The Rising Heat of DAC Drugs: ADC and PROTAC Sparking Innovation

In the realm of new technologies, pharmaceutical giants have always been generous in their investments. On December 12th, C4Therapeutics (C4T) announced an exclusive licensing and collaboration agreement with Merck, with the aim of developing antibody-conjugated protein degraders (DACs). While the initial payment for this partnership is relatively modest at $10 million, the potential total payments reaching $2.5 billion signify Merck's high expectations for DACs. Merck's entry into the field also signals that the development of DAC drugs is becoming increasingly promising.

ADC and PROTAC: Igniting Innovation:
Structurally, the drug conjugate family, including DACs, shares many similarities. DAC drugs are derived from modifications to antibody-drug conjugates (ADCs). ADC drugs consist of three components: a monoclonal antibody that targets a specific antigen, a cytotoxic payload, and a chemical linker that connects the two. DACs, on the other hand, replace the cytotoxic payload of ADCs with PROTAC, enabling it to bind with monoclonal antibodies.

So, what can the combination of ADC and PROTAC technologies achieve? In theory, DAC drugs have the potential to overcome the shortcomings of both ADC and PROTAC. Currently, both PROTAC and ADC technologies are experiencing significant development but also face their own challenges.

PROTAC technology, while capable of degrading undruggable disease-causing target proteins, lacks selectivity between normal and cancer cells, which may give rise to off-target toxicities. Additionally, due to the larger molecular weight of PROTAC molecules, these drugs exhibit poor drug metabolism and pharmacokinetic (DMPK) properties, resulting in low oral bioavailability and rapid clearance from the body.

DAC drugs, acting as a drug delivery strategy, can selectively deliver degraders to cancer-associated cells while minimizing off-target toxicity to non-target tissues. The antibody component of DAC drugs recognizes tumor-associated antigens on the cell surface. The DAC-antibody complex undergoes receptor-mediated endocytosis, enhancing overall cellular permeability and bioavailability of PROTAC drugs.

ADC technology, while potent, faces challenges primarily related to off-target toxicities, which DAC drugs are expected to address, offering improved safety. ADC drugs act like highly potent missiles, where antibodies carry toxins directly to the tumor cells. In contrast, DAC drugs function as reconnaissance troops, not directly killing tumor cells, but rather marking them for degradation by the proteasome system.

The Increasingly Competitive Landscape:
With high expectations, global pharmaceutical companies have embarked on the race to develop DAC drugs. In September of this year, Seagen entered a collaboration worth up to $3.46 billion with Nurix, a leader in the PROTAC field, aiming to develop degrader antibody hybrids with novel mechanisms of action. In November, Bristol Myers Squibb announced an agreement to acquire potential "first-in-class" antibody-conjugated protein degrader ORM-6151 from Orum Therapeutics for approximately $180 million.

Now, with Merck's entry into the field, the competition continues to intensify. However, the cautious initial payments from these giants indicate that DAC drug development remains a high-risk endeavor.

Currently, DAC development globally is still in its early stages, and there is no consensus on the actual performance of DACs. Moreover, unlike the well-established development and manufacturing of ADC drugs, DAC drugs face significant challenges in research, design, and production.

In conclusion, the majority of pharmaceutical companies involved in DAC drug development are still in the early clinical stages. While the entry of more companies elevates the field's heat, the challenges should not be underestimated. The rising interest in DAC drugs stems from their potential to overcome the limitations of ADC and PROTAC technologies, offering enhanced efficacy and safety. As research and development efforts progress, the future of DAC drugs holds promise for revolutionizing targeted therapies in the pharmaceutical industry.