Editor's Note: Since the German scientist Paul Ehrlich introduced the concept of the "magic bullet" in 1913, antibody-drug conjugates (ADCs) have revolutionized cancer treatment, leading to significant breakthroughs and providing highly effective therapeutic options for patients. To date, more than 300 ADCs have been investigated for various cancer indications, and several have achieved clinical approval. However, as research has advanced, challenges such as changes in antigen expression, ADC processing efficiency, and payload release have emerged, giving rise to resistance. Addressing these challenges has become a priority for the field.Recently, Dr. Yongsheng Li’s team from Chongqing University Cancer Hospital published a comprehensive review titled “Antibody-drug conjugates in cancer therapy: mechanisms and clinical studies” in the high-impact journal MedComm (IF: 10.7). This review offers a detailed overview of ADCs, covering their historical evolution, structure, mechanisms of action, advancements in components, target selection, completed and ongoing clinical trials, resistance mechanisms, and future prospects. Below is an analysis of the key insights from their study.
The Evolution of ADCs: A Historical Perspective
The concept of ADCs was first proposed in 1967, but it wasn’t until 2000 that gemtuzumab ozogamicin (GO) became the first ADC approved by the FDA, marking a pivotal moment in targeted cancer therapy. GO’s approval for treating acute myeloid leukemia (AML) signified the beginning of the ADC era in oncology.
ADCs are engineered by conjugating an antibody to a cytotoxic drug via a linker. This innovative structure enables ADCs to combine the potent cell-killing power of traditional chemotherapy with the precision targeting of antibodies. Once administered, the antibody component binds to specific antigens on the surface of tumor cells, facilitating internalization of the ADC into the cell. Within the endosome, the ADC can interact with Fc receptors, resulting in partial transport back to the cell surface and subsequent extracellular release through FcRn-mediated transcytosis. Alternatively, ADC-antigen complexes are directed to lysosomes, where enzymatic degradation or acidic conditions release the cytotoxic payload. This payload then disrupts DNA or inhibits tumor cell division, ultimately inducing cell death.
Advances in ADC Development and Applications
Advancements in ADC technology have led to the development of a growing number of drugs for various types of cancer. Currently, more than 300 ADC candidates are being evaluated in clinical trials, spanning different stages of development. In oncology, approved ADCs target specific proteins that are overexpressed on tumor cells, such as HER2, Trop2, Nectin4, and EGFR in solid tumors, as well as CD19, CD22, CD33, CD30, and CD79b in hematologic malignancies. The success of drugs like T-DM1 and recent approvals of T-Dxd, sacituzumab govitecan, and enfortumab vedotin have significantly expanded the use of ADCs in solid tumor treatment.
Beyond traditional tumor cell antigens, ADC research has extended to targets in the tumor microenvironment, including stromal and vascular system components. Recent evidence from preclinical and clinical studies highlights the potential of targeting neovascularization, extracellular matrix components, and tumor stroma for ADC development, signaling a shift in how these drugs may be utilized in the future.
Challenges and Mechanisms of Resistance
Despite significant progress, ADCs face challenges, particularly with resistance. Clinical data shows a wide range of progression-free survival (PFS) outcomes, from as short as 2.0 months to as long as 28.8 months. Resistance can arise from abnormalities in any component of the ADC structure or as a result of therapeutic pressure during treatment. Resistance mechanisms include the downregulation, deletion, or mutation of target antigen genes, which can make the tumor cells less responsive to ADCs. Impaired internalization pathways and reduced lysosomal proteolytic function can also diminish the effectiveness of the ADC once inside the cell. Additional factors, such as cell cycle arrest, overexpression of drug efflux transport proteins, dysregulation of apoptotic pathways, and the activation of alternative signaling pathways, further complicate the issue.
The Promise of ADCs and Future Directions
ADCs offer several advantages, including high specificity, strong efficacy, a long half-life, fewer adverse effects, and favorable prognoses for patients. These attributes have established ADCs as a critical focus in global drug development. Optimizing ADC design requires a deeper understanding of the interplay between structure, clinical activity, and mechanisms of action. Identifying novel antigens and cytotoxic payloads will be essential for improving therapeutic efficacy. Furthermore, advancing ADCs with innovative biomarkers, linkers, payloads, and mechanisms of action holds promise for expanding cancer treatment options.
The development of ADCs has also led to the emergence of combination therapies, which show potential in enhancing treatment efficacy. As the field moves forward, researchers will focus on refining ADC design, overcoming resistance, and exploring new therapeutic combinations to improve outcomes for patients with cancer.
