EpoxySEAKER and onSEAKER: CAR T-Cell Systems for Targeted Local Biosynthesis of Therapeutic Warheads
EpoxySEAKER and onSEAKER: CAR T-Cell Systems for Targeted Local Biosynthesis of Therapeutic Warheads
批准号:
10634571
负责人:
Broderick C Corless
金额:
$2.7万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-05-28 至 2023-09-22
关键词:
AcidsAdverse effectsAnabolismAntigensAntineoplastic AgentsB-LymphocytesBindingBiochemicalBiological AssayCAR T cell therapyCancerousCarboxylic AcidsCell SurvivalCellsClassificationClinical TreatmentClinical TrialsCytotoxic agentDecarboxylationDevelopmentDiseaseDoseEngineeringEnvironmentEnzyme ActivationEnzymesFDA approvedGenerationsHistone DeacetylaseHistone Deacetylase InhibitorImmune responseImmunologicsImmunosuppressionIn SituIn VitroKeto AcidsKiller CellsKineticsMediatingModelingMultiple MyelomaMusPatientsPharmaceutical PreparationsPharmacy facilityPhaseProdrugsPropertyProteasome InhibitorRecombinantsSiteStreptomycesSystemT-Cell ProliferationT-LymphocyteTherapeuticTherapeutic EffectThreonineToxic effectTreatment EffectivenessTrichostatin AVariantVorinostatZincanalogcancer cellchelationchimeric antigen receptorchimeric antigen receptor T cellscovalent bondcytokine release syndromecytotoxicdehydrogenationdesignenzyme activityexhaustexhaustionhydroxamateimmunoengineeringin vitro activityin vitro testingin vivoin vivo evaluationinhibitorinterestmulticatalytic endopeptidase complexnovelnovel therapeutic interventionoff-target sitepharmacologicsmall moleculesynthetic enzymetumor
中文摘要
EPOXYSEAKER和ONSEAKER:用于靶向局部生物合成的CAR T细胞系统
治疗性弹头
我们的实验室已经开发出新型的表达酶的SEAKER(合成酶-武装杀手)CAR T细胞
这将遮盖组与系统管理的无毒前药分开。Seaker的本土化
细胞转化为肿瘤允许在感兴趣的部位将前药特异性地转化为抗癌剂。这些
Seaker细胞克服了CAR T细胞治疗的局限性,如T细胞耗竭、免疫抑制和
通过T细胞的增殖、酶的结构性分泌而产生级联效应的抗原变异
活性药物的催化生成。这些酶继续在肿瘤中产生细胞毒性化合物。
即使站点后的T细胞功能衰竭。我们将对这个系统进行改造,以产生新的
表达细菌生物合成酶并将非生物合成酶转化为
通过酶介导的治疗性弹头将毒性前药底物转化为细胞毒性化合物
安装。通过消除对遮盖部分的需要来限制前药的体积,我们预计会有更大的
前药的药理性质。将弹头部分安装到前药上,而不是切割
掩蔽组将消除细胞毒剂的非特异性激活,并减少靶点上、场外
与目标化合物相关的毒性。
我们计划使用我们的两个新的Seaker系统来靶向肿瘤环境,引发免疫反应,
随后分泌EpnF或TsnB9,其将酶激活FDA批准的前药物变体
就地用药。我们将为两个Seaker系统生成多个前药,并评估它们的转换为
这些活性化合物在体外使用重组酶。卡非佐米和帕诺比妥等化合物
在治疗多发性骨髓瘤时,与靶点外毒性有关。肿瘤
靶向“Epoxy Seaker”或“On Seaker”细胞将合成酶的分泌定位到
肿瘤部位,允许全身给药无毒前药,随后的原位化合物
合成并降低了目标化合物的异地毒性。相加疗法
CAR-T细胞和小分子的作用将增加治疗的有效性,并可能扩大
CAR-T细胞治疗的靶点范围。
英文摘要
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.
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EpoxySEAKER and onSEAKER: CAR T-Cell Systems for Targeted Local Biosynthesis of Therapeutic Warheads
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批准号:10418643
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项目类别:
-
资助金额:$4.68万
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财政年份:2021
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负责人:Broderick C Corless
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依托单位:
海外基金