Abstract
PURPOSE: To assess the antitumor efficacy, pharmacokinetics, and safety of NV103, a CD99-targeted liposomal irinotecan nanoparticle, in a preclinical Ewing sarcoma model. EXPERIMENTAL DESIGN: NV103 is a CD99-antibody targeted irinotecan containing nanoparticle, engineered to selectively deliver irinotecan to CD99 expressing tumor cells. In vitro studies measured binding, internalization, and cytotoxic IC(50) values in several Ewing sarcoma cell lines. In vivo, mice bearing xenografts derived from treatment-naïve and chemoresistant Ewing lines were treated. NV103 was compared with free irinotecan, untargeted nanoparticles, and Onivyde(™) at multiple dosages. Plasma pharmacokinetics of irinotecan and SN-38, biodistribution of the nanoparticles, and toxicity (body weight, organ function, and hematology) were assessed. RESULTS: NV103 bound selectively to tumor cells (>80× over control), was rapidly internalized, and showed enhanced potency in vitro (IC(50) ≈ 3-4 nM at 0.5-1 h). In vivo, biweekly dosing at 5 mg/kg resulted in full tumor regression sustained for 140 days, even after stopping treatment at day 70. Effective suppression and survival benefit were observed at doses as low as 1 mg/kg; the ED(50) was estimated to be between 1-2.5 mg/kg versus 50mg/kg for free irinotecan. In a chemoresistant Ewing tumor cell line, NV103 induced similar tumor-free remission. Pharmacokinetics revealed prolonged and elevated plasma levels of irinotecan with NV103 versus free drug. No systemic toxicity was detected at doses of 10 mg/kg. Biodistribution showed tumor-preferential accumulation. CONCLUSIONS: NV103 displays potent and durable antitumor activity in Ewing sarcoma at low doses with no toxicity and favorable pharmacokinetics. These findings support further development for clinical translation.