Directing HIV-1 for degradation by non-target cells, using bi-specific single-chain llama antibodies.

Autor: Stam JC; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands. jcstam@ziggo.nl., de Maat S; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands., de Jong D; Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Arens M; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands., van Lint F; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands., Gharu L; Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., van Roosmalen MH; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands.; Intervet, Wim de Körverstraat 35, 5831 AN, Boxmeer, The Netherlands., Roovers RC; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands.; LAVA Therapeutics, Yalelaan 60, 3584CM, Utrecht, The Netherlands., Strokappe NM; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands., Wagner R; Molecular Microbiology and Gene Therapy, Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany., Kliche A; Molecular Microbiology and Gene Therapy, Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany., de Haard HJ; Argenx, Industriepark Zwijnaarde 7, 9052, Zwijnaarde, Belgium., van Bergen En Henegouwen PM; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands., Nijhuis M; Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Verrips CT; Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CH, Utrecht, The Netherlands.; QVQ Holding BV, Yalelaan 1, 3584 CL, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Aug 04; Vol. 12 (1), pp. 13413. Date of Electronic Publication: 2022 Aug 04.
DOI: 10.1038/s41598-022-15993-y
Abstrakt: While vaccination against HIV-1 has been so far unsuccessful, recently broadly neutralizing antibodies (bNAbs) against HIV-1 envelope glycoprotein were shown to induce long-term suppression in the absence of antiretroviral therapy in patients with antibody-sensitive viral reservoirs. The requirement of neutralizing antibodies indicates that the antibody mediated removal (clearance) of HIV-1 in itself is not efficient enough in these immune compromised patients. Here we present a novel, alternative approach that is independent of a functional immune system to clear HIV-1, by capturing the virus and redirecting it to non-target cells where it is internalized and degraded. We use bispecific antibodies with domains derived from small single chain Llama antibodies (VHHs). These bind with one domain to HIV-1 envelope proteins and with the other domain direct the virus to cells expressing epidermal growth factor receptor (EGFR), a receptor that is ubiquitously expressed in the body. We show that HIV envelope proteins, virus-like particles and HIV-1 viruses (representing HIV-1 subtypes A, B and C) are efficiently recruited to EGFR, internalized and degraded in the lysosomal pathway at low nM concentrations of bispecific VHHs. This directed degradation in non-target cells may provide a clearance platform for the removal of viruses and other unwanted agents from the circulation, including toxins, and may thus provide a novel method for curing.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje