Antibodies that selectively bind and destroy cancer cells represent some of the most promising cancer therapy approaches being developed today. Several of these antibodies have reached the market, including cetuximab (Erbituxฎ, ImClone Systems), which targets the epidermal growth factor receptor (EGFR) protein. However, a study conducted at the Dana-Farber Cancer Institute and the Ludwig Center at Dana-Farber/Harvard Medical School now suggests that antibodies binding a particular protein conformation, caused by hyperactivation, might have distinct therapeutic advantages over antibodies, like cetuximab, that bind to wild-type (normal) target proteins.
The study, led by Dana-Farber Cancer Institute's Dr. Kwok-Kin Wong, and published today in the Journal of Clinical Investigation, is part of a multi-center, international effort to assess the clinical potential of the 806 antibody. The 806 antibody was discovered by scientists at the Ludwig Institute for Cancer Research. The antibody targets EGFR only when the receptor has been activated by mutations, by the protein's over-expression or by amplification of the EGFR gene. In the present study, Dr. Wong compared the action of cetuximab and 806 in a mouse model of non-small cell lung cancer (NSCLC) caused by different activating mutations in EGFR.. The 806 antibody caused a dramatic tumor regression in the mice, while cetuximab did not.
"Cetuximab only works on a subset of patients with lung cancers," says Wong. "We think the 806 antibody might benefit those patients who respond to cetuximab but, more importantly, might also be effective for those patients who don't." According to Dr. Wong, approximately 10-30 percent of patients with NSCLC and 5 percent of patients with squamous cell lung cancers have EGFR activating mutations. Some brain tumors also have EGFR activating mutations that are -- in animal studies -- responsive to the 806 antibody. A phase I clinical trial of the 806 antibody has been completed in Melbourne, Australia by the Ludwig Institute for Cancer Research co-authors. The antibody was shown to target a variety of cancers, including squamous cell lung cancer, with no targeting of normal tissues and no toxicity.
The paper's co-authors are Danan Li, Hongbin Ji, Sara Zaghlul, Kate McNamara, and George Demetri of the Ludwig Center at Dana-Farber/Harvard Medical School, Shigeto Kubo, Robert Padera and Kwok-Kin Wong of Dana-Farber Cancer Institute, Shigeto Kubo, Masaya Takahashi and Lucian R. Chirieac of the Brigham and Women's Hospital and Andrew Scott and Lloyd Old of the Ludwig Institute for Cancer Research.
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