EVALUATION OF CH2 DELETED HUCC49 FOR INTRAPERITONEAL RIT

提高临床治愈率的新策略 放射免疫治疗(RIT)试验。CC49的人性化构建 (HuCC49)高亲和力抗TAG-72单抗现已面市 CH2区缺失(HuCC49deltaCH2)。CH2结构域已删除 单抗可能具有更快的肿瘤侵袭速度，循环减少 计时并保留肿瘤的定位/持久性特征。 基于在卵巢癌方面取得的有希望的临床结果 UAB患者使用177Lu-CC49，在UAB中确定 131|-或177LU-HuCC49deltaCH2的临床前研究 腹膜内给药联合给药 干扰素上调TAG-72抗原产生更高的 腹膜内肿瘤结节的相对肿瘤摄取与 血液，并确定最大的相对肿瘤疗效 耐受量131|-或177 Lu-HuCC49 deltaCH2 ve。131|-或177鲁- 沪CC49。具体目的是：1)用放射标记单抗 带有131的HUCC49deltaCH2|使用直接lodoGen过程或 间接ATE程序和使用PA-DOTA或CHX-A DTPA的177LU 双功能螯合剂；2)免疫反应性表征， 131Lu和177Lu标记单抗的体内外稳定性 HuCC49和HuCC49deltaCH2；3)比较肿瘤的定位和 ~(131)LU和~(177)LU标记单抗HuCC49和 HuCC49deltaCH2基因在荷人胸腺裸鼠体内的表达 注射后不同时间的肿瘤移植模型；4) 上调人卵巢和卵巢组织中TAG-72抗原的表达 注射干扰素，基因转移，结肠癌 或持续缓释，以改善肿瘤定位 以及使用放射性单抗HuCC49和HuCC49deltaCh2进行治疗；以及5) ~(131)U与~(177)Lu标记的相对疗效比较 MabHuCC49和HuCC49deltaCH2在荷瘤裸鼠胸腺中的表达 放射性核素升高时人癌腹膜内移植瘤的研究 可比最大耐受量的剂量。我们假设 HuCC49deltaCH2抗体与干扰素联合使用将导致 经腹膜后肿瘤的高结合率 注射相对HuCC49抗体，但要快得多 清除了血迹。还有待于确定是否在区域范围内 向腹膜注射CH2缺失抗体 会对腹膜腔内注射产生更大的治疗效果 与完整抗体相比，癌症处于其最大耐受量。 这份提案中描述的实验将提供以下答案 这些问题。这些研究将为 腹膜癌患者的人类临床RIT试验 利用HuCC49deltaCH2和干扰素的最佳给药方法。

Novel strategies to increase the therapeutic ratio in clinical radioimmunotherapy (RIT) trials. A humanized construct of the CC49 (HuCC49) high affinity anti-TAG-72 MAb is now available, as well aw with the CH2 region deleted (HuCC49deltaCH2). The CH2 domain deleted MAb may have more rapid tumor penetration, a decreased circulation time and retain tumor localization/persistence characteristics. Based on the promising clinical results obtained in ovarian cancer patients at UAB with 177Lu-CC49, it would be valuable to determine in preclinical studies whether 131|- or 177LU-HuCC49deltaCh2 administered in the peritoneum combined with administration of interferon (IFN)to upregulate TAG-72 antigen produces a higher relative tumor uptake in intraperitoneal tumor nodules compared to blood, and to determine the relative tumor efficacy at the maximum tolerated dose of 131|- or 177Lu-HuCC49deltaCH2 ve. 131|- or 177Lu- HuCC49. The specific aims are to: 1)radiolabel the Mabs HUCC49deltaCH2 with 131| using the direct lodoGen procedure or the indirect ATE procedure and with 177LU using the PA-DOTA or CHX-A DTPA bifunctional chelating agent; 2)characterize the immuno reactivity, and in vitro and in vivo stabilities of 131|- and 177Lu-labeled Mabs HuCC49 and HuCC49deltaCH2; 3)compare the tumor localization and biodistribution of 131|- and 177LU-labeled Mabs HuCC49 and HuCC49deltaCH2 in thymic nude mice bearing an intraperitoneal human cancer xenograft model at various times after injection; 4) upregulate the expression of TAG-72 antigen in human ovarian and colon caner following administration of IFN by bolus, gene transfer, or continuous slow release , in order to improve tumor localization and therapy with radiolabled Mabs HuCC49 and HuCC49deltaCh2; and 5) compare the relative therapeutic efficacy of 131|- and 177 Lu-labeled MabsHuCC49 and HuCC49deltaCH2; in thymic nude mice bearing intraperitneal human cancer xenografts at escalating radionuclide doses at comparable maximum tolerated doses. We hypothesize that the use of HuCC49deltaCH2 antibody in combination with Ifn will result in highintraperitoneal tumor binding following tingraperitoneal injection relative to HuCC49 antibody, but a much more rapid clearance from blood. It remains to be determine whether regionally administered CH2 deleted antibody administered into the peritoneum will produce a greater therapeutic effect against intraperitoneal cancer at its maximum tolerated dose compared to intact antibody. The experiments descried in this proposal will provide answers to these questions. These studies would establish the rationale for human clinical RIT trials in patients with intraperitoneal cancer using HuCC49deltaCH2 and the optimum method of administration of IFN.