Preexisting Insulin Autoantibodies Predict Efficacy of Otelixizumab in Preserving Residual β-Cell Function in Recent-Onset Type 1 Diabetes

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. RESEARCH DESIGN AND 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), insulinoma-associated protein-2 IA-2 (IA-2A), and zinc transporter 8 (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 insulin autoantibodies (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 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.