title: A detailed examination of the antibody prevalence and characteristics of anti-ESA antibodies.
abstract: BACKGROUND
  The antibody characteristics in erythropoiesis-stimulating agent (ESA)-treated patients who develop antibody-mediated pure red cell aplasia (PRCA; amPRCA) can be described as high-affinity, neutralizing anti-ESA antibodies with a mixed immunoglobulin G (IgG) subclass. The characteristics of an early-onset anti-ESA antibody response are not well documented, especially in the months prior to the development of amPRCA. Therefore, a detailed characterization of anti-ESA antibodies was performed in patients in both clinical studies and in a post-market setting. Both baseline and post-dose samples were tested and antibody-positive samples were characterized. Antibody characteristics such as concentration, isotype and specificity were evaluated in subjects with non-neutralizing anti-ESA antibodies and subjects that developed neutralizing anti-ESA antibodies associated with amPRCA.
  
  
  METHODS
  Serum samples were analyzed for the presence of anti-ESA antibodies, using a validated surface plasmon resonance (SPR)-based immunoassay or SPRIA.
  
  
  RESULTS
  Among the clinical studies, pre-existing non-neutralizing anti-ESA antibodies were found in 6% of the subjects from clinical studies in nephrology, oncology and congestive heart failure (CHF). After ESA treatment, 2.3% of the subjects developed binding, non-neutralizing antibodies with 0.1% confirmed as having an IgG isotype and were specific to the ESA protein. IgM antibodies were detected at baseline and post-ESA treatment and reported to be specific to the glycosylation of the ESA. No clinical study subjects progressed to amPRCA. In contrast, anti-ESA antibody-positive subjects from the post-market setting with a confirmed IgG subclass were specific to the ESA protein. Subjects that had progressed to amPRCA were noted to have high antibody concentrations with neutralizing activity and a diverse IgG subtype.
  
  
  CONCLUSIONS
  A low prevalence of non-neutralizing anti-ESA IgM specific to glycosylation on the ESA and IgG1 antibodies specific to the ESA protein was detected across all clinical patient populations. Patients with amPRCA were noted to have high IgG antibody concentrations, neutralizing antibodies and the presence of anti-ESA IgG4 antibodies.
authors.affiliation: Department of Clinical Immunology, Amgen, Thousand Oaks, CA, USA.
authors.forename: Troy E
authors.initials: TE
authors.lastname: Barger
authors.forename: Deborah
authors.initials: D
authors.lastname: Wrona
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Goletz
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Mytych
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood; D004921:Erythropoietin / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology; D006031:Glycosylation; D006397:Hematinics / Q000009:adverse effects* / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007075:Immunoglobulin M / Q000097:blood*; D011358:Product Surveillance, Postmarketing; D011994:Recombinant Proteins / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology; D012010:Red-Cell Aplasia, Pure / Q000209:etiology / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; C554270:EPO protein, human; D006397:Hematinics; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011994:Recombinant Proteins; D004921:Erythropoietin