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

项目总结。 对实验性或FDA批准的疫苗佐剂制剂的临床相关细胞反应 已经很难生成和/或检测。我们一直在研究一种联合佐剂 制剂(由TLR激动剂和激动型抗CD40抗体组成)可产生细胞 免疫力与观察到的对感染性攻击的免疫力相当。这种三部分疫苗(抗原)的复杂性 加上TLR/CD40)限制了其临床应用。然而，脂质纳米粒(LNP)的成功 Covid的微囊化mRNA疫苗为我们的联合佐剂提供了一条可能的途径 成功地转化为治疗慢性传染病和癌症的临床应用。我们的预赛 结果表明，我们可以激动CD40途径，足以增强CD8T细胞的反应，通过mRNA- 介导的激动型抗CD40抗体FGK45的重链和轻链的传递。的成功之处 这种以CD40为靶点的方法强烈支持这样的假设，即针对其他 免疫治疗分子靶点(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和强大的手段，通过 我们联合佐剂的既定效力可能会被用于临床应用，他们打开了一个 使用信使核糖核酸疫苗靶向免疫相关分子治疗的全新范例 目的：肿瘤学检查点治疗及其他。

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.