Combinatorial Peptide Libraries for Biodegradable Linkers to Decrease Normal Tiss

可生物降解接头的组合肽文库可减少正常的尿频

• 批准号: 6989503
• 负责人: KIT S LAM
• 金额: $ 11.8万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989503
• 关键词: athymic mouse; biodegradable product; biomaterial development /preparation; biotechnology; chelating agents; chemical cleavage; combinatorial chemistry; immunoconjugates; immunologic substance development /preparation; neoplasm /cancer radioimmunotherapy; peptide library; pharmacokinetics; plasminogen activator; radiation dosage; therapy design /development

The goal of this project is to develop highly effective cancer-targeting agents for cancer therapy. Radioimmunotherapy (RIT) has proven to be useful in cancer patients. However, the dose-limiting toxicities of RIT are due to excessive radiation to normal organs such as liver, kidney, and bone marrow. There is a need to develop new strategies to increase the therapeutic index of cancer-targeting agents not only by enhancing rapid removal of the radioactivity from normal tissues but also improving the delivery of the radiopharmaceutical to the tumor. One strategy is to develop highly specific bio-degradable peptides to link the radio-metal chelate to the targeting agents. Our hypothesis is that bio-degradable linkers that can be cleaved on demand when incorporated in a tumor targeting agent such as monoclonal antibody, will result in an effective anti-cancer agent with high therapeutic index. A "one-bead one-compound" combinatorial peptide library method will be used to discover highly specific peptide substrates for tissue plasminogen activator (serine protease (TNKase(R), Activase(R))) to develop an "on-demand-cleavable" linker. In the past, we have shown that, when a cathepsin B sensitive linker was used in either of three radio-immunoconjugates, there was a 30-60% decrease in radiation dose to the liver but the radiation dose to the tumor was maintained. In this project, we have screened peptide libraries, with much higher diversity than the ones that were used in the past, for the discovery of highly specific peptide substrates for serine protease. We have explored the possibility of using TNKase (R) or Activase(R), FDA-approved thrombolytic agents, to cleave a linker between the radio-metal chelate and the antibody molecule so that free radio-metal chelate can be rapidly cleared through the kidney. Now identified, candidate peptides have been tested in vitro for specificity and efficiency and shown to be stable in plasma and media from malignant cells, yet readily clearable by low doses of TNKase. Peptides will be selected for final testing in mouse xenograft models. In year 3, a clinical protocol for evaluating the pharmacokinetics and efficacy of peptides with superior performance in the mouse model will be developed. This project interacts very closely with the other projects by providing them with novel bio-degradable linkers. This project also interacts very closely with the radiopharmacy core as well as the imaging and dosimetry core for both pre-clinical and clinical development.

该项目的目的是开发高效的癌症治疗剂。事实证明，放射免疫疗法（RIT）对癌症患者很有用。但是，RIT的剂量限制毒性是由于对肝脏，肾脏和骨髓等正常器官的过度辐射。有必要制定新的策略，不仅通过提高正常组织中的放射性去除，而且改善了放射性药物对肿瘤的递送，不仅可以通过提高放射性的快速去除来增加靶向癌症的剂的治疗指数。一种策略是开发高度特异性的生物降解肽，以将射量螯合物与靶向剂联系起来。我们的假设是，在肿瘤靶向剂（如单克隆抗体）中掺入时，可以按需切割的生物降解接头将导致 具有高治疗指数的有效抗癌剂。一种“单珠一体化合物”组合肽文库方法将用于发现组织纤溶酶原激活剂（丝氨酸蛋白酶（TNKase（r），Activans（r）））的高度特异性肽底物，以开发一个“可裂开的可裂解”链接。过去，我们表明，当在三个放射性免疫缀合物中使用组织蛋白酶B敏感的连接器时，肝脏的辐射剂量降低了30-60％，但辐射剂量却保持了肿瘤的辐射剂量。在这个项目中，我们筛选了肽库，其多样性比过去使用的肽库高得多，以发现丝氨酸蛋白酶的高度特异性肽底物。我们探索了使用TNKase（R）或Activans（R），FDA批准的溶栓液的可能性 代理，要在射电螯合物和抗体分子之间裂开接头，以便可以通过肾脏快速清除自由射射螯合物。现在已经鉴定出来的是，已在体外测试了候选肽的特异性和效率，并在血浆中显示出来自恶性细胞的血浆和培养基稳定，但可以通过低剂量的TNKase易于清除。将在小鼠异种移植模型中选择肽进行最终测试。在第3年中，将开发出一种用于评估具有较高性能的肽的临床方案和疗效。该项目通过为它们提供新颖的生物降解连接器而与其他项目进行了非常紧密的互动。该项目还与放射性药物核心以及临床前和临床的成像和剂量测定核心都非常紧密相互作用 发展。