CD99Targeted Irinotecan Containing Nanoparticles Show Twenty-Fold Greater Anti-Tumor Effect Than Free Irinotecan For Treatment of Ewing Sarcoma

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 TM 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. Translational Relevance Although Irinotecan has shown activity against Ewing sarcoma, its clinical utility is limited by systemic toxicity and poor tumor selectivity. NV103, a CD99-targeted nanoparticle formulation of irinotecan delivers irinotecan selectively to Ewing sarcoma cells. CD99 is a surface antigen that is highly expressed in Ewing sarcoma cells but largely absent from irinotecan-sensitive organs like liver, kidney, and bone marrow. In preclinical xenograft models, NV103 induced complete and durable tumor regression at doses >10 fold lower than those of free irinotecan or untargeted nanoparticles, with no detectable systemic toxicity. These findings suggest that NV103 is a promising translational therapeutic agent that enhances the therapeutic index of irinotecan and other cytotoxic agents. This platform offers a broadly adaptable approach to tumor-specific drug delivery, which could significantly improve treatment outcomes and reduce long-term toxicity in children and young adults with Ewing sarcoma and other solid tumors.