High throughput camelid antibody screening as drug discovery platform

作为药物发现平台的高通量骆驼抗体筛选

• 批准号: 8647986
• 负责人: Hiep T Tran
• 金额: $ 21.81万
• 依托单位: ABZYME THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647986
• 关键词: 10p; Adhesions; Affinity; Agar; Agglutinins; Animal Model; Animals; Antibodies; Antibody Affinity; Antigen Targeting; Antigens; Autoantigens; Avian Influenza; Biological Assay; Catalytic Antibodies; Cell surface; Cells; Communicable Diseases; Copper; Cytidine Deaminase; DNA; Development; Diploidy; Disease; Drug Targeting; Escherichia coli; Flu virus; Galactose; Generations; Genes; Glucose; Human; Immunization; In Vitro; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Investigation; Libraries; Malignant Neoplasms; Membrane; Mono-S; Monoclonal Antibodies; Mutagens; Mutation; Nature; Neuraminidase; Nose; Petromyzon marinus; Phase; Polyploidy; Process; Production; Proteins; Research; Specificity; Surface; System; Targeted Research; Techniques; Technology; Therapeutic; Therapeutic Effect; Therapeutic antibodies; Time; Toxin; Validation; Vision; Work; Yeasts; analog; base; commercialization; cost effective; cross reactivity; disulfide bond; drug discovery; flu; high throughput technology; humanized antibody; immunogenicity; improved; mutant; pathogen; promoter; public health relevance; screening; swine flu; technology development; vector

DESCRIPTION (provided by applicant): Monoclonal antibodies are used for treatment of a wide range of diseases from cancer to infectious diseases. However, development of antibodies with high affinity and specificity is still time-consuming, labor-intensive and unpredictable. Abzyme Therapeutics LLC is actively developing animal-free antibody discovery platforms to accelerate generation of therapeutic antibodies. In Phase I, we will create a so-called Self-Diversifying Antibody Library or SDALib as a monoclonal antibody generating system that will provide a diverse array of complete antibodies in vitro, without using immunization. The main feature of the system is the ability to self-generate a cell library with diversified antibodies by means of hypermutation induction in antibody encoding genes. Using the SDALib system, generation time of monoclonal antibodies against any antigen will be reduced to about two weeks as compared to 6 to 9 months normally required using conventional techniques. The platform is adaptable for simultaneous screening for multiple antibodies specific for different target antigens. Since there is no need to immunize whole animals, the SDALib system can generate specific antibodies against toxins, pathogens, self-antigens, and the like which were by nature difficult to obtain in the past. As a proof-of-principle, we will develop camelid single domain antibodies capable of inhibiting the enzymatic activity of influenza A virus neuraminidases (NA) of different suptypes. Once obtained, candidate antibodies will be humanized to reduce immunogenicity in humans. Multivalent and multi-specific antibodies will be produced as linear fusions to increase anti-NA potency and cross-reactivity. Such anti-NA antibodies can be used as a component of a nasal spray for flu treatment by stopping the spread of the flu virus in Phase II.

描述（由申请人提供）：单克隆抗体用于治疗从癌症到传染病的多种疾病。但是，具有高亲和力和特异性的抗体的开发仍然很耗时，劳动密集型和不可预测。 Abzyme Therapeutics LLC正在积极开发无动物的抗体发现平台，以加速产生治疗性抗体。在第一阶段，我们将创建一个所谓的自我描述抗体库或Sdalib作为单克隆抗体生成系统，该系统将在不使用免疫的情况下在体外提供多种完整的抗体。该系统的主要特征是能够自行生成具有多种抗体的细胞库 编码基因的抗体超数诱导的平均值。使用SDALIB系统，单克隆抗体对任何抗原的产生时间将减少到大约两周，而通常使用常规技术通常需要的6至9个月。该平台适用于同时筛选对不同靶抗原特异的多种抗体。由于不需要免疫全动物，因此Sdalib系统可以生成针对毒素，病原体，自我抗原等的特定抗体，而这种抗体本质上很难获得。作为原理证明，我们将开发能够抑制不同suptypes的流感A病毒神经氨酸酶（NA）酶活性的Camelid单域抗体。一旦获得，候选抗体将被人性化以降低人类的免疫原性。多价和多特异性抗体将作为线性融合产生，以提高抗NA效力和交叉反应性。通过阻止流感病毒在II期中的扩散，可以将这种抗NA抗体用作鼻喷雾剂的成分进行流感治疗。