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

Area of Science:

• Immunology and Cancer Therapy
• Molecular Biology and Genetic Engineering

Background:

• Specific antibody therapies like monoclonal antibodies (mAbs) and bispecific T cell engagers (BiTEs) are crucial for cancer immunotherapy.
• Current antibody therapies face challenges in development speed, production scalability, and short in vivo half-lives, limiting patient access.
• A simplified approach for in vivo development, delivery, and production of these immunotherapies is needed.

Purpose of the Study:

• To develop a novel DNA-based platform for simplified in vivo production of antibody-based cancer immunotherapies.
• To engineer and evaluate a DNA-encoded bispecific T cell engager (DBiTE) targeting HER2 for potential use in HER2+ cancers.

Main Methods:

• Designed and optimized a synthetic DNA plasmid for high expression of an anti-HER2 antibody (HER2dMAb).
• Utilized adaptive electroporation for DNA delivery into animals.
• Engineered a DNA-encoded BiTE (DBiTE) using the HER2dMAb fragment and evaluated its in vivo expression, efficacy, and duration.

Main Results:

• Achieved efficient in vitro and in vivo expression of HER2dMAb, reaching therapeutic levels in mouse serum.
• Demonstrated that HER2dMAb effectively blocked HER2 signaling, induced antibody-dependent cytotoxicity, and delayed tumor progression in HER2+ models.
• Showcased sustained in vivo expression of the engineered HER2DBiTE for up to 4 months post-single administration, with potent cytolytic activity and significant cancer progression delay in mice.

Conclusions:

• The developed DNA plasmid and adaptive electroporation system enable efficient in vivo production of therapeutic antibodies.
• DNA-encoded BiTEs (DBiTEs) represent a promising, simplified approach for generating potent immunotherapies against HER2+ tumors.
• This platform has potential applications for ovarian cancer and other HER2-expressing malignancies.