The scientific concept of ADCs was first explored in the early 1980s, and it took another two decades before the first ADC reached the clinic. [1] First, as a clinician caring for cancer patients, and then as a researcher in pharmaceutical R&D, I have had the opportunity to see the vast progress made. 
Early ADCs showed promise but also presented challenges, including optimizing toxicity, fine-tuning the “drug to antibody” ratio, improving stability, and understanding the role of tumor heterogeneity, which can lead to differential sensitivity to different anticancer payloads. Fast forward to the last decade, and it’s been exciting to see the substantial evolution in design concepts and technologies behind antibody-based targeted therapeutics.
Hallmarks now include: [2]
- Target strategy characterized by tighter biomarker definitions and context-specific and mechanism-based antigen biology
- Site-specific or controlled conjugation to stabilize drug-to-antibody ratios (DARs) and pharmacokinetics
- Modern linkers (protease, pH, or enzyme cleavable; tandem/conditioned designs) to balance stability in plasma with efficient intracellular release and optionality for inducing a bystander effect, improving activity when antigen density is heterogeneous
- Payload diversification, notably the DNA topoisomerase 1 inhibitor (Top1i) payload.
These levers help address key limitations of early-generation ADCs, such as systemic toxicity and insufficient tumor delivery.
Clinically, today’s ADC engineering choices are already reshaping who may benefit. For example, the conjugation of a HER2-directed antibody to Top1i at a high DAR provides a substantial survival benefit in HER2-low metastatic breast cancer, effectively redraws biomarker boundaries, and illustrates how linker/payload choices can enable efficacy at lower antigen expression levels. [3]
Another approach towards engineering ADCs with a potentially improved therapeutic index focuses on payload innovation beyond conventional cytotoxics. A recent example of this concept has been the recruitment of innate immune components, for example, by including a STING (Stimulator of interferon genes) agonist domain. [4] STING agonist ADCs aim to turn “cold” tumors “hot,” delivering local innate immune activation while avoiding the systemic inflammatory adverse events that limited early small-molecule STING agonists. If translatable, such constructs could reframe how ADCs synergize with checkpoint blockade or cellular engagers.
Research into dual-payload ADCs aims to address intra-tumoral heterogeneity and treatment resistance. These are foundational concepts, given that tumor progression is generally driven by resistance to the payload rather than the antigen. In development today are dual-payload ADCs, in which two cytotoxic drugs with complementary mechanisms of action are conjugated to the same antibody framework (e.g., Top1i plus tubulin inhibitors), to suppress multiple resistance pathways while preserving single-agent convenience. [5]
In parallel, dual-target ADCs (dual-epitope or dual-antigen) are under development. These antibodies seek to improve uptake and maintain activity by binding two epitopes, derived from the same or distinct antigens. For example, prostate cancer cells overexpress prostate-specific membrane antigen (PSMA) and/or six transmembrane epithelial antigen of the prostate 1 (STEAP1)—both are proteins associated with tumor growth and survival. Because prostate cancers may overexpress at least one of these targets, or both, a dual-targeting approach could increase the likelihood of ADC binding to more tumor cells than focusing on a single target alone. [6] Together, these architectures exemplify “next generation” intent: deeper, more durable responses across broader biomarker windows with safer systemic exposure. [5][6]
ADC science and innovation at AbbVie
Despite their growing adoption, treatment resistance – encompassing antigen loss/heterogeneity, reduced internalization, lysosomal dysfunction, efflux/repair upregulation – and toxicity management remain major constraints of today’s ADCs. Our Oncology Early Development (OED) team at AbbVie is driving scientific innovation to help address these unmet needs by prioritizing mechanism-based target selection, identifying and characterizing translational biomarkers, and developing and acquiring novel technologies across linkers, payloads, and conjugation methods to broaden tumor coverage and expand eligible patient populations.
A vital part of my role is to bring my vantage point of an ex-treating physician and a ‘bedside to bench’ perspective to our overall approach to R&D. Through the generation of rigorous, high quality preclinical data, we work to de-risk potential assets early, to accelerate progress towards patient-centric Phase 1 and clinical PoC clinical trials designed to address real problems and medical needs patients and physicians face and enable the initiation of registrational studies faster.
Our aim is to elevate standards of care and bring transformative therapies to patients worldwide living with difficult-to-treat cancers. We are advancing a dynamic pipeline of investigational therapies across a range of cancer types, including blood cancers and solid tumors, where survival rates remain low and the standard of care needs to be transformed. Historically, AbbVie’s oncology focus was on hematologic malignancies. Still, in recent years, this experience and heritage have been translated to drive the development of complex biologics for the treatment of solid tumors with high unmet needs, such as advanced lung cancer, ovarian cancer, and colorectal cancer.
AbbVie has developed a novel ADC platform through several decades of research and brings unique strengths in antibody engineering, drug-linker chemistry, and toxin research. AbbVie’s robust portfolio of novel ADCs targets unique cancer biomarkers and is armed with novel payloads such as monomethyl auristatin E (MMAE) and a proprietary Top1i payload. Our ADC platform is advancing with biomarker-targeted approaches focusing on both validated and novel targets, including c-Met, SEZ6, Fra, CD123, PSMA, and STEAP1, which are associated with hard-to-treat, prevalent, and rare solid tumor types.
Collectively, these programs illustrate our strategy centered on resistance-aware engineering, biomarker enrichment, and modality synergy to translate next-generation designs into meaningful clinical options. This is exemplified by the impact of our approved ADCs in folate receptor alpha (FRα) positive platinum-resistant ovarian cancer (8) and in previously treated, nonsquamous non-small lung cancer with high c-Met overexpression.(9)
Future outlook
The evolution of next-generation ADCs is well underway; dual-payload and dual-target ADCs are already moving from concept to preclinical and clinical evaluation as chemistries and analytics mature, offering practical ways to blunt clonal heterogeneity, limit antigen escape, and mitigate single-payload resistance. At the same time, payload innovation will broaden immunostimulatory ADCs (e.g., STING agonist ADCs) and dual-target ADCs provide options for deeper and more durable responses, while improved conjugation/linkers and companion diagnostics optimize patient selection.
In parallel, valuable lessons from hematologic multispecific antibodies (including BCMA×CD3) are informing efforts to design selective, tissue-sparing immune modulation for non-oncology indications. While still very early, these modalities illustrate how precise, multipathway targeting could recalibrate the efficacy/safety trade-offs in immune diseases —an area to watch as scientific and manufacturing know-how from oncology diffuses into immunology.
In terms of the bigger picture, sustained progress in the ADC space will depend on mechanism-first discovery approaches (resistance mapping, spatial biology, and circulating biomarkers); fit-for-purpose platforms (e.g., Top1i vs. tubulin payloads; single vs. dual-target formats) matched to tumor context; and agile early development (adaptive designs, rational combinations, and patient-centric dosing). AbbVie’s deep expertise and commitment to innovation in oncology is helping drive this next chapter for ADC scientific discovery and development, as the field seeks to unlock new targets and deliver novel treatments that raise the standards of care globally for patients.
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Highlights of Prescribing Information
Mirvetuximab Soravtansine (Elahere®; AbbVie)[Prescribing Information]
Telisotuzumab vedotin (Emrelis®; AbbVie)[Prescribing Information]
References
[1] Shastry M, Gupta A, Chandarlapaty S, Y et al. Rise of Antibody-Drug Conjugates: The Present and Future. Am Soc Clin Oncol Educ Book. 2023;43:e390094.
[2] Tsuchikama K, Anami Y, Ha SYY, et al. Exploring the next generation of antibody-drug conjugates. Nat Rev Clin Oncol. 2024;21(3):203-23.
[3] Modi S, Jacot W, Yamashita T et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20.
[4] Malli Cetinbas N, Monnell T, Soomer-James J et al. Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses. Nat Commun. 2024;15(1):5842.
[5] Tao J, Gu Y, Zhou W et al. Dual-payload antibody-drug conjugates: Taking a dual shot. Eur J Med Chem. 2025;281:116995.
[6] Reilly RM. Abstract ND03: ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant prostate cancer. Cancer Research. 2025;85(8_Supplement_2):ND03-ND.
[7] Klein C, Brinkmann U, Reichert JM et al. The present and future of bispecific antibodies for cancer therapy. Nat Rev Drug Discov. 2024;23(4):301-19.
[8] FDA. ELAHERE (mirvetuximab soravtansine-gynx) injection, for intravenous use, 2022 Online Last accessed on November 8, 2025.
[9] FDA. EMRELIS (telisotuzumab vedotin-tllv) for injection, for intravenous use 2025. Online. Last accessed on November 8, 2025.
Featured image: AbbVie R&D has focused on developing biologics. In particular, antibody therapeutics have been clinically proven effective in oncology and immunology. Photo courtesy: © 2019 – 2025 AbbVie. Used with permission.
DOI: 10.14229/jadc.2025.10.08.001.
