The Experts below are selected from a list of 351 Experts worldwide ranked by ideXlab platform
Davi D J Kuter - One of the best experts on this subject based on the ideXlab platform.
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assessment of romiplostim immunogenicity in adult patients in clinical trials and in a global postmarketing registry
British Journal of Haematology, 2020Co-Authors: Daniel T Mytych, Vibha Jawa, Joseph Park, Troy E Barger, Andy Boshier, Davi D J KuterAbstract:: Antibodies to first-generation Recombinant Thrombopoietin (TPO) neutralized endogenous TPO and caused thrombocytopenia in some healthy subjects and chemotherapy patients. The second-generation TPO receptor agonist romiplostim, having no sequence homology to TPO, was developed to avoid immunogenicity. This analysis examined development of binding and neutralising antibodies to romiplostim or TPO among adults with immune thrombocytopenia (ITP) in 13 clinical trials and a global postmarketing registry. 60/961 (6·2%) patients from clinical trials developed anti-romiplostim-binding antibodies post-baseline. The first positive binding antibody was detected 14 weeks (median) after starting romiplostim, at median romiplostim dose of 2 µg/kg and median platelet count of 29.5 × 109 /l; most subjects had ≥98·5% of platelet assessments showing response. Neutralising antibodies to romiplostim developed in 0·4% of patients, but were unrelated to romiplostim dose and did not affect platelet count. Thirty-three patients (3·4%) developed anti-TPO-binding antibodies; none developed anti-TPO-neutralising antibodies. In the global postmarketing registry, 9/184 (4·9%) patients with spontaneously submitted samples had binding antibodies. One patient with loss of response had anti-romiplostim-neutralising antibodies (negative at follow-up). Collectively, anti-romiplostim-binding antibodies developed infrequently. In the few patients who developed neutralising antibodies to romiplostim, there was no cross-reactivity with TPO and no associated loss of platelet response.
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thrombocytopenia caused by the development of antibodies to Thrombopoietin
Blood, 2001Co-Authors: Chun Yang, Yuping Xia, Amy M Bertino, John A Glaspy, Michael S Roberts, Davi D J KuterAbstract:Thrombocytopenia developed in some individuals treated with a Recombinant Thrombopoietin (TPO), pegylated Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). Three of the subjects who developed severe thrombocytopenia were analyzed in detail to determine the cause of their thrombocytopenia. Except for easy bruising and heavy menses, none of these subjects had major bleeding episodes; none responded to intravenous immunoglobulin or prednisone. Bone marrow examination revealed a marked reduction in megakaryocytes. All 3 thrombocytopenic subjects had antibody to PEG-rHuMGDF that cross-reacted with endogenous TPO and neutralized its biological activity. All anti-TPO antibodies were immunoglobulin G (IgG), with increased amounts of IgG4; no IgM antibodies to TPO were detected at any time. A quantitative assay for IgG antibody to TPO was developed and showed that the antibody concentration varied inversely with the platelet count. Anti-TPO antibody recognized epitopes located in the first 163 amino acids of TPO and prevented TPO from binding to its receptor. In 2 subjects, endogenous TPO levels were elevated, but the TPO circulated as a biologically inactive immune complex with anti-TPO IgG; the endogenous TPO in these complexes had an apparent molecular weight of 95 000, slightly larger than the full-length Recombinant TPO. None of the subjects had atypical HLA or platelet antigens, and the TPO cDNA was normal in both that were sequenced. Treatment of one subject with cyclosporine eliminated the antibody and normalized the platelet count. These data demonstrate a new mechanism for thrombocytopenia in which antibody develops to TPO; because endogenous TPO is produced constitutively, thrombocytopenia ensues.
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Thrombopoietins and Thrombopoiesis: A Clinical Perspective
Vox Sanguinis, 1998Co-Authors: Davi D J KuterAbstract:Since the discovery of Thrombopoietin four years ago there has been much interest in the clinical use of this growth factor and its impact on platelet transfusions. Two Recombinant Thrombopoietin molecules are currently under intense clinical investigation. One is a full-length, glycosylated Thrombopoietin (rHuTPO) and the other is a non-glycosylated, truncated Thrombopoietin coupled to polyethylene glycol (PEG-rHuMGDF). Both bind to the Thrombopoietin receptor, c-mpl, and stimulate megakaryocyte growth and platelet production in vitro and in vivo. In early clinical studies these Mpl ligands have been effective in reducing thrombocytopenia after non-myeloablative but not after myeloablative chemotherapy. In transfusion medicine, they may serve to increase the yield of stem cell harvests, expand progenitor cells ex vivo and stimulate platelet apheresis donors. Their impact on platelet usage is still unclear but may be less than initially estimated.
Giorgio Zauli - One of the best experts on this subject based on the ideXlab platform.
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Selective modulation of the cyclin B/CDK1 and cyclin D/CDK4 complexes during in vitro human megakaryocyte development.
British Journal of Haematology, 1999Co-Authors: Alessandra Bassini, Sabina Pierpaoli, Elisabetta Falcieri, Marco Vitale, Lia Guidotti, Silvano Capitani, Giorgio ZauliAbstract:Mammalian megakaryocyte development is characterized by a progressive accumulation of cells exhibiting a polylobated nucleus with a polyploid DNA content. In this study human megakaryocytes were obtained from CD34+ haemopoietic progenitors by in vitro liquid culture in the presence of 100 ng/ml of Recombinant Thrombopoietin (TPO). Ultrastructural examination of polyploid megakaryocytes showed the presence of a large number of centrioles, the breakdown of the nuclear envelope, and the progressive chromatin condensation, all aspects characteristic of mitosis. At both indirect immunofluorescence and Western blot analyses, cyclin B and its related cyclin-dependent kinase (CDK)1, which forms the mitosis promoting factor (MPF), showed an increased expression in maturating megakaryoblasts and megakaryocytes (day 8 of culture) with respect to freshly isolated CD34+ progenitors. This expression tended to decline in fully developed megakaryocytes (day 15 of culture). The amount of cyclin D and of the related CDK4, governing the G1 phase of the cell cycle, increased during megakaryocyte development, maintaining high levels of expression also in mature megakaryocytes. These results indicate that megakaryocyte polyploidization depends on a true, although incomplete, mitotic process, and that cyclin D/CDK4 probably plays a crucial role throughout megakaryocytopoiesis.
Eaton D.l. - One of the best experts on this subject based on the ideXlab platform.
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The efficacy of Recombinant Thrombopoietin in murine and nonhuman primate models for radiation-induced myelosuppression and stem cell transplantation
1998Co-Authors: Wagemaker G., Neelis K.j., Hartong S.c.c., Wognum A.w., Thomas G.r., Fielder P.j., Eaton D.l.Abstract:Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying Thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed
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The efficacy of Recombinant Thrombopoietin in murine and nonhuman primate models for radiation-induced myelosuppression and stem cell transplantation
1998Co-Authors: Wagemaker Gerard, Fielder P.j., Neelis Karen, Hartong Simone, Wognum Albert, Thomas Roger, Eaton D.l.Abstract:textabstractRadiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying Thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed
Graham Molineux - One of the best experts on this subject based on the ideXlab platform.
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the development of romiplostim for patients with immune thrombocytopenia
Annals of the New York Academy of Sciences, 2011Co-Authors: Graham MolineuxAbstract:Comprised of peptide and carrier components in an overall structure superficially resembling an antibody, romiplostim is the prototype of a new class of protein therapeutics called peptibodies. Romiplostim (AMG 531, Nplate ™ ) was designed to evade the immune response to Recombinant Thrombopoietin and offer a new method of treatment for patients with immune thrombocytopenia (ITP), an "orphan" disease. In contrast with agents designed to suppress immune function or hinder the processes of platelet destruction, romiplostim works by stimulating the production of new platelets. It was proven to increase platelet counts, reduce the need for other ITP therapies and emergency treatments, and demonstrate an acceptable safety profile. In addition, romiplostim improves patient-reported outcomes and quality of life in those suffering from this rare disease.
Alessandra Bassini - One of the best experts on this subject based on the ideXlab platform.
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Selective modulation of the cyclin B/CDK1 and cyclin D/CDK4 complexes during in vitro human megakaryocyte development.
British Journal of Haematology, 1999Co-Authors: Alessandra Bassini, Sabina Pierpaoli, Elisabetta Falcieri, Marco Vitale, Lia Guidotti, Silvano Capitani, Giorgio ZauliAbstract:Mammalian megakaryocyte development is characterized by a progressive accumulation of cells exhibiting a polylobated nucleus with a polyploid DNA content. In this study human megakaryocytes were obtained from CD34+ haemopoietic progenitors by in vitro liquid culture in the presence of 100 ng/ml of Recombinant Thrombopoietin (TPO). Ultrastructural examination of polyploid megakaryocytes showed the presence of a large number of centrioles, the breakdown of the nuclear envelope, and the progressive chromatin condensation, all aspects characteristic of mitosis. At both indirect immunofluorescence and Western blot analyses, cyclin B and its related cyclin-dependent kinase (CDK)1, which forms the mitosis promoting factor (MPF), showed an increased expression in maturating megakaryoblasts and megakaryocytes (day 8 of culture) with respect to freshly isolated CD34+ progenitors. This expression tended to decline in fully developed megakaryocytes (day 15 of culture). The amount of cyclin D and of the related CDK4, governing the G1 phase of the cell cycle, increased during megakaryocyte development, maintaining high levels of expression also in mature megakaryocytes. These results indicate that megakaryocyte polyploidization depends on a true, although incomplete, mitotic process, and that cyclin D/CDK4 probably plays a crucial role throughout megakaryocytopoiesis.