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EpoxySEAKER and onSEAKER: CAR T-Cell Systems for Targeted Local Biosynthesis of Therapeutic Warheads

EpoxySEAKER 和 onSEAKER：用于治疗性弹头局部靶向生物合成的 CAR T 细胞系统

基本信息

批准号：
10634571
负责人：
Broderick C Corless
金额：
$ 2.7万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-28 至 2023-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10634571
关键词：
Acids Adverse effects Anabolism Antigens Antineoplastic Agents B-Lymphocytes Binding Biochemical Biological Assay CAR T cell therapy Cancerous Carboxylic Acids Cell Survival Cells Classification Clinical Treatment Clinical Trials Cytotoxic agent Decarboxylation Development Disease Dose Engineering Environment Enzyme Activation Enzymes FDA approved Generations Histone Deacetylase Histone Deacetylase Inhibitor Immune response Immunologics Immunosuppression In Situ In Vitro Keto Acids Killer Cells Kinetics Mediating Modeling Multiple Myeloma Mus Patients Pharmaceutical Preparations Pharmacy facility Phase Prodrugs Property Proteasome Inhibitor Recombinants Site Streptomyces System T-Cell Proliferation T-Lymphocyte Therapeutic Therapeutic Effect Threonine Toxic effect Treatment Effectiveness Trichostatin A Variant Vorinostat Zinc analog cancer cell chelation chimeric antigen receptor chimeric antigen receptor T cells covalent bond cytokine release syndrome cytotoxic dehydrogenation design enzyme activity exhaust exhaustion hydroxamate immunoengineering in vitro activity in vitro testing in vivo in vivo evaluation inhibitor interest multicatalytic endopeptidase complex novel novel therapeutic intervention off-target site pharmacologic small molecule synthetic enzyme tumor

项目摘要

EPOXYSEAKER AND ONSEAKER: CAR T-CELL SYSTEMS FOR TARGETED LOCAL BIOSYNTHESIS OF THERAPEUTIC WARHEADS Our labs have developed novel SEAKER (Synthetic Enzyme-Armed KillER) CAR T-cells that express enzymes that cleave masking groups from systemically administered non-toxic prodrugs. The localization of SEAKER cells to tumors allows for specific conversion of the prodrug to anticancer agent at the site of interest. These SEAKER cells overcome limitations of CAR T-cell therapy such as T-cell exhaustion, immunosuppression and antigen variance by creating a cascade effect through proliferation of T-cells, constitutive secretion of enzymes and catalytic generation of the active drugs. The enzymes continue to produce cytotoxic compounds at the tumor site even after the T-cells functionally exhaust. We will engineer this system to produce novel “epoxySEAKER” and “onSEAKER” cells that express bacterial biosynthetic enzymes and convert non- toxic prodrug substrates into cytotoxic compounds through an enzyme-mediated therapeutic warhead installation. Limiting the bulkiness of the prodrug by eliminating the need for masking moieties we expect greater pharmacological properties of the prodrugs. Installing the warhead moiety onto the prodrug rather than cleaving a masking group will eliminate the non-specific activation of cytotoxic agents and reduce the on-target, off-site toxicity associated with the target compounds. We plan to use our two novel SEAKER systems to target the tumor environment, elicit immunologic responses, and subsequently secrete EpnF or TsnB9 which will enzymatically activate prodrug variants of FDA approved drugs in situ. We will generate multiple prodrugs for the two SEAKER systems and evaluate their conversion to the active compounds using recombinant enzymes in vitro. Compounds such as carfilzomib and panobinostat are associated with on-target off-site toxicity when administered for the treatment of multiple myeloma. Tumor targeting “epoxySEAKER” or “onSEAKER” cells will localize the secretion of synthetic enzyme to the tumor site, allowing systemic administration of non-toxic prodrug, subsequent in situ compound synthesis and reduced off-site toxicity demonstrated by the target compounds. The additive therapeutic effect of the CAR-T cells and small-molecules will increase the effectiveness of treatment and may expand the target scope of CAR-T cell therapy.

EPOXYSEAKER 和 ONSEAKER：用于靶向局部生物合成的 CAR T 细胞系统治疗弹头我们的实验室开发了新型 SEAKER（合成酶武装 KillER）CAR T 细胞，可表达酶从全身施用的无毒前药中裂解掩蔽基团。 SEAKER的本地化细胞到肿瘤允许前药在感兴趣的部位特异性转化为抗癌剂。这些 SEAKER细胞克服了CAR T细胞疗法的局限性，例如T细胞耗竭、免疫抑制和通过 T 细胞增殖、酶的组成型分泌产生级联效应，从而产生抗原变异以及活性药物的催化生成。这些酶继续在肿瘤处产生细胞毒性化合物即使 T 细胞功能耗尽后，该位点仍然存在。我们将设计这个系统来生产新颖的 “epoxySEAKER”和“onSEAKER”细胞表达细菌生物合成酶并将非- 通过酶介导的治疗弹头将有毒前药底物转化为细胞毒性化合物安装。通过消除我们期望更大的掩蔽部分的需要来限制前药的体积前药的药理学特性。将弹头部分安装到前药上而不是裂解掩蔽基团将消除细胞毒性剂的非特异性激活并减少靶向、非位点与目标化合物相关的毒性。我们计划使用我们的两个新颖的 SEAKER 系统来靶向肿瘤环境，引发免疫反应，随后分泌 EpnF 或 TsnB9，这将酶促激活 FDA 批准的前药变体药物就地。我们将为两个 SEAKER 系统生成多种前药并评估它们的转化体外使用重组酶的活性化合物。卡非佐米和帕比司他等化合物当用于治疗多发性骨髓瘤时，这些药物与靶向异位毒性相关。瘤靶向“epoxySEAKER”或“onSEAKER”细胞将合成酶的分泌定位于肿瘤部位，允许全身施用无毒前药，随后进行原位化合物目标化合物的合成并降低了场外毒性。附加治疗 CAR-T细胞和小分子的作用将提高治疗效果并可能扩大治疗范围 CAR-T细胞治疗的目标范围。