401. In Vivo Expression of Plasmid Encoded IgG for PD-1 or LAG3 by Synthetic DNA as a New Tool for Cancer Immunotherapy

Cancers employ various strategies to escape immune surveillance including the exploitation of immune checkpoint inhibitors. Checkpoint inhibitors are receptors found on immune and stromal cells whose function can impact the duration or potency of an immune response. Tumor cells often upregulate ligands for these receptors to protect themselves from the host immune response. Monoclonal antibody (MAb) therapeutics which block checkpoint inhibitor-ligand interactions restore T cell destruction of cancer cells in vivo. MAbs that target the inhibitory T cell signaling mediated by CTLA-4 and/or PD-1 checkpoint inhibitors have recently gained regulatory approval for the treatment of some cancers based on remarkable clinical outcomes.Here we have focused on a new method to improve MAb delivery through direct engineering of MAb in the form of synthetic DNA plasmids. This technology would improve many aspects of such a therapy by lowering cost, increasing in vivo expression times and allowing for simple combination formulations in the absence of a host anti-vector immune response, possibly extending use of these groundbreaking therapies to disadvantaged patient populations. We report that “enhanced and optimized” DNA plasmid technology can be used to direct in vivo production of immunoglobulin heavy and light chains of established monoclonal antibodies which can target the immune checkpoint inhibitors LAG3 and PD-1 as determined in Flow cytometry, ELISA and Western blot assays. Both antibodies are produced at physiologically relevant levels in blood and other tissues of mice using electroporation-enhanced delivery of DNA plasmids encoding genes for each antibody. We report that serum antibodies from inoculated animals retain the ability to bind to their targets and are bioactive in vivo and exhibit immune stimulatory effects for host T cells. These studies have significant implications for prophylactic and therapeutic strategies for cancer and other important diseases and warrants further attention.