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

Frontiers in Immunology

Arthur E. H. Bentlage²  Gestur Vidarsson²  Teunis B. H. Geijtenbeek³  Neeltje A. Kootstra³  Meliawati Poniman⁴  Marlies M. van Haaren⁴  Steven W. de Taeye⁴  Marit J. van Gils⁴  Angela I. Schriek⁴  Marloes Grobben⁴  Rogier W. Sanders⁵  Gillian Dekkers⁶  Raimond Heukers⁶  Theo Verrips⁷ 

[1] Department of Biology, Faculty of Sciences, Utrecht University, Utrecht, Netherlands;Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands;Department of Experimental Immunology, Amsterdam UMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands;Department of Medical Microbiology, Amsterdam UMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands;Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, United States;QVQ Holding BV, Utrecht, Netherlands;VerLin BV, Utrecht, Netherlands;

关键词: HIV-1;    nanobodies;    neutralization;    Fc fusion;    Fc-mediated effector functions;   

DOI  :  10.3389/fimmu.2022.893648

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown