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Engineering Cell-Cell Interactions by Chemically Self-Assembled CARS

通过化学自组装 CARS 改造细胞间相互作用

基本信息

批准号：
8986165
负责人：
CARSTON R. WAGNER
金额：
$ 19.11万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-12 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8986165
关键词：
Address Antibiotics Antibodies Biological Markers Breast Cancer Cell CD3 Antigens Cancer Patient Carcinoma Cell Communication Cell Therapy Cell membrane Cell surface Cells Chemistry Chimeric Proteins Data Development Dihydrofolate Reductase Dimerization Engineering Escherichia coli FDA approved Fatty Acids Future Generations Genetic Engineering Goals Health Immune In Vitro Kinetics Lead Length Libraries Lipids Malignant Neoplasms Membrane Methods Methotrexate Modification Molecular Mus Oligonucleotides Patients Peptides Pharmaceutical Preparations Phospholipids Preparation Role Stem cells Structure Sulfhydryl Compounds System T-Lymphocyte TACSTD1 gene Testing Therapeutic Therapeutic Uses Time Tissues Toxic effect Trimethoprim Xenograft Model arm base cancer cell cancer stem cell cell killing cellular engineering chemical addition chimeric antigen receptor clinically relevant cost effective cytotoxicity fluorophore genetically modified cells in vivo malignant breast neoplasm neoplastic cell programs repaired synthetic antibodies tissue regeneration tumor

项目摘要

DESCRIPTION (provided by applicant): The ability to engineer and re-program the surfaces of cells has the potential to expand and enable the therapeutic use of cell based therapies for both tissue regeneration and cancer. To achieve this goal a number of cell surface engineering approaches have been devised. Clinically, genetic engineering of cells is by far the most commonly used approach for the modification of cell surfaces. Nevertheless, the preparation of the engineered cells is time consuming, requires several sophisticated steps and can lead to long term immune toxicities. Our group has employed the power of chemically induced protein dimerization to develop a method to produce chemically self-assembled nanorings (CSANs). We have shown that two E. coli dihydrofolate reductase molecules (DHFR2) fused to a single chain antibody (scFv) or targeting peptide can be engineered to spontaneously self-assemble, upon the addition of the chemical dimerizer, bis-methotrexate (Bis-MTX), into either highly stable bivalent or octavalent synthetic antibody CSANs. Recently, using a Bis-MTX phospholipid conjugate, we have prepared CSANs that rapidly (min) and stably (days) insert into cell membranes. In addition, when a scFv targeting EpCAM, a carcinoma and cancer stem cell marker, was fused to the DHFR2 building block, our first generation anti-EpCam chemically self-assembled chimeric antigen receptors (anti-EpCAM-CS-CARs) were formed and found to direct selective Tcell cell killing of EpCAM positive breast cancer cells. A unique feature of our approach is the ability to remove the anti-EpCAM-CS-CARs from the T-cells pharmacologically with a non-toxic drug. Therefore, we propose to prepare a small library of structurally different anti-EpCAM-CS-CARs and determine their ability to stably functionalize T-cell membranes and induce cytotoxicity toward EpCam positive tumor cells both in vitro and in vivo. This preliminary data will allow us to establish the potential for chemically self-assembled chimeric antigen receptors (CS-CARs) to serve as an alternative and complementary approach for the engineering of stable, yet pharmacologically reversible, therapeutic cell-cell interactions.

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells.

通过化学自我组装的标记T细胞消除已建立的肿瘤。

DOI：
10.1021/acsnano.8b01308
发表时间：
2018-07-24
期刊：
ACS nano
影响因子：
17.1
作者：
Petersburg JR;Shen J;Csizmar CM;Murphy KA;Spanier J;Gabrielse K;Griffith TS;Fife B;Wagner CR
通讯作者：
Wagner CR

In Vivo Evaluation of Site-Specifically PEGylated Chemically Self-Assembled Protein Nanostructures.

体内特定于定位的化学自我组装蛋白纳米结构的体内评估。

DOI：
10.1021/acs.molpharmaceut.6b00110
发表时间：
2016-07-05
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Shah R;Petersburg J;Gangar AC;Fegan A;Wagner CR;Kumarapperuma SC
通讯作者：
Kumarapperuma SC

Titratable Avidity Reduction Enhances Affinity Discrimination in Mammalian Cellular Selections of Yeast-Displayed Ligands.

可滴定亲和力降低增强了酵母展示配体的哺乳动物细胞选择中的亲和力辨别力。

DOI：
10.1021/acscombsci.6b00191
发表时间：
2017
期刊：
ACS combinatorial science
影响因子：
0
作者：
Stern,LawrenceA;Csizmar,CliffordM;Woldring,DanielR;Wagner,CarstonR;Hackel,BenjaminJ
通讯作者：
Hackel,BenjaminJ

Eradication of Heterogeneous Tumors by T Cells Targeted with Combination Bispecific Chemically Self-assembled Nanorings.