Humanizing CXCL13 and CXCR5 in mice

在小鼠中人性化 CXCL13 和 CXCR5

基本信息

批准号：
10357214
负责人：
ELIAS LOLIS
金额：
$ 23.49万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357214
关键词：
Agonist Antibodies Autoimmune Diseases B-Cell Lymphomas B-Lymphocytes BLR1 gene Bioinformatics Biological Response Modifier Therapy Breast Diseases Breeding C57BL/6 Mouse CRISPR/Cas technology CXCL13 gene Cells Clinic Clinical Code Colon Carcinoma Colonic Diseases Cutaneous T-cell lymphoma Cytotoxic Chemotherapy Development Disease Doctor of Philosophy Embryo Exploratory/Developmental Grant Future G-Protein-Coupled Receptors Genes Genetic Goals Helper-Inducer T-Lymphocyte Hematopathology Human Immune system Immunoblastic Lymphadenopathy Immunologic Deficiency Syndromes In Vitro Individual Knock-in Knock-in Mouse Knock-out Letters Libraries Lung diseases Lymphoma cell Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Membrane Membrane Proteins Memory B-Lymphocyte Methodology Modeling Mus Mutation Oncologist Patients Phage Display Pharmacodynamics Pharmacology Plasma Cells Positron-Emission Tomography Process Property Prostatic Diseases Proteins Research Personnel Scheme Sequence Homology Signal Transduction Specificity Surface Survival Rate T-Lymphocyte Technology Testing Therapeutic Therapeutic Effect Therapeutic Studies Therapeutic Use Study Tumor Tissue Variant antagonist base cell motility chemokine chemokine receptor cross reactivity experimental study humanized mouse in vivo inhibitor insight interest leukemia/lymphoma lymph nodes malignant breast neoplasm mouse model patient derived xenograft model personalized medicine pharmacokinetics and pharmacodynamics pre-clinical preclinical study radiotracer receptor response small molecule therapeutic target transcriptome sequencing tumor microenvironment

项目摘要

Summary/Abstract Angioimmunoblastic T-cell lymphoma (AITL) has a 47% survival rate over a two-year period despite aggressive cytotoxic therapy, with no significant increase in survival for over two decades. CXCR5 is a chemokine G protein-coupled receptor (GPCR) that is localized on the membrane of AITL cells. We have identified a small molecule compound that antagonizes CXCR5 and shown beneficial effects in AITL-PDX study. We also used phage display technologies and bioinformatics to identify 102 potential antagonists from a library of ~168,000 CXCL13 variants. With a collaborator at Yale (Samuel Katz, MD/PhD), we are also developing a CAR-T by targeting CXCR5. This application intends to make a humanized CXCL13 and CXCR5 strain of C57Bl/6. The ultimate goal is to test the small molecule antagonist and the CXCL13-based biotherapeutic in the context of a tumor microenvironment, which is not possible with PDX mice. The expression of humanized CXCL13 and CXCR5 will be quantitated and compared to vivo levels of normal expression of C57Bl/6. Cells from humanized mice and normal C57Bl/6 mice will be functionally compared in vitro, and the pharmacodynamics of the 18F-antagonist will be determined by in vivo PET studies to more accurately characterize the mouse model. The humanized CXCL13 and CXCR5 mice will not only be available for future AITL studies but also for mouse models of cutaneous T-cell lymphoma, a variety of CXCR5- expressing B-cell lymphomas, cancers of the prostate, colon, lung, and breast, and autoimmune diseases.

摘要/摘要尽管血管免疫母细胞 T 细胞淋巴瘤 (AITL) 的两年生存率为 47% 积极的细胞毒治疗，二十多年来生存率没有显着提高。 CXCR5 是趋化因子 G 蛋白偶联受体 (GPCR) 位于 AITL 细胞膜上。我们有鉴定出一种拮抗 CXCR5 的小分子化合物，并在 AITL-PDX 中显示出有益作用学习。我们还使用噬菌体展示技术和生物信息学从一个细菌中鉴定出 102 种潜在的拮抗剂。包含约 168,000 个 CXCL13 变体的库。与耶鲁大学的合作者（塞缪尔·卡茨，医学博士/博士）一起，我们还通过针对 CXCR5 开发 CAR-T。本申请旨在制作人源化CXCL13和CXCR5 C57Bl/6 菌株。最终目标是测试小分子拮抗剂和基于 CXCL13 的药物在肿瘤微环境中进行生物治疗，这对于 PDX 小鼠来说是不可能的。这人源化 CXCL13 和 CXCR5 的表达将被定量并与正常体内水平进行比较 C57Bl/6 的表达。来自人源化小鼠和正常 C57Bl/6 小鼠的细胞将在功能上进行比较体外，18F拮抗剂的药效学将通过体内PET研究来确定，以更多地了解准确表征小鼠模型。人源化CXCL13和CXCR5小鼠不仅将上市用于未来的 AITL 研究，也用于皮肤 T 细胞淋巴瘤的小鼠模型，各种 CXCR5- 表达 B 细胞淋巴瘤、前列腺癌、结肠癌、肺癌和乳腺癌以及自身免疫性疾病。