Modular antibody engineering to overcome the blood brain barrier

抽象的。免疫疗法是治疗各种人类疾病最有前途的方法之一。 包括癌症、自身免疫和传染病。然而，系统性免疫疗法一直没有效果。 对于中枢神经系统(CNS)障碍，因为血脑屏障(BBB)限制了它们向大脑的传递。 开发能够克服血脑屏障的新型抗体制剂是免疫治疗的新前沿。一种策略 是使用受体介导的运输，通过血脑屏障运送生物制品。Abzyme提议使用其专有技术 SDALib平台，用于快速生成针对中枢神经系统中存在的受体的抗体，其Abz2技术用于 重组传统抗体以产生可通过受体介导克服血脑屏障的双特异性抗体 跨细胞和结合其在大脑中的特定靶点。 利用Abzyme的SDALib平台，抗人转铁蛋白受体(TFR)的驼状单域抗体具有 瘦素受体(Lepr)的VHH抗体已经开发出来，并且正在产生中。此外，还有一套 在15个具有诊断和治疗意义的小鼠抗人类蛋白靶点的单抗中， 我们的财产。第一阶段的重点是论证快速转化特定疾病的可行性 将传统抗体转化为类Ig G双特异性抗体，保留抗体Fc效应器功能和抗体 结合亲和力，以及新获得的双特异性分子跨越血脑屏障的能力。具体地说，双特异型 一只手臂针对HER2或EGFR，另一只手臂针对TFR或Lepr的重组抗体将 发展起来的。细胞为基础的双特异性抗体产生和血脑屏障穿透的稳健性 BBB模型和小动物将作为第二阶段申请提交的基础。 第二阶段工作重点包括：(一)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)利用SDALib抗体生成平台和Abz2双特异性方法生产一套BBB- 穿透性抗体与中枢神经系统疾病相关。 2.

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