Fully modified bispecific aptamer for effective combination therapy of neovascular ocular diseases

完全修饰的双特异性适体可有效联合治疗新生血管性眼病

基本信息

批准号：
9909857
负责人：
Qiang Gong
金额：
$ 22.5万
依托单位：
APTITUDE MEDICAL SYSTEMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909857
关键词：
Address Adverse event Affinity Age Angiopoietin-2 Aptamer Technology Aptitude Binding Biological Biological Assay Biological Markers Bispecific Antibodies Blindness Clinical Clinical Trials Combined Modality Therapy Complement Data Development Diabetic Retinopathy Disadvantaged Disease Dose Dropout Drug Kinetics Edema Ensure Exudative age-related macular degeneration FDA approved Funding Future Half-Life High Pressure Liquid Chromatography Human Hyperglycemia Immune Injections Letters Maximum Tolerated Dose Measures Methods Modality Modeling Molecular Target Monoclonal Antibodies Mus Nucleic Acids Ocular Physiology Oligonucleotides Oryctolagus cuniculus Pathway interactions Patients Penetration Performance Pharmaceutical Preparations Phase Phenotype Play Regimen Regulation Regulatory Pathway Reporting Research Personnel Retina Retinal Diseases Risk Role Safety Sampling Severities Small Business Innovation Research Grant Solubility Testing Therapeutic Therapeutic Agents Thick Tissues Toxic effect Transgenic Mice Treatment Efficacy Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factors Vegf inhibition Vision aging population angiogenesis aptamer bevacizumab cost diabetic dosage drug candidate experience first-in-human follow-up immunogenicity improved in vivo insight intravitreal injection macular edema neovascular next generation novel particle phase I trial phase III trial pre-clinical pre-clinical research programs ranibizumab response single molecule standard of care systemic toxicity targeted agent treatment response

项目摘要

PROJECT ABSTRACT Diabetic Macular Edema (DME) is the leading cause of blindness in the working age population. The anti- VEGF agents Ranibizumab and Aflibercept are currently the standard of care for DME. However, these treatments are far from optimal: ~40% of the DME patients have an inadequate response to the treatment. Mover, patients have to receive regular intravitreal injections indefinitely, creating significant treatment burden. Two more anti-VEGF agents have since been tested in phase 3 trials; although they moderately increased drug duration (from 1-2 months to 3 months), both failed to further improve vision gain. Thus, relying on anti- VEGF agents alone is clearly insufficient to improve efficacy. Combination therapies, which combine an anti-VEGF agent with disease modifying agents that target other important biomarkers such as Ang2 and VEGF-C/D, have shown great promise in further improving efficacy and/or reducing treatment burden. However, they often require the use of multiple therapeutic agents and sometimes multiple injections, which further increase the cost and treatment burden. In order to address this shortcoming, the ideal next-generation DME treatment should meet the following criteria: a) small in size, in order to achieve high molar dosage and longer duration of efficacy, and facilitate tissue penetration; b) devoid of immunogenicity and immune-stimulatory effects, in order to ensure long-term safety; c) most importantly, capable of inhibiting multiple biomarkers with one molecule, in order to improve efficacy without increasing treatment burden and cost. Aptamers are single stranded oligonucleotides that bind to molecular targets in a manner similar to monoclonal antibodies (mAbs). Although aptamers were invented much more recently than mAbs, they have already shown significant potential as ocular therapeutics: Macugen, the first anti-VEGF agent approved by FDA for wet AMD treatment, is an aptamer; two more aptamers (Fovista and Zimura) have been tested in human trials for multiple retinal indications, making aptamers one of the most evaluated modality for retinal diseases, with a favorable safety profile and a clear regulatory pathway. The purpose of this SBIR is to develop highly stable, multi-specific aptamers that may serve as the optimal combination treatment for DME. To that end, the Aptitude team has accumulated extensive experience in aptamer discovery. We have previously developed the Particle Display method that significantly improves the aptamer performance. We have also developed the method to screen for the optimal linker for a bispecific aptamer. Moreover, we have made further improvement to directly screen for fully modified aptamers that may enable longer duration of efficacy. Our expertise in aptamer discovery is complemented by our collaborators’ expertise in DME preclinical research and clinical trials. If successful, this project has the potential of bringing more efficacious and affordable treatment to DME patients.

项目摘要糖尿病性黄斑水肿 (DME) 是工作年龄人群失明的主要原因。 VEGF 药物雷珠单抗和阿柏西普目前是 DME 的标准治疗方法。治疗远非最佳：约 40% 的 DME 患者对治疗反应不足。此外，患者必须无限期地定期接受玻璃体内注射，造成巨大的治疗负担。此后，另外两种抗 VEGF 药物已在 3 期试验中进行了测试，尽管它们的剂量有所增加；药物持续时间（从1-2个月到3个月），均未能进一步提高视力增益，因此只能靠抗。单独使用 VEGF 药物显然不足以提高疗效。联合疗法，将抗 VEGF 药物与针对其他疾病的疾病调节药物相结合 Ang2和VEGF-C/D等重要生物标志物在进一步提高疗效方面显示出巨大的希望然而，它们通常需要使用多种治疗剂和/或减轻治疗负担。有时需要多次注射，这进一步增加了费用和治疗负担。缺点，理想的下一代 DME 处理应满足以下标准： a) 体积小，为了达到高摩尔剂量和更长的药效持续时间，并促进组织渗透；b) 免疫原性和免疫刺激作用，以确保长期安全；能够用一个分子抑制多种生物标志物，以提高疗效而不增加治疗负担和费用。适体是单链寡核苷酸，以类似于单克隆抗体的方式与分子靶标结合尽管适配体的发明时间比 mAb 晚得多，但它们已经出现了。显示出作为眼部治疗的巨大潜力：Macugen，FDA 批准的第一个抗 VEGF 药物湿性 AMD 治疗，是一种适体；另外两种适体（Fovista 和 Zimura）已在人体试验中进行了测试针对多种视网膜适应症，使适体成为评估最多的视网膜疾病治疗方式之一良好的安全性和明确的监管途径。该 SBIR 的目的是开发高度稳定、多特异性的适体，作为最佳的适体为此，Aptitude 团队在 DME 的联合治疗方面积累了丰富的经验。我们之前开发了粒子显示方法，可以显着改善核酸适配体的发现。我们还开发了筛选双特异性最佳接头的方法。此外，我们还进行了进一步的改进，可以直接筛选可能的完全修饰的适体。我们在适体发现方面的专业知识得到了我们合作者的补充。如果成功，该项目有潜力带来 DME 临床前研究和临床试验方面的专业知识。为 DME 患者提供更有效且负担得起的治疗。