title: Preexisting insulin autoantibodies predict efficacy of otelixizumab in preserving residual β-cell function in recent-onset type 1 diabetes.
abstract: OBJECTIVE
  Immune intervention trials in recent-onset type 1 diabetes would benefit from biomarkers associated with good therapeutic response. In the previously reported randomized placebo-controlled anti-CD3 study (otelixizumab; GlaxoSmithKline), we tested the hypothesis that specific diabetes autoantibodies might serve this purpose.
  
  
  METHODS
  In the included patients (n = 40 otelixizumab, n = 40 placebo), β-cell function was assessed as area under the curve (AUC) C-peptide release during a hyperglycemic glucose clamp at baseline (median duration of insulin treatment: 6 days) and every 6 months until 18 months after randomization. (Auto)antibodies against insulin (I[A]A), GAD (GADA), IA-2 (IA-2A), and ZnT8 (ZnT8A) were determined on stored sera by liquid-phase radiobinding assay.
  
  
  RESULTS
  At baseline, only better preserved AUC C-peptide release and higher levels of IAA were associated with better preservation of β-cell function and lower insulin needs under anti-CD3 treatment. In multivariate analysis, IAA (P = 0.022) or the interaction of IAA and C-peptide (P = 0.013) independently predicted outcome together with treatment. During follow-up, good responders to anti-CD3 treatment (i.e., IAA(+) participants with relatively preserved β-cell function [≥ 25% of healthy control subjects]) experienced a less pronounced insulin-induced rise in I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced by anti-CD3 treatment, and their changes showed no relation to functional outcome.
  
  
  CONCLUSIONS
  There is important specificity of IAA among other diabetes autoantibodies to predict good therapeutic response of recent-onset type 1 diabetic patients to anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 diabetes should consider both relatively preserved functional β-cell mass and presence of IAA as inclusion criteria.
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Simke
authors.initials: S
authors.lastname: Demeester
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Keymeulen
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Leonard
authors.initials: L
authors.lastname: Kaufman
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Annelien
authors.initials: A
authors.lastname: Van Dalem
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Balti
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ursule
authors.initials: U
authors.lastname: Van de Velde
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Goubert
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Verhaeghen
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver, Aurora, CO.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Davidson
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver, Aurora, CO.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Wenzlau
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium ilse.weets@uzbrussel.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Weets
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pipeleers
authors.affiliation: Diabetes Research Center and University Hospital Brussels (UZ Brussel), Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Frans K
authors.initials: FK
authors.lastname: Gorus
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D007330:Insulin Antibodies / Q000097:blood*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D011379:Prognosis; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D007328:Insulin; D007330:Insulin Antibodies; C550701:otelixizumab