The purpose of this study is to identify new methods to improve the immunodiagnostic and therapeutic potential of monoclonal antibodies for the treatment of the human malignant lymphomas and related diseases. Previous studies in experimental animals and man have shown that two monoclonal antibodies developed in our laboratory (Lym-1 and Lym-2) have marked specificity and reactivity for the human lumphomas. Clinical trials conducted with Lym-1 and other monoclonal antibodies have shown that only very small amounts of antibody are able to olcalize to the tumor despite the high binding reactivities of these reagents. Methods to enhance the extravascular penetration of monoclonal antibodies at the tumor site would significantly alter the in vivo diagnostic and theraputic potential of these reagents. Moreover, methods to facilitate the rapid removal of unbound material from the circulating blood pool would improve imaging results and would minimize the exposure of healthy tissues to radiation and other cytotoxic agents linked to the monoclonal antibodies. In this proposal, we intend to explore the potential of new methods designed to alter the binding and clearance of monoclonal antibodies in vivo. For these studies, I-131 or I-125 labeled Lym- 1 and Lym-2 will be used with radioimaging, biodistribution, histological, and autoradiographic methods in lymphoma-bearing nude mice. To enhance the extravascular penetration of these monoclonal antibodies in the lymphoma transplants, vasoactive drugs and immunoconjugates will be tested in vivo along with agents designed to induce a localized inflammatory reaction at the tumor site. Specifically, novel immunoconjugates will be produced by carbodiimide, SPDP, or N-hydroxysuccinimide methods to conjugate bioactive and chemoattractant peptides to Lym-1 and Lym-2 for in vivo testing. Preliminary data presented in the proposal indicate that these methods are promising and worthy of further study. Radiation induced inflammation will also be studied for its ability to increase the binding of monoclonal antibody to tumor. In addition, diuretic drugs with different modes of action and dose concentrations will be tested for their effects on the clearance of unbound label in the lymphoma-bearing nude mice. It is anticipated that combinations of the above treatments may give better results than single agents alone. The data generated by these investigations should be broadly applicable to monoclonal antibodies being used to treat other types of cancer and should provide the basis for future clinical investigations in man.
