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

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.

Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy

“…Wallace et al described the synthesis of a glycopolymer called p(Man), which effectively targeted the liver and reduced antigen-specific cellular and humoral responses to various immunogenic proteins 21 . Here, we conjugated the polymer to BLG using a self-immolative DBCO linker ( Figure 1A, Figure S1, S2 ).…”

“…We have previously shown that glycosylation-modified conjugated antigens are successful at inducing both cellular and humoral tolerance through liver targeting, preventing the onset of autoimmune disease 18 and ADA responses 22 . However, s.c. administration could be clinically preferable for preventing food allergy in infants and children and may present fewer systemic safety concerns if administered to patients with existing food allergies.…”

“…Our group has previously investigated mechanisms of prophylactic antigen tolerance induced by glycopolymer-conjugated antigens administered via both i.v. and s.c. routes 18, 19, 21 . I.v.…”

“…Treatment durability was achieved 5 weeks following the first oral challenge and extended ∼4 weeks beyond B cell reconstitution ( Figure S8 ), suggesting that repeated anti-CD20 administration might not be required, minimizing potential immunosuppressive adverse events such as severe infections resulting from its use 51 . The obvious caveat of the study is that the effect of multiple rounds of anti-CD20 treatment cycles was not evaluated on pMan-BLG treatment efficacy and durability, but we do not expect this will be needed because the tolerance signatures induced by treatment with glycopolymer-conjugated antigen occur at the transcriptional level and are translated to a durable effect 21 .…”

“…The glycosylation modification, when applied to gluten antigen in celiac disease, has safely progressed through a phase I clinical trial (ClinicalTrials.gov Identifier: NCT04248855) 20, 21 , showing that the platform was safe and reduced T cell responses following a gluten challenge; another phase I clinical trial in multiple sclerosis (NCT04602390 ) is underway. Our latest endeavors of applying synthetic glycosylation technology include preventing anti-drug antibody (ADA) responses to prolong the efficacy of immunogenic protein drugs 22 , and here we further applied this technology in preventing and treating food allergies.…”