Tolerx, Inc., Cambridge, MA 02139-3515, USA.
Immunology. 2010 May;130(1):103-13. doi: 10.1111/j.1365-2567.2009.03217.x. Epub 2010 Jan 6.
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.
已经确定，每天给予 250 微克单克隆抗鼠 CD3 F(ab')(2)片段（每次 50 微克），通过防止β细胞遭受进一步的自身免疫攻击，可诱导非肥胖型糖尿病（NOD）小鼠模型中的自身免疫性糖尿病缓解。我们评估了较低剂量方案的单克隆抗 CD3 F(ab')(2)在糖尿病 NOD 小鼠中的疗效及其相关药效学（PD）效应，包括 CD3-T 细胞受体（TCR）复合物的调节、全血细胞计数以及循环 CD4(+)、CD8(+)和 CD4(+)FoxP3(+)T 细胞的比例。4 次给予 2 微克（总剂量 8 微克）可诱导 53%的糖尿病缓解，与 250 微克剂量方案相似，而 4 次给予 1 微克仅诱导 16%的缓解。虽然 250 微克剂量方案产生了几乎完全和持续的 CD3-TCR 复合物调节，但间隔 3 天给予 4 次较低剂量，诱导了相似的缓解率，但引起了短暂和部分调节的模式。在治疗的小鼠中，循环 CD4(+)和 CD8(+)T 细胞的比例下降，而 CD4(+)FoxP3(+)T 细胞的比例增加；这些效应是短暂的。用治疗开始时的血糖和 C 肽水平估计具有更大残余β细胞功能的小鼠比具有更严重疾病的小鼠更有可能进入缓解期。因此，仅产生 CD3-TCR 复合物部分和短暂调节的较低剂量单克隆抗 CD3 诱导了与较高剂量单克隆抗 CD3 相当的缓解率。因此，在临床环境中，较低剂量方案可能有效，并且还可以改善单克隆抗 CD3 治疗的安全性特征，包括降低细胞因子释放相关综合征和在治疗期间维持病原体特异性免疫监视。
