Redirecting T Cells to Tumor Targets With Functionally Diverse CD3-Binding Antibodies
Natural immune systems provide powerful protection against cancer. When cancer cells form, immune cells — called T cells — find and destroy them. But cancer can adapt and hide from T cells, allowing it to grow, spread, and take up residence in the body, undetected.
The Opportunity
Immunotherapies, including bispecific antibodies called CD3 T cell engagers, are a type of cancer treatment that help immune systems find and destroy cancer cells. CD3 T cell engagers simultaneously bind to T cells and cancer cells in order to redirect T cells to tumor cells, regardless of T cell specificity. And by specifically binding to a protein on T cells called CD3, they activate the T cell’s cancer killing functions.
The Challenge
CD3 T cell engagers have the potential to be a cornerstone of immuno-oncology. However, a limited pool of CD3-binding antibodies and technological challenges in engineering bispecifics have hindered development.
Creating effective CD3 T cell engagers requires two different parental antibodies — a CD3-targeting antibody that fine-tunes T cell activation and a tumor-targeting antibody with high specificity for cancer cells. Highly diverse panels of developable and functionally validated parental antibodies increase the probability of finding effective and manufacturable CD3 T cell engagers and reduce the need for downstream engineering to eliminate liabilities.
Our Solution
To help partners unlock CD3 T cell engager discovery and streamline the development of new cancer treatments, AbCellera used its technology stack to discover a panel of CD3-binding antibodies that are diverse, developable, and validated.
- Diversity: Bioinformatic analysis of 275 unique CD3-binding antibody sequences revealed high diversity, including somatic hypermutation, a range of CDR3 lengths, and diverse V gene usage. The panel was also found to have functional diversity, including a broad range of CD3 affinities and T cell activation potencies.
- Developability: Biophysical characterization demonstrated that AbCellera’s CD3-binding antibodies have favorable developability properties that may reduce the time and technical risks of downstream protein engineering, including low mean hydrophobicity, self-association, and polyspecificity.
- Validation: AbCellera used its clinically-validated bispecifics platform, OrthoMab™, to pair the CD3-binding antibodies with a single EGFR-binding arm to validate the panel in bispecific formats. The resulting bispecific antibodies activated T cells with a range of potencies and led to T cell-mediated tumor cell killing of EGFR-expressing cell lines.
AbCellera’s poster presentation at the American Association for Cancer Research (AACR) 2022 Annual Meeting demonstrates that the integration of its diverse panel of CD3-binding antibodies with its bispecific engineering and high-throughput antibody assessment capabilities enable identification of promising CD3 T cell engagers.
