Synthetically mannosylated antigens induce antigen-specific humoral tolerance and reduce anti-drug antibody responses to immunogenic biologics

Wallace, R. P.; Refvik, K. C.; Antane, J. T.; Brünggel, K.; Tremain, A. C.; Raczy, M. R.; Alpar, A. T.; Nguyen, M.; Solanki, A.; Slezak, A. J.; Watkins, E. A.; Lauterbach, A. L.; Wilson, D. S.; Hubbell, J. A.

doi:10.1101/2023.04.07.534593

bioRxiv · 10.1101/2023.04.07.534593

Synthetically mannosylated antigens induce antigen-specific humoral tolerance and reduce anti-drug antibody responses to immunogenic biologics

Wallace, R. P.·Refvik, K. C.·Antane, J. T.·Brünggel, K.·Tremain, A. C.·Raczy, M. R.·Alpar, A. T.·Nguyen, M.·Solanki, A.·Slezak, A. J.·Watkins, E. A.·Lauterbach, A. L.·Wilson, D. S.·Hubbell, J. A.

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Abstract

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.

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Wallace, R. P., Refvik, K. C., Antane, J. T., Brünggel, K., Tremain, A. C., Raczy, M. R., Alpar, A. T., Nguyen, M., Solanki, A., Slezak, A. J., Watkins, E. A., Lauterbach, A. L., Wilson, D. S., Hubbell, J. A.. 2023-04-07. Synthetically mannosylated antigens induce antigen-specific humoral tolerance and reduce anti-drug antibody responses to immunogenic biologics. https://doi.org/10.1101/2023.04.07.534593

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