Synthetic DNA-Encoded Monoclonal Antibody Delivery of Anti-CTLA-4 Antibodies Induces Tumor Shrinkage In Vivo

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-11, Vol.78 (22), p.6363-6370
• Main Authors: Duperret, Elizabeth K, Trautz, Aspen, Stoltz, Regina, Patel, Ami, Wise, Megan C, Perales-Puchalt, Alfredo, Smith, Trevor, Broderick, Kate E, Masteller, Emma, Kim, J Joseph, Humeau, Laurent, Muthumani, Kar, Weiner, David B
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; DNA - chemistry; HEK293 Cells; Humans; Immunoglobulin G - chemistry; Immunotherapy; Inhibitory Concentration 50; Ipilimumab - pharmacology; Leukocytes, Mononuclear - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms - immunology; Neoplasms - therapy; Plasmids - metabolism; T-Lymphocytes - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-1429

Antibody-based immune therapies targeting the T-cell checkpoint molecules CTLA-4 and PD-1 have affected 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 With this technology, engineered and formulated DMAb plasmids encoding IgG inserts were directly injected into muscle and delivered intracellularly by electroporation, leading to 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 85 and 58 μg/mL, respectively. These DMAb exhibited prolonged expression, with maintenance of serum levels at or above 15 μg/mL for over a year. Anti-human CTLA-4 DMAbs produced bound to human CTLA-4 protein expressed on stimulated human peripheral blood mononuclear cells and induced T-cell activation in a functional assay In summary, direct expression of DMAb encoding checkpoint inhibitors serves as a novel tool for immunotherapy that could significantly improve availability and provide broader access to such therapies. DNA-encoded monoclonal antibodies represent a novel technology for delivery and expression of immune checkpoint blockade antibodies, thus expanding patient access to, and possible clinical applications of, these therapies. .