This proposal is a competitive renewal for a Program grant whose purpose is to develop effective therapy for incurable B cell malignancies and breast adenocarcinoma using radiolabeled antibodies. Durable clinical responses have been achieved in the majority of 58 patients with B cell malignancies, primarily NHL, that were treated with Lym-1 and 20 patients with breast adenocarcinoma using primarily Chimeric L6 antibody. All of these patients were resistant to standard therapy. chimeric L6 showed profound biological activity that may have enhanced the radiation effect in the patients, but therapy was sometimes interrupted by an antiglobulin response. The efficacy of these radiolabeled antibodies is remarkable when one considers that they were used in isolation, and improvements could lead to cure of incurable disease. Enhancement strategies to improve the therapeutic index including various radionuclides and radiochemistries for conjugation, fractionation of therapy, agents to increase delivery to the tumor, immunoabsorption to decrease radiation to normal tissues, colony stimulating factors and stem cell marrow reconstitution were found to have merit. Of these factors we have chosen to focus on the radionuclide and radiochemistry to increase radiation to the malignancy, Interleukin-2 to increase tumor uptake and radiation, and stem cell marrow reconstitution to extend the maximum tolerated dose. Because state of the art macrocyclic chelates are available through Project 4, Project 1 proposes a Phase II trial of 67Cu-BAT-Lym-1 and 90Y- BAD-ChL6 with stem cell marrow reconstitution. Cyclosporin A will be used in Project to prevent antiglobulin response. The therapeutic index of 67 Cu-BAT-Lym-1 and 90Y-BAD-ChL6 is several times that of the corresponding 131I antibody because of tumor retention. Interleukin-2 is to be used to enhance tumor uptake in Project 1 and, if effective, will be used in Project 2. Similarly, strategies found to be effective in Project 2 will be added to the trials in Project 1. In addition to the development of macrocycles for 67 Cu, 111In and 90Y, and methods for site specific attachment to specific antibodies residues, Lym-1 has been sequenced and a single chain antibody prepared by genetic engineering in Project 4. this proposal includes generation of additional engineered constructs and their exploration as therapeutic agents. Strengths of the Program include an interdisciplinary group that has established their commitment and cohesiveness, and the clinical relevance of the proposed therapeutic agents. Projects 1 and 2 benefit from new constructs and radiochemistry generated in Project 4 and from opportunities for comparisons of the biology of breast cancer and B cell malignancies. Project 4 benefits from feedback of biologic and clinical information generated in Projects 1 and 2 for new constructs and radiochemistry. The information form this Program is relevant to the use of other conjugated and unconjugated antibodies.
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