Front Cell Dev Biol. 2025 Oct 8;13:1669592. doi: 10.3389/fcell.2025.1669592… # Antibody-drug conjugates in cancer therapy: current advances and prospects for breakthroughs
Dan Wu
^1^ Cancer Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
^2^ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, Sichuan, China… ^1,^^2,^^†^, Runjia He
^4^ Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
^4,^^†^, Rutie Yin
^1^ Cancer Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China… ^2^ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, Sichuan, China
^1,^^2^, Lin Shui
^1^ Cancer Center, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
^2^ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, Sichuan, China… ## Abstract
Antibody-drug conjugates (ADCs), often referred to as “intelligent biological missiles,” have garnered significant attention in the rapidly evolving landscape of cancer therapy. ADCs represent a sophisticated approach by integrating monoclonal antibodies (mAbs), which are particular targeting tumor antigens, with cytotoxic payloads, which deliver lethal effects…. Compared with the combination of chemotherapy and mAbs, ADCs precisely deliver highly potent cytotoxins directly to tumor cells while minimizing damage to healthy tissues. However, limitations such as significant adverse effects, suboptimal therapeutic efficacy, and drug resistance require carefully evaluation and further optimization. Further studies are necessary to explore the next-generation of ADCs, such as the combination of ADCs with other anti-tumor strategies, bispecific ADCs, dual-payload ADCs and radionuclide drug conjugates (RDCs)…. This review provides a comprehensive overview of recent developments in oncology treatment, focusing on the historical evolution, structural design, clinical advancements, and mechanisms of action of approved ADCs. Each structural element, including the target antigen, mAb, linker system, and cytotoxic payload, as well as advancements in payload conjugation technology, plays a critical role in the development of ADCs. Through ongoing refinement and innovation, it is anticipated that next-generation ADCs with enhanced therapeutic benefits for patient populations can be realized.
**Keywords:** antibody drug conjugate (ADC), antitumor treatment, linker, payload, drug approval… ## 2 Core components of ADCs
Generally, ADCs consist of three critical components: a mAb, a cytotoxic payload, and a chemical linker (Figure 1B). Each of these elements plays an indispensable role in determining the efficacy and safety profile of ADCs…. ### 2.1 Targeting module–monoclonal antibody (mAb)
MAbs function as the targeting component in ADCs, enabling the specific recognition and binding to antigens expressed on the surface of cancer cells. To achieve optimal performance, mAbs need to exhibit low immunogenicity, high specificity and affinity for the target antigen, an extended half-life, and stability during circulation in the bloodstream (Köhler and Milstein, 1975; Goldmacher and Kovtun, 2011)…. Humanized or fully human mAbs are favored due to the high specificity for cell targeting, extended circulation time in human blood, and diminished immunogenicity (Tsuchikama and An, 2016). Due to its sustained efficacy, adaptability for engineering, and well-established conjugation methods, IgG has become the preferred choice for ADCs…. Additionally, IgG demonstrates potent effector functions mediated by its Fc segment (Hoffmann et al., 2018), such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Besides IgG antibodies, innovative antibody formats, such as single-chain fragment variables (scFvs) and nanobodies have gained increasing attention in the development of ADCs…. #### 2.2.1 Tubulin inhibitors
Most second-generation ADCs incorporate tubulin inhibitors as payloads. Microtubules function as critical cytoskeletal components, playing a pivotal role in intracellular transport, cell division, cellular motility, and the maintenance of cellular morphology (Hohmann and Dehghani, 2019). Specifically, the entire microtubule network rearranges to form the mitotic spindle during cell division, thus providing the structural framework for the physical segregation of sister chromatids…. #### 2.2.2 DNA-damaging agents
Although tubulin inhibitors demonstrate high efficacy against rapidly proliferating tumor cells, their activity is significantly diminished in quiescent cancer cell populations. To overcome this limitation, third-generation ADCs primarily utilize DNA-damaging agents capable of targeting all phases of the cell cycle as cytotoxic payloads. These agents disrupt DNA structure through mechanisms such as double-strand breaks, alkylation, intercalation, and cross-linking (Roos and Kaina, 2013; Brinkman et al., 2021)…. Notable examples of DNA inhibitors encompass topoisomerase I (Top1) inhibitors, calicheamicin, and the pyrrolobenzodiazepines (PBDs). In recent years, 8 ADCs based on DNA-damaging agents are approved for anti-tumor treatment in clinical practice. Detailed mechanisms and approved drugs are listed in Figure 3…. ### 2.3 Conjugation bridge–linker
As a critical component in ADCs, the linker serves as the “bridge” by securely connecting the antibody to the cytotoxin. A fundamental requirement for linkers is to maintain chemical stability within the bloodstream while enabling rapid and efficient payload release at the target site following cellular internalization (Aoyama et al., 2024; Lucas et al., 2018). Diverse types of linkers can generally be classified into cleavable and non-cleavable categories (Tsuchikama and An, 2016; Bargh et al., 2019)…. #### 2.3.1 Cleavable linkers
Cleavable linkers constitute a major category employed in ADC development. In contrast to non-cleavable linkers, cleavable linkers facilitate drug release within target cells under specific intracellular conditions, such as acidic environments, reducible conditions, specific enzymes and external stimuli (e.g., photons). Although cleavable linkers generally exhibit lower systemic stability and carry a higher risk of off-target toxicity, they offer greater versatility and can be paired with a broader range of payloads…. ## 3 Mechanism of ADCs
ADCs are a class of large molecular that undergo cellular internalization through membrane encapsulation, forming vesicular structures that facilitate transport into the cytoplasm-a process called endocytosis. Specifically, ADCs selectively bind to tumor antigen and form ADC-antigen complexes, subsequently internalized into the cell through clathrin- or caveolin-mediated endocytosis and enclosed in early endosomes, which progressively mature into late endosomes before fusing with lysosomes (Fu et al., 2022)…. ## 4 The application of approved ADC drugs in hematological tumors
The initial ADCs that entered the market were predominantly used for hematological tumors. Currently, seven ADCs have been approved for hematological tumors, providing a novel option for later-stage treatment…. ### 4.1 Gemtuzumab ozogamicin (Mylotarg ®, Pfizer)
Chemotherapy and hematopoietic stem-cell transplantation (HSCT) are among the limited therapeutic options available for AML patients (Alibhai et al., 2009; Mayer et al., 1994; Fernandez et al., 2009; Pulte et al., 2009). More than 90% of AML patients exhibit leukemia cells with high CD33 expression levels, thereby rendering CD33 an attractive target for ADC drugs…. #### TABLE 3.
Clinical endpoints of ADCs.
|Cancer|Targets|Name|Trial design|Indication|Clinical outcome|
|–|–|–|–|–|–|
|B-cell malignant tumors|CD30|Brentuximab vedotin|phase II|R/R la/m cHLand sALCL|cHL: ORR is 73%, CR is 34% (Younes et al., 2012b)sALCL: ORR is 86%, CR is 57% (Pro et al., 2012)|… This approval was based on the findings from an open-label, global, multicenter, phase Ib/II clinical trial (GO29365) (Deeks, 2019; Urquhart, 2019)…. ### 4.6 CD22-targeting ADC
CD22 is a key factor in the development, differentiation, and function of B cells, and is expressed in 60%–90% cases of B-ALL (Singh et al., 2021; Lanza et al., 2020; Shah et al., 2015) as well as in the majority of hairy cell leukemia (HCL) cells (Grever et al., 2014). CD22 exhibits rapid internalization upon binding to its cognate antigen, representing an attractive target for the development of ADCs. As of the latest updates, two CD22-ADCs have received global marketing approval…. ## 5 The application of approved ADC drugs in solid tumors
With advancements in technology, ADCs have overcome their application limitations and are now equally effective in treating both solid and hematological tumors.