Antibody-drug conjugate (ADCs) combine cytotoxic agents with specific antibodies through chemical linkers, with the goal of delivering drugs directly to a target within a patient’s body, and offer the potential of selective treatments and a reduction in side effects. Development and interest in this area is on the rise, with a focus on oncology targets, however, there are applications beyond this, with the potential to treat inflammatory disorders, infectious diseases, and cardiovascular disease.
The history of these treatments has been a challenging one, since the approval of the first, Mylotarg® (Pfizer/Wyeth›s drug gemtuzumab ozogamicin), in 2000. Since then, the field has been limited by a small number of validated targets and a narrow range of payloads, with modest clinical success. As of mid-2025, over 3,400 ADC assets have been developed, with more than 2,300 in active development. Approximately 600 of these are in clinical stages, and 33 have received regulatory approval (1). Interest in the area has led to advancements in the technology for manufacturing ADCs, resulting in drugs with greater stability and less variability in their structure.
More recently, the technology for manufacturing ADCs has advanced, resulting in molecules that have less variability in structure and greater stability. This article will discuss three of the transformative trends shaping the global ADC landscape: the emergence of novel targets, the rise of bispecific ADCs, and the strategic deployment of dual payloads. These advances are redefining therapeutic potential, especially in oncology, and signaling a new era of precision medicine.
Novel Targets: Expanding the Therapeutic Frontier
Historically, ADC development focused on a small number of successful, and well-characterized antigens, but with limited scope of ADC application.
Development today is focused on a much wider number of targets, particularly in solid-tumor therapies (2), which are associated with tumor-specific expression patterns, and offer improved selectivity and reduced off-target toxicity.
Additionally, research and development is moving beyond single-antigen targeting, with a number of dual-target approaches gaining traction (3). These combinations are designed to address tumor heterogeneity and resistance mechanisms, particularly in cancers such as non-small cell lung cancer, breast cancer, and gastrointestinal malignancies. This reflects an expanding understanding of tumor biology and a strategic shift toward more personalized, biomarker-driven therapies. By aligning ADC design with the molecular profile of individual tumors, developers are enhancing both efficacy and safety.
Bispecific ADCs: Combining Precision and Versatility
Bispecific ADCs (BsADCs) represent one of the most exciting advances in ADC innovation, and are engineered to recognize two distinct antigens, offering several advantages over traditional monospecific ADCs (4). There has been a huge growth in research since 2019, when there were just 15 therapies in development, whereas now this number has grown to over 240.
BsADCs offer enhanced tumor selectivity by requiring co-expression of two antigens for effective binding and internalization. This allows for more precise targeting of heterogeneous tumors and reduces potential side-effects. There is also growing interest in biparatopic formats, where both arms of the antibody bind different epitopes on the same antigen.
Beyond selectivity, BsADCs offer functional versatility. They can be designed to target and interact with immune cells within the body, modulating the tumor microenvironment or deliver payloads more efficiently (5). This would offer the potential for a number of novel therapeutic strategies, including combination and immune-oncology therapies.
Importantly, BsADCs are not just limited to academic and preclinical research. There are a number of programs that have already entered clinical trials, and early data for these suggest promising efficacy and safety profiles. As manufacturing and regulatory guidance becomes more established, BsADCs have the potential to become a next-generation ADC technology for new drugs.
Dual Payload ADCs: A Single Construct with Multiple Mechanisms
Dual payload ADCs (DpADCs) are another area of rapid innovation within the field (6). These molecules incorporate two distinct cytotoxic agents within a single ADC drug, allowing for the simultaneous targeting of multiple cellular pathways. The rationale behind the development is that by combining mechanisms of action, DpADCs can overcome drug resistance, enhance efficacy, and reduce the likelihood of tumor escape, which is where the cancer cells avoid detection and destruction by the immune system.
Since 2023, the number of active DpADCs programs has nearly doubled, with developers exploring a wide range of payload combinations. Common pairings include topoisomerase inhibitors with tubulin disruptors, as well as DNA-damaging agents with immunomodulators, and offer the opportunity to tailor payloads to specific indications.
For researchers, DpADCs have great interest because of their potential to address tumors with complex resistance mechanisms. For example, combining a DNA-damaging agent with a TLR agonist can induce direct cytotoxicity while stimulating an immune response. This dual action is particularly valuable in immunologically “cold” tumors that are resistant to checkpoint inhibitors (7).
Additionally, DpADCs offer advantages in dosing and scheduling, which can improve the patient experience. By delivering two cytotoxic agents in a single molecule, developers have the opportunity to optimize pharmacokinetics and reduce the need for combination regimens, which can simplify clinical development and potentially improve patient adherence.
Although DpADCs are still in the early stages of clinical validation, there is clear interest in this area, and as more assets enter the clinic and understanding of the strategy becomes wider, the opportunity for further development increases.
Challenges and Considerations
Despite growing interest and investment, progress in the ADC field is not without challenges (8). Bispecific and dual payload ADCs are inherently more complex to design, manufacture, and regulate (9). They require advanced linker technologies, robust analytical methods, and sophisticated clinical trial designs. Additionally, the expansion into novel targets raises questions about biomarker validation, patient selection, and regulatory approval. To support innovators’ claims, there must be investment in companion diagnostics and much broader real-world evidence to advance the research towards potential approvals and commercialization.
Drug innovators rely heavily on CDMO partners for the development and manufacturing of ADCs, as the knowledge and expertise are concentrated within them. However, the evolving nature of the drugs brings new challenges for CDMOs, as the complexity of the molecules has increased and puts a greater burden on the resources and available capacity.
Chemical development work, for both the cytotoxic warhead(s) and linker(s) involves more steps, often involving chromatography, and this increases the time and cost of projects. The analytical work in method development also becomes more complex, with the need for greater sensitivity in instruments, especially mass spectrometers. This work is vital to ensure the integrity of the product being developed, so that the methods can ultimately be transferred over to quality assurance and product release.
For manufacturing, the additional steps also mean processes require longer within specialist facilities, again putting pressure on an already capacity-limited sector. The adoption of single-use technology is an advantage that can mitigate some of the time delays between the changeovers of projects for manufacturers.
Within this complex area of drug development, advances may be outside of current regulations (10), and these may have to change to match the new molecules. CDMOs will need to actively engage with authorities to ensure any future guidance and frameworks match the existing technologies available.
Although these molecules are relatively new, for CDMOs working with innovators that have specific development platforms, experience from initial projects can be leveraged to reduce subsequent projects from the same platform, reducing the overall timescales on these. Building long-term, sustainable partnerships between innovators and CDMOs will see an acceleration in process advancement and increase efficiency, and as the number of projects becoming successful grows, costs should reduce and increase the opportunity for new drugs of this nature.
With these advances, there will also be commercial considerations to programs. As the field becomes more crowded, differentiation between drugs of the future will be key, with companies not only needing to demonstrate not novelty, but also clinical and economic value, focusing on patients’ outcomes and quality of life, and the cost-effectiveness to the payors (11).
Conclusion
Despite all of the historic challenges associated with ADCs over the last 25 years, there is a resurgence of interest in the field, fueled by a number of recent approvals. Understanding of mechanisms of action has improved, and manufacturing experience and innovation has led to more robust technologies and improved products.
The nature of ADC products is transforming, the limitations of the first- and second-generation drugs have been understood, and the innovations such as novel targets, bispecific formats, and dual payloads are redefining what ADCs can achieve.
These innovations are offering new hope to patients with cancers that are currently difficult to treat, and their families. As these trends advance, they have the potential to unlock new indications, improve patient outcomes, and reshape the future of oncology treatment, and potentially diseases beyond that.
References and notes
- Beacon Intelligence. ADC Landscape: From Preclinical to Clinical. Hanson Wade. 2025; p.4.
- Wang R, Hu B, Pan Z, Mo C, Zhao X, Liu G, et al. Antibody–Drug Conjugates (ADCs): current and future biopharmaceuticals. J Hematol Oncol. 2025;18:51.
- Kathad U, Biyani N, Peru y Colón De Portugal RL, Zhou J, Kochat H, Bhatia K. Expanding the repertoire of Antibody Drug Conjugate (ADC) targets with improved tumor selectivity and range of potent payloads through insilico analysis. PLoS One. 2024;19(8)
- Caserta S, Campo C, Cancemi G, Neri S, Stagno F, Mannina D, et al. Bispecific Antibodies and Antibody–Drug Conjugates in Relapsed/Refractory Aggressive NonHodgkin Lymphoma. Cancers (Basel). 2025;17(15):2479
- Maruani A..Bispecifics and antibody–drug conjugates: a positive synergy. Review Article. University College London.
- Wen M, Yu A, Park Y, Calarese D, Gerber HP, Yin G. Homogeneous antibodydrug conjugates with dual payloads: potential, methods and considerations. mAbs. 2025;17(1):2498162
- Zhou Z, Si Y, Zhang J, Chen K, George A, Kim S, et al. A DualPayload Antibody–Drug Conjugate Targeting CD276/B7H3 Elicits Cytotoxicity and Immune Activation in TripleNegative Breast Cancer. Cancer Res. 2024;84(22):38483863
- Scanlan C, Zhao J, Rogers M, Waghmare R, Xu S, Cross S, et al. AntibodyDrug Conjugates: Manufacturing Challenges and Trends. ADC Rev. 2017 Mar 21
- Li M, Zhao X, Yu C, Wang L. AntibodyDrug Conjugate Overview: a Stateoftheart Manufacturing Process and Control Strategy. Pharm Res. 2024;41:419440.
- Hotha KK. The ABC of ADCs (AntibodyDrug Conjugates): A Comprehensive Review of Technical, Regulatory, and Clinical Challenges. Adv Chem Eng Sci. 2023;13:363381.
- Zhou W, Xu Z, Liu S, Lou X, Liu P, Xie H, et al. Landscape of clinical drug development of ADCs used for the pharmacotherapy of cancers: an overview of clinical trial registry data from 2002 to 2022. BMC Cancer. 2024;24:898.
