Dokumentenart: | Artikel | ||||||
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Titel eines Journals oder einer Zeitschrift: | European Journal of Pharmaceutics and Biopharmaceutics | ||||||
Verlag: | Elsevier | ||||||
Ort der Veröffentlichung: | AMSTERDAM | ||||||
Band: | 181 | ||||||
Seitenbereich: | S. 88-101 | ||||||
Datum: | 2022 | ||||||
Institutionen: | Medizin > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Biologie und Vorklinische Medizin > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie III > Prof. Dr. Gernot Längst Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmazeutische Technologie (Prof. Göpferich) Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmazeutische Technologie (Prof. Göpferich) | ||||||
Identifikationsnummer: |
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Stichwörter / Keywords: | BROADLY NEUTRALIZING ANTIBODIES; ANTI-HIV-1 ANTIBODIES; RESPONSES; VACCINE; RECEPTORS; PROTEIN; DESIGN; STABILIZATION; IMMUNIZATION; DOMAIN; Nanotechnology; Silica nanoparticles; HIV-1; Vaccine; Immunogen design; Germline-targeting; Env; B cells; Multivalent interaction; Affinity; Avidity | ||||||
Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin 600 Technik, Medizin, angewandte Wissenschaften > 615 Pharmazie 600 Technik, Medizin, angewandte Wissenschaften > 615 Pharmazie | ||||||
Status: | Veröffentlicht | ||||||
Begutachtet: | Ja, diese Version wurde begutachtet | ||||||
An der Universität Regensburg entstanden: | Ja | ||||||
Dokumenten-ID: | 53245 |
Zusammenfassung
Selective targeting of germline B cells with specifically designed germline-targeting HIV-1 envelope immunogens (GT-Env) is considered a feasible vaccination strategy to elicit broadly neutralizing antibodies (bnAbs). BnAbs are extremely valuable because they neutralize genetically distant viral strains at the same time. To overcome its inherently low affinity to germline B cells, the aim of the ...
Zusammenfassung
Selective targeting of germline B cells with specifically designed germline-targeting HIV-1 envelope immunogens (GT-Env) is considered a feasible vaccination strategy to elicit broadly neutralizing antibodies (bnAbs). BnAbs are extremely valuable because they neutralize genetically distant viral strains at the same time. To overcome its inherently low affinity to germline B cells, the aim of the study was to present GT-Env via different immobili-zation strategies densely arrayed on the surface of nanoparticles. We engineered a prefusion-stabilized GT-Env trimer with affinity to VRC01 germline B cells using a bioinformatics-supported design approach. Distinct glycan modifications and amino acid substitutions yielded a GT-Env trimer which bound to the receptor with a KD of 11.5 mu M. Silica nanoparticles with 200 nm diameter (SiNPs) were used for the multivalent display of the novel GT-Env with a 15 nm mean centre-to-centre spacing either by site-specific, covalent conjugation or at random, non-specific adsorption. Oriented, covalent GT-Env conjugation revealed better binding of structure dependent bnAbs as compared to non-specifically adsorbed GT-Env. In addition, GT-Env covalently attached activated a B cell line expressing the germline VRC01 receptor at an EC50 value in the nanomolar range (4 nM), while soluble GT-Env required 1,000-fold higher concentrations to induce signalling. The significantly lower GT-Env con-centration was likely required due to avidity effects, which were in the picomolar range. Thus, low affinity antigens may particularly benefit from a particulate and multivalent delivery. In future, SiNPs are ideal to be modified in a modular design with various GT-Env variants that target different stages of germline and bnAb precursor B cells.
Metadaten zuletzt geändert: 23 Nov 2022 14:56