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.

Journal article

It has been established that a total of 250 microg of monoclonal anti-mouse CD3 F(ab')(2) fragments, administered daily (50 microg per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing beta 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 microg (total dose 8 microg) induced 53% remission of diabetes, similarly to the 250 microg dose regimen, whereas four doses of 1 microg induced only 16% remission. While the 250 microg 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 beta-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.

Authors: Mehta, D; Christmas, R; Waldmann, H; Rosenzweig, M

• Publication status: Published
• Journal: Immunology
• Volume: 130
• Issue: 1
• Pages: 103-113
• Publication date: 2010-05-01
• DOI: 10.1111/j.1365-2567.2009.03217.x
• EISSN: 1365-2567
• ISSN: 0019-2805
• Language: English
• Keywords: Remission Induction; Female; Mice, Inbred BALB C; Cell Separation; Antibodies, Monoclonal; Dose-Response Relationship, Drug; Pancreas; Flow Cytometry; Diabetes Mellitus, Type 1; Antigens, CD3; Mice; Animals; CD8-Positive T-Lymphocytes; T-Lymphocyte Subsets; CD4-Positive T-Lymphocytes; Mice, Inbred NOD