The objective of drug targeting, especially for cancer chemotherapy and radioimmunotherapy, is to enhance the effectiveness of the drug by concentrating it at the target site, and minimizing its effects in non-target sites. Lexrite's long-term goals are to create a pretargeted radiotherapy system using multivalent target binding followed by irreversible capture of a radionuclide, to achieve high tumor uptake and radiation combined with low normal tissue uptake and radiation toxicity. This combined with long residence time in the tumor and low immunogenicity, will enable repeated therapeutic doses to be given. We will use Lexrite's proprietary new Irreversible Antibody to test the feasibility of a novel 3-step pretargeting protocol using monoclonal antibody B72.3 to image cancer sites. The human LS174T nude mouse xenograft model will be used. B72.3 is a well-studied antibody that has been used clinically for imaging and experimental radioimmunotherapy in TAG-72 positive tumors such as colorectal, breast, prostate and ovarian cancer. Effective treatment of these important cancers is a major goal. In Phase II, this system will be further developed to optimize tumor uptake and reduce background in non-target organs to facilitate pretargeted radioimmunotherapy. Successful accomplishment of the 6 milestones described in this grant application and achievement of the Phase II goals, will lay the groundwork for clinical trials with the optimized pretargeting protocol. The approach described herein will lead to innovations in other areas of targeted imaging and therapy of disease.
Thesaurus Terms: drug delivery system, drug design /synthesis /production, drug metabolism, immunologic substance development /preparation, monoclonal antibody, neoplasm /cancer radioimmunotherapy, polyethylene glycol neoplasm /cancer site laboratory mouse
