Roche has entered the emerging degrader-antibody conjugate (DAC) space alongside other major pharmaceutical players, striking a deal with C4 Therapeutics that includes a $20 million upfront payment and the potential for more than $1 billion in milestone-based payouts tied to two oncology programs.
DACs combine elements of antibody-drug conjugates (ADCs) and targeted protein degraders (TPDs). Similar to ADCs, they use antibodies linked to therapeutic payloads to direct treatment toward cells expressing specific receptors. However, instead of carrying traditional cytotoxic agents, DACs deliver protein degraders designed to break down disease-causing proteins, including those that have historically been difficult to target with drugs.
According to Barbara Lueckel, who leads the company’s research technologies partnering, the company sees DACs as a promising way to address limitations associated with ADCs, such as toxicity and resistance. By relying on targeted protein degradation rather than broad cell-killing mechanisms, DACs may offer a more precise and potentially safer therapeutic approach.
Under the agreement, Roche will be responsible for identifying cancer targets and developing the corresponding antibodies, while C4 Therapeutics will generate degrader payloads using its Torpedo platform. Roche will then combine the two components and advance the resulting candidates through preclinical development and beyond. The deal also includes an option to expand the collaboration to a third target.
Although the specific targets have not been disclosed, Andrew Hirsch, CEO of C4 Therapeutics, indicated that DACs may be particularly useful for targets where toxicity is a concern, as antibodies can help localize the degrader to specific tissues. In some cases, the antibody itself may also contribute therapeutic activity by engaging its target receptor.
Despite their potential, DACs present technical challenges. Traditional ADCs work in part because their highly potent payloads require only minimal loading, preserving the antibody’s targeting function and reducing issues like aggregation. Protein degraders, while powerful, may require higher payload levels, increasing complexity in design and development.
Even so, Roche appears committed to advancing this next-generation modality. Lueckel said the field must become proficient in handling more advanced therapeutic approaches, noting that while some programs may still result in traditional small-molecule drugs, there is a growing need to work confidently with more intricate formats. He added that such approaches can include combining a larger small-molecule component with an antibody to create more sophisticated treatments.
The latest agreement builds on a long-running collaboration between Roche and C4 Therapeutics, which dates back to 2016, when the biotech first revealed its partnership with the Swiss drugmaker after emerging from stealth. Although the alliance has evolved over time, including the discontinuation of an EGFR-targeting program, the two companies have maintained joint efforts in the field of traditional targeted protein degraders.
Lueckel, who was involved in business development for the original agreement, noted that Roche’s initial decision to collaborate with C4 Therapeutics was largely based on very early-stage data, describing it as a “leap of faith.” She added that while the company is once again taking a risk with the new DAC collaboration, this decision is now supported by years of experience and a well-established working relationship between the two organizations.
Roche’s Strategic Investment in C4T
Roche has committed $20 million to partner with C4 Therapeutics (C4T), aiming to accelerate the development of antibody-directed protein degraders. Roche’s investment highlights confidence in C4T’s proprietary platform designed to selectively eliminate disease-causing proteins.
Through this collaboration, Roche seeks to expand its oncology and immunology pipelines using cutting-edge degradation technologies.
What Are Antibody-Focused Protein Degraders?
Roche is betting on a novel therapeutic approach that combines antibodies with targeted protein degradation. These therapies are designed to:
- Bind specifically to disease-related proteins
- Trigger their destruction within cells
- Offer higher precision compared to traditional inhibitors
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