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Bombesin/Gastrin-Releasing Peptide Receptor

A Potential Target for Antibody-Mediated Therapy of Small Cell Lung Cancer

Division of Blood and Marrow Transplantation, Department of Medicine and University of California San Diego Cancer Center, University of California San Diego, La Jolla, California 92093-0960 [J. Z., J. C., R. Z., E. D. B.]; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 [M. M.]; and The Jackson Laboratory, Bar Harbor, Maine 04609 [L. D. S.]

Purpose: Bombesin/gastrin releasing peptide (BN/GRP) is a growth factor for small cell lung cancer (SCLC). The receptor (R) for BN/GRP is overexpressed on SCLC cells and other solid tumors. BN/GRP and its receptor form an autocrine loop to promote tumor growth. We developed a novel immunotherapeutic approach targeting cell surface BN/GRP-R on SCLC cells and an immune trigger molecule on host immune effector cells to direct immune effector cells to SCLC cells and mediate targeted cancer cell destruction. Targeted immunotherapy combined with chemotherapy enhanced cell killing.

Experimental Design: We designed a synthetic BN/GRP antagonist (Antag 2) and constructed a bispecific molecule (BsMol), H22xAntag 2 (humanized monoclonal antibody) for FcRI. We tested the binding of the BsMol to several SCLC cell lines, its ability to mediate cytotoxicity of SCLC by IFN--activated human monocytes with chemotherapy, and BsMol-mediated immunotherapy in an animal model of SCLC human xenograft.

Results: Common chemotherapy (cisplatin, etoposide, and paclitaxel) inhibited thymidine uptake into SCLC cells in a dose-dependent pattern. Antibody-dependent cellular cytotoxicity mediated by the BsMol inhibited thymidine uptake into SCLC cells and was largely dependent on E:T cell ratio. When SCLC cells were treated with antibody-dependent cellular cytotoxicity followed by exposure to chemotherapy agents an additional 25–40% inhibition of thymidine uptake into SCLC cells was observed consistently. With BsMol and IFN--activated human monocytes, tumor burdens were reduced significantly in immunodeficient mice bearing human SCLC xenografts.

Conclusions: Combined chemotherapy and immunotherapy targeting BN/GRP-R with a BsMol significantly enhances targeted SCLC cell killing.

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