TY - JOUR
T1 - Anti-HIV-1 Nanobody-IgG1 Constructs With Improved Neutralization Potency and the Ability to Mediate Fc Effector Functions
AU - Schriek, Angela I.
AU - van Haaren, Marlies M.
AU - Poniman, Meliawati
AU - Dekkers, Gillian
AU - Bentlage, Arthur E. H.
AU - Grobben, Marloes
AU - Vidarsson, Gestur
AU - Sanders, Rogier W.
AU - Verrips, Theo
AU - Geijtenbeek, Teunis B. H.
AU - Heukers, Raimond
AU - Kootstra, Neeltje A.
AU - de Taeye, Steven W.
AU - van Gils, Marit J.
N1 - Funding Information: We thank Fondation Dormeur, Vaduz for their contribution of the Nanodrop. We thank Karel van Dort, from the department Laboratory for Viral Immune Pathogenesis at the AMC, for kindly sharing the THP-1 cells that were used for the ADCP assay. We thank VerLin b.v. for providing the sequences of the VHH. Publisher Copyright: Copyright © 2022 Schriek, van Haaren, Poniman, Dekkers, Bentlage, Grobben, Vidarsson, Sanders, Verrips, Geijtenbeek, Heukers, Kootstra, de Taeye and van Gils.
PY - 2022/5/16
Y1 - 2022/5/16
N2 - 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.
AB - 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.
KW - Fc fusion
KW - Fc-mediated effector functions
KW - HIV-1
KW - nanobodies
KW - neutralization
UR - http://www.scopus.com/inward/record.url?scp=85131270548&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2022.893648
DO - https://doi.org/10.3389/fimmu.2022.893648
M3 - Article
C2 - 35651621
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 893648
ER -