Modular Polymer Antigens To Optimize Immunity

Abstract

Subunit vaccines can have excellent safety profiles, but their ability to give rise to robust immune responses is often compromised. For glycan-based vaccines, insufficient understanding of B and T cell epitope combinations that yield optimal immune activation hinders optimization. To determine which antigen features promote desired IgG responses, we synthesized epitope-functionalized polymers using ring-opening metathesis polymerization (ROMP) and assessed the effect of B and T cell epitope loading. The most robust responses were induced by polymers with a high valency of B and T cell epitopes. Additionally, IgG responses were greater for polymers with T cell epitopes that are readily liberated upon endosomal processing. Combining these criteria, we used ROMP to generate a non-toxic, polymeric antigen that elicited stronger antibody responses than a comparable protein conjugate. These findings highlight principles for designing synthetic antigens that elicit strong IgG responses against inherently weak immune targets such as glycans.

Multivalent Scaffolds to Promote B cell Tolerance

“…(F) Magnitude of the IgG antibody response is positively correlated with the valency of both DNP and Ova323. Reprinted with permission from ref . Copyright 2019 American Chemical Society.…”

“…To determine which antigen features promote desired IgG antibody responses, the Kiessling group recently reported the use of synthetic polymers as vaccines in mouse models. 68 The authors assembled a polymer library that varied in length and degree of epitope substitution and probed how these factors influence immune response in vivo. They found that the magnitude of the B cell response positively correlated with the valency of both the B and T cell epitopes (Figure 5F).…”

Design of biomaterials through direct ring-opening metathesis polymerisation of functionalised cyclic alkenes

“…38) that affords multivalent norbornene imide in extremely high yield, high efficiency, and simplicity, 289 achieving the establishment of a modular, scalable, and well-defined bottlebrush prodrug (BPD) platform. 263–265,290–295…”

“…38) that affords multivalent norbornene imide in extremely high yield, high efficiency, and simplicity, 289 achieving the establishment of a modular, scalable, and welldefined bottlebrush prodrug (BPD) platform. [263][264][265][290][291][292][293][294][295] Recently, they reported using this BPD platform to explore combinations of drugs for optimal cancer treatment effects. 295 In this report, they conducted a study aimed at treating multiple myeloma, and demonstrated that a monotherapy of BPD based on a proteasome inhibitor (bortezomib) can slow tumor progression in vivo.…”

Chemical synthesis and immunological evaluation of entirely carbohydrate conjugate Globo H-PS A1

“…35 However, the imperfections of TACA-protein conjugates have also been unmasked and hindered success in clinical trials as a direct result of the "epitope suppression" effect which negatively affects immunization efficacy. [36][37][38][39] Additionally, less chemically well-dened conjugation methods can lead to inconsistencies in chemical composition from batch-to-batch samples. 40 The non-protein carrier approach, therefore, can be an attractive alternative towards cancer vaccine development and to this end, our group has been dedicated to developing TACA specic immunity employing an entirely carbohydrate conjugate strategy utilizing bacterial polysaccharide PS A1 from Bacteroides fragilis (ATCC 25285/NCTC 9343) as the immune stimulating "carrier" (Fig.…”