Different biodistribution of 99mTc-labelled chimeric mouse-human monoclonal antibody between athymic mice model and human

Abstract

Sinary Biodistribution of chimeric mouse/human monoclonal antibody against non-specific cross-reacting antigen (chNCA Ab) was studied in athymic mice and patients with metastatic bone disease. 9=-rc-chNCA Ab showed a high labelling efficiency, stability and also a high binding ratio to human granulocytes. Since NCA showed cross-reactivity with carcinoembryonic antigen (CEA), animal experiments showed that 99"c-chNCA Ab was accumulated in the xenografted tumour which expressed CEA, suggesting the preserved immunoreactivity of labelled materials. In the clnical study, injected 99rc-chNCA Ab formed a high molcular weight complex immediately after intravenous aministration and was trapped mainly in liver. The first-phase plasma half-life was 6.4+ 1. Locher et al., 1986; CourtenayLuck et al., 1984). Production of the human anti-murine antibody (HAMA) is one of the most serious problems as far as murine MAbs are concerned. HAMA, produced in the sera of patients who received murine MAbs repeatedly, may result in the neutralisation of infused MAb or in allergic reactions (Schroff et al., 1985;Shawler et al., 1985). Recent developments in genetic engineering enable us to use chimeric mouse-human MAbs which are expected to decrease the HAMA production, since chimeric MAbs consist of mouse variable regions and human constant regions (Boulianne et al., 1984). However, there has been a report which describes the production of HAMA in serum samples of metastatic colorectal cancer patients after administration of chimeric MAb designated B72.3 (Khazaeli et al., 1991).Non-specific cross-reacting antigen (NCA) is expressed on the surface of human granulocytes and cross-reacts with carcinoembryonic antigen (CEA) (von Kleist et al., 1972). Therefore, radiolabelled anti-NCA Ab has been successfully used for the diagnosis of infectious diseases and bone metastases of malignancies, although the distinction would not be made between sites of inflammation and sites of cancer expressing CEA (Locher et al., 1986;Reuland et al., 1991;Munz et al., 1990).In this study, chimenrc antibody against the NCA (chNCA Ab) was labelled with 9Tc pertechnetate, since 99'Tc was an ideal radionuclide for radioimmunodetection, and administered into tumour-beanng athymic mice and patients to compare the biodistribution. Patients with bone metastasis from prostate cancer were chosen for the clinical application, since prostate cancer often shows osteogenic metastasis, which could be imaged as a photopenic area on the immunoscintigraphy using radiolabelled anti-NCA Ab. Materids and methodsMurine and chimeric mouse-human anti-NCA antibodies Murine anti-NCA Ab (mNCA Ab), IgG, isotype, was purified from ascites of Balb/c mouse inoculated intraperitoneally with hybridoma cells that were produced by the fusion of mouse myeloma cells and anti-NCA Ab-producing B-cells derived from Balb/c mouse immunised with CEA. Derived mNCA Ab reacted to NCA 50 and NCA 90. chNCA Ab was prepared by the method previously reported (Koga et al., 1990). VY(VK) gene, isolated from hybr...