Anti-HIV-1 Nanobody-IgG1 Constructs With Improved Neutralization Potency and the Ability to Mediate Fc Effector Functions

Angela I Schriek, Marlies M van Haaren, Meliawati Poniman, Gillian Dekkers, Arthur E H Bentlage, Marloes Grobben, Gestur Vidarsson, Rogier W Sanders, Theo Verrips, Teunis B H Geijtenbeek, Raimond Heukers, Neeltje A Kootstra, Steven W de Taeye, Marit J van Gils

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The most effective treatment for HIV-1, antiretroviral therapy, suppresses viral replication and averts the disease from progression. Nonetheless, there is a need for alternative treatments as it requires daily administration with the possibility of side effects and occurrence of drug resistance. Broadly neutralizing antibodies or nanobodies targeting the HIV-1 envelope glycoprotein are explored as alternative treatment, since they mediate viral suppression and contribute to the elimination of virus-infected cells. Besides neutralization potency and breadth, Fc-mediated effector functions of bNAbs also contribute to the in vivo efficacy. In this study multivalent J3, 2E7 and 1F10 anti-HIV-1 broadly neutralizing nanobodies were generated to improve neutralization potency and IgG1 Fc fusion was utilized to gain Fc-mediated effector functions. Bivalent and trivalent nanobodies, coupled using long glycine-serine linkers, showed increased binding to the HIV-1 Env and enhanced neutralization potency compared to the monovalent variant. Fusion of an IgG1 Fc domain to J3 improved neutralization potency compared to the J3-bihead and restored Fc-mediated effector functions such as antibody-dependent cellular phagocytosis and trogocytosis, and natural killer cell activation. Due to their neutralization breadth and potency and their ability to induce effector functions these nanobody-IgG1 constructs may prove to be valuable towards alternative HIV-1 therapies.

Original languageEnglish
Article number893648
Pages (from-to)1-14
JournalFrontiers in Immunology
Volume13
DOIs
Publication statusPublished - 16 May 2022

Keywords

  • Antibodies, Neutralizing/pharmacology
  • Broadly Neutralizing Antibodies
  • HIV Antibodies
  • HIV Seropositivity
  • HIV-1
  • Humans
  • Immunoglobulin G
  • Single-Domain Antibodies/pharmacology

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