Lym-1 is a monoclonal antibody that reacts with most malignant B-cells relatively specifically. We have observed tumor regression in most of the patients with B-cell malignancies that have been treated with 131l Lym-1. Toxicity has been mild and transient with occasional fever and rash acutely after a single treatment dose and thrombocytopenia upon completion of a series of treatment doses. Several patients developed redness and swelling over superficial lesions, suggesting a biologic response to treatment. Treatment of mice and patients in this fractionated manner has provided evidence for the potential of this antibody and for some of the factors that must be manipulated in order to achieve this potential. In a maximum tolerated single dose protocol, complete remissions have been common after one or two doses. The objectives of this project are to examine the influence of amount of administered MoAb, and amount and schedule for administered radionuclide, radiation dose rate, and alterations to tumor delivery by preceding BRM, for example, unlabeled MoAb, interleukin, interferon, or radiation. We are interested in a variety of enhancement strategies, such as, better radionuclides and radiochemistry and vehicles for increasing tumor uptake of radiolabeled antibody (tumor radiation) or decreasing critical organ (bone marrow) radiation. Our observations on the pharmacokinetics of 67Cu and 90Y conjugated to Lym-1 with specifically generated macrocyclic chelates suggest considerable potential for therapy. Furthermore, interleukin-2 provides a mechanism for decreasing radiation to the bone marrow. Methods to be used include: quantitative imaging that provides absolute amounts (and concentrations) of Lym-1 in tumor and organs for pharmacokinetics and radiation dosimetry; tomographic imaging estimates of tumor volume; and in vitro tests for in vivo cytotoxicity. Strengths of this project include an investigative group that has already established the clinical relevance of Lym-1 treatment and identified problems to be resolved. Investigations have been designed so that they provide information relevant to this and also to other antibodies. The investigative results and the improvements in methods to used are generally applicable to treatment with radiolabeled antibodies, other immunoconjugates and antibodies alone (if a radiotracer is used in the latter instances). This project benefits from radiochemical developments from Project 3 and provides opportunities for comparisons and contrasts of B-cell malignancies with adenocarcinomas, specifically breast cancer in Project 2. Finally, this approach using Lym-1 or similar antibodies may be applicable to the treatment of the neoplasms associated with AIDS and immunologic disorders such as lupus erythematosus.
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