Thrombocytopenia caused by the development of antibodies to thrombopoietin

Abstract

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 fulllength 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. (Blood. 2001;98:3241-3248)

Improving stem cell mobilization strategies: future directions

“…145 AEs associated with the use of rhTPO plus G-CSF appear to be similar to those seen with the use of G-CSF alone; 144,145 however, cytopenias owing to neutralizing antibodies to TPO have been reported in a small number of patients who were given rhTPO to treat chemotherapy-induced thrombocytopenia. 146,147 Currently, no TPOs have been approved by the FDA for mobilization. 148 Parathyroid hormone Parathyroid hormone (PTH) activates osteoblasts, which produce hematopoietic growth factors in the stem cell niche, thereby increasing the numbers of circulating stem cells.…”

Thrombocytopenia and hemostatic disorders in chronic graft versus host disease

“…107 However, the use of these drugs was complicated by development of antibodies that cross-reacted to native TPO, and in the case of PEG-rHuMGDG recipients, neutralized TPO (resulting in prolonged thrombocytopenia). 108 For this reason, subsequent drug development in this field has focused on finding molecules that either interact with the TPO receptors on the megakaryocyte surface, or stimulate the downstream intracellular signaling pathway that is activated by TPO. Two such molecules have been identified that act to increase platelet counts by stimulating platelet production in megakaryocytes: eltrombopag, a synthetic molecule with oral bioavailability that interacts non-competitively with the TPO receptor to increase thrombopoiesis, 109 and romiplostim, a novel peptide in which two IgG Fc domains are fused to four copies of a TPO-mimetic peptide.…”

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium

“…An unwanted consequence of BP therapy is the development of immunogenic responses, which in some cases have little or no impact but in other cases affect safety significantly, with induction of infusion reactions, hypersensitivity reactions and autoimmune syndromes occurring due to cross‐reactivity of anti‐drug antibody (ADA) with endogenous counterparts of the BP 3, 4, 5, 6, and/or decreased efficacy related to neutralization of the BP's biological activity or increasing its clearance 7, 8, 9. For these reasons, immunogenic potential of a BP is determined during clinical trials by measurement and characterization of ADA that develop during treatment; in some cases, monitoring for biopharmaceutical and ADA levels may be conducted during routine use of approved BPs to guide patient care 10, 11, 12.…”