Three decades of intensive cancer research led to the identification of a family of receptors, known as HER, that sit antenna-like on the outside of the cell wall and are implicated in certain types of cancer. A team of researchers under Prof. Yosef Yarden, Dean of the Weizmann Institute's Feinberg Graduate School and a professor in the Institute's Biological Regulation Department, had previously found that, under certain conditions, the HER2 receptor amplifies the growth signal received by the cell. Yarden and Prof. Michael Sela, former president of the Weizmann Institute of Science, and currently a professor in the Institute's Immunology Department, teamed up to create a strategy for the customization of antibodies that work independently to engage these cancer-specific receptors and shut down the attendant signaling network. The study was carried out in cooperation with researchers from Targeted Molecular Diagnostics, Westmont, IL, USA.
In experiments conducted in vitro and in lab mice, the researchers exposed the cancer cells to two different antibodies that link up to HER2 receptors. In a synergistic action, the antibodies were shown to cooperate rather than compete for distinctly different attachment points on the architecture of the receptors, resulting in the assembly of a large, springy molecular scaffolding between the receptor towers. The interlocking system grips and pulls the receptors towards each other until they collapse inward like overloaded laundry lines. The stressed receptors become engulfed by the cell, and thus cease signaling. In response, the cell halts growth and, when chemotherapy is used in combination with the immunotherapy, it dies.
According to Sela, the study sheds light on the synergy at work in the antibody-receptor therapy system. The results demonstrate that with the right combination of antibodies, receptor degradation is accelerated: it's more than three times as effective as a single antibody in inhibiting HER2 signaling.
"Understanding how HER receptor degradation works could enhance weak therapeutic efficacy, as well as provide ways to sensitize patients to overcome inherent or acquired resistance to cancer treatment," says Yarden.
Prof. Yosef Yarden's research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the Dolfi and Lola Ebner Center for Biomedical Research; the J & R Center for Scientific Research; the Aharon Katzir-Katchalsky Center; the M.D. Moross Institute for Cancer Research; the Willner Family Center for Vascular Biology; the Batsheva De Rothschild Foundation; Dr. Marvin Klein, Farmington Hills, MI; Mr. & Mrs. Bram Laub, Belgium; and the Herbert J. Seligmann Charitable Trust. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.
Prof. Michael Sela's research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine, and the Dolfi and Lola Ebner Center for Biomedical Research. Prof. Sela is the incumbent of the W. Garfield Weston Professorial Chair of Immunology.