CLINICAL RADIOIMMUNODETECTION AND RADIOIMMUNOTHERAPY IN THE MANAGEMENT OF CANCER

本计划项目的长期目标是确定 放射性标记的抗体将改善以下疾病的检测或治疗： 结肠直肠癌和胰腺癌。 为此，该项目将 用放射性标记的单克隆抗体 抗体，以确定其成像或治疗潜力。 在这 在新的资助期内，将使用3种人源化抗体（hMAb）：MN-14 （抗癌胚抗原）和Mu-9（抗结肠特异性抗原- p），均与结肠直肠癌和胰腺癌反应，以及PAM 4 （抗MUC 1）。 PAM 4对胰腺癌具有特异性，因此可能具有 诊断意义 I期放射免疫治疗试验开始 试验. 在每个方案中，2项治疗前靶向/剂量测定研究 使用131 I和111 In标记的hMAb在同一患者中进行。 这将提供每个代理的直接比较，以便我们可以评估 哪种药剂将在最大耐受下给予最高肿瘤剂量 剂量（MTD）。 这些患者将接受高剂量的 131 I或90 Y标记的单克隆抗体。 临床前研究无法 确定131 I-或90 Y-是否将提供最佳治疗效果， 这些试验将回答这个问题。 审判地点 第一个资助期建议131 I-MN-14 F（ab）2可能提供更高的 肿瘤剂量比完整的IgG，因此I期治疗试验将 用131 I-hMN-14 F（ab ′）2进行。当这些抗体的MTD 已知，将进行II期试验，以确定治疗 这些特工的能力。 此外，还将考虑 在I期试验中继续升级或放射性， 骨髓移植I期和II期试验将共同 为确定剂量学与以下因素的相关性提供了依据 毒性和抗肿瘤作用，他们将更好地定义如何 放射性标记的单克隆抗体将在未来使用。 一个主要目标是 确定是否应选择任何一种单克隆抗体用于未来研究，或 如果应考虑每种MAb，则需要进行预治疗 在个案基础上进行筛选研究，以选择最佳药剂。 除了治疗试验，几种新的药物，包括 hMN-14 IgG 1的IgG 3衍生物和hMN-14 IgG 1的CH 2缺失变体 将使用99 mTc测试hMN-14作为成像剂。 因此， 该项目将实现本计划项目的长期目标 使用目前最先进的技术和试剂。

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.