While Antibody-Drug Conjugates (ADCs) have fundamentally shifted the landscape of targeted therapy, clinical challenges such as narrow therapeutic windows and emerging resistance have driven the search for more robust modalities. Degrader-Antibody Conjugates (DACs) represent this next frontier, merging the high specificity of monoclonal antibodies with the catalytic power of Targeted Protein Degradation (TPD). 

Unlike traditional ADCs, which rely on cytotoxic payloads (e.g., MMAE or topoisomerase I inhibitors) to induce cell death, DACs combine antibody-mediated delivery with PROTACs or molecular glues to enable catalytic protein degradation. The efficacy of the DAC platform relies on a synergistic triad: 

● A targeting antibody for precise antigen recognition (e.g., HER2 or CD33) 

● A degrader payload that recruits E3 ligases such as CRBN or TRIP12 to trigger the ubiquitin-proteasome pathway

● A cleavable linker ensures stability in systemic circulation and controlled release of the degrader within the lysosomal environment to maximize therapeutic activity.

By focusing on the complete degradation of disease-driving proteins rather than simple occupancy-based inhibition, DACs provide a potent mechanism to overcome resistance and achieve more durable clinical outcomes.

This dual-precision architecture provides three critical mechanistic advantages that set it apart from conventional targeted therapies:

Expanding the Reach to Undruggable Targets

Traditional therapeutics often rely on binding to well-defined active sites. In contrast, the degradation mechanism of DACs enables targeting of transcription factors, scaffold proteins, and proteins lacking well-defined binding pockets. These undruggable targets are pervasive in oncology and immunological diseases but have historically remained beyond the reach of traditional medicinal chemistry.

Catalytic Potency

Conventional ADCs typically require high levels of antigen expression to deliver a sufficient cytotoxic payload. In contrast, DACs leverage the catalytic, recycling nature of degrader payloads, enabling potent activity even in tumor cells with low antigen expression.

Overcoming Clinical Resistance

Most approved ADCs rely on a limited set of payloads, which are increasingly prone to clinical resistance. DACs utilize degrader payloads with a distinct mechanism of action, specifically designed to bypass these existing resistance pathways.

Development Timeline and Industrial Landscape

The DAC field traces its origins back to 2017 when Genentech filed the first foundational patents. In 2020, Genentech researchers published the first detailed characterization of a DAC molecule targeting the BRD4 protein, providing the industry's inaugural Proof of Concept (POC).

Since then, this emerging modality has rapidly gained traction across the biopharmaceutical sector. 

● September 2023: Nurix Therapeutics entered into a multi-year strategic collaboration with Seagen (now part of Pfizer) to develop a portfolio of DACs for cancer. Under the agreement, Nurix received a $60 million upfront payment, with the potential to earn up to $3.4 billion in total research, regulatory, and commercial milestones, plus tiered royalties. 

● November 2023: Bristol Myers Squibb (BMS) acquired ORM-6151 from Orum Therapeutics for an upfront payment of $100 million, and Orum Therapeutics is eligible to receive milestone payments for a total deal value of $180 million. 

● December 2023: C4 Therapeutics (C4T) established an exclusive licensing and collaboration agreement with Merck (MSD) to develop DACs. C4T received a $10 million upfront payment to focus on an initial undisclosed oncology target. The deal includes potential milestones totaling approximately $600 million for the first target, with an option for Merck to extend the collaboration to three additional targets. If all options are exercised, the total deal value could reach approximately $2.5 billion.

● July 2024: Orum Therapeutics and Vertex Pharmaceuticals hass agreed to develop novel targeted conditioning agents for gene editing using Orum’s Dual-Precision Targeted Protein Degradation (TPD²) technology. Vertex paid Orum $15 million for rights to study the company’s DACs. Orum can receive as much as $310 million in development and commercial milestone payments for each of up to three targets.

Clinical Pipepines

The primary challenge in DAC development lies in achieving an incredibly delicate equilibrium between Drug-to-Antibody Ratio (DAR), linker stability, and internalization efficiency. This balance has proven difficult to master, as evidenced by the recent shifts in the clinical pipeline.

BMS-986497 (ORM-6151, Active, Phase I): This currently stands as the only DAC candidate globally remaining in active clinical development. By conjugating a GSPT1 degrader to a CD33-targeted antibody, it specifically addresses Acute Myeloid Leukemia (AML). Supported by Bristol Myers Squibb’s robust clinical infrastructure, its development remains the most stable in the field.

ORM-5029 (Inactive): Formerly a frontrunner, Orum announced the termination of this HER2-targeted GSPT1 DAC in April 2025. The decision followed a critical setback in a Phase I trial involving a serious adverse event (SAE)—a patient death due to liver failure. After an immediate halt to recruitment and a comprehensive safety assessment, the program was shuttered. This served as a stark wake-up call for the industry: excessive payload potency is not the goal; a manageable therapeutic window is paramount.

ABBV-787 (Inactive): AbbVie’s strategic withdrawal from this program reflects broader concerns among big pharma regarding the narrow therapeutic windows characteristic of first-generation DACs.

ORM-1153 (Preclinical): Also built on the proprietary TPD² platform, ORM-1153 targets GSPT1 with a specific design focus on enhancing selectivity and widening the therapeutic index. At the 2025 ASH Annual Meeting, Orum presented updated preclinical data showing that ORM-1153 was approximately 1,000-fold more potent than the unconjugated degrader. In disseminated AML xenograft models, the candidate demonstrated dose-dependent tumor regression, with the highest dose cohorts achieving complete and durable remissions.

Figure 1. Orum's Pipelines, source: https://www.orumrx.com/pipeline-page 

Challenges and Future Perspectives

Despite its potential, DAC technology is still in its infancy. Most candidates are currently in Phase I trials and the perclinical phase, meaning we lack the Phase III data necessary to confirm long-term safety and efficacy. First, finding the optimal balance between the antibody and the degrader payload requires extensive exploration. Second, combining large-molecule antibodies with small-molecule degraders makes controlling the DAR and managing impurities much harder than with traditional drugs. Additionally, while new linker designs are improving stability, large-scale production processes are not yet mature. This complexity could lead to higher costs, potentially limiting patient access.

All in all, DACs are not a simple replacement for ADCs; rather, they represent a vital evolution in payload diversity. By shifting the strategy from "cell killing" to "functional protein clearance," DACs offer a brand-new therapeutic path for patients who do not respond to traditional treatments. As more clinical data emerges, DACs are poised to drive the next major wave of biopharmaceutical innovation.

References:

Hong KB, An H. Degrader-Antibody Conjugates: Emerging New Modality. J Med Chem. 2023 Jan 12;66(1):140-148. doi: 10.1021/acs.jmedchem.2c01791. Epub 2022 Dec 29. PMID: 36580273.