Targeting Agents for Human and Canine Lymphoma

人类和犬淋巴瘤的靶向药物

• 批准号: 7617481
• 负责人: KIT S LAM
• 金额: $ 6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-19 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617481
• 关键词: 90Y; Acute Lymphocytic Leukemia; Affinity; Amino Acids; Animal Model; Avidity; Binding; Binding Sites; Canis familiaris; Cell Line; Cell Surface Receptors; Cell surface; Cells; Chinese Hamster Ovary Cell; Clinical; Companions; Development; Evaluation; Genes; Goals; Human; Image; Integrins; Label; Laboratories; Lead; Libraries; Ligands; Lymphoid; Lymphoma; Malignant Neoplasms; Malignant lymphoid neoplasm; Maps; Mutation; Nude Mice; Patients; Peptides; Pharmaceutical Chemistry; Positron-Emission Tomography; Proteolysis; Radio; Range; Resistance; Screening procedure; Series; Signal Transduction; Synthesis Chemistry; T-Cell Lymphoma; Therapeutic; Therapeutic Agents; Therapeutic Studies; Time; Xenograft procedure; analog; cancer cell; chemical conjugate; combinatorial chemistry; computational chemistry; crosslink; design; in vivo; leukemia; mutant; peptidomimetics; peripheral blood; programs; response; therapeutic target

Overall Program The overall goal of this NCDDG is to develop our lymphoid cancer targeting peptidomimetic leads into useful therapeutic and imaging agents. Through combinatorial chemistry, we have identified a series of peptidomimetic compounds that bind to activated oc4|31 of lymphoid malignancies. These compounds contain an organic moiety, D-amino acids, and unnatural amino acids, and therefore they are expected to be resistant to proteolysis. They bind to both T- and B-lymphoma cell lines as well as fresh leukemia cells derived from patients with acute lymphocytic leukemia, but they do not bind to normal human peripheral blood. Furthermore, they bind strongly to dog lymphoma cells. These peptidomimetic leads have great potential to be developed into therapeutic and imaging agents for both human and canine lymphoid malignancies. This NCDDG application has three programs and two cores. Program 1 is responsible for further optimization and characterization of these peptidomimetic leads. Computational chemistry and combinatorial chemistry will be used for lead optimization. Program 2 involves the use of a series of CHO cells, that have been stably transfected with wild type or mutant a4 and/or pi integrin genes, to evaluate the molecular interactions between a4pl integrin and the targeting agents developed in Program 1. This study will enable us to map the binding site, and to develop high affinity ligand analogues that can overcome the mutation of the critical residues on the integrin. Program 3 involves in vivo evaluation of the targeting agents, developed in Program 1 and synthesized by Core B. DOTA-labeled targeting agents will be loaded with ^Cu for PET imaging and 90Y for therapeutics studies in nude mice with human lymphoma xenograft, and in spontaneous canine lymphoma in companion dog. Core A is the administrative core. The synthetic chemistry core (Core B), with input from corresponding programs, will be responsible for the design and synthesis of compound-bead libaries, targeting agents, and any other chemical conjugates required by all three programs. Program 1, 2, and 3 as well as Core B are highly interactive and synergistic. Our goal is to fully optimize and evaluate the targeting potential of our radio-targeting agents for lymphoid malignancies by the end of year 5, at which time one targeting agent will be selected for clinical development.

总体计划 该NCDG的总体目标是开发靶向肽型的淋巴癌导致有用 治疗和成像剂。通过组合化学，我们已经确定了一系列肽类似物 与激活的OC4 | 31结合淋巴恶性肿瘤的化合物。这些化合物包含一个有机部分， D-氨基酸和非自然氨基酸，因此预计它们对蛋白水解具有抗性。他们 与T-和B淋巴瘤细胞系结合，以及来自急性患者的新鲜白血病细胞 淋巴细胞性白血病，但它们不与正常的人外周血结合。此外，它们与 狗淋巴瘤细胞。这些肽含量的铅具有很大的潜力，可以发展为治疗性和 人类和犬淋巴恶性肿瘤的成像剂。该NCDDG应用程序有三个程序 和两个核心。程序1负责进一步的优化和表征这些肽分性 铅。计算化学和组合化学将用于铅优化。程序2 涉及使用一系列CHO细胞，这些细胞已稳定地用野生型或突变体A4和/或Pi转染 整联蛋白基因，评估A4PL整合素与靶向剂之间形成的分子相互作用 程序1。这项研究将使我们能够映射绑定位点，并开发高亲和力的配体类似物 可以克服整联蛋白上临界残基的突变。程序3涉及对体内评估 在程序1中开发的靶向剂并由核心B. dota标记的靶向剂合成的靶向代理将是 用人类淋巴瘤异种移植物载有用于PET成像的 ^Cu和90年的裸鼠治疗研究 并在同伴狗的自发犬淋巴瘤中。核心A是管理核心。合成 化学核心（核心B），并带有相应程序的输入，将负责设计和合成 所有三个程序都需要的化合物诽谤，靶向剂和任何其他化学共轭物。 程序1、2和3以及核心B具有高度交互性和协同作用。我们的目标是完全优化和 在第5年底，评估我们无线电目标对淋巴恶性肿瘤的靶向潜力 哪个时间将选择一个靶向剂进行临床开发。