Antibodies against Recombinant Human Erythropoietin in a Patient with Erythropoietin-Resistant Anemia

Peces, R; M, de la Torre; Alcázar, Roberto; Jm, Urra

doi:10.1056/nejm199608153350717

Cited by 99 publications

(64 citation statements)

References 3 publications

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“…One patient with chronic renal failure was observed to have onset of EPO-resistant anemia after an initial response to EPO. 20 Multicycle GM-CSF therapy has resulted in anti-GM-CSF antibodies that blunted the GM-CSF response. 21 Development of antibodies to G-CSF did not alter resting blood counts or G-CSF response.…”

Section: Resultsmentioning

confidence: 99%

Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor

Basser

O’Flaherty

Green

et al. 2002

Blood

229

140

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Clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis, have revealed few side effects associated with its use. We here report a case of pancytopenia associated with the development of neutralizing antibodies to TPO that occurred in a patient who had undergone multicycle chemotherapy with multiple cycles of subcutaneous administration of pegylated recombinant human megakaryocyte growth and development factor. Samples of the patient's bone marrow showed trilineage hypoplasia with absence of myeloid, erythroid, and megakaryocyte progenitor cells but with elevated endogenous levels of erythropoietin, granulocyte colony-stimulating factor, and stem-cell factor. To our knowledge, this is the first report of an aplastic anemia-like syndrome associated with neutralizing antibodies to TPO. IntroductionTwo different forms of thrombopoietin (TPO) have entered clinical trials. 1 One is a recombinant form of the native molecule (rhTPO) and the other a pegylated, truncated version (pegylated recombinant human megakaryocyte growth and development factor [PEG-rHuMGDF]) with biologic activity similar to that of the native molecule. Early studies showed that both rhTPO 2 and PEG-rHuMGDF 3 are potent stimulators of thrombopoiesis and enhance platelet recovery when given after chemotherapy. 4,5 Both agents were reported to have minimal toxic effects; in particular, platelets produced after their administration function normally and have no evidence of activation. 2,5,6 Although antibodies to TPO were observed in the initial study of rhTPO, they were nonneutralizing and transient. 2 Here, we describe a case in which prolonged pancytopenia with neutralizing antibodies to TPO developed in a woman with ovarian cancer who had undergone 6 cycles of chemotherapy associated with administration of PEG-rHuMGDF. Study designGranulocyte-macrophage colony-forming cells, erythroid burst-forming units, and megakaryocyte colony-forming cells were assayed as described previously 7-9 by using freshly obtained bone marrow cells. Serum from the patient (stored at Ϫ20°C) was incubated with growth factors for in vitro cultures at 37°C for 60 minutes and examined for its activity on normal bone marrow cells. The highest concentration of patient's serum used was 10% of the final culture volume.Standard solid-phase sandwich enzyme immunoassays were used to measure serum levels of TPO, 10 granulocyte colony-stimulating factor (G-CSF), and erythropoietin (EPO) (R&D Systems, Minneapolis, MN). Cytokine levels were calculated from a standard curve generated by analysis of recombinant cytokines. Stem-cell factor (SCF) was assayed as described previously. 11 More than 200 samples of normal human serum were used to establish the SCF standard of 0.78 Ϯ 0.25 ng/mL (range, 0.29-1.62 ng/mL).Two established assays were used to detect neutralizing antibodies. The first was a solid-phase radioimmunoassay (RIA). 12 Reactivity was determined on the basis of the ratio of counts per minute in the posttreatment sample to the counts per mi...

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Section: Resultsmentioning

confidence: 99%

Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor

Basser

O’Flaherty

Green

et al. 2002

Blood

229

140

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“…25,26 Equally uncommon are antibodies formed against recombinant human EPO. 27 Low levels of antibody to G-CSF have been found in 11% of healthy adults and in 13% of cord blood samples but with no effect on the neutrophil count. 28 These autoantibodies rose after administration of G-CSF but lacked clinical significance.…”

Section: Discussionmentioning

confidence: 99%

Thrombocytopenia caused by the development of antibodies to thrombopoietin

Yang

Xia

et al. 2001

Blood

626

372

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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)

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“…Recombinant human proteins have been reported to induce Ab production (12,41,42), and the therapeutic administration of humanized or chimeric Abs, in which the murine constant regions are replaced with human ones, has led to an anti-Ab response (43). In addition, there is extensive overlap between the induction of Abs to therapeutic mAbs between anti-humanized and anti-chimera Abs, making the advantage of humanization less obvious (43).…”

Section: Discussionmentioning

confidence: 99%

A Protein’s Conformational Stability Is an Immunologically Dominant Factor: Evidence That Free-Energy Barriers for Protein Unfolding Limit the Immunogenicity of Foreign Proteins

Ohkuri

Nagatomo

Oda

et al. 2010

The Journal of Immunology

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Antibodies against Recombinant Human Erythropoietin in a Patient with Erythropoietin-Resistant Anemia

Cited by 99 publications

References 3 publications

Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor

Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor

Thrombocytopenia caused by the development of antibodies to thrombopoietin

A Protein’s Conformational Stability Is an Immunologically Dominant Factor: Evidence That Free-Energy Barriers for Protein Unfolding Limit the Immunogenicity of Foreign Proteins

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