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.

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The sensitization potencies of twenty custom-designed monomer-depleted polymeric polyisocyanate prepolymer substances and their associated toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), hexamethylene diisocyanate (HDI), and isophorone diisocyanate (IPDI) monomer precursors were investigated by means of the mouse Local Lymph Node Assay (LLNA). These polymeric prepolymers were designed to represent the structural features and physical-chemical properties exhibited by a broad range of commercial polymeric polyisocyanate prepolymers that are produced from the reaction of aromatic and aliphatic diisocyanate monomers with aliphatic polyether and polyester polyols. The normalization of LLNA responses to the applied (15-45-135 mM) concentrations showed that the skin sensitization potency of polymeric polyisocyanate prepolymers is at least 300 times less than that of the diisocyanate monomers from which they are derived. The sensitization potency of the prepolymers was shown to be mainly governed by their hydrophobicity (as expressed by the calculated octanol-water partition coefficient, log Kow) and surfactant properties. Neither hydrophilic (log Kow <0) nor very hydrophobic (log Kow >25) prepolymers stimulated lymphocyte proliferation beyond that of the dosing vehicle control. The findings of this investigation challenge the generally held assumption that all isocyanate (-N=C=O) bearing substances are potential skin (and respiratory) sensitizers. Further, these findings can guide the future development of isocyanate chemistries and associated polyurethane applications toward reduced exposure and health hazard potentials.

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