of B cell repertoires of HIV-1-infected individuals has resulted in the isolation of dozens of HIV-1 broadly neutralizing antibodies (bNAbs). Yet, it remains uncertain whether any such bNAbs alone are sufficiently broad and potent to deploy therapeutically. Here, we engineered HIV-1 bNAbs for their combination on a single multispecific and avid molecule via direct genetic fusion of their Fab fragments to the human apoferritin light chain. The resulting molecule demonstrated a remarkable median IC50 value of 0.0009 µg/mL and 100% neutralization coverage of a broad HIV-1 pseudovirus panel (118 isolates) at a 4 µg/mL cutoff-a 32-fold enhancement in viral neutralization potency compared to a mixture of the corresponding HIV-1 bNAbs. Importantly, Fc incorporation on the molecule and engineering to modulate Fc receptor binding resulted in IgG-like bioavailability in vivo. This robust plug-and-play antibody design is relevant against indications where multispecificity and avidity are leveraged simultaneously to mediate optimal biological activity.

Keywords: HIV-1; antibody; neutralization; protein engineering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibody Affinity / immunology*
  • Broadly Neutralizing Antibodies / chemistry
  • Broadly Neutralizing Antibodies / immunology
  • Epitopes / chemistry
  • Epitopes / immunology
  • HIV Antibodies / chemistry
  • HIV Antibodies / genetics
  • HIV Antibodies / immunology*
  • HIV-1 / immunology
  • Humans
  • Models, Molecular
  • Neutralization Tests* / methods
  • Protein Conformation
  • Protein Engineering* / methods
  • Structure-Activity Relationship

Substances

  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • Epitopes
  • HIV Antibodies