Christopher L. Reyes
Biogen Idec
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Featured researches published by Christopher L. Reyes.
Journal of Biological Chemistry | 2009
Adam Doern; Xianjun Cao; Arlene Sereno; Christopher L. Reyes; Angelina E. Altshuler; Flora Huang; Cathy Hession; Albert Flavier; Michael Favis; Hon Tran; Eric Ailor; Melissa Levesque; Tracey Murphy; Lisa Berquist; Susan Tamraz; Tracey Snipas; Ellen Garber; William S. Shestowsky; Rachel Rennard; Christilyn Graff; Xiufeng Wu; William Snyder; Lindsay J. Cole; David Gregson; Michael Shields; Steffan N. Ho; Mitchell E Reff; Scott Glaser; Jianying Dong; Stephen J. Demarest
Therapeutic antibodies directed against the type 1 insulin-like growth factor receptor (IGF-1R) have recently gained significant momentum in the clinic because of preliminary data generated in human patients with cancer. These antibodies inhibit ligand-mediated activation of IGF-1R and the resulting down-stream signaling cascade. Here we generated a panel of antibodies against IGF-1R and screened them for their ability to block the binding of both IGF-1 and IGF-2 at escalating ligand concentrations (>1 μm) to investigate allosteric versus competitive blocking mechanisms. Four distinct inhibitory classes were found as follows: 1) allosteric IGF-1 blockers, 2) allosteric IGF-2 blockers, 3) allosteric IGF-1 and IGF-2 blockers, and 4) competitive IGF-1 and IGF-2 blockers. The epitopes of representative antibodies from each of these classes were mapped using a purified IGF-1R library containing 64 mutations. Most of these antibodies bound overlapping surfaces on the cysteine-rich repeat and L2 domains. One class of allosteric IGF-1 and IGF-2 blocker was identified that bound a separate epitope on the outer surface of the FnIII-1 domain. Using various biophysical techniques, we show that the dual IGF blockers inhibit ligand binding using a spectrum of mechanisms ranging from highly allosteric to purely competitive. Binding of IGF-1 or the inhibitory antibodies was associated with conformational changes in IGF-1R, linked to the ordering of dynamic or unstructured regions of the receptor. These results suggest IGF-1R uses disorder/order within its polypeptide sequence to regulate its activity. Interestingly, the activity of representative allosteric and competitive inhibitors on H322M tumor cell growth in vitro was reflective of their individual ligand-blocking properties. Many of the antibodies in the clinic likely adopt one of the inhibitory mechanisms described here, and the outcome of future clinical studies may reveal whether a particular inhibitory mechanism leads to optimal clinical efficacy.
Archive | 2009
Kandasamy Hariharan; Scott Glaser; Ellen Garber; Christilyn Graff; Christopher L. Reyes; Stephen J. Demarest
Archive | 2010
Christopher L. Reyes; Eric Chan; Frederick R. Taylor; Ellen Garber; Brian Robert Miller; Stephen J. Demarest; Scott Glaser
Archive | 2012
Christopher L. Reyes; Peter Chu; Xiangyang Tan; Weixing Yang; Christilyn Graff
Archive | 2012
Christopher L. Reyes; Peter Chu; Xiangyang Tan; Weixing Yang; Christilyn Graff
Archive | 2007
Kandasamy Hariharan; Christilyn Graff; Scott Glaser; Ellen Garber; Christopher L. Reyes; Stephen J. Demarest
Archive | 2012
Christopher L. Reyes; Peter Chu; Xiangyang Tan; Weixing Yang; Christilyn Graff
Archive | 2015
Christopher L. Reyes; Kristen M. Smith; Peter Chu; Eric Ailor; Lioudmila A. Campbell
Archive | 2015
Christopher L. Reyes; Peter Chu; Kristen M. Smith; Lioudmila A. Campbell; Farbod Shojaei; John Thomas Norton
Archive | 2012
Christopher L. Reyes; Peter Chu; Xiangyang Tan; Weixing Yang; Christilyn Graff