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DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity
Alfredo Perales-Puchalt, … , Kar Muthumani, David B. Weiner
Alfredo Perales-Puchalt, … , Kar Muthumani, David B. Weiner
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e126086. https://doi.org/10.1172/jci.insight.126086.
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Research Article Immunology Oncology

DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity

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Abstract

Specific antibody therapy, including mAbs and bispecific T cell engagers (BiTEs), are important new tools for cancer immunotherapy. However, these approaches are slow to develop and may be limited in their production, thus restricting the patients who can access these treatments. BiTEs exhibit a particularly short half-life and difficult production. The development of an approach allowing simplified development, delivery, and in vivo production would be an important advance. Here we describe the development of a designed synthetic DNA plasmid, which we optimized to permit high expression of an anti-HER2 antibody (HER2dMAb) and delivered it into animals through adaptive electroporation. HER2dMAb was efficiently expressed in vitro and in vivo, reaching levels of 50 μg/ml in mouse sera. Mechanistically, HER2dMAb blocked HER2 signaling and induced antibody-dependent cytotoxicity. HER2dMAb delayed tumor progression for HER2-expressing ovarian and breast cancer models. We next used the HER2dMAb single-chain variable fragment portion to engineer a DNA-encoded BiTE (DBiTE). This HER2DBiTE was expressed in vivo for approximately 4 months after a single administration. The HER2DBiTE was highly cytolytic and delayed cancer progression in mice. These studies illustrate an approach to generate DBiTEs in vivo, which represent promising immunotherapies for HER2+ tumors, including ovarian and potentially other cancers.

Authors

Alfredo Perales-Puchalt, Elizabeth K. Duperret, Xue Yang, Patricia Hernandez, Krzysztof Wojtak, Xizhou Zhu, Seang-Hwan Jung, Edgar Tello-Ruiz, Megan C. Wise, Luis J. Montaner, Kar Muthumani, David B. Weiner

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Figure 3

HER2dMAb blocks HER2 signaling, induces antibody-dependent cellular cytotoxicity, and delays cancer progression in vivo.

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HER2dMAb blocks HER2 signaling, induces antibody-dependent cellular cyto...
(A) Western blot showing total Akt and phosphorylated Akt (p-Akt) and β-actin from OVCAR3 cells treated with or without HRG in the presence of HER2dMAb or control and quantification (representative of 3 independent experiments). (B) Histogram showing ADCC assay of HER2dMAb or irrelevant IgG with OVCAR3 (triplicates, representative of 3 independent experiments). (C) Growth curve of OVCAR3 tumors grafted into nude mice treated with HER2dMAb or empty vector (2 independent experiments, n = 5 mice per group). (D) Levels of HER2dMAb in serum of OVCAR3-bearing mice treated with HER2dMAb or empty vector (representative of 2 independent experiments, n = 5 mice per group). (E) Flow cytometry plot showing expression of HER2 by OVCAR3, Brpkp110, and Brpkp110-hHER2 tumor cells (n = 3 mice per group). (F) Growth curve of Brpkp110-hHER2 tumors grafted into C57BL/6 mice treated with HER2dMAb or empty pVax plasmid (representative of 2 independent experiments, n = 5 mice per group). Two-way ANOVA, t test, log-rank test. ***P < 0.001.

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