The major aim of this proposal is to develop 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 a monoclonal antibody developed in our laboratory, designated Lym-1, has marked specificity and reactivity for the human lymphomas. Clinical trials in man conducted with I-131 labeled Lym-1 and other radiolabeled monoclonal antibodies have shown that only a small amount of the injected antibody actually binds to the tumor (0.05-0.1% of the injected dose). Methods to enhance the extravascular penetration of monoclonal antibodies at the tumor site would significantly alter the in vivo diagnostic and therapeutic potential of these reagents. Moreover, methods that decrease the circulating residence time of radiolabeled monoclonal antibodies would improve imaging results and minimize the exposure of healthy tissues to radiation and other cytotoxic agents linked to monoclonal antibodies. In this proposal, we have focused our attention on the development of novel methods to improve antibody penetration and binding at the tumor site in order to increase the amount of antibody and radiolabel reaching the tumor. These methods include the use of vasoactive immunoconjugates which specifically increase the vascular permeability of the tumor endothelium. In particular, a novel vasoactive immunoconjugate, Lym-1/IL-2, has been developed which reversibly induces a 3-4 fold increase in the vascular permeability of the tumor. It is proposed that additional vasoactive peptides, including Tumor Necrosis Factor-alpha, Interleukin-1beta, physalaemin, and bradykinin be tested using the Lym-1/Raji lymphoma model for their proinflammatory and vasopermeability effects in vivo. Genetic engineering methods are currently being performed to generate a chimeric Lym-1/IL-2 fusion protein which will act as a prototype for the development of additional vasoactive and proinflammatory immunoconjugates. Finally, studies are planned to investigate the effects of vasoactive drugs on the enhancement of Lym-1/IL-2 and other immunoconjugates. The data generated by these investigations should be broadly applicable to monoclonal antibodies being used to treat other types of cancers and should provide the basis for future clinical studies with radiolabeled Lym-1 in man.
