Carbohydrate-Based Polymers for Immune Modulation.

Carbohydrates play prominent roles in immune surveillance and response to infection. Multivalency, molecular weight control, and molecular architecture control are properties that polymer science is well suited to address. Each of these properties has been demonstrated to impact the biological interaction of carbohydrate-bearing chains with their binding partners. This viewpoint highlights synthetic advances and potential applications of carbohydrate-based polymers for immune modulation. It also offers future directions in polymer science necessary for carbohydrate polymers to fulfill their potential as immune modulators.

Biological polymers include DNA, RNA, proteins, and polysaccharides. DNA, RNA, and proteins are sequence-specific linear polymers with fixed molecular weights; they generally lack polydispersity in chain length, other than for different isoforms. In contrast, natural polysaccharides tend to be less exact in chain length (exhibit broader polydispersities), molecular architecture (incorporate branches), connectivity (multiple reactive sites on each glycoside), and sequence (i.e., glycosaminoglycans exhibit variations in patterns of sulfation). In terms of these structural properties, polysaccharides are conceptually similar to synthetic polymers. The complex nature of polysaccharides makes their precise synthesis difficult for chemists. However, polymer chemists are becoming adept at synthesizing glycomimetics which recapture many of the properties of naturally occurring polysaccharides. Polysaccharides play a myriad of roles in human health and disease; they play crucial roles in our immune system, including in pathogen recognition and viral entry. Polymers in general, and glycomimetics specifically, are therefore promising candidates for immune system modulation.

Immune system modulation induces, enhances, or suppresses the body’s natural immune response toward a particular disease state. The polymer community has contributed significantly to recent advances in the field through the design of polymeric vehicles that improve or enhance the delivery of immunomodulatory signals to cells of the immune system. For example, lipid or polymer nanoparticles loaded with adjuvant drugs have been covalently conjugated to T cells to provide sustained stimulation to the lymphocyte.[1] In another example, tumor lysates were loaded into a polymer scaffold along with GM-CSF (a dendritic cell chemoattractant) and cytosine-guanosine oligonucleotides (a danger signal that would mimic a bacterial infection) to activate dendritic cells in vivo and generate antitumor immunity.[2] In both these cases, the primary immune modulatory component was a donor immune cell or tumor lysate, which have the drawbacks of any natural product: difficulty with the isolation, purification, and verification of the safety of products, batch to batch variability, limited supply, and complexity in determining structure–property relationships of compounds.

As an alternative to their use as delivery vehicles for immune signals, biomimetic polymers can be used as the immunomodulatory cues themselves (synthetic antigens). Compared to immune cells, tumor lysates, or other natural extracts, synthetic antigens present far fewer concerns about their purity and availability. Additionally, synthetic antigens exhibit defined and reproducible structures so that mechanistic studies linking structure and activity can be conducted. Accordingly, many immune modulators are synthetic, such as polyinosinic:polycytidylic acid (analogues of double-stranded RNA present in viral genomes) or aminoalkyl glucosaminide 4-phosphates[3] (analogues of bacterial lipopolysaccharides). Structures based on carbohydrates have also been used as immune modulators due to the prominent role carbohydrates play in immune recognition and response. This research path was pioneered with the use of bacterial conjugate vaccines derived from natural bacterial membrane polysaccharides. Along similar lines, tumor-associated carbohydrate antigens (TACA) have been investigated as targets for prophylactic or therapeutic vaccination against cancer.[4] The first generation of these vaccines presented TACAs in their monomeric form,[5] but later iterations used clustered antigens on a peptide backbone[6] or dendrimers functionalized with exterior carbohydrates.[7] This evolution of vaccine design toward larger multivalent structures[8] reflects the need to account for carbohydrate heterogeneity on tumor cell surfaces, as well as the increased protein binding seen for structures with higher carbohydrate density and loading.[9]

Polymer science is well-suited to address the requirement for multivalent structures. While dendritic structures allow for sufficient multivalency, their synthesis is plagued by significant limitations such as the need for repeated protection/deprotection steps, low overall yields, and difficulty in fully characterizing higher generations. Synthetic carbohydrate-based polymers represent the most facile route toward creating well-defined, high-valency structures. Automated solid-phase synthesis[10] allows for smaller synthetic polysaccharides (sugars connected through glycosidic bonds), and controlled polymerization techniques[11] allow for synthesis of glycopolymers (sugars connected through a synthetic backbone). Polymerization techniques, including controlled polymerization methods, offer the opportunity to introduce other structural variables such as branching or variations in monomer density or chain sequence into synthetic antigens, permitting the establishment of structure–bioactivity relationships and introducing the possibility of molecular-based attenuation.

These carbohydrate-containing polymers have immunotherapy applications beyond cancer vaccinations, including vaccination against bacterial pathogens, complement activation, macrophage targeting, viral inhibition, and transplant rejection. In this viewpoint, we provide an overview of the role glycopolymers have played in basic and clinical research and conclude with thoughts about future progress necessary to advance the field.