(517d) Immunotherapeutic Targeting of Cancer Cell-Associated Polysialic Acid

The glycocalyx consists of a dense meshwork of sugar polymers called glycans that are interspersed with transmembrane proteins and other cell surface machinery. Glycans are believed to encode the structural organization of the glycocalyx, and in doing so, tune how these systems perceive and process critical information from the microenvironment. Moreover, the glycocalyx undergoes changes with the onset of cancer and the altered glycans play functional roles in tumor growth and metastasis. One example is polysialic acid (polySia), a polymer of α2, 8-linked sialic acid residues that accumulates on the surface of different cancers including breast, lung, neuroblastoma, and pancreatic. In addition to functioning as a diagnostic indicator, polySia also impacts the biology of the affected cells by inhibiting adhesion and promoting metastasis. To better understand the important roles played by polySia in cancer, we are developing highly specific glycan-binding reagents for imaging studies as well as for potential therapeutic intervention. This presentation will discuss our efforts to develop and characterize polySia-specific monoclonal, Fab and scFv antibodies, including glycan microarray profiling of binding specificity, Biacore analysis of binding affinity, internalization assays to measure antibody-mediated receptor endocytosis, and evaluation of antibody-mediated tumor cell killing capabilities. Collectively, our results are helping to delineate the connection between aberrant polySia glycosylation and the invasive and metastatic potential of different cancers, as well as revealing the potential of high-affinity polySia antibodies for therapeutic use. This work contributes to a growing body of evidence that demonstrates the importance of investigating carbohydrate epitopes as targets for immunotherapy.