mRNA编码的抗Claudin 18.2抗体的临床前特征。

IF 6.5 2区 医学 Q1 IMMUNOLOGY
Oncoimmunology Pub Date : 2023-10-16 eCollection Date: 2023-01-01 DOI:10.1080/2162402X.2023.2255041
Hayat Bähr-Mahmud, Ursula Ellinghaus, Christiane R Stadler, Leyla Fischer, Claudia Lindemann, Anuhar Chaturvedi, Jan Diekmann, Stefan Wöll, Imke Biermann, Bernhard Hebich, Caroline Scharf, Manuela Siefke, Alexandra S Roth, Martin Rao, Kerstin Brettschneider, Eva-Maria Ewen, Uğur Şahin, Özlem Türeci
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引用次数: 0

摘要

IMAB362/Zolbetoximab是一种针对癌症相关的胃小细胞标志物CLDN18.2的第一类IgG1抗体,最近有报道称,在两项3期试验中,它已达到其主要终点,作为CLDN18.2阳性Her2阴性晚期癌症的一线治疗和标准护理化疗。在这里,我们描述了BNT141的临床前药理学,BNT141是一种核苷修饰的RNA治疗剂,编码IMAB362/唑贝妥昔单抗序列,在脂质纳米颗粒(LNP)中配制用于肝脏摄取。我们发现,mRNA编码的抗体在临床前动物模型中显示出稳定的药代动力学特征,介导与IMAB362重组蛋白相当的CLDN18.2限制的细胞毒性,并抑制免疫受损小鼠中的人类肿瘤异种移植物生长。在动物研究中,BNT141给药没有造成死亡率、毒性临床症状或胃病理学。BNT141信使核糖核酸LNP的1/2期临床试验已在晚期CLDN18.2出口实体癌中启动(NCT04683939)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody.

IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).

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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
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