The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform

Peter R. Young - One of the best experts on this subject based on the ideXlab platform.

  • corrigendum to Peginesatide and erythropoietin stimulate similar erythropoietin receptor mediated signal transduction and gene induction events experimental hematology 40 2012 575 587
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • Corrigendum to “Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events” [Experimental Hematology 40 (2012) 575–587]
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • the erythropoiesis stimulating agent omontys Peginesatide up modulates erythroid progenitor formation and cell surface erythropoietin receptor levels
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

  • The Erythropoiesis Stimulating Agent Omontys/Peginesatide up-Modulates Erythroid Progenitor Formation, and Cell Surface Erythropoietin Receptor Levels.
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

  • Peginesatide and erythropoietin stimulate similar erythropoietin receptor-mediated signal transduction and gene induction events.
    Experimental Hematology, 2012
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    Peginesatide is a synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. Peginesatide has a unique structure that consists of a synthetic peptide dimer (with no sequence similarity to erythropoietin) conjugated to a 40-kDa PEG moiety. Peginesatide is being developed for the treatment of anemia associated with chronic kidney disease in dialysis patients. To compare signaling effects of Peginesatide to recombinant human erythropoietin (rHuEPO), dose-dependent effects on protein phosphorylation and gene expression were evaluated using phosphoproteomics, quantitative signal transduction analyses, and gene profiling. After stimulation with Peginesatide or rHuEPO, cell lysates were prepared from UT-7/EPO cells. Liquid chromatography-tandem mass spectrometry and MesoScale arrays were used to quantify phosphorylation events. Transcriptional changes were analyzed using microarrays and quantitative reverse transcription polymerase chain reaction. Peginesatide and rHuEPO were found to regulate the tyrosine phosphorylation of an essentially equivalent set of protein substrates, and modulate the expression of a similar set of target genes. Consistent with their roles in stimulating erythropoiesis, Peginesatide and rHuEPO regulate similar cellular pathways.

Peter J. Schatz - One of the best experts on this subject based on the ideXlab platform.

  • A dimeric peptide with erythropoiesis-stimulating activity uniquely affects erythropoietin receptor ligation and cell surface expression
    Experimental Hematology, 2016
    Co-Authors: Rakesh Verma, Jennifer M. Green, Peter J. Schatz, Don M. Wojchowski
    Abstract:

    Erythropoiesis-stimulating agents (ESAs) that exert long-acting antianemia effects have been developed recently, but their mechanisms are poorly understood. Analyses reveal unique erythropoietin receptor (EPOR)-binding properties for one such ESA, the synthetic EPOR agonist Peginesatide. Compared with recombinant human EPO and darbepoietin, Peginesatide exhibited a slow on rate, but sustained EPOR residency and resistant displacement. In EPO-dependent human erythroid progenitor UT7epo cells, culture in Peginesatide unexpectedly upmodulated endogenous cell surface EPOR levels with parallel increases in full-length EPOR-68K levels. These unique properties are suggested to contribute to the durable activity of this (and perhaps additional) dimeric peptide hematopoietic growth factor receptor agonist.

  • corrigendum to Peginesatide and erythropoietin stimulate similar erythropoietin receptor mediated signal transduction and gene induction events experimental hematology 40 2012 575 587
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • Corrigendum to “Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events” [Experimental Hematology 40 (2012) 575–587]
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • The Erythropoiesis Stimulating Agent Omontys/Peginesatide up-Modulates Erythroid Progenitor Formation, and Cell Surface Erythropoietin Receptor Levels.
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

  • the erythropoiesis stimulating agent omontys Peginesatide up modulates erythroid progenitor formation and cell surface erythropoietin receptor levels
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

Jennifer M. Green - One of the best experts on this subject based on the ideXlab platform.

  • A dimeric peptide with erythropoiesis-stimulating activity uniquely affects erythropoietin receptor ligation and cell surface expression
    Experimental Hematology, 2016
    Co-Authors: Rakesh Verma, Jennifer M. Green, Peter J. Schatz, Don M. Wojchowski
    Abstract:

    Erythropoiesis-stimulating agents (ESAs) that exert long-acting antianemia effects have been developed recently, but their mechanisms are poorly understood. Analyses reveal unique erythropoietin receptor (EPOR)-binding properties for one such ESA, the synthetic EPOR agonist Peginesatide. Compared with recombinant human EPO and darbepoietin, Peginesatide exhibited a slow on rate, but sustained EPOR residency and resistant displacement. In EPO-dependent human erythroid progenitor UT7epo cells, culture in Peginesatide unexpectedly upmodulated endogenous cell surface EPOR levels with parallel increases in full-length EPOR-68K levels. These unique properties are suggested to contribute to the durable activity of this (and perhaps additional) dimeric peptide hematopoietic growth factor receptor agonist.

  • corrigendum to Peginesatide and erythropoietin stimulate similar erythropoietin receptor mediated signal transduction and gene induction events experimental hematology 40 2012 575 587
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • Corrigendum to “Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events” [Experimental Hematology 40 (2012) 575–587]
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • The Erythropoiesis Stimulating Agent Omontys/Peginesatide up-Modulates Erythroid Progenitor Formation, and Cell Surface Erythropoietin Receptor Levels.
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

  • the erythropoiesis stimulating agent omontys Peginesatide up modulates erythroid progenitor formation and cell surface erythropoietin receptor levels
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

Richard B. Mortensen - One of the best experts on this subject based on the ideXlab platform.

  • corrigendum to Peginesatide and erythropoietin stimulate similar erythropoietin receptor mediated signal transduction and gene induction events experimental hematology 40 2012 575 587
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • Corrigendum to “Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events” [Experimental Hematology 40 (2012) 575–587]
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • The Erythropoiesis Stimulating Agent Omontys/Peginesatide up-Modulates Erythroid Progenitor Formation, and Cell Surface Erythropoietin Receptor Levels.
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

  • the erythropoiesis stimulating agent omontys Peginesatide up modulates erythroid progenitor formation and cell surface erythropoietin receptor levels
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

  • Peginesatide and erythropoietin stimulate similar erythropoietin receptor-mediated signal transduction and gene induction events.
    Experimental Hematology, 2012
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    Peginesatide is a synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. Peginesatide has a unique structure that consists of a synthetic peptide dimer (with no sequence similarity to erythropoietin) conjugated to a 40-kDa PEG moiety. Peginesatide is being developed for the treatment of anemia associated with chronic kidney disease in dialysis patients. To compare signaling effects of Peginesatide to recombinant human erythropoietin (rHuEPO), dose-dependent effects on protein phosphorylation and gene expression were evaluated using phosphoproteomics, quantitative signal transduction analyses, and gene profiling. After stimulation with Peginesatide or rHuEPO, cell lysates were prepared from UT-7/EPO cells. Liquid chromatography-tandem mass spectrometry and MesoScale arrays were used to quantify phosphorylation events. Transcriptional changes were analyzed using microarrays and quantitative reverse transcription polymerase chain reaction. Peginesatide and rHuEPO were found to regulate the tyrosine phosphorylation of an essentially equivalent set of protein substrates, and modulate the expression of a similar set of target genes. Consistent with their roles in stimulating erythropoiesis, Peginesatide and rHuEPO regulate similar cellular pathways.

Don M. Wojchowski - One of the best experts on this subject based on the ideXlab platform.

  • A dimeric peptide with erythropoiesis-stimulating activity uniquely affects erythropoietin receptor ligation and cell surface expression
    Experimental Hematology, 2016
    Co-Authors: Rakesh Verma, Jennifer M. Green, Peter J. Schatz, Don M. Wojchowski
    Abstract:

    Erythropoiesis-stimulating agents (ESAs) that exert long-acting antianemia effects have been developed recently, but their mechanisms are poorly understood. Analyses reveal unique erythropoietin receptor (EPOR)-binding properties for one such ESA, the synthetic EPOR agonist Peginesatide. Compared with recombinant human EPO and darbepoietin, Peginesatide exhibited a slow on rate, but sustained EPOR residency and resistant displacement. In EPO-dependent human erythroid progenitor UT7epo cells, culture in Peginesatide unexpectedly upmodulated endogenous cell surface EPOR levels with parallel increases in full-length EPOR-68K levels. These unique properties are suggested to contribute to the durable activity of this (and perhaps additional) dimeric peptide hematopoietic growth factor receptor agonist.

  • corrigendum to Peginesatide and erythropoietin stimulate similar erythropoietin receptor mediated signal transduction and gene induction events experimental hematology 40 2012 575 587
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • Corrigendum to “Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events” [Experimental Hematology 40 (2012) 575–587]
    Experimental Hematology, 2014
    Co-Authors: Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, Peter R. Young
    Abstract:

    68 69 70 71 72 73 74 75 76 77 78 79 80 81 Corrigendum to ‘‘Peginesatide and erythropoietin stimulate similar erythropoietin receptor–mediated signal transduction and gene induction events’’ [Experimental Hematology 40 (2012) 575–587] Jennifer M. Green, Karen Leu, Angela Worth, Richard B. Mortensen, David K. Martinez, Peter J. Schatz, Don M. Wojchowski, and Peter R. Young Affymax, Inc., Palo Alto, CA, USA; Maine Medical Center Research Institute, Scarborough, ME, USA 82 83 84 85 86 87 88 The authors regret that an affiliation was left out of the Acknowledgments. Investigations were supported in part by National Institutes of Health (NIH) grants R01HL044491 and R01DK089439 (D.M. Wojchowski). The authors would like to apologize for any inconvenience caused. 89

  • The Erythropoiesis Stimulating Agent Omontys/Peginesatide up-Modulates Erythroid Progenitor Formation, and Cell Surface Erythropoietin Receptor Levels.
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.

  • the erythropoiesis stimulating agent omontys Peginesatide up modulates erythroid progenitor formation and cell surface erythropoietin receptor levels
    Blood, 2012
    Co-Authors: Rakesh Verma, Jennifer M. Green, Karen Leu, Richard B. Mortensen, Peter J. Schatz, Peter R. Young, Don M. Wojchowski
    Abstract:

    Abstract 2089 Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although Peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to Peginesatide9s durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, Peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, Peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in Peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR9s. Furthermore, in studies that compared Peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, Peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in Peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that Peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in Peginesatide. Peginesatide9s persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms. Disclosures: Green:Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity9s Board of Directors or advisory committees.