Resistance to antibody–drug conjugates: A review

Resistance to antibody–drug conjugates: A review

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Sijia Li^a, Xinyu Zhao^a, Kai Fu^a, Shuangli Zhu^a, Can Pan^a, Chuan Yang^a, Fang Wang^a, Kenneth K.W. To^b, Liwu Fu^a^,^*

Acta Pharmaceutica Sinica B | 2025, 15(2) : 737 - 756

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Acta Pharmaceutica Sinica B | 2025, 15(2): 737-756

• REVIEW •

Resistance to antibody–drug conjugates: A review

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Sijia Li^a, Xinyu Zhao^a, Kai Fu^a, Shuangli Zhu^a, Can Pan^a, Chuan Yang^a, Fang Wang^a, Kenneth K.W. To^b, Liwu Fu^a^,^*

Affiliations

^aState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

^bSchool of Pharmacy, the Chinese University of Hong Kong, Hong Kong 999077, China

About Author:

^†

These authors made equal contributions to this work.

E-mail address:fulw@mail.sysu.edu.cn (Liwu Fu).

Author contributions

Liwu Fu conceived the study and revised the manuscript. Kenneth Kin Wah To and Fang Wang revised the manuscript. Sijia Li and Xinyu Zhao retrieved the related literatures and wrote the manuscript. Kai Fu, Can Pan and Shuangli Zhu created the pictures. Sijia Li and Chuan Yang retri1eved the clinical trials and produced the tables. All authors have read and approved this version of manuscript.

doi: 10.1016/j.apsb.2024.12.036

Outline

Abstract

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Antibody–drug conjugates (ADCs) are antitumor drugs composed of monoclonal antibodies and cytotoxic payload covalently coupled by a linker. Currently, 15 ADCs have been clinically approved worldwide. More than 100 clinical trials at different phases are underway to investigate the newly developed ADCs. ADCs represent one of the fastest growing classes of targeted antitumor drugs in oncology drug development. It takes advantage of the specific targeting of tumor-specific antigen by antibodies to deliver cytotoxic chemotherapeutic drugs precisely to tumor cells, thereby producing promising antitumor efficacy and favorable adverse effect profiles. However, emergence of drug resistance has severely hindered the clinical efficacy of ADCs. In this review, we introduce the structure and mechanism of ADCs, describe the development of ADCs, summarized the latest research about the mechanisms of ADC resistance, discussed the strategies to overcome ADCs resistance, and predicted biomarkers for treatment response to ADC, aiming to contribute to the development of ADCs in the future.

Key words

Antibody–drug conjugates / Drug resistance / Combination therapy / Targeted therapy / Cytotoxic therapy / Cancer / Oncotherapy / Predictive biomarker

Cite this Article

Sijia Li, Xinyu Zhao, Kai Fu, Shuangli Zhu, Can Pan, Chuan Yang, Fang Wang, Kenneth K.W. To, Liwu Fu. Resistance to antibody–drug conjugates: A review[J]. Acta Pharmaceutica Sinica B, 2025 , 15 (2) : 737 -756 . DOI: 10.1016/j.apsb.2024.12.036

Full Text

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1.　Introduction

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Cancer is the major cause of mortality and morbidity worldwide. Despite the advances in the discovery of novel therapeutic approaches for cancer treatment, cytotoxic chemotherapeutic drugs remain an indispensable component of most treatment regimens for cancer patients¹. However, conventional chemotherapeutic drugs are notorious for their severe side effects and the emergence of drug resistance poses great barrier to effective cancer therapy. There is an unmet need to develop novel anti-tumor drugs with high specificity, few side effects, and low risk of drug resistance.

In the late 20th century, with the emergence of monoclonal antibodies such as anti-cluster of differentiate 20 (CD20) and anti-human epidermal growth factor receptor 2 (HER2), targeted therapy became feasible^2,3. However, most monoclonal antibodies do not exhibit anti-tumor activity, and their cytotoxicity to tumor cells is weaker than that of traditional chemotherapy drugs. Therefore, cancer treatment by monoclonal antibodies alone often does not achieve the desirable outcome^4,5.

Antibody–drug conjugates (ADCs) are biopharmaceutical drugs designed to achieve tumor targeting and cytotoxicity in a single moiety. A typical ADC molecule consists of a monoclonal antibody (mAb) covalently attached to a cytotoxic drug via a linker⁶. The mAb component provides the specific tumor targeting ability whereas the cytotoxic drug gives the powerful tumor killing effect⁷. Gemtuzumab ozogamicin (GO) is the first ADC approved by the United States Food and Drug Administration (FDA) for treatment of acute myeloid leukemia (AML) in 2000⁴. As of June 2024, a total of 15 ADCs have been clinically approved by the major drug regulatory authorities worldwide for treating solid and hematological tumors. More than 100 clinical trials are currently underway at various stages to investigate the newly developed ADCs. While ADCs have received unprecedented clinical response in cancer patients, drug resistance to ADC is severely hindering their clinical efficacies. A thorough understanding about the mechanisms contributing to ADC resistance is needed in order to promote the clinical utility of this novel class of antitumor agents.

This review summarizes the recent advances in the discovery of novel ADCs and mechanisms contributing to ADC resistance. Moreover, novel approaches to overcome ADC resistance and biomarkers for predicting treatment response to ADCs are also discussed.

2.　ADCs design and construction

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The typical structure of an ADC, consisting of a monoclonal antibody, linkers, and payloads (cytotoxic drugs), is depicted in Fig. 1. The changes of each component and the mode of their connection are expected to affect the efficacy and adverse effects of the resulting ADCs.

2.1.　 Antibody

The earliest ADCs used murine mAbs and they caused severe immunogenic reactions. On the other hand, most ADCs designed in recent years utilized fully human or humanized antibodies to achieve tumor targeting⁷. The IgG1 immunoglobulin, as the most commonly used ADC antibody subtype, is easy to prepare, abundant in serum, has high affinity with Fc receptors, and has strong ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent phagocytosis (ADCP)^8,9.

Antibodies that recognize antigens that are specifically expressed on the surface of cancer cells but not expressed at all on the surface of normal cells represent an ideal framework for constructing ADCs¹⁰. However, most ADC targets (e.g., HER2 and TROP2) are also expressed to some extent on the surface of normal cells^11,12. There have been clinical trials that have been stopped because of nonspecific toxicity of this target^13-15. In order to further enhance the tumor specificity of ADC, antibodies that can recognize tumor-specific antigen variants with structural changes, such as truncation antibodies, incision antibodies, and post-translational modification antibodies, have been developed^16-18.

2.2.　 Linker

According to the mechanism of payload release, the linkers can be categorized as cleavable and non-cleavable¹⁹. Cleavable linkers were designed with a built-in chemical trigger to cleave the linker. They exploit the distinct characteristics between tumor cells and the systemic circulation to precisely release cytotoxic drugs. In contrast, non-cleavable linkers were usually designed with amino acid functional group to connect to the payload. Upon entering into the cells and particularly lysosomes, the amino acid-based linkage is cleaved via a proteolytic reaction to release the payload with an amino acid appendage²⁰. The chemical properties of the linker affect the stability of the ADCs and the release of the payloads, which is also the major factor determining the toxicity of the ADCs²¹. An ideal linker is expected to be stable in the blood circulation and the anticancer drug payload should not be released prematurely in the blood to avoid causing non-specific toxicity to healthy tissues. When the ADCs reach the tumor surface and are transported into the lysosome, the linker should be rapidly disassembled to release the payload and exert an antitumor effect^7,22. Another important property of the linker is hydrophilicity. It has been shown that linkers with too many hydrophobic groups tend to promote aggregation of the ADC molecules and cause severe hepatotoxicity^23,24.

2.3.　 Payload

Payload, also known as cytotoxic molecule, is the ultimate effector component of ADCs to produce the antitumor effect⁷. Ideal payload should be highly cytotoxic and can kill tumor cells at sub-nanometer concentrations^25-27. Moreover, its molecular weight should be relatively small to minimize immunogenicity. In addition, the payload should also be stable and soluble. It should also contain a functional group to facilitate the linkage to the antibody fragment⁶. Currently, the cytotoxic payload employed in most ADCs includes microtubule inhibitors, DNA interaction inhibitors and topoisomerase I inhibitors²⁶.

2.4.　 Drug-to-antibody ratio (DAR)

An important parameter for evaluating ADCs is the DAR, which represents the number of cytotoxic molecules attaching to a single monoclonal antibody²⁶. Low DAR usually suggests low antitumor activity. On the other hand, ADCs with a higher DAR are usually more potent but they may give rise to more severe toxicity due to increased accumulation in circulation, slower clearance rate, and the risk of premature release¹⁹. Therefore, it is desirable to achieve an optimal DAR value for a potent and safe ADC. The DAR value is maintained between 2 and 8 in the most contemporary ADC design^28,29.

3.　Mechanism of action of ADCs in vivo

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ADCs are known to exert anti-tumor effects synergistically through multiple pathways in vivo. Upon administration of ADCs intravenously into the body, they reach the cancer cells expressing the target antigen via the blood circulation³⁰. Afterwards, ADCs are endocytosed into the cell to exert their direct cytotoxic effect^31,32. Meanwhile, some ADCs can also initiate paracrine mechanisms to produce bystander effects by modifying the tumor microenvironment³³. Furthermore, the mAb component of ADCs could also possess anti-tumor activity on their own²¹ (Fig. 2).

ADCs are usually administered by intravenous injection. Intravenous administration results in rapid distribution of ADC throughout the body³⁰. The long half-life of the ADC antibody moiety in the blood circulation allows it to reach tumor epitopes, in which the antibody binds to target antigens that are highly expressed on the surface of tumor cells^6,34. Typically, target tumor cells should have moderate levels of antigen expression on the cell surface³⁵. The ADC-antigen complex is internalized by antigen-dependent endocytosis or antigen-independent pinocytosis^31,32. Clathrin-mediated endocytosis is the most important pathway for ADC internalization. Clathrins can encapsulate the ADC-antigen complex and form vesicles with a diameter of 100–150 nm, which are transported into tumor cells by the GTPase^36-38. In cells, ADCs containing cleavable linkers are cleaved by specific PH environments, proteases or certain chemicals. In contrast, ADCs carrying uncleavable connectomes would be internalized into early endosomes, further mature into late endosomes, and finally fuse with lysosomes³⁹. Cytotoxic loadings are released through lysosomes, target DNA or microtubules, or enable topoisomerase or RNA polymerase inhibition, ultimately leading to apoptosis or death¹⁹.

In addition to the cytotoxic effects of ADC payloads, mAbs can exert their inherent antitumor activity²¹. After ADC enters the body, some of the Fab fragments of ADC antibodies can bind to the antigen epitopes of tumor cells, while the Fc fragment can bind to the FcR on the surface of killer cells, thus directly mediating the killing effect, that is ADCC. Monoclonal antibodies can also induce CDC, and ADCP^40-42. Ado-trastuzumab emtansine (T-DM1) for HER2⁺ metastatic breast cancer has a similar mechanism to Trastuzumab, which inhibits HER2 signaling pathway and triggers ADCC and CDC⁴³.

Bystander effects can be induced when the payload released by the ADC is permeable or transmembrane, thereby enhancing the efficacy of the ADC. Bystander effect refers to the escape or release of a cytotoxic payload from a cell to the outside of the cell and killing neighboring cells, including non-antigen expressing tumor cells³³. Both Fam-trastuzumab deruxtecan (DS-8201), which is FDA-approved for patients with HER2⁺ metastatic breast cancer, and Sacituzumab Govitecan (IMMU-132) for triple-negative breast cancer induce bystander effects⁴⁴. In addition, studies have shown that ADCs that induce bystander effects may also alter the tumor microenvironment and further enhance the killing effect of ADCs³³. Most ADCs currently in the late stages of clinical investigation have cleavable linkers and nonpolar payloads that would induce a more powerful bystander effect⁴⁵.

4.　The various generations of ADCs

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When ADCs were first developed in the 1980s, mouse mAbs were linked to conventional chemotherapeutic drugs through unstable connections⁴⁶. Due to its high immunogenicity, instability, poor efficacy, and high incidence of adverse reactions, the ADCs developed back then were not marketed. Until 2000, GO was the first ADC clinically approved by the FDA and it becomes the prototype of the first-generation ADCs. The first-generation ADCs are characterized by the random coupling of the payload to various regions on the mAb and a heterogeneous mixture of ADC molecules having different DAR ratio. They exhibit a short half-life, high clearance, and high immunogenicity. DAR inconsistency affects the pharmacokinetic and pharmacodynamic parameters of ADCs, thus resulting in a suboptimal therapeutic window^47,48.

The second-generation ADCs are designed by using humanized IgG1 mAbs and more potent cytotoxic drugs, with improved water solubility and coupling efficiency^49,50. The ADC stability was improved by optimizing the chemical features of the linker. A more uniform DAR distribution was achieved by applying either cleavable or non-cleavable linkers⁵¹. Representative members of second-generation ADCs are Brentuximab vedotin (BV) and T-DM1. However, the second-generation ADCs are still not satisfactory due to low tolerability, high plasma clearance rate (for the ones with high DAR), and off-target toxicity. These drawbacks were further improved by the development of the third-generation ADCs.

Since the approval of Moxetumomab pasudotox in 2018, the third generation ADCs have been kicked off⁵². They employ fully humanized antibodies or antigen-binding fragments instead of chimeric antibodies⁵³. More potent or novel cytotoxic payloads, such as immunomodulators, were used⁵⁴. The linkers having more hydrophilic groups were used⁵⁵. The DAR of the third-generation ADCs is typically 2–4, with favorable toxicity profile, significantly improved stability and pharmacokinetics properties, and potent anticancer effect in vitro at low levels of antigen expression⁴⁷. Representative examples of third-generation ADCs are DS-8201 and polatuzumab vedotin.

After decades of research, as of June 2024, 15 ADCs had received clinical approval, and nearly 100 ADCs were in various stages of clinical investigation. The clinically approved ADCs are summarized in Table 1^56-98. Approximately half of the approved ADCs are indicated for solid tumors and the rest are indicated for hematological malignancies. Table 2 summaries the ADCs currently in various phases of clinical investigation. The development of ADCs and characteristics of each generation of ADCs are depicted in Fig. 3.

5.　Mechanisms of ADCs resistance

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While ADCs exhibit superior specificity and antitumor potency than the classical chemotherapeutic drugs, most cancer patients initially responding to the therapy inevitably develop resistance. The mechanisms causing ADCs resistance are multifactorial. They include alteration of antigen–antibody binding, impaired drug transport, lysosomal dysfunction, increased drug efflux, alteration of payload, enhanced cancer cell survival, and the changes in tumor microenvironment (Fig. 4).

5.1.　 Antigen-antibody mediated drug resistance

Antigen-antibody binding is the first step for ADC to exert its effect. Decreased antigen expression, antigen loss or mutation, impaired antigen–antibody binding sites, and tumor heterogeneity are common causes of ADC resistance.

5.1.1.　 Low/loss of target antigen expression

Combination targeted therapy is known to reduce the expression of tumor cell target antigens and induce tumor cell tolerance. For example, the tumoral expression of HER2 protein was reported to decrease in HER2⁺ breast cancer patients after multiple lines of anti-HER2 therapy. T-DM1 is a clinically approved HER2-targeting ADC. Importantly, while high HER2 levels are positively correlated with high T-DM1 efficacy⁹⁹, reduced HER2 expression or binding was found in T-DM1-resistant cell lines^100,101. Reduced HER2 expression impairs T-DM1 binding and internalization, thereby limiting the intracellular release and cytotoxicity of payload. Similarly, in Hodgkin lymphoma, the malignant Reed-Sternberg cells express high level of a cell surface marker cluster of differentiate 30 (CD30). BV is an ADC designed to deliver a potent anticancer drug (monomethyl auristatin E, MMAE) to CD30-positive cells. Preclinical studies have shown that BV-resistant Karpas-R cell line express remarkably lower levels of CD30 than the sensitive counterpart¹⁰².

5.1.2.　 Consumption of ADC by peripheral target antigens

The presence of the targeting antigens in peripheral blood may limit ADC penetration into tumor sites by consuming them. In leukemia patients, the maximum level of GO binding to cluster of differentiate 33 (CD33) on AML blast cells in bone marrow was shown to be reduced with the emergence of a high CD33-antigen load in the peripheral blood. Consequently, patients with more AML blasts (CD33-overexpressing cells) in peripheral blood exhibit diminished therapeutic response to GO treatment¹⁰³. On the other hand, CD20 has been detected in exosomes secreted by B-cell lymphoma cells. These extracellular CD20 molecules can bind and consume anti-CD20 mAbs, thereby abolishing the efficacy of CD20-targeted therapy¹⁰⁴. Similar outcomes were observed in HER2-overexpressing tumor cell linesSKBR3 and BT474. High level of HER2 proteins encapsulated in their exosomes has been shown to act as decoy that sequestered trastuzumab and shielded tumor cells from antibody attacks¹⁰⁵. However, it remains uncertain whether the secretion of HER2 via exosomes also contributes to T-DM1 resistance. Further research is warranted to determine if tumors can release specific antigens via exosomes to consume the ADCs in the extracellular space.

5.1.3.　 Impaired binding site of the mAbs

The binding of antibodies in ADCs to the targeted receptors on tumor surface is essential for their antitumor activity. Consistently, a truncated HER2 receptor, p95HER2, has been shown to cause trastuzumab resistance¹⁰⁶. Although lacking the extracellular domain targeted by trastuzumab, the truncated HER2 receptor still possess the necessary fragment to form homodimers via intermolecular disulfide and thus promoting breast cancer progression¹⁰⁷. Moreover, TNF-α can increase the expression of MUC4, which masks the trastuzumab-targeting epitope on HER2, consequently impairing trastuzumab efficacy¹⁰⁸. To this end, both TNF-α blockade and MUC4 silencing have been shown to significantly unmask the epitope of trastuzumab on HER2, subsequently overcoming trastuzumab and T-DM1 resistance¹⁰⁸. Junttila et al.⁴³ reported that the conjugation of DM1 to HER2-targeting mAb in T-DM1 does not affect the binding ability and affinity of the mAb. Therefore, p95HER2 and MUC4 may attenuate ADC efficacy. However, several preclinical models have demonstrated that impaired binding sites are not necessarily responsible for ADC resistance^109,110.

5.1.4.　 Tumor heterogeneity

Tumor heterogeneity refers to the variation in antigen expression among the individual cancer cells within the same tumor tissue. For anticancer drugs that rely on antigen expression for recognition and/or cytotoxic effect, any change in antigen expression level will lead to drug resistance. A more heterogeneous antigen expression has been shown to correlate with a higher recurrence rate and a lower survival rate¹¹¹. In breast cancer patients, the presence of HER2 heterogeneity before treatment, defined as HER2 amplification or HER2-FISH negative regions in 5%–50% of tumor cells, was found to inversely predict treatment response. Intriguingly, none of the patients with heterogeneous pretreatment biopsies had a pathological complete response. In the cohort that received T-DM1 plus pertuzumab, 55% of the non-heterogeneous patients had a pathological complete response^112,113.

5.2.　 Impaired drug transport

Upon the binding of ADC to tumor cell surface antigen, endocytosis plays a critical role to facilitate the drug uptake into the tumor cells to exert cytotoxic effect. It follows that decreased internalization efficiency and impaired endosomal transport pathways may compromise the efficacy of ADC.

5.2.1.　 Poor internalization and increased recycling

Endophilin A2 (Endo II) is known to mediate clathrin-independent endocytosis of various materials under physiological conditions¹¹⁴. Baldassarre et al.¹¹⁵ reported that Endo II silencing impedes HER2 internalization, consequently impairing the cytotoxicity of trastuzumab and T-DM1 in HCC1954 and SKBR3 cell lines. The downregulation of Endo II represents an important mechanism of ADC resistance.

Following internalization, epidermal growth factor receptor (EGFR) complexes are recycled through two mechanistically distinct pathways. The rapid pathway involves early endosomes and EGFR is recycled to the cell surface. Importantly, at the pH environment of approximately 6.0–6.5 in endosomes, ADC-receptor complexes are not adequately processed to release payloads. The second pathway, which exhibits slower recycling kinetics, occurs through tubular extension of the multivesicular body boundary membrane^116-118. Importantly, HER2 is internalized and targeted to endosomes less efficiently than EGFR. HER2 primarily remains at the plasma membrane following antibody or ligand binding rather than sorted into lysosomes¹¹⁹. This represents a major resistance mechanism to HER2-targeted ADC.

The endocytosis and recycling of two commonly targeted cancer cell surface antigens (HER2 and CD22) were compared⁵⁸. Cluster of differentiate 22 (CD22) is a cell surface glycoprotein predominated expressed in normal and malignant B-cells whereas HER2 is highly expressed on breast cancer cell surface. MMAE is a common ADC payload conjugated to different mAbs to target specific cancer types. Although the abundance of HER2 in overexpressed epithelial cells is almost three orders of magnitude higher than that of CD22 in lymphoid cells, only 20-fold more MMAEs were localized in upregulated HER2 cells compared to CD22 cells following incubation with anti-HER2-MMAE and anti-CD22-MMAE ADCs, respectively. This discrepancy suggests that the majority of CD22 is transported to lysosomes, while only 15% of HER2 is trafficked there, with the remaining HER2 recycled back to the plasma membrane^120-122. The differential sorting of trafficking receptors into recycling or degradation pathways remains to be elucidated, which may be relevant to the different mechanisms of resistance to specific ADC.

5.2.2.　 Alternation of the mechanism for internalization

Mammalian endocytosis mechanisms can be categorized into clathrin-mediated and clathrin-independent pathways, with caveolae-mediated endocytosis being a significant component of the latter¹²³. Caveolin-1(CAV1) is a major structural protein of caveolae in lipid rafts of plasma membrane, whose expression and association with caveolae regulate the selection of cargo and rate of internalization. Interestingly, after internalization, ADCs were preferentially localized in lysosomes in sensitive cancer cells but colocalized with the CAV1 proteins in resistant cancer cells^124,125. In a panel of HER2⁺ breast cancer cell lines, the selective colocalization of T-DM1 intracellular CAV-1 puncta was also shown to correlate well with the reduced treatment response to T-DM1¹²⁶. Some cancer cell lines resistant to ADCs were found to express higher levels of CAV-1 protein, yet the CAV-1 expression level was not correlated with the drug resistance phenotype. It is also noteworthy that caveolae-mediated endocytosis was observed in both sensitive and resistant cancer cell lines following ADC treatment. Taken together, the propensity for the ADC to adopt the caveolae-mediated endocytosis pathway, instead of the CAV-1 expression alone, is responsible for the drug resistance to ADC¹²⁶.

On the other hand, in lung cancer cell lines and patient-derived tumor xenograft models, the classical caveolae-mediated endocytosis pathway to direct the ADCs towards lysosomes has been shown to be the key mechanism facilitating the internalization and the consequent antitumor efficacy of ADCs (e.g., T-DM1)¹²⁷. However, the high expression of CAV-1 in resistant cancer cells might direct T-DM1 to caveosomes rather than the lysosomes. The neutral pH environment within caveosomes (but not the acidic environment in lysosomes) could impair cellular processing of the ADC and the subsequent payload release to exert the ultimate antitumor effect. Therefore, the role of caveolae-mediated endocytosis in ADC processing and drug response is still controversial. More detailed investigation is warranted to elucidate its precise role in therapeutic response to ADCs.

5.3.　 Lysosomal dysfunction

ADC releases the payload in lysosomes after specific binding to the target antigen. Therefore, alterations in lysosomal function can also affect ADC activity. Among them, the increase of lysosomal pH and lysosomal sequestration have been reported to cause ADC resistance.

5.3.1.　 The increase of pH in lysosomes

Non-cleavable ADCs rely heavily on lysosomal degradation to release the cytotoxic payloads¹²⁸. The acidic pH environment in lysosomes is maintained by the vacuolar H+-ATPase (V-ATPase) that pumps protons from the cytosols to the lysosomal lumen¹²⁹. The reduction in lysosomal pH has been reported in T-DM1-resistant N87-R cell lines^109,130. Given that lysosomal pH is maintained by V-ATPase, a V-ATPase inhibitor bafilomycin A1 has been shown to induce drug resistance to T-DM1 in T-DM1-sensitive N87 cells. The decrease of V-ATPase activity will lead to the decrease of T-DM1 metabolism and the emergence of drug resistance phenotype¹⁰⁹. Interestingly, a cleavable ADC, such as hertuzumab-vc-monomethylauristatin E, appears to be unaffected by this resistance mechanism¹⁰⁹.

Moreover, an acidic pH can trap hydrophobic weak-base cytotoxic agents such as doxorubicin^131,132, topotecan¹³³, and sunitinib^134,135 in the subcellular compartment. Hydrophobic drugs can penetrate across the lysosomal membrane readily from the neutral cytosol. However, upon entering the lysosomal compartments, these weakly basic drugs become charged due to the acidic environment, subsequently leading to drug accumulation or lysosomal sequestration^136-139. Pretreatment with a V-ATPase inhibitor can prevent lysosomal sequestration of hydrophobic and weakly basic drugs whereas lysosomal alkalinization can release the trapped drugs into the cytoplasm, thereby restoring drug activity¹⁴⁰.

Collectively, cellular V-ATPase activity can facilitate the processing of non-cleavable ADCs and impede the release of their payloads from lysosomes to the cytoplasm. To exploit this, hydrophobic and weakly acidic payloads can be included in ADC design, which can be more readily released from mildly acidic lysosomes and avoid lysosomal sequestration. Furthermore, in resistant cancer harboring lysosomal dysfunction, the combination of non-cleavable ADCs and traditional chemotherapy agents will still be useful, due to the reduced impact of lysosomal sequestration.

5.3.2.　 Lysosomal sequestration

In contrast to non-cleavable ADCs, the antitumor effect of the cleavable ADCs does not appear to be associated with V-ATPases. With the built-in cleavable linkers, the payloads of cleavable ADCs are readily released under the desired tumoral conditions either chemically or enzymatically²⁰. The payload release can occur during their internalization journey to lysosomes or even in the extracellular space. Therefore, the drug resistance mechanism of cleavable ADCs for endosomal trafficking is the lysosomal sequestration of free payloads, akin to traditional antitumor drugs.

Hamlett et al.¹⁴¹ reported that SLC46A3 (a lysosomal membrane protein) can recognize the payload maytansine or other closely related catabolites, thus facilitating their transport from the lysosome to the cytosol. SLC46A3 is believed to participate in the delivery of the cytotoxic payloads after they are released from ADCs. To this end, reduced SLC46A3 expression was reported as a drug resistance mechanism to non-cleavable BCMA-targeting DM1 and SG3376 ADCs in multiple myeloma cell lines¹⁴¹, and a T-DM1 resistant cell line BT-474-R¹⁴². However, SLC46A3 expression did not affect the antitumor effect of auristatin-based non-cleavable ADCs. Further research is needed to identify additional proteins that govern the release of catabolites from non-cleavable ADCs out of lysosomes.

5.4.　 Payload-related drug resistance

ADC is also a means of chemotherapy in essence. The resistance mechanism is closely related to the resistance of the payload.

5.4.1.　 Direct resistance against the payloads

Currently, the cytotoxic payloads selected for inclusion in ADCs are mostly DNA intercalating agents, and inhibitors against the microtubule or topoisomerase I (TOP I). The common payload of ADCs (MMAE and DM1) are microtubule inhibitors, which bind to tubulin and inhibit microtubule function. DM1 binds to β-tubulin, inhibiting microtubule polymerization^143-146. It has been reported that T-DM1-resistant cells exhibit high expression of βII and βIII isoforms and post-translational modifications of tubulin, including reduced acetylated and detyrosinated tubulin levels¹⁴⁷.

Camptothecin analogs (TOP I inhibitors) are also widely used in ADC design, including DS-8201 and IMMU-132. Similar to chemotherapy resistance, since TOP I is a unique target of camptothecin, several studies have shown that point mutations in the TOP I gene or conformational changes catalyzed by the enzyme are detected in camptothecin resistant cell lines. Interactions between TOP I and other proteins also affect the sensitivity of tumor cells to camptothecin. TOP I is known to move rapidly from the nucleolus to the cytoplasm after cells are exposed to camptothecin, and this change in localization would reduce the interaction between TOP I and DNA, thereby reducing camptothecin-induced DNA damage and subsequent drug resistance^148-150. Furthermore, pyrrolobenzodiazepine dimer (PBD)-conjugated ADC-resistant cell lines exhibit downregulated DNA replication checkpoint protein SLFN11¹⁵¹, which normally binds replication forks and irreversibly arrests replication in response to S-phase DNA damage, leading to cell death¹⁵².

ADC resistance can also be caused by changes in payload targets. IMMU-132 is an anti-Trop-2-SN-38 ADC designed to treat various epithelial cancers. The molecular target of the cytotoxic payload (SN-38) is TOP I. In IMMU-132 refractory cancer patients, a TOP I frameshift mutation was reported in the post-progression tumor specimens, presumably contributing to the resistance to IMMU-132¹⁵³. This mutation has been previously reported to induce resistance to TOP I inhibitors. In addition, proficiency in homologous recombination repair was also associated with SN38 resistance in IMMU-132¹⁵⁴.

5.4.2.　 Drug efflux by ABC transporters

Most cytotoxic payloads of ADCs are substrates of the ATP-binding cassette (ABC) drug efflux transporters^155,156. Elimination of cytotoxic drugs from the cytoplasm by ABC transporters has been well-established as a common resistance mechanism in chemotherapy¹⁵⁷. It follows that resistance to ADCs could also be induced by up-regulation of the drug efflux ABC transporters and thus reduction in drug accumulation²¹. Interestingly, antitumor effect of the cleavable ADCs appear to be more significantly affected by ABC transporters-mediated resistance. To this end, multidrug resistance 1 (MDR1) was upregulated in GO, Inotuzumab ozogamicin and BV resistant cells, and the expression of MDR1 was significantly correlated with the prognosis of cancer patients^158-160.

ABC transporters also contribute to resistance to non-cleavable ADCs, with upregulation of a variety of resistance genes observed in T-DM1-resistant cell lines such as Karpas-299-R, NCI-N87-R, MDA-MB-231-R, MDA-MB-361-R, and OE-19-R^100,110,161. However, other studies reported that changes in drug efflux transporters do not account for T-DM1 resistance phenotype, suggesting that charged lysine-MCC-DM1 extrusion may not be the primary resistance mechanism in all cases^130,147.

5.5.　 Enhanced cancer cell survival

The change of the proliferation pattern of tumor cells has also been shown to affect the efficacy of ADCs.

5.5.1.　 Changes in the cell cycle dynamics

The spindle assembly checkpoint (SAC) is a key surveillance mechanism during the transition phase of mid-late cell division. It ensures the proper segregation of the duplicated chromosomes after mitotic spindle assembly has completed, thus maintaining cell function and the identity of the resulting daughter cells¹⁶². By impeding microtubule assembly, T-DM1 is known to cause tumor cell cycle arrest at the SAC checkpoint. In a T-DM1-resistant HER2⁺ breast cancer cell line, the SAC checkpoint was due to overexpression of a mitotic kinase Polo-like kinase 1 (PLK1) or degradation of cyclin B1¹⁶³. Importantly, PLK1 inhibition with volasertib was found to dramatically sensitize the T-DM1-resistant cells, which was accompanied by SAC-dependent mitotic arrest, caspase activation, and DNA damage through cyclin-dependent kinases 1 (CDK1)-dependent phosphorylation⁹⁷.

PLK1 assists in SAC closure by inactivating SAC proteins, thus allowing cell division to proceed¹⁶⁴. Previous studies have demonstrated that PLK1 overexpression correlates with poor prognosis in cancer patients^165-167. A strong association exists between elevated PLK1 expression and resistance phenotypes to numerous newly developed targeted drugs including palbociclib, sunitinib, and imatinib^167-169.

Cancer cells have been reported to evade the SAC checkpoint through a process termed mitotic slippage, which entails the breakdown of cyclin B, a ubiquitination-dependent degradation required for mitotic exit¹⁷⁰. This allows cancer cells to prematurely proceed from mitosis to interphase without proper chromosome separation, giving rise to multinucleated cells. A small proportion of these cells may continue to divide into aneuploidy via aberrant mitosis, thereby resisting anti-microtubule cancer drugs or ADCs treatment¹⁷⁰. Consequently, resistance to tubulin-binding payloads of ADCs may arise from the loss of cyclin B1, enabling tumor cells to slip from SAC.

5.5.2.　 Activation of cell survival pathways

The Bcl-2 protein family regulates mitochondrial death signaling via cytochrome c release. The ability to resist apoptosis is considered an important hallmark of cancer¹⁷¹. The expression of cytoprotective proteins has been linked to reduced ADC sensitivity in tumor cells. In numerous non-Hodgkin lymphoma cell lines, resistance to anti-CD79b-vcMMAE is associated with overexpression of the anti-apoptotic protein Bcl-xL, a member of the Bcl-2 family¹⁷². PK11195, an antagonist of antiapoptotic proteins Bcl-2 and Bcl-xL, has been shown to sensitize AML cell lines to GO¹⁷³. Synergistic cancer killing was achieved by combining the Bcl-2/xL inhibitor ABT-263 with an immunotoxin targeting the transferrin receptor in small cell lung cancer cell lines¹⁷⁴. Similarly, significant tumor regression was also achieved by co-administering Bcl-2/xL inhibitors navitoclax/ABT-263 and T-DM1 or EGFR-targeted ADCs, thus demonstrating the effectiveness of Bcl-2/xL antagonists in augmenting ADC efficacy and overcoming ADC drug resistance^175,176. In line with the observations with the antiapoptotic proteins (Bcl-2/xL), decreased expression of the pro-apoptotic proteins (Bax and Bak) has also been reported to contribute to ADC resistance^177,178.

5.6.　 Tumor microenvironment

In addition to the factors of ADC itself, tumor cell microenvironment, immune microenvironment and tumor heterogeneity also play a certain role in drug resistance.

5.6.1.　 Tumor-microenvironment exploiting the redundancy of RTK signaling

Receptor tyrosine kinases (RTKs) represent a group of cell surface receptors for numerous ligands, including growth factors. RTKs play a significant role in cell growth, motility, differentiation, and metabolism. Abnormal RTK activation has been observed in various tumors¹⁷⁹, such as the upregulation of HER2 in numerous breast cancer cell lines, providing the foundation for T-DM1, a non-cleavable ADC targeting HER2. The redundancy of RTK signaling serves as a resistance mechanism for many anti-tumor drugs. This potential mechanism will be discussed in two parts: overexpression of alternative RTKs and diversity of associated ligands.

Long-term use of lapatinib or trastuzumab may result in compensation for the inhibitory effect on HER2 tyrosine kinase through the upregulation of HER3 and EGFR. These receptors bind with residual HER2, activating the PI3K/Akt pathway and leading to resistance to HER2 inhibitors^180,181. Compensation signaling via alternative RTKs could contribute to ADC resistance. However, in two clinical trials, HER3 expression did not alter T-DM1 activity^182,183.

Researchers have explored various strategies of tumor cells to mitigate the anticancer drug activity of inhibitors targeting EGFR family receptors. Observations have shown that hepatocyte growth factor, a ligand for the c-Met receptor, and fibroblast growth factors can diminish the efficacy of drugs targeting oncogenic kinases by amplifying the PI3K/Akt and MAPK pathways^184-188. Similarly, neuregulin-1β (NRG-1β), a soluble secreted growth factor that binds and activates ErbB3 and ErbB4 transmembrane receptor tyrosine kinases¹⁸⁹, can promote resistance to therapies targeting the ErbB family of proteins^190,191. Notably, NRG-1β has been reported to reduce T-DM1 activity in breast cancer cells by promoting HER3 homodimerization or heterodimerization with HER2, thereby intensively activating the PI3K pathway¹⁹². Pertuzumab, a HER2-HER3 dimerization inhibitor, can restore T-DM1 toxicity in SK-BR-3-R cell lines by inhibiting Akt phosphorylation¹⁹². Thus, it appears that resistance induced by RTK-ligands is non-specific and effective against a wide array of anti-neoplastic drugs. Moreover, it is plausible that increased levels of fibroblast growth factors, hepatocyte growth factors, and other RTK-ligands, resulting from autocrine tumor-cell production or paracrine contribution from tumor stroma¹⁹³, could confer an ADC resistance phenotype. However, the generalizability of these hypotheses faces certain limitations, as only a slight increase in response rate was observed in patients treated with T-DM1 plus pertuzumab compared to T-DM1 alone in randomized clinical trials^194,195.

In summary, these findings suggest that the extensive redundancy of RTK signaling in cancer cells and the tumor microenvironment may play a critical role in mediating drug resistance mechanisms.

5.6.2.　 Tumor immune microenvironment

The immunosuppressive tumor microenvironment can diminish ADC activity. Studies have shown that CD8⁺ T cell depletion significantly impairs ADC efficacy^196,197. However, emerging evidence suggests that ADCs can stimulate antitumor immunity. DS-6157a, an anti-GPR20 ADC, mediates ADCC¹⁹⁸. Combining T-DM1 with anti-PD1 and anti-CTLA-4 enhances tumor eradication in immunotherapy-insensitive tumor models by inducing inflammatory responses^199,200. Enapotamab vedotin, an ADC targeting AXL, effectively elicits antitumor immunity and immunologic memory in melanoma and lung tumor models with primary resistance to immunotherapy and tumor-specific T cells²⁰¹. Co-treatment with a novel HER2-targeting ADC bearing a potent anthracycline derivative as payload (T-PNU) and immune checkpoint inhibitors produces synergistic antitumor responses in HER2⁺ breast cancer¹⁹⁷. Rios-Doria et al.¹⁹⁶ described the therapeutic potential of appropriately dosed ADCs conjugated with PBD or tubulysin, which induce immunogenic cell death and memory-like phenotypes in cytotoxic T cells when combined with immuno-oncology drugs such as PD-1 or PD-L1 antibodies. These effects have been confirmed in clinical responses, warranting more investigation^201,202.

In conclusion, the changes of each component of ADC and the process of transporting and releasing load of ADC in vivo may occur drug resistance. To prevent and avoid this problem as much as possible, it is very promising to develop dual-head ADCs with different antigens or tumor heterogeneity and dual-load ADCs with different payloads. It is also necessary to optimize the ADC connector and connection technology. Combination with other targeted drugs and immunotherapy drugs can also counteract the drug resistance of ADC to a certain extent.

6.　Strategies to overcome ADCs resistance

Less

ADCs resistance is a major challenge in the development of them. Strategies to overcome drug resistance of ADCs mainly include the development of novel ADCs and ADCs combined with other drugs.

6.1.　 Novel ADCs development

As mentioned earlier, upregulation of drug transporters is one of the main causes of ADCs resistance. In the development of novel ADCs, the cytotoxic payload can be swapped for drugs or toxins with poor substrate efflux. For example, DS-8201, a targeted HER2 ADC that uses a novel DNA topoisomerase inhibitor, overcomes T-DM1 resistance caused by aberrant expression of ABC transporters in HER2⁺ gastric cancer²⁰³. SGN-CD33A, an ADC conjugated to PBD against CD33, has anti-leukemic activity in preclinical models of drug-resistant AML²⁰⁴. Anti-CD22-NMS249 designed using anthracycline analogues instead of MMAE had the same effect as CD22-vc-MMAE in xenograft models and maintained efficacy in resistant cell lines²⁰⁵.

Optimizing the structure of ADCs payload to give full play to bystander effect is an important method to solve drug resistance caused by tumor heterogeneity. The ADC-induced bystander effect essentially depends on the charge of the payload²⁰⁶. For example, the maytanin-type tubulin inhibitor DM4 exerts a bystander effect by releasing neutral catabolites²⁰⁷. Another strategy to develop new ADCs is to modify the linker to make it more hydrophilic and reduce MDR expression. In ADCs with sulfo-SPDB and PEG (4) Mal linker, they had higher validity for the model of MDR1(+)^155,208.

To overcome ADCs resistance, the current development of ADCs has begun to explore the method of recombinant antibodies. Bispecific antibodies, bispecific ADCs targeting different sites of the same antigen, can achieve better lysosomal aggregation and load delivery^209,210. In addition, similar to bispecific antibodies, dual payloads with different mechanisms can reduce drug resistance, and two synergistic payloads can be selected for delivery to cancer cells to achieve higher efficacy¹¹¹. Furthermore, the molecular weight of the antibody is also an important factor to consider when designing an ADC. The molecular weight of IgG is about 150 kDa. It is difficult for IgG to penetrate the capillaries and matrix of tumor tissue, and it penetrates slowly in the treatment of solid tumors^211,212. To solve this problem, scientists have miniaturized the antibody through wiping out Fc segment. The modified antibody not only retains high specificity and affinity, but also easily penetrates blood vessels into solid tumors, greatly enhancing the effect of killing on solid tumors. However, this change will shorten the half-life of ADC in vivo²¹³. Therefore, it is necessary to comprehensively consider various influencing factors when designing ADC.

6.2.　 Combination of drugs

The combination of ADC and chemotherapy or targeted therapy with different mechanisms of action is a solution to the problem that ADC cannot act on target antigen loss and heterogeneous tumors²¹⁴. At present, a number of clinical trials of ADC combined with chemotherapy and/or targeted therapy are ongoing. T-DM1 combined with lapatinib and paclitaxel has significant efficacy in early and advanced HER2⁺ breast cancer²¹⁵. However, the combination of T-DM1 and docetaxel has good efficacy in clinical practice, but the adverse reactions are more serious²¹⁶. Therefore, the side effects of drugs should also be fully considered in the combination of drugs, and the balance between efficacy and safety should be done well.

The combination of ADC and immune checkpoint inhibitors (ICIs) can increase the recruitment of CD8⁺ T cells to tumor tissues and increase the efficacy of immunotherapy²¹⁷. At present, ADC combined with immunotherapy mainly focuses on PD-1/PD-L1 and CTLA4, which involves a variety of mechanisms, including inducing immunogenic cell death, increasing T lymphocyte infiltration, enhancing the expression of immunomodulatory proteins, and inducing the maturation of dendritic cells¹⁹⁹. In preclinical models, the combination of ADC and PD-1 inhibitor was more effective than either agent alone^197,217. There are a number of ADCs and ICIs combination therapy clinical trial is under way (NCT05547321, NCT03288545, NCT05701527, NCT04042701, NCT05629585, NCT04925284, NCT05687266, NCT05609968).

7.　Possible biomarkers of ADCs resistance

Less

While ADCs have greatly enriched the treatment of choice for different tumor types by combining the potent cytotoxic nature of chemotherapeutic drugs with the selectivity of targeted therapies. However, there is generally a lack of robust predictive biomarkers to predict treatment response (or drug resistance) to ADCs. To date, measurement of the target antigen expression in tissue biopsies is the method used clinically to predict ADC resistance. Decreased expression or mutation of target antigen is expected to trigger ADC resistance. The c-Met expression level has been identified as a predictive biomarker for the efficacy of SHR-A1403, an ADC targeting c-Met²¹⁸. Similarly, the expression of several proteins has been shown to be independent predictors of ADCs resistance. MUC4 is known to regulate HER2 expression by enhancing its stability. Consistently, MUC4 has been reported as an independent predictor of T-DM1 sensitivity¹⁰⁸. During clathrin-mediated endocytosis, RAB5A is a small GTPase that regulates the fusion of endocytic vesicles to early endosomes²¹⁹. The binding of RAB5A to HER2 is an important determinant for sensitivity of T-DM1. Several studies have shown that cancer patients bearing RAB5A highly expressing tumors have better prognosis with T-DM1 therapy^220,221. Recently, Wang et al.¹⁰⁹ proposed that V-ATPase activity in lysosomes is a new marker for predicting T-DM1 resistance. SLC46A3 is a lysosomal drug efflux transporter, and its expression level can also indirectly predict the drug resistance to ADCs²²². In addition to Trop-2 expression, homologous recombinational repair proficiency can also reflect IMMU-132 sensitivity¹⁵⁴. It is noteworthy that assessment of antigen expression in tissue biopsy could only reveal the parameter at a specific tumor site. The method is not able to capture the heterogeneous patterns of antigen expression. On the other hand, the assessment can be performed over time to provide information about the evolvement of the resistance mechanisms.

8.　Conclusions

Less

The class of ADCs is considered one of the fastest-growing segments in model oncologydrug development, which demonstrates excellent efficacy in treating different cancer types. At present, 15 ADCs have been clinically approved worldwide, and more than 100 clinical trials in different phases are currently ongoing to investigate the newly developed ADCs. While ADCs produce encouraging therapeutic outcomes in cancer patients, the emergence of drug resistance is severely hindering their clinical utilities. ADC resistance is caused multifactorial mechanisms into the body of any change will cause resistance. The development of new ADC entities and the combination of ADC with various modulators according to the causes of drug resistance are the direction of their future development. It is expected that this “biological missile” will bring a glimmer of light to cancer patients.

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doi: 10.1016/j.apsb.2024.12.036

Receive Date：2024-11-20
Online Date：2026-09-17

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Received：2024-11-20
Revised：2024-12-18
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^bSchool of Pharmacy, the Chinese University of Hong Kong, Hong Kong 999077, China

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Table 1 Summary of clinically approved ADCs.

ADC name	Trade name	Manufacturer	Target cancer antigen	Linker	Cytotoxic Payload	Average of DAR	Approval year	Indication	Common adverse event	Ref.
Gemtuzumab ozogamicin	Mylotarg®	Pfizer	CD33	Hydrazone	N-Acetyl-γ-calicheamicin	2–3	2000;2017	AML	Hepatotoxicity	56–58
Inotuzumab ozogamicin	Besponsa®	Pfizer	CD22	Hydrazone	N-Acetyl-γ-calicheamicin	5–7	2017	ALL	Hematologic toxicity	59,60
Moxetumomab pasudotox	Lumoxiti®	AstraZeneca	CD22	mc-VC-PABC	PE38	–	2018	HCL	Infusion reaction	61–63
Brentuximab vedotin	Adcetris®	Seagen	CD30	mc-VC-PABC	MMAE	4	2011	HL	Peripheral neuritis	64–66
Polatuzumab vedotin	Polivy®	Roche	CD79b	mc-VC-PABC	MMAE	3.5	2019	DLBCL	Hematologic toxicity	67–69
Belantamab mafodotin	Blenrep®	GSK	BCMA	mc	MMAF	4	2020	MM	Ocular toxicity	70,71
Loncastuximab tesirine	Zynlonta®	ADC Therapeutics	CD19	Dipeptide	PBD	2.3	2021	DLBCL	Hematologic toxicity	72,73
Ado-trastuzumab emtansine	Kadcyla®	Roche	HER2	SMCC	DM1	3.5	2013	BC	Hematologic toxicity	50,74,75
Fam-trastuzumab deruxtecan	Enhertu®	DaiichiSankyo	HER2	Tetrapeptide	DXd	8	2020	BC, GC,NSCLC	ILD	76–79
Disitamab vedotin	Aidixi®	RemeGen	HER2	mc-VC-PABC	MMAE	4	2021	GC,UC	Hematologic toxicity	80–83
Sacituzumab govitecan	Trodelvy®	Immunomedics	Trop-2	CL2A	SN38	7.6	2020	TNBC, UC	Hematologic toxicity	84–86
Enfortumab vedotin	Padcev®	Seagen	Nectin-4	mc-VC-PABC	MMAE	3.8	2019	UC	Hematologic toxicity	87–90
Tisotumab vedotin	Tivdak®	Genmab/Seagen	TF	mc-VC-PABC	MMAE	4	2021	CC	Hematologic toxicity	91–93
Mirvetuximab soravtansine	Elahere®	ImmunoGen/Huadong Medicine	FRα	Disulfide bond	DM4	3.5	2022	OC	Ocular toxicity	94–96
Cetuximab sarotalocan	Akalux®	Rakuten Medical	EGFR	–	IRDye700DX	1.3–3.8	2020	HNSCC	Skin reaction	97,98

HER2, human epidermal growth factor receptor 2; Trop-2, trophoblast cell-surface antigen 2; TF, tissue factor; FRα, folate receptor α; EGFR, epidermal growth factor receptor; mc-VC-PABC, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl; SMCC, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate; PE38, a 38kD fragment of Pseudomonas exotoxin A; MMAE, monomethyl auristatin E; MMAF, monomethyl auristatin-F; PBD, pyrrolobenzodiazepine dimer; DM1, derivative of maytansine 1; DXd, Exatecan derivative; SN38, active metabolite of irinotecan; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; HCL, hairy cell leukemia; HL, Hodgkin's lymphoma; DLBCL, diffuse large B-cell lymphoma; MM, multiple myeloma; BC, breast cancer; GC, gastric cancer; TNBC, triple negative breast cancer; UC, urothelial carcinoma; CC, cervical cancer; OC, ovarian cancer; HNSCC, head and neck squamous cell carcinoma.

Table 2 ADCs currently under investigation in different phases of clinical trials.

ADC name	Manufacturer	Target cancer antigen	Linker	Cytotoxic payload	Clinical stage	Clinical trial identifier number	Indications	Drug combination
TR1801	MedImmune	cMET		PBD	Phase I	NCT03859752	Solid tumors
M9140	Sutro	CEACAM5		Topoisomerase I inhibitors	Phase I	NCT05464030	Solid tumors
M1231	Sutro	MUC1/EGFR	vc	Hemiasterlin derivant	Phase I	NCT04695847	Solid tumors
MYTX-011	Mythic Therapeutics	cMET		MMAE	Phase I	NCT05652868	Nsclc
STI-3258	Silverback Therapeutics	Trop-2			Phase I	NCT05060276	Solid tumors
BYON3521	Byondis B.V.	cMET	Vc-seco-DUBA	Duocarmycin	Phase I	NCT05323045	Solid tumors
SYD1875	Byondis B.V.	5T4		Duocarmycin	Phase I	NCT04202705	Solid tumors
EO-3021	Elevation Oncology	CLDN18.2	Cleavable	MMAE	Phase I	NCT05980416	Solid tumors
Cofetuzumab Pelidotin	AbbVie	PTK7	vc	Aur0101	Phase I	NCT04189614	NSCLC
GQ1001	GeneQuantum Healthcare	HER2		DM1	Phase I	NCT04450732	Solid tumors
MBRC-101	MBrace Therapeutics	EphA5		MMAE	Phase I	NCT06014658	Solid tumors
BAY2701439	Bayer	HER2			Phase I	NCT04147819	BC, GC
BAY94-9343	Bayer	MSLN	SPDB	DM4	Phase I	NCT01439152	Solid tumors
CPO102	Conjupro Biotherapeutics	CLDN18.2		MMAE	Phase I	NCT05043987	PC, GC
CPO301	Conjupro Biotherapeutics	EGFR			Phase I	NCT05948865	Solid tumors
CS5001	CStone Pharmaceuticals	ROR1	Cleavable	PBD	Phase I	NCT05279300	Solid tumors and lymphomas
IKS014	Iksuda Therapeutics	HER2		MMAF	Phase I	NCT05872295	Solid tumors
EBC-129	A∗STAR	CEACAM5/6		MMAE	Phase I	NCT05701527	Solid tumors	Pembrolizumab
IMGN151	ImmunoGen	FRα	Tripeptidase	DM21	Phase I	NCT05527184	EC, FTC, PPC
XB002	Exelixis	TF	Dipeptide	MMAE	Phase I	NCT04925284	Solid tumors	Nivolumab or bevacizumab
ASN004	Kirilys Therapeutics	5T4	Dolaflexin	AF-HPA	Phase I	NCT04410224	Solid tumors
FDA018	Fudan-Zhangjiang	Trop-2	BB05	Topoisomerase I inhibitors	Phase I	NCT05174637	Solid tumors
HS-20093	Hansoh Biomedical	B7-H3	Cleavable	Topoisomerase I inhibitors	Phase IPhase II	NCT05276609NCT06052423	Solid tumorsES-SCLC
MRG001	Shanghai Miracogen	CD20	vc	MMAE	Phase I	NCT05155839	NHL
AZD9592	AstraZeneca	EGFR/c-Met	Cleavable	Topoisomerase I inhibitors	Phase I	NCT05647122	Solid tumors	Osimertinib
FDA022-BB05	Fudan-Zhangjiang	HER2	BB05	Topoisomerase I inhibitors	Phase I	NCT05564858	Solid tumors
ORM-5029	Orum Therapeutics USA	HER2	vc	Smol007	Phase I	NCT05511844	Solid tumors
ARX788	Ambrx	HER2		AS269	Phase I	NCT03255070	Solid tumors
SGN-LIV1A	Seagen	HER2	vc	MMAE	Phase I	NCT01969643	BC	Trastuzumab
SBT6050	Silverback Therapeutics	HER2		TLR8	Phase I	NCT04460456	Solid tumors	PD-1 inhibitors
CC-99712	Celgene	BCMA		MMAE	Phase I	NCT04036461	MM
OMTX705	Oncomatryx	FAP		TAM558	Phase I	NCT05547321	Solid tumors	Pembrolizumab
STRO-001	Sutro Biopharma	CD74	Non-cleavable	DM1	Phase IPhaseI/II	NCT03424603 NCT05611853	BCLNHL
STRO-002	Sutro Biopharma	FRα	Cleavable	SC209	Phase IPhase I	NCT03748186NCT04610528	OC, ECOC
ADCT-701	ADC Therapeutics	DLK-1		PBD dimer	Phase I	NCT06041516	Nens
AMT-151	Multitude Therapeutics	FRα	K-lock	DUO-5	Phase I	NCT05498597	Solid tumors
AZD8205	AstraZeneca	B7-H4		AZD0132	Phase I/II	NCT05123482	Solid tumors
ARX517	Ambrx	PSMA		AS269	Phase I/II	NCT04662580	Prostate cancer
MGC018	MacroGenics	B7-H3	Cleavable	Duocarmycin	Phase I/II	NCT03729596	Solid tumors
W0101	Pierre Fabre Medicament	IGF-1R			Phase I/II	NCT03316638	Solid tumors
IMGC936	ImmunoGen	ADAM9	Tripeptide	DM21C	Phase I/II	NCT04622774	Solid tumors
MORAb-202	Eisai Inc.	FRα	Disulfide bond	Eribulin	Phase I/IIPhase IIPhase II	NCT04300556NCT05577715NCT05613088	Solid tumorsNSCLCOC, FTC, PPC
SOT102	Sotio Biotech	CLDN18.2	Non-cleavable linker	Anthracycline derivatives	Phase I/II	NCT05525286	GC, PC
LCB84	LegoChem Biosciences	Trop-2		MMAE	Phase I/II	NCT05941507	Solid tumors	PD-1 inhibitors
YL201	MediLink Therapeutics	B7-H3			Phase IPhase I/II	NCT05434234NCT06057922	Solid tumorsSolid tumors
OBI-999	OBI Pharma	Globo H		MMAE	Phase I/II	NCT04084366	Solid tumors
CX-2029	CytomX Therapeutics	CD71	vc	MMAE	Phase I/II	NCT03543813	Solid tumors, DLBCL
MRG004A	Shanghai Miracogen	TF	vc	MMAE	Phase I/II	NCT04843709	Solid tumors
IMGN632	ImmunoGen	CD123		IGN	Phase I/II	NCT03386513	BPDCN
PRO1184	ProfoundBio US	FRα	Novel hydrophilic linker	Exinotecan	Phase I/II	NCT05579366	Solid tumors
NBE-002	NBE-Therapeutics AG	ROR1		Anthracycline derivatives	Phase I/II	NCT04441099	Solid tumors
STI-6129	ACEA Pharma	CD38		Duostatin	Phase IPhase IPhase IPhase I/IIPhase I/IIPhase I/II	NCT05519527NCT05584709;NCT05692908NCT05308225NCT05565807;NCT04316442;	All, AMLSolid tumorsAL amyloidosisMMMMAL amyloidosis
REGN5093-M114	Regeneron Pharmaceuticals	cMET	M114	M24	Phase I/II	NCT04982224	NSCLC
U3-1402	SOLTI	HER3	Tetrapeptide	DXd	Early Phase I	NCT04610528	BC
					Phase I/II	NCT02980341	BC
					Phase II	NCT04965766	BC
I-DXd	Daiichi Sankyo	B7-H3		DXd	Phase II	NCT05280470	ES-SCLC
HS-20089	Hansoh BioMedical	B7-H4			Phase II	NCT06014190	OC, EC
Luveltamab Tazevibulin	Sutro Biopharma	FRα	Cleavable	3-Aminophenyl hemiasterlin	Phase II	NCT05870748	OC, FTC, PPC
ABBV-399	AbbVie	cMET		MMAE	Phase IPhase IIPhase IIPhase III	NCT02099058NCT03539536NCT05513703NCT04928846	Solid tumorsNSCLCNSCLCNSCLC	Docetaxel
SYD985	Byondis B.V.	HER2	vc	Duocarmycin	Phase IPhase IIPhase III	NCT04235101NCT04205630NCT03262935	Solid tumorsECBC	Niraparib
MRG003	Shanghai Miracogen	EGFR	vc	MMAE	Phase I/IIPhase IIPhase IIPhase IIPhase IIPhase IIPhase III	NCT05688605NCT05126719NCT04838964NCT05188209NCT04838548NCT04868162NCT05751512	SOLID TUMORSNCBTCGCNSCLCHNSCCHNSCC
MRG002	Shanghai Miracogen	HER2	vc	MMAE	Phase I/IIPhase I/IIPhase IIPhase IIPhase IIPhase IIPhase IIPhase II/IIIPhase IIIPhase III	NCT05338957NCT04492488NCT05263869NCT04837508NCT04742153NCT05141747NCT05141786NCT04924699NCT04924699NCT05754853	Solid tumorsGC, GEJCBCBTCBCGCNSCLCBCBCUC
Dato-DXd	DaiichiSankyo	Trop-2	Tetrapeptide	DXd	Phase IIPhase IIPhase IIIPhase IIIPhase IIIPhase III	NCT04940325NCT05489211NCT05629585NCT05374512NCT05104866NCT05687266	NSCLCSolid tumorsBCBCBCNSCLC
XMT-1536	Mersana Therapeutics	NaPi2b	Fleximer	AF-HPA	Phase III	NCT05329545	OC
SHR-A1811	Fudan-Zhangjiang	HER2	Tetrapeptide	SHR9265	Phase I/IIPhase IIIPhase III	NCT05824325NCT05104866NCT05424835	BCBCBC

PBD: antramycin; CEACAM5: carcinoembryonic antigen-related cell adhesion molecules 5; MUC1: type I transmembrane glycoprotein; EGFR: epidermal growth factor receptor; vc: valine-citrulline peptide; c-MET: mesenchymal epidermal transformation factor; NSCLC: non-small-cell lung cancer; MMAE: monomethyl auristatin E; Trop-2: trophoblast cell-surface antigen 2; CLDN18.2: integrin membrane proteins; PTK7: protein tyrosine kinase 7; Aur0101: inhibitors of tubulin; HER2: human epidermal growth factor receptor 2; DM1: derivative of maytansine 1; EphA5: tyrosine protein kinase receptor A5; BC: breast cancer; GC: gastric cancer; MSLN: mesothelin; SPDB: N-succinimidyl-4-(2-pyridyldithio) butanoate; DM4: derivative of maytansine 4; PC: pancreatic cancer; ROR1: inactive tyrosine-protein kinase transmembrane receptor 1; FRα: folate receptor α; EC: endometrial cancer; FTC: fallopian tube cancer; PPC: primary peritoneal cancer; TF: tissue factor; 5T4: trophoblast cell glycoproteins; AF-HPA: auristatin F-hydroxypropylamide; B7-H3: immune checkpoints; ES-SCLC: extensive-stage small cell lung cancer; NHL: non-hodgkin's lymphoma; Smol002: GSPT1 degrades the molecular glue; AS269: microtubule inhibitors; TLR8: Toll-like receptor 8; BCMA: B cell maturation antigen; MM: multiple myeloma; FAP: fibroblast activation protein; TAM558: cytolysin; BCL: B-cell lymphoma; SC209: microtubule inhibitors; OC: ovarian cancer; DLK-1: delta-like1homologue; NENs: neuroendocrine neoplasms; DUO-5: microtubule inhibitors; AZD0132: novel topoisomerase 1 inhibitors; PSMA: prostate-specific membrane antigen; IGF-1R: insulin-like growth factor 1; ADAM9: A distegrinin and a metalloprotease 9; Globo H: glycolipid antigen; DLBCL: diffuse large B-cell lymphoma; IGN: indolino-benzodiazepine; BPDCN: blastic plasmacytoid dendritic cell neoplasm; AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; HER3: human epidermal growth factor receptor 3; DXd: exatecan derivative; NaPi2b: sodium-dependent phosphate transport protein 2B; NC: nasopharyngeal carcinoma; HNSCC: head and neck squamous cell carcinoma; BTC: biliary Tract Cancer; GEJC: gastroesophageal junction cancer; UC: urothelial carcinoma; SHR9265: exatecan derivative.

Figure 1 Structural characteristics of ADCs. Created with Adobe Illustrator.

Figure 2 The mechanism of ADCs. After ADCs enter the body, the antibody targets the surface antigen of cancer cells, and endocytosis occurs to release the payloads. At the same time, ADCs can also produce the ADCC and bystander effects. Created with Adobe Illustrator.

Figure 3 Development of different generations of ADCs and their characteristic features. a. Timeline showing the clinical development and approval of ADCs by major regulatory authorities (by June 2024). b. Characteristic features of the three generations of ADCs. ADC, antibody–drug conjugate; DAR, drug-to-antibody ratio; MMAE, monomethyl auristatin E; MMAF, monomethyl auristatin-F; DM1, derivative of maytansine 1; DXd, exatecan derivative; PBD, pyrrolobenzodiazepine dimer. Created with Adobe Illustrator.

Figure 4 Mechanisms of ADCs resistance. During the process of ADC binding to the target and entering the circulation, the changes of each component and transport environment may lead to ADC drug resistance. Created with Adobe Illustrator.

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