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Immunosafety of Recombinant Human C1-Inhibitor in Hereditary Angioedema: Evaluation of IgE Antibodies

Abstract

Background

Recombinant human C1-inhibitor (rhC1INH) purified from milk of transgenic rabbits is used for the treatment of acute attacks in patients with hereditary angioedema (HAE) due to C1-inhibitor (C1INH) deficiency.

Objective

The objective was to investigate the risk of rhC1INH inducing IgE antibodies or eliciting anaphylactic reactions.

Methods

In subjects treated with rhC1INH, we retrospectively analysed the frequency and clinical relevance of pre-exposure and potentially newly induced IgE antibodies against rabbit and other animal allergens including cow’s milk by the ImmunoCAP® Specific IgE blood test system.

Results

130 HAE patients and 14 healthy subjects received 300 administrations of rhC1INH, 65 subjects (47.4 %) on one occasion; 72 (52.6 %) on at least two occasions (range 2–12; median 2). Five subjects had pre-existing anti-rabbit epithelium IgE; the subject with the highest levels and a previously undisclosed rabbit allergy developed an anaphylactic reaction upon first exposure to rhC1INH, whereas the other four subjects with lower pre-existing IgE levels (Class 1–3), did not. No other anaphylactic reactions were identified in any of the subjects exposed to rhC1INH. Analysis of post-exposure samples revealed that the risk of inducing new or boosting existing IgE responses to rabbit or cow’s milk allergens was negligible.

Conclusion

The propensity of rhC1INH to induce IgE antibodies following repeated administration of rhC1INH is low. Subjects with substantially elevated anti-rabbit epithelium IgE antibodies and/or clinical allergy to rabbits may have an increased risk for an allergic reaction. No other risk factors for allergic reactions to rhC1INH have been identified.

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References

  1. 1.

    Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol. 2010;126:821–7.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Davis B, Bernstein JA. Conestat alfa for the treatment of angioedema attacks. Ther Clin Risk Manag. 2011;7:265–73.

    PubMed  CAS  Google Scholar 

  3. 3.

    Varga L, Farkas H. RhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency. Expert Rev Clin Immunol. 2011;7:143–53.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Agostoni A, Aygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(suppl):S51–131.

    PubMed  Article  Google Scholar 

  5. 5.

    Jahn EM, Schneider CK. How to systematically evaluate immunogenicity of therapeutic proteins—regulatory considerations. N Biotechnol. 2009;25:280–6.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Schellekens H. The immunogenicity of therapeutic proteins. Discov Med. 2010;9:560–4.

    PubMed  Google Scholar 

  7. 7.

    Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391–7.

    PubMed  Article  Google Scholar 

  8. 8.

    Kobayashi K. Summary of recombinant human serum albumin development. Biologicals. 2006;34:55–9.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    van Doorn MB, Burggraaf J, van Dam T, et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol. 2005;116:876–83.

    PubMed  Article  Google Scholar 

  10. 10.

    Choi G, Soeters MR, Farkas H, et al. Recombinant human C1-inhibitor in the treatment of acute angioedema attacks. Transfusion. 2007;47:1028–32.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Restani P, Gaiaschi A, Plebani A, et al. Cross-reactivity between milk proteins from different animal species. Clin Exp Allergy. 1999;29:997–1004.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359:1027–36.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Hack CE, Relan A, Baboeram A, et al. Immunogenicity assessment of recombinant human C1-inhibitor: an integrated analysis of clinical studies. Accepted for publication by BioDrugs on 08 May 12.

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Acknowledgements

All studies were funded by Pharming Technologies BV, Leiden, The Netherlands. Medical writing support was provided by Rick Flemming PhD, CMPP at The Word Bureau and was funded by Pharming Technologies BV. CEH has been a consultant to Pharming Technologies; AR, AB, BO and RP are (former) employees of Pharming Technologies.

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Correspondence to C. Erik Hack.

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Hack, C.E., Relan, A., Baboeram, A. et al. Immunosafety of Recombinant Human C1-Inhibitor in Hereditary Angioedema: Evaluation of IgE Antibodies. Clin Drug Investig 33, 275–281 (2013). https://doi.org/10.1007/s40261-013-0064-2

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Keywords

  • Anaphylactic Reaction
  • Hereditary Angioedema
  • C1INH Deficiency
  • Animal Allergen
  • Rabbit Meat