Antibody–Drug Conjugates: Types and Clinical Challenges
- Fay
- 10 minutes ago
- 5 min read
Introduction
Antibody–drug conjugates (ADCs) have rapidly evolved from a theoretical concept into a validated class of targeted cancer therapies. Over the past two decades, successive generations of ADCs have introduced innovations in antibody engineering, linker chemistry, and cytotoxic payloads, leading to a growing number of regulatory approvals across both hematologic malignancies and solid tumors. Today, more than a dozen ADCs are commercially available, and hundreds of candidates are being tested in clinical trials worldwide. By examining their types, approval milestones, and clinical lessons learned, we can better understand how ADCs are reshaping the oncology treatment landscape and where the field is heading next.
FDA-Approved ADCs
After decades of exploration and continuous optimization of key components, ADCs have evolved from early experimental attempts into an indispensable class of drugs in clinical oncology. Currently, over 100 ADCs worldwide are undergoing clinical trials at various stages. By the end of 2021, a total of 14 ADCs had been approved and entered clinical use. Notably, among these marketed drugs, approximately half are primarily used to treat hematologic malignancies, while the other half target solid tumors. Their success not only signifies the maturation of the technological platform but also provides patients with expanded treatment options.
In the field of hematologic malignancies, Mylotarg (Brentuximab Vedotin, Pfizer) was the first ADC to gain approval, marking the birth of this novel therapeutic modality. Subsequently, Brentuximab vedotin (Adcetris), Enotuzumab ozumabine (Besponsa), Moxituximab (Lumoxiti), and Polatuzumab vedotin (Polivy) have been introduced. These drugs target distinct antigens (e.g., CD33, CD30, CD22, CD79b) and incorporate optimized linkers and payloads, achieving enhanced targeting and efficacy. They have introduced novel treatment options for conditions including acute myeloid leukemia, Hodgkin lymphoma, B-cell acute lymphoblastic leukemia, and diffuse large B-cell lymphoma.
In solid tumors, Ado-trastuzumab emtansine (Kadcyla) became the first ADC approved for HER2-positive breast cancer, opening new treatment pathways for patients. Subsequently, ADCs targeting different molecular targets gained approval, including: Cetuximab sarotalocan (Akalux) targeting EGFR, and Tisotumab vedotin (Tivdak) targeting tissue factor (TF). These drugs cover multiple indications ranging from breast cancer and gastric cancer to urothelial carcinoma and cervical cancer, significantly expanding the application landscape of ADCs in solid tumor treatment.
Overall, approved ADCs demonstrate the clinical success achievable through diverse combinations of their three core components: targeting antibodies, linkers, and payloads. From hematologic malignancies to solid tumors, ADCs are progressively reshaping the landscape of cancer treatment while laying a solid foundation for more precise and efficient anti-cancer strategies in the future.
Upcoming ADCs
Beyond the 14 approved ADC drugs mentioned above, hundreds of ADCs utilizing newer technologies and targeting novel indications are currently undergoing clinical trials worldwide, with many having advanced to pivotal Phase 3 studies. Representative candidates include Mirvetuximab soravtansine (IMGN853), Datopotamab deruxtecan (DS-1062, Dato-DXd), and Tusamitamab ravtansine (SAR-408701). IMGN853 targets folate receptor alpha (FRα) through an innovative cleavable linker coupled with cytotoxic DM4. It demonstrated superior efficacy in high FRα-expressing populations in ovarian cancer studies and is currently advancing in Phase 3 trials such as SORAYA and MIRASOL. Dato-DXd is a Trop2-targeted ADC based on the DXd payload. It is currently being evaluated against docetaxel in the TROPION-Lung01 study for advanced non-small cell lung cancer (NSCLC) patients, with early data showing favorable safety and antitumor activity. Another candidate, SAR-408701, targets CEACAM5 and has demonstrated partial response potential in a Phase 1 study of NSCLC patients. Its efficacy and safety have been further validated in multiple Phase 2 and Phase 3 studies. The development of these late-stage ADCs not only expands the range of indications but also reflects the latest advances in linker design, payload selection, and target diversification, signaling the continued rapid evolution of the ADC field.
Challenges and Next-Generation ADCs
As evidenced by approved and investigational drugs, next-generation ADCs demonstrate significant improvements in targeting precision and cytotoxic potency compared to earlier products. However, the clinical application of ADCs still faces a series of pressing challenges. The foremost is the complexity of pharmacokinetics. Following intravenous administration, ADCs coexist in the body as intact antibody-drug conjugates, free antibodies, and released payloads, with the proportions of these forms dynamically shifting over time. Antibody clearance involves the mononuclear phagocyte system and FcRn-mediated circulatory recycling, while free small-molecule payloads are primarily metabolized by the liver and excreted via the kidneys or feces. This complexity makes establishing reliable PK/PD models to predict ADC clinical behavior particularly challenging and imposes higher demands on new drug design.
Another significant concern is toxicity. Hematologic adverse events are most common in most ADCs, including neutropenia, thrombocytopenia, and anemia. Additionally, premature release of cytotoxic payloads may trigger hepatotoxicity and gastrointestinal reactions, potentially leading to renal injury. In some clinical studies of anti-HER2 ADCs, severe adverse reactions associated with interstitial lung disease (ILD) have been observed, some of which were fatal. Although the exact mechanism remains incompletely understood, it is widely believed to be related to the non-specific uptake of ADCs by healthy lung tissue and the local accumulation of free payloads. This underscores the need for future ADCs to achieve greater breakthroughs in safety optimization and therapeutic monitoring.
At the drug delivery level, the large molecular weight of ADCs means only a small fraction successfully penetrates tumor cells. Payload release efficiency depends not only on the chemical properties of the linker but also on tumor antigen expression and endocytosis. While some ADCs exhibit a “bystander effect” capable of affecting neighboring cells lacking the target antigen, the strength of this effect is largely constrained by the physicochemical properties of the payload. Achieving a balance between precise targeting and broad-spectrum killing remains a central challenge in drug design.
Drug resistance also poses a significant bottleneck in ADC development. Unlike small-molecule inhibitors, which can be evaded through gene mutations, resistance mechanisms for ADCs are often more complex. Evidence suggests tumor cells may reduce antigen expression, alter intracellular transport pathways, or even utilize drug efflux pumps to expel payloads, thereby diminishing ADC efficacy. While clinical evidence remains limited, preclinical studies indicate long-term administration may induce resistance phenotypes, increasing therapeutic uncertainty.
Despite these challenges, next-generation ADC development continues to explore novel approaches. Optimizing the antibody component can enhance recognition precision for mutated proteins or low-abundance antigens, thereby improving specificity. Bispecific antibody technology holds promise for promoting receptor clustering and rapid internalization, boosting drug delivery efficiency. Concurrently, dual-payload strategies are demonstrating potential to overcome resistance in experiments by carrying two payloads with distinct mechanisms within the same ADC to achieve synergistic killing. Beyond antibodies themselves, researchers are experimenting with smaller fragments or peptides as carriers to improve tumor penetration. Some teams have even developed non-internalizing ADCs that deliver payloads directly within the tumor microenvironment for diffusion-based killing.
Finally, payload selection continues to expand. Traditional cytotoxic small molecules are no longer the sole option, with increasing numbers of researchers exploring targeted therapeutics or immunomodulators as novel payloads. For instance, some novel ADCs utilizing BCL-XL inhibitors to promote apoptosis have already entered early-stage clinical trials. These explorations unlock greater possibilities for future ADCs, signaling their potential to overcome current limitations and emerge as truly effective and safe weapons in cancer therapy.
Conclusion
Over the past two decades, ADCs have evolved from experimental concepts into an established class of cancer therapeutics, with more than a dozen agents now approved by the FDA. These agents have demonstrated that selective delivery of potent cytotoxins through antibody targeting can achieve clinically meaningful efficacy across diverse malignancies. At the same time, ongoing clinical programs continue to expand the spectrum of potential indications, tumor targets, and payload chemistries.
Nevertheless, challenges remain. Complex pharmacokinetics, dose-limiting toxicities, heterogeneous antigen expression, and the emergence of resistance all hinder the broader application of ADCs. Addressing these barriers will require not only incremental optimization of current designs but also bold innovation, including bispecific formats, dual-payload strategies, non-traditional antibody scaffolds, and novel classes of payloads.
Looking ahead, the field is moving rapidly toward next-generation ADCs that combine greater tumor specificity with improved safety profiles. If these innovations succeed, ADCs have the potential to shift from a niche therapeutic option to a cornerstone of modern oncology, offering durable responses to a wider range of patients who currently lack effective treatment choices.
Source
Assessed and Endorsed by the MedReport Medical Review Board
