PO.CH01.03 · 化学
KBD880是一种用于治疗HCC的强效且选择性的GPC3多肽结合剂
KBD880 is a potent and selective GPC3 peptide binder for treatment of HCC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景:膜相关糖蛋白磷脂酰肌醇蛋白聚糖3(GPC3)在肝细胞癌(HCC)中高度过表达,而在正常组织中几乎或完全不表达。这种肿瘤特异性表达谱使GPC3成为开发放射性药物疗法治疗HCC(全球癌症相关死亡的主要原因之一)的理想靶点。
方法:DOTA-KBD-GPC3(KBD880)是一种放射性药物偶联物,由一种新型GPC3结合大环肽、一个连接子以及一个用于与治疗性放射性同位素络合的DOTA螯合剂组成。通过表面等离子体共振和竞争性流式细胞术表征了175Lu标记偶联物的结合亲和力。随后,通过放射测量法量化了靶点介导的细胞内化动力学。在体内,于HepG2 HCC异种移植模型中评估了177Lu标记偶联物的生物分布和治疗疗效。
结果:经表面等离子体共振测定,175Lu-KBD880对人源和鼠源GPC3均表现出高亲和力结合,平衡解离常数(KD)分别为2.20 nM和2.02 nM。此外,175Lu-KBD880对表达GPC3的HepG2细胞显示出强效结合(IC50 = 9.3 nM)。为实现效力、通透性和理化性质之间的平衡,采用了高比例的非天然氨基酸及具有良好类药性质的片段。175Lu-KBD880在小鼠中表现出优异的通透性、理想的半衰期和显著的系统暴露量。治疗性偶联物177Lu-KBD880表现出快速高效的内化,细胞摄取比率达到50-60%。177Lu-KBD880展现出优异的体内特征,表现为高肿瘤滞留、快速肾脏清除以及极低的脱靶摄取。这种良好的生物分布转化为在GPC3阳性HCC异种移植中单药治疗后显著且持续的肿瘤生长抑制。
结论:KBD880是一种强效且选择性的、基于多肽的放射性药物,专为靶向表达GPC3的肿瘤而开发。其良好的临床前特征——包括理想的药代动力学特征、靶向的生物分布以及持久的单药疗效——有力支持将其开发为针对GPC3阳性恶性肿瘤患者的诊疗一体化(theranostic)药物。
查看英文原文 English abstract
Background: The membrane-associated glycoprotein Glypican-3 (GPC3) is highly overexpressed in hepatocellular carcinoma (HCC) while exhibiting minimal to no expression in normal tissues. This tumor-specific expression profile makes GPC3 an ideal target for developing radiopharmaceutical therapies to treat HCC, a leading cause of cancer-related deaths worldwide.
Methods: DOTA-KBD-GPC3 (KBD880) is a radiopharmaceutical conjugate composed of a novel GPC3-binding macrocyclic peptide, a linker, and a DOTA chelator for complexation with therapeutic radioisotopes. The binding affinity of the 175 Lu-labeled conjugate was characterized by surface plasmon resonance and competitive flow cytometry. Subsequently, Target-mediated cellular internalization kinetics were quantified via radiometric assays. In vivo, the biodistribution and therapeutic efficacy of the 177 Lu-labeled conjugate were evaluated in HepG2 HCC xenograft model.
Results: 175 Lu-KBD880 exhibited high-affinity binding to both human and murine GPC3, with equilibrium dissociation constants (KD) of 2.20 nM and 2.02 nM, respectively, as determined by surface plasmon resonance. In addition, 175 Lu-KBD880 showed potent binding to GPC3-expressing HepG2 cells (IC 50 = 9.3 nM). A high proportion of non-canonical amino acids and fragments with favorable drug-like properties were used to achieve a balance of potency, permeability, and physicochemical properties. 175 Lu-KBD880 exhibited excellent permeability, an optimal half-life and substantial systemic exposure in mice. The therapeutic conjugate, 177 Lu-KBD880, exhibited rapid and efficient internalization, achieving cellular uptake ratios of 50-60%. 177 Lu-KBD880 displayed an excellent in vivo profile, characterized by high tumor retention, rapid renal clearance, and minimal off-target uptake. This favorable biodistribution translated into significant and sustained tumor growth inhibition following monotherapy in GPC3-positive HCC xenografts.
Conclusions: KBD880 is a potent and selective, peptide-based radiopharmaceutical agent developed for targeting GPC3-expressing tumors. Its favorable preclinical characteristics-including an optimal pharmacokinetic profile, targeted biodistribution, and durable monotherapy efficacy-strongly support its development as a theranostic agent for patients with GPC3-positive malignancies.
利益披露 Disclosure
H. Chu, None..
Y. Chen, None..
Y. Wei, None..
F. Ye, None..
J. Zhang, None..
Z. Li, None..
X. Liu, None..
J. Cui, None.