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

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
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 8 (04 18 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 30996140 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• Antibodies, Monoclonal
• Antineoplastic Agents, Immunological
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Animals
• Antibodies, Bispecific (administration & dosage, genetics)
• Antibodies, Monoclonal (administration & dosage, genetics)
• Antineoplastic Agents, Immunological (administration & dosage)
• Cell Line, Tumor
• Drug Delivery Systems (methods)
• Electroporation (methods)
• Female
• Humans
• Male
• Mice
• Neoplasms (drug therapy, immunology, pathology)
• Plasmids (administration & dosage, genetics)
• Receptor, ErbB-2 (antagonists & inhibitors, immunology, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Xenograft Model Antitumor Assays