) Small cell carcinoma of the lung (SCCL) accounts for about 15 percent to 25 percent of all lung cancers. The prognosis for SCCL remains poor. More than 40,000 cases of SCCL are diagnosed and over 35,000 people die of this disease in the United States per year. While chemotherapy is the mainstay of treatment for SCCL, many combinations of chemotherapeutic agents have been tried clinically without much improvement in the long-term survival rate. We have developed a novel bispecific immunoconjugate designed for the therapy of SCCL. The targeting structure on the cancer cell is important to the overall activity of the immunoconjugate. We have chosen to target the receptor for the bombesin-like peptides. Bombesin is a 14-amino acid peptide which was initially isolated from the skin of the frog Bombina bombina. The mammalian analogue of bombesin, gastrin-releasing peptide (GRP) has been shown to contain a carboxy-terminal heptapeptide sequence identical to that of bombesin. The majority of human SCCL cell lines produce GRP, and express high-affinity receptors for BN/GRP. We reasoned that these cell surface receptors for GRP, and expressed on the majority of SCCL cells but only rarely on normal tissues, might serve as ideal targets for specific immunotherapy. Thus, we have developed a novel approach for immunotherapy against SCCL by making an immunoconjugate between a BN-like peptide and a monoclonal antibody (mAb) against the receptor for immuno-globulin (FcgammaRI) which is expressed on normal monocytes, macrophages, and neutrophils. We hypothesized that the immunoconjugates would be able to direct monocytes towards SCCL cells and elicit a specific antibody-dependent cell-mediated cytotoxicity (ADCC) against SCCL cells. Our preliminary data show that high-levels of ADCC can be elicited with a conjugate of mAb 22 (anti-FcgammaRI) and the peptide Lys3-BN, a bombesin-receptor agonist. We propose to develop this immunoconjugate directed to the BN/GRP receptor using mAb to FcgammaRI (CD64) for clinical application. We propose to initiate a phase I clinical trial of the Lys3-mAb22 immunoconjugate in patients with SCCL to determine the safety and activity of this new therapeutic reagent. These study will determine the potential for a novel form of immunotherapy for SCCL to improve treatment outcomes.
