An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes

Kevan C. Herold, Brian N. Bundy, S. Alice Long, Jeffrey A. Bluestone, Linda A. DiMeglio, Matthew J. Dufort, Stephen E. Gitelman, Peter A. Gottlieb, Jeffrey P. Krischer, Peter S. Linsley, Jennifer B. Marks, Wayne Moore, Antoinette Moran, Henry Rodriguez, William E. Russell, Desmond Schatz, Jay S Skyler, Eva Tsalikian, Diane K. Wherrett, Anette Gabriele ZieglerCarla J. Greenbaum

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

BACKGROUND Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulinproducing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS A total of 76 participants (55 [72%] of whom were =18 years of age) underwent randomization-44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P=0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

Original languageEnglish (US)
Pages (from-to)603-613
Number of pages11
JournalNew England Journal of Medicine
Volume381
Issue number7
DOIs
StatePublished - Aug 15 2019

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Type 1 Diabetes Mellitus
Anti-Idiotypic Antibodies
Placebos
teplizumab
HLA-DR3 Antigen
HLA-DR4 Antigen
Insulin
Lymphopenia
Fc Receptors
National Institutes of Health (U.S.)
Glucose Tolerance Test
Random Allocation
Exanthema
Proportional Hazards Models
Autoimmune Diseases
Chronic Disease
Monoclonal Antibodies
Confidence Intervals
T-Lymphocytes
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Herold, K. C., Bundy, B. N., Alice Long, S., Bluestone, J. A., DiMeglio, L. A., Dufort, M. J., ... Greenbaum, C. J. (2019). An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. New England Journal of Medicine, 381(7), 603-613. https://doi.org/10.1056/NEJMoa1902226

An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. / Herold, Kevan C.; Bundy, Brian N.; Alice Long, S.; Bluestone, Jeffrey A.; DiMeglio, Linda A.; Dufort, Matthew J.; Gitelman, Stephen E.; Gottlieb, Peter A.; Krischer, Jeffrey P.; Linsley, Peter S.; Marks, Jennifer B.; Moore, Wayne; Moran, Antoinette; Rodriguez, Henry; Russell, William E.; Schatz, Desmond; Skyler, Jay S; Tsalikian, Eva; Wherrett, Diane K.; Ziegler, Anette Gabriele; Greenbaum, Carla J.

In: New England Journal of Medicine, Vol. 381, No. 7, 15.08.2019, p. 603-613.

Research output: Contribution to journalArticle

Herold, KC, Bundy, BN, Alice Long, S, Bluestone, JA, DiMeglio, LA, Dufort, MJ, Gitelman, SE, Gottlieb, PA, Krischer, JP, Linsley, PS, Marks, JB, Moore, W, Moran, A, Rodriguez, H, Russell, WE, Schatz, D, Skyler, JS, Tsalikian, E, Wherrett, DK, Ziegler, AG & Greenbaum, CJ 2019, 'An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes', New England Journal of Medicine, vol. 381, no. 7, pp. 603-613. https://doi.org/10.1056/NEJMoa1902226
Herold KC, Bundy BN, Alice Long S, Bluestone JA, DiMeglio LA, Dufort MJ et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. New England Journal of Medicine. 2019 Aug 15;381(7):603-613. https://doi.org/10.1056/NEJMoa1902226
Herold, Kevan C. ; Bundy, Brian N. ; Alice Long, S. ; Bluestone, Jeffrey A. ; DiMeglio, Linda A. ; Dufort, Matthew J. ; Gitelman, Stephen E. ; Gottlieb, Peter A. ; Krischer, Jeffrey P. ; Linsley, Peter S. ; Marks, Jennifer B. ; Moore, Wayne ; Moran, Antoinette ; Rodriguez, Henry ; Russell, William E. ; Schatz, Desmond ; Skyler, Jay S ; Tsalikian, Eva ; Wherrett, Diane K. ; Ziegler, Anette Gabriele ; Greenbaum, Carla J. / An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. In: New England Journal of Medicine. 2019 ; Vol. 381, No. 7. pp. 603-613.
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abstract = "BACKGROUND Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulinproducing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS A total of 76 participants (55 [72{\%}] of whom were =18 years of age) underwent randomization-44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43{\%}) of the participants who received teplizumab and in 23 (72{\%}) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95{\%} confidence interval, 0.22 to 0.78; P=0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9{\%} per year in the teplizumab group and 35.9{\%} per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).",
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T1 - An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes

AU - Herold, Kevan C.

AU - Bundy, Brian N.

AU - Alice Long, S.

AU - Bluestone, Jeffrey A.

AU - DiMeglio, Linda A.

AU - Dufort, Matthew J.

AU - Gitelman, Stephen E.

AU - Gottlieb, Peter A.

AU - Krischer, Jeffrey P.

AU - Linsley, Peter S.

AU - Marks, Jennifer B.

AU - Moore, Wayne

AU - Moran, Antoinette

AU - Rodriguez, Henry

AU - Russell, William E.

AU - Schatz, Desmond

AU - Skyler, Jay S

AU - Tsalikian, Eva

AU - Wherrett, Diane K.

AU - Ziegler, Anette Gabriele

AU - Greenbaum, Carla J.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - BACKGROUND Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulinproducing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS A total of 76 participants (55 [72%] of whom were =18 years of age) underwent randomization-44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P=0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

AB - BACKGROUND Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulinproducing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS A total of 76 participants (55 [72%] of whom were =18 years of age) underwent randomization-44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P=0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

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