Molecular engineering and systematic evaluation of bispecific aptamers to develop potent and efficacious therapies for the immunomodulation of Non-Small Cell Lung Cancer

双特异性适体的分子工程和系统评估，以开发有效的非小细胞肺癌免疫调节疗法

• 批准号: 10751309
• 负责人: Brian J Thomas
• 金额: $ 3.34万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2027-08-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751309
• 关键词: Address; Adenocarcinoma; Adjuvant; Adverse event; Affect; Affinity; Antibodies; Antigen Presentation; Antitumor Response; Aptamer Technology; Attention; Automobile Driving; Binding; Biodistribution; Biological Products; Bispecific Antibodies; Bypass; Cancer Biology; Cancer Patient; Cardiovascular Diseases; Categories; Cause of Death; Cell Cycle; Cells; Clinical; Clinical Trials; Development; Disease; Disease Progression; Dose Limiting; Drug Kinetics; Effectiveness; Emotional; Engineering; Epidermal Growth Factor Receptor; Evaluation; Excision; Exclusion; Exercise; Family; Financial Hardship; Future; Generations; Goals; Hematologic Neoplasms; Heterogeneous-Nuclear Ribonucleoproteins; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune system; In Vitro; Intercellular Junctions; Kinetics; Length; Life; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Memory; Mentors; Methods; Modeling; Modification; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Nucleic Acids; Oligonucleotides; Oncogenes; PTPRC gene; Patients; Peptide/MHC Complex; Phenotype; Phosphoric Monoester Hydrolases; Play; Prevalence; Process; Productivity; Property; Psyche structure; Pulmonary Inflammation; Radiation; Radon; Rationalization; Reagent; Recurrence; Relapse; Research; Resistance; Role; Signal Transduction; Smoker; Solid; Specificity; Squamous cell carcinoma; Synapses; T-Cell Activation; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Index; Training; Tumor Antigens; Tumor-Infiltrating Lymphocytes; Tyrosine Kinase Inhibitor; United States; anti-cancer; anti-tumor immune response; aptamer; burden of illness; cancer cell; cancer subtypes; cancer therapy; cell type; chemotherapy; chimeric antigen receptor T cells; clinical translation; conventional therapy; defined contribution; design; efficacious treatment; exhaustion; humanized mouse; immune activation; immune-related adverse events; immunogenicity; immunological synapse; immunomodulatory therapies; immunoregulation; improved; in vivo; long term memory; lung cancer cell; mouse model; non-smoker; novel; novel therapeutics; patient derived xenograft model; pre-clinical; prevent; rational design; resistance mechanism; response; segregation; side effect; small molecule inhibitor; statistics; targeted treatment; transcriptomics; tumor; tumor heterogeneity

PROJECT SUMMARY Cancer is set to bypass cardiovascular disease as the number one cause of death in United States and it is a leading cause of death worldwide. Non-Small Cell Lung Cancer (NSCLC) is a major contributing factor to this statistic. Recent advancements in chemotherapeutic delivery and the development small molecule inhibitors, such as tyrosine kinase inhibitors, have been indispensable in decreasing disease prevalence and burden. Additionally, the recent FDA approvals of immunomodulating therapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T cells, and bispecific antibodies, emphasizes the importance that immune system evasion plays in disease progression and relapse. Unfortunately, administration of these targeted and immunomodulating therapies is often met with tumor acquired resistance (e.g., secondary mutations; T cell exhaustion) and incites non-specific or on-target/off tumor side effects (e.g., immune related adverse events). This suggests a need for alternative or adjuvant NSCLC therapies that are not only potent and efficacious but exercise a wide therapeutic index. We propose to exploit aptamer technology as one potential way to address this need. Aptamers are single strand oligonucleotides that bind to their targets with high specificity and affinity and their relative lack of immunogenicity as a foreign substance, compared to antibodies, make them ideal reagents to modulate the immune system. Furthermore, their ease of manipulation makes molecular engineering to design and optimize such reagents relatively straightforward. Our goal is to develop novel immunomodulating bispecific aptamers (bsApts) that dually bind to immune cell CD3ε and NSCLC tumor associated antigens (TAAs) to induce formation of effective immune synapses. We propose to use molecular engineering techniques to rationally design bsApts and systematically evaluate specific bsApt properties, such as (i) valency, (ii) affinity, and (iii) linker length/type in their ability to induce artificial immune cell activation in vitro and anti-tumor responses in vivo. We also propose to take a transcriptomics approach to better understand how designs/targets affect tumor heterogeneity, tumor infiltrating lymphocyte phenotypes, and off-target immune cell activation. Secondary goals look at improving pharmacokinetic properties that limit bsApt clinical translatability while long-term goals look to generalize our findings on these properties to current and future bispecific therapies that target a wide range of solid and hematological cancers.

项目概要 癌症将超越心血管疾病成为美国第一大死因， 非小细胞肺癌（NSCLC）是全球死亡的主要原因。 统计数据。化疗递送和小分子抑制剂开发的最新进展， 例如酪氨酸激酶抑制剂，对于降低疾病患病率和负担是不可或缺的。 此外，FDA 最近批准了免疫调节疗法，例如免疫检查点抑制剂 （ICIs）、嵌合抗原受体（CAR）T 细胞和双特异性抗体强调了以下重要性： 不幸的是，免疫系统逃避会导致疾病进展和复发。 靶向和免疫调节治疗经常会遇到肿瘤获得性耐药（例如继发性耐药） 突变；T 细胞耗竭）并引发非特异性或靶向/脱靶肿瘤副作用（例如，免疫相关） （不良事件）这表明需要有效且有效的非小细胞肺癌替代疗法或辅助疗法。 有效但具有广泛的治疗指数，我们建议将适配体技术作为一种潜力。 解决这一需求的方法是适体是单链寡核苷酸，其与靶标的结合度高。 与抗体相比，特异性和亲和力以及作为外来物质相对缺乏免疫原性， 使它们成为调节免疫系统的理想试剂，此外，它们易于操作。 我们的目标是开发分子工程来设计和优化此类试剂。 新型免疫调节双特异性适体 (bsApts)，可与免疫细胞 CD3ε 和 NSCLC 肿瘤双重结合 我们建议使用分子相关抗原（TAA）来诱导有效免疫突触的形成。 合理设计 bsApt 并系统评估特定 bsApt 属性的工程技术，例如 作为（i）化合价，（ii）亲和力，和（iii）接头长度/类型，它们诱导人工免疫细胞激活的能力 我们还建议采用转录组学方法来更好地了解体外和体内的抗肿瘤反应。 设计/靶标如何影响肿瘤异质性、肿瘤浸润淋巴细胞表型和脱靶免疫 次要目标是改善限制 bsApt 临床的药代动力学特性。 可翻译性，而长期目标则希望将我们对这些属性的发现推广到当前和未来 针对多种实体癌和血液癌的双特异性疗法。