TY - JOUR
T1 - Nanobody-mediated complement activation to kill HIV-infected cells
AU - Pedersen, Maria Lange
AU - Pedersen, Dennis Vestergaard
AU - Winkler, Mikael Becher Lykkegaard
AU - Olesen, Heidi Gytz
AU - Søgaard, Ole Schmeltz
AU - Østergaard, Lars
AU - Laursen, Nick Stub
AU - Rahimic, Anna Halling Folkmar
AU - Tolstrup, Martin
N1 - © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2023/4
Y1 - 2023/4
N2 - The complement system which is part of the innate immune response against invading pathogens represents a powerful mechanism for killing of infected cells. Utilizing direct complement recruitment for complement-mediated elimination of HIV-1-infected cells is underexplored. We developed a novel therapeutic modality to direct complement activity to the surface of HIV-1-infected cells. This bispecific complement engager (BiCE) is comprised of a nanobody recruiting the complement-initiating protein C1q, and single-chain variable fragments of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope (Env) protein. Here, we show that two anti-HIV BiCEs targeting the V3 loop and the CD4 binding site, respectively, increase C3 deposition and mediate complement-dependent cytotoxicity (CDC) of HIV-1 Env-expressing Raji cells. Furthermore, anti-HIV BiCEs trigger complement activation on primary CD4 T cells infected with laboratory-adapted HIV-1 strain and facilitates elimination of HIV-1-infected cells over time. In summary, we present a novel approach to direct complement deposition to the surface of HIV-1-infected cells leading to complement-mediated killing of these cells.
AB - The complement system which is part of the innate immune response against invading pathogens represents a powerful mechanism for killing of infected cells. Utilizing direct complement recruitment for complement-mediated elimination of HIV-1-infected cells is underexplored. We developed a novel therapeutic modality to direct complement activity to the surface of HIV-1-infected cells. This bispecific complement engager (BiCE) is comprised of a nanobody recruiting the complement-initiating protein C1q, and single-chain variable fragments of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope (Env) protein. Here, we show that two anti-HIV BiCEs targeting the V3 loop and the CD4 binding site, respectively, increase C3 deposition and mediate complement-dependent cytotoxicity (CDC) of HIV-1 Env-expressing Raji cells. Furthermore, anti-HIV BiCEs trigger complement activation on primary CD4 T cells infected with laboratory-adapted HIV-1 strain and facilitates elimination of HIV-1-infected cells over time. In summary, we present a novel approach to direct complement deposition to the surface of HIV-1-infected cells leading to complement-mediated killing of these cells.
KW - HIV-1
KW - bispecific complement engager
KW - complement
KW - immunotherapy
KW - nanobody
U2 - 10.15252/emmm.202216422
DO - 10.15252/emmm.202216422
M3 - Journal article
C2 - 36799046
SN - 1757-4676
VL - 15
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
M1 - e16422
ER -