Abstract
BackgroundChlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide. Radiolabeled Cltx therapeutic (131I-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.MethodsA 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.ResultsNeuropilin-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.ConclusionsNRP1 was identified as a novel Cltx target which enhances tumor drug uptake. This finding should facilitate tumor selection for chlorotoxin-based therapeutics and diagnostics.
Highlights
Chlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide
To generate the peptide drug conjugate (PDC) PDC of Cltx linked to cryptophycin (ER-472), Cltx was conjugated at lysine 27 to a novel analog of cryptophycin via a cleavable dimethyl disulfide linker (Fig. 1b, Additional file 1: Figure S1)
In vivo metabolism of ER-472 and release of the warhead cryptophycin from the PDC previously revealed that S-methyl cryptophycin is the active metabolite generated a b c d
Summary
Chlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide. Chlorotoxin (Cltx) is a small basic peptide first isolated from the venom of the scorpion Leiurus quinquestriatus and named for its ability to block chloride channels and cause neurotoxicity [1]. The tumor targeting property of Cltx was first described in 1998 by Soroceanu et al [2]. They reported high affinity binding of Cltx to glioma cells with. Cltx’s tumor selectivity was originally attributed to binding of chloride ion channels (CLC-3) in glioma cells, and functionally, Cltx inhibited migration and invasion by glioma cells in a dose dependent manner [7]. In follow up studies a direct interaction between Cltx and MMP2 could not be established [10]
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