Interference of thrombin in immunological assays for hirudin specific antibodies

Robert G. Hamilton, Jerrold H. Levy, Victor J. Marder, David C. Sane

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Abstract

Recombinant hirudins (desirudin, lepirudin) are direct thrombin inhibitors administered as anticoagulants for heparin-induced thrombocytopenia (HIT) and venous thromboembolism (VTE) prophylaxis. Although these small polypeptides are widely used, concern exists over reports of antigenicity. In the largest study of r-hirudin immunogenicity to-date, we evaluated the prevalence, quantity and specificity of IgG immune responses to desirudin (15. mg SC q12h for as long as clinically required) in 245 surgical and medically-ill subjects enrolled in DESIRABLE, a multicenter, open-label, clinical trial of hospitalized patients requiring VTE prophylaxis. Sera obtained before and 30. days after desirudin administration were analyzed for IgG anti-desirudin by immunoenzymetric assay using immobilized desirudin to bind desirudin-reactive antibody and peroxidase conjugated monoclonal-anti-human IgG Fc to detect bound IgG antibody. Of 245 study subjects, 19 (7.7%) were antibody "responders" (>. 2-fold increase in IgG antibody levels with >. 50% inhibition by desirudin 30. days post-treatment). There were no differences between responders and non-responders in incidence of clinical outcomes or bleeding-related adverse events. Forty-six patients had detectable desirudin-reactive IgG antibody prior to treatment, with no significant increase in antibody levels after exposure and no increase in clinical events. The origin of pre-existing hirudin-reactive IgG antibody requires further investigation involving suspected anti-thrombin-thrombin interactions. These results indicate a low potential for immunogenicity, with <. 8% of patients developing IgG antibodies after desirudin administration for VTE prophylaxis. In contrast to reports on lepirudin, production of anti-hirudin antibodies to desirudin has no apparent effect on clinical events.

Original languageEnglish (US)
Pages (from-to)50-58
Number of pages9
JournalJournal of Immunological Methods
Volume381
Issue number1-2
DOIs
StatePublished - Jul 31 2012

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Keywords

  • Desirudin
  • Hirudin
  • Human IgG antibody
  • Humoral immune responses
  • IgG anti-thrombin
  • Lepirudin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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