title: Evaluation of anti-activated protein C antibody development in patients with severe sepsis from four clinical studies with drotrecogin alpha (activated).
abstract: BACKGROUND
  Drotrecogin alpha (activated) (DAA) is a recombinant human activated protein C (APC), which is an antithrombotic protein.
  
  
  OBJECTIVE
  To evaluate the development of anti-APC antibodies in severe sepsis patients in DAA clinical studies.
  
  
  METHODS
  Serum and plasma samples were collected in placebo-controlled studies (PROWESS, ADDRESS) and studies where all patients were DAA-treated (ENHANCE, XPRESS). An enzyme-linked immunosorbent assay detecting anti-APC IgA/IgG/IgM antibodies was used. IgG isolated from plasma of positive samples was tested for neutralizing activity against DAA-induced prolongation of activated partial thromboplastin time.
  
  
  RESULTS
  The proportions of patients with negative baseline but positive postbaseline anti-APC antibodies were 1.5% (27/1855) and 1.6% (24/1493) in the DAA and placebo cohorts, respectively (P = 0.72 for the difference). Of the 27 DAA and 24 placebo patients with positive anti-APC antibodies, all but one (DAA) were alive at day 28, and all but seven (four DAA and three placebo) were alive at hospital discharge, including eight (five DAA and three placebo) patients who tested positive for anti-APC neutralizing antibodies. Two of the 51 patients who tested positive for the development of anti-APC antibodies experienced a thrombotic event (one DAA, one placebo). In ADDRESS, no anti-APC antibody was detected in the six DAA-treated patients who had received a previous course of DAA therapy.
  
  
  CONCLUSIONS
  The proportion of patients with anti-APC antibodies was low and was similar between DAA-treated and placebo-treated patients. No relationship between anti-APC antibody development and adverse reactions was observed. There was no evidence that the anti-APC antibodies detected represented a specific immune response to DAA therapy.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. s.betty_yan@lilly.com
authors.forename: S B
authors.initials: SB
authors.lastname: Yan
authors.forename: J T
authors.initials: JT
authors.lastname: Brandt
authors.forename: N L
authors.initials: NL
authors.lastname: Correll
authors.forename: S L
authors.initials: SL
authors.lastname: Um
authors.forename: J S
authors.initials: JS
authors.lastname: Bourdage
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D011486:Protein C / Q000276:immunology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D015996:Survival Rate
chemical_list: D001323:Autoantibodies; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated