Historical Aspects of Polyclonal IgG Preparations

  • Volker Wahn
  • Peter Späth


Today we can choose between several polyclonal IgG products for both replacement and immunomodulation. However, it was a long way to go to reach this stage. In this chapter, we try to illustrate the major stages of IgG product development which began more than 70 years ago.


  1. Ammann AJ, Ashman RF, Buckley RH, Hardie WR, Krantmann HJ. Use of intravenous gammaglobulin in antibody immunodeficiency: results of a multicenter controlled trial. Clin Immunol Immunopathol. 1982;22(1):60–7.CrossRefPubMedGoogle Scholar
  2. Ammann EM, Haskins CB, Fillman KM, Ritter RL, Gu X, Winiecki SK, Carnahan RM, Torner JC, Fireman BH, Jones MP, Chrischilles EA. Intravenous immune globulin and thromboembolic adverse events: a systematic review and meta-analysis of RCTs. 2016. Am J Hematol. 2016;91(6):594–605.CrossRefPubMedGoogle Scholar
  3. Berg R, Fuellenhals E. Aseptic meningitis following therapy with immune globulins: a combination of product features and patient characteristics? Transfusion (Paris). 2016;56(12):3021–8.CrossRefGoogle Scholar
  4. Berger M. Adverse effects of IgG therapy. J Allergy Clin Immunol Pract. 2013;1(6):558–66.CrossRefPubMedGoogle Scholar
  5. Björkander J, Cunningham-Rundles C, Lundin P, Olsson R, Söderström R, Hanson LA. Intravenous immunoglobulin prophylaxis causing liver damage in 16 of 77 patients with hypogammaglobulinemia or IgG subclass deficiency. Am J Med. 1988;84(1):107–11.CrossRefPubMedGoogle Scholar
  6. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722–8.PubMedGoogle Scholar
  7. Cherin P, Marie I, Michallet M, Pelus E, Dantal J, Crave JC, Delain JC, Viallard JF. Management of adverse events in the treatment of patients with immunoglobulin therapy: a review of evidence. Autoimmun Rev. 2016;15(1):71–81.CrossRefPubMedGoogle Scholar
  8. Cohn EJ, Oncley JL, Strong LE, Hughes WL, Armstrong SH. Chemical, clinical and immunological studies on the product of human plasma fractionation. I. The characterization of the protein fractions of human plasma. J Clin Invest. 1944;23:417–32.CrossRefPubMedCentralPubMedGoogle Scholar
  9. Cuthbertson B, Perry RJ, Foster PR, Reid KG, Crawford RJ, Yap PL. The viral safety of intravenous immunoglobulin. J Infect. 1987;15(2):125–33.CrossRefPubMedGoogle Scholar
  10. Dantal J. Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am J Nephrol. 2013;38(4):275–84.CrossRefPubMedGoogle Scholar
  11. Dhainaut F, Guillaumat PO, Dib H, Perret G, Sauger A, De Coupade C, et al. In vitro and in vivo properties differ among liquid intravenous immunoglobulin preparations. Vox Sang. 2013;104(2):115–26.CrossRefPubMedCentralPubMedGoogle Scholar
  12. Elkayam O, Paran D, Milo R, Davidovitz Y, Almoznino-Sarafian D, Zeltser D, Yaron M, Caspi D. Acute myocardial infarction associated with high dose intravenous immunoglobulin infusion for autoimmune disorders. A study of four cases. Ann Rheum Dis. 2000;59(1):77–80.CrossRefPubMedCentralPubMedGoogle Scholar
  13. Feldmeyer L, Benden C, Haile SR, Boehler A, Speich R, French LE, et al. Not all intravenous immunoglobulin preparations are equally well tolerated. Acta Derm Venereol. 2010;90(5):494–7.CrossRefPubMedGoogle Scholar
  14. Figueras-Aloy J, Rodríguez-Miguélez JM, Iriondo-Sanz M, Salvia-Roiges MD, Botet-Mussons F, Carbonell-Estrany X. Intravenous immunoglobulin and necrotizing enterocolitis in newborns with hemolytic disease. Pediatrics. 2010;125:139–44.CrossRefPubMedGoogle Scholar
  15. Garbett ND, Currie DC, Cole PJ. Comparison of the clinical efficacy and safety of an intramuscular and an intravenous immunoglobulin preparation for replacement therapy in idiopathic adult onset panhypogammaglobulinaemia. Clin Exp Immunol. 1989;76(1):1–7.PubMedCentralPubMedGoogle Scholar
  16. Geha RS. Charles A. Janeway and Fred S. Rosen: the discovery of gamma globulin therapy and primary immunodeficiency diseases at Boston Children’s Hospital. J Allergy Clin Immunol. 2005;116(4):937–40.CrossRefPubMedGoogle Scholar
  17. Gelfand EW. Differences between IGIV products: impact on clinical outcome. Int Immunopharmacol. 2006;6(4):592–9.CrossRefPubMedGoogle Scholar
  18. Gelli SS, Neefe JR, Stokes J, Janeway CA, Scatchard G. Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXXVI. Inactivation of the virus of homologous serum hepatitis in solutions of normal human serum albumin by means of heat. J Clin Invest. 1948;27(2):239.CrossRefGoogle Scholar
  19. Gerber S, Gaida A, Spiegl N, Wymann S, Antunes AM, Menyawi IE, et al. Reduction of isoagglutinin in intravenous immunoglobulin (IVIG) using blood group A- and B-specific immunoaffinity chromatography: industry-scale assessment. BioDrugs. 2016;30(5):441–51.CrossRefPubMedCentralPubMedGoogle Scholar
  20. Hague RA, Eden OB, Yap PL, Mok JY, Rae P. Hyperviscosity in HIV infected children--a potential hazard during intravenous immunoglobulin therapy. Blut. 1990;61(2–3):66–7.CrossRefPubMedGoogle Scholar
  21. Heath J, Goldman FD. Idiopathic thrombocytopenic purpura in a boy with ataxia telangiectasia on immunoglobulin replacement therapy. J Pediatr Hematol Oncol. 2010;32(1):e25–7.CrossRefPubMedGoogle Scholar
  22. Hefer D, Jaloudi M. Thromboembolic events as an emerging adverse effect during high-dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature. Ann Hematol. 2004;83(10):661–5.CrossRefPubMedGoogle Scholar
  23. Helbert MR, Bangs C, Bishop M, Molesworth A, Ironside J. No evidence of asymptomatic variant CJD infection in immunodeficiency patients treated with UK-sourced immunoglobulin. Vox Sang. 2016;110(3):282–4.CrossRefPubMedGoogle Scholar
  24. Hopkins S, Jolles S. Drug-induced aseptic meningitis. Expert Opin Drug Saf. 2005;4:285–97.CrossRefPubMedGoogle Scholar
  25. IUIS/WHO NOTICE. Appropriate uses of human immunoglobulin in clinical practice. Clin Exp Immunol. 1983;52:417–22.Google Scholar
  26. Janeway CA. The plasma proteins; their functions and clinical uses. Pediatrics. 1948;2(4):489–97.PubMedGoogle Scholar
  27. José M, Marzo N, Pons B, Herrerias A, López L, Faro M, López M, Jorquera JI. Pasteurization inactivates clotting enzymes during Flebogamma® and Flebogamma® DIF production. Biologicals. 2013;41(6):393.CrossRefPubMedGoogle Scholar
  28. Kallenberg CGM. A 10% ready-to-use intravenous human immunoglobulin offers potential economic advantages over a lyophilized product in the treatment of primary immunodeficiency. Clin Exp Immunol. 2007;150(3):437–41.CrossRefPubMedCentralPubMedGoogle Scholar
  29. Kara S, Ulu-ozkan H, Yilmaz Y, Arikan FI, Dilmen U, Bilge YD. Necrotizing enterocolitis in a newborn following intravenous immunoglobulin treatment for haemolytic disease. J Coll Physicians Surg Pak. 2013;23(8):598–600.PubMedGoogle Scholar
  30. Lamari F, Karamanos NK, Papadopoulou-Alataki E, Kanakoudi-Tsakalidou F, Dimitracopoulos G, Anastassiou ED. Monitoring of two intravenous immunoglobulin preparations for immunoglobulin G subclasses and specific antibodies to bacterial surface antigens and relation with their levels in treated immunodeficient patients. J Pharm Biomed Anal. 2000;22(6):1029–36.CrossRefPubMedGoogle Scholar
  31. Lane RS. Non-A, non-B hepatitis from intravenous immunoglobulin. Lancet. 1983;2(8356):974–5.CrossRefPubMedGoogle Scholar
  32. Lever AM, Webster AD, Brown D, Thomas HC. Non-A, non-B hepatitis occurring in agammaglobulinaemic patients after intravenous immunoglobulin. Lancet. 1984;2(8411):1062–4.CrossRefPubMedGoogle Scholar
  33. Masuho Y, Tomibe K, Matsuzawa K, Watanabe T, Ishimoto S. Reconstruction of intact gamma-globulin from S-sulfonated gamma-globulin in vivo. J Biochem. 1976;79(6):1377–9.CrossRefPubMedGoogle Scholar
  34. Navarro M, Negre S, Matoses ML, Golombek SG, Vento M. Necrotizing enterocolitis following the use of intravenous immunoglobulin for haemolytic disease of the newborn. Acta Paediatr. 2009;98:1214–7.CrossRefPubMedGoogle Scholar
  35. Nitschmann H, Kistler P, Lergier W. Vereinfachtes Verfahren zur Gewinnung von humanem Albumin und g-Globulin aus Blutplasma mittels Alkoholfällung – [Simplified method for isolation of human albimin and g-globulin from plasma using the ethnol precipitation method]. Helv Chim Acta. 1954;37:866–73.CrossRefGoogle Scholar
  36. Oh KT, Boldt HC, Danis RP. Iatrogenic central retinal vein occlusion and hyperviscosity associated with high-dose intravenous immunoglobulin administration. Am J Ophthalmol. 1997;124(3):416–8.CrossRefPubMedGoogle Scholar
  37. Oncley JL, Melin M, Richert DA, Cameron JW, Gross PM. The separation of the antibodies, isoagglutinins, prothrombin, plasminogen and b1-lipoprotein into subfractions of human plasma. J Am Chem Soc. 1949;71:541–50.CrossRefPubMedGoogle Scholar
  38. Ordman CW, Tenning CG, Janeway CA. Chemical, clinical and immunological studies on the products of human plasma fractions. XII. The use of concentrated normal human serum gamma globulin (human immune serum globulin) in the prevention and attenuation of measles. J Clin Immunol. 1944;23(4):541–9.Google Scholar
  39. Razvi S, Schneider L, Jonas MM, Cunningham-Rundles C. Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency. Clin Immunol. 2001;101(3):284–8.CrossRefPubMedGoogle Scholar
  40. Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, Buckley RH, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency. A randomized double-blind trial. Int Immunopharmacol. 2003;3(9):1325–33.CrossRefPubMedGoogle Scholar
  41. Rosen FS, Janeway CA. J Pediatr. 1994;125(1):167–8.CrossRefPubMedGoogle Scholar
  42. Schiff RI, Williams LW, Nelson RP, Buckley RH, Burks W, Good RA. Multicenter crossover comparison of the safety and efficacy of Intraglobin-F with Gamimune-N, Sandoglobulin and Gammagard in patients with primary immunodeficiency diseases. J Clin Immunol. 1997;17(1):21–8.CrossRefPubMedGoogle Scholar
  43. Schultze HE, Schwick G. Über neue Möglichkeiten intravenöser Gammaglobulin-Applikation – [on new possibilities of intravenous gamma globulin administration]. Dt Med Wochenschr. 1962;87(34):1643–50.CrossRefGoogle Scholar
  44. Scribner CL, Kapit RM, Phillips ET, Rickles NM. Aseptic meningitis and intravenous immunoglobulin therapy. Ann Intern Med. 1994;121:305–6.CrossRefPubMedGoogle Scholar
  45. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med. 1994;121:259–62.CrossRefPubMedGoogle Scholar
  46. Sgouris JT. The preparation of plasmin-treated immune serum globulin for intravenous use. XXIst Scientific Meeting of the Protein Foundation, Cambridge, 1966 Nov 21-1966 Nov 22;1967:p. 71–84.Google Scholar
  47. Siani B, Willimann K, Wymann S, Marques AA, Widmer E. Isoagglutinin reduction in human immunoglobulin products by donor screening. Biol Ther. 2014;4(1–2):15–26.CrossRefPubMedCentralPubMedGoogle Scholar
  48. Smith CA. Dr. Janeway and American pediatrics. Pediatrics. 1977;59(2):149–50.PubMedGoogle Scholar
  49. Späth PJ, Granata G, La Marra F, Kuijpers TW, Quinti I. On the dark side of therapies with immunoglobulin concentrates: the adverse events. Front Immunol. 2015;6:11.CrossRefPubMedCentralPubMedGoogle Scholar
  50. Spurling N, Shone J, Vaughan J. The incidence, incubation period, and symptomatology of homologous serum jaundice. Br Med J. 1946;2(4472):409.CrossRefPubMedCentralGoogle Scholar
  51. Steele RW, Augustine RA, Tannenbaum AS, Charlton RK. A comparison of native and modified intravenous immunoglobulin for the management of hypogammaglobulinemia. Am J Med. 1987;293(2):69–74.CrossRefGoogle Scholar
  52. Stephan W. Beseitigung der Komplementfixierung von g-globulin durch chemische Modifizierung mit b-Propiolacton – [Elimination of complement fixation of g-globulin by chemical modification with b-propiolactone]. Z Klin Chem Klin Biochem. 1969;7(3):282–6.PubMedGoogle Scholar
  53. Stephan W, Dichtelmüller H. Non-A, non-B hepatitis from intravenous immunoglobulins. Lancet. 1983;2(8365–66):1488.CrossRefPubMedGoogle Scholar
  54. Weiland O, Mattsson L, Glaumann H. Non-A, non-B hepatitis after intravenous gammaglobulin. Lancet. 1986;1(8487):976–7.CrossRefPubMedGoogle Scholar
  55. Welch AG, Cuthbertson B, McIntosh RV, Foster PR. Non-A, non-B hepatitis from intravenous immunoglobulin. Lancet. 1983;2(8360):1198–9.CrossRefPubMedGoogle Scholar
  56. Williams M, Willey J, Tull K, Stevenson G, Parks M, McElrath LT, Golovko L, Russ C, Griffin J, Vandeberg P. Removal of coagulation factors by the Gamunex®-C purification process. J Allergy Clin Immunol. 2013;131(2, Suppl.) AB10 [Congress abstract].Google Scholar
  57. Williams PE, Yap PL, Gillon J, Crawford RJ, Urbaniak SJ, Galea G. Transmission of non-A, non-B hepatitis by pH4-treated intravenous immunoglobulin. Vox Sang. 1989;57(1):15–8.CrossRefPubMedGoogle Scholar
  58. Wright JK. Reduced immunoglobulin G activates complement system with decreased cooperativity. Biochem Biophys Res Commun. 1978;83(4):1284–90.CrossRefPubMedGoogle Scholar
  59. Yang Y, Pan JJ, Zhou XG, Zhou XY, Cheng R, YH H. The effect of immunoglobulin treatment for hemolysis on the incidence of necrotizing enterocolitis – a meta-analysis. Eur Rev Med Pharmacol Sci. 2016;20(18):3902–10.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatric Pneumology and ImmunologyCharité University HospitalBerlinGermany
  2. 2.Institute of Pharmacology, University of BernBernSwitzerland

Personalised recommendations