Gastrin-Releasing Protein (GRP) is the mammalian analog of bombesin, a 14- amino acid peptide initially isolated from the skin of the frog Bombina bombina. GRP receptors are expressed on a variety of human tumors including small cell carcinoma of the lung (SCCL), and breast cancer, but are rarely present on normal cells. Previous studies have shown that an immunoconjugate between CRP and a monoclonal antibody against the receptor for immunoglobulin (expressed on normal monocytes, macrophages, and lymphocytes) can solicit a specific antibody-dependent cell-mediated cytotoxicity (ADCC) directed towards SCCL cells. The mechanism of action is to bring into proximity targeted tumor cells and immune competent elements in the patient. The category of bifunctional proteins can be produced by different methods, such as fusion of the monoclonal antibody and GRP molecule, or by chemically linking the structures together. It is also possible that other surface makers can be used in the linkage. Thus, the specific aim for this Phase I SBIR application is to investigate whether or not different methods for producing the bifunctional molecules [fusion versus chemical linkage, and receptor for immunoglobulins (Fc-gamma-RI versus Fc-alpha-R)] can affect the effectiveness of the conjugates.
This research will lead to potentially therapeutic and minimally toxic agents for the treatment of small cell carcinomas of the lung and other GRP-receptor expressing tumors. Development of such therapeutics are greatly needed for SCCL for which currently available treatments provide only short-term remissions.
