Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent

Abstract

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and non-human primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89,400 ng/mL and 436,000 ng/mL and area-under-the-curve exposure values of 130,000 hr*ng/mL and 1,240,000 hr*ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are > 100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc.). The severity of the reactions was not dose-related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine-based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.

CAR T cells for brain tumors: Lessons learned and road ahead

“…Studies have confirmed the specificity of CTLX binding to GBM, demonstrating its exquisite ability to distinguish between tumor and normal brain tissues . A fluorescently labeled CLTX agent is currently under clinical investigation as a tumor imaging agent to enable more precise surgical resection . When incorporated into CARs, CLTX redirects T cells for specific tumor recognition with negligible off‐target effects on normal cells or tissues .…”

“…130 A fluorescently labeled CLTX agent is currently under clinical investigation as a tumor imaging agent to enable more precise surgical resection. 131,132 When incorporated into CARs, CLTX redirects T cells for specific tumor recognition with negligible off-target effects on normal cells or tissues. 129 The development of a CLTX-CAR has shown the potential for peptide binding to redirect CAR T cell cytotoxicity.…”

In Vivo Molecular Imaging for Biomedical Analysis and Therapies

“…Other promising candidates for target biomolecules for cancer imaging include the prostatespecific membrane antigen (PSMA), 57,58 cycloxygenase-2 (COX-2) 59,60 and chlorotoxin venom (CTX). 61,62 A preclinical study 63 and Phase I clinical trial of the NIR optical imaging agent for CTX have been completed, and its safety and promising results were demonstrated (NCT02496065).…”

Chlorotoxin Redirects Chimeric Antigen Receptor T Cells for Specific and Effective Targeting of Glioblastoma

“…The classification of GBM subtypes has illustrated the heterogeneity across patients, and more recent studies using single cell sequencing also revealed considerable genetic variations among intratumoral of delivery vehicles to administer chemotherapy drugs as well as small interfering RNAs (siRNAs) (30,31). More recently, the potential of CLTX to deliver fluorescent signal specifically to tumors (named "Tumor Paint") has been demonstrated in preclinical models and is currently under clinical investigation (29,32,33). These studies have indicated that CLTX can be manipulated and harnessed for specific tumor targeting.…”