Technical Sharing: Clinical Bioanalytical Case Study of Antibody-Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) represent one of the fastest-growing cancer therapies developed over the past few decades. By combining the potent cytotoxic effects of payload molecules with the high specificity and selectivity of monoclonal antibodies toward tumor cell membrane antigens, ADCs have demonstrated encouraging results in oncology. Since the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) — the first ADC drug — in August 2011, global research and clinical application of ADCs have advanced rapidly. 1. Mechanism of Action of ADCs Like most cytotoxic agents, ADCs used as monotherapy have limited durability due to drug resistance and high tumor heterogeneity, necessitating multi-pronged attacks on tumor cells. Evidence suggests that ADCs can effectively enhance the efficacy of immunotherapeutics [1]. Typically, an ADC comprises a highly specific and high-affinity antibody (which may be a chimeric antibody, an antibody fragment, or a bispecific antibody), a highly stable linker, and a small-molecule cytotoxic payload. Linkers are classified as either cleavable or non-cleavable. Cleavable linkers exploit environmental differences between systemic circulation and tumor cells to precisely release free active payloads; they are further subdivided into chemically cleavable linkers (e.g., hydrazone and disulfide bonds) and enzymatically cleavable linkers (e.g., glucuronide and peptide bonds) [2]. In contrast, non-cleavable linkers require degradation of the antibody itself to release the payload. Small-molecule cytotoxic payloads generally fall into two categories: DNA-targeting cytotoxins and microtubule inhibitors [3]. Common DNA-targeting cytotoxins include calicheamicin, pyrrolobenzodiazepine (PBD), duocarmycin, and camptothecin (CPT); common microtubule inhibitors include monomethyl auristatin E/F (MMAE/MMAF), maytansinoid derivatives (DM2/DM4), tubulysins, and cryptomycins (CR). The antibody component specifically recognizes antigens on target cells, promoting formation of the antigen–antibody conjugate and interacting with both cancer and immune cells via immunological mechanisms — such as inducing immunogenic cell death, dendritic cell maturation, and increased T-lymphocyte infiltration — thereby exerting antitumor effects. First, the monoclonal antibody selectively binds tumor surface antigens via its targeting function; the resulting complex is internalized via endocytosis, trafficked through endosomes into lysosomes, where the acidic environment and proteolytic enzymes degrade the ADC and release the payload into the cytoplasm. The payload then induces tumor cell apoptosis via mechanisms such as DNA intercalation or inhibition of microtubule synthesis [4]. 2. Adverse Reactions Associated with ADCs The effective payload of ADCs is released and exerts its biological activity, leading to cancer cell death. The intracellular payload quantity per cell depends on three key factors: the number of antigens expressed on each cell’s surface, the number of payload molecules per ADC molecule (also known as the drug-to-antibody ratio, DAR), and the time required for antigen recycling back to the cell surface.

The 40-Year Development Journey of Antibody-Drug Conjugates (ADCs)

This article provides an overview: ADCs constitute a rapidly evolving therapeutic modality in oncology. To date, a total of 15 ADC drugs have received global regulatory approval, including 11 approved by the FDA. In China, seven ADCs have been approved: trastuzumab emtansine, brentuximab vedotin, inotuzumab ozogamicin, disitamab vedotin, sacituzumab govitecan, and datopotamab deruxtecan. Over 210 ADC candidates are currently undergoing clinical trials. The dominant payload classes have evolved across different eras: from vinca alkaloids and DNA-damaging agents in the 1980s, to calicheamicin, auristatins, maytansinoids, and PBDs in subsequent decades, and more recently to camptothecin-based ADCs — reflecting an ongoing pursuit of more potent, stable, and selective payloads. Highly stable ADCs ensure minimal premature payload release prior to reaching the tumor site, thereby reducing off-target tissue toxicity. Stability can be enhanced through improved linker design and conjugation technologies. Conversely, instability increases drug distribution to non-tumor tissues, elevating toxicity while diminishing efficacy. For instance, certain ADCs suffer from unstable linker–payload or antibody–linker bonds, resulting in premature release of free payload into systemic circulation. Although ADCs utilize antibody-mediated targeting to deliver payloads to tumor cells, only a small fraction (typically <1%) actually reaches the tumor to exert therapeutic effects; the majority is taken up by normal tissues. Payload release and metabolism occur both in tumor and non-tumor tissues, and the resulting metabolites are commonly eliminated via conventional small-molecule drug clearance pathways. Following ADC administration, concentrations of total antibody and released payload decline gradually over time, with half-lives measured in days — indicating prolonged systemic residence. Thus, the ADC serves as a ‘reservoir’ for the payload. In contrast, conventional small-molecule chemotherapeutics exhibit half-lives measured in hours — far shorter than those of ADCs. ADCs exert indirect antitumor effects through payload release and metabolism in normal tissues, which also helps explain their characteristic adverse-effect profile.

ESMO: Bristol Myers CMO touts '5 out of 5' positive phase 3 trials for bispecific ADC iza-bren

1 day ago

Bristol Myers Squibb's CMO highlighted five consecutive positive Phase 3 trials for its bispecific ADC iza-bren, showing significant progression-free survival benefits in lung and breast cancers. Global trials are now underway following these successful results in China.

Fierce Pharma

2026-10-26

ESMO: Bristol Myers CMO touts '5 out of 5' positive phase 3 trials for bispecific ADC iza-bren

ESMO: Bristol Myers CMO touts '5 out of 5' positive phase 3 trials for bispecific ADC iza-bren

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