The role of the lymphatic system in the absorption and biodistribution of antitumor agents and monoclonal antibodies in normal and tumor-bearing rodents is under investigation. Monoclonal antibodies given by subcutaneous injection are delivered via lymphatic channels to regional lymph nodes with greater efficiency than when administered intravenously. Typically, 30 to 50% of the injected antibody binds specifically to cells in these nodes, a finding now confirmed for a variety of antibodies with specificity for lymphoid cells. Pharmacokinetic studies and modelling indicate that optimal conditions for antibody uptake in target tissue will be achieved by a careful choice of dose, osmolarity, volume, and site of injection. Comparing the biodistribution of intact antibody with that of its F(ab')2 and Fab fragments suggest that the latter may be more appropriate for clinical use than intact antibody. Fragments were cleared from the bloodstream and excreted more rapidly than intact antibody which may be important in reducing toxicity due to circulating antibdody and lowering background radioactivity when radiolabelled antibodies are used for diagnostic imaging. Information obtained froms tudies in animals is currently being applied to clinical studies for detection of lymph node metastases in patients with malignant melanoma, carcinoma of the breast and T-cell lymphoma. Studies in patients with T-cell lymphoma have demonstrated the most efficient imaging of tumor cells yet achieved in humans by any technique. In an attempt to utilize conjugates of monoclonal antibodies with cytotoxic agents for the treatment of lymph node metastases, we have synthesized conjugates of antibody covalently coupled to the plant toxin, ricin A-chain, and antibody labelled with the alpha-emitting radiometal, bismuth-212. Both conjugates were found to bind specifically to target cells and were highly cytotoxic in vitro. Studies to demonstrate cytotoxicity in vivo using the guinea pig hepatocarcinoma model for lymph node metastasis are currently underway.
