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Drug development: Sweet talk to receptors

In vivo fluorescence microscopy showing extravasation of human HCELL⁺ MSCs in mouse marrow after 1h (top) and 24h (bottom). Click here for a larger picture. From Sackstein et al.

Processes as diverse as blood cell migration to target tissues (homing) and virus-host cell interactions are largely dependent upon receptor-glycan interactions. Two recent studies now highlight how glycoengineering can harness these interactions for therapeutic strategies. In Nature Medicine, Sackstein et al. discuss their attempt to treat generalized skeletal diseases such as osteoporosis by directing the migration of human mesenchymal stem cells (MSCs) to bone proliferation zones. In Nature Biotechnology, Yang et al. describe a strategy to elicit a cytotoxic T cell response against tumors by targeting glycosylated antigens to the DC-SIGN (dendritic cell (DC)-specific intercellular adhesion molecule 3 grabbing nonintegrin) receptor.

Homing requires circulating cells to escape from blood vessels — a process initiated by the tethering of flowing cells to E-selectin on the vessel endothelium. Sackstein et al. observed that the terminal N-glycan structures of the human MSC CD44 molecule lack a fucose molecule required to form HCELL, a CD44 glycoform which is a potent E-selectin ligand terminated by sialyl Lewis X glycans. The authors synthesized HCELL using a cation-free fucosylation reaction that prevented death of the cells, which occurs with conventional fucosylation reaction conditions. After confirming that the glycoengineered human MSCs were viable and phenotypically multipotent under cell culture conditions, the authors injected the MSCs into mice and observed that the cells tethered to the E-selectin-expressing microvascular endothelium of marrow and infiltrated the marrow parenchyma. These results show that osteotropic migration can be induced in MSCs by ex vivo addition of a single carbohydrate to CD44 glycans. Moreover, the engineered MSCs exhibited osteogenic activity in vivo, suggesting that this approach has the potential to achieve bone regeneration. The creation of HCELL by glycan engineering may have important implications in tissue delivery for all forms of adoptive cellular therapy as CD44 is expressed on most cell types.

In a separate study, Yang et al. have removed the heparan sulfate (HS) binding site from the Sindbis virus envelope glycoprotein (SVG). The engineered SVG (SVGmu) bound solely to DCs through the DC-SIGN receptor, instead of binding to both DCs and HS which occurs abundantly on mammalian host cells. A similar specificity had been achieved previously by another group that also showed that the DC-SIGN-bound antigen is presented to DCs via the antigen-presenting pathway, thus eliciting a proliferation of CD4⁺ helper T cells. Yang et al. coupled SVGmu to the immunogenic chicken ovalbumin fragment (OVAp) — a known antigen for the mouse CD8⁺ T-cell receptor — and noticed an increase in cytotoxic CD8⁺ T-cell proliferation in a cell culture assay. When Yang et al. injected the SVGmu/OVAp construct into mice, the authors observed a dose-dependent OVAp-specific CD8⁺ T-cell response, as well as the production of antigen-specific immunoglobulins. Lastly, Yang et al. analyzed the vaccination potential of the SVGmu/OVAp construct in an E.G7 tumor model where mice develop ovalbumin-expressing tumors after injection of E.G7 lymphoma cells. Tumor development was entirely blocked in mice that received a SVGmu/OVAp vaccination before E.G7 injection, and existing E.G7 tumors receded after SVGmu/OVAP injection. Thus, the results of Yang et al. underscore the potential of tumor therapy by targeting carbohydrate-binding receptors, which is based on on the increasing knowledge about the specificity of lectin receptor binding.

Author: Mirko von Elstermann