Non-clinical pharmacology, pharmacokinetics, and safety evaluation of TAX2, a first-in-class peptide targeting the...

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in the regulation of angiogenesis, immune responses, and extracellular matrix remodeling within the tumor microenvironment. Its overexpression and interaction with receptor CD47 have been associated with tumor progression and resistance to therapy. In contrast to CD47/SIRPα blockade, which is constrained by hematological and immunotoxic adverse effects, selective inhibition of the TSP-1/CD47 interaction axis may represent a mechanistically distinct and potentially safer therapeutic approach. TAX2, a 12-amino-acid cyclic peptide, was designed as an orthosteric antagonist of this interaction. Its non-clinical profile was characterized through cross-species binding assays, receptor selectivity profiling, pharmacokinetic and biodistribution analyses in rodents and dogs, in vitro off-target and cytokine release assays, and GLP-compliant toxicology studies. Human pharmacokinetics were predicted using multiple-species allometric scaling. TAX2 demonstrated binding to TSP-1 from human, rodent, and canine origin, without measurable interference with CD47/SIRPα signaling under the conditions tested. The peptide exhibited rapid plasma clearance (1-4 h), dose-proportional exposure, and detectable signal in TSP-1-rich tissues and tumor-associated regions in biodistribution studies. No relevant off-target activity or unexpected immunostimulatory effects were observed. TAX2 was well tolerated at doses up to 400 mg/kg in rats and 100 mg/kg in dogs, with no hematological or systemic toxicity, and exposures exceeding the projected clinical range. Overall, these findings establish a translational non-clinical framework for TAX2 as a first-in-class TSP-1/CD47 antagonist with cross-species reactivity and a favorable pharmacokinetic and safety profile².