Synthetically mannosylated antigens impair the antigen-specific humoral immune response and prolong the therapeutic efficacy of immunogenic protein drugs

Abstract Immunogenic protein drugs trigger an anti-drug antibody (ADA) response in patients which reduces drug efficacy and increases adverse reactions. Our lab has previously shown that targeting antigen to the liver microenvironment can reduce antigen-specific T cell responses; herein, we present a novel strategy to further increase delivery of an antigen to the tolerogenic microenvironment of 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) treatment impairs the antibody response against recombinant uricase, a highly immunogenic biologic, without a dependence on hapten-skewing or control by Tregs. Through transcriptomic analysis we identified increased TCR signaling and increased apoptosis and exhaustion in T cells as effects of p(Man)-antigen treatment, which may inform the underlying mechanism driving the reduction in ADAs. This modular platform may enhance tolerance to current and future biologics, enabling long-term therapeutic solutions for an ever-increasing healthcare problem.