Interference of thrombin in immunological assays for hirudin specific antibodies.

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.

• Authors: Robert G Hamilton, Jerrold H Levy, Victor J Marder, David C Sane
• Journal: Journal of immunological methods (J Immunol Methods) Vol. 381 Issue 1-2 Pg. 50-8 (Jul 31 2012) ISSN: 1872-7905 [Electronic] Netherlands
• PMID: 22542931 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Antibodies
• Antibodies, Monoclonal
• Antithrombins
• Hirudins
• Immunoglobulin G
• Recombinant Proteins
• Heparin
• Thrombin
• desirudin

Topics

• Aged
• Antibodies (blood, immunology)
• Antibodies, Monoclonal (immunology)
• Antibody Specificity
• Antithrombins (administration & dosage, immunology)
• Female
• Heparin (adverse effects)
• Hirudin Therapy
• Hirudins (administration & dosage, genetics, immunology)
• Humans
• Immunoenzyme Techniques (methods)
• Immunoglobulin G (blood, immunology)
• Male
• Middle Aged
• Recombinant Proteins (administration & dosage, genetics, immunology)
• Reproducibility of Results
• Thrombin (immunology)
• Thrombocytopenia (chemically induced, prevention & control)
• Time Factors
• Venous Thromboembolism (chemically induced, prevention & control)