Antibodies for the treatment of chronic kidney disease: Technical proof of concept

“据估计，15.1%的成年人将在其一生中发展为晚期慢性肾脏疾病（CKD）。在英国，NHS每年花费12.3亿英镑治疗CKD，其中约5亿英镑用于终末期肾衰竭患者的透析。这些患者需要每周至少3次到医院就诊，每次4-6小时，每天液体摄入量限制为700 mL。因此，让这些患者远离透析是一项重大的医疗挑战。然而，即使在不需要透析的CKD患者中，与年龄匹配的对照组相比，16-49岁患者的死亡率高出36倍，50-64岁患者的死亡率高出12倍。唯一被证实有好处的药物是肾素-血管紧张素系统抑制剂，它通过控制血压起作用。然而，使用这些药物的患者仍然会出现进行性肾功能丧失。因此，迫切需要通过不同机制发挥作用的新治疗方法，这些方法可以在现有标准治疗的基础上分层。有重要证据表明，单细胞膜蛋白在纤维化和血管渗漏中发挥作用--这是CKD进展的核心过程。不幸的是，这种蛋白质被证明很难用药。一种小分子抑制剂最近在一种不同疾病的II期临床中显示出显著的益处，其中纤维化和血管渗漏也是病理性的。然而，该抑制剂也显示出脱靶毒性。其他公司一直在努力生产完全抑制该靶点信号传导的分子。DJS Antibodies通过利用我们独特的抗体发现平台来解决这一目标。在以前的工作中，我们发现了世界上第一个与靶标结合并具有功能特性的先导mAb。现在，我们计划将这些先导抗体开发成开发候选抗体，并在人类和啮齿动物疾病模型中进行测试，以获得全面的临床前概念验证数据包。该项目的成功将直接导致DJS与主要制药合作伙伴合作开发我们的抗体，或筹集A轮投资开发先导候选抗体以获得IND批准。凭借由啮齿动物体内和人类体外数据包支持的同类最佳治疗，DJS将定位于利用与这一巨大的未满足的医疗需求相关的重大商业机会。"

"It is estimated that 15.1% of adults will develop advanced chronic kidney disease (CKD) during their lifetime. In the UK, NHS spends £1.23 billion treating CKD each year, with approximately £500 million being spent on dialysis for patients with end-stage renal failure. These patients need to visit hospital at least 3 times weekly for sessions of 4-6 hours, and are limited to 700 mL fluid intake per day. Keeping these patients off dialysis is a therefore a major healthcare challenge. However, even among CKD patients who do not need dialysis, the mortality rate is 36 times higher in patients aged 16-49, and 12 times higher in patients aged 50-64, than age matched controls.In spite of the enormous need, CKD patients are poorly served by current treatments. The only medications with any proven benefits are renin-angiotensin system inhibitors, which work by controlling blood pressure. However patients on these medications still experience progressive kidney loss. There is therefore an urgent need for new treatments that work through separate mechanisms, which can be layered on top of the existing standard-of-care.There is significant evidence for the role of a single cell membrane protein in fibrosis and vascular leak -- processes central to the progression of CKD. Unfortunately, this protein has proven difficult to drug. A small molecule inhibitor recently showed significant benefit in a Phase II clinical a different disease, where fibrosis and vascular leak are also pathological. However, the inhibitor also showed off-target toxicity. Other companies have struggled to produce molecules that fully inhibit signalling by this target.DJS Antibodies has addressed this target by leveraging our unique antibody discovery platform. In previous work, we discovered the world's first lead mAbs that bind to the target and have functional properties. Now we plan to develop these lead antibodies into development candidates, and test them in human and rodent models of disease to obtain a comprehensive preclinical proof-of-concept data package.Success in this project will directly result in DJS either partnering our antibody for development with a major pharma partner, or raising Series A investment to develop the lead candidate to IND approval. With a best-in-class therapeutic supported by rodent _in vivo_ and human _ex vivo_ data packages, DJS will be positioned to exploit the significant commercial opportunity associated with this huge unmet medical need."