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

项目摘要。 对实验性或FDA批准的疫苗佐剂制剂的临床相关细胞应答 难以产生和/或检测。我们长期以来一直在研究一种复合佐剂 制剂（由TLR激动剂和激动性抗CD 40抗体组成），其产生细胞免疫应答。 免疫力与观察到的感染性攻击相当。这种三部分疫苗（抗原）的复杂性 加上TLR/CD 40）限制了其临床应用。脂质纳米颗粒（LNP）的成功 用于Covid的封装mRNA疫苗提供了一种可能的途径， 成功转化为临床应用，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-1激动CD 40通路，足以增强CD 8 T细胞应答。 介导的激动性抗CD 40抗体FGK 45的重链和轻链的递送。的成功 这种靶向CD 40的方法强烈支持这样的假设，即对其他细胞特异性的抗体， 免疫分子靶点（例如，CTLA 4，PD 1）也可能通过mRNA成功地递送。 疫苗接种战略。该项目的完成不仅将确定一种新的强有力的手段， 我们的组合佐剂的已建立的效力可用于临床应用，它们打开了一个新的途径， 使用mRNA疫苗接种靶向免疫相关分子的全新范例， 目的肿瘤检查点治疗和超越。

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.