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。免疫疗法是治疗多种人类疾病最有前途的方法之一 包括癌症、自身免疫性疾病和传染病。然而，全身免疫疗法一直无效 用于中枢神经系统 (CNS) 疾病，因为血脑屏障 (BBB) 限制了它们向大脑的输送。 开发能够克服血脑屏障的新型抗体药物是免疫治疗的新领域。一个策略 是利用受体介导的转运来跨血脑屏障输送生物制剂。 Abzyme 提议使用其专有技术 SDALib 平台可快速生成中枢神经系统中受体的抗体，其 Abz2 技术可用于 重新格式化传统抗体以创建可通过受体介导克服 BBB 的双特异性抗体 转胞吞作用并结合其在大脑中的特定目标。 使用 Abzyme 的 SDALib 平台，骆驼科动物抗人转铁蛋白受体 (TfR) 的单域抗体具有 已经开发出来，针对瘦素受体 (LepR) 的 VHH 抗体的生成正在进行中。另外，还有一套 15 种针对人类蛋白靶标的鼠单克隆抗体具有诊断和治疗意义 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 将传统抗体转化为类IgG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抗体穿过 BBB 的能力。具体来说，双特异性 重组抗体的一个臂针对 HER2 或 EGFR，另一臂针对 TfR 或 LepR 发达。展示基于细胞的双特异性抗体生产和 BBB 渗透的稳健性 BBB模型和小动物将作为二期申请提交的基础。 II期工作重点包括：（i）获得临床前体内治疗效果、药效学、 提交 IND 所需的第一阶段开发的抗体的药代动力学和毒性数据； (ii)使用SDALib抗体生成平台和Abz2双特异性方法来生产一套BBB- 与中枢神经系统疾病相关的穿透性抗体。 2