Modular antibody engineering to overcome the blood brain barrier

模块化抗体工程克服血脑屏障

• 批准号: 9464412
• 负责人: Hiep T Tran
• 金额: $ 23.66万
• 依托单位: ABZYME THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9464412
• 关键词: Affinity; Amyloid; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Formation; Antigens; Autoimmune Diseases; Binding; Biological Assay; Bispecific Antibodies; Blood - brain barrier anatomy; Brain; Catalytic Antibodies; Cell Surface Proteins; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cleaved cell; Communicable Diseases; Data; Development; Diagnostic; Disease; Drug Kinetics; ERBB2 gene; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidermal Growth Factor Receptor; Extracellular Protein; Fc Receptor; Flow Cytometry; Foundations; Generations; Genes; Goals; Half-Life; Human; Hybridomas; Immunoassay; Immunoglobulin G; Immunotherapy; In Vitro; Ligands; Light; Malignant Neoplasms; Mammalian Cell; Mediating; Medicine; Modeling; Mus; Neuraxis; Noise; Penetration; Pharmacodynamics; Phase; Process; Production; Proteins; Recombinant Antibody; Serum; Signal Transduction; Specificity; System; TFRC gene; Technology; Therapeutic; Toxic effect; Treatment Efficacy; Work; antibody engineering; arm; base; beta-site APP cleaving enzyme 1; brain research; comparative; frontier; human disease; in vivo; intravenous administration; leptin receptor; murine monoclonal antibody; nervous system disorder; novel; novel strategies; pre-clinical; prevent; receptor; scale up; secretase; trafficking; transcytosis; uptake

Abstract. Immunotherapy is one of the most promising approaches for treatment of various human diseases including cancers, autoimmune and infectious diseases. However, systemic immunotherapies have been ineffective for central nervous system (CNS) disorders because the blood-brain barrier (BBB) limits their delivery to the brain. Development of new antibody agents able to overcome the BBB is a new frontier of immunotherapy. One strategy is to use receptor-mediated transport to deliver biologics across the BBB. Abzyme proposes to use its proprietary SDALib platform for rapid generation of antibodies to receptors present in the CNS, and its Abz2 technology for reformatting traditional antibodies to create bispecific antibodies that can overcome the BBB via receptor-mediated transcytosis and binding its specific target in the brain. Using Abzyme's SDALib platform, camelid single domain antibodies against human transferrin receptor (TfR) have already been developed and generation of VHH antibodies to leptin receptor (LepR) is in progress. In addition, a set of 15 murine monoclonal antibodies against human protein targets of diagnostic and therapeutic significance is in our possession. The focus of Phase I is to demonstrate the feasibility of rapidly transforming disease-specific traditional antibodies into IgG-like bispecific antibodies, preserving antibody Fc effector functions and antibody binding affinity, and the ability of the newly obtained bispecifics to cross the BBB. Specifically, bispecific recombinant antibodies with one arm targeting HER2 or EGFR and another arm against TfR or LepR will be developed. Demonstration of the robustness of bispecific antibody production and BBB penetration in cell-based BBB models and small animals will be the basis for Phase II application submission. Phase II work focus includes: (i) obtaining the preclinical in vivo therapeutic efficacy, pharmacodynamics, pharmacokinetics and toxicity data for antibodies developed in Phase I that are necessary for submission of an IND; (ii) using the SDALib antibody generation platform and Abz2 bispecific approach to produce of a suite of BBB- penetrating antibodies relevant to CNS disorders. 2

抽象的。免疫疗法是治疗各种人类疾病的最有希望的方法之一 包括癌症，自身免疫和传染病。但是，全身免疫疗法无效 对于中枢神经系统（CNS）疾病，因为血脑屏障（BBB）限制了它们向大脑的传递。 开发能够克服BBB的新抗体剂是免疫疗法的新领域。一种策略 是使用受体介导的运输来跨BBB提供生物制剂。 Abzyme建议使用其专有 SDALIB的平台，用于快速生成CNS中存在的受体的抗体，其ABZ2技术用于 重新格式化传统抗体，以创建可以通过受体介导的BBB克服BBB的双特异性抗体 转胞胞病并结合其在大脑中的特定靶标。 使用Abzyme的Sdalib平台，针对人类转铁蛋白受体（TFR）的Camelid单域抗体具有 已经开发并生成了对瘦素受体（LEPR）的VHH抗体。另外，一套 诊断和治疗意义的15种针对人蛋白蛋白靶标的鼠单克隆抗体 我们的财产。第一阶段的重点是证明快速转化疾病特异性的可行性 传统抗体中的IgG样双特异性抗体，保留抗体FC效应功能和抗体 结合亲和力，以及新获得的双特异性越过BBB的能力。具体来说，双特异性 一个针对HER2或EGFR的手臂的重组抗体，另一只针对TFR或LEPR为 发达。表明双特异性抗体产生和基于细胞中BBB渗透的鲁棒性 BBB模型和小动物将成为II期应用提交的基础。 第二阶段的工作重点包括：（i）获得体内临床前治疗功效，药效学，， 在第一阶段开发的抗体的药代动力学和毒性数据是提交IND所必需的； （ii）使用Sdalib抗体生成平台和ABZ2双特异性方法生产一套BBB- 与中枢神经系统疾病有关的穿透性抗体。 2