In our continuing attempt to select monoclonal antibodies for immunotargeting of small cell lung carcinoma (SCLC) we have developed the IgG1 murine antibody SEN7 which by immunofluorescence stained all SCLC cell lines tested. On frozen tumor section six of seven SCLCs were positively stained. The reactivity of this antibody in a series of lung tumors and on normal tissues has some similarities with cluster 1 antibodies and cluster w4 antibodies, as defined by the First and Second International Workshop on Lung Cancer Antigens [P.C.L. Beverley, Y. Olabrian, J.A. Ledermann, L.G. Bobrow, and R.L. Souhami, Br. J. Cancer, 63 (Suppl): 10-19, 1991], particularly with regard to staining of neuroendocrine tissues. The similarities in staining of neuroendocrine tissues between antibody SEN7 and cluster 1 and cluster w4 antibodies prompted us to examine the binding of SEN7 with transfectants expressing the respective antigens. On the murine lymphoma cells B-9, stably transfected with a complementary DNA clone coding for an M(r) 140,000 isoform of human SCLC neural cell adhesion molecule (NCAM), antibody SEN7 reacted positively whereas the cluster w4 antibody was negative. The reaction of antibody SEN7 with the NCAM transfected murine lymphoma cells was unexpected in view of its lack of binding to peripheral blood mononuclear cells which regularly stain positive with NCAM antibodies. Western blotting of a renatured SCLC extract revealed a strong band around M(r) 180,000 in contrast to other cluster 1 antibodies which recognized a broad polydisperse band with a molecular weight of 140,000 to 210,000. Antibody binding was sensitive to tunicamycin treatment, suggesting the epitope to reside on an N-linked carbohydrate structure. No significant competition for SEN7 binding on SCLC cells was seen with other NCAM antibodies against the three distinct epitopes described on SCLC. This finding together with the lack of staining of peripheral blood mononuclear cells and the selected reactivity with the M(r) 180,000 band of NCAM indicate the antibody SEN7 recognizes an epitope on NCAM which has not been described previously. Biodistribution studies with radiolabeled SEN7 in nude mice bearing s.c. SCLC xenografts demonstrated the selective localization of more than 30% of the total injected dose per g tissue at day 4 following i.v. injection. The homogeneous binding to SCLC, the lack of binding to peripheral blood mononuclear cells, and the favorable tumor localization in a xenograft model indicates that SEN7 is a good antibody for immunotargeting of SCLC.