In the early 1900s, German Nobel Laureate Paul Ehrlich imagined an ideal therapy for disease, a drug precisely targeted to an invader, which if linked to a toxic chemical would act like a missile, carrying a destructive payload directly to the disease. Ehrlich said the drug would be a ‘Magische Kugel,’ which in English means ‘Magic Bullet.’ Such a therapy, he theorized, would be ideal for countless diseases, including cancer. Science had the payload. What it didn’t have was the missile.
Whether the idea came in a dream, whether it arrived as a classical “aha” moment in a dusty lab, or at a patient’s bedside while scribbling notes, the search for Ehrlich’s Magic Bullet took a huge leap when someone asked, “Why not antibodies?”
Antibodies are proteins made by the immune system. In the body, they bind with high specificity to antigens, receptors on the surface of foreign invaders, such as viruses and bacteria. Fitting like a lock in a key, such binding enables immune cells to “see” and attack invaders. And because Nature has innumerable invaders, the human body has many antibodies–10 million to be exact.
Scientists had their missile.
In 1975, Georges Kohler and Cesar Milstein created the first laboratory-produced antibodies, called monoclonal antibodies (mAbs). A year later, on Thanksgiving Day, a doctor named Ron Levy ran a groundbreaking experiment, inspiring him to run through the halls of his lab with joy. He’d created monoclonal antibodies that specifically recognized cancer cells.
In 1979, immunologist and cancer researcher Lee Nadler teamed up with Phil Stashenko, another immunologist, and created a monoclonal antibody targeted to antigens on non-Hodgkin’s lymphoma cells. Their drug failed. When given to a man with advanced lymphoma, the mAb bound to few tumor cells. And the patient’s immune system rejected the drug, due to the fact it was created from mouse cells.
To avoid rejection, scientists from IDEC Pharmaceuticals Corporation used recombinant technology to create a part human, part mouse antibody called a chimera. In clinical studies, their “humanized” drug, Rituxamab, cut tumor sizes in half. And when combined with other chemotherapies, it cured 79% of patients. The drug’s approval in 1997 led to the development of similar antibody-based therapies, some of which worked by killing cells directly (e.g. Rituxamab), others which slowed or stopped tumor growth by interfering with surface receptors on cancer cells, or some which better enabled the immune system to fight the disease.
Unfortunately these mAbs required additional treatments with chemotherapeutic agents, which damaged healthy cells and caused severe side effects, such as the loss of hair, nausea, vomiting and extreme fatigue.
Researchers got around this problem by directly attaching the monoclonal antibody to the chemotherapeutic agent, and as of late, by linking it to even more potent radioactive isotopes, which if given alone would be lethal. When administered, this so-called “armed antibody,” or Antibody Drug Conjugate (ADC), floats in the bloodstream sticking only to cancer cells. Once attached, it drops its toxic cargo, killing the cancer cell in a highly targeted way.
There are 25 ADCs in development currently. Genenetch has 17 in early development and eight in clinical trials, one of which is a drug called T-DM1, indicated for breast cancer patients with high amounts of HER-2, a receptor protein elevated in 20% of women with breast cancer.
T-DM1 consists of three components. The first is the already-approved breast cancer drug Trastuzumab (Herceptin), a monoclonal antibody developed by Genenetch, which in clinical trials increased survival rates in women with HER-2-positive metastatic breast cancer (20.3 to 25.1 months). Herceptin is linked to the second part, a toxic chemical called emtansine (DM1). And the third component is a chemical which delays DM1’s release.
Linking DM1 to Herceptin keeps the toxic chemical inactive until cancer cells are reached, leaving healthy cells untouched. Once bound to cancer cells, T-DM1 is internalized and the toxic payload is delivered, greatly reducing side effects compared to using Herceptin with a chemotherapeutic agent. For patients, decreased toxicity means no hair loss and less nausea and fatigue.
In a Phase III trial, 991 HER-2 breast cancer patients received T-DM1. Compared to conventional cancer treatments, results showed that 43.6% of patients given the ADC showed tumor shrinkage, compared to 30.8% on standard anti-cancer therapy. Survival rate was improved as well (9.6 months vs. 6.4 months). The results were published in an October paper in The New England Journal of Medicine.
In 2011, the FDA approved Seattle Genetics’ antibody-drug conjugate, Adcetris, after results showed it shrank tumors in 93% of patients with Hodgkin’s lymphoma, and 73% went into partial or total remission.
While early ADCs have proven effective, the price tags on such drugs are high; Adcetris’s treatment costs about $100,000, for example. And according to drug makers, linking the antibodies to the toxic chemicals is challenging. Sometimes the chemical can fall off the mAb; this happened with the first ADC, Mylotarg, approved in 2000, but then taken off the market in 2010. And T-DM1, which could be approved next year, is not indicated for all breast cancers, only those with the elevated HER-2 protein.
But like most antibody-based therapies, ADCs are profoundly less expensive to develop than traditional drugs. And because they are so specific and therefore less toxic, market approval can come faster due to fewer side effects.
It took 75 years to go from Ehrlich’s magic bullet theory to a laboratory-created monoclonal antibody. It took almost 30 to successfully link them to a toxic payload. In all, antibody-drug conjugates represent the next evolution in targeted cancer therapy and a monumental leap forward in the fight against cancer.