Advertisement

Case Study: Immunogenicity of rhEPO

  • Arno Kromminga
  • Gilbert Deray
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume VIII)

Abstract

Erythropoietin is an endogenous growth factor that is required for erythropoiesis. The hormone consists of a single acidic polypeptide chain of 165 amino acids and three N-linked and one O-linked carbohydrate side chains. Autoantibodies against endogenous EPO are extremely rare in humans. Since its introduction as a drug for the treatment of renal and non-renal anemia, antibodies against recombinant human erythropoietin were observed in low frequencies in single cases only. Due to a steep increase in the number of patients developing anti-erythropoietin antibodies during the course of therapy from 1999 to 2004 there is an increased interest in the observation of patients treated with erythropoietin. Moreover, new products as well as modified versions of the natural hormone have entered the market. In addition, modified versions with optimized features as well as peptides mimicking the erythropoietin action are under development and will enter clinical trials soon. These aspects make it essential to screen patients for the presence of anti-EPO antibodies. Despite the lack of a common calibrator, screening assays for the detection of anti-erythropoietin antibodies are available.

Keywords

Chronic Kidney Disease Renal Anemia Common Calibrator Pharmacovigilance Plan EMEA Guideline 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Asari, A. and Gokal, R. 2004. Pure red cell aplasia secondary to epoetin alpha responding to darbepoeitin alpha in a patient on peritoneal dialysis. J. Am. Soc. Nephrol. 15:2204–2207.PubMedCrossRefGoogle Scholar
  2. Bennett, C. L., Luminari, S., Nissenson, A. R., Tallman, M. S., Klinge, S. A., McWilliams, N., McKoy, J. M., Kim, B., Lyons, E. A., Trifilio, S. M., Raisch, D. W., Evens, A. M., Kuzel, T. M., Schumock, G. T., Belknap, S. M., Locatelli, F., Rossert, J., and Casadevall, N. 2004. Pure red cell aplasia and epoetin therapy. N. Engl. J. Med. 351:1403–1408.PubMedCrossRefGoogle Scholar
  3. Besarab, A., Ross, R. P., and Nasca, T. J. 1995. The use of recombinant human erythropoietin in predialysis patient. Current Opin. Nephrol. Hypertens. 4:155–161.CrossRefGoogle Scholar
  4. Besarab, A., Bolton, W. K., Browne, J. K., Egrie, J. C., Nissension, A. R., Okamoto, D. M., Schwab, S. J., and Goodkin, D. A. 1998. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N. Engl. J. Med. 339:584–590.PubMedCrossRefGoogle Scholar
  5. Boven, K., Stryker, S., Knight, J., Thomas, A., van Regenmortel, M., Kemeny, D. M., Power, D., Rossert, J., and Casadevall, N. 2005. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int. 67:2346–2353.PubMedCrossRefGoogle Scholar
  6. Bunn, H. F. 2007. New agents that stimulate erythropoiesis. Blood 109:868–873.PubMedCrossRefGoogle Scholar
  7. Casadevall, N., Nataf, J., Viron, B., Kolta, A., Kiladjian, J. J., Martin-Dupont, P., Michaud, P., Papo, T., Ugo, V., Teyssandier, I., Varet, B., and Mayeux, P. 2002a. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346:469–475.CrossRefGoogle Scholar
  8. Casadevall, N. 2002b. Antibodies against rhuEPO: Native and recombinant. Nephrol. Dial. Transplant. 17(Suppl. 5):42–47.CrossRefGoogle Scholar
  9. Castelli, G., Famularo, A., Semino, C., Machi, A. M., Ceci, A., Cannella, G., and Melioli, G. 2000. Detection of anti-erythropoietin antibodies in haemodialysis patients treated with recombinant human-erythropoietin. Pharmacol. Res. 41:313–318.PubMedCrossRefGoogle Scholar
  10. Collins, A. J., Ma, J. Z., and Keshavish, P. 1994. Urea index and other predictors of hemodialysis patient survival. Am. J. Kidney Dis. 23:272–282.PubMedGoogle Scholar
  11. D’Andrea, A. D. and Zon, L. I. 1990. Erythropoietin receptor. Subunit structure and activation. J. Clin. Invest. 86:681–687.PubMedCrossRefGoogle Scholar
  12. Drüeke, T. B., Locatelli, F., Clyne, N., Eckardt, K. U., Macdougall, I. C., Tsakiris, D., Burger, H. U., and Scherhab, A. 2006. Normalization of hemoglobin level in patients with chronic kidney disease and anaemia. N. Engl. J. Med. 355:2071–2083.PubMedCrossRefGoogle Scholar
  13. Eckardt, K. U. and Casadevall, N. 2003. Pure red cell aplasia due to anti-erythropoietin antibodies. Nephrol. Dial. Transplant. 18:865–869.PubMedCrossRefGoogle Scholar
  14. Eckardt, K. U. 2001. Anemia in end stage renal disease: Pathophysiological considerations. Nephrol. Dial. Transplant. 16(Suppl. 7):2–8.PubMedGoogle Scholar
  15. Ehrenreich, H., Hasselblatt, M., Dembowski, C., Cepek, L., Lewczuk, P., Stiefel, M., Rustenbeck, H. H., Breiter, N., Jacob, S., Knerlich, F., Bohn, M., Poser, W., Ruther, E., Kochen, M., Gefeller, O., Gleiter, C., Wessel, T. C., De Ryck, M., Itri, L., Prange, H., Cerami, A., Brines, M., and Siren, A. L. 2002. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med. 8:495–505.PubMedGoogle Scholar
  16. Eschbach, J. W. 1989. The anemia of chronic renal failure: Pathophysiological and the effects of recombinant erythropoietin. Kidney Int. 35:134–148.PubMedCrossRefGoogle Scholar
  17. Eschbach, J. W. and Adamson, J. 1985. Anemia of end stage renal disease (ESRD). Kidney Int. 28:1–5.PubMedCrossRefGoogle Scholar
  18. Fan, Q., Leuther, K. K., Holmes, C. P., Fong, K. L., Zhang, J., Velkovska, S., Chen, M. J., Mortensen, R. B., Leu, K., Green, J. M., Schatz, P. J., and Woodburn, K. W. 2006. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp. Hematol. 34:1303–1311.PubMedCrossRefGoogle Scholar
  19. Foley, F. N., Parfrey, P. S., Harnett, J. D., Kent, G. M., Murray, D. C., and Barre, P. E. 1996. The impact of anemia on cardiomyopathy, morbidity and mortality in end stage renal disease. Am. J. Kidney Dis. 28:53–61.PubMedGoogle Scholar
  20. Gross, J., Moller, R., Henke, W., and Hoesel, W. 2006. Detection of anti-EPO antibodies in human sera by a bridging ELISA is much more sensitive when coating biotinylated rhEPO to streptavidin rather than using direct coating of rhEPO. J. Immunol. Method. 313:176–182.CrossRefGoogle Scholar
  21. Hoesel, W., Gross, J., Moller, R., Kanne, B., Wessner, A., Muller, G., Muller, A., Gromnica-Ihle, E., Fromme, M., Bischoff, S., and Haselbeck, A. 2004. Development and evaluation of a new ELISA for the detection and quantification of antierythropoietin antibodies in human sera. J. Immunol. Method. 294:101–110.CrossRefGoogle Scholar
  22. Jelkmann, W. 2007. Erythropoietin after a century of research: younger than ever. Eur. J. Haematol. 78:183–205.PubMedCrossRefGoogle Scholar
  23. Kaufman, J. S., Reda, D. J., Fye, C. L., Goldfarb, D. S., Henderson, W. G., Kleinman, J. G., and Vaamonde, C. A. 1998. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. N. Engl. J. Med. 339:578–583.PubMedCrossRefGoogle Scholar
  24. Kelley, M., Cooper, C., Matticoli, A., and Greway, A. 2005. The detection of anti-erythropoietin antibodies in human serum and plasma: part II. Validation of a semi-quantitative 3H-thymidine uptake assay for neutralizing antibodies J. Immunol. Method. 300:179–191.CrossRefGoogle Scholar
  25. Kessler, M., Goldsmith, D., and Schellekens, H. 2006. Immunogenicity of biopharmaceuticals. Nephrol. Dial. Transplant. 21(Suppl. 5):9–12.CrossRefGoogle Scholar
  26. Kientsch-Engel, R., Hallermayer, K., Dessauer, A., and Wieczorek, L. 1990. New enzyme-linked immunosorbent assay methods for measurement of serum erythropoietin levels and erythropoietin antibodies. Blood Purif. 8:255–259.PubMedGoogle Scholar
  27. Krantz, S. B. 1974. Pure red cell aplasia. N. Engl. J. Med. 291:345–350.PubMedCrossRefGoogle Scholar
  28. Kromminga, A. and Schellekens, H. 2005. Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann. N.Y. Acad. Sci. 1050:257–265.PubMedCrossRefGoogle Scholar
  29. Kuhlmann, M. and Covic, A. 2006. The protein science of biosimilars. Nephrol. Dial. Transplant. 21(Suppl. 5):4–8.CrossRefGoogle Scholar
  30. Locatelli, F., Aljama, P., Barany, P., Canaud, B., Carrera, F., Eckardt, K. U., Hörl, W. H., Mac Dougall, I. C., Macleod, A., Wiecek, A., and Cameron, S. 2004. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol. Dial. Transpl. 19(Suppl. 2):ii1–ii47.Google Scholar
  31. Mac Dougall, I. C. 2002. Optimizing the use of erythropoietic agents. Pharmacokinetic and pharmacodynamic considerations. Nephrol. Dial. Transplant. 17(Suppl. 5):66–70.CrossRefGoogle Scholar
  32. Mac Dougall, I. C. 2005. Adverse event issue management: What have we learnt from pure red cell aplasia (PRCA)? Nephrol. Dial. Transplant. 20(Suppl. 8):18–21.Google Scholar
  33. Marti, H. H., Bernaudin, M., Petit, E., and Bauer, C. 2000. Neuroprotection and Angiogenesis: Dual Role of Erythropoietin in Brain Ischemia. News Physiol. Sci. 15:225–229.PubMedGoogle Scholar
  34. Mason, S., La, S., Mytych, D., Swanson, S. J., and Ferbas, J. 2003. Validation of the BIACORE 3000 platform for detection of antibodies against erythropoietic agents in human serum samples. Curr. Med. Res. Opin. 19:651–659.PubMedCrossRefGoogle Scholar
  35. NKF-K/DOQI. 2001. Clinical practice guidelines for anemia of chronic kidney disease. Am. J. Kidney Dis. 37:S182–S238.Google Scholar
  36. Sasaki, H., Ochi, N., Dell, A., and Fukuda, M. 1988. Site-specific glycosylation of human recombinant erythropoietin: analysis of glycopeptides or peptides at each glycosylation site by fast atom bombardment mass spectrometry. Biochemistry 27:8618–8626.PubMedCrossRefGoogle Scholar
  37. Schellekens, H. 2002. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat. Rev. Drug Discov. 1:457–462.PubMedCrossRefGoogle Scholar
  38. Schellekens, H. 2005. Follow-on biologics: challenges of the “next generation”. Nephrol. Dial. Transplant. 20(Suppl. 4):31–36.Google Scholar
  39. Schett, G., Firbas, U., Fureder, W., Hiesberger, H., Winkler, S., Wachauer, D., Koller, M., Kapiotis, S., and Smolen, J. 2001. Decreased serum erythropoietin and its relation to anti-erythropoietin antibodies in anaemia of systemic lupus erythematosus. Rheumatology (Oxford) 40:424–431.CrossRefGoogle Scholar
  40. Singh, A. K., Szczech, L., Tang, K. L., Barnhart, H., Sapp, S., Wolfson, M., and Reddan, D. 2006. Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 355:2085–2098.PubMedCrossRefGoogle Scholar
  41. Sipsas, N. V., Kokori, S. I., Ioannidis, J. P., Kyriaki, D., Tzioufas, A. G., and Kordossis, T. 1999. Circulating autoantibodies to erythropoietin are associated with human immunodeficiency virus type 1-related anemia. J. Infect. Dis. 180: 2044–2047.PubMedCrossRefGoogle Scholar
  42. Stoffel, M. P., Haverkamp, H., Kromminga, A., Lauterbach, K. W., and Baldamus, C. A. 2007. Prevalence of anti-erythropoietin antibodies in hemodialysis patients without clinical signs of pure red cell aplasia. Comparison between hypo- and normoresponsive patients treated with epoetins for renal anemia. Nephron. Clin. Pract. 105:c90–c98.PubMedCrossRefGoogle Scholar
  43. Stravitz, R. T., Chung, H., Sterling, R. K., Luketic, V. A., Sanyal, A. J., Price, A. S., Purrington, A., and Shiffman, M. L. 2005. Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C. Am. J. Gastroenterol. 100:1415–1419.PubMedCrossRefGoogle Scholar
  44. Swanson, S. J., Ferbas, J., Mayeux, P., and Casadevall, N. 2004. Evaluation of methods to detect and characterize antibodies against recombinant human erythropoietin. Nephron. Clin. Pract. 96:c88–c95.PubMedCrossRefGoogle Scholar
  45. Tacey, R., Greway, A., Smiell, J., Power, D., Kromminga, A., Daha, M., Casadevall, N., and Kelley, M. 2003. The detection of anti-erythropoietin antibodies in human serum and plasma. Part I. Validation of the protocol for a radioimmunoprecipitation assay. J. Immunol. Methods. 283:317–329.PubMedCrossRefGoogle Scholar
  46. Thorpe, R. and Swanson, S. J. 2005. Assays for detecting and diagnosing antibody-mediated pure red cell aplasia (PRCA): an assessment of available procedures. Nephrol. Dial. Transplant. 20(Suppl. 4):16–22.Google Scholar
  47. Tzioufas, A. G., Kokori, S. I., Petrovas, C. I., and Moutsopoulos, H. M. 1997. Autoantibodies to human recombinant erythropoietin in patients with systemic lupus erythematosus: correlation with anemia. Arthritis Rheum. 40:2212–2216.PubMedCrossRefGoogle Scholar
  48. Urra, J. M., Torre, M., Alcazar, R., and Peces, R. 1997. Rapid method for detection of anti-recombinant human erythropoietin antibodies as a new form of erythropoietin resistance. Clin. Chem. 43:848–849.PubMedGoogle Scholar
  49. Verhelst, D., Rossert, J., Casadevall, N., Kruger, A., Eckardt, K. U., and Macdougall, I. C. 2004. Treatment of erythropoietin induced pure red cell aplasia: a retrospective study. Lancet 363:1768–1771.PubMedCrossRefGoogle Scholar
  50. Weber, G., Gross, J., Kromminga, A., Loew, H. H., and Eckardt, K. U. 2002. Allergic skin and systemic reactions in a patient with pure red cell aplasia and anti-erythropoietin antibodies challenged with different epoetins. J. Am. Soc. Nephrol. 13:2381–2383.PubMedCrossRefGoogle Scholar
  51. Wiecek, A. and Mikhail, A. 2006. European regulatory guidelines for biosimilars. Nephrol. Dial. Transplant. 21(Suppl. 5):17–20.CrossRefGoogle Scholar
  52. Winearls, C. G., Oliver, D. O., Pippard, M. J., Reid, C., Downing, M. R., and Cotes, P. M. 1986. Effect of human erythropoietin derived from recombinant DNA on the anemia of patients maintained by chronic haemodialysis. Lancet 2: 1175–1178.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2008

Authors and Affiliations

  • Arno Kromminga
  • Gilbert Deray

There are no affiliations available

Personalised recommendations