Delivering antibodies (molecular weight = 150 kDa) to the brain

在过去的三十年里，一种新的治疗方法，抗体已经被引入。抗体是大分子，比通常用于治疗病人的分子至少大300倍。这些抗体是非常成功的治疗方法，也是制药行业最近繁荣的基础。然而，与抗体药物相关的两个关键问题。一个问题是，抗体必须通过注射，因为它们在胃和肠道中被破坏，不能穿过肠壁进入血液；抗体需要存在于血液中才能对治疗目标起作用。这使得抗体药物变得昂贵。然而，一个更重要的问题是，当抗体在血液中时，它们不能穿过大脑中的血管到达脑组织。这种无法进入大脑的原因是它们的体积大，在血液中的溶解性好。排除在大脑之外使得抗体很难用于治疗脑部疾病，如阿尔茨海默病（AD）和脑肿瘤，然而这些疾病在我们的人群中变得越来越普遍，例如，在英国有近50万AD患者。目前的合作旨在开发在大脑中活跃的抗体药物，从而有助于治疗痴呆症和脑癌等疾病。在以前的合作中（资助参考编号：EP/G061483/1和EP/G028362/1），申请人已经确定了支持当前申请的关键技术进步。他们发现，一种特殊类型的纳米颗粒，直径只有人类头发厚度的1/1000，能够使被称为肽的精细药物从肠道吸收；多肽通常不被口服吸收。这些微小颗粒的作用是保护肽在肠道和胃中不被降解，并将被包裹的肽从肠道运送到血液中。之前的工作与目前的研究计划相关，因为在目前的研究中，申请人假设具有类似化学成分的抗体颗粒应该能够通过鼻子将抗体输送到大脑。申请人已经证明，当多肽通过鼻子在这些相同的颗粒中剂量时，颗粒被大脑吸收，多肽几乎只在大脑中起作用。这一令人兴奋的发现构成了该小组希望开发的鼻抗体剂型的基础。Nanomerics有限公司是伦敦大学学院的衍生公司，也是当前联盟的成员，实际上正在开发一种治疗慢性疼痛的止痛药，其基础是早期资助项目中研究的肽。据估计，20%的欧洲成年人患有慢性疼痛，目前的药物治疗效果很差。只有四分之一的慢性神经性疼痛患者，在现有的治疗方法下，症状有所缓解。因此，该小组在旨在将科学发现转化为现实世界解决方案的活动中具有经验，抗体输送项目旨在为痴呆症和癌症患者提供新的治疗方法。该项目将由伦敦大学学院、埃克塞特大学、Nanomerics和H. Lundbeck的科学家完成。灵北公司是一家年收入20亿英镑的全球性制药公司，专门从事脑部疾病的治疗。Nanomerics（拥有输送系统知识产权的独家许可）、H. Lundbeck（拥有将产品推向市场的经验）和学术科学家的结合，是将新概念从早期测试阶段推向市场的理想选择。该项目将涉及化学反应、纳米科学实验、专业激光显微镜检查、基于细胞的测试和动物测试。

Over the last three decades a new therapeutic, the antibody has been introduced. Antibodies are large molecules which are at least 300 times larger than the molecules that are usually used to treat patients. These antibodies are very successful therapies and form the basis of the pharmaceutical industry's recent prosperity. However there are two key problems associated with antibody medicines. One problem is that antibodies have to be given by injection as they are destroyed in the stomach and intestines and cannot cross the intestinal wall to get into the blood; antibodies need to be in the blood to act on their therapeutic target. This makes antibody medicines expensive. However a more important problem is that when antibodies are in the blood, they cannot cross the blood vessels in the brain to get to the brain tissue. This inability to access the brain is due to their large size and good solubility in the blood. Exclusion from the brain makes it hard for antibodies to be used to treat brain diseases such as Alzheimer's disease (AD) and brain tumours and yet these are diseases that are becoming more widespread in our populations, e.g. there are almost half a million AD sufferers in the UK. The current consortium aims to develop antibody medicines that are active in the brain and hence useful for the treatment of conditions such as dementia and brain cancer. In previous collaborations (grant reference numbers - EP/G061483/1 and EP/G028362/1), the applicants had identified a key technological advance that underpins the current application. They found that a particular type of nanoparticle, with a diameter 1/1000th of the thickness of a human hair, is able to cause delicate drugs known as peptides to be absorbed from the intestines; peptides are not normally absorbed when taken by mouth. These tiny particles act by protecting the peptide from degradation in the intestines and stomach and transporting the encapsulated peptide from the intestine to the blood. This former work is pertinent to the current initiative as in the current work, the applicants hypothesise that antibody particles of a similar chemistry should be able to deliver antibodies to the brain via the nose. The applicants have shown that when peptides are dosed in these same particles through the nose the particles are taken up by the brain and the peptides act almost exclusively in the brain. This exciting finding forms the bases of the nasal antibody dosage forms that the group wish to develop. Nanomerics Ltd, a UCL spin out company and member of the current consortium is actually developing an analgesic for the treatment of chronic pain, based on the peptides studied in the earlier funded projects. Chronic pain is a condition suffered by an estimated 20% of European adults and it is poorly served by current drugs. Only a quarter of patients, suffering from the extremely painful chronic neuropathic pain, experience any relief from their symptoms with existing therapies.The group thus has experience in activities aimed at translating scientific findings into real world solutions and the antibody delivery project is aimed at new therapeutics for dementia and cancer patients. The project will be delivered by scientists at UCL, Exeter University, Nanomerics and H. Lundbeck. H. Lundbeck, a global pharmaceutical company with annual revenues of £2 billion, specialises in the treatment of brain diseases. The combination of Nanomerics (which has an exclusive licence to the delivery system's intellectual property), H. Lundbeck (with experience of taking products to market) and academic scientists is ideal for taking a new concept from early stage testing on to a marketed product. The project will involve chemical reactions, nanoscience experiments, microscopical examinations with specialist lasers, cell based tests and animal testing.