Pharmacokinetic analysis of an improved humanized monoclonal antibody designed for radioimmunotherapy ( RIT )

Many adenocarcinomas of the digestive tract develop from premalignant lesions, induced by bacteria, chemicals or nutritional components. Early detection, differential analysis and treatment of these cancer precursors is very often crucial for survival. Conventional human hybridoma technology offers the unique possibility to generate new fully human monoclonal antibodies for diagnosis and therapy of diseases and to characterise new tumour related membrane receptors within one experimental approach. By somatic hybridisation of lymph node B-cells from patients with stomach carcinomas to the heteromyeloma HAB1/X, a fully human germ-line coded monoclonal IgM antibody PAM-1 (Clone 103/51) was isolated. Tested immunohistochemically on paraffin sections, the PAM-1 antibody reacts with a membrane receptor of nearly all epithelial cancers of all type and origin. Evaluated on non-malignant tissue, the only specific reactivity was found intracellular with proteins in Golgi apparatus. The receptor was purified from tumor cell membrane extracts and was found to be a 130 kDa integral membrane glycoprotein, homologous to CFR-1 (cysteinerich fibroblast growth factor receptor), which has so far only been detected and described in Golgi of embryonic chicken cells and in CHO cells. The receptor is homologous to a rat protein, cloned as a Golgi-specific protein, designated MG160, involved in processing and secreting of growth factors. The human homologue, E-selectin binding protein (ESL-1) is a cytokine, expressed on myeloid and some lymphoma cells and modulated by cell adhesion molecules that cause the binding of neutrophils to the endothelium. The PAM1/CFR-1 receptor is, in contrast to the other members of this multi-functional protein family, predominantly expressed on membranes of malignant cells. Most interestingly, PAM-1 antibody does not only react with epithelial cancers, but also with it’s precursors like H . pylori induced gastritis, metaplasia and dysplasia of stomach, ulcerative colitis and adenomas of colon and barrett dysplasia of esophagus. The unique features of PAM-1 antibody and the unique expression of this new CFR-1 receptor offers the possibility to study specific proliferation processes of malignant and premalignant cells, because the biological function of this CFR family is still unknown. In addition the PAM-1 antibody is also of diagnostic and therapeutical value.