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Design of de novo interleukin mimics for targeted immunotherapy

用于靶向免疫治疗的从头白细胞介素模拟物的设计

基本信息

批准号：
10475003
负责人：
DAVID BAKER
金额：
$ 33.9万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475003
关键词：
Affinity Binding Biological Assay Biological Markers Biophysics Categories Cell surface Cells Clinic Cytokine Signaling DNA Dose-Limiting ERBB2 gene Effector Cell Elements Engineering Epidermal Growth Factor Receptor Escherichia coli Extracellular Domain Flow Cytometry Goals Human Immune Immune system Immunologics Immunotherapeutic agent Immunotherapy In Vitro Interferometry Interleukin Receptor Interleukin-12 Interleukin-2 Interleukin-4 Interleukins Label Malignant Neoplasms Measures Mission Modeling Molecular Sieve Chromatography Monitor Mus Oncogenes Peptide Synthesis Phosphorylation Population Property Protein Engineering Proteins Public Health Regenerative Medicine Renal Cell Carcinoma Research Proposals Signal Transduction Structure Surface T-Lymphocyte Therapeutic Toxic effect Transactivation Tumor Markers United States National Institutes of Health X-Ray Crystallography Yeasts anti-cancer base cancer cell cancer immunotherapy cancer therapy clinical application combat cytokine deep sequencing design disability extracellular frontier immunogenicity improved in vivo innovation interleukin-21 manufacturability melanoma mimetics nanobodies novel programmed cell death ligand 1 receptor reconstitution tumor tumor growth tumor xenograft

项目摘要

PROJECT SUMMARY Although immunostimulatory cytokines can be used to combat cancer, their poor stability and high off-target toxicity has limited their application in the clinic. The long-term goal of this project is to produce targeted anti-cancer cytokine mimetics with reduced toxicity. The overall objective is to apply recent breakthroughs in de novo protein design to yield a new category of targeted, non-toxic, immunostimulatory proteins. The central hypothesis is that the beneficial stimulatory effects of natural cytokines can be engineered into de novo designed proteins which do not engage in off-target binding, thereby circumventing the dose-limiting toxicities seen in clinical applications of natural/reengineered cytokines. The specific aims are to: (1) use de novo protein design to generate hyperstable, bioactive mimetics of interleukin-2, -4, -12, -15, and -21 which function by engaging with (i.e. binding to) interleukin receptors in vivo; (2) to split these mimics into inactive parts which can regain activity by reassembling in vivo; and (3) to fuse each of these inactive parts to specific targeting domains, thereby yielding conditionally-active cytokine mimics that stimulate T-cells by reassembling only on the surface of a targeted cells (i.e. cancer cells displaying two specific surface biomarkers). As proof of principle, the first such de novo designed cytokine mimetic has been produced, split, and shown to reduce tumors in mice without accompanying toxicity or immunogenicity. This research proposal is innovative because it seeks to resolve a long-standing barrier to cancer immunotherapy (namely, the off-target toxicity of cytokine-based therapeutics) by designing from scratch a new class of non-toxic cytokine mimics. The proposal is significant because it would be the first example of computational protein design yielding targeted, biosuperior cancer therapeutics. Ultimately, such molecules have the potential to treat a wide range of cancers, including malignant melanoma, renal cell carcinoma, and more.

项目总结虽然免疫刺激细胞因子可以用于抗癌，但它们的稳定性差，靶向性高。毒性限制了它们在临床上的应用。这个项目的长期目标是生产有针对性的毒性较低的抗癌细胞因子模拟物。的总体目标是将最近的突破应用于de Novo蛋白质设计以产生一种新的靶向、无毒、免疫刺激蛋白质。中心假设天然细胞因子的有益刺激作用可以被改造成de nevo 设计了不参与脱靶结合的蛋白质，从而绕过了剂量限制的毒性可见于天然/重组细胞因子的临床应用。的特定目的是：(1)使用从头蛋白设计以产生白细胞介素2、-4、-12、-15和-21的超稳定的生物活性模拟物，其功能是通过在体内与白细胞介素受体结合(即结合)；(2)将这些模拟物分解成非活性部分，可以通过在体内重组来恢复活性；以及(3)将这些非活性部分中的每一个融合到特定的靶向结构域，从而产生有条件地激活的细胞因子模拟物，通过仅在靶细胞的表面(即癌细胞显示两个特定的表面生物标志物)。作为证据原理，第一个这样的从头设计的细胞因子模拟物已经被产生，分裂，并显示出减少无伴随毒性或免疫原性的小鼠肿瘤。这项研究建议是的创新，因为它寻求解决癌症免疫治疗的长期障碍(即，基于细胞因子的疗法)，从零开始设计一类新的无毒细胞因子模拟物。这个该提议具有意义，因为它将是第一个计算蛋白质设计的例子，产生靶向，生物优势癌症疗法。最终，这种分子有可能治疗多种癌症，包括恶性黑色素瘤、肾细胞癌等。