EPHA3 as a Target in the Hematological Malignancies
EPHA3 as a Target in the Hematological Malignancies
The Eph receptors are promising therapeutic, diagnostic and prognostic targets. EPHA3 is expressed in abundance in hemato-logical malignancies and may be expressed ubiquitously in the more advanced and aggressive stages of these diseases, even if not expressed by malignant cells at initial diagnosis. These findings further fuel excitement about the potential therapeutic effects of agents targeting EPHA3. Data on the monoclonal antibody targeting EPHA3 now entering clinical study will be eagerly awaited. Ephs are highly conserved, capable of promiscuous interactions, may induce antagonistic cellular responses and are involved in stem cell function. This profile leads to caution in terms of potential acute and/or chronic adverse effects associated with Eph modulation in humans. The preclinical data on KB004 are encouraging in terms of being consistent with relative selectivity for tumor cells in terms of cytotoxicity. How predictive these data are for clinical reality remains to be established. The degree to which one can extrapolate data on a monoclonal antibody modulator to other potential EPHA3-directed therapies, with small molecules being of particular interest, has yet to be established. Will an 'armed' toxin or radioactive substance-bearing monoclonal be more potent than a 'naked' monoclonal? How predictive will our clinical experience with EPHA3 modulators be of other Eph RTK modulator activities and toxicities? KB004 has a very significant regulatory advantage as a true 'first-in-class' agent directed against a novel target. We expect that experience gained in the development of EPHA3 modulators will inform and accelerate exploration of other Eph RTK as therapeutic targets
Five-year View
The Eph receptors are promising therapeutic, diagnostic and prognostic targets. EPHA3 is expressed in abundance in hemato-logical malignancies and may be expressed ubiquitously in the more advanced and aggressive stages of these diseases, even if not expressed by malignant cells at initial diagnosis. These findings further fuel excitement about the potential therapeutic effects of agents targeting EPHA3. Data on the monoclonal antibody targeting EPHA3 now entering clinical study will be eagerly awaited. Ephs are highly conserved, capable of promiscuous interactions, may induce antagonistic cellular responses and are involved in stem cell function. This profile leads to caution in terms of potential acute and/or chronic adverse effects associated with Eph modulation in humans. The preclinical data on KB004 are encouraging in terms of being consistent with relative selectivity for tumor cells in terms of cytotoxicity. How predictive these data are for clinical reality remains to be established. The degree to which one can extrapolate data on a monoclonal antibody modulator to other potential EPHA3-directed therapies, with small molecules being of particular interest, has yet to be established. Will an 'armed' toxin or radioactive substance-bearing monoclonal be more potent than a 'naked' monoclonal? How predictive will our clinical experience with EPHA3 modulators be of other Eph RTK modulator activities and toxicities? KB004 has a very significant regulatory advantage as a true 'first-in-class' agent directed against a novel target. We expect that experience gained in the development of EPHA3 modulators will inform and accelerate exploration of other Eph RTK as therapeutic targets
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