Antibody-drug conjugates (ADCs) represent a transformative approach in cancer therapy, combining the specificity of monoclonal antibodies with the potency of cytotoxic drugs. Over the last decade, the field has rapidly evolved, with growing clinical success and an expanding pipeline of candidates.
ADCs are complex molecules designed to deliver highly potent cytotoxic agents directly to tumor cells while sparing healthy tissue. They are composed of three key components:
A monoclonal antibody (mAb) that specifically targets antigens on tumor cells.
A cytotoxic payload (e.g., auristatins, maytansinoids, calicheamicin, PBDs, or topoisomerase I inhibitors).
A chemical linker that joins the payload to the antibody and controls its release.
One of the parameters influencing ADC performance is the drug-to-antibody ratio (DAR), which refers to the average number of payload molecules attached to each antibody. Approved ADCs generally have DARs ranging from 2 to 8. Higher DARs can improve therapeutic efficacy, but may increase toxicity or reduce stability and half-life.1 For instance:
Trastuzumab deruxtecan: DAR 7.8
Sacituzumab govitecan: DAR 7.6
Trastuzumab emtansine: DAR 3.5
Innovations in linker and conjugation chemistry have improved ADC homogeneity and pharmacokinetics, enabling higher DARs without compromising stability or safety.
Related: ADC Production
The global ADC market continues to expand, fueled by rising cancer incidence, enhanced targeting strategies, and technological advances in ADC engineering. As of 2025:
15 ADCs have been approved by the FDA, but there are 19 approved by at least one regulatory agency in the world, in total.2
These include 7 for hematological malignancies and 8 for solid tumors.
Dozens more are in late-stage trials or under regulatory review.
The market size surpassed USD 10 billion in 2024 and is projected to grow at a CAGR of over 16% through 2030.
Roche remains a leading ADC innovator with two FDA-approved products:
Kadcyla® (trastuzumab emtansine): Approved for HER2-positive breast cancer and early-stage breast cancer (adjuvant setting).
Polivy® (polatuzumab vedotin): Approved for both relapsed and untreated diffuse large B-cell lymphoma (DLBCL), now part of the first-line pola-R-CHP regimen.
Seagen developed several pivotal ADCs:
Adcetris® (brentuximab vedotin): For Hodgkin lymphoma, anaplastic large cell lymphoma, and CD30+ peripheral T-cell lymphoma.
Padcev® (enfortumab vedotin): Approved for metastatic urothelial carcinoma, with expanding use in combination with immunotherapy.
Tivdak® (tisotumab vedotin): Targets tissue factor (TF) and is approved for recurrent or metastatic cervical cancer.
This partnership has been instrumental in developing high-DAR, topoisomerase I inhibitor-based ADCs:
Enhertu® (trastuzumab deruxtecan): Approved for HER2+ and HER2-low metastatic breast cancer, gastric cancer, and lung cancer.
Dato-DXd and other DXd-based ADCs are in late-stage clinical trials targeting TROP2, HER3, and more.
Elahere® (mirvetuximab soravtansine): First ADC approved for folate receptor alpha (FRα)-positive, platinum-resistant ovarian cancer. Combination strategies are being explored to enhance efficacy and reduce ocular toxicity.
Trodelvy® (sacituzumab govitecan): First TROP2-targeting ADC approved for metastatic triple-negative breast cancer (TNBC), with additional indications in urothelial carcinoma and ongoing studies in other tumor types.
Blenrep® (belantamab mafodotin): Approved in 2020 for relapsed/refractory multiple myeloma, withdrawn in 2022 due to confirmatory trial failure but remains in development through combination regimens.
Zynlonta® (loncastuximab tesirine): Approved for relapsed/refractory DLBCL; utilizes a pyrrolobenzodiazepine (PBD) dimer payload.
Mylotarg® (gemtuzumab ozogamicin): The first ADC ever approved, targeting CD33 in AML. Initially withdrawn, later re-approved with a fractionated dosing strategy to reduce toxicity.
Besponsa® (inotuzumab ozogamicin): Targets CD22 in relapsed/refractory B-cell ALL and was recently approved for pediatric use.
Related: ADC Production
RemeGen - Disitamab vedotin: Approved in China for HER2-positive gastric cancer and advancing globally in multiple HER2-positive and HER2-low indications, including breast, bladder, and lung cancers.
Rakuten Medical - Cetuximab sarotalocan: A first-in-class photoimmunotherapy ADC approved in Japan for head and neck squamous cell carcinoma (HNSCC), utilizing light-activated payload release.
Byondis - Trastuzumab duocarmazine (SYD985): A next-gen HER2 ADC with a DNA alkylating payload (seco-DUBA). Phase III trials in HER2-positive breast cancer have completed with promising results.
Mersana Therapeutics - Developer of XMT-1660 and other candidates using proprietary Dolaflexin and Immunosynthen platforms to enhance tumor penetration and immune activation.
Zymeworks - Focuses on conditionally activated ADCs like ZW49, improving tumor specificity while minimizing systemic toxicity.
ProfoundBio - Advancing exatecan-based ADCs, such as PRO1184, targeting folate receptor alpha with innovative linker and conjugation technologies.
Linkers and Payloads: ADC design continues to benefit from advances in linker chemistry and payload diversification. Cleavable linkers, such as Val-Cit-PABC, are responsive to lysosomal enzymes and enable tumor-specific release of cytotoxic agents. In contrast, non-cleavable linkers offer enhanced plasma stability, as demonstrated by the SMCC linker in Kadcyla®. Payload development has also evolved, with newer classes including DNA crosslinkers like pyrrolobenzodiazepines (PBDs), topoisomerase I inhibitors such as DXd and SN-38, immune-stimulatory agents that engage innate immunity, and photosensitizers like IRDye700DX used in photoimmunotherapy.
Conjugation Techniques: Precise control over drug-to-antibody ratio (DAR) and molecular uniformity is increasingly achieved through site-specific conjugation methods. Platforms such as THIOMAB, SMARTag, and Synaffix enable conjugation at defined sites, reducing product heterogeneity and improving pharmacokinetics. Additionally, advances in linker engineering have made it feasible to construct high-DAR ADCs without compromising molecular stability or increasing systemic toxicity.
As of 2025, over 24 ADCs are in phase III trials, with notable agents including:
Tusamitamab ravtansine (Sanofi): Targets CEACAM5 in NSCLC.
Oportuzumab monatox (Sesen Bio): EpCAM-targeting ADC for non-muscle-invasive bladder cancer.
Depatuxizumab mafodotin: EGFR-targeted ADC in glioblastoma.
Zilovertamab vedotin (Oncternal): ROR1-targeted ADC for hematologic malignancies.
HER2 remains the most targeted antigen, but new targets such as CDH6, EpCAM, ITGB6, CD276, and CEACAM5 are gaining momentum.
Developing a successful ADC requires:
Antibody Engineering: Selection of highly specific monoclonal antibodies.
Linker Chemistry: Stability in plasma and efficient release inside the tumor cell.
Potent Payloads: Such as MMAE, DM1, or topoisomerase inhibitors.
Conjugation Process: Site-specific or stochastic methods depending on platform.
CROs like Biointron offer ADC production.
At Biointron, we are dedicated to accelerating antibody discovery, optimization, and production. Our team of experts can provide customized solutions that meet your specific research needs, including HTP Recombinant Antibody Production, Bispecific Antibody Production, Large-Scale Antibody Production, and Afucosylated Antibody Expression. Contact us to learn more about our services and how we can help accelerate your research and drug development projects.
References:
Wang, R., Hu, B., Pan, Z., Mo, C., Zhao, X., Liu, G., Hou, P., Cui, Q., Xu, Z., Wang, W., Yu, Z., Zhao, L., He, M., Wang, Y., Fu, C., Wei, M., & Yu, L. (2025). Antibody–Drug Conjugates (ADCs): current and future biopharmaceuticals. Journal of Hematology & Oncology, 18(1). https://doi.org/10.1186/s13045-025-01704-3
The Antibody Society. Therapeutic monoclonal antibodies approved or in regulatory review. (date accessed); www.antibodysociety.org/antibody-therapeutics-product-data
PEGS Europe2025 conference was held inLisbon, Portugal, fromNovember11to Novembe……
Antibody discovery has traditionally relied on selecting clones based on target ……
The Society for Immunotherapy of Cancer (SITC) 2025 conference was held in Natio……
A VHH library is a collection of variable domains of heavy-chain antibodies (VHH……
You can also contact us on the Scientist and Science Exchange marketplaces.
