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：
10578645
负责人：
Qiang Gong
金额：
$ 74.44万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578645
关键词：
Address Adverse event Affinity 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 Permeability 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 clinical practice cost diabetic dosage drug candidate experience first-in-human follow-up immunogenicity improved in vivo insight intravitreal injection macular edema mouse model neovascular next generation novel particle phase I trial phase III trial pre-clinical pre-clinical research programs ranibizumab single molecule standard of care systemic toxicity targeted agent treatment response

Address Adverse event Affinity 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 Permeability 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 clinical practice cost diabetic dosage drug candidate experience first-in-human follow-up immunogenicity improved in vivo insight intravitreal injection macular edema mouse model neovascular next generation novel particle phase I trial phase III trial pre-clinical pre-clinical research programs ranibizumab single molecule standard of care systemic toxicity targeted agent treatment response

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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。反 - VEGF代理商Ranibizumab和Aflibercept目前是DME的护理标准。但是，这些治疗远非最佳：约40％的DME患者对治疗的反应不足。搬运工，患者必须无限期地进行定期玻璃体内注射，从而产生大量的治疗伯嫩。此后，在第3阶段试验中对另外两种抗VEGF代理进行了测试。尽管他们适度增加药物持续时间（从1-2个月到3个月），都无法进一步改善视力增长。依靠反 - 仅VEGF代理显然不足以提高效率。联合疗法，将抗VEGF剂与疾病的疾病结合起来，将其他针对其他的药物 ANG2和VEGF-C/D等重要的生物标志物在进一步提高效率方面表现出巨大的希望和/或减少伯宁的治疗。但是，他们通常需要使用多种治疗剂，并且有时多次注射，这进一步增加了成本和治疗。为了解决这个问题缺点，理想的下一代DME处理应符合以下标准：a）大小较小，在为了达到高摩尔剂量和效率更长的持续时间，并促进组织穿透； b）没有免疫原性和免疫刺激作用，以确保长期安全； c）最重要的是，能够抑制一个分子的多种生物标志物，以提高效率而不提高治疗燃烧和成本。 APATMER是单链寡核苷酸，以类似于单克隆的方式与分子靶标结合抗体（mabs）。尽管化适体最近发明了比mabs，但它们已经显示出具有眼疗法的巨大潜力：Macugen，FDA批准的第一种抗VEGF代理湿AMD治疗是一种apatamer；在人类试验中已经测试了另外两名APTAMER（Fovista和Zimura）对于多种视网膜适应症，使适体是残留疾病评估最多的模态之一，有利的安全性和明确的监管途径。该SBIR的目的是开发高度稳定的多特异性适体，可以作为最佳 DME的组合处理。为此，能力团队已经积累了丰富的经验 apatamer发现。我们以前已经开发了粒子显示方法，该方法显着改善了 apatamer性能。我们还开发了筛选双特异性的最佳链接器的方法 apatamer。此外，我们已经进一步改进了，直接筛选了可以完全修改的适体实现更长的效率。我们在Atamer Discovery方面的专业知识是由我们的合作者完成的 DME临床前研究和临床试验方面的专业知识。如果成功，该项目有可能带来对DME患者的更有效和负担得起的治疗。