Monoclonal Antibody Drugs for Cancer Treatment

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Monoclonal Antibody Drugs for Cancer Treatment
Newswise — The strategy of using monoclonal antibodies for cancer treatment was first described in the late 1970s with the promise that they could be developed into therapies that were highly specific to cancer cells, killing them with few or no side effects. For several types of cancer, monoclonal antibodies have already offered this advantage to patients. For other cancer types, they have provided an additional therapeutic weapon, but with smaller benefits and sometimes new side effects.
"The first efforts for monoclonal antibody cancer therapy were to find antibodies that would home in on tumors and bind to proteins on the surface of cancer cells," explained physician-scientist David A. Scheinberg. "We looked for unique proteins that were specific only to cancer cells. The idea was that the antibody would be used to stimulate an immune response in the body, which would kill the cancer cell." Dr. Scheinberg, who is Chair of Memorial Sloan-Kettering's Experimental Therapeutics Center and the Molecular Pharmacology and Chemistry Program within the Sloan-Kettering Institute, developed an antibody called M195, which targets a protein on leukemia cells, when working as a research fellow in collaboration with Memorial Sloan-Kettering immunologist Lloyd Old in the 1980s.
This approach further evolved when researchers realized they could use the antibody as a carrier to deliver a radioactive isotope or a toxic drug directly to the cancer cell, where it would kill the cell while sparing nearby healthy tissue.
Antibodies are proteins that help the immune system to identify foreign substances by binding to them and marking them as foreign. Monoclonal antibodies are manufactured using a type of cell called a hybridoma. The hybridoma -- which is engineered in the laboratory by fusing an antibody-producing immune cell called a B cell to a tumor cell -- multiplies to produce a continuous supply of a specific antibody. Early monoclonal antibodies were made exclusively from mouse cells, but because the immune system can recognize these antibodies as foreign, leading to unwanted reactions, most monoclonal antibodies used today are either chimeric, consisting of both mouse and human parts, or fully human.
For patients whose neuroblastoma spreads to the brain, one of the sites of metastasis when the disease relapses, 3F8 and another antibody called 8H9 can also be armed with radioactive iodine. Because antibodies are large molecules that are unable to cross the blood-brain barrier, the treatment is injected directly into the cerebrospinal fluid. This experimental treatment has been given to only a handful of pediatric patients so far -- some with brain metastases and some with primary brain tumors -- but preliminary results look very promising, and about three-quarters of neuroblastoma patients who received the treatment are doing well up to five years later.
"Brain metastases are not a trivial issue in cancer," Dr. Cheung said. "More than 20 percent of metastatic cancers, including adult cancers such as breast cancer, have the tendency to spread to the brain. We think this form of 'liquid radiation,' which delivers radioisotopes directly to the tumor, can minimize side effects seen with external-beam radiation and can eventually be developed for treating a range of pediatric and adult cancers that attack the brain."
Another strategy for treating solid tumors is by inhibiting angiogenesis, the flow of blood supply to tumors that allows them to grow. The monoclonal antibody bevacizumab (Avastin®) works by blocking a protein called vascular endothelial growth factor (VEGF). When the VEGF protein is blocked, existing blood vessels on tumors are destroyed and the growth of additional blood vessels is prevented. Bevacizumab, developed by Genentech scientist Napoleone Ferrara, is also is used in combination with chemotherapy and is approved for the treatment of colorectal, lung, and breast cancers. However, for most patients with advanced disease the improvement in survival times is small.
"Overall, the majority of monoclonal antibodies developed for solid tumors have been relatively disappointing compared to our early hopes and expectations," said Memorial Sloan-Kettering medical oncologist Leonard Saltz, who led some of the large trials for cetuximab. "They are useful, but our original hope was that these drugs would be able to replace chemotherapy, rather than be combined with chemotherapy. Patients still have the side effects of the original chemotherapy treatment, and in some cases extra side effects from the antibodies. In addition, these drugs are very expensive, and most of them have only modest benefits."
Targeting Signaling Pathways in Breast Cancer
A solid tumor for which monoclonal antibodies have shown a more meaningful benefit, at least for a subset of patients, is breast cancer. About 20 percent of breast cancers have high levels of a protein called human epidermal growth factor receptor-2 (HER2). Tumor growth in HER2-positive tumors is caused by signaling from the excess of HER2 protein: HER2 binds to other proteins in the HER family and sends signals telling cancer cells to grow and to not undergo programmed cell death.
"HER2 is a good target for anticancer agents because HER2-positive cancers tend to be more aggressive," said Clifford A. Hudis, Chief of Memorial Sloan-Kettering's Breast Cancer Medicine Service. "When these tumors come back after surgery, they usually come back early."
Trastuzumab (Herceptin®) was developed to stop HER2 signaling. "We still don't know exactly how trastuzumab works," Dr. Hudis explained. "In part, it may be making changes to the receptor on the cell's surface. It may be turning on an immune reaction via ADCC. It may also activate a process called endocytosis, where it binds to the receptor and then the whole complex is swallowed up by the cell, and it may inhibit a protein called p95."


Trastuzumab, jointly developed by Genentech and Dennis Slamon of the University of California, Los Angeles, usually is given in combination with chemotherapy, and for women with late-stage disease it has been shown to improve average survival about 25 percent compared with chemotherapy alone. For women with earlier-stage disease, it can be given as an adjuvant (additional) treatment after surgery. For those patients, the drug can provide a substantial benefit, killing microscopic metastatic disease that is not clinically apparent, improving the rate of cure by 50 percent compared with chemotherapy alone.
One problem with trastuzumab, as with other targeted therapies, is that many patients eventually develop resistance to the treatment. An approved drug for such patients is the small-molecule drug lapatinib (Tykerb®), which blocks HER2 signaling via a different mechanism. In addition, there are several experimental therapies in clinical trials at the Center that help get around that resistance. One is a drug called T-DM1, which consists of trastuzumab linked to a cytotoxic chemotherapy agent. Another monoclonal antibody in studies around the world is pertuzumab, which binds to the HER2 receptor in a different location than trastuzumab does. There is also a family of new small-molecule drugs, called heat shock protein 90 inhibitors, developed in part in the laboratory of Memorial Sloan-Kettering investigator Neal Rosen, that can help amplify the trastuzumab effect even in patients for whom the antibody seems to have stopped working.
For patients with HER2-normal (meaning not HER2-positive) breast cancer who have experienced relapse or recurrence after other treatments, bevacizumab can be given in combination with chemotherapy drugs. "Bevacizumab is currently being evaluated as an adjuvant treatment for patients with an earlier stage of disease," Dr. Hudis said, "but it is too early to know if patients will benefit from it."
Researchers agree that while the use of monoclonal antibodies has yet to be fully optimized and has not reached its full potential, the antibodies can still clearly benefit a large number of patients and teach investigators more about the biology of cancer.


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