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。 CC 49的人源化构建体 （HuCC 49）高亲和力抗TAG-72单克隆抗体现已上市， 其中CH 2区域缺失（HuCC 49 deltaCH 2）。 CH 2结构域缺失 单克隆抗体可能具有更快的肿瘤渗透， 时间和保留肿瘤定位/持久性特征。 基于在卵巢癌中获得的有希望的临床结果， 在UAB患者与177 Lu-CC 49，这将是有价值的，以确定在 临床前研究是否131|- 或177 LU-HuCC 49 deltaCh 2 在腹膜中给药， 干扰素（IFN）上调TAG-72抗原产生更高的 腹腔内肿瘤结节中的相对肿瘤摄取与 血液，并确定最大的相对肿瘤疗效 耐受剂量131|- 或177 Lu-HuCC 49 deltaCH 2 ve。131|- 或177 Lu- HuCC 49。 具体目的是：1）放射性标记单克隆抗体 HUCC 49 deltaCH 2与131|使用直接lodoGen程序或 间接ATE程序和使用PA-DOTA或CHX-A DTPA的177 LU 双功能螯合剂; 2）表征免疫反应性， 体外和体内稳定性为131|- 和177 Lu标记的单克隆抗体 HuCC 49和HuCC 49 deltaCH 2; 3）比较肿瘤定位， 生物分布131|- 和177 LU标记的单克隆抗体HuCC 49和 HuCC 49 deltaCH 2在携带腹膜内人免疫球蛋白的胸腺裸鼠中的表达 注射后不同时间的癌症异种移植模型; 4） 上调人卵巢TAG-72抗原的表达， 结肠癌后给予干扰素推注，基因转移， 或持续缓释，以改善肿瘤定位 以及用放射性标记的单克隆抗体HuCC 49和HuCC 49 deltaCh 2治疗;以及5） 比较131例患者的相对疗效，|- 和177 Lu标记 MabsHuCC 49和HuCC 49 deltaCH 2;在携带 递增放射性核素腹腔内人癌异种移植物 剂量与最大耐受剂量相当。 我们假设 HuCC 49 Δ CH 2抗体与Ifn组合使用将导致 腹膜穿刺后高腹膜内肿瘤结合率 注射相对于HuCC 49抗体，但更快速 血液清除率。 还有待确定的是， 施用的CH 2缺失抗体施用到腹膜中 将产生更大的治疗效果， 与完整抗体相比，其在最大耐受剂量下的癌症。 本提案中所述的实验将为以下问题提供答案： 这些问题。 这些研究将确立以下理由： 腹膜内癌患者的人体临床RIT试验 使用HuCC 49 Δ CH 2和IFN的最佳施用方法。

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.