Rational Design of Chemically Controlled Antibodies and Protein Therapeutics

Area of Science:

• Biotechnology
• Protein Engineering
• Drug Development

Background:

• Protein therapeutics like antibodies and cytokines are vital for treating cancer, autoimmune disorders, and infections.
• Their clinical use is limited by toxicities such as cytokine storm syndrome and organ failure.
• Spatiotemporal control over protein activity is essential for broader therapeutic applications.

Purpose of the Study:

• To design and validate small-molecule-controlled, switchable protein therapeutics.
• To engineer a drug-inducible OFF-switch system for enhanced safety and efficacy.
• To demonstrate the feasibility of controlling biologics using a competing drug.

Main Methods:

• Computational optimization using Rosetta to fine-tune protein-protein interactions (Bcl-2 and LD3).
• Engineered an OFF-switch system for rapid heterodimer disruption triggered by Venetoclax.
• Incorporated the switch system into anti-CTLA4 antibodies, anti-HER2 antibodies, and an Fc-fused IL-15 cytokine.

Main Results:

• Demonstrated efficient in vitro disruption of engineered protein therapeutics upon drug addition.
• Showcased rapid in vivo clearance of switchable biologics after Venetoclax administration.
• Validated the OFF-switch system's functionality across different protein-based therapeutic modalities.

Conclusions:

• The study provides a proof-of-concept for rationally designing controllable biologics.
• Introducing drug-induced OFF-switches into protein therapeutics enhances safety and control.
• This approach holds promise for expanding the therapeutic window of protein-based drugs.