Anti-CD3 antibodies for type 1 diabetes: beyond expectations

JF Bach - The Lancet, 2011 - thelancet.com
JF Bach
The Lancet, 2011thelancet.com
For the past 25 years, efforts have been made to stop progression of type 1 diabetes by
immunotherapeutic strategies targeting autoimmune mechanism (s) involved in the disease.
In the mid-1980s, chemical immunosuppression with ciclosporin proved a successful
intervention in advanced disease, once hyperglycaemia had been established. 1 As
expected, however, the effect persisted only during drug administration, which implied a
requirement for chronic treatment that would be incompatible with the prerequisites of safety …
For the past 25 years, efforts have been made to stop progression of type 1 diabetes by immunotherapeutic strategies targeting autoimmune mechanism (s) involved in the disease. In the mid-1980s, chemical immunosuppression with ciclosporin proved a successful intervention in advanced disease, once hyperglycaemia had been established. 1 As expected, however, the effect persisted only during drug administration, which implied a requirement for chronic treatment that would be incompatible with the prerequisites of safety in type 1 diabetes—a disease that preferentially affects children and young adults.
The administration by various routes of different β-cell autoantigens has been widely explored, with disappointing results. 2–5 Another approach, based on the use of monoclonal antibodies against CD3, is to restore immune self-tolerance by targeting of pathogenic T cells (activated by the autoantigen) and by amplification of regulatory T cells, whose role in control of disease progression is well known. 6 This strategy, which was initially established in the non-obese diabetic mouse model, 7 has proven effective in two trials8, 9 using a short treatment with two humanised antibodies to CD3 (teplizumab and otelixizumab) in patients with recentonset type 1 diabetes. The first of these randomised trials, 8 which did not have a placebo group, used the CD3 antibody teplizumab at a cumulative dose of 34 mg equivalent for a patient weighing 70 kg. The second placebo-controlled trial9 used the CD3 antibody otelixizumab at a cumulative dose of 48 mg. In both trials, endogenous C-peptide secretion was maintained and insulin need decreased. With otelixizumab, these effects were significant up to 4 years after the initial 1-week treatment. 10
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