Validation of CD6 as a New Target for Treating Multiple Sclerosis

描述(申请人提供)：CD6是一种细胞表面糖蛋白，主要表达在T细胞上。此前的体外研究表明，CD6在调节T细胞功能中起着关键作用。 它可能成为治疗自身免疫性疾病的靶点。然而，这一领域的研究一直停滞不前，部分原因是缺乏CD6基因工程动物来证实体外结果，并探索体内生物治疗的潜力。最近几个小组的基因组扫描研究一致确认CD6是多发性硬化症(MS)的危险基因，这增加了将CD6作为靶点开发治疗多发性硬化症的新方法的可能性。我们研究了CD6基因敲除(KO)小鼠，发现它们在实验性自身免疫性脑脊髓炎(EAE)(人类多发性硬化症的动物模型)中免受中枢神经系统损伤，进一步支持了靶向CD6可能有效治疗多发性硬化症的假说。为了验证这一假说，我们用鼠抗鼠CD6单抗对EAE发作后的野生型(WT)小鼠进行治疗，发现这阻止了疾病的进展。但由于治疗小鼠体内产生了抗大鼠免疫球蛋白抗体，治疗效果迅速下降。为了解决这个问题并能够在体内测试人CD6靶向试剂，我们开发了CD6人源化小鼠，在其T细胞上表达人CD6而不是小鼠CD6。在使用这些CD6人源化小鼠进行的初步治疗研究中，我们发现在EAE的早期阶段(临床评分H1)或晚期(临床评分H2.5)注射小鼠抗人CD6单抗(UMCD6)显著逆转了疾病的进展，而且这种效果是长期的。在这项应用中，使用CD6人源化的小鼠，我们将进一步测试该单抗和另一种具有良好特性的小鼠抗人CD6单抗和一种可溶性的人CD6-Fc嵌合蛋白，以确定它们在治疗慢性进展型和缓解型EAE方面的相对有效性。本研究将验证CD6作为MS治疗的新靶点，并为进一步开发抗CD6单抗和可溶性CD6-Fc蛋白作为治疗MS的新药物奠定基础。

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.