title: 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.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rhamilt2@jhmi.edu
authors.forename: Robert G
authors.initials: RG
authors.lastname: Hamilton
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Marder
authors.forename: David C
authors.initials: DC
authors.lastname: Sane
mesh_terms: D000368:Aged; D000906:Antibodies / Q000097:blood / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D000991:Antithrombins / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006493:Heparin / Q000009:adverse effects; D024764:Hirudin Therapy; D006629:Hirudins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015203:Reproducibility of Results; D013917:Thrombin / Q000276:immunology*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control; D013997:Time Factors; D054556:Venous Thromboembolism / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000991:Antithrombins; D006629:Hirudins; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D006493:Heparin; D013917:Thrombin; C060225:desirudin