[cv]

Immunotherapy of Cancer: Targeting the Tight Junction

The A33 antigen is a membrane protein with highly specific expression in colon epithelium. This restricted pattern of expression has led investigators to test it as a potential target for radioimmunotherapy of colon cancer. Radiolabeled antibodies tested in the clinic against this antigen thus far have suffered from two flaws: the bone marrow toxicity common to directly radiolabeled antibodies; and despite humanization, an anti-antibody immune response. This project aims to correct these flaws. First, as antibodies developed to bind to A33 antigen show specific labeling of the colon one week after administration, two-step, pretargeted strategies appear to have promise in avoiding bone marrow toxicity. Accordingly I will study the trafficking properties and kinetics of the antigen in order to determine its appropriateness as a target in 2-step therapies. Secondly, I will use a yeast-displayed scFv library derived from the clinical antibody as a means of epitope-mapping the immunogenic site.