Anti-HIV-1 Nanobody-IgG1 Constructs With Improved Neutralization Potency and the Ability to Mediate Fc Effector Functions
Schriek, Angela I; van Haaren, Marlies M; Poniman, Meliawati; Dekkers, Gillian; Bentlage, Arthur E H; Grobben, Marloes; Vidarsson, Gestur; Sanders, Rogier W; Verrips, Theo; Geijtenbeek, Teunis B H; Heukers, Raimond; Kootstra, Neeltje A; de Taeye, Steven W; van Gils, Marit J
(2022) Frontiers in Immunology, volume 13, pp. 1 - 14
(Article)
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
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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.
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Keywords: Antibodies, Neutralizing/pharmacology, Broadly Neutralizing Antibodies, HIV Antibodies, HIV Seropositivity, HIV-1, Humans, Immunoglobulin G, Single-Domain Antibodies/pharmacology
ISSN: 1664-3224
Publisher: Frontiers Media S.A.
Note: Copyright © 2022 Schriek, van Haaren, Poniman, Dekkers, Bentlage, Grobben, Vidarsson, Sanders, Verrips, Geijtenbeek, Heukers, Kootstra, de Taeye and van Gils.
(Peer reviewed)