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Free Content Partial and transient modulation of the CD3–T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice

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It has been established that a total of 250 μg of monoclonal anti-mouse CD3 F(ab′)2 fragments, administered daily (50 μg per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing β cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab′)2 in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3–T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4+, CD8+ and CD4+ FoxP3+ T cells. Four doses of 2 μg (total dose 8 μg) induced 53% remission of diabetes, similarly to the 250 μg dose regimen, whereas four doses of 1 μg induced only 16% remission. While the 250 μg dose regimen produced nearly complete and sustained modulation of the CD3 –TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4+ and CD8+ T cells decreased, whereas the proportions of CD4+ FoxP3+ T cells increased; these effects were transient. Mice with greater residual β-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3–TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment.
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Keywords: T-regulatory cells; anti-CD3 therapy; autoimmunity; diabetes; non-obese diabetic (NOD)

Document Type: Research Article

Affiliations: 1: Tolerx, Inc., Cambridge, MA, USA 2: Sir William Dunn School of Pathology, University of Oxford, UK

Publication date: May 1, 2010

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