The goal of our group is to understand how antibodies to carbohydrates are generated, what they do, and how we can use them to improve cancer care. We focus in two main areas: 1) improving access to carbohydrate binding monoclonal antibodies, and 2) understanding the roles of serum anti-glycan antibodies for cancer treatment, especially immunotherapies. To facilitate these studies, we have developed a carbohydrate microarray, or glycan array, that allows high-throughput analysis of antibody binding properties and profiling of serum anti-glycan antibody populations. The array has over 700 array components, including a diverse collection of glycans, glycopeptides, and natural glycoproteins. Our array is unique in that we use multivalent neoglycoproteins as our primary array components. This format allows us to readily translate array results to other applications and affords novel approaches to vary glycan presentation.
Monoclonal Antibodies to Carbohydrates
Anti-glycan antibodies have significant potential for cancer applications such as diagnostics and therapeutics. Unfortunately, there are relatively few good carbohydrate binding antibodies available for the community. The lack of antibodies is a major problem for basic research in the field of glycobiology and limits antibody-based diagnostics and therapeutics. We have been taking a multipronged approach to improving access to carbohydrate binding antibodies. First, we have developed a database of glycan binding antibodies and reagent lectins, called Database of Anti-Glycan Reagents or DAGR, https://ccr2.cancer.gov/resources/Cbl/Tools/Antibody/). DAGR provides a unique resource where researchers can locate antibodies of interest and find information about those antibodies. Second, we have screened hundreds of antibodies and lectins on our microarray to better define selectivity with the goal of making it easier to select the optimal antibody for a project. More recently, we are investigating how the immune system initiates an antibody response to a glycan and how the antibodies evolve during the immune response. The array allows us to investigate the affinity and selectivity of the initially formed germline antibodies and compare them to the affinity matured antibodies. Additionally, we have been investigating new strategies to modulate the response to carbohydrate antigens and new strategies to obtain good antibodies with the aid of our microarray.
Antibody Responses to Vaccines and Other Immunotherapies
We have a long-standing interest in understanding the roles of anti-glycan serum antibodies in the treatment of cancer. We are especially interested in studying antibody responses induced by cancer vaccines and other immunotherapies. We have evaluated responses by whole cell vaccines (e.g.GVAX Pancreas), poxvirus-based vaccines (e.g. PROSTVAC), and carbohydrate-based cancer vaccines. These projects are shedding new light on how cancer vaccines and other immunotherapies work and are uncovering new biomarkers for precision medicine.
Glycan microarray technology
We rely heavily on glycan array technology to study immune responses to carbohydrates, and we continually strive to improve this technology. First, carbohydrate-protein interactions often involve formation of multivalent complexes. Therefore, presentation is a key feature of recognition. We have developed several new approaches to vary carbohydrate presentation on the surface of the array, including methods to vary glycan density and neoglycoprotein density. Second, we use synthetic organic chemistry to obtain a diverse set of tumor-associated carbohydrates and glycopeptides to populate our array.
Collaborations and Carbohydrate Microarray Screening
We are frequently asked to screen lectins, antibodies, and other entities on our array. Although we are not a core facility and do not provide screening services per se, we are happy to collaborate on many projects, especially those related to cancer. Please contact Jeff Gildersleeve for more details.