NEW BCAS FOR RADIOIMMUNOTHERAPY WITH RADIOMETALS

描述：（改编自申请人的摘要）：增加 在临床放射免疫治疗（RIT）研究中需要治疗比。 主要的剂量限制性毒性是血液学毒性。人源化 CC49（HuCC49）高亲和力抗TAG-72单克隆抗体的构建体 (MAb)现在可用，以及CH2区域缺失（HuCC49ACH2）。 CH2结构域缺失的MAb可能具有更快的肿瘤穿透，降低了肿瘤细胞的增殖。 循环时间和保留肿瘤定位/持久性特征。 本项目主要致力于双功能螯合剂的开发 （BCA），衍生自异羟肟酸类有机化合物，用于 用188Re放射性金属标记单克隆抗体用于治疗。基于有希望的 在UAB的卵巢癌患者中获得的177Lu-CC49的临床结果， 在临床前研究中确定188Re-HuCC49ACH2 在腹膜中施用产生在Jp中更高的相对肿瘤摄取。 结肠癌结节与血液比较，并确定相对肿瘤 在最大耐受剂量的188Re-HuCC49ACH2对比188Re-HuCC49的功效。 具体目标是：1）通过以下方法扩大BCA的异羟肟酸盐家族： 合理设计和合成具有改进特性的新构件; 2） 优化新型、合理设计的抗体缀合化学， 吡啶二甘氨酸二异羟肟酸盐（PG 2H2），吡啶二异羟肟酸盐（PH 2），环 肽三异羟肟酸盐（cyc-PH 3）和二亚乙基三胺五异羟肟酸 （DTPH）BCAs; 3）放射性标记的异羟肟酸-MAb与99mTc和188Re的偶联物; 4） 表征免疫反应性以及体外和体内稳定性 99mTc-和188Re-标记的异羟肟酸盐缀合的MAb HuCC49和HuCC49ACH 2; 5） 比较188Re标记的肿瘤定位和生物分布 异羟肟酸-MAb HuCC 49和HuCC 49ACH 2与188Re标记的MAG 2-GABA的那些相比 缀合的MAb;和6）比较 ~（188）Re标记单克隆抗体HuCC 49和HuCC 49ACH 2在荷瘤裸鼠体内的表达 放射性核素剂量递增的腹膜内人癌异种移植物 相似的最大耐受剂量，并与188重新标记的 MAG2-GABA缀合的MAb。研究人员假设， HuCC49ACH2将导致高Jp. IP后的肿瘤结合。注射 相对于HuCC49，它具有更快的清除率，但从血液中清除要快得多。还有待 确定区域施用的CH2缺失抗体是否施用 将产生更大的抗Jp的治疗效果。 与完整抗体相比，其在最大耐受剂量下的癌症。的 本申请中描述的实验将提供这些问题的答案 问题.这些研究将确立人类临床RIT的基本原理 在Jp患者中进行试验。使用HuCC 49 ACH 2治疗癌症。

DESCRIPTION: (Adapted from applicant's abstract): Novel strategies to increase the therapeutic ratio in clinical radio-immunotherapy (RIT) studies are needed. The primary dose-limiting toxicity has been hematological. A humanized construct of the CC49 (HuCC49) high affinity anti-TAG-72 monoclonal antibody (MAb) is now available, as well as with the CH2 region deleted (HuCC49ACH2). The CH2 domain deleted MAb may have more rapid tumor penetration, a decreased circulation time and retain tumor localization/persistence characteristics. This project focuses on the development of bifunctional chelating agents (BCAs), derived from the hydroxamic acid class of organic compounds, for radiometal labeling of MAbs with 188Re for therapy. 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 188Re-HuCC49ACH2 administered in the peritoneum produces a higher relative tumor uptake in Jp. colon cancer nodules compared to blood, and to determine the relative tumor efficacy at the maximum tolerated dose of 188Re-HuCC49ACH2 VS. 188Re-HuCC49. The specific aims are to: 1) expand the hydroxamate family of BCAs by the rational design and synthesis of new members with improved characteristics; 2) optimize antibody conjugation chemistries of novel, rationally designed pyridine diglycine dihydroxamate (PG2H2), pyridine dihydroxamate (PH2), cyclic peptide trihydroxamate (cyc-PH3), and diethylene triamine pentahydroxamic acid (DTPH) BCAs; 3) radiolabel hydroxamate-MAb conjugates with 99mTc and 188Re; 4) characterize the immunoreactivity and the in vitro and in vivo stabilities of 99mTc- and 188Re-labeled hydroxamate-conjugated MAbs HuCC49 and HuCC49ACH2; 5) compare the tumor localization and biodistribution of 188Re-labeled hydroxamate-MAbs HuCC49 and HuCC49ACH2 to those of 188Re-labeled MAG2-GABA conjugated MAbs; and 6) compare the relative therapeutic efficacy of 188Re-labeled MAbs HuCC49 and HuCC49ACH2 in athymic nude mice bearing intraperitoneal human cancer xenografts at escalating radionuclide doses at comparable maximum tolerated doses, and to compare to those of 188Relabeled MAG2-GABA conjugated MAbs. The investigators hypothesize that the use of HuCC49ACH2 will result in high Jp. tumor binding following ip. injection relative to HuCC49, but a much more rapid clearance from blood. It remains to be determined whether regionally administered CH2 deleted antibody administered into the peritoneum will produce a greater therapeutic effect against Jp. cancer at its maximum tolerated dose compared to intact antibody. The experiments described in this application will provide answers to these questions. These studies would establish the rationale for human clinical RIT trials in patients with Jp. cancer using HuCC49ACH2.