Item type: | Article | ||||||
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Journal or Publication Title: | European Journal of Pharmaceutics and Biopharmaceutics | ||||||
Publisher: | Elsevier | ||||||
Volume: | 181 | ||||||
Page Range: | pp. 88-101 | ||||||
Date: | 2022 | ||||||
Institutions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Prof. Dr. Rainer Merkl Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Technology (Prof. Göpferich) | ||||||
Identification Number: |
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Dewey Decimal Classification: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy | ||||||
Status: | Published | ||||||
Refereed: | Yes, this version has been refereed | ||||||
Created at the University of Regensburg: | Yes | ||||||
Item ID: | 53245 |
Abstract
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 ...

Abstract
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 immobilization 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 µM. 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 concentration 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.
Metadata last modified: 23 Nov 2022 14:56