RADIOIMMUNOTHERAPY AND MICROHETEROGENEITY

晚期结肠癌的治疗与可用的方式一直是不成功的，部分原因是缺乏足够的抗肿瘤活性，影响生存的试剂。最近，基于抗体的疗法已经在实体瘤患者中显示出显著的抗肿瘤效果，无论是作为单一药剂还是与化学疗法组合。与结肠癌细胞反应的三种人源化抗体（huA 33、huF 19、huS 193）已被鉴定为有前景的肿瘤靶向剂，并且患者再治疗的可行性已被证明。 该提议解决了单一抗体作为免疫或放射治疗剂在癌症治疗中的局限性。由于异质性抗原表达、微分布，导致治疗不足的肿瘤区域并最终导致对治疗的抗性。该提案的主题是抗体和小分子量构建体的组合可以改善抗体结合的均匀性和治疗功效;并且具有针对每个抗体/构建体的适当能量和发射路径长度的治疗性同位素将增加肿瘤细胞的辐解。目的是通过定量放射性测定法分析来自用放射性标记的抗体/构建体的组合治疗的患者的切除组织;并确定I期和II期研究中抗体组合的毒性和功效。结肠癌的两个组成部分，癌细胞和支持基质细胞，现在可以有效地靶向这些抗体。可以在肿瘤中实现真正均匀的辐射场，其中抗体/构建体的组合与肿瘤的组合、药代动力学、放射性同位素选择、剂量测定建模和I期研究中毒性特征的定义将确定用于结肠直肠癌的免疫和放射免疫治疗的最佳试剂组合。

The treatment of advanced colon cancer with available modalities has been consistently unsuccessfully, partially due to the lack of reagents with sufficient anti-tumor activity to impact on survival. Recently, antibody based therapies have shown significant anti-tumor effects in solid-tumor patients either as single agents or in combination with chemotherapy. Three humanized antibodies (huA33, huF19, huS193) reactive with colon cancer cells have been identified as promising tumor targeting agents and the feasibility of patient re-treatment has been demonstrated. This proposal addresses the limitation of single antibodies as immuno or radiotherapeutic agents in the treatment of cancer. Due to heterogeneous antigen expression, micro-distribution, leading to under-treated tumor regions and ultimately to resistance to treatment. The theme of this proposal is that combinations of antibodies and small-molecular -weight constructs may improve uniformity of antibody binding and therapeutic efficacy; and therapeutic isotopes with the proper energy and emission path length for each antibody/construct will increase the radiolysis of tumor cells. The aims are to analyze, by quantitative radiosimetry, resected tissues from patients treated with combinations of radiolabeled antibodies/constructs; and to determine toxicity and efficacy of antibody combinations in phase I and II studies. Each of the two components of colon cancer, carcinoma cells and the supporting stromal cells, can now be effectively targeted with these antibodies. A truly uniform radiation field may be achieved in tumors with combinations of antibodies/constructs combinations to tumors, pharmacokinetics, radio- isotope selection, dosimetry modeling, and definition of toxicity profiles in phase I studies will identify the optimal reagent combination for immuno- and radio-immunotherapy of colorectal cancer.