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Review

Antibody–Drug Conjugates: Pharmacotherapeutic Properties and Future Perspectives

by
André Augusto
1,2,3,
Maria L. S. Cristiano
1,2 and
Jaime Conceição
1,3,4,*
1
Faculty of Sciences and Technology, Universidade do Algarve, 8005-139 Faro, Portugal
2
Centre for Marine Sciences (CCMAR), Universidade do Algarve, 8005-139 Faro, Portugal
3
Algarve Biomedical Centre Research Institute (ABC-Ri), Universidade do Algarve, 8005-139 Faro, Portugal
4
Centre for Interdisciplinary Studies (CEIS20), Universidade de Coimbra, 3000-457 Coimbra, Portugal
*
Author to whom correspondence should be addressed.
Pharmaceutics 2026, 18(4), 468; https://doi.org/10.3390/pharmaceutics18040468
Submission received: 5 March 2026 / Revised: 7 April 2026 / Accepted: 9 April 2026 / Published: 12 April 2026
(This article belongs to the Special Issue Antibody–Drug Conjugates Therapeutics)
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Abstract

Background: The clinical landscape for antibody–drug conjugates (ADCs) is currently experiencing an unprecedented expansion, with more than 20 agents approved to date and hundreds presently under clinical evaluation, underscoring their growing impact in precision oncology. By combining the cytotoxic potency of chemotherapy with the selectivity of monoclonal antibodies, ADCs have redefined targeted cancer therapy. Nevertheless, challenges related to toxicity, resistance, and suboptimal drug delivery continue to limit their full clinical potential. Objectives: This review provides a comprehensive description of currently approved ADCs, with a particular focus on their pharmacotherapeutic properties, mechanisms of action, therapeutic indications, and safety profiles. By integrating currently available clinical data and pharmacological properties, it is possible to identify key translational gaps between ADC design and their real-world performance. This article also evaluates how the structural components contribute to both efficacy and toxicity of ADCs, offering a framework for rational molecular optimizations. Conclusions: Beyond the current oncology-centric paradigm, this review highlights the imminent pivot toward non-oncology applications, including targeted therapies for autoimmune, infectious, and neurodegenerative diseases. Importantly, this article highlights emerging innovations shaping the next generation of ADCs, including bispecific antibodies, novel cytotoxic payloads with improved therapeutic indices, and advanced linker technologies enabling more precise payload release. Despite current limitations, ongoing advances in ADC development, along with a rapidly expanding clinical pipeline, position these drugs in a dynamic therapeutic class with the potential to transform multiple complex diseases and improve the quality of life of patients who have them.

Graphical Abstract

1. Introduction

Cancer remains one of the most devastating diseases worldwide, not only because of its high mortality and morbidity, but also due to the emotional and financial burdens it places on patients, families, and healthcare systems. Although major advances have been made in cancer research, current treatments are mostly ineffective, leading to poor prognosis and disease management. In addition, they are frequently associated with significant undesirable effects that further reduce the quality of life of patients and entail high costs due to drug pricing and the need for repeated administrations [1,2]. Over the years, new cancer therapies have been developed to address the limitations of existing treatments. For example, targeted therapies with antibody–drug conjugates (ADCs) emerged as an innovative way of delivering highly cytotoxic agents, also known as payloads, by taking advantage of the selectivity of certain antibodies to specific receptors that are overly expressed on the surface of cancer cells when compared to their healthy counterparts [3,4]. Although this approach to targeted therapies was first conceptualized in the 60s, based on the “magic bullet” concept of Paul Ehrlich, it was only during the year 2000 that the first ADC (gemtuzumab ozogamicin) obtained its market approval for clinical use [5]. Structurally, ADCs are composed of three main components [6]: (i) an antibody moiety responsible for directing the ADC to the targeted cells, promoting the internalization of the ADC upon interacting with its complementary cell surface receptor or, if not internalized, stimulating the activation of the immune system via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC); (ii) a certain number of payloads (commonly between two to eight) that induce cell death through their specific mechanisms of action (e.g., they can act as mitotic inhibitors, topoisomerase I inhibitors, or damaging the genetic material of cancer cells); and (iii) a certain number of linkers (equal to the number of payloads) responsible for maintaining the payloads covalently bound to the antibody moiety and for promoting their rapid release whenever the original ADC is exposed to certain chemical or enzymatic stimuli that are frequently found within tumoral microenvironments or inside cancer cells.
The concept of using ADCs to treat some types of cancer seems very promising, as patients can be submitted to highly effective treatments, like the ones used in conventional chemotherapy, while minimizing the risk of adverse side effects, since ADCs use antibody moieties that are very selective to a tumor-associated antigens (TAA), like the ones used in immunotherapies with monoclonal antibodies (mAbs) or, ideally, to a tumor-specific antigen (TSA) [7]. However, the collected evidence has shown that ADCs still exhibit some limitations that need to be addressed in order to optimize their efficacy/effectiveness and safety profiles [8]. Considering the aforementioned information, this review aims to provide a summarized overview of ADC pharmacotherapy, outline the current limitations restricting their optimal use, explore novel strategies addressing these challenges, and examine emerging therapeutic applications. To achieve these objectives, the methodology adopted in this article involved a bibliographic review of the available scientific literature on topics related to ADC-based targeted therapies. The information required to elaborate this review was mostly obtained from a few searchable bibliographic online databases (like PubMed® and ScienceDirect®), books, e-books, and other kinds of documents published by international health societies and regulatory agencies. During the research phase, some of the terms inserted in the query box included “Antibody-Drug Conjugate*”, “Mechanism of Action[MeSH Terms]”, “Pharmacotherapy[MeSH Terms]”, “Pharmacovigilance[MeSH Terms]”, “Adverse Drug Reaction[MeSH Terms]”, “Limitation* OR Challenge*”, and “Future Perspective* OR Future Prospect*”.

2. Pharmacotherapy of ADCs

ADCs are a specialized group of biopharmaceutical products that belong to the family of targeted therapeutic agents for the treatment of cancer. As previously mentioned, they were introduced into the clinical setting to overcome the toxicity issues associated with the use of conventional chemotherapy, as well as the susceptibility for the development of drug resistance of immunotherapy with mAbs, by combining the two most favorable attributes of each of these types of cancer treatments [6]. For instance, brentuximab vedotin, an ADC used to treat stage III/IV Hodgkin’s lymphoma obtained a 2-year modified progression-free survival (PFS) of 82.1%, when compared to 77.2% with standard adriamicyn, bleomycin, vinblastine, and dacarbazine, while having a hazard ratio (HR) of 0.77 when compared to the same standard-of-care treatment [9,10]. For non-hematologic malignancies, trastuzumab emtansine, for example, extended the median overall survival (OS) to 30.9 months compared to 25.1 months with standard-of-care treatment and an HR of 0.68 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer [10,11]. In terms of biological activity, ADCs can exert multiple mechanisms of action. They can act similarly to mAbs by either inducing the activation of the immune system (via ADCC, ADCP, or CDC) or by blocking the signaling transduction pathways of some surface receptors involved in the proliferation of malignant cells [12]. Moreover, ADCs also possess a mechanism of action that is unique to this class of targeted therapies [13]: (i) first, the antibody moiety binds to overexpressed or specific receptors that are present on the surface of targeted cells; (ii) the interaction creates signals in the cell to internalize the newly formed ADC–antigen complex via endocytosis; (iii) the resulting endosome then fuses with a lysosome, forming an endolysosome where the internalized ADC is going to be digested, releasing the payloads from the antibody moiety through a specific release mechanism that is correlated with the type of linker used. For instance, while acid-sensitive cleavable linkers depend on the presence of lower pH values within the endolysosome to release the payloads, glutathione-sensitive disulfide linkers rely on the presence of intracellular reducing agents, such as glutathione (whose levels are typically elevated in malignant cells), to promote the release of these cytotoxic agents. Linkers can also be classified as enzymatically cleavable linkers (if they release the payloads in the presence of specific hydrolytic enzymes, particularly those that are found inside the endolysosomal lumen) or as non-cleavable linkers (if the payload release relies on the complete degradation of the antibody moiety); (iv) once released from the digested ADC, payloads leave the endolysosome and reach their specific intracellular target where they will exert their unique mechanisms of action and induce the death of targeted cells; and (v) due to their small, apolar, and uncharged molecular structure, some payloads can passively diffuse across cellular membranes, enabling them to enter the cytoplasm of adjacent tumor cells and produce a bystander killing effect, ensuring that multiple cancer cells are effectively killed, even in highly heterogeneous tumors and/or with low rates of internalization [14]. Figure 1 depicts a schematic representation of the multiple mechanisms of action that current ADCs can exert on tumoral cells. However, it does not account for several factors that can substantially impact their clinical effectiveness in real-world settings. For instance, while the figure suggests an equal (1:1) distribution between the primary and alternative mechanisms of action, in reality, only about 1–2% of administered ADCs reach, and are internalized by, the targeted tumor cells [3]. This limited uptake can be attributed to variability among tumor cells, even within the same cancer type, in terms of target antigen expression, as well as endocytic and intracellular trafficking pathways, all of which can directly affect the therapeutic response [15]. Furthermore, heterogeneity in ADC-related properties, such as the drug-to-antibody ratio (DAR, the average number of payloads per antibody moiety), can contribute to differences in clinical efficacy, as ADCs with higher DARs generally show greater therapeutic activity but also carry an increased risk of adverse effects [16].
The introduction of ADCs into the drug market was initially hindered by their structural complexity and the limited clinical benefit observed in early studies [17]. However, their clinical implementation has accelerated in recent years, partly driven by the need for improved therapeutic responses in cancers where mAb-based immunotherapies have shown limited effectiveness [18]. By the end of 2025, there was a total of twenty-one ADCs approved globally for clinical use. Of these, twenty retained their marketing authorizations at that time, while only moxetumomab pasudotox had been withdrawn from the market due to commercial reasons unrelated to its safety or efficacy. According to their therapeutic applications, ADCs can be divided into those used in hematologic malignancies or those used in non-hematologic malignancies [6]. Table 1 summarizes the most important characteristics regarding molecular composition and the main pharmacotherapeutic indications of the previously mentioned twenty-one ADCs ever approved in at least one of the major drug markets by the end of 2025. Data were extracted from both regulatory documents and the published literature. When discrepancies were identified between these two sources of information, priority was given to the most authoritative source, i.e., the regulatory documents. However, when relevant data were not available in regulatory documentation, information was supplemented from the scientific literature. Potential off-label uses were not considered. Table 2, on the other hand, summarizes the most relevant undesirable effects, drug interactions, effects on fertility, pregnancy, and lactation, alongside the most important precautions and contraindications of the ADCs previously mentioned in Table 1. The data were extracted based on the same search strategy as the one used to collect the data presented in Table 1.

3. Current Limitations

Although the introduction of ADCs into the clinical setting has brought several promising therapeutic advantages, particularly in relapsed, refractory, and metastatic cancers, there are still some drawbacks that need to be addressed in order to design and develop new ADCs with optimized chemical and biological properties. Some of these limitations include: (i) toxicity; (ii) susceptibility to the development of drug resistances; (iii) complex pharmacokinetic profiles; and (iv) stability issues.
Even though ADCs were conceptualized with the intent of overcoming the toxicity issues associated with the use of conventional chemotherapy (which was achieved, to a certain extent), they still retain a suboptimal safety profile, mainly attributed to the emergence of off-target toxicities related to the untimely release of payloads into the bloodstream instead of at the actual site of the tumor(s) [102]. This phenomenon is typically associated with the use of cleavable linkers that are susceptible to release of the payloads when they are exposed to certain chemical or enzymatic stimuli that are exacerbated within tumoral microenvironments and inside cancer cells but are also present in normal physiological conditions, although to a lower extent [103]. Other causes of off-target toxicity may involve the excessive bystander killing effect and the non-specific uptake of these drugs by healthy cells. For instance, the temporary withdrawal of belantamab mafodotin, an ADC bearing a non-cleavable linker, was partially associated with the excessive uptake of this drug by the corneal epithelial cells and due to the incapacity of the charged amino acid–linker–payload complex that is released from the antibody moiety to diffuse out of these cells, resulting in the emergence of frequent episodes of ocular toxicity [104]. It is worth mentioning that on-target toxicity issues may also occur with this type of targeted therapy, because until now, every antibody moiety used in currently market-approved ADCs can only target TAAs instead of TSAs [6]. In addition to the toxicity issues correlated with the cytotoxicity of the payloads used in this kind of targeted therapy, the risk of unwanted immunogenicity is another issue that is observed with the use of biologic drugs, including ADCs [105].
A major limitation associated with the use of targeted therapies is their susceptibility to drug resistances developed by cancer cells. Although ADCs were (in part) introduced into the market to overcome resistances that rapidly emerged with other treatments, such as mAb-based immunotherapies, clinical evidence indicates that resistance to ADCs can also occur [106]: (i) antigen–antibody-mediated drug resistances are a group of resistances that negatively impair the effectiveness of antibody-based therapies by reducing the expression of targeted antigens on cancer cells, increasing receptor degradation, altering receptor structure, and/or by decreasing antigen–antibody affinity [106,107,108]; (ii) upon binding the antibody moiety to its corresponding receptor, ADCs should be internalized into the targeted cell via receptor-mediated endocytosis. However, in this step, tumoral cells may develop mechanisms of decreased internalization efficiency and/or induce alterations in the endosomal transport pathways of ADCs, preventing them from exerting their expected efficacy [106,107,109]; (iii) lysosomal degradation can also contribute to drug resistance by blocking the release of payloads from ADCs and preventing their exit from the endolysosomal lumen. For example, elevated endolysosomal pH can hinder ADCs with non-cleavable and acid-labile linkers from releasing their cytotoxic agents and impede the diffusion of weakly acidic payloads into the cytosol [106]. Conversely, lowered pH may prevent hydrophobic weak-base payloads from reaching the cytosol [110]. Moreover, reduced expression of the lysosomal membrane protein solute carrier family 46 member 3 (SLC46A3) has been associated with decreased payload release from ADCs bearing non-cleavable linkers such as those derived from maytansine and SG3376 [106,111]; (iv) even if the payloads are released from the ADC and from the endolysosome, it is still possible for the targeted cell to develop resistances to the payloads themselves, similar to what is observed with the use of conventional chemotherapy. Genetic mutations, decreased expression rates of susceptible intracellular targets, increased expression rates of resistant isoforms, post-translational modifications to the targets, and upregulation of the adenosine triphosphate (ATP)-binding cassette efflux transporters are examples of payload-related drug resistance mechanisms that may arise with the use of ADCs [109,112]; (v) tumor cells can increase survival by exploiting redundancy in receptor tyrosine kinase signaling, altering cell-cycle dynamics (particularly relevant for cell-cycle dependent payloads), upregulating cytoprotective proteins, and downregulating pro-apoptotic proteins, thereby reducing the efficacy of ADCs and other cancer therapies [106,107,113]; and (vi) in addition to the resistance mechanisms that can emerge from individual cells, the tumoral microenvironment where these cells reside may also be involved in further drug resistance, as they possess immunosuppressive properties and have poor accessibility that can hinder the penetration of antibody-based therapies because of the large molecular size of these drugs and due to the elevated interstitial fluid pressure created within tumoral microenvironments, which neutralizes the pressure gradient needed for drugs to leave the bloodstream and reach the tissues [114].
In addition to the primary limitations, ADCs exhibit a complex pharmacokinetic profile that makes it difficult to predict their behavior inside the body and, consequently, adjust the dosing to each individual patient. Unlike other drugs, the pharmacokinetic profile of ADCs requires measuring not only the concentration of intact ADCs (antibody moieties and conjugated payloads) but also non-conjugated antibody moieties, unconjugated payloads, and their metabolites in the bloodstream to predict therapeutic efficacy and toxicity risk [115]. Moreover, ADCs face an increased likelihood of aggregation, even more than mAb therapies, since the hydrophobic nature of the attached payloads might facilitate the exposure of aggregation-prone regions and induce the formation of strong inter-molecular interactions with other protein-based drugs [116]. The formed aggregates not only prevent the sequestered molecules from binding to their intended targets and exerting their expected mechanism of action; however, they can also trigger unwanted immune reactions and increase the risk of off-target payload release into the bloodstream, reducing efficacy and raising safety concerns at the same time with the use of ADCs [116].

4. Novel Approaches to the Concept of ADC and New Therapeutic Applications

The introduction of ADCs revolutionized targeted therapies for cancer by leveraging the selectivity of mAbs to deliver potent cytotoxic agents directly to cancer cells, offering therapeutic advantages over other treatments. However, clinical use has revealed limitations that must be addressed to enhance the efficacy and safety of future ADCs. Key proposed improvements for next-generation ADC design and development include the following aspects [117]: (i) better tumor penetration capacity; (ii) improved microenvironment targeting activity, instead of just targeting individual tumoral cells; (iii) flexibility to comprise novel payloads with new mechanisms of action and innovative approaches that promote enhanced activity against tumoral cells, while causing minimal damages to healthy cells; (iv) adjustable linker chemistry and its conjugation techniques, which should be improved to prevent the premature discharge of payloads into the bloodstream, whilst facilitating their release inside cancer cells or within tumoral microenvironments; (v) reduced risk of unwanted immunogenicity and on-target toxicity caused by the antibody moiety; and (vi) enhanced internalization trafficking and capacity to target multiple and, preferably, highly conserved cellular structures within tumoral cells.
As was previously mentioned, one of the main limitations with the use of large biomolecules in the treatment of solid tumors is their accessibility, especially to deeper cells within the tumoral microenvironments. Instead of using a fully assembled antibody moiety, it is possible to enhance the penetration capacity of ADCs by using smaller molecules or antibody derivatives that can still interact with similar selectivity to their complementary targets, when compared to their fully assembled counterparts [13]. Furthermore, using smaller molecules or antibody fragments can significantly reduce the production cost and complexity of these types of drugs, as they could be produced in microbial expression systems instead of using mammalian expression systems, allowing for the fragments to be produced more quickly and at higher yield rates [118]. In addition, smaller molecules (e.g., aptamers, peptides, and other small-molecule linkers) or antibody fragments can substantially decrease the potential risk of unwanted immunogenicity, as they possess fewer domains recognizable by the immune system [118,119]. However, smaller formats can also exhibit altered pharmacokinetics, including reduced circulation half-life; the absence of a fragment crystallizable (Fc) region in these fragments prevents the activation of immune effector functions (e.g., ADCC, ADCP, and CDC) [120,121]. Examples of some novel alternatives to ADCs using antibody fragments and smaller molecules include the fragment antigen-binding (Fab)-drug conjugate (a type of ADC comprising just one of two Fab regions of an antibody, instead of using the entire molecular structure of the antibody), the single-chain variable fragment (scFv)–drug conjugate (a conjugate-based drug incorporating a fragment containing the variable region of one heavy and one light chain connected by a peptide linker with 15–20 amino acids), the nanobody–drug conjugate (a small conjugated drug that uses the variable domain of a single antibody heavy chain instead of the entire antibody), and the aptamer–drug conjugate (which, instead of using an antibody derivative, uses a single-stranded oligonucleotide that folds on its own to acquire a unique three-dimensional structure, enabling it to bind to specific targets with high affinity and specificity) [122,123]. Another approach is the use of heavy-chain ADCs, where the antibody moiety is modified to lack the two light chains and the first constant domain of each heavy chain. While this novel alternative shows limited improvement in penetration capacity, compared to other drug conjugation strategies, heavy-chain ADCs are unique in their ability to activate the immune system, given the presence of the Fc region [124]. Figure 2 shows a schematic representation of the novel approaches that have been considered to overcome the poor penetration capacity of ADCs in solid tumors.
Tumoral microenvironments are known to be enriched with various types of proteases, such as matrix metalloproteases and serine proteases, that can be used to enhance the selectivity of antibody moieties that target TAAs [125]. One such strategy involves protecting the antigen-binding sites of the antibody moiety with small masking peptides that are covalently bound to the antibody on each antigen-binding site through a cleavable linker sensitive to these proteases [126]. Upon reaching the protease-enriched medium of tumoral microenvironments, the protease-sensitive linkers are cleaved, and the masking peptides are released from the antibody, restoring the availability of the antigen-binding sites. This allows probody–drug conjugates (Figure 3) to remain inactive in circulation, preventing them from interacting with the membrane receptors of healthy cells, ensuring that the probody is only going to be bioactivated near tumoral cells [126].
Future improvements to antibody moieties in ADCs should focus on enhancing the penetration of large biomolecules, while optimizing the overall therapeutic efficacy and safety of this component. For instance, by using bispecific antibodies (Figure 3) it is possible to overcome some safety concerns related to on-target toxicity, as they can target two distinct TAAs that, ideally, are not present simultaneously on healthy cells but coexist on tumor cells, enabling selective internalization or activation of the immune system only when both antigen-binding sites interact with their respective targets [127]. Antibody moieties that interact with highly conserved structures that are less likely to undergo molecular alteration have a lower probability to fall prey to the development of drug resistance [128]. Engineering the Fc region can also be considered to enhance Fc-mediated effectors functions and to optimize the structure of the antibody moiety, so the latter can act as an independent drug. Therefore, the original ADC becomes less dependent on the cytotoxicity of the small fraction of payloads that are internalized to exert an effective therapeutic response [129]. Beyond what was previously stated, the use of human-derived antibodies should be taken into account to reduce the risk of unwanted immunogenicity associated with the use of non-human antibodies [117].
Most adverse drug reactions associated with ADCs arise from the on- and off-target cytotoxicity of payloads to healthy cells. On-target toxicity is primarily due to antibody moieties binding to TAAs on healthy cell membranes, while off-target toxicity is often linked to linker instability, leading to premature payload release into the bloodstream. Additionally, payload chemistry plays a significant role [103]. Excessive hydrophobicity can increase aggregation, immunogenicity, and unwanted diffusion to healthy cells, while high hydrophilicity may prevent effective bystander killing of receptor-negative cancer cells [103]. In addition, novel payloads need to overcome drug resistance [106]. Some of the most innovative developments proposed for new payloads include the use of multiple payloads with different intracellular mechanisms of action and the exploitation of new types of payloads, such as, for example, immune stimulator compounds used as agonists of stimulator of interferon genes (STING) and toll-like receptors (TLRs), two crucial receptors involved in the activation of the innate immune system [130]. The use of antisense oligonucleotides (short sequences of single-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) designed to bind to specific messenger RNA (mRNA) sequences in order to alter the mRNA involved in the pathogenesis of the disease and modulate protein expression through several distinct biological mechanisms) have also been considered, as well as the use of radionuclides and protein degraders such as proteolysis targeting chimeras (PROTACs, a type of heterobifunctional molecules containing a protein-of-interest binding domain connected to an E3 ubiquitin ligand by a linker. PROTACs target specific proteins to be degraded by taking advantage of the ubiquitin–protease system to bring together the target protein and an E3 ligase) [131,132,133]. Figure 3 provides a schematic representation of some of these novel approaches to the development of future payloads.
Finally, the linker chemistry is another critical factor involved in both the safety and efficacy of ADCs. As mentioned earlier, premature off-target release, caused by poor linker stability, is a major factor in ADC toxicity. However, the aggregation phenomena that is associated with decreased serum stability is closely correlated with the conjugation technique used to bind the payloads to the antibody moiety [134]. For instance, while low DARs are linked to reduced therapeutic outcomes, ADCs with high DARs tend to exhibit stability issues, potentially resulting in the premature release of conjugated payloads, increasing the risk of off-target toxicity [6]. To address the limitations of current linkers, it is important to improve their stability in solution and ensure a rapid payload release only when they are exposed to unique chemical or enzymatic triggers solely found inside cancer cells and within their microenvironments. Additionally, innovative controlled homogenous conjugation techniques can help to produce more uniform molecules with better DAR values and a more predictable pharmacokinetic behavior, while maintaining the antibody’s integrity [135]. Examples of such techniques include the engineered amino acid approaches (which use engineered cysteines and non-natural amino acids) (Figure 4), enzyme-mediated approaches (with transglutaminase, formylglycine-generating enzyme, sortase A, glycotransferases, and endoglycosidase), and linker-based approaches (with dibromopyridazinediones, dibromomaleimides and other enhanced maleimides, with hydrophilic linkers, and/or with bis-alkylating linkers) [136]. Figure 4 presents a simplified diagram of the reactional steps that need to be conducted in order to produce new ADCs with homogeneous DARs through engineered amino acid approaches. While enzymatic and linker-based conjugation strategies are increasingly prominent in industrial pipelines, site-specific conjugation techniques with engineered cysteine and non-natural amino acid are presented here as representative models due to their conceptual clarity.
Given the success of ADCs, researchers have already proposed expanding their therapeutic applications [6]. While most ADCs are in clinical trials for other stages and cancer types, a few ADC candidates are also being explored for non-oncological conditions such as inflammatory diseases and infectious diseases (especially, against Staphylococcus aureus infectious) [140]. Although not yet in clinical trials, the use of ADCs in neurodegenerative diseases has also been proposed and is under development [141]. Notwithstanding the fact that all the non-oncological clinical trials form only around 1% of the currently running clinical trials involving ADCs, the potential use of this type of targeted therapy in the future for some diseases beyond cancer is bound to mark one of the biggest advancements in the history of targeted therapies [141]. Figure 5 illustrates the unique mechanism of action proposed for antibody–antibiotic conjugates, the ADC-derivative approach that uses antibiotics as payloads instead of cytotoxic agents.

5. ADCs in Clinical Trials

Table 3 shows examples of ADCs in phase I–III clinical trials identified in the Clinicaltrials.gov database, indicating targets, payload, condition/disease, and other important observations. Several targets for ADCs are highlighted such as human epidermal growth factor receptor 2 (HER2), trophoblast cell surface antigen 2 (TROP2), human epidermal growth factor receptor 3 (HER3), and claudin 18.2 (CLDN18.2).

6. Conclusions

The history of ADCs is a remarkable example of how precision pharmacotherapy has evolved since the day Paul Ehrlich proposed the concept of “magic bullets”. Although ADCs faced a challenging beginning, they are now believed to have changed the paradigm regarding targeted therapies, a type of treatment that takes advantage of the presence of cell surface receptors to promote the selective delivery of potent cytotoxic agents inside the cytoplasm of cancer cells, while at the same time minimizing unwanted damage to healthy cells.
The introduction of ADCs into the therapeutic drug arsenal available against oncological diseases (hematologic and non-hematologic) has led to significant improvements in the treatment of some types of cancer, specifically in advanced or metastatic stages. However, their clinical use still faces some limitations and challenges that need to be overcome to optimize their therapeutic potential. Several improvements to the target selection and the characteristics of ADC components have been proposed; however, further investigation is still needed. The overall great success achieved with the introduction of ADCs into the drug market has sparked significant interest regarding the expansion of their therapeutic applications to new diseases beyond cancer, such as inflammatory, infectious, and neurodegenerative diseases.

Author Contributions

Conceptualization, A.A., M.L.S.C. and J.C.; methodology, A.A., M.L.S.C. and J.C.; software, A.A., M.L.S.C. and J.C.; validation, M.L.S.C. and J.C.; formal analysis, M.L.S.C. and J.C.; investigation, A.A., M.L.S.C. and J.C.; resources, A.A., M.L.S.C. and J.C.; data curation, M.L.S.C. and J.C.; writing—original draft preparation, A.A.; writing—review and editing, M.L.S.C. and J.C.; visualization, A.A., M.L.S.C. and J.C.; supervision, M.L.S.C. and J.C.; project administration, A.A., M.L.S.C. and J.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ADCCAntibody-dependent cell-mediated cytotoxicity
ADCPAntibody-dependent cellular phagocytosis
ADCsAntibody–drug conjugates
ATPAdenosine triphosphate
CDCComplement-dependent cytotoxicity
CLDN18.2Claudin 18.2
DARDrug-to-antibody ratios
DNADeoxyribonucleic acid
FabFragment antigen-binding
FcFragment crystallizable
HER2Human epidermal growth factor receptor 2
HER3Human epidermal growth factor receptor 3
mAbsMonoclonal antibodies
mRNAMessenger ribonucleic acid
PROTACsProteolysis targeting chimeras
RNARibonucleic acid
scFvSingle-chain variable fragment
STINGStimulator of interferon genes
TAATumor-associated antigen
TLRsToll-like receptors
TROP2Trophoblast cell surface antigen 2
TSATumor-specific antigen

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Figure 1. Schematic representation of the multiple mechanisms of action that antibody–drug conjugates (ADCs) can exert on tumoral cells. In addition to their main mechanism of action (the one enumerated in the figure), ADCs can also exert alternative mechanisms when they are not internalized by the targeted cell. Legend: 1—The antibody moiety of the ADC interacts with its complementary surface receptor; 2—The interaction created signals in the cell to internalize the formed complex via endocytosis; 3—The generated endosome fuses with a lysosome to promote the degradation of the internalized ADC and release of the payloads; 4—The released payloads leave the endolysosome and reach the cell cytosol where they will exert their mechanism of action on their intracellular targets or enter the nucleus, if the intracellular target is present inside this organelle; and 5—Due to the cytotoxicity of the payloads, the targeted cell undergoes cell death. When using relatively small, uncharged, and apolar payload molecules, it is sometimes observed that free payloads can easily diffuse to other adjacent cells and exert their cytotoxic mechanism of action on them, ensuring that multiple cancer cells are effectively killed, even in tumors with low internalization rates and/or heterogeneous levels of expression of the targeted surface receptor. Abbreviation: Fc, Fragment Crystallizable. Created in BioRender. Augusto, A. (2026) https://BioRender.com/hztmi6y, (accessed on 6 February 2026).
Figure 1. Schematic representation of the multiple mechanisms of action that antibody–drug conjugates (ADCs) can exert on tumoral cells. In addition to their main mechanism of action (the one enumerated in the figure), ADCs can also exert alternative mechanisms when they are not internalized by the targeted cell. Legend: 1—The antibody moiety of the ADC interacts with its complementary surface receptor; 2—The interaction created signals in the cell to internalize the formed complex via endocytosis; 3—The generated endosome fuses with a lysosome to promote the degradation of the internalized ADC and release of the payloads; 4—The released payloads leave the endolysosome and reach the cell cytosol where they will exert their mechanism of action on their intracellular targets or enter the nucleus, if the intracellular target is present inside this organelle; and 5—Due to the cytotoxicity of the payloads, the targeted cell undergoes cell death. When using relatively small, uncharged, and apolar payload molecules, it is sometimes observed that free payloads can easily diffuse to other adjacent cells and exert their cytotoxic mechanism of action on them, ensuring that multiple cancer cells are effectively killed, even in tumors with low internalization rates and/or heterogeneous levels of expression of the targeted surface receptor. Abbreviation: Fc, Fragment Crystallizable. Created in BioRender. Augusto, A. (2026) https://BioRender.com/hztmi6y, (accessed on 6 February 2026).
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Figure 2. Schematic representation of the novel approaches designed to overcome the limitations associated with the poor penetration capacity of market approved antibody–drug conjugates to the tumoral microenvironment of solid tumors. Abbreviations: CH1, Constant domain 1 of the heavy chain; CH2, Constant domain 2 of the heavy chain; CH3, Constant domain 3 of the heavy chain; CL, Constant domain of the light chain; Fab, Fragment antigen-binding; scFv, Single-chain variable fragment; VH, Variable domain of the heavy chain; and VL, Variable domain of the light chain. Created in BioRender. Augusto, A. (2026) https://BioRender.com/bl37z7p, (accessed on 14 February 2026).
Figure 2. Schematic representation of the novel approaches designed to overcome the limitations associated with the poor penetration capacity of market approved antibody–drug conjugates to the tumoral microenvironment of solid tumors. Abbreviations: CH1, Constant domain 1 of the heavy chain; CH2, Constant domain 2 of the heavy chain; CH3, Constant domain 3 of the heavy chain; CL, Constant domain of the light chain; Fab, Fragment antigen-binding; scFv, Single-chain variable fragment; VH, Variable domain of the heavy chain; and VL, Variable domain of the light chain. Created in BioRender. Augusto, A. (2026) https://BioRender.com/bl37z7p, (accessed on 14 February 2026).
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Figure 3. Schematic representation of some of the strategies that are being considered for the development of new antibody–drug conjugates with improved efficacy, better capacity to overcome drug resistance, and higher safety profiles. Abbreviations: ADC, Antibody–drug conjugate. Created in BioRender. Augusto, A. (2026) https://BioRender.com/31ofzwe, (accessed on 14 February 2026).
Figure 3. Schematic representation of some of the strategies that are being considered for the development of new antibody–drug conjugates with improved efficacy, better capacity to overcome drug resistance, and higher safety profiles. Abbreviations: ADC, Antibody–drug conjugate. Created in BioRender. Augusto, A. (2026) https://BioRender.com/31ofzwe, (accessed on 14 February 2026).
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Figure 4. Emerging site-specific ADC conjugation techniques with engineered cysteines (on the left) and non-natural amino acids (on the right). Engineered cysteines conjugation technique: (1) A number (n) of single nucleotide replacements are made in the heavy- and/or light-chain genes that encode the antibody moiety to promote synthesis of a modified antibody with 2n strategically introduced cysteine residues at predetermined positions. Upon being synthesized, the antibody chains spontaneously assemble the antibody structure through the formation of disulfide bonds between the free thiol groups of natural cysteines present within the molecular structure of the antibody chains. During this process, engineered cysteines also form disulfide bonds with other free thiol groups (–SSR); (2) In order to make it possible for 2n payloads conjugate with the antibody moiety, the engineered cysteines must to be reduced and the natural ones need to be maintained as oxidized; (3) Then, the desired payload carrying a reactive maleimide group is added into the reactional medium to promote the conjugation of the ADC components; (4) The newly formed ADCs are expected to possess a DAR equal to two times the number of nucleotide replacements that led to the substitution of a natural amino acid with an engineered cysteine. Non-natural amino acid conjugation technique: (1) A nucleotide from an encoding triplet is replaced with another one that leads the formation of an amber stop codon (UAG, i.e., uracil–adenine–guanine); (2) An orthogonal transfer RNA (tRNA) specific for the amber stop codon is submitted to the reaction catalyzed by an engineered aminoacyl-tRNA synthetase, which selectively charges the tRNA with a desired non-natural amino acid (nnAA); (3) Upon the formation of the modified antibody, the engineered nnAAs become readily available to react with the specialized and highly reactive groups of desired payloads; (4) The newly formed ADCs, similar to what is observed with the conjugation technique with engineered cysteines, possess a DAR equal to 2n. Legend: Cys, Cysteine; DAR, Drug-to-antibody ratio; n, Number of nucleotide replacements; nnAA, Non-natural amino acid; RSS or SSR, Disulfide bond between the engineered cysteine and other molecules with free thiol groups; SH, Free thiol group; tRNA, Transfer ribonucleic acid. Please note that, for schematic purposes, it was considered that the conjugation site of engineered cysteines and non-natural amino acid conjugation processes was within the heavy and light chain, respectively. However, it could be the other way around. It will depend on the gene where the nucleotide replacement was made. Adapted from [137,138,139]. Created in BioRender. Augusto, A. (2026) https://BioRender.com/zumgxye, (accessed on 5 April 2026).
Figure 4. Emerging site-specific ADC conjugation techniques with engineered cysteines (on the left) and non-natural amino acids (on the right). Engineered cysteines conjugation technique: (1) A number (n) of single nucleotide replacements are made in the heavy- and/or light-chain genes that encode the antibody moiety to promote synthesis of a modified antibody with 2n strategically introduced cysteine residues at predetermined positions. Upon being synthesized, the antibody chains spontaneously assemble the antibody structure through the formation of disulfide bonds between the free thiol groups of natural cysteines present within the molecular structure of the antibody chains. During this process, engineered cysteines also form disulfide bonds with other free thiol groups (–SSR); (2) In order to make it possible for 2n payloads conjugate with the antibody moiety, the engineered cysteines must to be reduced and the natural ones need to be maintained as oxidized; (3) Then, the desired payload carrying a reactive maleimide group is added into the reactional medium to promote the conjugation of the ADC components; (4) The newly formed ADCs are expected to possess a DAR equal to two times the number of nucleotide replacements that led to the substitution of a natural amino acid with an engineered cysteine. Non-natural amino acid conjugation technique: (1) A nucleotide from an encoding triplet is replaced with another one that leads the formation of an amber stop codon (UAG, i.e., uracil–adenine–guanine); (2) An orthogonal transfer RNA (tRNA) specific for the amber stop codon is submitted to the reaction catalyzed by an engineered aminoacyl-tRNA synthetase, which selectively charges the tRNA with a desired non-natural amino acid (nnAA); (3) Upon the formation of the modified antibody, the engineered nnAAs become readily available to react with the specialized and highly reactive groups of desired payloads; (4) The newly formed ADCs, similar to what is observed with the conjugation technique with engineered cysteines, possess a DAR equal to 2n. Legend: Cys, Cysteine; DAR, Drug-to-antibody ratio; n, Number of nucleotide replacements; nnAA, Non-natural amino acid; RSS or SSR, Disulfide bond between the engineered cysteine and other molecules with free thiol groups; SH, Free thiol group; tRNA, Transfer ribonucleic acid. Please note that, for schematic purposes, it was considered that the conjugation site of engineered cysteines and non-natural amino acid conjugation processes was within the heavy and light chain, respectively. However, it could be the other way around. It will depend on the gene where the nucleotide replacement was made. Adapted from [137,138,139]. Created in BioRender. Augusto, A. (2026) https://BioRender.com/zumgxye, (accessed on 5 April 2026).
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Figure 5. Proposed mechanism of action of antibody–antibiotic conjugates, a new therapeutic approach that facilitates the activation of the immune system against severe bacterial infections that failed previous treatments with unconjugated antibiotics. Legend: 1—The antibody–antibiotic conjugate interacts with a targeted antigen present on the surface of the bacterium through its specific antibody moiety. Upon interaction, phagocytic cells recognize the exposed Fc region of the antibody moiety through their complementary Fc receptor present on the surface of effector cells. Following the recognition, the phagocytic engulfs the opsonized bacterium (opsonization is not shown in the figure); 2—The newly formed phagocytic vesicle fuses with a lysosome to promote the degradation of the pathogen; 3—During the degradation step, proteolytic enzymes also digest the antibody moiety, allowing for the conjugated antibiotics to be released; and 4—The released antibiotics aid the immune system eliminate the pathogens by exerting their specific mechanism of action on the targeted bacterium. Abbreviations: FcR, Fragment crystallizable receptor. Adapted from [142]. Created in BioRender. Augusto, A. (2026) https://BioRender.com/q32cuub, (accessed on 19 February 2026).
Figure 5. Proposed mechanism of action of antibody–antibiotic conjugates, a new therapeutic approach that facilitates the activation of the immune system against severe bacterial infections that failed previous treatments with unconjugated antibiotics. Legend: 1—The antibody–antibiotic conjugate interacts with a targeted antigen present on the surface of the bacterium through its specific antibody moiety. Upon interaction, phagocytic cells recognize the exposed Fc region of the antibody moiety through their complementary Fc receptor present on the surface of effector cells. Following the recognition, the phagocytic engulfs the opsonized bacterium (opsonization is not shown in the figure); 2—The newly formed phagocytic vesicle fuses with a lysosome to promote the degradation of the pathogen; 3—During the degradation step, proteolytic enzymes also digest the antibody moiety, allowing for the conjugated antibiotics to be released; and 4—The released antibiotics aid the immune system eliminate the pathogens by exerting their specific mechanism of action on the targeted bacterium. Abbreviations: FcR, Fragment crystallizable receptor. Adapted from [142]. Created in BioRender. Augusto, A. (2026) https://BioRender.com/q32cuub, (accessed on 19 February 2026).
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Table 1. Molecular composition and main pharmacotherapeutic indications of most clinically relevant antibody–drug conjugates worldwide. Abbreviations: AcBut, 4-(4-Acetylphenoxy)butanoic acid; Ala, Alanine; BCMA, B-Cell Maturation Antigen; CD, Cluster of Differentiation; Cit, Citrulline; c-Met, Cellular Mesenchymal-Epithelial Transition factor; DAR, Drug-to-Antibody Ratio; DM1, Mertansine; DM4, Ravtansine; EGFR, Epidermal Growth Factor Receptor; Frα, Folate Receptor alpha; Gly, Glycine; HER2, Human Epidermal growth factor Receptor 2; HR, Hormone Receptor; IgG1, Immunoglobulin G1; IgG4, Immunoglobulin G4; INN, International Non-proprietary Name; Mal, Maleimide; Mc, Maleimidocaproyl; MCC, 4-(N-maleimidomethyl)cyclohexane-1-carboxylate; MMAE, Monomethyl Auristatin E; MMAF, Monomethyl Auristatin F; NSCLC, Non-Small Cell Lung Cancer; PABC, para-Aminobenzyl Carbamate; PD-1, Programmed Death protein 1; PD-L1, Programmed Death-Ligand 1; PEG, Polyethylene Glycol; Ph+, Chromosome Philadelphia-positive; Phe, Phenylalanine; TF, Tissue Factor; TNBC, Triple-Negative Breast Cancer; Trop2, Trophoblast Cell-Surface Antigen 2; and Val, Valine.
Table 1. Molecular composition and main pharmacotherapeutic indications of most clinically relevant antibody–drug conjugates worldwide. Abbreviations: AcBut, 4-(4-Acetylphenoxy)butanoic acid; Ala, Alanine; BCMA, B-Cell Maturation Antigen; CD, Cluster of Differentiation; Cit, Citrulline; c-Met, Cellular Mesenchymal-Epithelial Transition factor; DAR, Drug-to-Antibody Ratio; DM1, Mertansine; DM4, Ravtansine; EGFR, Epidermal Growth Factor Receptor; Frα, Folate Receptor alpha; Gly, Glycine; HER2, Human Epidermal growth factor Receptor 2; HR, Hormone Receptor; IgG1, Immunoglobulin G1; IgG4, Immunoglobulin G4; INN, International Non-proprietary Name; Mal, Maleimide; Mc, Maleimidocaproyl; MCC, 4-(N-maleimidomethyl)cyclohexane-1-carboxylate; MMAE, Monomethyl Auristatin E; MMAF, Monomethyl Auristatin F; NSCLC, Non-Small Cell Lung Cancer; PABC, para-Aminobenzyl Carbamate; PD-1, Programmed Death protein 1; PD-L1, Programmed Death-Ligand 1; PEG, Polyethylene Glycol; Ph+, Chromosome Philadelphia-positive; Phe, Phenylalanine; TF, Tissue Factor; TNBC, Triple-Negative Breast Cancer; Trop2, Trophoblast Cell-Surface Antigen 2; and Val, Valine.
INNAntibody MoietyLinkerPayloadDARTherapeutic Indication(s)Reference
Antibody–Drug Conjugates used in Hematologic Malignancies
Belantamab mafodotinAnti-BCMA IgG1Maleimido-Caproyl
(non-cleavable)		MMAF
(Antimitotic Agent)		4Adult patients with relapsed or refractory multiple myeloma
(combination therapy)		[19,20]
Brentuximab vedotinAnti-CD30
IgG1		Mc-Val-Cit-PABC
(protease-sensitive)		MMAE
(Antimitotic Agent)		4First-line treatment of adult patients with stage III/IV CD30+ Hodgkin lymphoma (combination therapy). It can also be used in adult patients with systemic anaplastic large cell lymphoma (in combination) or with CD30+ cutaneous T-cell lymphoma (monotherapy)[9,21]
Gemtuzumab ozogamicinAnti-CD33
IgG4		AcBut
(acid, and glutathione-sensitive)		N-Acetyl-Calicheamicin γ1 I (DNA Damaging Agent)2–3Patients aged 15 years or above, with previously untreated de novo CD33+ core binding factor acute myeloid leukemia (combination therapy)[22,23]
Inotuzumab ozogamicinAnti-CD22
IgG4		AcBut
(acid and glutathione-sensitive)		N-Acetyl-Calicheamicin γ1 I (DNA Damaging Agent)6Adult patients with relapsed or refractory CD22+ (first line)
and Ph+ (second line) B cell
precursor acute lymphoblastic leukemia (monotherapy)		[24,25]
Loncastuximab tesirineAnti-CD19
IgG1		Mal-PEG8-Val-Ala-PABC
(protease-sensitive)		SG3199
(DNA Damaging Agent)		2.3Adult patients with relapsed or refractory diffuse large B-cell lymphoma and high-grade
B-cell lymphoma
(monotherapy)		[26,27]
Moxetumomab pasudotox
(Not authorised)		Anti-CD22 IgG1Mc-Val-Cit-PABC
(protease-sensitive)		Truncated form of Pseudomonas exotoxin A
(Protein Synthesis Inhibitor)		1Adult patients with relapsed or refractory hairy cell leukemia after receiving at least two prior systemic therapies (monotherapy)[28,29]
Polatuzumab vedotinAnti-CD79b IgG1Mc-Val-Cit-PABC
(protease-sensitive)		MMAE
(Antimitotic Agent)		3–4Adult patients with previously untreated diffuse B-cell lymphoma or with relapsed/refractory diffuse B-cell lymphoma who cannot undergo transplantation (combination therapy)[30,31]
Antibody–Drug Conjugates used in Non-Hematologic Malignancies
Becotatug vedotinAnti-EGFR IgG1Mc-Val-Cit-PABC
(protease-sensitive)		MMAE (Antimitotic Agent)3.8Adult patients with recurrent or metastatic nasopharyngeal carcinoma[32,33]
Cetuximab sarotalocanAnti-EGFR IgG1Linear alkyl/alkoxy linker (non-cleavable)IRDye 700DX (Near-Infrared Photosensitizer)Between 1.3–3.8Adult patients with unresectable locally recurrent head and neck squamous cell carcinoma[34,35]
Datopotamab deruxtecanAnti-Trop2 IgG1Mc-Gly-Gly-Phe-Gly
(protease-sensitive)		DXd
(Topoisomerase I Inhibitor)		4Adult patients with unresectable or metastatic HR+, HER2− breast cancer who have received other treatments (monotherapy)[36,37]
Disitamab vedotinAnti-HER2 IgG1Mc-Val-Cit-PABC (protease-sensitive)MMAE (Antimitotic Agent)4Adult patients with HER2-overexpressed locally advanced or metastatic gastric cancer or urothelial carcinoma. It can also be used for HER2+ and for HER2-low-expressing metastatic breast cancer with liver metastases (monotherapy)[38,39]
Enfortumab vedotinAnti-Nectin-4 IgG1Mc-Val-Cit-PABC
(protease-sensitive)		MMAE
(Antimitotic Agent)		3.8First-line treatment for adult patients with advanced or metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy (combination therapy). It can also be used in adult patients with locally advanced or metastatic urothelial cancer who have received prior platinum-containing chemotherapy and a PD-1 or a PD-L1 inhibitor (monotherapy)[40,41]
Mirvetuximab soravtansineAnti-FRα
IgG1		Sulfo-TBA
(glutathione-sensitive)		DM4
(Antimitotic Agent)		3.4Alternative treatment of adult patients with FRα+, platinum-resistant high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer (monotherapy)[42,43]
Sacituzumab govitecanAnti-Trop2 IgG1CL2A (acid-sensitive)SN-38
(Topoisomerase I Inhibitor)		7.6Adult patients with unresectable or metastatic TNBC or HR+, and HER2- breast cancer (monotherapy)[44,45]
Sacituzumab tirumotecanAnti-Trop2 IgG1Pyrimidine-CL2A-carbonate (acid-sensitive)KL610023 (Topoisomerase I Inhibitor)7.4Adult patients with unresectable locally advanced or metastatic TNBC and metastatic HR+/HER2- breast cancer (monotherapy). It can also be used in EGFR-mutant locally advanced or metastatic non-squamous NSCLC following tyrosine kinase inhibitors and platinum-based chemotherapy (monotherapy)[46,47]
Telisotuzumab vedotinc-Met-directed IgG1Mc-Val-Cit-PABC (protease-sensitive)MMAE (Antimitotic Agent)3.1Adult patients with locally advanced or metastatic, NSCLC with high c-Met protein overexpression (monotherapy)[48,49]
Tisotumab vedotinAnti-TF
IgG1		Mc-Val-Cit-PABC
(protease-sensitive)		MMAE
(Antimitotic Agent)		3–4Adult patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy (monotherapy)[50,51]
Trastuzumab botidotinAnti-HER2 IgG1K-lock-Val-Cit-PABC (protease-sensitive)Duostatin 5 (Antimitotic Agent)2Adult patients with unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2 therapies (monotherapy)[52,53]
Trastuzumab deruxtecanAnti-HER2 IgG1Mc-Gly-Gly-Phe-Gly
(protease-sensitive)		DXd
(Topoisomerase I Inhibitor)		8Second-line treatment for adult patients with HER2+ metastatic breast cancer with stable or undetectable brain metastases after disease progression or with active brain metastases who cannot undergo local intervention (monotherapy). It can also be used in adult patients with advanced HER2+ non-small cell lung cancer or with advanced HER2+ gastric cancer or gastroesophageal junction adenocarcinoma (monotherapy)[54,55]
Trastuzumab emtansineAnti-HER2 IgG1MCC
(non-cleavable)		DM1
(Antimitotic Agent)		3.5Adjuvant treatment of adult patients with HER2+ early breast cancer with residual invasive disease (monotherapy). It can also be used as a second- or third-line alternative to HER2+ metastatic breast cancer in adult patients with non-existent or stabilized brain metastases (monotherapy)[56,57]
Trastuzumab rezetecanAnti-HER2 IgG1Mc-Gly-Gly-Phe-Gly
(protease-sensitive)		SHR9265
(Topoisomerase I Inhibitor)		5.7Adult patients with HER2-mutant NSCLC (monotherapy)[58,59]
Table 2. Undesirable effects, drug interactions, influence on fertility, pregnancy and lactation, as well as the key precautions and contraindications of the most clinically relevant antibody–drug conjugates worldwide. Abbreviations: CYP3A4, Cytochrome P450 3A4; CYP3A5, Cytochrome P450 3A5; G-CSF, Granulocyte colony-stimulating factor; HUS, Hemolytic uremic syndrome; ILD, Interstitial lung disease; INN, International non-proprietary name; N/A, Not applicable; SJS, Stevens–Johnson syndrome; TLS, Tumor lysis syndrome; UGT1A1, Uridine diphosphate-glucuronosyl transferase; and VOD/SOS, Veno-occlusive disease/Sinusoidal obstruction syndrome.
Table 2. Undesirable effects, drug interactions, influence on fertility, pregnancy and lactation, as well as the key precautions and contraindications of the most clinically relevant antibody–drug conjugates worldwide. Abbreviations: CYP3A4, Cytochrome P450 3A4; CYP3A5, Cytochrome P450 3A5; G-CSF, Granulocyte colony-stimulating factor; HUS, Hemolytic uremic syndrome; ILD, Interstitial lung disease; INN, International non-proprietary name; N/A, Not applicable; SJS, Stevens–Johnson syndrome; TLS, Tumor lysis syndrome; UGT1A1, Uridine diphosphate-glucuronosyl transferase; and VOD/SOS, Veno-occlusive disease/Sinusoidal obstruction syndrome.
INNUndesirable EffectsDrug InteractionsFertility, Pregnancy, and
Lactation		Special Precautions and ContraindicationsReference
Antibody–Drug Conjugates used in Hematologic Malignancies
Belantamab mafodotinOcular toxicity, neutropenia, anemia, diarrhea, neuropathies, pneumonia, pyrexia and reactivation of Hepatitis BN/ALimited data. Usually, not recommended for use during pregnancy neither during breastfeeding. May cause reproductive and embryo–fetal toxicityRegular ophthalmologic monitoring recommended. Patients should be advised to avoid driving or operating heavy machinery, when visual acuity is affected[60,61]
Brentuximab vedotinPulmonary toxicity, progressive multifocal leukoencephalopathy, pancreatitis, serious and opportunistic infections, TLS, peripheral neuropathy, hematological toxicities, severe cutaneous adverse reactions, gastrointestinal complications, hepatotoxicity and hyperglycemiaInhibitors and inducers
of CYP3A4		Limited data. Usually, not recommended for use
during pregnancy neither
during breastfeeding. May cause reproductive toxicity		Combined use with bleomycin is contraindicated, due to
increased risk of pulmonary toxicity		[62,63]
Gemtuzumab ozogamicinHepatotoxicity (including VOD/SOS), hemorrhage,
risk of infection, TLS, myelosuppression, pyrexia and
tachycardia		Minor interactions.
Not clinically significant		Limited data. Usually, not recommended for use during pregnancy neither during breastfeeding. May cause reproductive toxicityDue to elevated risk of infections and hemorrhagic reactions, patients should undergo complete blood count prior to each administration[64,65]
Inotuzumab ozogamicinHepatotoxicity (especially, VOD/SOS), myelosuppression, QT interval prolongation, TLS and increased amylase and lipaseDrugs that increase
QT interval		Limited data. Usually, not recommended for use during pregnancy neither during breastfeedingContraindicated use on patients with prior VOD/SOS or serious ongoing hepatic diseases. Concomitant use with other drugs that prolong QT interval should be carefully assessed, due to the increased risk for torsade de pointes[66,67]
Loncastuximab tesirineEffusion and oedema, myelosuppression, risk of infections, photosensitivity and cutaneous reactionsMinor interactions.
Not clinically significant		Testicular and embryo–fetal toxicity. General use is not recommendedSerious effusion, edema, serious or severe myelosuppression, fatal and serious infections, and serious cutaneous reactions have been reported. Complete blood cell counts should be monitored prior to each dose[68,69]
Moxetumomab pasudotox
(Not authorised)		HUS, CLS, hypoalbuminemia, nausea, edema, infusion related reactions, increased transaminases and/or blood creatinineN/AMaternal and embryo–fetal toxicity when administered in pregnant womanContraindicated use in patients with pre-existing severe renal impairment
(creatinine clearance ≤ 29 mL/min)		[70,71]
Polatuzumab vedotinMyelosuppression, risk of infections, TLS, hepatotoxicity, peripheral neuropathy, and progressive multifocal leukoencephalopathyInhibitors and inducers of CYP3A4Testicular and
embryo–fetal toxicity.
General use is not recommended		Neutropenia, severe and severe febrile neutropenia, severe infections, and peripheral neuropathy have been reported. Blood cell counts should be determined before each dose[72,73]
Antibody–Drug Conjugates used in Non-Hematologic Malignancies
Becotatug vedotinMyelosuppression, elevated transaminases, skin rash, hair loss, itching, decreased sensation, decreased appetite, myalgia, weight loss, weakness, constipation, intestinal obstruction, peripheral neuropathy, and pneumoniaInhibitors and inducers of CYP3A4Limited data. Usually, not recommended for use during pregnancy neither during breastfeeding. May cause reproductive toxicityPatients should be monitored for the emergence or worsening of myelosuppression signs and symptoms, especially for febrile neutropenia[74,75]
Cetuximab sarotalocanArterial and tumor hemorrhage, swollen tongue, laryngeal oedema, infusion reaction, photosensitivity, severe skin disorders, fatigue, dysphagia, constipation, hyponatremia, and tumor painLimited data. May interact with photosensitizing agents and drugs that cause hypomagnesaemiaLimited data. May induce miscarriage or embryonic death. Usually, not recommended during pregnancyContraindicated in patients with tumor invasion in the carotid artery. Only patients considered eligible may receive this therapy[76,77]
Datopotamab deruxtecanInterstitial lung disease or pneumonitis, keratitis and stomatitisMinor interactions. Not clinically significantCauses embryo–fetal toxicity. General use is not recommendedPatients may need to consider undergoing preventive treatment prior to the infusion to prevent the occurrence of infusion related reactions[78,79]
Disitamab vedotinGastrointestinal issues, fever,
fatigue, peripheral sensory
neuropathy (including hypoesthesia), hematologic toxicity (including neutropenia and leukopenia), increased aminotransferases and conjugated blood bilirubin		Inhibitors and
inducers of CYP3A4		Embryo–fetal toxicity and impair fertility. General use is not recommendedPatients should be monitored for the emergence of hematological abnormalities, peripheral neuropathy, or liver disfunction[80,81]
Enfortumab vedotinSkin reactions, pneumonitis or interstitial lung disease, hyperglycemia, severe infections, peripheral neuropathy and ocular disordersInhibitors and
inducers of CYP3A4		Embryo–fetal toxicity.
General use is not recommended. May cause testicular toxicity		Patients should be
monitored for eye conditions		[82,83]
Mirvetuximab soravtansineOcular disorders, pneumonitis,
peripheral neuropathy, nausea and vomiting		Inhibitors and
inducers of CYP3A4		Embryo–fetal toxicity.
General use is not
recommended		Patients may need to consider undergoing preventive treatment prior to the infusion to prevent the occurrence of nausea and vomiting and/or infusion related reactions[84,85]
Sacituzumab govitecanNeutropenia, severe diarrhea, nausea and vomiting and life-threatening
hypersensitivity reactions		Inhibitors and inducers of UGT1A1Embryo–fetal toxicity.
General use is not recommended		Loperamide should be used to reduce the severity of diarrhea. Patients may need to consider undergoing preventive treatment prior to the infusion to prevent the occurrence of nausea and vomiting and/or hypersensitivity side effects. Genetic variants of UGT1A1 have an increased risk of higher exposure to SN-38[86,87]
Sacituzumab tirumotecanNeutropenia, anemia, leukopenia, diarrhea, nausea, and fatigueInhibitors and inducers of UGT1A1Teratogenicity and/or embryo–fetal lethality.
It might cause serious adverse reactions in a breastfed child. Generally, use is not recommended		Treatment should be withheld for absolute neutrophil count below 1500/mm3 or neutropenic fever. Administration of G-CSF for secondary prophylaxis may be considered.
Patients with diarrhea should be monitored and, if needed, treated for fluid and electrolyte imbalances		[88,89]
Telisotuzumab vedotinPeripheral neuropathy, ILD/pneumonitis, ocular surface disorders, and infusion-related reactionsInhibitors and inducers of CYP3A4Embryo–fetal toxicity and impair fertility. General use is not recommendedPatients should be monitored for the appearance or worsening of signs and symptoms associated with the undesirable effects[90,91]
Tisotumab vedotinOcular toxicity, peripheral neuropathy and severe cutaneous adverse reactions (including SJS)Inhibitors and inducers of CYP3A4Embryo–fetal toxicity.
General use is not recommended		Patients should be monitored for the appearance or worsening of ocular signs and symptoms[92,93]
Trastuzumab botidotinCorneal disorders, dry eye, and
blurred vision		Limited data but may be sensitive to CYP3A4 inhibitors and inducersLimited data. General use is not recommendedPatients should be monitored for the appearance or worsening of
ocular signs and symptoms		[94,95]
Trastuzumab deruxtecanPneumonitis or ILD, neutropenia and left ventricular dysfunctionMinor interactions. Not clinically significantEmbryo–fetal toxicity.
General use is not recommended		Patients should be monitored with complete blood counts and for signs and symptoms of
ILD/pneumonitis		[96,97]
Trastuzumab emtansineThrombocytopenia, hemorrhage,
hepatotoxicity, neurotoxicity, left
ventricular dysfunction and
pulmonary toxicity		Inhibitors and inducers of CYP3A4 and CYP3A5Limited data. Usually not
recommended for use during pregnancy neither during breastfeeding		Monitoring of platelet count and liver function is recommended. Patients should be carefully observed for the appearance of hypersensitivity/allergic reactions[98,99]
Trastuzumab rezetecanLeukopenia (especially, neutropenia), anemia, thrombocytopenia, and ILDMinor interactions. Not clinically significantCarries significant risks to fetal development. A negative
pregnancy test is required within 7 days before starting the treatment. Use is generally not recommended		Requires close monitoring for
serious treatment-related adverse events, especially for ILD/pneumonitis and hematologic toxicity		[100,101]
Table 3. Names and other important characteristics of antibody–drug conjugates currently in clinical trials. Abbreviations: CDH3, Cadherin-3; CDH17, Cadherin-17; CEACAM5, Carcinoembryonic antigen-related cell adhesion molecule 5; CLDN6, Claudin 6; CLDN18.2, Claudin 18.2; c-Met, Mesenchymal–epithelial transition factor; DLK1, Delta-like 1 homolog; DLL3, Delta-like ligand 3; DNA, Deoxyribonucleic acid; EGFR, Epidermal growth factor receptor; FAP-alpha, Fibroblast activation protein alpha; FGFR2b, Fibroblast growth factor receptor 2b; FOLR1, Folate receptor alpha; GPC3, Glypican-3; HER2, Human epidermal growth factor receptor 2; HER3, Human epidermal growth factor receptor 3; MUC16, Mucin-16; PARP, Poly ADP-ribose polymerase; PD-L1, Programmed death-ligand 1; PSMA, Prostate-specific membrane antigen; ROR1, Receptor tyrosine kinase like orphan receptor 1; ROR2, Receptor tyrosine kinase-like orphan receptor 2; TF, Tissue factor; and TROP2, Trophoblast cell surface antigen 2.
Table 3. Names and other important characteristics of antibody–drug conjugates currently in clinical trials. Abbreviations: CDH3, Cadherin-3; CDH17, Cadherin-17; CEACAM5, Carcinoembryonic antigen-related cell adhesion molecule 5; CLDN6, Claudin 6; CLDN18.2, Claudin 18.2; c-Met, Mesenchymal–epithelial transition factor; DLK1, Delta-like 1 homolog; DLL3, Delta-like ligand 3; DNA, Deoxyribonucleic acid; EGFR, Epidermal growth factor receptor; FAP-alpha, Fibroblast activation protein alpha; FGFR2b, Fibroblast growth factor receptor 2b; FOLR1, Folate receptor alpha; GPC3, Glypican-3; HER2, Human epidermal growth factor receptor 2; HER3, Human epidermal growth factor receptor 3; MUC16, Mucin-16; PARP, Poly ADP-ribose polymerase; PD-L1, Programmed death-ligand 1; PSMA, Prostate-specific membrane antigen; ROR1, Receptor tyrosine kinase like orphan receptor 1; ROR2, Receptor tyrosine kinase-like orphan receptor 2; TF, Tissue factor; and TROP2, Trophoblast cell surface antigen 2.
ADCTargetPayloadCondition/DiseaseOther ObservationsClinical Trial Phase
AGX101TM4SF1Microtubule
inhibitor		Advanced solid tumorsPancreatic adenocarcinoma, triple-negative breast cancer, gastrointestinal cancers can be therapeutic indicationsI
ALX2004EGFRTopoisomerase I inhibitorAdvanced or metastatic solid tumorsNon-small cell lung cancer, colorectal cancer, and head and neck squamous cell carcinoma are the main therapeutic indicationsI
ARX517PSMAMicrotubule
inhibitor		Metastatic castration-resistant prostate cancerHigh serum stability with significant
antitumor activity		I/II
AZD0901 CLDN18.2Microtubule
inhibitor		Advanced solid tumorsAdvanced gastric or gastroesophageal junction adenocarcinoma can be therapeutic indicationsII
AZD4512CD22Topoisomerase I inhibitorAcute lymphoblastic leukemiaIts key advantages include high efficacy, a unique mechanism to overcome resistance, and a well-tolerated safety
profile		I/II
BAT8008TROP2Topoisomerase I inhibitorAdvanced solid tumorsIt includes breast cancer as a
therapeutic indication		I
BAY 3547926GPC3Radioactive
isotope		Advanced hepatocellular carcinomaThe radioactive isotope emits
high-energy alpha particles to induce
lethal DNA double-strand breaks in
tumor cells		I
BC3195CDH3Microtubule
inhibitor		Advanced or metastatic solid tumorsNon-small cell lung cancer, breast
cancer, and esophageal cancer can be therapeutic indications		I
BG-C137FGFR2bTopoisomerase I inhibitorAdvanced solid tumorsGastric and breast cancer can be
therapeutic indications		I
BNT329CA19-9Topoisomerase I inhibitorAdvanced solid tumorsThe CA19-9 is present in cancers of the pancreas, bladder, and ovaryI/II
CAB-ROR2-ADCROR2Microtubule
inhibitor		Advanced solid tumorsLung, breast, and head and neck cancers can be therapeutic indicationsII
CRB-701Nectin-4Microtubule
inhibitor		Advanced solid tumorsImproved stability and reduced payload release in plasmaI/II
DS-7300aB7-H3
(also known as CD276)		Topoisomerase I inhibitorAdvanced esophageal cancerAdvanced-stage small cell lung cancer, non-small cell lung cancer, and
metastatic castration-resistant prostate cancer studies are underway		II
FOR46
(also known as FG-3246)		CD46Microtubule inhibitorMetastatic castration-resistant prostate cancerBeyond direct cytotoxicity, it has been shown to induce immune-priming effects, such as increasing effector CD8+ T cellsII
GSK5733584
(also known as HS-20089)		B7-H4Topoisomerase I inhibitorEndometrial cancerOvarian and breast cancers can be other therapeutic indicationsIII
GSK5764227
(also known as HS-20093)		B7-H3Topoisomerase I inhibitorRelapsed small cell lung cancerRelapsed/refractory osteosarcoma can be other therapeutic indicationIII
HLX43PD-L1Topoisomerase I inhibitorAdvanced solid tumorsNon-small cell lung cancer, cervical cancer, and esophageal squamous cell carcinoma can be therapeutic indicationsI
HMBD-501HER3Topoisomerase I inhibitorAdvanced-stage, relapsed and/or refractory HER3-expressing solid tumorsIt has a stable conjugation profile with increased hydrophilicityI/II
HS-20110CDH17Topoisomerase I inhibitorAdvanced colorectal cancerCan be used in other solid tumorsI/II
HWK-016-101MUC16Topoisomerase I inhibitorAdvanced or metastatic solid tumorsOvarian and endometrial cancer are the main therapeutic indicationsI
IMGN632CD123DNA
alkylating agent		Acute myeloid leukemia and other CD123-positive hematologic
malignancies		Its advantages stem from its unique payload, high selectivity for cancer cells over normal cells, and potent synergistic effects in combination treatmentsI/II
JS212EGFR/HER3Topoisomerase I inhibitorMetastatic colorectal cancerBispecific ADCII
LY4170156FOLR1Topoisomerase I inhibitorOvarian cancerIn addition, it is being studied for peritoneal and fallopian tube cancersIII
M3554GD2Topoisomerase I inhibitorAdvanced solid tumorsNeuroblastoma, sarcoma, and glioma can be therapeutic indicationsI
M9140CEACAM5Topoisomerase I inhibitorColorectal cancerAbsence of specific toxicities, high stability, and targeted releaseI
MHB088CB7-H3Topoisomerase I inhibitorAdvanced solid tumorsIt is designed to have superior potency compared to other B7-H3 ADCs, with high internalization rates and high stabilityI/II
MRG004ATFMicrotubule
inhibitor		Metastatic or unresectable solid tumorsCervical cancer, pancreatic cancer, and triple-negative breast cancer can be therapeutic indicationsI/II
MRG006AGPC3Topoisomerase I inhibitorAdvanced solid tumorsHepatocellular carcinoma can be a therapeutic indicationI/II
NN3201c-KitMicrotubule
inhibitor		Advanced and/or metastatic solid tumorsTherapeutic indications can be gastrointestinal stromal tumors and small cell lung cancerI
OBI-902TROP2Topoisomerase I inhibitorAdvanced solid tumorsOrphan drug status is awarded to cholangiocarcinomaI/II
OBI-992TROP2Topoisomerase I inhibitorAdvanced solid tumorsHigh stability, bystander effect, and synergy (e.g., combined with PARP inhibitors)I/II
OBT076
(also known as MEN1309)		CD205Microtubule
inhibitor		Recurrent and/or metastatic
CD205+ solid tumors		CD205-positive malignancies include pancreatic, bladder, triple-negative breast cancer, and non-Hodgkin lymphomaI
OMTX705FAP-alphaMicrotubule
inhibitor		Advanced/metastatic pancreatic
adenocarcinoma		A strategy for cancer treatment, including tumors resistant to immunotherapyI
QLS5132CLDN6Topoisomerase I inhibitorAdvanced solid tumorsOvarian and non-small cell lung cancer can be therapeutic indicationsI
REGN5093-M114c-MetMicrotubule
inhibitor		Advanced non-small cell lung cancerBiparatopic ADC, acting through binding to two different and non-overlapping epitopes on the MET receptorI/II
SAR3419CD19Microtubule
inhibitor		B-cell malignanciesPrimarily studied for B-cell
non-Hodgkin lymphoma and acute
lymphoblastic leukemia		I/II
SHR-A1811HER2Topoisomerase I inhibitorLocally advanced/metastatic
HER2 positive breast cancer		In combination with pyrotinibII
SKB315CLDN18.2Topoisomerase I inhibitorAdvanced solid tumorsSpecific use in gastric/gastroesophageal junction cancerI
STI-6129CD38Microtubule
inhibitor		Relapsed/refractory
multiple myeloma		Amyloid light-chain amyloidosis can be a therapeutic indicationI/II
SYS6010
(also known as CPO301)		EGFRTopoisomerase I inhibitorAdvanced or metastatic esophageal squamous cell carcinomaNon-small cell lung cancer can be other therapeutic indicationII/III
TORL-4–500DLK1Microtubule
inhibitor		Advanced or metastatic solid tumorsAdrenocortical carcinoma can be a
therapeutic option		I
TQB2101ROR1Topoisomerase I inhibitorAdvanced hematologic malignanciesAdvanced solid tumors are a potential therapeutic optionI
TQB2102HER2Topoisomerase I inhibitorRecurrent/metastatic advanced
gynecological tumors		Advanced or metastatic non-small cell lung cancer with HER2 gene abnormality can be other therapeutic indicationII
TQB6411EGFR/c-MetTopoisomerase I inhibitorAdvanced malignant tumors,
including non-small cell lung cancer		Bispecific ADCI
ZL-1310DLL3Topoisomerase I inhibitorRelapsed small cell lung cancerPromising antitumor activity, including in brain metastasesIII
ZW251GPC3Topoisomerase I inhibitorAdvanced solid tumorsHepatocellular carcinoma can be a therapeutic indicationI
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Augusto, A.; Cristiano, M.L.S.; Conceição, J. Antibody–Drug Conjugates: Pharmacotherapeutic Properties and Future Perspectives. Pharmaceutics 2026, 18, 468. https://doi.org/10.3390/pharmaceutics18040468

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Augusto A, Cristiano MLS, Conceição J. Antibody–Drug Conjugates: Pharmacotherapeutic Properties and Future Perspectives. Pharmaceutics. 2026; 18(4):468. https://doi.org/10.3390/pharmaceutics18040468

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Augusto, André, Maria L. S. Cristiano, and Jaime Conceição. 2026. "Antibody–Drug Conjugates: Pharmacotherapeutic Properties and Future Perspectives" Pharmaceutics 18, no. 4: 468. https://doi.org/10.3390/pharmaceutics18040468

APA Style

Augusto, A., Cristiano, M. L. S., & Conceição, J. (2026). Antibody–Drug Conjugates: Pharmacotherapeutic Properties and Future Perspectives. Pharmaceutics, 18(4), 468. https://doi.org/10.3390/pharmaceutics18040468

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