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/摘要血管免疫细胞T细胞淋巴瘤（AITL）在两年内生存率为47％积极的细胞毒性疗法，二十年来生存率无显着增加。 CXCR5是a 趋化因子G蛋白偶联受体（GPCR）位于AITL细胞的膜上。我们有鉴定出一种拮抗CXCR5并在AITL-PDX中显示出有益作用的小分子化合物学习。我们还使用噬菌体展示技术和生物信息学来识别102个潜在的拮抗剂〜168,000 CXCL13变体的库。与耶鲁大学的合作者（塞缪尔·卡兹（Samuel Katz），医学博士/博士），我们也是通过靶向CXCR5来开发CAR-T。该应用程序打算制造人源化的CXCL13和CXCR5 C57BL/6的应变。最终目标是测试小分子拮抗剂和基于CXCL13的拮抗剂在肿瘤微环境的背景下，PDX小鼠不可能进行生物治疗。这人源化CXCL13和CXCR5的表达将被定量，并将其与正常的体内水平进行比较 C57BL/6的表达。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和18F抗抗逆邦剂的药效学将通过体内PET研究来确定更多准确表征鼠标模型。人源化的CXCL13和CXCR5小鼠不仅可以使用对于将来的AITL研究，但对于皮肤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，结肠，肺和乳腺癌以及自身免疫性疾病的癌症。