Abstract B036: Synthetic DNA-encoded monoclonal antibody delivery (DMAb^TM) of anti-CTLA4 antibodies induces tumor shrinkage in vivo

Antibody-based immune therapies targeting the T-cell checkpoint inhibitors CTLA4 and PD1 have made incredible advances in cancer therapy. In particular, the combination of CTLA4 and PD1 blockade (using ipilimumab and nivolumab, respectively) was recently shown to be the most effective immune therapy for improving progression-free survival in advanced melanoma patients. However, this immune therapy combination strategy is extraordinarily expensive due to high manufacturing costs of monoclonal antibodies, with an estimated annual cost of almost one million dollars per patient. In this study, we focused on the development of a DNA-encoded monoclonal antibody (DMAb TM ) approach for delivery of anti-CTLA4 monoclonal antibodies in vivo. With this technology, formulated DMAb TM plasmids are injected into the muscle with electroporation, allowing for muscle cells to produce and secrete the DMAb TM for a prolonged period of time without the need for repeated administration. In proof-of-concept studies in mice, we show that delivery of a DMAb TM plasmid for a monoclonal antibody targeting mouse CTLA4 (clone 9D9) elicits high serum expression (peak expression of 7.9µg/mL in immune-competent C57Bl/6 mice with one injection of DNA). This anti-mouse CTLA4 DMAb TM is capable of inducing tumor regression in A/J mice that were implanted with the immunogenic Sa1N tumor cell line without repeated administration. Furthermore, this anti-mouse CTLA4 DMAb TM is capable of synergizing with a DNA vaccine targeting the tumor antigen TERT in slowing tumor growth for the nonimmunogenic TC-1 tumor cell line. We also examined DNA delivery of the anti-human CTLA4 antibodies ipilimumab and tremelimumab. For these anti-human CTLA4 DMAbs TM , we achieved steady-state levels of approximately 75µg/mL and 50ug/mL for ipilimumab and tremelimumab, respectively, in mice, which is greater than the mean trough levels of ipilimumab achieved in patients (21.8µg/mL serum concentration for 3mg/kg dose). These anti-human CTLA4 DMAbs TM produced in vivo bind to human CTLA4 protein and induce T-cell activation in a functional assay ex vivo. These results demonstrate the feasibility of delivering immune checkpoint blockade monoclonal antibodies using DNA for cancer immune therapy. Future studies will explore combination therapies with CTLA4 DMAbs TM and chemotherapy. Citation Format: Elizabeth Duperret, Aspen Trautz, Ami Patel, Joseph Kim, Kar Muthumani, David B. Weiner. Synthetic DNA-encoded monoclonal antibody delivery (DMAb TM ) of anti-CTLA4 antibodies induces tumor shrinkage in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B036.