Poly-L-Lysine-Based αGal-Glycoconjugates for Treating Anti-αGal IgE-Mediated Diseases
Olivera-Ardid, Sara (RemAb Therapeutics)
Bello-Gil, Daniel (RemAb Therapeutics)
Tuzikov, Alexander (Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences)
Araujo, Ricardo N. (Laboratório de Artrópodes Hematófagos (Brasil))
Ferrero-Alves, Yara (Universitat Autònoma de Barcelona)
García Figueroa, Blanca Esther (Instituto de Salud Carlos III)
Labrador Horrillo, Moises (Hospital Universitari Vall d'Hebron. Institut de Recerca)
García-Pérez, Ana L. (Instituto Vasco de Investigación de Desarrollo Agrario)
Bovin, Nicolai (Institute of Bioorganic Chemistry Russian Academy of Sciences)
Mañez, Rafael (Institut d'Investigació Biomèdica de Bellvitge)
Universitat Autònoma de Barcelona. Departament de Medicina

Date:	2022
Abstract:	Anti-αGal IgE antibodies mediate a spreading allergic condition known as αGal-syndrome (AGS). People exposed to hard tick bites are sensitized to αGal, producing elevated levels of anti-αGal IgE, which are responsible for AGS. This work presents an immunotherapy based on polymeric αGal-glycoconjugates for potentially treating allergic disorders by selectively inhibiting anti-αGal IgE antibodies. We synthesized a set of αGal-glycoconjugates, based on poly-L-lysine of different degrees of polymerization (DP1000, DP600, and DP100), to specifically inhibit in vitro the anti-αGal IgE antibodies in the serum of αGal-sensitized patients (n=13). Moreover, an animal model for αGal sensitization in GalT-KO mice was developed by intradermal administration of hard tick' salivary gland extract, mimicking the sensitization mechanism postulated in humans. The in vitro exposure to all polymeric glycoconjugates (5-10-20-50-100 µg/mL) mainly inhibited anti-αGal IgE and IgM isotypes, with a lower inhibition effect on the IgA and IgG, respectively. We demonstrated a differential anti-αGal isotype inhibition as a function of the length of the poly-L-lysine and the number of αGal residues exposed in the glycoconjugates. These results defined a minimum of 27 αGal residues to inhibit most of the induced anti-αGal IgE in vitro. Furthermore, the αGal-glycoconjugate DP1000-RA0118 (10 mg/kg sc. ) showed a high capacity to remove the anti-αGal IgE antibodies (≥75% on average) induced in GalT-KO mice, together with similar inhibition for circulating anti-αGal IgG and IgM. Our study suggests the potential clinical use of poly-L-lysine-based αGal-glycoconjugates for treating allergic disorders mediated by anti-αGal IgE antibodies.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	αGal-syndrome ; Poly-l-lysine-based αGal-glycoconjugates ; Anti-αgal IgE inhibition ; GalT-KO mice ; Immunotherapy
Published in:	Frontiers in immunology, Vol. 13 (march 2022) , ISSN 1664-3224

DOI: 10.3389/fimmu.2022.873019
PMID: 35432370

13 p, 4.3 MB

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