How do treatments using monoclonal antibodies (mAbs) work?

From the Guidelines

Monoclonal antibody treatments work by using laboratory-produced molecules designed to serve as substitute antibodies that can restore, enhance, or mimic the immune system's attack on specific targets, as seen in the use of ipilimumab, pembrolizumab, and nivolumab in cancer treatment 1. These antibodies are created by cloning a unique white blood cell and are all identical, targeting a specific antigen found on cells like cancer cells or infectious agents. When administered to patients, monoclonal antibodies bind to their targets with high specificity, triggering various mechanisms to eliminate the threat, such as blocking the cytotoxic T lymphocyte-antigen-4 (CTLA-4) or the protein programmed death 1 (PD-1) 1. Some monoclonal antibodies mark target cells for destruction by the immune system, while others block growth signals or deliver toxic substances directly to diseased cells. Common examples include rituximab (Rituxan) for certain blood cancers, trastuzumab (Herceptin) for HER2-positive breast cancer, and more recently, COVID-19 treatments like casirivimab/imdevimab. These medications are typically administered via intravenous infusion in healthcare settings, with dosing and duration varying by condition. Side effects can include infusion reactions, so patients are monitored during administration, and immune-related adverse events (irAEs) can occur, affecting almost any organ system, with varying severity and incidence 1. Monoclonal antibodies have revolutionized treatment for many conditions by offering targeted therapy that spares healthy cells, resulting in fewer side effects than traditional treatments. Key considerations in their use include the potential for irAEs, the importance of patient monitoring, and the need for education on recognizing and managing these adverse events 1. In the context of cancer treatment, monoclonal antibodies like ipilimumab, pembrolizumab, and nivolumab have been shown to be effective in targeting specific immune checkpoint molecules, leading to improved outcomes for patients with various types of cancer 1. Overall, the use of monoclonal antibodies has transformed the treatment landscape for many diseases, offering new hope for patients and highlighting the importance of continued research and development in this field.

From the FDA Drug Label

Trastuzumab products have been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2 Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.

Treatments using monoclonal antibodies, such as trastuzumab, work by:

• Inhibiting the proliferation of human tumor cells that overexpress specific proteins, such as HER2
• Mediating antibody-dependent cellular cytotoxicity (ADCC), which preferentially targets cancer cells that overexpress specific proteins These mechanisms allow monoclonal antibodies to selectively target and destroy cancer cells, while minimizing harm to healthy cells. 2

From the Research

Mechanism of Action

• Monoclonal antibodies possess a diverse set of clinically relevant mechanisms of action, including directly targeting tumor cells and promoting the induction of long-lasting anti-tumor immune responses 3
• They can target and kill tumor cells while simultaneously activating immune effectors to kill tumor cells through the complement cascade or antibody-dependent cellular cytotoxicity (ADCC) 4
• Monoclonal antibodies can also target immune cells instead of tumor antigens, enhancing anti-tumor immune responses 3

Clinical Applications

• Monoclonal antibodies are used in the treatment of cancer, including hematological malignancies and solid tumors 5
• They are also used in the treatment of rheumatoid arthritis, with adalimumab, etanercept, infliximab, rituximab, and abatacept being used after the failure of a tumour necrosis factor inhibitor 6
• Engineered high-loaded mixed-monoclonal antibodies polymeric nanoparticles have been developed for the treatment of rheumatoid arthritis, showing increased therapeutic effect than conventional drugs 7

Targeting Tumor Suppressor Genes

• Monoclonal antibodies can target tumor suppressor genes, allowing for specific targeting of cancer-related genes and minimizing off-target side effects 5
• Examples of monoclonal antibody-mediated treatment regimens include the use of immunoconjugates, clinically targeting TGFβ with pan-TGFβ monoclonal antibodies, p53 by its monoclonal antibodies, and EGFR-targeted monoclonal antibodies 5

Combination Therapies

• Monoclonal antibody-based strategies have moved towards enhancing anti-tumor immune responses by targeting immune cells instead of tumor antigens, as well as combination therapies 3
• The use of combination therapies, such as the combination of adalimumab, rituximab, and trastuzumab, has shown increased therapeutic effect in the treatment of rheumatoid arthritis 7