NEW BCAS FOR RADIOIMMUNOTHERAPY WITH RADIOMETALS

描述：(改编自申请者摘要)：增加的新策略 在临床放射免疫治疗(RIT)研究中需要确定治疗比率。 主要的剂量限制毒性一直是血液毒性。一个人性化的 CC49(HuCC49)高亲和力抗TAG-72单抗的构建 (MAb)现已可用，并且CH2区域被删除(HuCC49ACH2)。 CH2结构域缺失的单抗可能具有更快的肿瘤侵袭速度， 循环时间和保留肿瘤定位/持久性的特点。 本项目致力于双功能螯合剂的开发。 (BCAS)，源自异羟肟酸类有机化合物，用于 188Re标记治疗用单抗的放射性金属标记基于前景看好的 UAB治疗卵巢癌177Lu-CC49的临床结果 在临床前研究中确定188Re-HuCC49ACH2是否有价值 在腹膜内给药，JP的相对肿瘤摄取率较高。 结肠癌结节与血液的比较，并确定其与肿瘤的关系 188Re-HuCC49ACH2对最大耐受量的疗效。188Re-HuCC49. 具体目标是：1)通过以下方式扩大BCA的异羟甲酸酯家族 合理设计和合成具有改进特性的新成员；2) 优化新型、合理设计的抗体偶联化学 吡啶二甘氨酸二羟基甲酸酯(PG2H2)，吡啶二羟基甲酸酯(PH2)，环状 多肽三羟甲酸酯(Cyc-PH3)和二乙烯三胺五异羟肟酸 (DTPH)BCA；3)~(99m)Tc和~(188)Re的放射性标记异羟甲酸酯-单抗结合物；4) 鉴定其免疫反应性和体内外稳定性 99mTc和188Re标记的羟胺酸单抗HuCC49和HuCC49ACH2；5) ~(188)Re标记肿瘤的定位和生物分布比较 羟甲酸单抗HuCC49和HuCC49ACH2对188Re标记的MAG2-GABA的作用 结合的单抗；6)比较两种药物的相对疗效。 188Re标记单抗HuCC49和HuCC49ACH2在荷瘤裸鼠体内的实验研究 放射性核素剂量递增的腹膜内人癌移植瘤 可比最大耐受剂量，并与188重新标记的剂量进行比较 MAG2-GABA偶联单抗。调查人员假设使用的是 HuCC49ACH2将导致高JP。IP后肿瘤结合。注射法 相对于HuCC49，但从血液中清除要快得多。它还有待于 确定区域注射CH2缺失抗体是否注射 进入腹膜会对JP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。这个 本应用程序中描述的实验将提供这些问题的答案 问题。这些研究将为人类临床RIT奠定理论基础 JP患者的临床试验。癌症使用HuCC49ACH2。

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.