Herold Kevan C, Burton Joshua B, Francois Fleur, Poumian-Ruiz Ena, Glandt Mariela, Bluestone Jeffrey A
Naomi Berrie Diabetes Center, Department of Medicine and Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
J Clin Invest. 2003 Feb;111(3):409-18. doi: 10.1172/JCI16090.
Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR-binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3gamma1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-alpha and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3gamma1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-gamma on a molar basis, was greater after culture with hOKT3gamma1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-gamma and IL-10 production, but hOKT3gamma1(Ala-Ala) induced only detectable IL-10 production in CD45RO(+) cells. Moreover, in vivo, we found IL-10(+)CD4(+) T cells after drug treatment. These cells were heterogeneous but generally CD45RO(+), CTLA-4(-), and expressed CCR4. A subgroup of these cells expressed TGF-beta. Thus, the non-FcR binding anti-CD3 mAb, hOKT3gamma1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on beta cell destruction in Type 1 diabetes.
已开发出二聚体Fc受体（FcR）非结合性抗CD3抗体，以尽量减少与经典抗CD3单克隆抗体（如OKT3）相关的毒性。与非FcR结合抗体的鼠类类似物的研究表明，与OKT3相比，其促有丝分裂活性降低。在一项使用FcR非结合性人源化抗CD3单克隆抗体hOKT3γ1（Ala-Ala）治疗1型糖尿病患者的试验中，我们发现分别有63%和72%的患者血清中IL-10和IL-5显著升高，且TNF-α和IL-6水平低于先前报道的OKT3治疗后的水平。hOKT3γ1（Ala-Ala）传递的激活信号与体外先前激活的人细胞的钙信号传导和细胞因子产生有关。然而，与IFN-γ相比，在与hOKT3γ1（Ala-Ala）培养后，IL-10的摩尔产量比与OKT3培养后更高。流式细胞术研究证实，OKT3诱导IFN-γ和IL-10产生，但hOKT3γ1（Ala-Ala）仅在CD45RO（+）细胞中诱导可检测到的IL-10产生。此外，在体内，我们在药物治疗后发现了IL-10（+）CD4（+）T细胞。这些细胞是异质性的，但通常为CD45RO（+）、CTLA-4（-），并表达CCR4。这些细胞的一个亚群表达TGF-β。因此，非FcR结合性抗CD3单克隆抗体hOKT3γ1（Ala-Ala）向T细胞传递的激活信号在数量和质量上与OKT3不同。它导致可能抑制自身免疫反应的T细胞的产生，并可能参与对1型糖尿病β细胞破坏的有益作用。
