Poly-L-Lysine-Based αGal-Glycoconjugates for Treating Anti-αGal IgE-Mediated Diseases

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.

Exploring the relationship between Faecalibacterium duncaniae and Escherichia coli in inflammatory bowel disease (IBD): Insights and implications

“…As explained above, anti-α-Gal antibodies could contribute to chronic inflammatory diseases including IBD [63] . In this case, the approach of reducing human anti-α-Gal antibody binding to mammalian cells by polyacrylamide-based or polylysine-based [108] , [109] α-Gal-glycoconjugates could potentially be used to reduce the risk of IBD associated with pro-inflammatory anti-α-Gal antibodies. This approach focuses on developing synthetic α-Gal epitope polymers that can inhibit the binding of anti-α-Gal antibodies to mammalian cells.…”

Removal of natural anti-αGal antibodies elicits protective immunity against Gram-negative bacterial infections

“…On the other hand, we also evidenced a reduced inhibitory effect of GAS914 over anti-aGal IgG1 and IgG3 in humans and IgG2a and IgG2b in mice, which react to protein antigens and are associated with induced antibodies, suggesting the potential preservation of these antibodies with the treatment. In addition, we have shown that distinct-sized polylysines, and different percentages of aGal attachment, modify the binding capacity of the glycopolymers to individual anti-aGal antibodies, suggesting the possibility of generating tailored molecules to remove specific isotypes (67).…”