Abstract 5216: Exosome as a vehicle for delivery of membrane protein therapeutics, PH20 for enhanced tumor penetration and anti-tumor efficacy

Abstract

Abstract As biochemical and functional studies of membrane protein remain a challenge, there is growing interest in the application of nanotechnology to solve the difficulties of developing membrane protein therapeutics. Exosome, composed of lipid bilayer enclosed nano-sized extracellular vesicles, is a successful platform for providing a native membrane composition. Here, we report an enzymatic exosome, which harbors native PH20 hyaluronidase (Exo-PH20), was able to penetrate deeply into tumor foci via hyaluronan degradation, allowing tumor growth inhibition and increased T cell infiltration into the tumor. This exosome-based strategy was developed to overcome the immunosuppressive and anti-cancer therapy-resistant tumor microenvironment, which is characterized by an overly accumulated extracellular matrix. Notably, our engineered exosome with the native GPI-anchored form of hyaluronidase had a higher enzymatic activity than a truncated form of the recombinant protein. In addition, the exosome-mediated co-delivery of PH20 hyaluronidase and a chemotherapeutic (doxorubicin) efficiently inhibited tumor growth. This exosome is designed to degrade hyaluronan along the path of its movement, thereby augmenting nanoparticle penetration and drug diffusion. Our results thus show that this is a promising exosome-based platform that harbors not only a membrane-associated enzyme with high activity but also therapeutic payloads. Citation Format: yoosoo yang, Yeonsun Hong, Gi Beom Kim, Gihoon Nam, In-san Kim. Exosome as a vehicle for delivery of membrane protein therapeutics, PH20 for enhanced tumor penetration and anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5216.