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。免疫治疗是治疗人类各种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，系统性免疫疗法一直无效 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递送。 开发能够克服BBB的新抗体药物是免疫治疗的新前沿。一种策略 是使用受体介导的转运来递送生物制剂穿过血脑屏障。Abzyme建议使用其专有的 SDALib平台，用于快速生成针对CNS中存在的受体的抗体，其Abz 2技术用于 重组传统抗体以产生双特异性抗体，其可以通过受体介导的免疫抑制来克服BBB。 转胞吞作用并结合其在脑中的特定靶点。 使用Abzyme的SDALib平台，针对人转铁蛋白受体（TfR）的骆驼科单域抗体具有 已经开发了，并且正在产生针对瘦素受体（LepR）的VHH抗体。此外，一套 的15个鼠单克隆抗体对人蛋白质的诊断和治疗意义的目标是在 我们的财产第一阶段的重点是证明快速转化疾病特异性 将传统抗体转化为IgG样双特异性抗体，保留抗体Fc效应子功能， 结合亲和力和新获得的双特异性抗体穿过BBB的能力。具体而言，双特异性 具有靶向HER 2或EGFR的一个臂和针对TfR或LepR的另一个臂的重组抗体将被 开发在基于细胞的免疫细胞化学中证明双特异性抗体产生和BBB渗透的稳健性。 BBB模型和小动物将作为II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I期开发抗体的药代动力学和毒性数据; (ii)使用SDALib抗体生成平台和Abz 2双特异性方法来产生一套BBB- 与CNS疾病相关的穿透性抗体。 2