The global ADC (Antibody–Drug Conjugate) market has been experiencing rapid growth, with 19 ADC drugs approved to date worldwide. In 2023, the market surpassed the US$10 billion milestone for the first time. While growth remains strong, the field is gradually becoming saturated. As a result, multinational corporations (MNCs) are shifting their attention beyond ADCs to other antibody–conjugate modalities, including peptide–drug conjugates (PDCs), radioisotope–drug conjugates (RDCs), antibody–oligonucleotide conjugates (AOCs), and degrader–antibody conjugates (DACs).

In recent years, targeted protein degradation (TPD) therapies—exemplified by proteolysis-targeting chimeras (PROTACs) and molecular glues—have gained significant momentum as a next-generation approach to drug discovery, with the potential to address up to 80% of previously “undruggable” targets. PROTACs offer clear advantages in tackling such targets and in overcoming drug resistance. However, despite their ability to efficiently degrade disease-causing proteins, they face notable challenges: limited selectivity between healthy and cancer cells, poor cell membrane permeability due to their large molecular weight, and toxicity linked to off-target effects.

To solve these issues, Degrader-Antibody Conjugates (DACs) have been developed, leveraging the targeting and internalization capabilities of antibodies.

What are Degrader-Antibody Conjugates?

DACs are an emerging molecular modality in which targeted protein degraders—such as PROTACs or molecular glues—are chemically linked to monoclonal antibodies via a linker. Structurally and mechanistically, DACs are similar to traditional ADCs, with one key difference: instead of a cytotoxic payload, DACs carry a protein degrader. Once the antibody binds to its target antigen, the complex is internalized into the cell. Inside the cell, the linker is cleaved in a specific intracellular environment, releasing the degrader to induce degradation of the target protein.

Figure 1. Degrader-Antibody Conjugates Structure [1]

The concept behind DACs lies in combining the strengths of both PROTACs and ADCs:

Advantages of PROTACs

• ✅ Catalytic action with high efficiency at low doses: The catalytic nature of PROTACs allows for lower dosing and catalyzing the degradation of multiple proteins of interest with reduced cytotoxicity.
• ✅ Ability to target “undruggable” proteins: Lower binding affinity requirements allow access to targets beyond the reach of conventional small molecules.
• ✅ Overcoming drug resistance: By degrading mutant proteins directly, DACs reduce the risk of resistance caused by epitope alterations.
• ✅ Broad applicability: In principle, degraders can target a wide range of intracellular proteins, with potential applications in oncology, neurology, immunology, and infectious diseases.

Advantages of ADCs

• ✅ Precise delivery: ADCs deliver potent chemotherapy drugs directly to cancer cells expressing specific antigens, minimizing systemic exposure to healthy tissues.
• ✅ Reduced off-target effects: The inherent specificity of antibodies reduces the chances of the cytotoxic payload affecting unintended cells or tissues, leading to a better safety profile.
• ✅ Tissue/cell-specific therapy: Antibodies can target antigens uniquely expressed on diseased cells, allowing for tailored therapies and potentially improved treatment outcomes.

What is the Difference between ADC and DAC Drugs?

While ADCs and DACs share highly similar molecular structures and mechanisms of action, they differ significantly in terms of payload characteristics, drug-to-antibody ratio (DAR), antigen selection, safety, and resistance mechanisms.

Payload and Mechanism of Action

ADCs: Typically carry highly potent, broadly cytotoxic chemotherapeutic agents that directly kill target cells. The DAR usually falls within the range of 2–8, optimized to achieve strong antitumor activity while minimizing systemic toxicity.

DACs: Deliver TPDs, such as PROTACs, which trigger the intracellular degradation of disease-causing proteins. Since these degraders generally exhibit lower intrinsic potency compared to ADC payloads, higher loading—often with a DAR greater than 4—may be necessary to achieve comparable efficacy. However, the larger, more lipophilic nature of PROTACs increases the risk of aggregation and can negatively impact pharmacokinetics, necessitating specialized linker designs and conjugation strategies beyond those used in conventional ADCs.

Antigen Selection and Safety

ADCs: Require antigens with high specificity and strong expression on tumor cells to avoid widespread off-target toxicity. Early release of the cytotoxic payload in circulation can cause significant systemic side effects, making antigen selection critical for safety.

DACs: Antigens must not only be highly expressed on target cells but also capable of mediating efficient internalization to deliver the degrader into the cytoplasm. Because DAC payloads act via targeted protein degradation rather than broad cytotoxicity, low-level expression in normal tissues may be tolerable if safety margins are acceptable. Moreover, the reliance on intracellular release mechanisms generally reduces systemic off-target toxicity compared with ADCs.

Overview of DAC Clinical Development

Globally, the development of DACs remains in its early stages. As of now, there are only around 20 DAC candidates in the pipeline worldwide. To date, only Orum Therapeutics’ ORM-6151 has entered Phase I clinical trials, while DAC programs ORM-5029 (also from Orum) and ABBV-787 (from AbbVie) have been discontinued.

ORM-6151 / BMS-986497

Developer: Orum Therapeutics (acquired by Bristol Myers Squibb)

ORM-6151 (also known as BMS-986497) is a first-in-class DAC engineered to target CD33-expressing malignancies. It combines a potent GSPT1 degrader (SMol006) with a CD33-directed antibody (OR000283) via a novel, lysosome-cleavable β-glucuronide linker. Once internalized, the linker releases SMol006, triggering targeted degradation of GSPT1 via the proteasome.

Preclinical Efficacy

• ✅ In CD33-expressing cell lines, ORM-6151 demonstrated picomolar potency, achieving 10–1,000-fold greater activity than other GSPT1 degraders, including CC-90009 and the ADC Mylotarg, and maintained strong efficacy in Mylotarg-resistant lines (AML193 and Kasumi6).
• ✅ In primary relapsed/refractory AML patient blasts, ORM-6151 similarly showed picomolar cytotoxicity, outperforming both CC-90009 and Mylotarg.
• ✅ In multiple in vivo disseminated xenograft models, a single administration at doses as low as 0.1 mg/kg produced robust and durable anti-tumor activity. [2]

Commercialization & Partnerships

In November 2023, Bristol-Myers Squibb (BMS) acquired ORM-6151 from Orum Therapeutics in a deal that included a US$100 million upfront payment and a milestone payment for a total deal value of $180 million. [3]

In July 2024, Orum entered a multi-target collaboration with Vertex Pharmaceuticals. Under this agreement, Vertex made a US$15 million upfront payment and holds development options for up to three DACs based on Orum’s TPD²® platform. The collaboration could total up to US$945 million in options and milestone payments, plus royalties. [4]

ORM-5029

Developer: Orum Therapeutics

ORM-5029 is a first-in-class HER2-targeted Antibody–neoDegrader Conjugate (AnDC™) engineered to deliver the potent GSPT1 degrader SMol006 directly to HER2-expressing tumor cells. It utilizes the clinically validated anti-HER2 antibody pertuzumab linked to SMol006 via Orum’s proprietary conjugation technology. Upon internalization, SMol006 is released to induce selective proteasomal degradation of GSPT1, a translation termination factor essential for tumor cell survival.

Preclinical Efficacy

• ✅ In multiple HER2-expressing models, ORM-5029 demonstrated potent in vitro and in vivo efficacy, with comparable anti-tumor activity to trastuzumab deruxtecan (Enhertu®) and superior activity in trastuzumab emtansine (Kadcyla®)-refractory models.
• ✅ In the BT-474 breast cancer xenograft model, a single 3 mg/kg dose achieved complete tumor regression, exceeding the efficacy of both Kadcyla and Enhertu. [5]

Clinical Development

In August 2022, ORM-5029 entered a Phase I clinical trial for advanced solid tumors, becoming the first molecular glue ADC to enter clinical testing.

On April 28, 2025, Orum Therapeutics announced a strategic portfolio realignment, discontinuing development of ORM-5029 to prioritize newer molecular glue ADC candidates, ORM-1153, in development for the treatment of hematologic malignancies.[6]

ABBV-787

Developer: AbbVie

ABBV-787 was an investigational ADC incorporating a degrader-based payload, representing AbbVie’s strategic push into next-generation targeted oncology therapeutics. The candidate was designed for the treatment of Acute Myeloid Leukemia (AML), leveraging a targeted antibody to deliver a proteolysis-inducing payload directly to AML cells, with the goal of improving efficacy while reducing off-target toxicity.

Clinical Development

In 2023, ABBV-787 entered Phase I clinical evaluation (NCT06068868) in patients with relapsed/refractory AML (second-line or later) across multiple regions, including the USA, South Korea, Japan, Israel, and Australia.

In 2025, AbbVie terminated the Phase I trial due to strategic considerations, discontinuing further development of ABBV-787. [7]

Outlook

DACs, which combine the precise delivery of ADCs with the event-driven degradation mechanism of PROTACs, are an innovative new class of drugs. They hold significant promise for targeting previously "undruggable" proteins, overcoming drug resistance, and minimizing off-target toxicity.

While there are still technical hurdles to overcome—like stability issues caused by high DAR, linker optimization, and payload chemical modifications—advances in molecular design and delivery technology could make DACs the next generation of blockbuster ADCs.
 

References:
[1] Guo, Y., Li, X., Xie, Y., & Wang, Y. (2024). What influences the activity of Degrader−Antibody conjugates (DACs). European Journal of Medicinal Chemistry, 268, 116216. https://doi.org/10.1016/j.ejmech.2024.116216
[2] https://aacrjournals.org/cancerres/article/83/7_Supplement/2700/722771/Abstract-2700-ORM-6151-A-first-in-class-CD33 Abstract 2700: ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML
[3] https://www.orumrx.com/news/orum-orm-6151-acquisition-by-bms Orum Therapeutics Announces Acquisition of ORM-6151 Program by Bristol Myers Squib
[4] https://www.adcreview.com/business-economics/south-korea-and-china-stand-at-forefront-of-degrader-antibody-conjugate-development-in-oncology-and-hematology/ South Korea and China Stand at forefront of Degrader antibody-conjugate Development in Oncology and Hematology
[5] https://aacrjournals.org/cancerres/article/82/12_Supplement/3933/703288/Abstract-3933-ORM-5029-A-first-in-class-targeted Abstract 3933: ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer
[6] https://www.orumrx.com/news/orum-therapeutics-provides-program-update-and-announces-drug-candidate-nomination Orum Therapeutics Provides Program Update and Announces Drug Candidate Nomination
[7] https://www.abbvieclinicaltrials.com/study/?id=M23-477 Study to Evaluate Adverse Events and Movement of Intravenously (IV) Infused ABBV-787 in Adult Participants With Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)