CTLA4 fusion proteins for the treatment of diabetes

A technology of fusion protein and diabetes, which is applied in the field of prevention or delay of type 1 diabetes progression and treatment, and can solve problems such as no cure

Inactive Publication Date: 2015-04-15
ORBAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the discovery of insulin allows the treatment of T1DM, there is currently no cure

Method used

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  • CTLA4 fusion proteins for the treatment of diabetes
  • CTLA4 fusion proteins for the treatment of diabetes
  • CTLA4 fusion proteins for the treatment of diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 - Study Design and Patients

[0073] Patients (6-45 years old) diagnosed with type 1 diabetes within the past 100 days were screened in parallel for this study. If patient has at least one diabetes-associated autoantibody (micromeasure insulin antibody [if duration of insulin therapy is less than 7 days]; glutamic acid decarboxylase-65 [GAD-65] antibody; islet cell antigen-512 [ICA-512] or islet cell autoantibodies) and have a stimulated C of 0.2 nmol / L or greater measured during the Mixed Meal Tolerance Test (MMTT) completed at least 21 days after diagnosis of diabetes and within the 37-day randomization period peptide concentration, then the patient is eligible to participate in the study.

[0074] Persons whose blood samples screened positive for serum antibodies to hepatitis B surface antigen, hepatitis C, or HIV were excluded from the study. Samples were also tested for Epstein-Barr virus (EBV). Individuals with evidence of active EBV infection at scre...

Embodiment 2-

[0081] Example 2 - Procedure

[0082] Abatacept (Orencia, Bristol-Myers Squibb, Princeton, NJ, USA) was given on days 1, 14, and 28, then every 28 days, with the last dose on day 700 (total of 27 doses), given The form is a 30-minute intravenous infusion at a dose of 10 mg / kg (maximum 1000 mg per dose) in 100 mL of 0.9% sodium chloride infusion. Standard saline infusion was used as placebo. Patients did not receive any premedication.

[0083] All patients received intensive diabetes management. The goal is to achieve intensive glycemic control as recommended by the American Diabetes Association. (American Diabetes Association. Diabetes Care 2011;33(Suppl 1):S11–61.) Patients used multiple daily insulin injections or an insulin pump. Blood glucose monitoring was performed by frequent daily blood glucose monitoring. Non-insulin drugs that affect blood sugar control are not allowed.

[0084]Central analysis of blood samples. C-peptide concentrations from frozen plasma were...

Embodiment 3

[0085] Example 3 - Statistical Analysis

[0086] Spotfire S+8.1 statistical analysis software was used for all analyses. A sample size of 108 participants was planned to provide 85% power to detect a 50% increase in geometric mean C-peptide relative to placebo using a 0.05 level (one-sided) test with a follow-up loss of 10% and assigned treatment compared to 2:1 compared to controls (based on estimated mean of 0.248 and SD of 0.179 on the transformed scale). All analyzes were based on prespecified intention-to-treat cohorts with known measurements. Missing values ​​were assumed to be missing at random. The p-values ​​associated with the intention-to-treat comparisons of the primary and secondary endpoints were two-sided, but the trial design was based on a one-sided hypothesis test. An interim analysis of the endpoint treatment effect was completed and reported once to the Data and Safety Monitoring Committee according to the Lan and DeMets method with O'Brien-Fleming bound...

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Abstract

A method of treating, preventing, or delaying the progression of Type 1 diabetes mellitus autoimmunity by administering an effective amount of a cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) molecule is provided herewith. The CTLA4 molecule may be a fusion protein of a CTLA4 extracellular region and an immunoglobulin, such as abatacept.

Description

field of invention [0001] The present invention relates generally to the field of autoimmune diseases, and in particular to treating, preventing or delaying the progression of type 1 diabetes. Background technique [0002] The most common form of type 1 diabetes (T1DM) is an immune-mediated disease in which insulin-secreting beta cells are destroyed by an autoimmune response. There are a number of genetic and environmental factors associated with the onset of disease involving the progressive inflammatory infiltration of pancreatic islets containing immune cells that specifically target insulin-secreting β cells. This lesion develops over an undetermined period of time (months to years). Although the discovery of insulin allowed the treatment of T1DM, there is currently no cure. The most common form of type 1 diabetes is immune-mediated, in which insulin-producing beta cells are destroyed. However, at the time of diagnosis, most patients still have appreciable insulin pro...

Claims

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Application Information

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IPC IPC(8): A61K38/17C07K14/705C07K14/47A61P3/10
CPCC07K16/2827C07K16/2818C07K2319/32A61K2039/505C07K14/70521C07K2317/76A61K9/0019C07K2319/30A61K38/1774A61P43/00A61P3/10A61K9/107
Inventor 泰汉摩·欧尔本
Owner ORBAN BIOTECH
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