Synthetic DNA-encoded monoclonal antibody delivery of anti-CTLA-4 antibodies induces tumor shrinkage in vivo

Antibody-based immune therapies targeting the T cell checkpoint molecules CTLA-4 and PD-1 have impacted cancer therapy. However, this immune therapy requires complex manufacturing and frequent dosing, limiting the global use of this treatment. Here we focused on the development of a DNA-encoded monoclonal antibody (DMAb) approach for delivery of anti-CTLA-4 monoclonal antibodies in vivo. With this technology, engineered and formulated DMAb plasmids encoding IgG inserts were directly injected into muscle and delivered intracellularly by electroporation, leading to in vivo expression and secretion of the encoded IgG. DMAb expression from a single dose can continue for several months without the need for repeated administration. Delivery of an optimized DMAb encoding anti-mouse CTLA-4 IgG resulted in high serum levels of the antibody as well as tumor regression in Sa1N and CT26 tumor models. DNA-delivery of the anti-human CTLA-4 antibodies ipilimumab and tremelimumab in mice achieved potent peak levels of approximately 85µg/mL and 58µg/mL, respectively. These DMAb exhibited prolonged expression, with maintenance of serum levels at or above 15µg/mL for over a year. Anti-human CTLA-4 DMAbs produced in vivo bound to human CTLA-4 protein expressed on stimulated human PBMC and induced T cell activation in a functional assay ex vivo. In summary, direct in vivo expression of DMAb encoding checkpoint inhibitors serve as a novel tool for immunotherapy that could significantly improve availability and provide broader access to such therapies.

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