PO.ET01.05 · 实验与分子治疗
新型CLDN18.2靶向ADC TRO-01的临床前表征:强效抗肿瘤疗效及良好的PK和安全性
Preclinical characterization of TRO-01, a novel CLDN18.2-targeting ADC, with potent anti-tumor efficacy and favorable PK and safety
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摘要 Abstract
中文摘要
Claudin 18.2(CLDN18.2)是一种紧密连接蛋白,通常局限于胃黏膜。恶性转化过程中上皮极性的丧失使CLDN18.2暴露于胃和胃食管交界处(G/GEJ)腺癌细胞表面。由于CLDN18.2在30-40%的G/GEJ癌症中高表达并与不良预后相关,它已成为胃癌一个有前景的治疗靶点,而胃癌有效的靶向疗法仍然有限。我们开发了TRO-01,一种抗体-药物偶联物(ADC),由一种全人源抗CLDN18.2单克隆抗体通过专有的TROSIG™连接子偶联至一种拓扑异构酶I抑制剂组成。这种可切割、高度稳定且亲水的连接子可实现8的高且均一的药物抗体比(DAR)。体外研究表明,TRO-01特异性结合CLDN18.2而不结合CLDN18.1,相较于竞争抗体表现出更强的亲和力,在受试细胞系中细胞结合亲和力处于个位数纳摩尔范围。此外,TRO-01在CLDN18.2阳性细胞系中表现出高效内化和强效细胞毒性,IC50值根据细胞类型在亚纳摩尔至两位数纳摩尔之间。在体内,TRO-01治疗在细胞系来源异种移植(CDX)和患者来源异种移植(PDX)模型中均实现了显著的肿瘤生长抑制(TGI)。在Patu8988s CDX模型中,单次3或6 mg/kg给药分别实现了86%和101%的TGI。在SNU-601 CDX模型中,0.3或0.5 mg/kg每周两次(BIW)给药4次分别实现了109%和111%的TGI。在两个胃癌和两个胰腺癌PDX模型中,TRO-01治疗(每周一次(QW)给药2次,2.7 mg/kg)在胃癌中实现89%和93%的TGI,在胰腺癌PDX中实现75%和84%的TGI,且无显著体重下降。猴体内的药代动力学研究显示出良好的PK特性(t1/2=7.2天,AUC=13,800 hr·μg/mL,CL=0.364 mL/hr/kg,Vd=0.082 L/kg,剂量5 mg/kg)。食蟹猴毒理学研究显示出良好的安全性特征,单次给药后最高非严重毒性剂量(HNSTD)为40 mg/kg。总体而言,这些发现凸显了TRO-01作为治疗CLDN18.2表达的胃肠道癌症的有前景的候选疗法。
查看英文原文 English abstract
Claudin 18.2 (CLDN18.2) is a tight junction protein normally restricted to the gastric mucosa. Loss of epithelial polarity during malignant transformation exposes CLDN18.2 on the surface of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma cells. As CLDN18.2 is highly expressed in 30-40% of G/GEJ cancers and is associated with poor prognosis, it has emerged as a promising therapeutic target for gastric cancer, where effective targeted therapies remain limited. We developed TRO-01, an antibody-drug conjugate (ADC) composed of a fully human anti-CLDN18.2 monoclonal antibody conjugated to a topoisomerase I inhibitor via the proprietary TROSIG TM linker. This cleavable, highly stable, and hydrophilic linker enables a high and uniform drug-to-antibody ratio (DAR) of 8. In vitro studies demonstrated that TRO-01 specifically binds to CLDN18.2 but not to CLDN18.1, exhibiting enhanced affinity compared with competitor antibodies, with cell binding affinities in the single nanomolar range across tested cell lines. Additionally, TRO-01 showed efficient internalization and potent cytotoxicity in CLDN18.2-positive cell lines, with IC 50 values ranging from sub-nanomolar to double-digit nanomolar depending on the cell type. In vivo, TRO-01 treatment resulted in significant tumor growth inhibition (TGI) in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. In the Patu8988s CDX model, a single dose of 3 or 6 mg/kg resulted in 86% and 101% TGI, respectively. In the SNU-601 CDX model, BIW x 4 dosing at 0.3 or 0.5 mg/kg resulted in 109% and 111% TGI. In two gastric and two pancreatic PDX models, TRO-01 treatment (QW x 2, 2.7 mg/kg) resulted in 89% and 93% TGI in gastric, and 75% and 84% TGI in pancreatic PDXs, with no significant body weight loss. Pharmacokinetic studies in monkeys demonstrated favorable PK properties (t 1/2 = 7.2 days, AUC = 13,800 hr·μg/mL, CL = 0.364 mL/hr/kg, Vd = 0.082 L/kg at 5 mg/kg). Toxicology studies in cynomolgus monkeys revealed a favorable safety profile, with a highest non-severely toxic dose (HNSTD) of 40 mg/kg after single dosing. Collectively, these findings highlight TRO-01 as a promising therapeutic candidate for the treatment of CLDN18.2-expressing gastrointestinal cancers.
利益披露 Disclosure
Y. Lee, None..
J. Kim, None..
H. Lee, None..
S. Lee, None..
D. Seo, None..
M. Baek, None..
S. Woo, None.