Antibody-drug conjugates (ADCs) are a class of targeted biotherapeutics that combine the specificity of monoclonal antibodies with the cytotoxic potency of small molecule drugs. ADCs are engineered to deliver payloads directly to tumor cells, reducing systemic exposure compared to traditional chemotherapy. As of the end of 2025, 21 ADCs have been approved globally, with four new approvals added in 2025 alone. This growth reflects expanding therapeutic indications, technological innovation, and increasing demand for effective treatments in oncology and beyond.
Monoclonal antibodies (mAbs) gained clinical prominence in the 1980s, but early dosimetry studies showed that tumor uptake was extremely low. Radiolabeled mAbs in clinical trials demonstrated a median of approximately 0.01% of the injected dose per gram of tumor one day post-injection, independent of tumor type or antibody used. These findings underscored the delivery limitations of unconjugated antibodies.
To address this limitation, ADCs were developed to harness antibodies as selective delivery vehicles for highly potent cytotoxic drugs. The key challenge was identifying payloads potent enough to kill tumor cells at sub-nanomolar concentrations, given the low antibody accumulation in tumors. Early immunotoxins used protein-based payloads like ricin, but these molecules were limited by short half-lives and high immunogenicity.
The first approved ADC, gemtuzumab ozogamicin (Mylotarg), was approved in 2000 for CD33-positive acute myeloid leukemia. Its approval marked the beginning of a new therapeutic modality. Since then, advances in linker chemistry, payload classes, and antibody formats have driven expansion of the ADC field.
ADCs are designed to bind to specific antigens on tumor cells, undergo internalization via receptor-mediated endocytosis, and release their cytotoxic payload following lysosomal degradation or cleavage. Efficient internalization and trafficking are critical to therapeutic activity.
For example, studies of trastuzumab-based ADCs such as T-DM1 (ado-trastuzumab emtansine) in HER2-overexpressing tumor models show that tumor accumulation can reach 9% of the injected dose per gram of tumor tissue. However, intracellular drug release remains a limiting factor, and a significant portion of the antibody may remain in circulation or be cleared before payload activation occurs. Tumor antigen density and internalization efficiency are key determinants of ADC efficacy.
Some next-generation ADCs utilize biparatopic or bispecific antibodies to improve internalization or broaden tumor targeting. These formats aim to overcome the limitations of single-epitope targeting and low receptor density in certain tumor types.
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The linker component of an ADC controls when and where the cytotoxic payload is released. Linkers must remain stable in systemic circulation while enabling efficient release in the tumor microenvironment or intracellularly. Common linker types include:
Cleavable linkers, which respond to intracellular conditions such as acidic pH or protease activity.
Non-cleavable linkers, which require complete antibody degradation to release the payload.
Disulfide and peptide linkers, such as those used in DM4- and MMAE-based ADCs, can generate a "bystander effect." In this phenomenon, the payload diffuses out of target-positive cells and kills adjacent target-negative cells. This property may enhance efficacy in tumors with heterogeneous antigen expression, although it also increases the risk of off-target toxicity.
Studies using disulfide-linked conjugates like anti-CanAg-DM4 demonstrated bystander killing in co-culture systems of antigen-positive and antigen-negative cells. Linker design, therefore, not only affects stability and release but also spatial cytotoxicity in the tumor microenvironment.
Most clinically approved ADCs utilize microtubule inhibitors such as auristatins (MMAE, MMAF) or maytansinoids (DM1, DM4). These compounds disrupt mitotic spindle formation and induce cell death at low nanomolar concentrations.
DNA-interacting agents are also widely used. These include calicheamicin (used in Mylotarg and Besponsa) and topoisomerase I inhibitors such as deruxtecan derivatives, which are employed in Enhertu and other investigational ADCs.
Emerging payload classes include:
Tubulysins, which are more potent than auristatins.
Indolinobenzodiazepines (IGNs) and PBD dimers, which alkylate DNA without requiring proliferation.
α-Amanitin, which inhibits RNA polymerase II.
Proteolysis-targeting chimeras (PROTACs), which induce selective protein degradation.
The choice of payload influences not only efficacy but also the therapeutic index, route of resistance, and safety profile.
In 2025, four ADCs were approved globally, reflecting both target and payload diversity:
Telisotuzumab vedotin (Emrelis): An anti-c-Met antibody conjugated to MMAE, approved in the United States for non-small cell lung cancer (NSCLC) with high c-Met expression (May 14, 2025).
Trastuzumab rezetecan: An anti-HER2 antibody linked to a topoisomerase I inhibitor, approved in China for IL-17-related autoimmune diseases (May 29, 2025), representing a rare non-oncology indication.
Trastuzumab botidotin: An anti-HER2 ADC carrying MMAF, approved in China for HER2-positive breast cancer (October 17, 2025).
Becotatug vedotin (美佑恒): An EGFR-targeting ADC using MMAE, approved for recurrent or metastatic nasopharyngeal carcinoma (October 30, 2025).
These approvals highlight expansion into solid tumors and demonstrate ADC adaptability for both oncology and inflammatory diseases.
According to Toward Healthcare, the global ADC market is projected to grow from USD 13.51 billion in 2025 to USD 32.66 billion by 2035, at a compound annual growth rate (CAGR) of 9.23%. The largest market share in 2023 was held by North America (53%), with Asia-Pacific experiencing the fastest growth due to increased clinical activity in China and regulatory support.
Breast cancer accounted for the largest application share (49%) in 2023, and HER2-targeted ADCs such as Kadcyla and Enhertu led the product category. The CD22 target segment is expected to grow fastest over the next decade, supported by ongoing development in hematologic malignancies.
Top contributors to the ADC market include Seagen, AstraZeneca, Daiichi Sankyo, Pfizer, and Roche. Pfizer’s acquisition of Seagen for $43 billion in 2023 and AstraZeneca’s construction of a $1.5 billion ADC manufacturing facility in Singapore in 2024 reflect increasing investment and strategic expansion.
Despite strong growth, ADC development remains complex and resource-intensive. Challenges include:
Antigen specificity and internalization: Ideal ADC targets must be tumor-specific, abundantly expressed, and internalized efficiently. Many antigens fail to meet all criteria.
Systemic toxicity: Cytotoxic payloads can cause off-target effects such as myelosuppression, hepatotoxicity, and neuropathy. Many patients require dose reductions or discontinuation due to adverse events.
Resistance mechanisms: Tumor cells may reduce target expression, enhance drug efflux, or alter endocytic pathways, reducing ADC effectiveness.
Low overall success rate: Although over 100 ADCs have entered clinical trials, only 16 had gained FDA approval by the end of 2025. Even with recent approvals, attrition remains high.
PTRS (probability of technical and regulatory success) analysis from 2025 shows ADCs outperform the oncology drug class average, with a 50% success rate in Phase 3, compared to 42% for oncology overall. However, high toxicity remains a major hurdle.
Technological advances continue to address the above limitations. Key areas include:
Biparatopic antibodies bind two epitopes on the same antigen, increasing internalization. For example, the biparatopic HER2-targeting ADC JSKN003 was developed by site-specific conjugation to the Fc glycans of anbenitamab, resulting in a homogeneous and stable ADC with a DAR of 4. JSKN003 binds to two HER2 epitopes on tumor cells and releases topoisomerase I inhibitors through cellular endocytosis, exerting anti-tumor effects. Bispecific ADCs, binding two different targets, aim to increase tumor specificity and broaden application.
Tumor-activated prodrugs (TAPs) are less toxic precursors designed to be selectively activated within tumor tissue. Activation can occur through tumor-specific enzymes, hypoxic conditions, or targeted delivery systems such as ADEPT (antibody-directed enzyme prodrug therapy) or GDEPT (gene-directed enzyme prodrug therapy). Since only a subset of tumor cells may activate the prodrug, effective TAPs must also produce a bystander effect to eliminate nearby non-activating cells. Activation chemistries include enzymatic reduction of nitroaromatics and N-oxides, peptide cleavage by proteases, and hydrolysis by exogenous enzymes such as phosphatases and glycosidases.
Bispecific apoptosis triggers, which engage death receptors such as DR5, activate extrinsic apoptotic signaling without requiring internalization or payloads. This mechanism avoids common resistance routes and offers a safer profile.
AI is increasingly integrated into ADC design and optimization. Algorithms assist in:
Identifying antibody-payload combinations
Predicting antigen expression patterns
Modeling conjugation efficiency
Forecasting patient response
AI also plays a role in process optimization during ADC manufacturing, enabling real-time monitoring and quality control. As data accumulates, AI will likely contribute to faster, more efficient ADC development pipelines.
As ADCs become more complex, with bispecific, biparatopic, and site-specific conjugation requirements, antibody CROs must provide flexible, scalable, and robust expression systems. Challenges include:
Engineering antibodies with unique conjugation handles
Ensuring consistent glycosylation and folding profiles
Supporting Fc modifications or unnatural amino acid incorporation
Reliable expression of these engineered antibodies is critical for the consistent production of high-purity ADC intermediates. CROs like Biointron, with expertise in recombinant antibody production and engineering, are well positioned to support this expanding therapeutic class.
ADC High-throughput Antibody Conjugation →
References:
Bross, P. F., Beitz, J., Chen, G., Chen, X. H., Duffy, E., Kieffer, L., Roy, S., Sridhara, R., Rahman, A., Williams, G., & Pazdur, R. (2001). Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clinical cancer research: an official journal of the American Association for Cancer Research, 7(6), 1490–1496.
Towards Healthcare. (2025, December 29). Antibody Drug Conjugate Market Evolution with Targeted Therapies. Towardshealthcare.com; Towards Healthcare. https://www.towardshealthcare.com/insights/antibody-drug-conjugate-market-sizing
Denny W. A. (2004). Tumor-activated prodrugs--a new approach to cancer therapy. Cancer investigation, 22(4), 604–619. https://doi.org/10.1081/cnv-200027148
Alphamab Oncology. (2025, October 27). Alphamab Oncology Announces Biparatopic HER2-targeting ADC JSKN003 Received Approval to Initiate a Phase III Clinical Study for Colorectal Cancer. Alphamabonc.com. https://www.alphamabonc.com/en/html/news/2727.html
Riccardi, F., Dal Bo, M., Macor, P., & Toffoli, G. (2023). A comprehensive overview on antibody-drug conjugates: From the conceptualization to cancer therapy. Frontiers in Pharmacology, 14, 1274088. https://doi.org/10.3389/fphar.2023.1274088
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