Targeting Agents for Human and Canine Lymphoma

人类和犬淋巴瘤的靶向药物

基本信息

批准号：
7495833
负责人：
KIT S LAM
金额：
$ 4.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/7495833
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

项目摘要

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 alpha4beta1 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 alpha4 and/or beta1 integrin genes, to evaluate the molecular interactions between alpha4beta1 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 64Cu for PET imaging and 90Y for therapeutics studies in nude mice with human lymphoma xenograft, and in spontaneous canine lymphoma in companion dog. 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.

该 NCDDG 的总体目标是将我们的淋巴癌靶向肽模拟先导物开发成有用的治疗剂和成像剂。通过组合化学，我们鉴定了一系列能够与淋巴恶性肿瘤的活化 α4β1 结合的拟肽化合物。这些化合物含有有机部分、D-氨基酸和非天然氨基酸，因此预计它们能够抵抗蛋白水解。它们与 T 和 B 淋巴瘤细胞系以及来自急性白血病患者的新鲜白血病细胞结合。淋巴细胞白血病，但它们不与正常人外周血结合。此外，它们与狗淋巴瘤细胞强烈结合。这些拟肽先导化合物具有开发成为人类和犬淋巴恶性肿瘤的治疗剂和成像剂的巨大潜力。该 NCDDG 应用程序具有三个程序和两个核心。程序 1 负责这些拟肽先导化合物的进一步优化和表征。计算化学和组合化学将用于先导化合物优化。项目 2 涉及使用一系列已用野生型或突变型 α4 和/或 β1 整联蛋白基因稳定转染的 CHO 细胞，以评估 α4β1 整联蛋白与项目 1 中开发的靶向剂之间的分子相互作用。使我们能够绘制结合位点图谱，并开发出能够克服整合素上关键残基突变的高亲和力配体类似物。计划 3 涉及体内评估靶向剂，在计划 1 中开发并由 Core B 合成。DOTA 标记的靶向剂将装载用于 PET 成像的 64Cu 和用于人类淋巴瘤异种移植裸鼠和伴侣犬自发性犬淋巴瘤的治疗研究的 90Y。合成化学核心（核心 B）通过相应程序的输入，将负责设计和合成化合物珠库、靶向剂以及所有三个程序所需的任何其他化学缀合物。计划1、2、3以及核心B具有高度互动性和协同性。我们的目标是在第 5 年年底之前全面优化和评估我们的放射靶向药物治疗淋巴恶性肿瘤的靶向潜力，届时将选择一种靶向药物进行临床开发。