Degrader Antibody Conjugates

As the targeted protein degradation (TPD) field has advanced, research has increasingly focused on leveraging the unique and powerful catalytic mechanism of degraders. A key emerging approach is the integration of degraders into antibody–drug conjugates (ADCs) to create degrader–antibody conjugates (DACs).

DACs utilize targeted protein degraders as drug payloads for antibody-drug conjugates to expand the number of intracellular targets that can be drugged with an ADC approach. The modality uses an antibody to deliver a targeted protein degrader to specific tumor cells. Antibody binding to tumor antigens triggers receptor-mediated transport into the cell where the degrader is released. Once released, the degrader recruits the cell’s ubiquitin-proteasome system, which tags and catalytically destroys multiple copies of the cancer-causing protein.

We can use our TORPEDO® platform to design degraders with the unique properties required for degrader payloads for DACs. Our research in this emerging modality is focused on unlocking a new therapy that expands the types of tumors and targets that ADCs can address today.

We believe DACs can offer several benefits over traditional ADCs:

• Potency and Catalytic Activity

  A single degrader molecule can remove thousands of copies of the disease-causing target protein, which means a lower amount of drug is required to fight disease. This feature makes degraders attractive as payloads for drug conjugates. By utilizing C4T’s ability to design highly catalytic and potent degraders, the resulting DAC may deliver durable responses for patients with a wide range of tumor types beyond what is currently treatable with traditional ADCs.

• Safety and Specificity

  ADCs are designed to precisely deliver toxic chemotherapeutic drugs to tumors. However, premature release of the payload can lead to indiscriminate cell killing that exposes healthy tissues to the chemotherapy. This is a common event and results in a high incidence of dose-limiting toxicities and a narrow therapeutic index. However, targeted protein degraders are designed to remove a single, cancer-causing protein. When delivered as antibody conjugates, degraders eliminate the targeted protein. This enables potent, sustained activity at lower exposure and the potential for a broader, more differentiated therapeutic window.