Two Antibodies Are Better Than One

Cancer drugs of the new, molecular generation destroy malignant breast tumors in a targeted manner:  They block characteristic molecules on tumor cells – receptors for the hormones estrogen or progesterone, or a co-receptor, called HER2, that binds to many growth factors. But about one in every six breast tumors has none of these receptors. Such cancers, called triple-negative, are particularly aggressive and notoriously difficult to treat.

Some of these therapy-resistant cancers have a potential molecular target for cancer drugs, a growth-factor receptor called EGFR, but an EGFR-blocking drug has proved ineffective in treating them. In a study published recently in the Proceedings of the National Academy of Sciences, Weizmann Institute researchers propose a potential solution: to simultaneously treat triple-negative breast cancer with two EGFR-blocking antibodies instead of one. In a study in mice, the scientists showed that a certain combination of two antibodies indeed prevented the growth and spread of triple-negative tumors. The research team, led by Prof. Yosef Yarden of the Biological Regulation Department and Prof. Michael Sela of the Immunology Department, included Drs. Daniela Ferraro, Nadège Gaborit, Ruth Maron,  Hadas Cohen-Dvashi,  Ziv Porat and Fresia Pareja, and Sara Lavi, Dr. Moshit Lindzen and Nir Ben-Chetrit.

Of the different combinations they tried, the scientists found that the approach worked when the two antibodies bound to different parts of the EGFR molecule. The combined action of the antibodies was stronger than would have been expected by simply adding up the separate effects of each.  Apparently, the use of the two antibodies created an entirely new anti-cancer mechanism: In addition to blocking the EGFR and recruiting the help of immune cells, the antibodies probably overwhelmed the EGFR by their sheer weight, causing it to collapse inward from the membrane into the tumor cell.

 

Deprived of EGFR on its surface, the cells were no longer receiving the growth signals, preventing the growth of the tumor. This approach resembles the natural functioning of the immune system, which tends to block essential antigens at several sites by targeting them with multiple antibodies.

If supported by further studies, the two-antibody approach, in combination with chemotherapy, might in the future be developed into an effective treatment for triple-negative breast cancer.

 

Prof. Michael Sela is the incumbent of the W. Garfield Weston Professorial Chair of Immunology.
 

Prof. Yosef Yarden’s research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the M.D. Moross Institute for Cancer Research; the Steven and Beverly Rubenstein Charitable Foundation , Inc.; Julie Charbonneau, Canada; the European Research Council; and the Marvin Tanner Laboratory for Research on Cancer. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.