title: 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 nonhuman 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 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·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.
authors.affiliation: 1 Blaze Bioscience, Inc, Seattle, WA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Parrish-Novak
authors.affiliation: 2 Northwest PK Solutions, LLC, Sultan, WA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Byrnes-Blake
authors.affiliation: 3 SNBL USA, Ltd, Everett, WA, USA.
authors.forename: Narine
authors.initials: N
authors.lastname: Lalayeva
authors.affiliation: 4 Burleson Research Technologies, Inc, Morrisville, NC, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Burleson
authors.affiliation: 5 Veterinary Teaching Hospital, Washington State University, Pullman, WA, USA.
authors.forename: Janean
authors.initials: J
authors.lastname: Fidel
authors.affiliation: 6 Xenometrics LLC, Stilwell, KS, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Gilmore
authors.affiliation: 6 Xenometrics LLC, Stilwell, KS, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Gayheart-Walsten
authors.affiliation: 6 Xenometrics LLC, Stilwell, KS, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Bricker
authors.affiliation: 7 CytoBiosciences, New Orleans, LA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Crumb
authors.affiliation: 8 Tarlo Toxicology Consulting, LLC, Applegate, MI, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Tarlo
authors.affiliation: 1 Blaze Bioscience, Inc, Seattle, WA, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Hansen
authors.affiliation: 5 Veterinary Teaching Hospital, Washington State University, Pullman, WA, USA.
authors.forename: Valorie
authors.initials: V
authors.lastname: Wiss
authors.affiliation: 9 Blaze Bioscience Australia Pty Ltd, Melbourne, Australia.
authors.forename: Errol
authors.initials: E
authors.lastname: Malta
authors.affiliation: 5 Veterinary Teaching Hospital, Washington State University, Pullman, WA, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Dernell
authors.affiliation: 10 Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.affiliation: 1 Blaze Bioscience, Inc, Seattle, WA, USA.|9 Blaze Bioscience Australia Pty Ltd, Melbourne, Australia.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Miller
mesh_terms: D000818:Animals; D003165:Complement System Proteins / Q000032:analysis; D004285:Dogs; D004342:Drug Hypersensitivity / Q000097:blood; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics / Q000633:toxicity; D057809:HEK293 Cells; D006632:Histamine / Q000097:blood; D006801:Humans; D007208:Indocyanine Green / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D005456:Fluorescent Dyes; D012604:Scorpion Venoms; D006632:Histamine; C000604732:tozuleristide; D003165:Complement System Proteins; D007208:Indocyanine Green
keywords: chlorotoxin; fluorescence-guided surgery; indocyanine green; intraoperative imaging; near-infrared; tumor resection