RADIOIMMUNOTHERAPY AND MICROHETEROGENEITY

现有方法治疗晚期结肠癌一直不成功，部分原因是缺乏具有足够抗肿瘤活性的试剂来影响生存。最近，基于抗体的治疗在实体瘤患者中显示出显著的抗肿瘤效果，无论是作为单一药物还是与化疗联合使用。与结肠癌细胞反应的三种人源化抗体(huA33、huF19、huS193)已被确定为有前途的肿瘤靶向药物，并证明了患者再治疗的可行性。这项建议解决了单一抗体作为免疫或放射治疗药物在癌症治疗中的局限性。由于抗原的异质性表达，微观分布，导致肿瘤区域治疗不足，最终导致耐药。这项建议的主题是，抗体和小分子构建体的组合可以改善抗体结合的一致性和治疗效果；每个抗体/构建体具有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射分解。其目的是通过定量放射计量学分析接受放射性标记抗体/构筑物组合治疗的患者的切除组织；并在I期和II期研究中确定抗体组合的毒性和有效性。结肠癌的两个组成部分，癌细胞和支持基质细胞，现在都可以有效地被这些抗体靶向。肿瘤的抗体/构造物组合、药代动力学、放射性同位素选择、剂量学建模和毒性曲线的定义在I期研究中将确定用于免疫和放射免疫治疗的最佳试剂组合，从而在肿瘤中实现真正统一的辐射场。

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.