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

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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
JournalFrontiers in immunology
Publication statusPublished - 16 May 2022


  • Fc fusion
  • Fc-mediated effector functions
  • HIV-1
  • nanobodies
  • neutralization

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