May 20, 2019, New York—A cell-surface protein known as the EGF receptor is mutated or over-expressed in a number of cancers. With the aim of targeting the protein for therapy, an international collaboration between Ludwig researchers developed an antibody, mAb806, that specifically and potently targets a specific mutant version of the receptor, EGFRvIII, as well as over-expressed EGF receptor.
Now, a study published in the Proceedings of the National Academy of Sciences—led by Ludwig Cancer Research scientists Web Cavenee and Frank Furnari along with researchers at Stockholm University and the University of Barcelona—indicates that the antibody might be made effective against a much broader swath of EGFR mutants, and even unmutated receptors. This could make the antibody useful for the treatment of a number of cancers.
EGFR extends across the membrane of the cell and a number of mutations, including the vIII mutation, alter the outer part of the receptor. A computational model of EGFR structure devised by the collaborating researchers predicted that many other mutations in the receptor’s outer domain would also, in different ways, expose the specific part of the protein, or “epitope”, targeted by mAb806. Studies reported in the current paper and led by Furnari and Cavenee in Ludwig San Diego confirmed that hypothesis, showing that mAb806 could indeed bind to about 15% of all the other known mutations to the receptor.
When active, two EGFRs ordinarily come together to form a symmetric structure inside the cell, in the part of the receptor that is responsible for its enzymatic activity. This, in turn, transiently exposes the epitope on the outer part of the cell recognized by mAb806. Furnari, Cavenee and their colleagues additionally showed that this structure could be locked into place by existing drugs that specifically recognize the symmetric structure inside the cell to silence EGFR’s enzymatic activity.
The drugs make EGFRs that ordinarily do not bind mAb806 susceptible to the antibody, and this occurs regardless of how, or even whether, the EGFR is mutated. “That elevates the utility of 806 antibody,” says Furnari.
The paper is available here.
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.
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