SBIR Phase I: Endogenously secreted bispecific natural killer cell engagers (BIKEs) for therapy of solid tumors

This Small Business Innovation Research (SBIR) Phase I project provides a novel, intramuscular gene delivery platform that supports sustained expression of any therapeutic protein, a capability yet to be commercially realized. The ability to provide sustained expression and endogenous secretion of bispecific natural killer cell engager (BiKE) therapeutics is expected to be paradigm shifting by providing a solution that bypasses current immunotherapy treatments for solid tumors. This approach, which is less invasive than the current state-of-the art, could eliminate the need for continuous/frequent repeated infusions of therapeutics and would circumvent the need for hospitalization during administration. The approach has a lower price point, potentially reducing the cost of therapy by tens to hundreds of thousands of dollars compared to other immunotherapies, and is amenable to low resource settings, significantly increasing the availability of treatment. The proof-of-concept therapeutic will target hepatocellular carcinoma, a solid tumor that accounts for 90% of liver cancers. The platform has broad applications, supporting delivery of any gene therapy application (e.g., monogenic disease) that can benefit from systemic expression of a secreted protein, including bi-specific antibody T cell engagers, therapeutic antibodies, and vaccine candidates (e.g., endogenous therapeutic antibody production, delivery of DNA vaccines, and expression of therapeutic proteins to treat monogenic rare diseases). Anticipated impacts of the platform include improved treatment efficacy and improved patient quality of life. This project seeks to advance the development of a safe, efficient intramuscular gene delivery system for redosable gene delivery as well as the demonstration of the platform’s ability to express endogenously secreted bispecific natural killer cell engagers (BIKEs) in vivo for treatment of hepatocellular carcinoma (HCC), a solid tumor. To date, gene therapy approaches to cancer treatment have been costly, labor intensive, and limited in efficacy. This platform is expected to enhance gene delivery by over 1,000-fold compared to the injection of naked DNA and to enable efficient secretion of the gene product into the blood stream, thereby allowing for systemic expression. Specific aims are to establish a cell expression system for production, purification, and functional validation of the recombinant BiKE in vitro and to make bioluminescent hepatoma cell lines transduced with a commercialized lentivirus co-expressing RedFLuc and secreted GLuc for more sensitive detection of tumor survival. The project will also validate the efficacy of the BiKE expression construct in a humanized, orthotopic hepatocellular carcinoma (HCC) mouse model. Proof of concept will be established with the demonstration of sustained systemic expression of the secretable BiKE for ≥ 1 month at serum levels of ≥100-500 ng/ml, as evaluated by enzyme-linked immunosorbent assay (ELISA) assays at days 3-60 post-intramuscular delivery. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.