MUC1 Humoral Immune Recognition: Mapping Antibody-Tumor Associated Antigen Interactions
EMSL Project ID
3321
Abstract
Mucin 1 (MUC1), a glycopeptide tumor associated antigen, provides an excellent target for the design of a breast cancer vaccine due to its overexpression in 90% of breast cancers. The MUC1 epithelial glycoprotein becomes a tumor antigen as a result of incomplete glycosylation and sparse distribution of remaining carbohydrate structures, leading to the exposure of a highly immunogenic core peptide sequence as well as cryptic core carbohydrate structures. While MUC1 peptide-based vaccines have generated strong humoral and cellular immune responses in animal models, they have not produced immune responses in breast cancer patients capable of rejecting solid tumor. The first step in the redesign of a MUC1 peptide vaccine is to more specifically characterize the structures present in the peptide ensemble of structures that are responsible for B cell receptor (or antibody) binding. Other groups have used combinatorial versions of these strategies to enhance epitope presentation in other systems. However, we propose a structure-based approach for the MUC1 system that capitalizes on a detailed molecular picture of MUC1 humoral and cellular immune recognition. This detailed molecular picture should allow us to intelligently direct a limited number of peptide modifications with the goal of both enhancing epitope presentation and also preserving immunospecificity of the anti-MUC1 response. To date, we have characterized the free MUC1 peptide structure and dynamics, as well as preliminary characterization of the bound state. Here, we propose to use the EMSL NMR facilities to fully characterize the antibody-bound state of uniformly 15N/13C-labeled MUC1 peptide. Initial studies will use the 750 or 800 MHz instruments to assign the bound resonances observed at 500 MHz.
Project Details
Project type
Capability Research
Start Date
2003-04-23
End Date
2004-04-26
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members