CLINICAL RADIOIMMUNODETECTION AND RADIOIMMUNOTHERAPY IN THE MANAGEMENT OF CANCER

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A long term objective of this Program Project is to determine if radiolabeled antibodies will improve the detection or treatment of colorectal and pancreatic cancers. To this end, the Project will conduct a series of clinical trials with radiolabeled monoclonal antibodies to determine their imaging or therapeutic potential. In this new funding period, 3 humanized antibodies (hMAbs) will be used: MN-14 (anti-carcinoembryonic antigen) and Mu-9 (anti-colon-specific antigen- p), both reactive with colorectal and pancreatic cancers, and PAM4 (anti-MUC1). PAM4 is specific for pancreatic cancer, and thus may have diagnostic significance. Phase I radioimmunotherapy trials begin the testing. In each protocol, 2 pre-therapy targeting/dosimetry studies are performed using 131I- and 111In-labeled hMAb in the same patient. This will provide direct comparisons of each agent so that we can assess which agent will give the highest tumor dose at the maximum tolerated doses (MTD). These patients will then be treated using high doses of 131I or 90Y-labeled MAbs. Preclinical studies have been unable to determine if 131I- or 90Y- will provide the optimal therapeutic effect, and thus these trials will answer this question. Trials conducted in the first funding period suggested 131I-MN-14 F(ab)2 may provide higher tumor doses than the intact IgG, and so Phase I therapy trials will be conducted with the 131I-hMN-14 F(ab')2. When the MTD of these antibodies are known, Phase II trials will be conducted to define the therapeutic ability of these agents. In addition, consideration will be given to continue escalation or radioactivity in the Phase I trials with the aid of bone marrow transplantation. Together, the Phase I and II trials will provide a basis for determining how well dosimetry correlates with toxicity and anti-tumor effects, and they will better define how radiolabeled MAbs will be used in the future. A major goal is to determine whether any one MAb should be selected for future studies, or if each MAb should be considered, thereby necessitating a pre-therapy screening study on a case-by-case basis to select the optimal agent. In addition to the therapy trials, several novel agents, including an IgG3 derivative of the hMN-14 IgG1 and a CH2-deletion variant of the hMN-14, will be tested as imaging agents using 99mTc. Thus, this project will address the long-range objectives of this Program Project using the most up to date technology and agents available at this time.