CLINICAL RADIOIMMUNODETECTION AND RADIOIMMUNOTHERAPY IN THE MANAGEMENT OF CANCER

该计划项目的长期目标是确定 放射性标记抗体将改进检测或治疗 结直肠癌和胰腺癌。为此，该项目将 用放射性标记的单抗进行一系列临床试验 抗体，以确定其成像或治疗潜力。在这 新的资助期，将使用3种人源化抗体(HMAbs)：MN-14 (抗癌胚抗原)和Mu-9(抗结肠特异性抗原- P)，对结直肠癌和胰腺癌都有反应，以及PAM4 (抗MUC1)。PAM4是胰腺癌的特异性基因，因此可能具有 诊断意义。I期放射免疫治疗试验开始 测试。在每个方案中，2项治疗前靶向/剂量学研究 在同一患者中使用~(131)I和~(111)In标记的hMAb。 这将提供每个代理的直接比较，以便我们可以评估 哪种药物会在最大耐受性下提供最大的肿瘤剂量 剂量(MTD)。然后，这些患者将接受大剂量的 131I或90Y标记的单抗。临床前研究一直无法 确定131I-或90Y-将提供最佳治疗效果， 因此，这些试验将回答这个问题。在以下地点进行试验 第一个资助期建议的131I-MN-14F(Ab)2可能会提供更高的 肿瘤剂量超过完整的免疫球蛋白，因此将进行I期治疗试验 用131I-HMN-14F(ab‘)2.当这些抗体的MTD 已知，将进行第二阶段试验以确定治疗 这些特工的能力。此外，我们亦会考虑 在援助下，在I期试验中继续升级或放射 骨髓移植。加在一起，第一阶段和第二阶段试验将 为确定剂量学在多大程度上与 毒性和抗肿瘤作用，它们将更好地定义 未来将使用放射性标记的单抗。一个主要目标是 确定是否应该选择任何一种单抗用于未来的研究，或者 如果应该考虑每一种单抗，因此有必要进行治疗前 在个案的基础上进行筛选研究，以选择最佳的药剂。 除了治疗试验，几种新型药物，包括一种 HMN-14 IgG1的IgG3衍生物和CH2缺失的变异体 HMN-14，将作为显像剂使用99mTc进行测试。因此，这一点 项目将解决该计划项目的长期目标 使用目前可用的最新技术和代理。

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.