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Preexisting Insulin Autoantibodies Predict Efficacy of Otelixizumab In 644 Diabetes Care Volume 38, April 2015 Simke Demeester,1 Bart Keymeulen,1 Preexisting Insulin Autoantibodies Leonard Kaufman,1 Annelien Van Dalem,1 Eric V. Balti,1 Ursule Van de Velde,1 Predict Efficacy of Otelixizumab in Patrick Goubert,1 Katrijn Verhaeghen,1 Howard W. Davidson,2 Janet M. Wenzlau,2 Preserving Residual b-Cell Ilse Weets,1 Daniel G. Pipeleers,1 and Function in Recent-Onset Type 1 Frans K. Gorus1 Diabetes Diabetes Care 2015;38:644–651 | DOI: 10.2337/dc14-1575 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 =40placebo),b-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 EMERGING TECHNOLOGIES AND THERAPEUTICS 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 b-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 1Diabetes Research Center and University Hospi- together with treatment. During follow-up, good responders to anti-CD3 treat- tal Brussels (UZ Brussel), Vrije Universiteit Brus- + b ‡ sel, Brussels, Belgium ment (i.e., IAA participants with relatively preserved -cell function [ 25% of 2Barbara Davis Center for Childhood Diabetes, healthy control subjects]) experienced a less pronounced insulin-induced rise in University of Colorado at Denver, Aurora, CO I(A)A and lower insulin needs. GADA, IA-2A, and ZnT8A levels were not influenced Corresponding author: Ilse Weets, ilse.weets@ by anti-CD3 treatment, and their changes showed no relation to functional uzbrussel.be. outcome. Received 27 June 2014 and accepted 14 Decem- ber 2014. CONCLUSIONS This article contains Supplementary Data online There is important specificity of IAA among other diabetes autoantibodies to at http://care.diabetesjournals.org/lookup/ predict good therapeutic response of recent-onset type 1 diabetic patients to suppl/doi:10.2337/dc14-1575/-/DC1. anti-CD3 treatment. If confirmed, future immune intervention trials in type 1 © 2015 by the American Diabetes Association. Readers may use this article as long as the work diabetes should consider both relatively preserved functional b-cell mass and is properly cited, the use is educational and not presence of IAA as inclusion criteria. for profit, and the work is not altered. care.diabetesjournals.org Demeester and Associates 645 Type 1 diabetes is a chronic T cell–mediated terms of preservation of functional 6 months, and positivity for Epstein- autoimmune disease ultimately leading to a b-cell mass, determined as area under Barr virus IgG. Patients received an infu- major loss of insulin-secreting b-cells, hy- the curve (AUC) of second-phase glucose- sion of ChAglyCD3 (otelixizumab, n =40) perglycemia due to insulinopenia, anddif stimulated C-peptide release during a hy- or placebo (n = 40), administered during not well controlleddlife-threatening perglycemic clamp in addition to already 2–4 h on 6 consecutive days (64 mg cumu- complications (1). Humanized nonmito- established factors (4,5), and might thus lative dose in the first 4 patients; 48 mg genic Fc-mutated monoclonal anti-CD3 serve as independent predictors of clinical cumulative dose in the following 36 pa- antibodiesdhOKT3g1(Ala-Ala) (teplizu- outcome. In addition, we investigated tients). Treatment was randomized accord- mab; Macrogenics) (2,3) and ChAglyCD3 whether treatment with anti-CD3 influ- ing to trial center (four in Belgium, one in (otelixizumab) (4,5)dcould slow dis- enced the natural history of diabetes anti- Germany), age (,15 or $15 years) and ease progression by targeting activated body patterns after diagnosis (i.e., the presence or absence of ICA (4). The initial T lymphocytes in recent-onset type 1 declining trend of GADA, IA-2A, and protocol was planned for an 18-month diabetic patients, but preservation of ZnT8A and the insulin treatment–induced study. Efficacy and safety data were re- functional b-cell mass was transient rise in insulin antibodies [IA]) (11–13). ported previously (4). Written informed and largely confined to individuals consent was obtained from each patient. with relatively intact C-peptide secre- RESEARCH DESIGN AND METHODS The primary end point was second-phase tion and young age (,27 years) at di- Patient Selection and Treatment AUC C-peptide release (min 60–140) during agnosis (2–5). Likewise, the efficacy of Eighty recent-onset type 1 diabetic pa- the hyperglycemic clamp test (4). Be- several other immune interventions in tients were included in a randomized cause the number of participants who recent-onset diabetes was highest in phase 2 placebo-controlled trial (4) (trial underwent hyperglycemic clamp testing participants with younger age at inclu- number NCT00627146) (Supplementary during a 48-month follow-up was insuf- sion, shorter disease duration, or higher Fig 1). They were selected according to ficient to use clamp-derived C-peptide residual insulin-producing capacity at the following criteria: age 12–39 years, release as a primary end point (n = 36) the start of treatment (1,6). positivity for ICA and/or GADA, random (5), we limited the current study on Future trials, particularly if planned at plasma C-peptide level $0.2 nmol/L at a autoantibody predictor ability to 18 the preclinical stage, would benefitfrom glycemia of 10.0–13.9 mmol/L, treat- months of follow-up. The anti-CD3–treated biomarkers that identify responders to a ment with insulin for #4 weeks before group and the placebo group did not dif- given intervention. This would avoid ex- enrollment, polyuria for ,6months, fer statistically in clinical or laboratory posing nonresponders needlessly to im- ,10% weight loss during the previous characteristics (Table 1) or in the munomodulators with potentially harmful adverse effects (1,7,8). Diabe- tes autoantibodies are obvious candi- Table 1—Characteristics of patients at screening and start of the treatment dates in this respect because (changes Placebo group ChAglyCD3 in) antibody status or levels have been Variable (n =40) (n =40) P associated with clinical outcome in islet At screening or pancreas transplantation protocols Men 26 (65) 25 (63) 0.816 and in the oral arm of the DPT-1 trial Age (years)* 26 (7) 27 (7) 0.596 (9,10). Taking advantage of the data Time of insulin treatment (days) 6 (2–12) 7 (3–14) 0.432 and sample base from the previously re- IAA+ 15 (38) 10 (25) 0.228 fi GADA+ 37 (93) 34 (85) 0.288 ported rst randomized placebo- + controlled anti-CD3 study originally IA-2A 21 (53) 23 (58) 0.653 ZnT8A+ 19 (48) 20 (50) 0.823 designed to test the safety and b-cell $1 autoAb+ 39 (98) 38 (95) 0.556 preserving effects of otelixizumab in $2 autoAb+ 28 (70) 27 (68) 0.809 recent-onset type 1 diabetes (4), we IAA levels in IAA+ patients wanted to test the hypothesis that spe- (% tracer binding) 1.3 (0.7–1.9) 0.9 (0.7–1.3) 0.276 cific autoantibody profiles at diagnosis GADA levels in GADA+ patients fi (WHO units/mL) 532 (267–3,551) 279 (110–1,585) 0.088 might predict the ef cacy of a short + course (6 days) of anti-CD3 treatment. IA-2A levels in IA-2A patients (WHO units/mL) 271 (93–1,407) 620 (95–1,852) 0.411 In the original study, only the presence ZnT8A levels in ZnT8A+ patients of islet cell antibodies (ICA) and/or GADA (index) 0.17 (0.08–0.38) 0.32 (0.10–0.54) 0.275 positivity were examined as potential pre- At start of treatment dictive autoantibody markers (4). We there- Time since diagnosis (days) 25 (19–27) 21 (18–24) 0.113 fore measured autoantibodies against Time of insulin treatment (days) 20 (13–25) 20 (16–24) 0.769 2 2 insulin (IAA), GAD (GADA), insulinoma- Insulin dose (units z day 1 z kg 1)* 0.38 (0.20) 0.46 (0.27) 0.201 associated protein-2 (IA-2A), and zinc HbA1c (%)* 8.1 (1.5) 8.6 (1.5) 0.059 transporter8(ZnT8A)atclinicalonsetin HbA1c (mmol/mol)* 65 (16) 71 (16) C-peptide release under glucose participants in this study (4). We investi- clamping (nmol z L21 z min21) gated whether autoantibody levels could AUC min 60–140* 0.61 (0.29) 0.54 (0.30) 0.160 help identify individuals who benefited Data are mean (SD)*, n (%), or median (IQR). most from otelixizumab treatment in 646 IAA Predict Otelixizumab Efficacy Diabetes Care Volume 38, April 2015 expression of susceptible or protective cold or labeled insulin was removed in .250 nondiabetic control subjects HLA haplotypes (data not shown) (4). by a washing step, and the radioactivity and amounted to $0.60% tracer binding of the polyethylene glycol precipitate for I(A)A, $23.0 WHO units/mL for Patient Follow-up was measured, averaged, and ex- GADA, $1.4 WHO units/mL for IA-2A, Patients received intensive insulin ther- pressed as percentage added tracer $0.039 index for ZnT8A, and $0.48 aU apy for the entire period, and at least bound (24,000 cpm/tube) after correc- for the I(A)A microassay.
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