Roche has joined its Big Pharma peers in the emerging degrader-antibody conjugate (DAC) space, paying C4 Therapeutics $20 million upfront and committing more than $1 billion in milestones to partner on two oncology targets.
DACs sit at the intersection of antibody-drug conjugates (ADCs) and targeted protein degraders (TPDs). Like ADCs, DACs feature payloads connected to targeting antibodies via linkers. In both cases, the design enables targeted payload delivery to cells that express certain receptors. The difference is that DACs carry TPDs, not cytotoxic chemotherapies, to drive degradation of proteins, including undruggable targets.
Roche is excited about the potential for DACs to overcome therapeutic window and resistance issues linked to ADC payloads, Barbara Lueckel, Ph.D., the drugmaker’s global head of research technologies partnering, told Fierce. DACs kill cancer cells via targeted protein degradation, rather than the broad cytotoxicity of ADCs, and as such could be less likely to cause toxicity or drive drug resistance.
Under the collaboration, Roche will select and design antibodies against two undisclosed cancer targets, while C4T will use its Torpedo platform to design degrader payloads. Roche will then conjugate its antibodies to C4T’s degrader payloads and advance the resulting DAC candidates through preclinical studies and beyond. The agreement includes an option to add a third target.
The partners are yet to disclose the targets, but C4T CEO Andrew Hirsch discussed with Fierce the type of targets that are amenable to DACs. Using an antibody to aim a degrader at certain tissue types is useful when engaging targets with toxicity concerns, according to Hirsch. For other targets, the antibody may have a dual purpose, delivering the payload while simultaneously driving desired effects by engaging the receptor.
Those potential benefits come at the cost of complexity. ADCs are viable because the payloads are so potent that only a few molecules need attaching to each antibody, preserving the targeting capabilities and avoiding problems such as aggregation. While protein degraders are more potent than many drugs, a higher loading ratio may be required than for ADCs.
Still, Roche is ready to tackle this complexity.
“We believe that more complex modalities have to be mastered,” Lueckel said. “Sometimes there’s complexity in the biology and maybe you come out with a more conventional, small molecule. But more and more, we need to get comfortable with potentially more complex modalities, linking a larger small molecule to an antibody.”
Today's deal extends Roche’s longstanding relationship with C4T, which disclosed an alliance with the Swiss drugmaker when it exited stealth in 2016. While the partnership has undergone changes over the past decade, including the termination of an EGFR asset, Roche and C4T have continued to collaborate on traditional TPDs.
Lueckel, who was business development project leader on the original C4T deal, said Roche’s decision to partner with the biotech in 2016 on the strength of little more than a mouse experiment was a “leap of faith.” Roche is now taking another leap of faith, Lueckel said, although this time the gamble is grounded in the trust and knowledge developed over a decade working with C4T.
Roche’s peers have shown an interest in DAC technology, including C4T’s capabilities. Merck & Co. paid $10 million to partner with C4T in 2023, securing exclusive rights to DACs against one target and options on three more targets. However, Merck terminated the deal last November, ending C4T’s hopes of receiving $600 million in milestones tied to the initial target.
In 2023, Bristol Myers Squibb paid Orum Therapeutics $100 million upfront for ORM-6151, a DAC that uses an anti-CD33 antibody to deliver a GSPT1 degrader. Now renamed BMS-986497, the candidate is in a phase 1 trial in the blood cancers, acute myeloid leukemia and myelodysplastic syndrome. Orum, which partnered with Vertex in 2024, raised $100 million to fund its internal DAC pipeline in December.
Seagen, now part of Pfizer, paid Nurix Therapeutics $60 million in 2023 to partner on DAC development. Pfizer retained the relationship after buying Seagen, with Nurix’s pipeline listing the collaboration as a discovery-stage project. While most DACs target cancers, Nurix’s internal discovery teams are exploring the modality in inflammatory and autoimmune conditions.