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268 Novel Antibody Epitope Mapping Technologies

Number of anticipated awards: 4
(Fast-Track proposals will be accepted.)
Budget (total costs): Phase I: $150,000;
Phase II: $750,000

The deadline for receipt of all contract proposals submitted in response to this solicitation is:
5:00 p.m. Eastern Standard Time
Monday, November 3, 2008

Summary:

The purpose of this initiative is to provide support for the development of novel epitope mapping technologies. Epitope Mapping encompasses all the major methods for the identification and definition of epitopes. The ability to characterize the epitope of an antibody on its target protein is now being extensively employed to develop new therapeutics and biomarkers. This epitope information can help researchers to understand the "mechanism of action" of an antibody, to predict the potential cross-reactivity and connecting a SNP polymorphism to a specific protein structure. In addition, epitope mapping has been used as a powerful tool for rational drug design. Studies have revealed that while off-rate is an important factor in determining antibody potency, it is not the critical factor. Antibodies can recognize a linear string of amino acids, but they frequently bind to discontinuous/conformational epitopes (i.e. amino acids in a protein sequence that are brought together in the three-dimensional protein fold but are disparate in its linear sequence). Therefore the quality of antibodies results from the fine specificity of the molecular interactions, rather than simple binding parameters. A number of computational algorithms are now available for mapping conformational discontinuous epitopes. Additionally, various methods namely use of synthetic peptides, expression cloning, site directed mutagenesis and protein footprinting have also been used for epitope mapping.

Specifically, the NCI is interested in proposals that focus on the development of novel, fast, reliable and economical epitope mapping techniques. Proposals should explicitly describe how the proposed technology/system will develop and characterize monoclonal antibody epitope mapping.

Project Goals:
Information about the epitopes of proteins recognized by antibodies is important for their use as biological or diagnostic tools as well as for understanding molecular recognition events. The information about Ab-antigen interactions gained from epitope mapping can be utilized in two important ways: either by using engineered Abs as bait for the detection of antigens in biologic samples; or by using recombinant proteins as diagnostic tools for the presence of Abs produced in an immune response. The purpose of this project is to stimulate the development of novel, fast, reliable and economical monoclonal antibody epitope mapping technologies including mass spectrometry (MS) based methods.
Offerors are encouraged to coordinate and pursue selected monoclonal Abs developed by the Clinical Cancer Proteomics community. These Abs are being generated from biomarkers listed in the following reference: Malu Polanski and N. Leigh Anderson. (2006) “A List of Candidate Cancer Biomarkers for Targeted Proteomics.” Biomarker Insights 2:1-48.

Phase I Activities and Expected Deliverables

• Demonstrate the feasibility of the innovative monoclonal Ab epitope mapping method (including MS-based techniques).
• Produce an initial product prototype in working with the Clinical Proteomic Technologies Initiative community.
• Demonstrate that epitope mapping method can be made reproducibly and economically.
• Epitope map at least 10 monoclonal Abs (offerors are encouraged to select targets in coordination with the Clinical Cancer Proteomics community).
• Functionally characterize the mapped epitopes e.g. demonstrate which amino acids are critical for binding.
• Present findings to NCI program staff.
• Research should be proposed with quantitative feasibility milestones.

Phase II Activities and Expected Deliverables

• Implement strategy and project plan for a fully functional novel, fast, reliable and economical epitope mapping technology. Achievement of such criteria could be derived by comparison with existing technologies.
• Epitope map at least 100 monoclonal Abs (targets to be selected in coordination with the Clinical Cancer Proteomics community).
• Functionally characterize the mapped epitopes e.g. demonstrate which amino acids are critical for binding.
• Work with the Clinical Proteomics community to integrate platform into the technology assessment programs and greater scientific community.
• Research should be proposed with quantitative feasibility milestones.