Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potent efficacy of highly cytotoxic drugs, delivering the therapeutic payload preferentially to tumor sites while mitigating the severity of adverse effects. ADCs are increasingly being combined with other agents as first-line cancer treatment regimens. With the maturation of technologies for producing these complex therapeutics, a growing number of ADCs have been approved or are in advanced clinical trials. The diversity of antigen targets and biologically active carriers is rapidly expanding the range of tumor indications for ADCs. Furthermore, novel carrier protein variants and tumor microenvironment-targeted "warheads" hold promise for enhancing ADC distribution or activation within tumors, thereby improving their anticancer efficacy against refractory tumor types. However, toxicity remains a critical challenge in ADC development, and better understanding and management of ADC-related toxicities are essential for further optimization. This issue provides an overview of recent advancements and challenges in the application of ADCs in cancer therapy.

Background of ADC structural component optimization and key characteristics of approved ADCs Antibody-drug conjugates (ADCs) are complex therapeutic agents composed of three key components: the antibody, linker, and payload (Figure 1). Optimization of these components enables the development of ADCs with superior performance.

Figure 1 Structure and mechanism of action of traditional antibody-drug conjugates (ADCs)

Over the past decade, there has been a significant trend toward diversification in the antigens targeted by ADCs, both in hematologic malignancies and solid tumors (Figure 2). Although other immunotherapeutic approaches targeting these antigens—such as bispecific antibodies or chimeric antigen receptor (CAR)-T cells—are currently under investigation, certain antigens cannot be effectively targeted by uncoupled native antibodies. Over the past two decades, coupling technologies have advanced substantially, leading to notable improvements in the chemical homogeneity and drug-to-antibody ratio (DAR) of ADC designs. The range of cytotoxic moieties employed in ADCs has also become increasingly diverse, encompassing various DNA-targeting agents, microtubule-binding agents, and recently developed topoisomerase I inhibitors.

Figure 2 Main characteristics of approved ADCs

Currently, there are 13 approved ADCs available on the global market (Figure 2), including 6 targeting six distinct antigens (CD33, CD30, CD22, CD79b, B-cell maturation antigen (BCMA, also known as TNFRSF17), and CD19) for the treatment of hematologic malignancies; and another 7 targeting five different antigens (HER2, nectin-4, tumor-associated calcium signaling protein 2 (TACSTD2, also known as TROP2), tissue factor, and folate receptor α (FRα)) for solid tumors. Approved ADCs primarily employ hinge cysteine coupling (DAR of 4–8) or random lysine coupling (DAR of 2/3–5). Although site-specific conjugation has demonstrated promising results in both in vitro and in vivo studies, it has not yet achieved success in clinical trials. Most approved ADCs (11 out of 13) and those currently in late-stage clinical trials utilize cleavable rather than non-cleavable linkers and carry non-polar payloads, enabling bystander killing effects (19 out of 21).

• Diversification of payload

Prior to the approval of trastuzumab drucetin in 2019, the payload components of marketed antibody-drug conjugates (ADCs) were primarily categorized into two types: microtubule-binding agents and DNA-targeting agents. However, numerous other substances have been evaluated as potential payloads. Auristatin derivatives exert potent effects by interfering with microtubule polymerization kinetics, disrupting mitotic spindle formation, thereby inducing mitotic arrest and ultimately leading to cell death. Additionally, since auristatin induces misfolded proteins on the surface of tumor cells, it can trigger immunogenic cell death. Currently, drugs containing auristatin represent the largest drug family within ADCs. The second major category of payloads consists of DNA-targeting agents, which inhibit cell replication through chemical modification of DNA. Caliche is a potent DNA damage agent that induces double-stranded DNA (dsDNA) breaks via free radical mechanisms and serves as the payload in two approved ADCs. PBD dimers are alkylating agents capable of cross-linking double-stranded DNA and are among the most potent cytotoxic agents known. PBD is associated with significant myelotoxicity and peripheral edema. Although many PBD-containing drugs have failed due to toxicity concerns, the first PBD-based ADC—locanstuximab tesirine—was approved in 2021.

• Application of Antibody-Drug Conjugates (ADCs) in Hematologic Malignancies

To date, six antibody-drug conjugates (ADCs) have been approved for the treatment of hematologic malignancies. One is indicated for acute myeloid leukemia (AML), while the remaining five are used for B-cell line malignancies, including lymphoma, chronic lymphocytic leukemia (CLL), and multiple myeloma. Given that some of these indications can also be treated with non-conjugated antibodies (e.g., rituximab for non-Hodgkin lymphoma and CLL, and daratumumab for multiple myeloma), and considering the growing availability of alternative therapies such as bispecific antibodies and CAR-T cells, it is essential to clarify under what circumstances ADCs provide significant added value compared to other antibody-based therapies or when used in combination with them.

• Application of Antibody-Drug Conjugates (ADCs) in Solid Tumors

HER2-positive cancers (including breast cancer and other types of solid tumors) currently account for a significant proportion of all patients receiving ADC therapy. Since HER2 is internalized after binding to an antibody, the first anti-HER2 ADC was developed using the approved and widely utilized "naked" antibody trastuzumab. In the large-scale Phase III EMILIA trial involving breast cancer patients, the anti-HER2 ADC trastuzumab emtansine (T-DM1) demonstrated higher objective response rates, longer progression-free survival and overall survival, as well as lower incidence of grade 3/4 adverse events compared to combination therapy with the small-molecule anti-HER2 agent lapatinib and the chemotherapeutic agent capecitabine. These findings led to T-DM1's approval one year later as the first ADC approved for the treatment of solid tumors. T-DM1 is currently approved for advanced breast cancer and as adjuvant therapy for early-stage HER2-positive breast cancer, and has been endorsed by the National Institute for Health and Care Excellence (NICE) for use in adjuvant therapy for HER2-positive breast cancer.

• Overcoming the limitations of ADCs

Like most drugs, the termination of ADC development is typically due to a combination of factors including insufficient efficacy, safety concerns, and commercial considerations (such as adjustments in product portfolio priorities). Since 2000, among the 97 ADCs that entered clinical trials but were ultimately discontinued, the majority (81; 84%) were terminated during Phase I or Phase I/II. Only 12 and 4 projects were discontinued during Phase II and Phase III, respectively. The majority of these drugs (67%) contained microtubule-binding payloads, 24% contained DNA-targeting agents (including two calichemicin-based payloads and 21 pyrrolobenzodiazepine [PBD] derivatives), and 3% contained topoisomerase 1 inhibitors. Many of these investigational drugs (80%) targeted tumor antigens not covered by approved therapies.

• How will antibody-drug conjugates (ADCs) evolve in the future?

Antibody-drug conjugates (ADCs) have firmly established their position among anticancer therapeutics. Currently, more than 1,500 ADC clinical studies are listed on clinicaltrials.gov, and the number of drugs entering clinical trials continues to grow. Consequently, we can anticipate that ADC market approvals will exhibit significant diversity, with their indications spanning an increasingly wide range of diseases.

The anticipated development of antibody-drug conjugates (ADCs) will encompass novel target antigens, payloads with innovative mechanisms of action, advanced linker technologies that deliver superior therapeutic indices, as well as novel antibody and carrier formulations. Among currently approved ADCs, nearly half are indicated for the treatment of hematologic malignancies. The challenges in developing ADCs for solid tumors may stem from their unique characteristics, including poor diffusivity, inherent resistance to cytotoxic agents, and reduced mitotic activity. Enhancing tumor penetration by employing smaller molecular weight formulations or utilizing probe antibodies for intratumoral targeted activation could improve ADC efficacy in solid tumor indications. Currently, several promising targets are being clinically evaluated for solid tumors, while numerous tumor-associated antigens are being investigated as potential targets for ADC-mediated drug delivery.

• brief summary ：

Antibody-drug conjugates (ADCs) have become a widely recognized component of the anticancer arsenal. Although their development is more complex compared to native antibodies, the number of approved ADCs is expected to increase significantly in the coming years, addressing the growing unmet medical needs arising from both common and rare diseases. Tek Biotechnology (Tianjin) Co., Ltd. has established a comprehensive targeted antibody drug development platform utilizing phage display technology and yeast display technology. The company is committed to providing global scientists with end-to-end ADC drug development and drug-likeness assessment services, including high-quality discovery of targeted antibody drug candidates, antibody humanization, antibody affinity maturation, ADC design and synthesis, cell binding validation, cytotoxicity validation, and animal model validation, thereby offering robust support for drug development targeting refractory tumors and diseases associated with "difficult-to-drug" targets.

References ：

[1] Dumontet, C., Reichert, J.M., Senter, P.D. Dumontet, C., Reichert, J.M., Senter, P.D.  et al. Antibody–drug conjugates come of age in oncology. Nat Rev Drug Discov 22, 641–661 (2023).