RESUMO
Immune thrombocytopenia (ITP) is an autoimmune disorder characterised by abnormally low platelet counts (<100 x 10(9)/l), purpura, and bleeding episodes, and can be categorised in three phases: newly-diagnosed, persistent, and chronic. As many patients become refractory to standard treatments (corticosteroids, danazol, azathioprine, splenectomy), there is an urgent need for alternative treatments. The successful isolation and cloning of thrombopoietin (TPO) in the mid-1990s and identification of its key role in platelet production was a major breakthrough, rapidly followed by the development of the recombinant thrombopoietins, recombinant human TPO and a pegylated truncated product, PEG-rHuMGDF. Both agents increased platelet counts but development was halted because of the development of antibodies that cross-reacted with native TPO, resulting in prolonged treatment-refractory thrombocytopenia. Experimentation with novel platforms for extending the circulating half-life of therapeutic peptides by combining them with antibody fragment crystallisable (Fc) constructs led to the development of a new family of molecules termed 'peptibodies'. The 60Da recombinant peptibody romiplostim was finally produced by linking several copies of an active TPO-binding peptide sequence to a carrier Fc fragment. In clinical trials, romiplostim was effective in ameliorating thrombocytopenia in patients with chronic ITP, was well tolerated and did not elicit cross-reacting antibodies. Romiplostim has recently been approved for the treatment of adults with chronic ITP.
Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Benzoatos/uso terapêutico , Doença Crônica , Ensaios Clínicos como Assunto , Descoberta de Drogas/história , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Hidrazinas/uso terapêutico , Camundongos , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/história , Pirazóis/uso terapêutico , Receptores Fc/história , Proteínas Recombinantes de Fusão/história , Trombopoetina/história , Trombopoetina/fisiologia , Adulto JovemAssuntos
Bioquímica/história , Corantes Fluorescentes/história , Proteínas Luminescentes/história , Prêmio Nobel , Equorina/química , Equorina/história , Equorina/isolamento & purificação , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/história , Cristalografia por Raios X , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/química , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/história , História do Século XX , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/históriaAssuntos
Corantes Fluorescentes/história , Proteínas de Fluorescência Verde/história , Biologia Molecular/história , Prêmio Nobel , Corantes Fluorescentes/química , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , História do Século XX , Neurônios/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/história , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/históriaAssuntos
Química Orgânica/história , Proteínas de Fluorescência Verde/história , Prêmio Nobel , Animais , Células Cultivadas , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , História do Século XX , História do Século XXI , Microscopia de Fluorescência , Conformação Proteica , Dobramento de Proteína , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/históriaRESUMO
Since the first publication by Kohler and Milstein on the production of mouse monoclonal antibodies (mAbs) by hybridoma technology, mAbs have had a profound impact on medicine by providing an almost limitless source of therapeutic and diagnostic reagents. Therapeutic use of mAbs has become a major part of treatments in various diseases including transplantation, oncology, autoimmune, cardiovascular, and infectious diseases. The limitation of murine mAbs due to immunogenicity was overcome by replacement of the murine sequences with their human counterpart leading to the development of chimeric, humanized, and human therapeutic antibodies. Remarkable progress has also been made following the development of the display technologies, enabling of engineering antibodies with modified properties such as molecular size, affinity, specificity, and valency. Moreover, antibody engineering technologies are constantly advancing to enable further tuning of the effector function and serum half life. Optimal delivery to the target tissue still remains to be addressed to avoid unwanted side effects as a result of systemic treatment while achieving meaningful therapeutic effect.
