Two antibodies are better than one 7 July 2013

Two antibodies are better than one

  •   In resistant breast cancer, two antibodies are better than one
    Israeli-devised ‘double whammy’ antibody is a promising approach to a deadly aggressive form of breast cancer
  • Prof. Yosef Yarden in his Weizmann lab
    By Rivka Borochov
    Breast cancer is often thought of as a curable disease if caught early. But there is an aggressive type with poor prognosis because existing drugs don’t seem to work. Called triple negative breast cancer, it occurs in about one in six women diagnosed with breast cancer -- usually black and
    Hispanic women, with black women seeing the worst outcomes.
    Israeli scientists from the Weizmann Institute of Science in Rehovot, Israel, have taken a new approach to tackling this nasty cancer. Prof. Yosef Yarden of the biological regulation department and his research partner, Prof. Michael Sela of the immunology department, have found that in the case of aggressive triple negative breast cancer, two antibodies are better than one.
    Their approach mimics the way the body defends itself against breast cancer to help cure those who have become resistant to therapy.
    "This research is about 10 to 15 percent of the overall breast cancer cases in the United States. We are talking about black women, generally, who are relatively young, in their 30s and 40s,” says Yarden. “This is quite a difficult disease for them. They are initially treated with chemotherapy and see a good response. But eventually they develop a resistance to it and the therapy fails.”
    These women usually live for seven or eight years after diagnosis.
    Triple negative breast cancer doesn’t come with a well-known biology, Yarden explains. The breast cancer cells are missing the three different receptors targeted by existing drugs, like Herceptin and what are known as steroid hormone blockers.
    There is a similarly aggressive breast cancer that can be treated with Herceptin, but “triple negative has no solution,” says Yarden.
    It takes two for synergy
    Herceptin is the trademarked name for trastuzumab, a new-generation molecular drug that destroys breast tumors by blocking the hormones that enable them to grow. But in one in six breast cancers, the receptors are lacking and the drug fails to work.
    Reading the literature, Yarden and his team came up with a new idea: Instead of targeting just one antibody on the cell surface, as Herceptin does, they would look at another cell receptor system and attack it in a fresh approach.
    “Researchers have reported that one-third of triple negative cancers have high receptor levels for EGFR, epidermal growth-factor receptor, much more than in a normal breast cell, so it is very different than other subtypes of triple negative cancers,” Yarden explains.
    “This gives us the idea that EGFR is important for the growth, survival and resistance of the cancer. Because it’s only appearing in one-third of triple negatives, this might be a clue that it might be relevant to the other two-thirds as well.”
    Until now, EGFR-blocking drugs have proved ineffective. Yarden’s team is the first to see positive cell-shrinking effects from a double-whammy antibody approach.
    “Even treating five percent of the entire breast cancer population overall is something,” he adds. In mice, the researchers simultaneously treated triple-negative breast cancer with two EGFR-blocking antibodies instead of just one. Together they appeared to overwhelm the EGFR with their
    weight, causing the cell to collapse in on itself.
    Cancer’s collapse and demise
    The tests have only been done on animal models so far, and Yarden currently seeks collaboration with a pharmaceutical company to develop a new antibody that could synergize with the two existing antibody therapies on the market.
    The two existing ones compete for the same receptor and therefore do not show this powerful synergistic effect, he notes. “We need to combine one of the existing ones with a new one which might be used as a starting point,” he says.
    Building a new antibody means taking a molecular approach using genetic engineering so that the antibody works in humans.
    A solution, if funded today, could be ready for clinical trials in about five or 10 years, he believes. This could help women now in their teens and twenties today.
    So far his research, published in the journal PNAS (Proceedings of the National Academy of Sciences), has “created a good response in the industry and among institutes of oncology,” says the researcher.
    The dream, he concludes, would be a vaccination against cancer, but for that the barrier of the immune system would need to be overcome. “This is the vision for my field but we have a much longer way to go.”