This proposal is a competitive renewal of a program grant that has begun its third year. The objectives of this grant are to improve the treatment of cancer using radiolabeled MoAb in B-cell malignancies and breast adenocarcinoma. The influence of factors, such as, the amount of administered MoAb; amount and schedule for administered radionuclide; radiation dose rate; alterations to tumor delivery by preceding biologic response modifiers including biologically active MoAb have been examined. Maximum tolerated dose and optimum biologic dose are determined for each system. Tumor response rates greater then 70% have been achieved in forty patients with B-cell malignancies and four patients with breast adenocarcinoma resistant to conventional therapies, when 131l Lym-1 or 131l L-6 MoAb were used. These results were achieved in patients with advanced disease and no other options, and despite the fact that we are only now approaching the MTD for the system. Complete remissions have uniformly occurred at the highest dose level of 131l per m2 in a small number of patients. A variety of enhancement strategies have been explored or are proposed for future exploration. The radiochemistry for 67Cu, 111ln and 90Y has provided excellent MoAb formulations that appear in mice to be superior to the iodinated MoAb equivalent. Pharmacokinetic studies in patients have confirmed these observations for 67Cu Lym-1. Lym-1 has been sequenced using PCr and chemical characterization of the residues of MoAb. Mechanisms for site specific attachment to specific residues to preserve biologic functions of importance to treatment of cancer, such as those that determine immunotargeting and those that stimulate cytotoxic systems in vivo, have been explored. Several enhancement strategies have been examined. PEG-IL-2 provided a two-fold enhancement of tumor uptake of 125l Lym-1 in mice implanted with lymphoma and irradiation induced a modest increase in tumor uptake of 125l Lym-1 in mice implanted with breast cancer. Response surface biostatistical and protocol designs were tested in these systems and found feasible and indeed desirable for use in patients. Data management systems and quantitative imaging for pharmacokinetic and radiation dosimetry in patients are in place. We propose to continue to explore enhancement strategies including the use of better radionuclides, superior radiochemistry, and biologic response modifiers such as interleukin or interferon in mice and patients. We also propose to examine the potential and plasmapheresis to reduce the limitations to treatment with radionuclide conjugated antibodies imposed by myelosuppression. While the investigators have chosen to pursue treatment with radionuclide conjugated antibodies, much of the information to be obtained is relevant to the use of unconjugated antibodies or antibodies conjugated to other toxins.
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