Human antibody-based chemically induced dimerizers for cell therapeutic applications

Area of Science:

• Biotechnology
• Molecular Biology
• Immunology

Background:

• Chemically induced dimerizers (CIDs) are crucial for regulating cellular signaling pathways.
• Existing CID systems have limitations for therapeutic applications.
• There is a need for novel CIDs with enhanced control and specificity.

Purpose of the Study:

• To develop human antibody-based chemically induced dimerizers (AbCIDs).
• To create AbCIDs that recognize specific small-molecule-protein complexes.
• To demonstrate the utility of AbCIDs in regulating cellular therapies.

Main Methods:

• Generated synthetic antibodies targeting chemical epitopes formed by small-molecule-protein interactions.
• Selected antibodies specific for the BCL-xL-ABT-737 complex.
• Applied AbCIDs to induce CRISPRa-mediated gene expression and regulate CAR T-cell activation.

Main Results:

• Developed three highly selective antibodies for the BCL-xL-ABT-737 complex.
• Demonstrated AbCIDs' ability to control CRISPRa gene expression.
• Showcased AbCIDs' potential in regulating CAR T-cell activity.

Conclusions:

• AbCIDs represent a powerful new tool for regulating cell therapies.
• The developed AbCIDs offer precise control over cellular functions.
• The AbCID development strategy enables creation of new, orthogonal CID systems.