LAUSR

Most anticancer therapies are unspecific and therefore inevitably lead to off-target toxicity. To overcome these shortcomings, targetable hybrid polymerization liposomal nanoparticles (HPLNs) have been invented. Multiple innovative and proprietary technologies have been developed to enable creation of this unique form of nanoparticle therapy with covalent attachment of targeting molecules such as tumor specific antibodies or peptides. Human monoclonal anti-CD99 antibody-targeted HPLNs encapsulating irinotecan (CD99-HPLN/Ir) can efficiently reach implanted Ewing sarcoma tumors in xenograft mice and dramatically reduce and/or eliminate the tumor burden. Complete tumor ablation has been observed at doses as low as 1 mg irinotecan/kg, treated twice per week. In other cases, animals who failed untargeted (HPLN/Ir) treatment showed complete tumor ablation after ‘salvage’ treatment with CD99-HPLN/Ir. Our CD99 targeted HPLN/irinotecan formulation, termed NV103 showed much better efficacy than the commercial untargeted liposomal irinotecan (Onivyde™) and doxorubicin (Doxil™). Toxic side effects, normally associated with systemic administration of free irinotecan, were minimized or undetectable. Our nanoparticles showed excellent bioavailability. Even the untargeted HPLN/Ir improve drug bioavailability six-fold in a comparison experiment with the drug in liposome form (Onivyde™), with no discernable systemic toxicity. Experiments using human antiCD99 antibody targeted HPLNs demonstrated they can be used for delivery of therapeutic nucleic acids including siRNA, ASO or functional CRISPR-Cas9 systems against EWS-FLI1. Targeted HPLN/ siRNA and ASO against EWS-Fli1 reduced the protein expression of EWS-Fli1 by 35% and 65%, respectively. Our results of HPLN/CRISPR-Cas9 systems showed the high efficient delivery of CRISPR-Cas9 components and a 70% knockdown of EWS-FLI1 expression in vitro. In the initial animal study our work showed the systemic administration of human monoclonal anti-CD99 antibody-targeted HPLNs encapsulating CRISPR-Cas9 against EWS-Fli1 could reduce the tumor growth of Ewing tumor successfully. In conclusion, our targeted HPLNs can be used as a clinically viable method for the targeted delivery of varied therapeutics including chemotherapeutic agents (Doxorubicin and Irinotecan), therapeutic nucleic acids (siRNA and ASO) and CRISPR-Cas9 systems. Ultimately, after development of other tumor-specific targeting agents and varied encapsulated therapeutics, this technology can be usefully adapted for the treatment of various cancers as well. Citation Format: HyungGyoo Kang, Jon Nagy, Sheetal Mitra, Triche Triche. Targeted therapy of Ewing’s sarcoma by human anti CD99 targeted hybrid polymerized liposomal nanoparticles (HPLNs) encapsulating anticancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2875.