Validation of CD6 as a New Target for Treating Multiple Sclerosis

描述（由申请方提供）：CD 6是一种主要在T细胞上表达的细胞表面糖蛋白。以前的体外研究表明，CD 6在调节T细胞增殖中起关键作用。 细胞反应，它可能是治疗自身免疫性疾病的靶点。然而，在这一领域的研究一直萎靡不振，部分原因是缺乏CD 6基因工程动物来证实体外结果和探索体内生物治疗的潜力。最近来自几个小组的基因组扫描研究一致将CD 6确定为多发性硬化症（MS）的风险基因，这提高了使用CD 6作为靶点开发MS新疗法的可能性。我们研究了CD 6敲除（KO）小鼠，发现它们在实验性自身免疫性脑脊髓炎（EAE）中免受中枢神经系统损伤，EAE是人类MS的动物模型，进一步支持靶向CD 6可有效治疗MS的假设。为了检验该假设，我们在EAE发作后用大鼠抗小鼠CD 6 mAb治疗野生型（WT）小鼠，发现这阻止了疾病进展，但由于在治疗的小鼠中产生抗大鼠IgG抗体，治疗的功效迅速降低。为了解决这个问题，并能够在体内测试人CD 6靶向试剂，我们开发了CD 6人源化小鼠，其在其T细胞上表达人CD 6而不是小鼠CD 6。在使用这些CD 6人源化小鼠的初步治疗研究中，我们发现在EAE的早期（临床评分H1）或晚期（临床评分H2.5）给予小鼠抗人CD 6 mAb（UMCD 6）可显著逆转疾病进展，并且这种作用是持久的。在本申请中，使用CD 6人源化小鼠，我们将进一步测试该mAb和另一种充分表征的小鼠抗人CD 6 mAb和可溶性人CD 6-Fc嵌合蛋白，以确定它们在治疗慢性进行性EAE和缓解-复发性EAE中的相对有效性。本研究将验证CD 6作为MS治疗的新靶点，并为进一步开发抗CD 6 mAb和可溶性CD 6-Fc蛋白作为MS患者的新型治疗药物奠定基础。

DESCRIPTION (provided by applicant): CD6 is a cell surface glycoprotein that is primarily expressed on T cells. Previous in vitro studies have indicated that CD6 is critical in regulating T cell responses and that it could be a target for treating autoimmune diseases. However, research in this field has languished, partially due to the lack of CD6 gene engineered animals to confirm the in vitro results and to explore the potential of biologic therapy in vivo. Recent genome scanning studies from several groups have unanimously identified CD6 as a risk gene for multiple sclerosis (MS), which raises the possibility of using CD6 as a target to develop new therapies for MS. We have studied CD6 knockout (KO) mice and discovered that they are protected from central nervous system injury in experimental autoimmune encephalomyelitis (EAE), an animal model of human MS, further supporting the hypothesis that targeting CD6 could be effective in treating MS. To test this hypothesis, we treated wild type (WT) mice after onset of EAE with a rat anti-mouse CD6 mAb and found that this halted disease progression, but the efficacy of treatment rapidly decreased due to the development of anti-rat IgG antibodies in the treated mice. To address this issue and to be able to test human CD6-targeted reagents in vivo, we have developed CD6 humanized mice that express human CD6 instead of mouse CD6 on their T cells. In pilot treatment studies using these CD6 humanized mice, we found that administration of a mouse anti-human CD6 mAb (UMCD6) at either an early stage (clinical score H1) or late stage (clinical score H2.5) of EAE significantly reversed disease progression and this effect was long-lasting. In this application, using the CD6 humanized mice, we will further test this mAb and another well-characterized mouse anti-human CD6 mAb and a soluble human CD6-Fc chimeric protein to determine their relative effectiveness in treating both chronic progressive EAE, and remitting-relapsing EAE. This study should validate CD6 as a new target for MS therapy and set the stage for further development of the anti-CD6 mAbs and soluble CD6-Fc protein as novel therapeutic agents for MS patients.