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Updated: Jul 28, 2025
Laboratory Scale Production and Purification of a Therapeutic Antibody
Published on: January 24, 2017
Rational Design of Chemically Controlled Antibodies and Protein Therapeutics
Anthony Marchand1, Lucia Bonati1,2, Sailan Shui1
1Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Abstract:
Protein-based therapeutics, such as monoclonal antibodies and cytokines, are important therapies for various pathophysiological conditions such as oncology, autoimmune disorders, and viral infections. However, the wide application of such protein therapeutics is often hindered by dose-limiting toxicities and adverse effects, namely, cytokine storm syndrome, organ failure, and others. Therefore, spatiotemporal control of the activities of these proteins is crucial to further expand their application. Here, we report the design and application of small-molecule-controlled switchable protein therapeutics by taking advantage of a previously engineered OFF-switch system. We used the Rosetta modeling suite to computationally optimize the affinity between B-cell lymphoma 2 (Bcl-2) protein and a previously developed computationally designed protein partner (LD3) to obtain a fast and efficient heterodimer disruption upon the addition of a competing drug (Venetoclax). The incorporation of the engineered OFF-switch system into anti-CTLA4, anti-HER2 antibodies, or an Fc-fused IL-15 cytokine demonstrated an efficient disruption in vitro, as well as fast clearance in vivo upon the addition of the competing drug Venetoclax. These results provide a proof-of-concept for the rational design of controllable biologics by introducing a drug-induced OFF-switch into existing protein-based therapeutics.
Insights
Scientists developed switchable protein therapeutics for better control. Adding a specific drug rapidly inactivates these biologics, reducing side effects and expanding therapeutic potential in oncology and autoimmune diseases.
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.
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