Pre-existing insulin autoantibodies predict efficacy of otelixizumab in preserving residual beta 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), ?-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 ?-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 ?-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 ?-cell mass and presence of IAA as inclusion criteria.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.