Antibody-Drug Conjugates (ADCs) vs. Traditional Chemotherapy: Targeted Therapy vs. Broad Spectrum Treatment

Introduction

Cancer treatment has constantly improved, aiming for better effectiveness and reduced side effects for patients. Traditional chemotherapy has been widely used for a long time, but it affects healthy cells along with cancer cells, causing side effects like hair loss, nausea, and fatigue. Antibody-Drug Conjugates (ADCs) are a new type of targeted therapy that offers a more precise way to kill cancer cells. This article will compare and contrast ADCs with traditional chemotherapy in terms of how well they work, side effects, and patient outcomes.

Mechanism of Action

  • Traditional Chemotherapy: These drugs target fast-growing cells, including cancer cells, by interfering with their division process. However, they can also harm healthy dividing cells, causing side effects.

The mechanisms of action of the main chemotherapeutic agents. There are several mechanisms by which chemotherapeutic agents act in the cancer cell (a) intercalate into DNA and disrupt topoisomerase-II-mediated DNA repair (doxorubicin); (b) promote microtubule polymerization and stabilization (paclitaxel and docetaxel); (c) form DNA crosslinks (cisplatin, carboplatin); (d) inhibit thymidylate synthase (TS) (5-fluorouracil); (e) act as pyrimidine nucleoside antimetabolite (gemcitabine); (f) bind to the minor groove of the DNA (trabectedin). Commonly, all of them cause inhibition the DNA replication and transcription and cancer cell death.

  • Antibody-Drug Conjugates (ADCs): ADCs have three main parts:
    1. Monoclonal Antibody: This molecule can identify and attach to a specific protein (antigen) on the surface of cancer cells.
    2. Cytotoxic Payload: A powerful chemotherapy drug that kills cancer cells.
    3. Linker: A chemical chain that connects the antibody and the cytotoxic payload. Ideally, the linker should be stable in the bloodstream but break apart inside the tumor, releasing the cytotoxic drug.

Schematic illustration of antibody-drug conjugate (ADC) mechanism of action. ADCs consist of a mAb which

When administered, the ADC uses the antibody to bind to cancer cells. The entire ADC is then taken up by the cell, and the linker releases the cytotoxic payload inside the tumor, maximizing its effect on cancer cells while minimizing exposure of healthy tissues to the drug.

Efficacy

Clinical trials have shown promising results for ADCs in treating various cancers, including breast, lung, and HER2-positive stomach cancers. ADCs can be just as effective or even more effective than traditional chemotherapy for certain groups of patients, especially those with tumors that have the targeted antigen.

For instance, a study by showed that Kadcyla (ado-trastuzumab emtansine), an ADC that targets HER2 receptors, significantly improved progression-free survival compared to standard chemotherapy in patients with HER2-positive metastatic breast cancer.

Mode of action of HER2 directed ADCs in HER2-low tumors. Classical mode of action of ADCs with cleavable linkers: (1) After binding of the monoclonal anti-HER antibody component to HER2 expressed on the cell surface of tumor cells, (2) the ADC-HER2 complex is internalized by endocytosis. (3) After linker cleavage by lysosomal proteases, the drug payload is released and (4) can induce the cytotoxic effect leading to tumor cell death. A high drug-to-antibody ratio can increase antitumoral efficacy despite a low HER2 antigen density on tumor cells. Bystander killing effect: Using cleavable linkers, ADCs can be designed to promote drug release from the target cell to the extracellular space. Thereby, surrounding and bystander cells, which may or may not express the ADC target antigen, can be killed by taking up the cytotoxic drug. (A) This bystander killing can occur if the cytotoxic drug is released from the antibody after antigen binding before internalization. (B) Additionally, the drug payload can be released from the tumor cell into the intracellular space due to a high membrane-permeability of the ADC drug payload.

Side Effects

A major advantage of ADCs is their targeted approach. By minimizing exposure of healthy tissues to the cytotoxic payload, ADCs may cause less severe and frequent side effects compared to traditional chemotherapy.

However, ADCs can still cause side effects. Depending on the specific antibody, linker, and payload combination, patients may experience fatigue, nausea, and neutropenia (low white blood cell count). Additionally, the targeted antigen itself may be present on healthy tissues, leading to specific side effects.

Schematic representation of antibody–drug conjugates (ADCs) with and without bystander killing effect. In the upper side of the figure, the mechanism of action of ADCs without bystander killing effect is represented. In the lower side of the figure, the mechanism of ADCs with a potential bystander killing effect is schematized.Each prototype is characterized by the three main features thought to be mostly responsible for bystander killing. 1) Antibody-Target: the potential release of the payload before ADC internalization makes it not always essential for exerting a cytotoxic effect. However, the chemical stability of the antibody-linker bond has been studied for years in order to reach a balance between the specificity of the ADC and the risk of damage to healthy tissues, in case of premature release of the payload. 2) Linker: they are typically classified as cleavable and non-cleavable. Cleavable linkers can be subdivided into “chemically labile” (e.g., hydrazone bonds, that are pH sensitive; disulfide bonds) and “enzyme labile” (e.g., dipeptides, typically cleavable by cathepsin B; β-glucuronidase-sensitive, β-galactosidase-sensitive). Non-cleavable linkers are mainly represented by covalent bonds, such as thioether ones. They usually require intra-cellular processing (e.g., through lysosomal enzymes) for cleavage and subsequent warhead release. Consequently, for ADCs equipped with non-cleavable linkers, internalization is essential for payload release. 3) Payload: the chemical structure of the payload – its electric charge, in particular – is believed to be a critical aspect for allowing bystander killing. In fact, a payload must be able to exit the target cell by diffusing across the phospholipid bilayer, in order to kill surrounding cancer cells. To do so, the payload should be nonpolar. Conversely, in case of ADCs equipped with a polar/charged payload, such as trastuzumab emtansine, the cytotoxic drug remains trapped into the target cell. As for efficacy, ADCs exerting bystander killing effect are considered particularly indicated in case of tumors expressing the target antigen (e.g., HER2) according to a heterogeneous spectrum. The miniature figure on the left represents intra-tumor heterogeneity also in the form of sub-clonal evolution, that is typical of solid tumors. On the left side of the figure, there is the representation of the histological heterogeneity of solid tumours: green cells: tumour cells with a high expression of target antigen; blue cells: tumour with a low expression of target antigen; yellow cells: cells with no expression of target antigen. Conversely, ADCs that do not allow bystander killing should be restricted to target antigens that are expressed in a more homogeneous pattern (e.g., cluster of differentiations in hematological diseases). As for toxicity, the increased potential of bystander killing may rise concerns related to off-tumor toxicity, with damage to healthy tissues, as the main worry (miniature figure on the right). In fact, the historical early-phase clinical trials investigating the first ADCs ancestors have been interrupted due to safety concerns. Keys: Ag, antigen; DNA, deoxyribonucleic acid; ADC, antibody–drug conjugate; HER2, human epidermal growth factor receptor 2.

Patient Outcomes

The targeted nature of ADCs has the potential to improve patient quality of life by reducing side effects from treatment. Additionally, some ADCs are more effective than traditional chemotherapy, potentially leading to better overall survival rates for specific patient populations.

It is important to note that ADCs are often more expensive than traditional chemotherapeutic agents. Furthermore, ongoing research is essential to improve linker design, enhance payload potency, and identify new targets for broader application of ADCs. Researchers around the world, along with suppliers of high-quality reagents like Maxanim, are continually working to advance ADC development for the benefit of patients.

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Conclusion

ADCs represent a significant advancement in cancer treatment, offering a more targeted approach with potentially fewer side effects compared to traditional chemotherapy. While ongoing research is required to optimize their efficacy and affordability, ADCs hold immense promise for improved patient outcomes and a more personalized approach to cancer therapy.


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Antibody-Drug Conjugates (ADCs) vs. Traditional Chemotherapy: Targeted Therapy vs. Broad Spectrum Treatment
Gen store June 24, 2024
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Antibody-Drug Conjugates (ADCs): How They Target Cancer Cells