Oncology Business Group, Eisai Inc, 4 Corporate Drive, Andover, MA, 01810, USA.
Present address: Solid Biosciences, 141 Portland Avenue, Cambridge, MA, 02139, USA.
Cell Commun Signal. 2019 Jun 17;17(1):67. doi: 10.1186/s12964-019-0368-9.
Chlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide. Radiolabeled Cltx therapeutic (I-TM601) yielded promising results in human glioma clinical studies, and the imaging agent tozuleristide, is under investigation in CNS cancer studies. Several binding targets have previously been proposed for Cltx but none effectively explain its pleiotropic effects; its true target remains ambiguous and is the focus of this study.
A peptide-drug conjugate (ER-472) composed of Cltx linked to cryptophycin as warhead was developed as a tool to probe the molecular target and mechanism of action of Cltx, using multiple xenograft models.
Neuropilin-1 (NRP1), an endocytic receptor on tumor and endothelial cells, was identified as a novel Cltx target, and NRP1 binding by Cltx increased drug uptake into tumor. Metabolism of Cltx to peptide bearing free C-terminal arginine, a prerequisite for NRP1 binding, took place in the tumor microenvironment, while native scorpion Cltx with amidated C-terminal arginine did not bind NRP1, and instead acts as a cryptic peptide. Antitumor activity of ER-472 in xenografts correlated to tumor NRP1 expression. Potency was significantly reduced by treatment with NRP1 blocking antibodies or knockout in tumor cells, confirming a role for NRP1-binding in ER-472 activity. Higher cryptophycin metabolite levels were measured in NRP1-expressing tumors, evidence of NRP1-mediated enhanced drug uptake and presumably responsible for the superior antitumor efficacy.
NRP1 was identified as a novel Cltx target which enhances tumor drug uptake. This finding should facilitate tumor selection for chlorotoxin-based therapeutics and diagnostics.
从蝎子毒液中分离出的氯毒素 (Cltx) 是一种已确立的肿瘤靶向和抗血管生成肽。放射性标记的 Cltx 治疗剂 (I-TM601) 在人类胶质母细胞瘤临床研究中取得了可喜的结果，而成像剂 tozuleristide 正在 CNS 癌症研究中进行研究。先前已经提出了几种 Cltx 的结合靶标，但没有一种能有效地解释其多效性作用；其真正的靶标仍然不明确，这是本研究的重点。
一种由 Cltx 与隐色霉素连接而成的肽药物偶联物 (ER-472) 被开发为一种工具，用于使用多种异种移植模型来探测 Cltx 的分子靶标和作用机制。
神经纤毛蛋白 1 (NRP1)，一种肿瘤和内皮细胞上的内吞受体，被鉴定为 Cltx 的一种新靶标，Cltx 通过 NRP1 结合增加了药物进入肿瘤的摄取。Cltx 代谢为带有游离 C 末端精氨酸的肽，这是 NRP1 结合的前提，发生在肿瘤微环境中，而带有酰胺化 C 末端精氨酸的天然蝎子 Cltx 不与 NRP1 结合，而是作为一种隐蔽肽。ER-472 在异种移植瘤中的抗肿瘤活性与肿瘤 NRP1 表达相关。用 NRP1 阻断抗体或肿瘤细胞中敲除处理显著降低了其效力，证实了 NRP1 结合在 ER-472 活性中的作用。在表达 NRP1 的肿瘤中测量到更高的隐色霉素代谢物水平，这是 NRP1 介导的增强药物摄取的证据，可能是其抗肿瘤疗效更好的原因。
NRP1 被鉴定为 Cltx 的一种新靶标，可增强肿瘤药物摄取。这一发现应有助于基于氯毒素的治疗剂和诊断剂的肿瘤选择。
