Monoclonal antibody therapy uses antibodies that are made in the lab rather than by a person’s own immune system. Once the antibodies are given, they may recruit other parts of the immune system to destroy the targeted antigen, such as a cancer cell.
The first monoclonal antibodies were typically made entirely from mouse cells. One problem with this is that the human immune system will see these antibodies as foreign (because they’re from a different species) and will mount a response against them. In the short term, this can sometimes cause an immune response. In the long term, it means that the antibodies may only work the first time they are given; after that, the body’s immune system is primed to destroy them before they can provide treatment.
Over time, researchers learned how to replace some parts of these mouse antibody proteins with human components. Antibodies with a mixture of mouse and human components are known as chimeric antibodies. As more human components were used in the mouse antibody, they were referred to as humanized antibodies. Some monoclonal antibodies are now fully human, which means they are likely to be even safer and may be more effective than earlier monoclonal antibodies. An even newer approach uses fragments of antibodies instead of whole ones. Smaller pieces may be better able to reach a tumor, which may make them more effective.
Clinical trials of monoclonal antibody therapy are being done on almost every type of cancer. As researchers have found more antigens that are linked to cancer, they have been able to make monoclonal antibodies against an array of cancers.
Two types of monoclonal antibodies are used in cancer treatments:
Naked monoclonal antibodies are the most commonly used monoclonal antibodies at this time. Although they all work by attaching themselves to specific antigens, they can be helpful in different ways. Some naked monoclonal antibodies attach to cancer cells to act as a marker for the body’s immune system to destroy them. An example of this is Campath® (alemtuzumab) which is used to treat some patients with B-cell chronic lymphocytic leukemia and is an antibody against the CD52 antigen, which is found on both B cells and T cells.
Some naked monoclonal antibodies don’t interact with a person’s immune system. Their effects come from their ability to attach to the specific antigens that are working parts of cancer cells or other cells that help cancer cells grow, and stop them from working. These monoclonal antibodies are also referred to as targeted therapies. Examples of FDA-approved monoclonal antibodies of this type include:
• Herceptin® (trastuzumab): Trastuzumab is an antibody against the HER2 protein. A large amount of this protein is present on tumor cells in some cancers. When HER2 is activated, it helps these cells grow. Trastuzumab stops these proteins from becoming active. It is used to treat breast cancers that have large amounts of the HER2 protein.
• Avastin® (bevacizumab): Bevacizumab targets the VEGF protein, which is made by tumor cells to develop new blood vessels to feed their growth. Bevacizumab attaches to VEGF, which blocks it from signaling for new blood vessels to form. This monoclonal antibody is used along with chemotherapy to treat some colorectal, lung, and breast cancers, and is being studied for use against other cancers.
Conjugated monoclonal antibodies are monoclonal antibodies that are attached to drugs, cancer killing agents, or radioactive substances. The monoclonal antibodies are used as homing devices to take these substances directly to the cancer cells. The monoclonal antibody circulates in the body until it can find and bind to the target antigen. It then delivers the toxic substance where it is needed most. This lessens the damage to normal cells in other parts of the body caused by the drug, cancer killing agent or radioactive substance.
The only conjugated antibody approved for treating cancer is Mylotarg® or gemtuzumab ozogamicin. It has a cancer killing agent called calicheamicin, attached to an antibody against the CD33 antigen, which is present on most leukemia cells. Mylotarg is used to treat some people with acute myelogenous leukemia. Clinical trials of other conjugates are also being done in people with certain leukemias, lymphomas, brain tumors, and breast cancer.
Humanized monoclonal antibodies have changed the cancer treatment landscape over the past decade. Both in hematologic and solid tumors, antibodies have become an integral component of treatment regimens that have improved and extended the lives of cancer patients. In addition, antibodies have been able to improve efficacy while not significantly adding more toxicity. In solid tumors, Avastin® in combination with chemotherapy is becoming a standard of care in colorectal, non-small cell, breast, and renal cancers. The traditional challenge in oncology drug development has been that incremental increases in efficacy have been accompanied by significant increases in toxicities as the number of chemotherapy drugs being combined became unwieldy. Antibodies have overcome this challenge by providing significant increases in efficacy with less toxicity, due to their targeted nature.
Today, antibodies have been developed to treat an increasing number of cancers that affect a larger proportion of patients and make a significant contribution to overall or disease-free survival as part of a combination regimen with established cytotoxic chemotherapies. The vast majority of antibodies are given as part of a combination chemotherapy regimen to realize their full potential. Enhancement approaches are designed to create more potent antibodies that work better in combination or possibly as single agent therapy. Companies are pursuing three types of enhancements to antibodies in search of improved product profiles. These enhancements include more precisely targeted antibodies, conjugated antibodies, and bi-specific antibodies. The enhancements all have a common goal of improving upon the efficacy seen with current antibody approaches without significantly increasing side effects.
Companies are refining or improving how antibodies bind to their targeted antigens. It is the hope that these more precisely targeted and more tightly binding antibodies will have increased efficacy. Companies are also seeking to increase the cancer cell killing capability of antibodies by linking or conjugating them to existing chemotherapeutics, radioisotopes or other cancer killing agents. While initial attempts to develop effective conjugated antibodies in the 1980’s and 1990s’ produced few successes, more recent efforts incorporating better linker technologies and better cancer killing agents are showing significant promise in clinical trials. In some cases, a disease process may involve more than a single protein biological pathway. Companies are responding to this biological complexity by developing antibodies known as bi-specific antibodies that are capable of binding two or more sites. The belief is that the bi-specific antibodies can be more effective because they block multiple biological pathways causing the disease state.
Monoclonal antibodies are generally given intravenously (injected into a vein). Compared with side effects of chemotherapy, the side effects of monoclonal antibodies are usually mild and similar to an allergic reaction. If they do occur, it is most often while the drug is first being given. Possible side effects can include: fever, chills, weakness, headache, nausea, vomiting, diarrhea, low blood pressure and rashes. Some monoclonal antibodies also have effects that are specific to the antigens they target