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

向大脑输送抗体（分子量 = 150 kDa）

• 批准号: EP/L024748/1
• 负责人: Ijeoma Uchegbu
• 金额: $ 94.49万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FL024748%2F1
• 关键词: Delivering; antibodies; molecular; weight; 150

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.

在过去的三十年里，一种新的治疗方法，抗体被引入。抗体是大分子，其比通常用于治疗患者的分子大至少300倍。这些抗体是非常成功的疗法，并形成了制药业最近繁荣的基础。然而，有两个关键问题与抗体药物有关。一个问题是，抗体必须通过注射给予，因为它们在胃和肠中被破坏，不能穿过肠壁进入血液;抗体需要在血液中才能作用于其治疗靶点。这使得抗体药物昂贵。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情况是由于它们体积大，在血液中溶解性好。从大脑中排除使抗体难以用于治疗脑疾病，如阿尔茨海默病（AD）和脑肿瘤，但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。目前的联盟旨在开发在大脑中具有活性的抗体药物，因此可用于治疗痴呆症和脑癌等疾病。在之前的合作中（授权参考号- EP/G 061483/1和EP/G 028362/1），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，直径为人类头发厚度的1/1000，能够使称为肽的微妙药物从肠道吸收;肽在口服时通常不会被吸收。这些微小的颗粒通过保护肽在肠道和胃中降解并将胶囊化的肽从肠道运输到血液中来发挥作用。这一先前的工作与当前的倡议有关，因为在当前的工作中，申请人假设类似化学的抗体颗粒应该能够通过鼻子将抗体递送到大脑。申请人已经表明，当肽通过鼻以这些相同的颗粒给药时，颗粒被脑摄取，并且肽几乎仅在脑中起作用。这一令人兴奋的发现形成了该小组希望开发的鼻抗体剂型的基础。Nanomerics Ltd是UCL的一家分拆公司，也是当前财团的成员，实际上正在开发一种用于治疗慢性疼痛的止痛药，该止痛药基于早期资助项目中研究的肽。慢性疼痛是一种估计有20%的欧洲成年人患有的疾病，目前的药物效果不佳。只有四分之一的慢性神经性疼痛患者通过现有的治疗方法缓解了症状。因此，该小组在将科学发现转化为真实的世界解决方案的活动中拥有丰富的经验，抗体递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、纳米学和H。伦德贝克。H. Lundbeck是一家年收入20亿英镑的全球制药公司，专门从事脑部疾病的治疗。Nanomerics（拥有该输送系统知识产权的独家许可）、H。Lundbeck（具有将产品推向市场的经验）和学术科学家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。

项目成果

Polymer Based Gene Silencing: In Vitro Delivery of SiRNA.

基于聚合物的基因沉默：SiRNA 的体外递送。

• DOI: 10.1007/978-1-4939-3718-9_9
• 发表时间: 2016
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Carlos MI

Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments.

• DOI: 10.1007/s11095-016-1872-x
• 发表时间: 2016-05
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Fisusi FA;Siew A;Chooi KW;Okubanjo O;Garrett N;Lalatsa K;Serrano D;Summers I;Moger J;Stapleton P;Satchi-Fainaro R;Schätzlein AG;Uchegbu IF
• 通讯作者: Uchegbu IF

Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes.

• DOI: 10.3390/biomedicines10092182
• 发表时间: 2022-09-03
• 期刊: Biomedicines
• 影响因子: 4.7

Abstract 5530: Chitosan amphiphile nanoparticles reduced the myelosuppressive effects of lomustine

摘要 5530：壳聚糖两亲纳米粒子降低洛莫司汀的骨髓抑制作用

• DOI: 10.1158/1538-7445.am2015-5530
• 发表时间: 2015
• 期刊: Cancer Research
• 影响因子: 11.2
• 作者: Fisusi F