| Autor: |
Wallace RP, Refvik KC, Antane JT, Brünggel K, Tremain AC, Raczy MR, Alpar AT, Nguyen M, Solanki A, Slezak AJ, Watkins EA, Lauterbach AL, Cao S, Wilson DS, Hubbell JA |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 19. Date of Electronic Publication: 2023 Sep 19. |
| DOI: |
10.1101/2023.04.07.534593 |
| Abstrakt: |
Immunogenic biologics trigger an anti-drug antibody (ADA) response in patients, which reduces efficacy and increases adverse reactions. Our laboratory has previously shown that targeting protein antigen to the liver microenvironment can reduce antigen-specific T cell responses; herein, we present a strategy to increase delivery of otherwise immunogenic biologics to the liver via conjugation to a synthetic mannose polymer (p(Man)). This delivery leads to reduced antigen-specific T follicular helper cell and B cell responses resulting in diminished ADA production, which is maintained throughout subsequent administrations of the native biologic. We found that p(Man)-antigen treatment impairs the ADA response against recombinant uricase, a highly immunogenic biologic, without a dependence on hapten immunodominance or control by Tregs. We identify increased TCR signaling and increased apoptosis and exhaustion in T cells as effects of p(Man)-antigen treatment via transcriptomic analyses. This modular platform may enhance tolerance to biologics, enabling long-term solutions for an ever-increasing healthcare problem. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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