Data Sheet 1_A novel monoclonal antibody against human thymic stromal lymphopoietin for the treatment of TSLP-mediated diseases.docx

IntroductionThymic stromal lymphopoietin (TSLP) is a master regulator of allergic inflammation against pathogens at barrier surfaces of the lung, skin, and gut. However, aberrant TSLP activity is implicated in various allergic, chronic inflammation and autoimmune diseases and cancers. Biologics drugs neutralizing excess TSLP activity represented by tezepelumab have been approved for severe asthma and are being evaluated for the treatments of other TSLP-mediated diseases.
Methods and resultsIn this study, we discovered and characterized a novel humanized anti-TSLP antibody TAVO101 with high binding affinity to human TSLP, which blocks TSLP binding to its receptor complexes on cell surface. TAVO101 showed potent neutralization of TSLP activities in the TSLP-driven STAT5 reporter assay and cell proliferation assay. Results from ex vivo studies showed that TAVO101 neutralized TSLP-mediated CCL17 release from primary human CD1c+ dendritic cells and proliferation of activated CD4+ T cells. In addition, TAVO101 showed strong efficacy in both TSLP/OVA-induced asthma and imiquimod induced psoriasis models in hTSLP/hTSLPR double knock-in mice. We further conducted Fc engineering to optimize TAVO101 antibody with reduced affinity to Fcγ receptors and C1q protein but with increased affinity to FcRn receptor for half-life extension.
DiscussionBy recognizing a different epitope, similarly potent neutralization of TSLP activities, and longer circulating half-life than tezepelumab, novel anti-TSLP antibody TAVO101 offers a potential best-in class therapeutics for various TSLP-mediated diseases.

引言
胸腺基质淋巴细胞生成素（Thymic stromal lymphopoietin, TSLP）是肺、皮肤与肠道屏障表面抵御病原体的过敏性炎症核心调控因子。然而，异常的TSLP活性与多种过敏性疾病、慢性炎症性疾病、自身免疫性疾病及癌症密切相关。以特泽鲁单抗（tezepelumab）为代表的可中和过量TSLP活性的生物制剂，已获批用于重症哮喘的治疗，且正被评估用于其他TSLP介导疾病的治疗。

方法与结果
本研究中，我们发现并表征了一种新型人源化抗TSLP单克隆抗体TAVO101，其与人TSLP具有高结合亲和力，可阻断TSLP与其细胞表面受体复合物的结合。在TSLP驱动的STAT5报告基因实验与细胞增殖实验中，TAVO101展现出强效的TSLP活性中和能力。离体实验结果显示，TAVO101可中和TSLP介导的原代人CD1c+树突状细胞释放CCL17，以及活化CD4+ T细胞的增殖。此外，在人源TSLP/人源TSLPR双基因敲入小鼠的TSLP/卵清蛋白（OVA）诱导哮喘模型以及咪喹莫特诱导银屑病模型中，TAVO101均展现出优异的治疗效果。我们还通过Fc工程化改造对TAVO101抗体进行优化，使其对Fcγ受体与C1q蛋白的亲和力降低，同时提升对FcRn受体的亲和力以延长药物半衰期。

讨论
相较于特泽鲁单抗，新型抗TSLP单克隆抗体TAVO101可识别不同的表位，具备同等强效的TSLP活性中和能力，且循环半衰期更长，有望成为针对各类TSLP介导疾病的同类最优（best-in-class）治疗药物。