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NCDG的总体目标是开发靶向肽瘤的淋巴癌促成有用的治疗剂和成像剂。通过组合化学，我们发现了一系列与淋巴恶性肿瘤激活的α4BETA1结合的肽型化合物。这些化合物含有有机部分，D-氨基酸和不自然的氨基酸，因此预计它们对蛋白水解具有抗性。它们与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强烈结合。这些肽型铅具有很大的潜力，可以发展为人类和犬淋巴恶性肿瘤的治疗和成像剂。该NCDDG应用程序具有三个程序和两个核心。程序1负责进一步优化和表征这些肽型铅。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α4和/或Beta1整合素基因转染，以评估Alpha4Beta1整合蛋白与程序1中开发的靶向代理之间的分子相互作用。这项研究将使我们能够绘制出高度亲和力的群体，从而使我们能够绘制出较高的核能，从而构图了越来越多的集成。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剂将装有64CU用于PET成像，并在患有人类淋巴瘤异种淋巴瘤的裸鼠和伴侣犬的自发性犬类淋巴瘤中，用于裸鼠的疗法研究。合成化学核心（Core B）及其相应程序的输入，将负责化合物型诽谤，靶向剂以及所有三个程序所需的任何其他化学共轭物的设计和合成。程序1、2和3以及核心B具有高度交互性和协同作用。我们的目标是在第5年底完全优化和评估我们无线电目标对淋巴恶性肿瘤的靶向潜力，这时将选择一种靶向剂进行临床开发。