PRECLINICAL AND CLINICAL-STUDIES OF 2 NEW BIFUNCTIONAL CHELATING-AGENTS FOR IMMUNOSCINTIGRAPHY WITH IN-111-ANTI-CEA MONOCLONAL-ANTIBODY

Anti-CEA F(ab')(2) monoclonal antibody fragments [F6 MAb F(ab')(2)] we re conjugated to two bifunctional semi-rigid chelating agents derived from trans-1,2-diaminocyclohexane tetraacetic acid (CDTA), the monolit hium salt of N-[methyl(2-isothiocyanatoethyl)carbamide] trans-1,2-diam inocyclohexane-N,N',N-triacetic acid (SCN), and 4 trans-1,2-diaminocyc lohexane-N,N,N',N'-tetraacetic acid (4-ICE) and labelled with In-111 t o obtain In-111-labelled-Fb MAb F(ab')(2) conjugates (In-111-F6-SCN an d (111)InF6-4-ICE respectively). Biodistribution in mice and clinical studies were undertaken to assess the potential of these two ligands i n the detection of colorectal adenocarcinoma recurrences and metastase s in humans. Toxicity studies were carried out on guinea pigs and Swis s mice injected with a dose proportionally 100 times greater than that used in human studies. Clinical studies were performed in patients wi th clinically and/or biologically suspected adenocarcinoma recurrences . No immunoconjugate-induced toxicity was found. The biodistribution s tudies in mice gave better visualization of tumour sites with In-111-F 6-SCN and In-111-F6-4-ICE than with In-111-F6-DTPA. Ten patients were included in the clinical protocol. In-111-F6-SCN and In-111-F6-4-ICE e ffectively visualized adenocarcinoma recurrences. However, in this sma ll series, In-111-F6-4-ICE performed somewhat better than In-111-F6-SC N. The present study has demonstrated the potential of new bifunctiona l semi-rigid chelating agents coupled to antibody and labelled with In -111 to localize recurrences (especially in liver) in humans using a o ne-step targeting method.