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。然而，开发具有高亲和力和特异性的抗体仍然耗时、费力且不可预测。 Abzyme Therapeutics LLC 正在积极开发非动物源抗体发现平台，以加速治疗性抗体的生成。在第一阶段，我们将创建一个所谓的自我多样化抗体库或 SDALib 作为单克隆抗体生成系统，它将在体外提供多种完整的抗体，而无需使用免疫。该系统的主要特点是能够通过自生成具有多样化抗体的细胞库 在抗体编码基因中诱导超突变的方法。使用 SDALib 系统，针对任何抗原的单克隆抗体的生成时间将缩短至约两周，而使用传统技术通常需要 6 至 9 个月。该平台适用于同时筛选针对不同靶抗原的多种抗体。由于不需要对整个动物进行免疫，SDALib系统可以产生针对毒素、病原体、自身抗原等的特异性抗体，而这些抗体在过去本质上很难获得。作为原理验证，我们将开发能够抑制不同亚型甲型流感病毒神经氨酸酶（NA）酶活性的骆驼科单域抗体。一旦获得，候选抗体将被人源化以降低人类的免疫原性。多价和多特异性抗体将以线性融合的形式产生，以增加抗 NA 效力和交叉反应性。这种抗NA抗体可以用作鼻喷雾剂的成分，通过在第二阶段阻止流感病毒的传播来治疗流感。