Methods for delaying onset of type 1 diabetes

Abstract

Provided herein, in one aspect, is a method of preventing or delaying the onset of clinical type 1 diabetes (T1D), comprising: providing a non-diabetic subject who is at risk for T1D; determining that the non-diabetic subject (1) is substantially free of antibodies against zinc transporter 8 (ZnT8), (2) is HLA-DR4+, and/or (3) is not HLA-DR3+; and administering a prophylactically effective amount of an anti-CD3 antibody to the non-diabetic subject.

1 . A method of delaying the onset of clinical type I diabetes (T1D), the method comprising:
 administering a prophylactically effective amount of teplizumab to a non-diabetic subject, wherein the non-diabetic subject is negative for zinc transporter 8 (ZnT8) antibodies.   
     
     
         2 . The method of  claim 1 , wherein the prophylactically effective amount comprises a 10 to 14 day course of daily subcutaneous (SC) injection of teplizumab from about 5 to about 1200 μg/m 2 . 
     
     
         3 . The method of  claim 1 , wherein the prophylactically effective amount comprises a 10 to 14 day course of daily intravenous (IV) infusion of teplizumab from about 5 to about 1200 μg/m 2 . 
     
     
         4 . The method of  claim 1 , wherein the prophylactically effective amount comprises a 10 to 14 day course of daily oral administration of teplizumab from about 5 to about 1200 μg/m 2 . 
     
     
         5 . The method of  claim 1 , wherein the prophylactically effective amount comprises a 10 to 14 day course of daily subcutaneous (SC) injection of teplizumab from about 10 to about 1000 μg/m 2 . 
     
     
         6 . The method of  claim 1 , wherein the prophylactically effective amount comprises a 10 to 14 day course of daily intravenous (IV) infusion of teplizumab from about 10 to about 1000 μg/m 2 . 
     
     
         7 . The method of  claim 1 , wherein the prophylactically effective amount comprises a 10 to 14 day course of daily oral administration of teplizumab from about 10 to about 1000 μg/m 2 . 
     
     
         8 . The method of  claim 1 , comprising administering a daily dose of from about 5 to about 1200 μg/m 2  over a 14 day course. 
     
     
         9 . The method of  claim 1 , wherein the prophylactically effective amount comprises a 14 day course IV infusion at about 51 μg/m 2  on day 0, about 103 μg/m 2  on day 1, about 207 μg/m 2  on day 2, and about 413 μg/m 2  on day 3, and one dose of about 826 μg/m 2  on each of days 4 to 13. 
     
     
         10 . The method of  claim 1 , wherein the non-diabetic subject is a relative of a patient with T1D. 
     
     
         11 . The method of  claim 1 , wherein the non-diabetic subject has two or more diabetes-related autoantibodies selected from islet cell antibodies (ICA), insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GAD), or antibodies to tyrosine phosphatase (IA-2/ICA512). 
     
     
         12 . The method of  claim 1 , wherein the non-diabetic subject has abnormal glucose tolerance on oral glucose tolerance test (OGTT). 
     
     
         13 . The method of  claim 12 , wherein the abnormal glucose tolerance on OGTT is a fasting glucose level of 110-125 mg/dL. 
     
     
         14 . The method of  claim 12 , wherein the abnormal glucose tolerance on OGTT is a 2 hour plasma of ≥140 and <200 mg/dL. 
     
     
         15 . The method of  claim 12 , wherein the abnormal glucose tolerance on OGTT is a glucose value at 30, 60, or 90 minutes on OGTT>200mg/dL. 
     
     
         16 . The method of  claim 1 , wherein the prophylactically effective amount delays median time to clinical diagnosis of T1D by from at least 50% to 90%. 
     
     
         17 . The method of  claim 1 , wherein the prophylactically effective amount delays median time to clinical diagnosis of T1D by from at least 12 months to 60 months. 
     
     
         18 . The method of  claim 1 , further comprising determining, by flow cytometry, a frequency of TIGIT+KLRG1+CD8+ T-cells in peripheral blood mononuclear cells of the non-diabetic subject, wherein an increase in the frequency after administrating teplizumab indicates responsiveness to teplizumab. 
     
     
         19 . A method of delaying the onset of clinical type I diabetes (T1D), the method comprising:
 administering intravenously a prophylactically effective amount of teplizumab to a non-diabetic subject,   wherein the prophylactically effective amount of teplizumab is administered to the non-diabetic subject at a daily dose of from about 5 to about 1200 μg/m 2  over a treatment course of 10 to 14 days, and   wherein the non-diabetic subject is negative for zinc transporter 8 (ZnT8) antibodies.   
     
     
         20 . The method of  claim 19 , wherein the treatment course is 14 days. 
     
     
         21 . A method of delaying the onset of clinical type I diabetes (T1D), the method comprising:
 administering subcutaneously a prophylactically effective amount of teplizumab to a non-diabetic subject,   wherein the prophylactically effective amount of teplizumab is administered to the non-diabetic subject at a daily dose of from about 5 to about 1200 μg/m 2  over a treatment course of 10 to 14 days, and   wherein the non-diabetic subject is negative for zinc transporter 8 (ZnT8) antibodies.   
     
     
         22 . The method of  claim 21 , wherein the treatment course is 14 days.