Li Jian, Davis Janet, Bracht Michelle, Carton Jill, Armstrong Jennifer, Gao Wei, Scallon Bernie, Fung Ramie, Emmell Eva, Zimmerman Mark, Griswold Don E, Li Li
Centocor Inc., 200 Great Valley Parkway, Malvern, PA 19355, United States.
Int Immunopharmacol. 2006 Jun;6(6):880-91. doi: 10.1016/j.intimp.2005.12.009. Epub 2006 Jan 27.
Suppression of T cell response is the key to enhance graft survival and control autoimmune diseases. A mitogenic anti-CD3 monoclonal antibody (mAb), OKT3, has been used for decades to control acute rejection in organ transplantation. Although effective, the clinical use was limited by its side effects, such as cytokine release mediated by T cell activation. A low mitogenic humanized OKT3 with reduced FcR-binding (hgammaOKT3 Ala-Ala) was generated and tested in several clinical studies. Although hgammaOKT3 Ala-Ala demonstrated maintained efficacy and better safety it still activated T cells. To investigate if a non-mitogenic anti-CD3 mAb can be equally effective in immune suppression, a chimeric non-FcR-binding anti-mouse CD3 mAb (anti-CD3 IgG2a Ala-Ala) was generated. Unlike the hgammaOKT3 Ala-Ala, the mouse IgG2a Ala-Ala anti-CD3 mAb did not induce T cell activation as measured by proliferation, cytokine production and apoptosis. Nevertheless, the IgG2a Ala-Ala anti-CD3 mAb was equally effective in the inhibition of antigen-specific CD4+ T cell activation in vitro to that of the mitogenic anti-CD3 mAb (Anti-CD3 IgG2a). In vivo, the IgG2a Ala-Ala anti-CD3 mAb only induced transient reduction of peripheral and spleen T cells and did not trigger detectable cytokine release. Nonetheless, this non-mitogenic anti-CD3 mAb significantly prolonged islet graft survival as effectively as the mitogenic anti-CD3 mAb in an allogenic islet transplantation model. These results demonstrated that a non-mitogenic anti-CD3 mAb could be used as an effective immune modulator. It may also indicate that a true non-mitogenic version of OKT3 could further improve its safety profile for clinical use.
抑制T细胞反应是提高移植物存活率和控制自身免疫性疾病的关键。一种促有丝分裂的抗CD3单克隆抗体（mAb），OKT3，已被用于控制器官移植中的急性排斥反应数十年。尽管有效，但其临床应用受到副作用的限制，如T细胞激活介导的细胞因子释放。一种低促有丝分裂的、降低了FcR结合能力的人源化OKT3（hgammaOKT3 Ala-Ala）被研发出来，并在多项临床研究中进行了测试。尽管hgammaOKT3 Ala-Ala显示出持续的疗效和更好的安全性，但它仍然会激活T细胞。为了研究非促有丝分裂的抗CD3 mAb在免疫抑制方面是否同样有效，一种嵌合的、不与FcR结合的抗小鼠CD3 mAb（抗CD3 IgG2a Ala-Ala）被研发出来。与hgammaOKT3 Ala-Ala不同，通过增殖、细胞因子产生和凋亡检测发现，小鼠IgG2a Ala-Ala抗CD3 mAb不会诱导T细胞激活。然而，IgG2a Ala-Ala抗CD3 mAb在体外抑制抗原特异性CD4+ T细胞激活方面与促有丝分裂的抗CD3 mAb（抗CD3 IgG2a）同样有效。在体内，IgG2a Ala-Ala抗CD3 mAb仅引起外周血和脾脏T细胞的短暂减少，且不会引发可检测到的细胞因子释放。尽管如此，在同种异体胰岛移植模型中，这种非促有丝分裂的抗CD3 mAb与促有丝分裂的抗CD3 mAb一样，能显著延长胰岛移植物的存活时间。这些结果表明，非促有丝分裂的抗CD3 mAb可作为一种有效的免疫调节剂。这也可能表明，真正的非促有丝分裂版本的OKT3可能会进一步改善其临床应用的安全性。
