Antibody-Drug Conjugates (ADCs) are assembled through chemical conjugation of three components: antibody, linker, and payload.
Over the past two decades, systematic progress has been achieved in antibody target selection, linker stability and release mechanisms, and homogeneity control of the drug-to-antibody ratio (DAR). Third-generation ADCs have already rewritten treatment standards across multiple solid tumor types.
However, when it comes to the payload—the core component that determines ADC efficacy and safety—its mechanism of action has long been confined to the single paradigm of "cytotoxic killing." From early microtubule inhibitors to recent topoisomerase I inhibitors, the evolution of payloads across generations has essentially been about "more potent and more controllable cytotoxins" rather than a fundamental change in mechanism of action.
In recent years, with the maturation of targeted protein degradation (TPD) technology, a novel class of conjugates featuring protein degraders as payloads—Degrader-Antibody Conjugates (DACs) and Molecular Glue-Antibody Conjugates (MACs)—have begun entering preclinical and early-stage clinical studies. The payloads of these conjugates no longer directly kill cells but instead hijack the intracellular ubiquitin-proteasome system to degrade specific disease-causing proteins, marking a paradigm shift in ADC payloads from "cytotoxicity" to "functionality."
This article systematically reviews the conceptual definition of functional payloads, the mechanistic basis for integrating TPD with antibody delivery, the molecular design and pharmacological characteristics of DAC/MAC, available preclinical and clinical evidence, as well as the global and Chinese R&D landscape, while also discussing the key challenges they face.
I. Overview: The Evolution of ADC Payloads and the Emergence of "Functional Payloads"
1.1 Classification and Evolution of ADC Payloads
The cytotoxic payloads employed by currently approved and investigational ADCs can be divided into three main categories.
Microtubule inhibitors: These interfere with tubulin polymerization/depolymerization, blocking mitosis. Representative payloads include monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and the maytansine derivatives DM1 and DM4. The potency of these payloads typically ranges from picomolar to nanomolar (pM–nM) levels, acting primarily on dividing cells.
DNA-damaging agents: These include pyrrolobenzodiazepine (PBD) dimers, duocarmycin, and other DNA minor-groove binders or crosslinkers. These payloads are extremely potent but have relatively narrow therapeutic windows.
Topoisomerase I inhibitors: These stabilize the topoisomerase I-DNA complex, inducing DNA double-strand breaks. Representative payloads include the exatecan derivative DXd (used in trastuzumab deruxtecan, among others) and SN-38 (used in sacituzumab govitecan). These payloads are the hallmark of third-generation ADCs, with their relatively moderate potency combined with high DAR and strong bystander effects broadening the therapeutic window.
The three core pharmacological parameters for evaluating ADC payloads are: potency (characterized by IC₅₀, typically at the pM–nM level), lipophilicity and membrane permeability (determining whether free payloads can cross cell membranes to produce bystander effects), and cell-cycle dependence (determining efficacy against low-proliferation tumors).
1.2 Inherent Limitations of Traditional Cytotoxic Payloads
Despite continued engineering optimization of cytotoxic payloads, inherent limitations at the mechanism-of-action level persist:
Advantages: Well-established mechanisms of action, high potency, and sufficient clinical validation, having supported over a dozen ADCs to market approval.
Limitations: First, dose-limiting toxicity (DLT)—the toxicity of most cytotoxic payloads is independent of target antigen expression, retaining potent killing even when off-target. Second, acquired resistance—tumors can develop resistance by upregulating drug efflux pumps (such as P-glycoprotein) or activating anti-apoptotic pathways. Third, limited efficacy against low-proliferation tumors—payloads that depend on the cell division cycle struggle to kill tumor cells in a quiescent state. Fourth, constrained target space—cytotoxic payloads can only act on their molecular targets (microtubules, DNA, topoisomerases) and cannot target tumor-driving signaling proteins.
1.3 Defining "Functional Payloads"
In response to the above limitations, a class of payloads that act through non-cytotoxic mechanisms has gradually gained attention, collectively referred to as functional payloads. They are defined as payloads whose mechanism of action is no longer direct cytotoxic killing, but rather exert anti-tumor effects through protein degradation, immune activation, or signaling pathway modulation. Based on mechanism, they can be divided into several categories:
Targeted protein degraders: PROTACs or molecular glues that induce degradation of disease-causing proteins (the focus of this article);
Immunostimulants: Toll-like receptor (TLR7/8) agonists and STING agonists that act by activating innate immunity in the tumor microenvironment;
Apoptosis/signaling modulators: Such as Bcl-xL inhibitors, which have shown synergistic efficacy in combination with genotoxic ADCs in metastatic castration-resistant prostate cancer (mCRPC) models;
Immunomodulators: Such as glucocorticoid receptor modulators, primarily applied in antibody conjugates for the immunology and inflammation (I&I) space.
Among the various categories of functional payloads, targeted protein degraders—owing to their well-defined mechanisms, ability to act on traditionally "undruggable" targets, and the fact that multiple assets have entered the clinic—have become the most deeply investigated class and are the core focus of this article.
II. Mechanistic Basis for Integrating Targeted Protein Degradation with Antibody Delivery
2.1 Overview of Targeted Protein Degradation (TPD) Mechanisms
Targeted protein degradation recruits intracellular E3 ubiquitin ligases to induce polyubiquitination of the target protein, followed by recognition and degradation by the 26S proteasome. The two main technology classes are:
PROTAC (Proteolysis-Targeting Chimera): A class of heterobifunctional small molecules composed of three parts—a target protein ligand, a linker, and an E3 ubiquitin ligase ligand. The PROTAC simultaneously binds the target protein and an E3 ligase (most commonly CRBN or VHL), forming a "target protein–PROTAC–E3" ternary complex that promotes ubiquitination and degradation of the target protein.
Molecular glue: A class of monovalent small molecules that do not themselves possess two binding domains. Instead, they modify the surface of an E3 ligase (mostly CRBN), inducing it to recruit neo-substrates that it would not otherwise bind. The classic example is thalidomide analogs (such as lenalidomide) inducing CRBN to degrade IKZF1/3.
Two key pharmacological features distinguish the TPD mechanism from traditional inhibitors: First, catalytic (event-driven) activity—a single degrader molecule can mediate the degradation of multiple copies of the target protein, acting in a sub-stoichiometric manner, theoretically achieving sufficient pharmacological effect at relatively low exposure. Second, expanded target space—the degradation mechanism does not depend on occupying the active site of the target protein, thus enabling action on "undruggable" targets lacking enzymatic pockets, such as transcription factors and scaffold proteins.
2.2 Druggability Bottlenecks of Free Degraders
Despite the advantages of the TPD mechanism, free (unconjugated) degraders face significant druggability bottlenecks under systemic administration:
PROTACs typically have large molecular weights (often exceeding 700–1000 Da) and high hydrophobicity, resulting in poor oral bioavailability and pharmacokinetic (PK) profiles;
Degraders lack tissue selectivity, and under systemic administration, degradation can occur in both normal and tumor tissues, limiting the therapeutic window;
Some degradation targets (such as GSPT1) also have dependencies in normal hematopoietic cells, further narrowing the safety window.
This bottleneck has clinical corroboration: the clinical trial of the GSPT1-targeting molecular glue degrader CC-90009 was terminated due to lack of efficacy in the short-term acute phase; concurrently, clinical development of the dual degrader BTX-1188, targeting both GSPT1 and IKZF1/3, was also discontinued. GSPT1 (G1-to-S phase transition protein, a GTPase involved in translation termination) as a degradation target has potent apoptosis-inducing potential, but free degraders struggle to balance efficacy and safety.
2.3 The Rationale for Antibody Delivery
The core logic of conjugating degraders as payloads to antibodies lies in using antibody-mediated targeted delivery to compensate for the two major deficiencies of free degraders: first, achieving selective delivery to tumors/specific cells through antigen-specific recognition, thereby broadening the therapeutic window; second, leveraging the favorable PK characteristics of antibodies to improve the in vivo exposure and distribution of degraders. In other words, DAC/MAC attempts to combine the mechanistic advantages of TPD (catalytic activity, expanded target space) with the delivery advantages of ADCs (targeting, favorable PK).
This integration serves as the foundational rationale for DAC/MAC technology—but whether it can deliver a meaningful broadening of the therapeutic window in humans remains to be clinically validated (see Sections V and VII).
III. Molecular Design and Conjugation Engineering of DAC/MAC
3.1 Terminology and Classification
Based on the type of degrader payload employed, these conjugates can be divided into two categories:
It should be noted that in the literature, the term "DAC" is sometimes used broadly (covering both PROTAC-type and molecular glue-type) and sometimes specifically for PROTAC-type. This article uses DAC and MAC separately when distinction is needed, and uses the general term "degrader conjugates" when referring to the technology class broadly.
3.2 Engineering Comparison of the Two Approaches
PROTAC-type (DAC)
Advantages: Possesses catalytic degradation capability; theoretically achieves higher degradation selectivity through dual specificity of the target protein ligand and E3 ligand.
Limitations: PROTACs have large molecular weights and strong hydrophobicity, which, upon conjugation, tend to exacerbate overall molecular hydrophobicity, thereby affecting conjugation homogeneity, stability, and aggregation tendency; their chemical synthesis and process scale-up (CMC) present greater difficulty; and as payloads, they impose more stringent requirements on linker design and conjugation sites.
Molecular glue-type (MAC)
Advantages: Molecular glues are monovalent small molecules with lower molecular weight and hydrophobicity than PROTACs, with physicochemical properties closer to traditional cytotoxic payloads, making conjugation processes relatively more controllable; druggability and homogeneity are more readily achievable.
Limitations: The neo-substrate spectrum of molecular glues is relatively restricted, mostly dependent on CRBN; they exhibit dependence on CRBN expression levels and may develop resistance through CRBN pathway mutations.
3.3 Key Parameters in Conjugation Chemistry
The conjugation engineering of DAC/MAC must balance multiple parameters:
Linker: Cleavable linkers (enzyme-sensitive, acid-sensitive, reduction-sensitive) facilitate intracellular release of free degraders and may enable "bystander" effects; non-cleavable linkers offer higher plasma stability, but the released degrader-linker residues may affect the ability to bind E3. The released form of the degrader payload must retain its ability to form ternary complexes or induce neo-substrate recruitment, imposing additional constraints on linker design beyond those for cytotoxic payloads.
DAR and Hydrophobicity: The high hydrophobicity of degraders (especially PROTACs) makes higher DAR more likely to trigger aggregation, reduced stability, and accelerated clearance. Therefore, conjugation techniques (such as hydrophilic linkers and site-specific conjugation) are particularly critical for maintaining favorable PK profiles.
Site-specific conjugation: Facilitates obtaining homogeneous DAR distribution, improving batch-to-batch consistency and therapeutic window.
IV. Mechanism of Action and Pharmacological Characteristics
4.1 Intracellular Delivery—The Degradation Pipeline
The mechanism of action of DAC/MAC can be summarized as a pipeline similar to traditional ADCs in the early stages but diverging thereafter: antibody recognizes and binds to tumor cell surface antigens → antigen-conjugate complex enters cells via receptor-mediated internalization → linker cleavage releases free degrader in lysosomes or the cytosol → degrader recruits E3 ubiquitin ligase (CRBN or VHL) and forms ternary complex with the target protein or induces neo-substrate recruitment → target protein undergoes polyubiquitination → degraded by the 26S proteasome.
Unlike traditional ADCs, which induce apoptosis through microtubule disruption or DNA damage within cells, the terminal effect of DAC/MAC is the elimination of specific proteins, with downstream biological consequences depending on the functional status of the degraded target protein in the tumor.
4.2 Mechanistic Differences from Traditional ADCs
From stoichiometric killing to catalytic degradation: Cytotoxic payloads must accumulate to a certain threshold within cells to induce apoptosis; degraders can theoretically catalytically degrade multiple copies of the target protein, acting in an event-driven manner.
Expanded target space: The degradation mechanism can act on intracellular non-enzymatic targets (transcription factors, scaffold proteins, etc.), which are typically difficult to directly target with small-molecule inhibitors or antibodies.
Potential resistance evasion: The degradation mechanism does not depend on sustained occupancy of the active site, theoretically potentially circumventing certain resistance mechanisms based on site mutations—though this point requires further evidence.
4.3 Bystander Degradation
In cytotoxic ADCs, the use of cleavable linkers with membrane-permeable payloads enables a "bystander effect"—the released free payload diffuses to neighboring cells and exerts killing, which is significant for solid tumors with heterogeneous target antigen expression. For DAC/MAC, a "bystander degradation" effect is theoretically possible—the released free degrader diffuses to neighboring cells and degrades its target protein.
However, compared to bystander killing, bystander degradation requires the free degrader to maintain sufficient concentration in neighboring cells and complete ternary complex formation. The transcellular evidence is currently relatively limited, and the conditions and boundaries require further investigation.
V. Preclinical and Clinical Evidence
5.1 Proof-of-Concept (Preclinical)
Multiple preclinical studies have provided proof-of-concept for the feasibility of DAC/MAC:
ROR1-targeted BRD4 degrader conjugate: A BRD4-degrading PROTAC conjugated to an anti-ROR1 antibody demonstrated improved PK profiles and stronger anti-tumor activity compared to free PROTAC, and promoted BRD4 degradation in solid tumor models.
CEACAM6-targeted BET degrader conjugate: A BET protein degrader delivered via an anti-CEACAM6 antibody as the payload inhibited tumor growth in pancreatic cancer models.
Molecular glue conjugate (c-Myc degradation): A group has designed a series of MACs based on CRBN molecular glues targeting c-Myc for degradation, demonstrating anti-tumor activity in animal models.
Collectively, these studies indicate that antibody delivery can improve the PK and targeting of degraders at the preclinical level, achieving degradation of target proteins.
5.2 Assets Entering the Clinic
In terms of clinical progress, GSPT1-targeting molecular glue conjugates represent the first MACs to enter the clinic. Among them, ORM-5029 (targeting HER2, delivering a GSPT1 degrader payload) and ORM-6151 (targeting CD33, for acute myeloid leukemia, AML) are among the earliest clinical-stage assets in this field.
It should be objectively noted that clinical readouts from these early-stage assets remain limited, and some trial statuses have undergone adjustments (for instance, the solid tumor clinical trial associated with ORM-5029 experienced termination). Additionally, assets originating from industry collaborations (such as BMS-986497) have entered early-stage human trials for AML and high-risk myelodysplastic syndromes (MDS). Overall, clinical data for DAC/MAC are still in their infancy.
VI. Global and Chinese R&D Landscape
6.1 Global Stage Distribution
Overall, the DAC/MAC sector is at a very early stage. According to industry analysis, the total number of assets under development globally is in the dozens, with only single-digit numbers having entered clinical stages; the majority remain in discovery or preclinical phases. This stage distribution indicates that the field has not yet established a stable competitive landscape, with technical approaches and target combinations still under extensive exploration.
6.2 Key Players
Orum Therapeutics, represented by its Dual-Precision Targeted Protein Degradation (TPD²) platform, combines GSPT1 molecular glue degraders with antibody delivery. Its pipeline includes ORM-5029 (HER2), ORM-6151 (CD33), and ORM-1153 (CD123, targeting AML), with collaborations established with multinational pharmaceutical companies (such as BMS and Vertex; assets from the BMS collaboration have entered early-stage human trials). Firefly Bio emerged from stealth mode in 2024, focusing on degrader-antibody conjugate development.
In addition, recent progress from two other players merits attention: C4 Therapeutics is entering the DAC space through its TORPEDO® degrader platform—its DAC collaboration with Merck terminated in November 2025, but in April 2026 it reached a new DAC collaboration with Roche (an upfront payment of approximately $20 million and milestones exceeding $1 billion, covering two oncology targets with an option for a third), with C4 responsible for degrader payloads and the partner responsible for antibody conjugation and subsequent development. Cullgen was acquired by Gyre Therapeutics in May 2026 in an all-stock transaction valued at approximately $300 million, forming a U.S.-China integrated company. Its clinical asset is the GSPT1 degrader CG009301 (Phase I for hematological malignancies), with DAC positioned as a next-generation preclinical platform.
Furthermore, Nurix Therapeutics (San Francisco, Nasdaq: NRIX), in addition to its core oral degrader programs (such as the BTK degrader Bexobrutideg and CBL-B inhibitors), is developing a portfolio of degrader-antibody conjugates through a strategic collaboration with Seagen (now part of Pfizer), with the relevant DAC projects at the preclinical stage. Overall, the leading participants in this field remain early-stage biotech companies focused on TPD and conjugation technologies, with multinational pharmaceutical companies such as Roche, BMS, Vertex, and Pfizer predominantly positioning themselves through collaborative arrangements.
6.3 Early-stage Landscape in China
It is noteworthy that China's positioning in the DAC/MAC space ranks among the forefront globally, with approximately nine DAC/MAC assets currently in R&D pipelines. Among them, Gluetacs (a portfolio company of Efung Capital), leveraging its GlueTacs molecular glue/bifunctional degrader platform, has further expanded into the DAC direction alongside its oral degrader pipeline (with the IKZF3 degrader GT919 already in the clinic), possessing dual capabilities in "small-molecule degraders + antibody delivery." Additionally, Medilink/Kintor Pharmaceutical is developing molecular glue-antibody conjugates (targeting c-Myc for degradation, among others), while Shanghai Haisen and other teams are pursuing degrader conjugates targeting IKZF1/3, among others.
A common misconception warrants correction: China is not a blank slate in this field, but rather is in a state of "early but already positioning"—although most assets remain in discovery or preclinical phases, the starting point is largely synchronized with the global frontier.
6.4 Industry Collaborations
The emergence of large-scale industry collaborations and financings at such an early stage reflects the strategic positioning intentions of multinational pharmaceutical companies in the "functional payload" direction. Such transactions are predominantly aimed at platform capabilities or early-stage assets, demonstrating strategic attention to next-generation payload technologies rather than a pursuit of mature clinical data.
VII. Key Challenges and Open Questions
As an early-stage technology, the translation and implementation of DAC/MAC face multiple challenges, discussed individually below:
CMC and Druggability: The high molecular weight and hydrophobicity of degraders (especially PROTACs) pose challenges to conjugation homogeneity, stability, and aggregation control, with process scale-up being more difficult than for traditional cytotoxic ADCs.
Scarcity of Clinical Evidence: Currently, human data are extremely limited, and the advantages of DAC/MAC over free degraders in terms of therapeutic window lack sufficient clinical confirmation.
Inherent Risks of Degraders: Including off-target degradation, neo-substrate-related toxicity, and potential resistance mediated by CRBN pathway dependence.
Constraints in Target Selection: DAC/MAC require the simultaneous fulfillment of two conditions—"a surface antigen with favorable internalization properties" and "an intracellular degradable disease-causing target"—resulting in relatively limited pairing options that meet this combination.
Conditions for Bystander Degradation: The mechanistic hypothesis requires more robust evidence, with boundaries and applicable scenarios yet to be clarified.
Window Issues of Degradation Targets Themselves: The dependence of targets such as GSPT1 in normal cells may limit their safety window, and whether antibody delivery can adequately mitigate this remains to be verified.
VIII. Summary
The technological advancement of ADCs is extending from optimization of antibodies, linkers, and DAR to diversification of payload mechanisms of action. DAC/MAC, which integrates targeted protein degradation with antibody delivery, represents the most mechanistically well-defined class within the "functional payload" direction: it attempts to combine the catalytic and expanded-target-space advantages of targeted protein degradation with the targeted delivery and PK advantages of antibody conjugation, thereby enabling degraders to overcome the druggability bottlenecks of free administration.
However, this technology is currently in its early validation stage overall, with limited clinical data. Whether it can convert the therapeutic window issues of free degraders into acceptable human safety profiles and meaningful clinical benefit remains a core unresolved question.
From an industry and investment perspective: this sector is at a very early stage, with single-asset clinical and technical risks being relatively high. By comparison, platform capabilities—including the depth of proprietary degrader/molecular glue libraries, the maturity of conjugation and linker technologies, and the differentiation of target-degrader pairing—offer greater evaluative value than single pipelines.
As for China specifically, the existing capabilities in antibody engineering, the conjugation/CDMO supply chain, and small-molecule degrader research provide a foundation for early participation in this field, with the starting point largely synchronized with the global frontier. At the same time, due attention must be paid to the prior clinical failure history of high-profile degradation targets (such as GSPT1), avoiding blind followership of any single payload modality.
Overall, DAC/MAC represents an important direction in the evolution of ADC payloads from "cytotoxic killing" toward "functional modulation." The ultimate validation of its technical value depends on the accumulation of human efficacy and safety data over the coming years.
References
Molecular glue meets antibody: next-generation antibody–drug conjugates. ScienceDirect (Drug Discovery Today series), 2025.
Merging Molecular Glue Degrader and Antibody-Drug Conjugate Modalities to Overcome Strategic Challenges. Journal of Medicinal Chemistry, 2024. PMID: 39231796.
A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment. PMC11729552.
Delivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models. PMC10928091.
Cancer Biology of GSPT1: Mechanisms and Targeted Therapy Opportunities of Molecular Glue Degraders. PMC12713026.
Orum Therapeutics corporate disclosures and conference data (TPD² platform; ORM-5029/ORM-6151/ORM-1153; BMS-986497).
Biopharma PEG. Molecular Glue Degraders in Clinical Trials: 2026 Update; Molecular Glue-Antibody Conjugates (MACs) review.
South Korea and China Stand at the Forefront of Degrader Antibody-Conjugate Development in Oncology and Hematology. ADC Review, 2025.
Note: The preclinical and clinical progress and pipeline information cited in this article are derived from the above public sources. The trial status of some early-stage assets may be updated as R&D progresses; please refer to the latest disclosures from regulatory agencies and the companies themselves. This article does not contain unverified NCT numbers or DOIs.