PO.ET02.05 · 实验与分子治疗
IPN60300的临床前表征——一种首创的ITGA2抗体偶联药物用于癌症治疗
Preclinical characterization of IPN60300, a first-in-class ITGA2 antibody-drug conjugate for cancer therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：整合素α-2（ITGA2）是异二聚体跨膜受体整合素α2/β1的一个组分，在细胞黏附和信号转导中发挥关键作用。尽管ITGA2在正常组织中表达水平较低，但在包括胰腺癌、胃癌和结直肠癌在内的多种实体瘤中显著过表达，并通过细胞外基质信号传导和上皮-间质转化促进肿瘤进展。我们报告IPN60300的开发，这是一种靶向ITGA2的新型抗体偶联药物（ADC），旨在将强效拓扑异构酶I抑制剂exatecan特异性递送至表达ITGA2的癌细胞。IPN60300由一种人源化Fc突变的单克隆抗体组成，通过组织蛋白酶可切割连接子位点特异性偶联至exatecan，药物抗体比为8。
方法：通过全面的体外和体内研究评估IPN60300的药理学特征，包括在表达ITGA2的细胞系、细胞来源异种移植模型以及因与人ITGA2具有同源性而选用的食蟹猴中的分析。
结果：IPN60300表现出对ITGA2的特异性高亲和力结合、高效的肿瘤细胞内化以及exatecan的胞内释放，从而对ITGA2阳性细胞系产生强效细胞毒性。抗体经工程化改造的Fc区域降低了FcγRI结合，减少了脱靶毒性，同时维持了FcRn相互作用。在荷瘤小鼠中，IPN60300表现出血浆稳定性，并导致exatecan在异种移植肿瘤中显著蓄积，从而在胆管癌、胰腺导管腺癌、胃癌和结直肠癌模型中产生高度剂量依赖性的抗肿瘤活性。食蟹猴毒理学研究显示出良好的耐受性和药代动力学特征，支持可接受的治疗指数。
结论：这些临床前发现支持IPN60300作为一种有前景的首创ITGA2靶向ADC，兼具强效抗肿瘤疗效和良好的安全性特征。IPN60300有望改善ITGA2表达恶性肿瘤患者的临床结局，并正推进至首次人体临床试验（NCT07213817）。
查看英文原文 English abstract
Background: Integrin alpha-2 (ITGA2), a component of the heterodimeric transmembrane receptor integrin alpha2/beta1, plays a key role in cell adhesion and transduction. Although ITGA2 is expressed at low levels across normal tissues, it is notably overexpressed in various solid tumors, including pancreatic, gastric and colorectal, where it contributes to tumor progression via extracellular matrix signaling and epithelial-mesenchymal transition. We report the development of IPN60300, a novel antibody-drug conjugate (ADC) targeting ITGA2, designed to specifically deliver exatecan, a potent topoisomerase I inhibitor, to ITGA2 expressing cancer cells. IPN60300 consists of a humanized Fc mutated monoclonal antibody site-specifically conjugated to exatecan via a cathepsin-cleavable linker, with a drug-to-antibody ratio of 8.
Methods: The pharmacological characteristics of IPN60300 were assessed through comprehensive in vitro and in vivo studies including analysis in ITGA2-expressing cell lines, cell-derived xenograft models, and cynomolgus monkey, chosen for its homology with human ITGA2.
Results: IPN60300 demonstrated a specific and high-affinity binding to ITGA2, efficient internalization into tumor cells, and intracellular release of exatecan, resulting in potent cytotoxicity in ITGA2-positive cell lines. The engineered Fc region of the antibody decreased FcgammaRI binding, reducing off-target toxicity while maintaining FcRn interaction. In tumor-bearing mice, IPN60300 exhibited plasma stability and led to significant exatecan accumulation in xenograft tumors, resulting in high, dose-dependent anti-tumor activity in models of cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric, and colorectal cancers. Toxicology studies in cynomolgus monkeys revealed favorable tolerability and pharmacokinetic characteristics supporting an acceptable therapeutic index.
Conclusion: These preclinical findings support IPN60300 as a promising first-in-class ITGA2-targeting ADC, combining potent anti-tumor efficacy with a favorable safety profile. IPN60300 holds potential to improve clinical outcomes for patients with ITGA2-expressing malignancies and is advancing to First-in-Human clinical trial (NCT07213817).
利益披露 Disclosure
A. Courtin,
Ipsen Employment.
B. Beaufils,
Ipsen Employment.
K. Brendel,
Ipsen Employment.
S. Colombo,
Ipsen Employment.
I. Esteves,
Ipsen Employment.
M. Galcera,
Ipsen Employment.
T. Guyon,
Ipsen Employment.
P. Han,
Foreesen Biotechnology Employment.
F. He,
Escugen Biotechnology Employment.
W. Li,
Foreseen Biotechnology Employment.
W. Nian,
Escugen Biotechnology Employment.
V. Martin,
Ipsen Employment.
L. Revellin,
Ipsen Employment.
S. Roqueviere,
Ipsen Employment.
P. Roubert,
Ipsen Employment.
Y. Song,
Foreseen Biotechnology Employment.
A. Thiongane,
Ipsen Employment.
C. C. Wong,
Foreseen Biotechnology Employment.
C. Xu,
Escugen Biotechnology Employment.
Q. Zhou,
Escugen Biotechnology Employment.
M. Hinrichs,
Ipsen Employment.
E. Leo,
Ipsen Employment.