David Fabrizio
Bristol-Myers Squibb
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Featured researches published by David Fabrizio.
Cancer Research | 2010
Stuart Emanuel; Linda Engle; Carolyn Cao; Ginger Chao; Zheng Lin; Rong-Rong Zhu; Aaron P. Yamniuk; Jennifer Hosbach; Jennifer S. Brown; Elizabeth Fitzpatrick; Jochem Gokemeijer; Paul E. Morin; Brent Morse; Irvith M. Carvajal; David Fabrizio; Martin C. Wright; Ruchira Dasgupta; Mike Gosselin; Rolf Ryseck; Michael L. Doyle; Tai W. Wong; Ray Camphausen; Sharon T. Cload; Nick Marsh; Eric Furfine; Marco M. Gottardis
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCnnThe epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGFR) are transmembrane receptor tyrosine kinases that mediate proliferative and invasive cell signaling in cancer. Inhibition of either receptor reduces tumor growth in both mouse models and in human clinical studies. Blocking the EGFR pathway can induce compensatory activation of the IGFR pathway to drive tumor growth and IGFR inhibition can result in activation of EGFR signaling in preclinical models. Therefore, blocking both receptors simultaneously may achieve superior efficacy to blocking either pathway alone. We developed individual optimized Adnectins™ specific for blocking either EGFR or IGFR signaling and engineered them into a single protein that linked both Adnectins together to construct a bi-specific Adnectin targeting the EGFR and IGFR (EI-tandem). The bifunctional molecule blocked activation of EGFR and IGFR, inhibited both EGF and IGF-induced down-stream cell signaling (MAPK and AKT pathways) and was antiproliferative in human cancer cell lines. Potency of the EI-tandem was comparable to anti-EGFR and anti-IGFR antibodies. The EI-tandem demonstrated a synergistic inhibition of IGFR phosphorylation and down-stream cell signaling compared to Adnectins specific for only EGFR or IGFR alone. Although Adnectins bound to the EGFR at a site distinct from the clinically approved anti-EGFR antibodies cetuximab, panitumumab and nimotuzumab, they still blocked binding of EGF to the EGFR. PEGylated EI-tandem inhibited the growth of human tumor xenografts driven by both EGFR and IGFR signaling, degraded EGFR and IGFR, and reduced phosphorylation of EGFR in tumors. Treatment of mice with EI-tandem caused increases in levels of the circulating ligands TGFα and IGF1 resulting from blockade of their respective receptors and provided convenient soluble biomarkers of target suppression. These results show that a bifunctional Adnectin can confer improved biological activity compared to monospecific biologics in tumors where growth is driven by multiple growth factors.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2586.
Antimicrobial Agents and Chemotherapy | 2017
David Wensel; Yongnian Sun; Zhufang Li; Sharon Zhang; Caryn Picarillo; Thomas McDonagh; David Fabrizio; Mark Cockett; Mark Krystal; Jonathan Davis
ABSTRACT A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using in vitro selection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity. Resistance profiling studies showed that this inhibitor required 30 passages (151 days) in culture to acquire sufficient resistance to result in viral titer breakthrough. Resistance mapped to the loss of multiple potential N-linked glycosylation sites in gp120, suggesting that inhibition is due to steric hindrance of CD4-binding-induced conformational changes.
Archive | 2011
Michael L. Gosselin; David Fabrizio; Joanna Swain; Tracy S. Mitchell; Ray Camphausen; Sharon T. Cload; Eric Furfine; Paul E. Morin; Ranjan Mukherjee; Simeon I. Taylor
Archive | 2007
Ray Camphausen; David Fabrizio; Martin C. Wright; Patrick Gage; John Mendlein
Archive | 2009
Ray Camphausen; Brent Morse; Stuart Emanuel; David Fabrizio
Archive | 2015
Tracy S. Mitchell; Michael L. Gosselin; Dasa Lipovsek; Rex A. Parker; Ray Camphausen; Jonathan Davis; David Fabrizio
Journal of Virology | 2018
David Wensel; Yongnian Sun; Jonathan Davis; Zhufang Li; Sharon Zhang; Thomas McDonagh; David Fabrizio; Mark Cockett; Mark Krystal
Archive | 2015
Paul E. Morin; David Donnelly; Dasa Lipovsek; Jochem Gokemeijer; Maria Jure-Kunkel; David Fabrizio; Martin C. Wright; Douglas D. Dischino; Samuel J. Bonacorsi; Ralph Adam Smith; Virginie Lafont
Archive | 2015
Paul E. Morin; David Donnelly; Dasa Lipovsek; Jochem Gokemeijer; Maria Jure-Kunkel; David Fabrizio; Martin C. Wright; Douglas D. Dischino; Samuel J. Bonacorsi; Ralph A. Smith; Virginie Lafont
Archive | 2014
David Fabrizio