Development of a new drug for treating autoimmune uveitis

摘要 自身免疫性葡萄膜炎是致盲的主要原因，视网膜抗原特异性T细胞 导致眼部发炎和视力丧失。类似于其他T细胞介导的治疗 自身免疫性疾病中，选择性抑制致病T细胞是治疗的“圣杯” 治疗方面的发展。在初步研究中，我们开发了一种新的抗体-药物结合物 (ADC)结合T细胞靶向和强大的抗有丝分裂活性，旨在 选择性地杀死增殖中的自身反应性T细胞，而保留包括正常在内的其他细胞 T细胞。在此阶段I应用程序中，我们将首先演示该ADC选择性地杀死 在体外和体外扩增葡萄膜生成T细胞，同时保留正常T细胞和其他细胞 然后在两个动物身上确定其体内治疗效果和潜在的靶外效应 自身免疫性葡萄膜炎模型。这些研究将提供所需的概念验证 这一前景看好的ADC的第二阶段开发将使IND研究和进一步的临床 发展。

Summary Autoimmune uveitis is a major cause of blindness in which retinal antigen-specific T cells lead to ocular inflammation and vision loss. Similar to the treatment of other T cell-mediated autoimmune diseases, selective suppression of the pathogenic T cells is the “holy grail” of therapeutic development. In pilot studies, we have developed a novel antibody-drug conjugate (ADC) with combined T cell targeting and potent anti-mitosis activity, which is designed to selectively kill the proliferating autoreactive T cells while sparing the other cells including normal T cells. In this Phase I application, we will first demonstrate that this ADC selectively kills proliferating uveitogenic T cells while sparing normal T cells and other cells both in vitro and in vivo, then determine its in vivo treatment efficacy and potential off-target effects in two animal models of autoimmune uveitis. These studies will provide the required proof-of-concept for a Phase II development of this promising ADC towards IND-enabling studies and further clinical development.