Introduction

Chemotherapy remain the most commonly used cancer treatments today. It is frequently administered, either alone or in combination with other therapies like surgery and radiotherapy, to treat a wide range of malignancies. Despite exhibiting potent anti-tumor effects, chemotherapy is limited by poor target specificity, harmful side effects, a narrow therapeutic window, and drug resistance. To address these limitations, extensive research has led to the development of antibody-drug conjugates (ADCs), which combine the specificity of monoclonal antibodies (mAbs) with the lethality of cytotoxic drugs. This advancement represents a significant milestone in cancer treatment, with the potential to selectively target cancer cells while reducing the adverse effects associated with conventional chemotherapy, leading to improved outcomes and quality of life.

Mechanism of action of ADCs

Often likened to “magic bullets”, ADCs consist of three key components: a highly specific mAb, a potent cytotoxic drug payload, and a linker that attaches the payload to the mAb. Their mechanism of action can be broken down into several key steps. The mAbs on the ADC are designed to recognize and bind to tumor-associated antigens present on the surface of the cancer cells. These antigens are either absent or minimally present on normal cells, ensuring that the drug is selectively directed to the tumor cells. Upon binding to the target antigen, the ADC is internalized by the cancer cell through a process known as endocytosis. Once the ADC is brought into the cell within an endosome, it is typically transported to the lysosome. The acidic environment and protein hydrolases within the lysosomes either break down the linker or degrade the ADC, causing the release of its payload. The release of the cytotoxic drug, such as microtubule inhibitor or DNA-damaging compound, disrupts critical cellular processes and leads to cell death. In addition to their direct cytotoxic effects, some ADCs exhibit bystander effects, mediated by the passive diffusion of the cytotoxic payload into neighboring cells. ADCs with bystander effects can kill not only antigen-positive cancer cells but also indirectly kill antigen-negative cancer cells. These bystander effects significantly enhance the therapeutic efficacy of ADCs, particularly in tumors with heterogenous antigen expression.

The first ADC approved by the U.S. FDA

ADCs represent a novel class of therapeutic agents capable of treating various cancers, including those that are challenging to treat with traditional therapies. Gemtuzumab ozogamicin, which targets leukemia cells expressing CD33 antigen on their surface and triggers cell death through calicheamicin-induced DNA damage, became the first ADC approved by the U.S. Food and Drug Administration (FDA) in 2000. The accelerated approval was granted after early-phase studies indicated that it could induce complete response in some acute myeloid leukemia (AML) patients with acceptable safety profile. However, it was withdrawn in 2010 after clinical data from phase 3 studies showed limited benefit and raised safety concerns, including liver damage and early deaths. It was then re-approved in 2017 for AML patients based on new studies demonstrating improved efficacy and safety using a lower dosing regimen. Research has shown that the linker of this first generation of ADC is susceptible to degradation in the bloodstream, which can lead to premature release of its payload, causing severe off-target toxicities. Additionally, the hydrophobic nature of calicheamicin often leads to antibody aggregation, which accelerates the clearance of ADCs, reducing their effectiveness.

More than a dozen of ADCs approved by the U.S. FDA for various malignancies

Innovations in antibody engineering, linker technology, target antigen selection, and cytotoxic payloads have led to the development of newer generations of ADCs with improved therapeutic efficacy, higher stability, and better safety profiles. To date, more than a dozen ADCs have been approved by the U.S. FDA for the treatment of various hematological malignancies and solid tumors: brentuximab vedotin for Hodgkin’s lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and large B-cell lymphoma; trastuzumab emtansine for HER2-positive breast cancer; inotuzumab ozogamicin for acute lymphoblastic leukemia; polatuzumab vedotin for large B-cell lymphoma; enfortumab vedotin for urothelial cancer; trastuzumab deruxtecan for HER2-positive solid tumors; sacituzumab govitecan for triple-negative breast cancer and HR-positive, HER2-negative breast cancer; loncastuximab tesirine for large B-cell lymphoma; tisotumab vedotin for cervical cancer; mirvetuximab soravtansine for ovarian cancer; datopotamab deruxtecan for HR-positive, HER2-negative breast cancer and non-small cell lung cancer with EGFR mutations; and telisotuzumab vedotin for non-small cell lung cancer with high c-Met protein overexpression.

Unlocking the promise of ADCs

ADCs represent a groundbreaking advancement in cancer therapy, revolutionizing the way chemotherapy is delivered. By linking potent cytotoxic drugs to mAbs, ADCs enable the targeted delivery of chemotherapy directly to malignant cells, reducing harm to healthy tissues and minimizing side effects. On-going research and development are crucial to maximizing therapeutic efficacy, minimizing adverse effects, and expanding the therapeutic applications of ADCs. Researchers are focused on identifying and validating new tumor-associated antigens, which can serve as more specific targets for the antibodies that drive ADCs. Efforts are also underway to develop more potent cytotoxic drugs with improved safety profiles, aiming to increase the therapeutic index of ADCs while reducing toxicity. Another key area of development is the design of more stable linkers that allow for controlled release of the payload directly inside the cancer cell. Additionally, innovative approaches such as ADCs with multiple payloads and multi-targeting ADCs are being explored to enhance efficacy, address tumor heterogeneity, and overcome drug resistance. As the technology continues to evolve, ADCs offer hope to transform cancer care by providing more precise, personalized, and effective therapies for patients worldwide.