mRNA encoding of immune receptor-targeting antibodies for the augmentation of vaccine-elicited cellular immunity.

编码免疫受体靶向抗体的 mRNA，用于增强疫苗引发的细胞免疫。

基本信息

批准号：
10662571
负责人：
Ross M Kedl
金额：
$ 19.44万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10662571
关键词：
Adjuvant Adjuvant Study Admission activity Agonist Anti-CD40 Antibodies Antibody Formation Antibody Response Antigens Area CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene COVID-19 COVID-19 vaccine CTLA4 gene Cells Cellular Immunity Chronic Clinical Communicable Diseases Data Development Encapsulated Engineering FDA approved Formulation Frequencies Genes Goals Humoral Immunities Immune Immune Targeting Immune response Immune system Immunity Immunization Immunologic Receptors Immunologics Immunotherapeutic agent Individual Infection Interferon Type I Intervention Intravenous infusion procedures Life Light Lipids Malignant Neoplasms Measures Mediating Memory Messenger RNA Methods Modeling Molecular Target Monoclonal Antibodies Mus Nature Oncology Pathway interactions Patients Phenotype Qualitative Evaluations RNA vaccination RNA vaccine Research Project Grants SARS-CoV-2 immunity Signal Pathway Signal Transduction Source Stimulus T cell response T memory cell T-Lymphocyte TNFRSF5 gene Technology Testing Therapeutic Therapeutic Intervention Translating Treatment Efficacy Treatment Protocols Tumor Promotion Vaccination Vaccine Adjuvant Vaccines Validation Variant Work anti-CTLA4 anti-PD-1 checkpoint therapy chronic infection clinical application clinical implementation clinically relevant cost experimental study immune checkpoint blockade in vivo lipid nanoparticle mRNA delivery manufacture nanoparticle nonhuman primate pandemic disease particle programmed cell death protein 1 protein purification research clinical testing response single-cell RNA sequencing stem cells success therapeutic target tumor vaccination strategy vaccine delivery vaccine platform vaccine-induced immunity viral transmission

项目摘要

Project summary. Clinically relevant cellular responses to either experimental or FDA approved vaccine adjuvant formulations have been difficult to generate and/or detect. We have long been investigating a combined adjuvant formulation (composed of a TLR agonist and an agonistic antiCD40 antibody) which generates cellular immunity on par with that observed to infectious challenge. The complexity of this three-part vaccine (antigen plus TLR/CD40) is limiting to its clinical application. However, the success of lipid nanoparticle (LNP) encapsulated mRNA vaccines for Covid provides a possible avenue by which our combination adjuvant might be successfully translated into clinical use against chronic infectious diseases and cancer. Our preliminary results show that we can agonize the CD40 pathway, sufficient to augment CD8 T cell responses, by mRNA- mediated delivery of the heavy and light chains of the agonistic anti-CD40 antibody FGK45. The success of this method for targeting CD40 strongly favors the hypothesis that antibodies specific for other immunotherapeutic molecular targets (eg. CTLA4, PD1) might also be successfully delivered via the mRNA vaccination strategy. Completion of this project would not only identify a new and powerful means by which the established potency of our combined adjuvant might be leveraged for clinical application, they open an entirely new paradigm in the use of mRNA vaccination for targeting immunologically relevant molecules for the purposes oncologic checkpoint therapy and beyond.

项目总结。对实验性或 FDA 批准的疫苗佐剂配方的临床相关细胞反应很难生成和/或检测。我们长期以来一直在研究组合佐剂制剂（由 TLR 激动剂和激动性抗 CD40 抗体组成），产生细胞免疫力与观察到的感染性挑战相当。这种三部分疫苗（抗原加TLR/CD40）限制了其临床应用。然而，脂质纳米颗粒（LNP）的成功 Covid 封装的 mRNA 疫苗为我们的组合佐剂提供了一种可能的途径成功转化为临床用于治疗慢性传染病和癌症。我们的初步结果表明，我们可以通过 mRNA 激动 CD40 通路，足以增强 CD8 T 细胞反应介导激动性抗CD40抗体FGK45的重链和轻链的递送。的成功这种靶向 CD40 的方法强烈支持以下假设：针对其他抗体具有特异性免疫治疗分子靶标（例如 CTLA4、PD1）也可能通过 mRNA 成功传递疫苗接种策略。该项目的完成不仅将确定一种新的、强有力的手段我们的组合佐剂的既定效力可能会用于临床应用，他们打开了一个新的领域使用 mRNA 疫苗接种来靶向免疫相关分子的全新范例肿瘤检查点治疗及其他目的。