The objective of the proposed research is to develop a therapeutic agent based on pretarget radioimmunotherapy that is superior to the current treatments of non-Hodgkin's B-cell lymphoma in terms of therapeutic efficacy and non-target organ toxicity. Fusion proteins of a single chain antibody and streptavidin (scFv/SA) will be developed that are reactive with CD2O and target in a lymphoma xenograft animal model. Two candidate scFv/SA constructs will be genetically modified (e.g., with changes to the linker region) for the purpose of improving the expression, purification, and/or biochemical characteristics. Additional fusion constructs will be generated from selection of a human Fab/phage display library on CD2O-positive peripheral blood lymphocytes. All scFv/SA candidates will be evaluated for meeting set criteria for E. coli expression level, purification yield, immunoreactivity and CD2O cell binding, biotin binding affinity, and targeting ability in a lymphoma xenograft animal model. These characteristics should be sufficient to warrant further Phase II efforts directed toward cGMP scale-up and formulation development for clinical trials. PROPOSED COMMERCIAL APPLICATIONS: The application of radioimmunotherapy toward the treatment of non- Hodgkin's lymphoma (NHL) has been constrained by dose limiting toxicity to the radiosensitive bone marrow. Antibody pretargeting provides a method to specifically deliver significantly greater doses to tumor sites without serious toxicities. A large number of patients with NHL are candidate's for this treatment. These patients represent a sizable market opportunity.
