A Phase I/IIa Clinical Trial of a Humanised Monoclonal Antibody Against LRG1

该提案的目的是针对一种名为富含亮氨酸的α -2糖蛋白1 （LRG1）的分泌蛋白进行新药的I/IIa期临床试验。我们的团队几年前在寻找视网膜血管疾病的新治疗靶点时发现了LRG1。我们发现LRG1刺激眼部异常血管生长，并通过多种实验策略证明抑制LRG1可以阻止病理性血管生成（新血管生长）。这使我们推测，我们可以通过使用针对该蛋白的功能阻断单克隆抗体来靶向LRG1在视网膜血管疾病中的作用。在MRC DPFS奖的支持下，我们最近完成了Magacizumab的开发，这是一种针对LRG1的完全人源化去免疫功能阻断单克隆抗体。抗体的人源化防止了患者免疫系统的排斥反应。该抗体对LRG1具有高亲和力和特异性，在“湿性”年龄相关性黄斑变性（AMD）小鼠模型中，我们证实该抗体在预防病变形成方面与目前的护理标准（SOC） Eylea一样有效。此外，与目前的SOC不同，我们的治疗针对不同的血管生成途径，因此单独或联合使用可能提供更大的益处。基于这些概念验证的观察结果，我们设计了LABINA试验，这是在患有“湿”型AMD的患者中首次对人源化LRG1抗体进行男性检查。LABINA试验包括两个部分。在I期，我们将进行一项剂量递增研究，在该研究中，个体患者被给予增加剂量的Magacizumab，以确定治疗的安全性和最大耐受剂量。在IIa期，我们将给药Magacizumab联合SOC，对照组患者单独接受SOC加假注射。虽然试验的主要终点是安全性和耐受性，但我们设计的研究是为了最大限度地提高临床获益的机会。LABINA试验的成功结果将为更大规模的试验和进一步的商业化铺平道路。我们在知识产权方面拥有强大的地位，鉴于抗体疗法的巨大经济潜力以及在其他临床适应症（如癌症）的应用范围，我们有信心找到制药合作伙伴或投资者来支持分拆公司。

The aim of this proposal is to conduct a Phase I/IIa clinical trial of a new drug targeting a secreted protein named leucine-rich alpha-2 glycoprotein 1 (LRG1). Our group discovered LRG1 a few years ago in a search for new therapeutic targets in retinal vascular disease. We showed that LRG1 stimulates abnormal blood vessel growth in the eye, and demonstrated using a variety of experimental strategies that pathological angiogenesis (new blood vessel growth) can be prevented by inhibiting LRG1. This led us to speculate that we could target LRG1 in retinal vascular disease by using a function-blocking monoclonal antibody directed against this protein.With support from a MRC DPFS award we recently completed the development of Magacizumab, a fully humanized de-immunised function-blocking monoclonal antibody against LRG1. The humanisation of the antibody prevents its rejection by the patients' immune system. This antibody has high affinity and specificity for LRG1, and in a mouse model of "wet" age-related macular degeneration (AMD) we established that the antibody is as effective as the current standard of care (SOC), Eylea, in preventing lesion formation. Moreover, unlike current SOC our therapy targets a different angiogenic pathway and as such may provide greater benefit when administered either alone or in combination. Based on these proof of concept observations we designed the LABINA trial, a first in man examination of the humanized LRG1 antibody, in patients with the 'wet' form of AMD.The LABINA trial comprises two parts. In Phase I we will perform a dose-escalation study in which individual patients are given increasing doses of Magacizumab in order to establish safety of the therapy and the maximum tolerated dose. In Phase IIa we will administer Magacizumab in combination with SOC, with a control group of patients receiving SOC alone plus sham injection. Although the primary endpoint of the trial is safety and tolerability, we have designed the study so as to maximize the chances of seeing clinical benefit.A successful outcome to the LABINA trial will pave the way for larger scale trials and onward commercialization. We have a strong position with regard to intellectual property, and given the substantial economic potential of antibody therapies plus the scope for application in other clinical indications, such as cancer, we are confident of finding either a pharmaceutical partner or investors to support a spin-out company.