Tumor targeting potential of the monoclonal antibody BC-1 against oncofetal fibronectin in nude mice bearing human tumor implants.

BACKGROUND: The immunoglobulin G1 (IgG1) monoclonal antibody (MoAb) BC-1 detects human oncofetal fibronectin, which has extremely restricted distribution in normal adult tissues and is highly expressed in fetal and tumor tissues. METHODS: We studied the biodistribution of 125I-labeled MoAb BC-1 in nude mice bearing subcutaneous human tumor implants of U87MG high-grade astrocytoma and SKMel28 melanoma. 125I-BC-1 was injected either intraperitoneally (i.p.) or intravenously (i.v.), and biodistribution was measured up to 144 hours after injection. In animals bearing SKMel28 implants, tumor targeting was also evaluated by in vivo imaging of the whole mouse by using a dedicated device based on transmitted light excitation after i.v. injection of MoAb BC-1 conjugated with the infrared fluorophore, CY7-bis(N-hydroxy-succinimido)-ester. RESULTS: 125I-BC-1 showed favorable uptake in the human tumor implants, reaching a maximum of 5.27 +/- 0.48% ID/g in the U87MG astrocytoma (72 hours after i.p. injection). The highest uptake in the SKMel28 melanoma implants was 3.49 +/- 0.25% ID/g (24 hours after i.v. injection). Microautoradiography of tumor specimens obtained after administration of 125I-BC-1 clearly showed radioactivity uptake within the two tumors replicating the same pattern of distribution as that of the oncofetal fibronectin shown by immunohistochemistry with MoAb BC-1. Nonspecific uptake of 125I-BC-1 in the bone marrow and skeletal muscle was much lower than in the tumors. In vivo imaging with the fluorophore-labeled MoAb clearly visualized the tumor implants 72-120 hours after i.v. injection. CONCLUSIONS: The experimental results obtained in this study demonstrate the favorable tumor targeting potential in vivo of the radiolabeled MoAb BC-1, a useful marker of neo angiogenesis induced by cancer.

A pilot pharmacokinetic and immunoscintigraphic study with the technetium-99m-labeled monoclonal antibody BC-1 directed against oncofetal fibronectin in patients with brain tumors.

BACKGROUND: Preliminary experiments in an animal model have shown the favorable tumor targeting potential in vivo of radiolabeled BC-1, an immunoglobulin (Ig)G1 monoclonal antibody (MoAb) that recognizes the human fibronectin isoform (B+) containing the ED-B oncofetal domain. This antigen has extremely restricted distribution in normal adult tissues. Instead, it is highly expressed in fetal and tumor tissues, especially in high grade astrocytomas and malignant gliomas of the brain, in which the process of neoangiogenesis linked to tumor growth is particularly important. METHODS: This study was carried out with five patients who had malignant brain tumors (four gliomas and one malignant angioblastic meningioma). The BC-1 MoAb was labeled with technetium-99m (99mTc) by MDP transchelation. Planar and single photon emission computed tomography (SPECT) imaging was acquired at 4-6 and 20 hours after intravenous injection of about 450 MBq/0.2 mg 99mTc-BC-1 and was compared with the nonspecific indicator of blood-brain barrier disruption, 99mTc-diethylenetriamine pentaacetic acid (DTPA). Plasma pharmacokinetic analysis was based on serial blood sampling. All patients underwent potentially curative surgery at the end of the study. RESULTS: The plasma clearance curves were biexponential, with average T(1/2) values of 2-4 hours and 28-33 hours, respectively. 99mTc-BC-1 showed very low nonspecific uptake in the bone marrow, liver, and spleen. Planar and SPECT imaging with 99mTc-BC-1 visualized brain tumors in all patients, with a pattern of intratumor distribution that specifically identified areas of peripheral tumor growth more accurately than the nonspecific indicator, 99mTc-DTPA. Tumor uptake of 99mTc-BC-1 was correlated with the expression of the specific oncofetal fibronectin, as shown by immunohistochemistry on surgical samples. CONCLUSIONS: These results indicate the diagnostic potential of MoAb 99mTc-BC-1 for immunoscintigraphy in cancer patients, at least when neoangiogenesis induced by cancer is particularly important.