Introduction
Cancer remains one of the most challenging diseases to treat, largely due to its complexity and the wide variety of ways it can metastasize or spread in the human body. There are more than 200 types of cancers (Cancer Research UK, n.d.), an estimated 2,001,140 new cancer cases diagnosed, and 611,720 cancer-related deaths in the United States in 2024 (National Cancer Institute, 2024). Conventional cancer treatments—such as surgery, radiation therapy, and chemotherapy—have long been the primary methods of combating the disease. However, these treatments come with significant limitations. Surgery is invasive and often cannot remove all cancerous cells (Mayo Clinic, 2022). Radiation and chemotherapy, while effective in targeting rapidly dividing cells, also damage healthy tissues, leading to severe side effects such as fatigue, nausea, and immunosuppression (Majeed & Gupta, 2023).
One of the main deficiencies in these traditional therapies is their lack of specificity. Cancer cells often fail to fully differentiate, meaning they remain in an immature state where they rapidly divide without specializing, making it hard to identify them based on their typical cell characteristics compared to mature, normal cells (Cooper, 2000). Therefore, there is an urgent need for more precise treatments that can distinguish cancer cells from healthy ones. This review will examine the field of targeted therapies, particularly antibody-based approaches in potentially eliminating cancer cells.
Antibody cytotoxicity mechanisms
Antibodies, also known as immunoglobulins, are proteins that help the body’s immune system fight disease. They identify, mark, and eliminate foreign invaders like viruses and bacteria (Balingit, 2021). Antibodies utilize several mechanisms to target and eliminate cancer cells. Three major mechanisms of action include complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).
Image Credit: Svar Life Sciences. (2024).
Figure 1: CDC mechanism. The binding of an antibody to its antigen on the cell surface can recruit complement proteins, activating the classical pathway of the complement system, which leads to cell lysis.
1. Complement-dependent cytotoxicity (CDC)
CDC is a process where antibodies bind to a target cell, triggering the activation of the complement system—a group of proteins in the blood. This activation leads to the killing of the targeted cell by forming pores in its membrane and causing it to be lysed, or killed. After activation of the complement system, a membrane attack complex (MAC) is formed, which creates pores in the cancer cell membrane, resulting in cell lysis and death (Xie et al., 2020). CDC is particularly effective against certain types of tumors that express high levels of complement-sensitive antigens.
Image Credit: Axion Biosystems. (n.d.).
Figure 2: ADCC mechanism. Antibodies bind to cancer cell antigens and activate Fc receptors on NK cells, which release proteins granzymes and perforin to lyse the cancer cells.
2. Antibody-dependent cellular cytotoxicity (ADCC)
ADCC involves recruiting immune effector cells, such as natural killer (NK) cells, to destroy antibody-coated cancer cells. When an antibody binds to a tumor antigen, it flags the cancer cell for destruction. The Fc binding region of the antibody interacts with Fc receptors on NK cells, activating them to release cytotoxic molecules that induce apoptosis (programmed cell death) in the target cell (Burrell et al., 2017). ADCC has been shown to play a significant role in the efficacy of several FDA-approved monoclonal antibodies, discussed in a later section.
Image Credit: iQ Biosciences. (2018).
Figure 3: ACDP mechanism. Antibodies specifically bind to antigens present on the surface of target cells, marking them for destruction and facilitating recognition by immune cells, such as macrophages and neutrophils, which activate the Fc receptors. Upon recognition, these phagocytic immune cells engulf and digest the target cells, leading to their elimination.
3. Antibody-dependent cellular phagocytosis (ADCP)
In ADCP, antibodies bound to cancer cells are recognized by phagocytic immune cells, white blood cells that engulf and destroy foreign particles by a process called phagocytosis (National Cancer Institute, 2011). Macrophages are an example of phagocytic immune cells. The binding of the antibody’s Fc region to receptors on macrophages facilitates the engulfment and subsequent destruction of the cancer cell (Cao et al., 2022). Beyond directly killing cancer cells through phagocytosis, ADCP can also stimulate an immune response by activating immune cells, potentially leading to a broader antitumor effect by promoting further immune cell recruitment and activation against cancer cells within the tumor microenvironment (Zhang et al., 2024).
Antibody-based therapies and tumor-associated antigens
Scientists can engineer monoclonal antibodies to specifically bind to cancer cells by leveraging their biological mechanisms. Once attached, these antibodies can act as a “homing signal,” recruiting the body’s immune system to destroy the malignant cell (Justesen et al., 2022). In some cases, they can also be linked to cytotoxic agents or radioisotopes to deliver chemotherapy or radiation directly to the cancer cells, enhancing the body’s killing power.
The key to this approach lies in identifying tumor-associated antigens (TAAs)—molecular markers that are either exclusively present or overexpressed on cancer cells compared to normal cells (Leko & Rosenberg, 2020). Antibodies are then designed to target these antigens with high specificity. However, identifying suitable TAAs is a challenge. Cancer cells within a single tumor can exhibit diverse genetic and phenotypic characteristics—intra-tumor heterogeneity (Pinto et al., 2013). Therefore, an antibody designed to target a specific antigen may not be effective against all tumor cells within a given patient. Additionally, tumors may evolve over time, leading to further antigenic changes that can render previously targeted therapies less effective or completely ineffective.
Current antibody-based cancer treatments
Several monoclonal antibodies have received FDA approval, marking significant advancements in cancer treatment. Notable examples include rituximab (Rituxan, n.d.). which targets CD20, a tumor marker protein found on B cells, and is commonly used in treating non-Hodgkin lymphoma and chronic lymphocytic leukemia, and trastuzumab (Herceptin, n.d.), which targets the HER2 receptor and is primarily used for HER2-positive breast cancer. Cell lysis mechanisms triggered by rituximab include CDC and ADCC (Drugbank, 2024), while trastuzumab uses primarily ADCC, attracting immune cells to tumor sites that overexpress HER2 (Vu & Claret, 2012).
These antibody therapies provide several advantages over traditional chemotherapy. They are designed to target specific antigens found on cancer cells. This specificity reduces the likelihood of damaging healthy cells, which is a significant drawback of conventional chemotherapies that affect rapidly dividing cells indiscriminately (McCluskey, 2016). Because antibody therapies are more selective, fewer side effects are generated compared to conventional therapies. Patients often report improved quality of life during treatment (Fragkiadakis & Spiliotopoulou, 2022).
Despite these advantages, there are notable limitations associated with antibody-based therapies. Antibodies are created so that ideally, they can specifically recognize and bind to cancer cells without triggering autoimmunity, an immune response directed against the body’s own tissues, where the immune system mistakenly identifies normal cells as foreign and launches an attack against them (Janeway et al., 2001). If an engineered antibody inadvertently binds to antigens present in normal cells, it can activate the
immune system against healthy tissue, leading to inflammatory responses and various autoimmune disorders. These reactions can range from mild side effects, such as skin rashes or fatigue, to more severe conditions that can affect multiple organ systems. Furthermore, the production and administration of monoclonal antibody therapeutics are complex, costly, and time-consuming (Chung et al., 2023). Treatment often necessitates inpatient stays and frequent dosing to sustain therapeutic levels, making these therapies less accessible to underserved populations and those in developing countries. Lastly, antibody-based therapies are not universally effective. Many solid tumors, for instance, do not express suitable target antigens or may possess a tumor microenvironment that inhibits the effectiveness of immune-mediated responses (Tormoen et al., 2018).
Conclusion
Antibody-based therapies have made significant progress in cancer treatment, yet there remains much work to be done in effectiveness and accessibility. One area of ongoing research focuses on enhancing antigen identification to discover more tumor-specific markers that can serve as precise therapeutic targets. By analyzing a tumor’s gene and protein profiles, researchers can gain a deeper understanding of cancer development, allowing them to identify unique tumor antigens that could be targeted with personalized therapies, essentially tailoring treatments to the specific characteristics of a patient’s cancer (Kwon et al., 2021).
Emerging technologies are also paving the way for next-generation antibody therapies. Bispecific antibodies, which are designed to bind to two different antigens simultaneously (Fahim 2014), and antibody-drug conjugates (ADCs), which deliver cytotoxic agents directly to cancer cells (Astra Zeneca, 2024), offer promising approaches for improving the precision and potency of treatments. Combining monoclonal antibodies with immune checkpoint inhibitors or other immunotherapies could also result in a more robust immune response against cancer.
While challenges remain with antibody-based therapies in terms of cost, accessibility, and resistance, the ongoing research and development of new technologies hold promise. As our understanding of cancer biology continues to grow, antibodies may offer even more accessible and life-saving treatments for patients around the world.