By Melissa Knopper

Imagine a tumor cell sprouting a satellite antenna on its surface that sends signals to other parts of the tumor that help it grow. Now imagine a drug that could act like the U.S. military‚ using high–tech equipment to scramble the enemy’s communications system and prevent them from building an army. Thats how biotech companies are using monoclonal antibody therapy to zero in on cancer tumors and shut them down.

Researchers have known about antibodies for more than a century‚ says Louis M. Weiner‚ MD‚ chairman of the department of medical oncology‚ Fox Chase Cancer Center‚ Philadelphia. In fact‚ pioneering immunologist Paul Ehrlich‚ MD‚ won the Nobel Prize in 1908 for his suggestion that antibodies could be used like “magic bullets” to treat all types of diseases. “He was a visionary‚” Dr. Weiner says. “But his vision went far beyond the available technology of the day.”

An antibody is a type of protein that seeks out foreign invaders‚ such as bacteria and viruses (antigens)‚ and binds to them‚ signaling to the immune system to destroy the invader. Doctors used the same concept to create vaccines for influenza‚ diphtheria‚ and tetanus. Patients receive an inactive form of the virus or bacteria that teaches their immune systems to recognize and destroy the particles if the person ever encounters the disease–causing pathogen.

Antibodies and Cancer
Dr. Ehrlich’s “magic bullet” theory rose again in 1975 when British researchers Cesar Milstein‚ PhD‚ and Georges KÖhler‚ PhD‚ figured out how to mass produce antibodies in mice of a single type in the laboratory. These “monoclonal” antibodies were injected into patients in an effort to treat a variety of conditions‚ from autoimmune diseases to cancer. But the technique had a flaw: Patients’ immune systems recognized the mouse antibodies as foreign invaders and destroyed them before they could deliver any significant therapeutic benefits.

Then‚ in the ’80s‚ new genetic engineering techniques led to important breakthroughs in the use of monoclonal antibody therapy. Using new DNA techniques‚ scientists could graft human antibodies to the mouse molecules so human patients could better tolerate them. “It’s like a molecular cutting and pasting‚” Dr. Weiner explains.

In research centers across the country‚ physicians began using antibodies like “magic bullets” to attack cancer cells in a very specific way. Some use the antibodies alone to bind to tumor cells and stop their growth. Others attach an additional weapon‚ such as chemotherapy drugs or radioactive isotopes to the antibody‚ thereby delivering a multipronged attack. The antibody—like a laser–guided missile—sends its toxic load directly to the tumor. Antibody therapy appeals to patients because it typically has fewer side effects than chemotherapy or radiation treatments.

While it sounds simple‚ monoclonal antibody therapy is complicated by the cancer growth process. Each cell can have different kinds of antigens‚ proteins on the surface of the cancer cell‚ meaning one antibody may work on one kind of cancer cell but not affect any others. So the challenge for researchers comes in identifying the antigens and then finding the right antibody and the right payload to send to that cell alone.

A New Era with Herceptin
For solid tumor treatment‚ Herceptin™ (trastuzumab) has been one of the biggest success stories as the first humanized antibody approved in 1998 by the U.S. Food and Drug Administration (FDA) for treatment of metastatic breast cancer‚ or cancer that has spread to other parts of the body. It works by binding to a receptor on tumor cells known as HER2 (human epidermal growth factor receptor)‚ explains Mark Pegram‚ MD‚ director of the Women’s Cancer Research Program‚ UCLA.

“The growth factor receptor is like a little antenna that sends a strong signal to the tumor to grow more rapidly‚” he says. “Herceptin blocks this antenna. It stuns the cell and prevents it from growing.”

Herceptin is only effective for patients whose tumors have a genetic alteration that causes their tumor cells to make more HER2 than normal. That‚ in turn‚ can lead to a more aggressive form of cancer that is more likely to recur after treatment. Approximately 25% of breast cancer patients have this genetic alteration‚ resulting in 150‚000 cases per year worldwide. (To find out if their tumors have the HER2 gene alteration‚ patients should ask their doctors to send a portion of their tumor tissue to the laboratory for evaluation.)
Studies show tumors were reduced by more than 50% in 34% of selected breast cancer patients who took Herceptin alone. When Herceptin was combined with the chemotherapy drugs Taxotere® (docetaxel) and platinum‚ tumors were reduced by more than 50% in nearly 80% of patients.
For Doris Lemonier‚ a 51–year–old elementary school French teacher from Fenton‚ Louisiana‚ Herceptin provided an added boost to the chemotherapy treatments she was given after her family doctor diagnosed her with breast cancer during a routine physical.

“They discovered I had ductal carcinoma in the left breast‚” she says. “They found so many tumors—some of them were 5 centimeters.” Her physician told her about a clinical study 150 miles away at M. D. Anderson Cancer Center in Houston‚ so she enrolled and started taking Herceptin in February 2002.
Two months later‚ the cancer center staff did a routine CT scan and found something remarkable: Lemonier’s tumors had nearly vanished. “The doctor came in and said‚ ‘You have 99% shrinkage‚’” Lemonier says. She says that she let out a sigh and said thank you.

“The doctor said‚ ‘You’re welcome‚’ and I said‚ ‘I’m talking to the master physician‚ but I thank you‚ too‚’” she recalls with a laugh.

As she continued weekly treatments‚ Lemonier was surprised to find the only side effects she experienced on Herceptin were dry mouth and slight loss of appetite. Soon‚ she noticed the pain and swelling in her arm went away.
UCLA physicians‚ working with the Breast Cancer International Research Group‚ are currently seeking participants for a new clinical study that will evaluate how effective Herceptin is when used for adjuvant therapy to prevent the recurrence of early–stage breast cancer after a woman has had her initial diagnosis and surgery. “If we can prove it works safely‚ then we can ask for approval from the FDA for these early–stage treatments‚” Dr. Pegram says. “We think there’s a strong rationale for moving forward.”

Blocking Tumor Growth Factor
Erbitux® (cetuximab or C225)‚ is another promising antibody‚ although it is more experimental than Herceptin. Both Herceptin and Erbitux target members of the same family of receptors‚ explains Leonard Saltz‚ MD‚ associate attending physician at Memorial Sloan–Kettering Cancer Center‚ New York.
“C225 blocks the binding site of the human epidermal growth factor (EGFR) 1‚ or HER1 receptor‚” he says. “That prevents signals from being sent into the cells that would normally facilitate the tumor’s growth and survival.” Erbitux is being considered as a potential treatment for several different tumor types‚ including cancer of the head and neck‚ colon‚ and lung.

Another antibody‚ ABX–EGF‚ works in a similar way. It was genetically engineered to bind to the epidermal growth factor receptors on tumors‚ preventing them from sending growth signals.

“ABX–EGF is yet another example of molecular engineering approaches to therapeutic antibodies‚” explains Dr. Pegram. “ABX–EGF is a fully human antibody with no mouse monoclonal–antibody sequences in its structure.”

ABX–EGF has been shown to shrink tumors in animal studies. Phase I and II clinical studies are under way to examine how effective ABX–EGF will be for patients with kidney cancer‚ non–small–cell lung cancer‚ and colorectal cancer.
Fred Clarke‚ of St. Charles‚ Illinois‚ recently enrolled in an ABX–EGF trial at the University of Chicago. He was diagnosed with renal cell carcinoma last spring. Surgeons removed one of his kidneys‚ but later determined the cancer had spread to his lungs. At first‚ they tried a conventional chemotherapy treatment‚ but Clarke developed severe side effects that prevented him from running the land development company he has owned since 1976. After he quit taking chemotherapy‚ his doctor suggested trying ABX–EGF. So last fall‚ Clarke started driving to Chicago’s south side for weekly intravenous treatments of the experimental antibody. “I had virtually no side effects at all‚ so that was pretty nice‚” Clarke said. “And the fact that I could still work was a plus.”

Several months later‚ Clarke received good news: Some of the tumors in his lung appeared to be shrinking. But then a CT scan showed a new tumor developing‚ so he stopped using ABX–EGF last May after 32 weeks.
“I don’t know whether I developed an immunity to it or what‚ but it stopped working‚” says Clarke‚ who is now recovering from a stem cell transplant.
Despite the disappointing outcome‚ Clarke says he is still glad there are promising new options like ABX–EGF for patients who do not respond to chemo. “Just in the last 10 years‚ it’s amazing what they have come up with and how many people they have saved‚” he says. “I would say in the next 10 years it’s going to take off even more.”

The Newest Delivery System
Researchers are taking antibody therapy to a new level by attaching antibodies to chemotherapy agents‚ such as a toxic compound called DM1. “The antibodies bind to the tumor and then they deliver their deadly cargo‚” says Anthony Tolcher‚ MD‚ associate director of clinical research at the Institute for Drug Development‚ the University of Texas Health Science Center‚ San Antonio.
Several phase I clinical trials are under way in Dr. Tolcher’s research center. If they are successful‚ this new type of antibody therapy could prevent cancer patients from having to endure the unpleasant side effects caused by traditional chemotherapy drugs when taken intravenously. They also would offer a more precise way to attack cancer tumors instead of assaulting both healthy and cancerous cells‚ he says.

In two studies of antibodies called SB408075 and BB–10901‚ in which both were attached to DM1‚ a few patients with colon‚ small–cell lung and neuroendocrine cancers had their tumors shrink by more than 50%. In other cases‚ the disease stabilized and did not progress‚ Dr. Tolcher says. More studies are needed to determine the true effectiveness of these therapies‚ however‚ because the first clinical trials used very low doses. “They have seen spectacular results with these molecules in the lab‚” Dr. Tolcher adds. “Now we have to find out if it’s going to be equally impressive in human beings.” While scientists have been tinkering with antibody therapy for 100 years‚ it has now begun to move forward.

“This is the beginning of the antibody–therapy age‚” Dr. Pegram says. “It’s a very exciting time to be part of the field.” Dozens of new antibodies are now in the pipeline to be developed as cancer drugs‚ he adds. By zeroing in on more targets with more specific mechanisms‚ scientists are starting to chip away at cancer. “We may not find a cure right away‚” Dr. Pegram says. “But we may be able to convert a deadly disease into a chronic disease.”

For cancer survivors like Lemonier‚ antibody therapy has turned the future into something to savor instead of fear. If it weren’t for Herceptin‚ she wouldn’t be able to dream of returning to her elementary school classroom next spring‚ but now it could be a reality.

“I’m a faithful person‚” she says. “I just need to get through this and everything will be fine.”