Degrader–antibody conjugates (DACs), including proteolysis-targeting chimeras (PROTACs) and molecular glue–based platforms, represent a paradigm shift from traditional cytotoxic antibody-drug conjugates (ADCs) in oncology. By leveraging antibody-mediated targeting with selective protein degradation, DACs promise both efficacy and specificity. However, these innovative modalities introduce a distinct and complex safety profile that requires careful consideration. This review summarizes the mechanistic advances, therapeutic potential, and emerging safety challenges of DAC technology, and highlights critical factors for their development and clinical translation.[1][2]
Traditional ADCs have delivered cytotoxic payloads—often tubulin or topoisomerase inhibitors—directly to antigen-positive tumor cells, providing targeted cell killing while limiting off-target effects. However, the emergence of DACs, particularly those based on PROTACs and molecular glues, has introduced a new therapeutic strategy: harnessing targeted protein degradation rather than inhibition. This approach holds significant potential to expand the druggable proteome, overcome resistance, and improve the therapeutic index in oncology and beyond.
Mechanistic Overview: From ADCs to DACs
Despite their clinical success, ADCs face several critical limitations, including: (a) premature release of the cytotoxic payload into systemic circulation due to linker degradation, resulting in toxicity to healthy tissues; (b) formation of albumin-linker-payload complexes that may contribute to off-target effects; (c) unintended uptake and toxicity in non-tumor cells, such as macrophages, via Fcγ receptor-mediated internalization; (d) inadequate localization of antibodies at the tumor site; and (e) slow or limited internalization by tumor cells, which restricts effective payload delivery and diminishes therapeutic efficacy.[3][4]
While some strategies have sought to inhibit ADC internalization to maximize immune-mediated cytotoxicity, optimal payload release typically requires successful internalization and subsequent degradation within the target cell. In practice, only a small fraction of ADCs reach and are internalized by tumor cells, significantly limiting their therapeutic impact. To address these challenges, novel approaches—such as combining ADCs with PROTACs—are being investigated. PROTACs can enhance internalization and cytotoxicity by promoting proteasomal degradation of target proteins and improving the intracellular delivery and release of cytotoxic agents.[3]
Importantly, binding of ADCs to cell-surface targets does not guarantee internalization. Recent research suggests that PROTACs can facilitate forced internalization of antibodies or their conjugates when both target the same oncogenic cell-surface proteins (e.g., EGFR, HER2, or MET), thereby enhancing cytotoxicity, as shown with HER2-targeting ADCs.[3]
A new class of biotherapeutics—degrader-antibody conjugates (DACs)—conjugates a protein degrader, such as a PROTAC or molecular glue, to a monoclonal antibody via a cleavable linker. Upon binding to antigen-expressing tumor cells, DACs are internalized and release the degrader payload, inducing ubiquitin-dependent proteasomal degradation of selected target proteins. This mechanism enables the elimination of oncogenic drivers previously considered ‘undruggable,’ while also providing modularity for rational design and therapeutic optimization.[5][6][7]
The versatility of PROTACs and molecular glues lies in their ability to recruit various E3 ligases (e.g., VHL, CRBN) and degrade multiple protein targets, as demonstrated by several DACs in preclinical and patent literature. Promising clinical data—such as with vepdegestrant (Veppanu®; Rigel Pharmaceuticals, formerly ARV-471) in estrogen receptor–positive cancers—further validate this approach.[1]
Therapeutic Potential Beyond Oncology
While the primary focus of DAC development has been oncology, the scope of PROTAC technology extends to viral infections (HIV, COVID-19), neurodegenerative diseases (Alzheimer’s, Huntington’s), and chronic inflammatory disorders (atherosclerosis, atopic dermatitis). Newer generations of PROTACs, such as TF-PROTACs and PhosphoTACs, are designed to enhance pharmacokinetic stability and cellular permeability, broadening their therapeutic applicability.
A New Safety Paradigm
Unlike cytotoxic ADCs, where the main concern is collateral cell death from off-target cytotoxicity, DACs introduce new and distinct safety challenges, including: [8]
- On-target/off-tumor degradation: Low-level antigen expression in normal tissues can lead to the delivery of active degraders and depletion of essential proteins, risking toxicity in healthy cells.
- Off-target protein degradation: PROTACs and molecular glues may degrade unintended proteins, necessitating comprehensive, unbiased proteomic profiling to predict and monitor adverse effects.
- Free degrader exposure: Premature linker cleavage or systemic catabolism may release active degrader into circulation, causing antigen-independent toxicity.
- Bone marrow and gastrointestinal toxicity: Especially concerning for molecular glues targeting essential proteins (e.g., GSPT1, IKZF family, CK1α), where depletion in proliferative tissues can lead to dose-limiting toxicities.
- FcγR-mediated immune-cell uptake: Macrophages, monocytes, Kupffer cells, and dendritic cells may internalize DACs via Fcγ receptors, inadvertently exposing immune cells to the protein degrader.
- Species-translation uncertainty: Toxicology profiles in animal models may not reliably predict human risk due to interspecies differences in E3 ligase expression, neosubstrate profiles, and degradation selectivity.
Additional challenges for PROTAC-ADCs include payload size, hydrophobicity, lysosomal escape, ternary complex formation, and potential ‘hook effects‘ at high concentrations. While molecular glue–based DACs may offer improved payload properties, they can carry a higher risk of systemic toxicity if free glue is released, owing to their potential for broad neosubstrate degradation. [2]
Key Considerations for Clinical Translation
Given these safety risks, the successful clinical development of DACs hinges on more than achieving ADC-like exposure and tumor targeting. The critical biomarker for DACs is not simply plasma pharmacokinetics, but the demonstration of controlled, selective, tumor-restricted protein degradation. Rational design (including antibody selection, linker chemistry, and degrader optimization), robust target validation, and comprehensive preclinical safety assessment—including unbiased proteomics—are essential.
The modular nature of PROTACs enables systematic optimization and logical design, informed by computational modeling and structure–activity relationships. Comparative studies with other targeted protein degraders, such as LYTACs and AUTOTACs, are crucial for contextualizing DACs within the broader field of targeted protein degradation.
Conclusion
DACs represent a transformative advance in targeted therapy, with the potential to expand the druggable proteome and overcome resistance mechanisms. While the clinical promise is substantial, the unique safety challenges posed by selective protein degradation demand a new paradigm in preclinical evaluation and patient monitoring.
Ultimately, the ‘winners’ in this space will be those who achieve not only effective delivery and exposure, but also precise, tumor-restricted protein degradation with minimal off-tumor effects. The future of DACs, particularly in oncology, will depend on innovative solutions to these safety challenges—and on the continued integration of mechanistic insight, technological advances, and clinical rigor.
__
Note: This review provides a comprehensive overview of the promise and challenges of DACs and will serve as a resource for clinicians, translational researchers, and drug developers navigating this rapidly evolving field. This article is part of a series: The Magic Bullet, Realized – Antibody-drug Conjugates in Modern Oncology
Clinical trials
A Study to Learn About a New Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People Who Have Advanced Metastatic Breast Cancer (VERITAC-2) – ClinicalTrials.gov ID NCT05654623
Highlights of Prescribing Information
Vepdegestrant (Veppanu®; Rigel Pharmaceuticals) [Prescribing Information]
Reference
[1] Hofland P. Vepdegestrant: The First FDA-Approved PROTAC for ESR1-Mutated, ER+/HER2− Advanced Breast Cancer. May 20, 2026. Onco’Zine. Online. Last accessed on May 21, 2026.
[2] Gao H, Sun X, Rao Y. PROTAC Technology: Opportunities and Challenges. ACS Med Chem Lett. 2020 Mar 12;11(3):237-240. doi: 10.1021/acsmedchemlett.9b00597. PMID: 32184950; PMCID: PMC7073876.
[3] Tolosa EJ, Yang L, Ayers-Ringler J, Suzuki S, Mallareddy JR, Schaefer-Klein J, Borad M, Kosari F, Natarajan A, Mansfield AS. Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors. Commun Biol. 2024 Dec 31;7(1):1719. doi: 10.1038/s42003-024-07439-0. PMID: 39741170; PMCID: PMC11688428.
[4] 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.
[5] Poudel YB, Thakore RR, Chekler EP. The New Frontier: Merging Molecular Glue Degrader and Antibody-Drug Conjugate Modalities To Overcome Strategic Challenges. J Med Chem. 2024 Sep 26;67(18):15996-16001. doi: 10.1021/acs.jmedchem.4c01289. Epub 2024 Sep 4. Erratum in: J Med Chem. 2024 Nov 14;67(21):19925. doi: 10.1021/acs.jmedchem.4c02447. PMID: 39231796.
[6] Guo Y, Li X, Xie Y, Wang Y. What influences the activity of Degrader-Antibody conjugates (DACs). Eur J Med Chem. 2024 Mar 15;268:116216. doi: 10.1016/j.ejmech.2024.116216. Epub 2024 Feb 3. PMID: 38387330.
[7] Dragovich PS. Degrader-antibody conjugates. Chem Soc Rev. 2022 May 23;51(10):3886-3897. doi: 10.1039/d2cs00141a. PMID: 35506708.
[8] Zhou X, Han Y, Fang Y, Ma P, Zhou J, Jiang Y, Xing S, Tang Q, Hou Y, Wang S, Li N. Antibody-drug conjugates: Current challenges and innovative solutions for precision cancer therapy. Med. 2025 Oct 10;6(10):100849. doi: 10.1016/j.medj.2025.100849. Epub 2025 Sep 30. PMID: 41033317.
Featured image: © 2022 Unsplash. Used with permission.
DOI
