Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus

Herold, Kevan C.; Hagopian, William; Auger, Julie; Poumian-Ruiz, Ena; Taylor, Lloyd A.; Donaldson, David; Gitelman, Stephen E.; Harlan, David M.; Xu, Danlin; Zivin, Robert A.; Bluestone, Jeffrey A.

doi:10.1056/nejmoa012864

Cited by 1,111 publications

(885 citation statements)

References 36 publications

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“…An influence of age was not detected in the trial conducted by Herold et al This might be related to the different age range (7.5-30 years) or distribution in their study, or to its shorter follow-up [4,6]. The present finding that the effects of ChAglyCD3 are much more pronounced in younger patients can be explained by an age-dependency of the insulitis process.…”

Section: Discussioncontrasting

confidence: 60%

“…This treatment was also tested in recent-onset type 1 diabetic patients using humanised Fc mutated anti-human CD3 antibodies [4][5][6], which are less mitogenic and cytokinereleasing than murine FcR-binding CD3 antibodies such as muronomab CD3 (orthoclone OKT3) [7][8][9]. In a Phase 1/2 trial, a CD3-specific monoclonal antibody, hOKT3γ1 (AlaAla), was administered for 2 weeks [4,6]. In our Phase 2 placebo-controlled trial, the aglycosylated recombinant ChAglyCD3 was administered for six consecutive days [5].…”

Section: Introductionmentioning

confidence: 99%

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Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

et al. 2010

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Aims/hypothesis The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3. Methods Eighty patients, aged 12-39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n=40) or ChAglyCD3 (n=40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg −1 day −1 ) over 48 months was chosen as primary endpoint and compared in 31 placeboand 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively. Results Treatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48 months (+0.09 vs +0.32 U kg −1 day −1 in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48 months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27 years old, antibody treatment preserved initial beta cell function for 36 months (vs >80% decline within 24 months in the placebo subgroup <27 years old), resulted in lower HbA 1c concentrations and tended to reduce glycaemic variability (p=0.08). No longterm adverse events were observed. Conclusions/interpretation A 6 day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials.

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Section: Discussioncontrasting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

et al. 2010

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“…A short treatment with humanised monoclonal anti-CD3 antibodies preserves beta cell function in recent-onset type 1 diabetes [2,3], particularly in individuals with residual beta cell function ≥25% of controls [3]. This opens perspectives for immunomodulatory interventions in the late preclinical phase where beta cell function is likely to be even better preserved [4] and where anti-CD3 antibodies have also shown efficacy in animal models [5].…”

Section: Introductionmentioning

confidence: 99%

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

Vandemeulebroucke

Keymeulen²,

Decochez

et al. 2009

Diabetologia

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Aims/hypothesis The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A + FDRs) of type 1 diabetic patients. Methods Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A + FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5-10 min) and second (120-150 min) release phase, and after glucagon injection (150-160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT. Results Seven (41%) FDRs developed diabetes 3-63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p<0.05) and HVs (p<0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3-21 months later. Two of seven FDRs with normal firstphase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp. Conclusions/interpretation Clamp-derived functional variables stratify risk of diabetes in IA-2A + FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage.Trial registration: ClinicalTrials.gov NCT00654121 Funding: The insulin trial was financially supported by Novo Nordisk Pharma nv.

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“…Based on the preclinical studies that showed efficacy in murine models of diabetes even at the time of presentation with hyperglycemia and the acceptable adverse event profile that was seen in studies of renal and renal/pancreas allograft recipients and patients with refractory psoriatic arthritis (19,20), we initiated a phase I/II randomized controlled study to study the safety and efficacy of a single course of treatment with hOKT3γ1(Ala-Ala) on the loss of insulin production over 2 years in patients with new onset type 1 diabetes. We previously reported that the mAb prevented the loss of insulin production over the 1st year after diagnosis of type 1 diabetes in the initial one-half of the study entrants (21). In this study, we provide our findings from the complete study participants who were followed for 2 years.…”

mentioning

confidence: 99%

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

et al. 2005

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Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3γ1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 ± 9.6% of response at study entry in drug-treated patients vs. 53 ± 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA1c and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8+ T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.

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Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus

Cited by 1,111 publications

References 36 publications

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

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