Human Proteolytic Beta-Amyloid Specific Antibodies for Treatment of Alzheimers Di

用于治疗阿尔茨海默病的人蛋白水解 β-淀粉样蛋白特异性抗体 Di

• 批准号: 8121071
• 负责人: Hiep T Tran
• 金额: $ 28.25万
• 依托单位: ABZYME THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121071
• 关键词: Affinity; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-Protein; Animal Model; Antibodies; Antibody Formation; Binding; Binding Proteins; Biotechnology; Cells; Characteristics; Chimeric Proteins; Chromosomes; Cleaved cell; Clinical Trials; Deaminase; Development; Dimerization; Diploidy; Disease; Estrogens; FOS gene; Gene Conversion; Genes; Genetic Crossing Over; Genetic Transcription; Goals; Human; Hydrolysis; Immunoglobulin G; JUN gene; Leucine Zippers; Libraries; Light; Mating Types; Mediating; Membrane; Modality; Monoclonal Antibodies; Oryctolagus cuniculus; Partner in relationship; Peptide Hydrolases; Phase; Phenotype; Plasmids; Property; Reporter; Reporter Genes; Research; Screening procedure; Site; Specificity; System; Technology; Testing; Therapeutic Monoclonal Antibodies; Toxic effect; VP 16; Validation; Western Blotting; Yeasts; activation-induced cytidine deaminase; amyloid peptide; base; beta-Galactosidase; combinatorial; cost; dosage; endodeoxyribonuclease SceI; expression vector; human monoclonal antibodies; improved; mouse model; mutant; neurotoxic; neurotoxicity; novel; novel strategies; novel therapeutics; peptide A; pre-clinical; preclinical study; research clinical testing; response; success; transcription factor; uracil-DNA glycosylase

DESCRIPTION (provided by applicant): Proteolytic antibodies are a novel therapeutic modality potentially impacting current antibody- based therapy. The ultimate goal of this project is to develop potent proteolytic human monoclonal antibodies (mAb) against beta Amyloids (Ab) for treatment of Alzheimer's disease. To achieve the objective, a novel approach was developed to produce a yeast intracellular human monoclonal antibody library (iHuMab) that can create 1016 possible unique antibodies. A (beta amyloid) specific monoclonal antibodies with protease activity will be screened using iHuMAbeta library and highly specific and tightly regulated multi-reporter system. At the end of phase I, we expect up to 10 unique A specific proteolytic antibodies will be expressed, purified and characterized. Their A40 specific hydrolysis, binding affinity and neutralization capacity will be validated. In phase II A specific antibodies having the highest affinity and protease activity will be produced in large scale quantities for further testing of A40 neutralization effects in mouse models of Alzhemer's disease. Also in Phase II, the most promising molecules would be subjected to pre-clinical evaluation in animal models, pursuant to submission of an IND application for clinical trials. PUBLIC HEALTH RELEVANCE: Therapeutic monoclonal antibodies are one of the fastest growing biotechnology sectors showing marked success for the treatment of various diseases. Proteolytic antibodies are a potential novel therapeutic that could provide a comparable or better benefit but requiring reduced dosages, therefore reducing the cost while increase efficacy. In this project, iHuMAbeta technology platform is developed to identify human proteolytic antibodies against beta-amyloid peptide, a promising target for the treatment of Alzheimer's Disease.

描述（由申请人提供）： 蛋白水解抗体是一种新的治疗方式，可能影响目前基于抗体的治疗。本项目的最终目标是开发针对β淀粉样蛋白（Ab）的有效蛋白水解人单克隆抗体（mAb），用于治疗阿尔茨海默病。为了实现这一目标，开发了一种新的方法来产生酵母细胞内人单克隆抗体文库（iHuMab），该文库可以产生1016种可能的独特抗体。将使用iHuMAbeta文库和高度特异性和严格调控的多报告系统筛选具有蛋白酶活性的A（β淀粉样蛋白）特异性单克隆抗体。在第一阶段结束时，我们预计将表达、纯化和表征多达10种独特的A特异性蛋白水解抗体。将验证其A40特异性水解、结合亲和力和中和能力。在II A期，将大规模生产具有最高亲和力和蛋白酶活性的特异性抗体，用于进一步测试Alzhemer病小鼠模型中的A40中和作用。同样在第二阶段，根据临床试验IND申请的提交，最有前途的分子将在动物模型中进行临床前评估。 公共卫生关系： 治疗性单克隆抗体是增长最快的生物技术领域之一，在治疗各种疾病方面取得了显着的成功。蛋白水解抗体是一种潜在的新型治疗剂，其可以提供相当或更好的益处，但需要减少的剂量，因此降低了成本，同时提高了功效。在该项目中，开发iHuMAbeta技术平台来识别针对β-淀粉样肽的人类蛋白水解抗体，β-淀粉样肽是治疗阿尔茨海默病的一个有前途的靶点。