ABSTRACT
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.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic/drug therapy , Receptors, Fc/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Thrombopoietin/therapeutic use , Adult , Aged , Aged, 80 and over , Animals , Benzoates/therapeutic use , Chronic Disease , Clinical Trials as Topic , Drug Discovery/history , History, 18th Century , History, 19th Century , History, 20th Century , History, 21st Century , Humans , Hydrazines/therapeutic use , Mice , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/history , Pyrazoles/therapeutic use , Receptors, Fc/history , Recombinant Fusion Proteins/history , Thrombopoietin/history , Thrombopoietin/physiology , Young AdultABSTRACT
Passive antibody can both suppress and augment immune responses. Until recently, there was virtual unanimity on the importance of the interaction of the Fc portion of modulating antibody with Fc-receptors (Fc-signalling), especially in experiments involving the suppression by antibody. Experiments reported in the last few years, that do not demonstrate the range of Fc-portion/Fc-receptor influences on the suppression of immune responses by passive antibody, have introduced new uncertainty into this field. The purpose of this paper is to review how the initial controversy on the influence of Fc-signalling in inhibition by passive antibody was resolved. Old and new approaches are suggested that may help in resolving the current uncertainty engendered by recent experimental results that were interpreted to mean that passive suppressive antibody does not utilize the inhibitory FcgammaRIIB receptor. An understanding of the factors that influence negative Fc-signalling is needed in order to optimize clinical therapies whose action depends on the suppressive property of antibody.
Subject(s)
Immunoglobulin Fc Fragments/metabolism , Receptors, Fc/metabolism , Animals , History, 20th Century , Humans , Immunization, Passive , Immunoglobulin Fc Fragments/history , Immunosuppression Therapy , Receptors, Fc/history , Signal TransductionABSTRACT
F. W. Rogers Brambell was the father of the field of transmission of immunity, which he entered 50 years before the present era. As part of his quantitative and temporal studies on transmission, he defined the first Fc receptor system for IgG, and furthermore recognized the link between transmission of passive immunity from mother to young and protection from catabolism for IgG. This article provides a historical overview of the efforts of Professor Brambell and summarizes the subsequent elaboration of the details of the physiology and molecular biology of this remarkable receptor system.