The use of monoclonal antibodies (mAbs) for cancer therapy is one of the major contributions of tumor immunology to advances in treating oncology patients. The success is built on decades of scientific research aimed at serological characterization of cancer cells.1
Immunoglobulin molecules (antibodies) are naturally produced in response to invading foreign particles or antigens to the human body such as bacteria and viruses. They are multifunctional components of the immune system (polyclonal) and play a very important role in the immune system’s defense against disease and infection by binding to antigens.1
An antigen may be a substance from the environment, such as chemicals, bacteria, viruses, or pollen, or it may be from inside the body, such as hormones or receptors on cancer cells. Antigens can also be part of the host itself, in the case of an autoimmune disease, and upon attacking the body, they are “targeted” by the antibodies. The part of an antigen that interacts with antibodies is called the epitope.1
Normally, during an attack, the immune system will generate a large group of antibodies that recognize several epitopes of a particular antigen. Each antibody is secreted by a different antibody-producing plasma cell, and since the antibodies found in serum are collectively produced by many plasma cells (clones), they are described as polyclonal antibodies. While this is an advantage for fighting infections in nature, the heterogeneity of polyclonal antibodies limits their use as research tools.2
An important discovery in the development of antibodies was a technique for producing mAbs in 1975 by Köhler and Milstein.2 The technique requires removing B cells from the spleen of an animal that has been affected by an antigen and then fusing them with a myeloma tumor cell line.This results in a single-cell hybrid known as a hybridoma. The B cells have antibody-production capability, while the myeloma cells enable hybridomas to divide indefinitely and grow well in culture. Hybridomas secrete only one antibody type, effectively ensuring a long-term supply of antibodies that are selective for a single epitope (also known as monoclonals). Today, mAbs are used to treat many diseases, including some types of cancer. Monoclonal antibodies can have monovalent affinity since they bind to the same epitope.2,3
Cancer Therapy
The immune system is composed of a complex network of components that detect and destroy disease-causing agents, such as bacteria and viruses. Similarly, this system may eliminate damaged or abnormal cells, such as cancer cells.
A major element in the immune system is the work of antibodies. As mentioned above, an antibody attaches itself to a specific molecule (antigen) on the surface of a problematic cell. This binding serves as a flag to attract disease-fighting molecules or as a trigger that promotes cell destruction by other immune-system processes.2
Monoclonal antibodies are laboratory-produced molecules engineered to enhance or mimic the immune system’s attack on cancer cells. They are designed to bind to antigens that are generally more numerous on the surface of cancer cells than healthy cells. There are many kinds of mAbs, and they bind to only one substance. Monoclonal antibodies can be used alone or to carry drugs and radioactive or toxic substances directly to cancer cells.2
Monoclonal antibodies that are used as drugs assist the natural immune system’s function in fighting cancer. These medications may be used in combination with other cancer treatments. Patients who are considered for receiving a mAb drug as part of their treatment regimen must be well informed about this therapy to decide whether it is right for them, because it is possible that cancer cells outpace the immune system, avoid detection, or block immune-system activity.1,3
Monoclonal Antibody Medications
Monoclonal antibody treatments have been developed for some, but not all, cancer; certain types of cancer cells are more vulnerable than others to mAb interventions. Nonetheless, treatments have been approved for a number of cancers, including brain cancer, breast cancer, chronic lymphocytic leukemia, colorectal cancer, head and neck cancers, Hodgkin’s lymphoma, lung cancer, melanoma, non-Hodgkin’s lymphoma, prostate cancer, and stomach cancer.4
Monoclonal antibodies are designed to function in variety of ways, and a particular drug may actually function in more than one way. The role of these drugs in helping the immune system in fighting cancer occurs in three different ways, as follows:
Naked mAbs: These drugs, by themselves, can work in different ways. Some boost a person’s immune response against cancer cells by attaching to them and acting as a marker for the body’s immune system to destroy them. An example is alemtuzumab (Campath), which is used to treat some patients with chronic lymphocytic leukemia (CLL). Alemtuzumab binds to the CD52 antigen, which is found on cells called lymphocytes (which include the leukemia cells). Once attached, the antibody attracts immune cells to destroy these cells. Alemtuzumab induces responses in about a third of patients with relapsed or refractory CLL following therapy with fludarabine and an alkylating agent.4
Some naked mAbs boost the immune response by targeting immune-system checkpoints—molecules on certain immune cells that need to be activated (or inactivated) to start an immune response.
Other naked mAbs work mainly by attaching to and blocking antigens on cancer cells (or other nearby cells) that help cancer cells grow or spread. For example, trastuzumab (Herceptin) is an antibody against the human epidermal growth factor 2 (HER2) protein. Breast and stomach cancer cells sometimes have large amounts of this protein on their surface. When HER2 is activated, it helps these cells grow. Trastuzumab binds to these proteins and stops them from becoming active.5
Radiolabeled mAbs: Radiotherapy uses high-energy radiation to destroy cancer cells and shrink tumors. Radiation may come from a device outside the body (external-beam radiation therapy) or, like ibritumomab tiuxetan (Zevalin), from radioactive material injected into the bloodstream.6
Radiolabeled antibodies have small radioactive particles attached to them. Ibritumomab tiuxetan is an example of a radiolabeled mAb. This is an antibody against the CD20 antigen, which is found on lymphocytes called B cells. The antibody delivers radioactivity directly to cancerous B cells and can be used to treat some types of non-Hodgkin’s lymphoma. Treatment with this type of antibody is known as radioimmunotherapy. Ibritumomab tiuxetan is delivered to certain targeted and neighboring cells in the body and can affect cells up to a 5-mm radius around targeted B cells.6
Chemolabeled mAbs: These mAbs have powerful chemotherapy drugs attached to them. They are also known as antibody-drug conjugates. (The drug is often too powerful to be used on its own; it would cause too many side effects if not attached to an antibody.) Some of chemolabeled antibodies used to treat cancer include:
Brentuximab vedotin (Adcetris), a CD30-specific, antibody-drug conjugate, was approved by the FDA in 2011 for the treatment of patients with Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma.7
• Ado-trastuzumab emtansine (Kadcyla, also called TDM-1), an antibody that targets the HER2 protein, attached to a chemotherapy drug called DM1. It is used to treat some breast cancer patients whose cancer cells have too much HER2, and it works both in early and advanced disease.8 This drug shows some cardiotoxicity, but this does not appear to be related to cumulation dose. It is reversible with treatment discontinuation.8
• Denileukin diftitox (Ontak) is an immune system protein known as interleukin-2 (IL-2) attached to a toxin from the germ that causes diphtheria. Although it is not an antibody, IL-2 normally attaches to certain cells in the body that contain the CD25 antigen, which makes it useful for delivering the toxin to these cells. Denileukin diftitox is used to treat lymphoma of the skin (also known as cutaneous T-cell lymphoma).9
Administration
Monoclonal antibodies are administered through a vein. For example, alemtuzumab is administered by IV infusion over 2 hours, and brentuximab is infused over 30 minutes. Premedication of patients with diphenhydramine 50 mg or APAP 500 to 1,000 mg 30 minutes before each infusion is a routine procedure. Intravenous corticosteroids have been effective in decreasing severe infusion-related events. Other drugs should not be given or mixed in the same IV line. None of the above drugs should be given as IV push or bolus.2
How often a patient undergoes mAb administration depends on the patient’s cancer and the drugs being received. Some mAb drugs may be used in combination with other drugs, such as chemotherapy or hormone therapy. Some mAb drugs are a part of standard treatment plans. Some of them are still experimental and used when other treatments have not been successful.
Possible Side Effects
Monoclonal antibodies are made using recombinant biotechnology. Therefore, they do not carry infectious risks associated with polyclonal-antibody preparations from human plasma. However, they are biologic products and can elicit a number of immune-mediated and other reactions and adverse effects. In general, mAb treatment carries fewer side effects than traditional chemotherapy treatments. However, mAb treatment for cancer may cause rare side effects that can be very serious. The standard infusion reactions or the most common side effects caused include: allergic reactions, such as hives or itching; flu-like signs and symptoms, including chills, fatigue, fever, and muscle aches and pains; nausea; vomiting; diarrhea; skin rashes; and low blood pressure.10
Severe allergy-like reactions can also occur and, in very few cases, lead to death during infusion. Patients may receive corticosteroids to block an allergic reaction before they begin mAb treatment. Infusion reactions usually occur while treatment is being administered or soon after, so the healthcare team will watch the patients closely for a reaction.10
Monoclonal antibodies that deliver radioactive particles or chemotherapy drugs may be associated with low blood cell counts that can be severe and persistent. Certain mAbs increase the risk of high blood pressure, congestive heart failure, and heart attacks. Some mAbs are associated with a higher risk of inflammatory lung disease. Sores and rashes on a patient’s skin can lead to serious infections in some cases. Serious sores can also occur on the tissue that lines a patient’s cheeks and gums (mucosa).2,10
Monoclonal antibody drugs designed to stop cancer from forming new blood vessels also have an increased risk of severe internal bleeding. Patients should discuss with their oncologists their concern about cancer-treatment options. Both can weigh the benefits and risks of each approach and decide whether mAb treatment is right for the patient.10
Conclusion
Monoclonal antibodies present an attractive option for the development of new therapies against a wide variety of common diseases, due to their specificity and flexibility. Monoclonal antibodies produced by recombinant biotechnology can target antigens or markers located on the surface of cancer cells. They target antigens and recruit immune cells to attack them. They can also interfere with cell signaling, helping to block the growth and communication of tumor cells. So far, about 80 mAbs have been approved by the FDA to detect, diagnose, and treat many different diseases.
REFERENCES
1. American Cancer Society. What is immunotherapy? www.cancer.org/treatment/ treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-what-is-immunotherapy. Assessed May 21, 2018.2. American Cancer Society. Monoclonal antibodies to treat cancer. www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/monoclonal-antibodies.html. Assessed May 15, 2018.3. National Cancer Institute. NCI dictionary of cancer terms. www.cancer.gov/dictionary. Assessed May 21, 2018.4. Cheson BD, Monoclonal antibody therapy of chronic lymphocytic leukemia. Cancer Immunology, Immunotherapy. 2006;55(2):188-196.5. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51.6. Ibritumomab tiuxetan (Zevalin) [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc. 2013. Assessed May 20, 2018.7. Han TH, Gopal AK, Ramchandren R, et al. CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30 positive hematologic malignancies. J Clin Pharmacol. 2013;53(8):866-877.8. Abraham J. Trastuzumab emtansine in advanced HER2-positive breast cancer. Community Oncol. 2013;10(3):71-73.9. Litzinger MT, Fernando R, Curiel TJ, et al. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood. 2007;110:319-320.10. Manis JP. Overview of therapeutic monoclonal antibodies. In JS Timauer, AM Feldweg, eds. 2018. UpToDate. www.uptodate.com.
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