title: Immunogenicity assessment of recombinant human c1-inhibitor: an integrated analysis of clinical studies.
abstract: OBJECTIVE
  Recombinant human C1-inhibitor (rhC1INH) is used to treat acute angioedema attacks in hereditary angioedema (HAE) due to a genetic C1INH deficiency. Recombinant proteins in general may induce antibody responses and therefore evaluation of such responses in the target population is an essential step in the clinical development program of a recombinant protein. Here we report the assessment of the immunogenicity of rhC1INH in symptomatic HAE patients.
  
  
  METHODS
  Blood samples collected before and after administration of rhC1INH were tested for antibodies against plasma-derived (pd) or rhC1INH, or against host-related impurities (HRI). Above cut-off screening results were confirmed with displacement assays, and also tested for neutralizing anti-C1INH antibodies. Finally, the relation of antibodies to clinical efficacy and safety of rhC1INH was analyzed.
  
  
  RESULTS
  Data from 155 HAE patients who received 424 treatments with rhC1INH were analyzed. 1.5% of all pre-exposure tests and 1.3% of all post-exposure tests were above the cut-off level in the screening assay for anti-C1INH antibodies. Six patients (3.9%) had anti-rhC1INH antibodies positive in the confirmatory assay. In two patients, confirmed antibodies were pre-existing with no increase post-exposure; in three patients, the antibodies occurred on a single occasion post-exposure; and in one patient, on subsequent occasions post-exposure. Neutralizing anti-pdC1INH antibodies were not found. Anti-HRI antibodies in the screening assay occurred in <0.7% of the tests before exposure to rhC1INH, in <1.9% after first exposure and in <3.1% after repeat treatment with rhC1INH. Five patients had anti-HRI antibodies positive in the confirmatory assay. In one patient, the antibodies were pre-existing, whereas in three of the 155 rhC1INH-treated patients (1.9%), confirmed anti-HRI antibodies occurred at more time points. Antibody findings were not associated with altered efficacy of rhC1INH or adverse events.
  
  
  CONCLUSIONS
  These results indicate a reassuring immunosafety profile of rhC1INH as a treatment for acute HAE attacks.
authors.affiliation: Department of Immunology, Rheumatology and Dermatology, University Medical Center Utrecht, The Netherlands. C.E.Hack@UMCUtrecht.nl
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
authors.forename: Maurice
authors.initials: M
authors.lastname: Mannesse
authors.forename: Aartie
authors.initials: A
authors.lastname: Baboeram
authors.forename: Beatrijs
authors.initials: B
authors.lastname: Oortwijn
authors.forename: Anurag
authors.initials: A
authors.lastname: Relan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D054179:Angioedemas, Hereditary / Q000188:drug therapy* / Q000276:immunology; D000906:Antibodies / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D002986:Clinical Trials as Topic; D050718:Complement C1 Inhibitor Protein / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D051056:Complement Inactivating Agents / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D050718:Complement C1 Inhibitor Protein; D051056:Complement Inactivating Agents; D011994:Recombinant Proteins