利用mRNA编码包含IL-12、CD137激动剂和TGF-β拮抗剂的嵌合蛋白构建体进行肿瘤内免疫治疗。
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists.
发表日期：2023 Sep 12
作者：
Assunta Cirella, Elixabet Bolaños, Carlos Luri-Rey, Claudia Augusta Di Trani, Irene Olivera, Gabriel Gomis, Javier Glez-Vaz, Beatrice Pinci, Saray Garasa, Sandra Sánchez-Gregorio, Arantza Azpilikueta, Iñaki Eguren-Santamaria, Karmele Valencia, Belén Palencia, Maite Alvarez, Maria C Ochoa, Álvaro Teijeira, Pedro Berraondo, Ignacio Melero
来源：
Molecular Therapy-Nucleic Acids
摘要：
基于癌症的胞内瘤内免疫疗法策略，结合抗PD-(L)1单克隆抗体，正在临床开发中，采用介导癌症干细胞的白细胞介素-12（IL-12）的编码cDNA和mRNA。为了充分发挥这些方法的作用，我们构建了编码单链IL-12融合单链抗体片段变异（scFv）的嵌合mRNA，该抗体可以与转化生长因子β（TGF-β）和CD137（4-1BB）结合。几种中和TGF-β剂和CD137激动剂也正在进行早期临床试验。为了达到结构的TGF-β和CD137结合，我们使用了1D11和1D8单克隆抗体（mAb）衍生的双特异性串联scFv抗体（taFv）。转染编码嵌合结构的mRNA实现了对能够作用于其靶标的蛋白质的功能表达。将mRNA注射到可移植的小鼠癌症模型CT26，MC38和B16OVA中，通过重复注射到肿瘤中观察到强效治疗效果。疗效取决于能够识别浸润恶性组织的肿瘤抗原的CD8 + T细胞的数量。尽管对未注射病变的远隔效应有限，但与系统性PD-1阻断结合在一起时，对未处理病变的远隔效应明显增加。© 2023 The Authors.
Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor β (TGF-β) and CD137 (4-1BB). Several neutralizing TGF-β agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-β and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8+ T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade.© 2023 The Authors.