我们介绍了 BNT142 的临床前药理学，BNT142 是一种脂质纳米颗粒 (LNP) 配制的 RNA (RNA-LNP)，编码 T 细胞接合双特异性抗体，该抗体单价结合 T 细胞标记 CD3 并二价结合紧密蛋白 6 (CLDN6)（一种致癌胎儿抗原）正常成人组织中不存在，但在各种实体瘤中表达。 BNT142 RNA-LNP 在细胞培养物、小鼠和食蟹猴中递送后，RNA 被翻译，然后自组装成功能性双特异性抗体 RiboMab02.1 并分泌。在体外，RiboMab02.1 介导 CLDN6 靶细胞特异性激活和 T 细胞增殖，以及有效的靶细胞杀伤。在小鼠和食蟹猴中，静脉注射 BNT142 RNA-LNP 可维持编码抗体的治疗血清浓度。 RNA 编码的 RiboMab02.1 浓度在小鼠体内循环中的维持时间比直接注射的序列相同蛋白质的浓度要长。每周向小鼠注射 0.1 至 1 μg 剂量范围的 BNT142 RNA-LNP 足以消除 CLDN6 阳性皮下人类异种移植肿瘤，并比对照组提高存活率。肿瘤消退与 T 细胞的流入和 CLDN6 阳性细胞的消耗有关。在用外周血单核细胞 (PBMC) 人源化的 CLDN6 阳性荷瘤小鼠中，BNT142 仅诱导短暂且低水平的细胞因子产生。在小鼠或食蟹猴中未观察到 BNT142 RNA-LNP 给药产生不良影响的迹象。基于这些和其他发现，一项 1/2 期首次人体临床试验已经启动，以评估 BNT142 RNA-LNP 在 CLDN6 阳性晚期实体瘤患者中的安全性和初步疗效（NCT05262530）。

We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell-specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).