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。

• 批准号: 10508093
• 负责人: Ross M Kedl
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/10508093
• 关键词: Adjuvant; Adjuvant Study; 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; Problem Solving; Proteins; 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; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Validation; Variant; Work; anti-CTLA4; anti-PD-1; base; checkpoint therapy; chronic infection; clinical application; clinical implementation; clinically relevant; coronavirus disease; cost; experimental study; immune checkpoint blockade; in vivo; lipid nanoparticle; mRNA delivery; nanoparticle; nonhuman primate; pandemic disease; particle; programmed cell death protein 1; 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

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。