Replication Data for: ‘Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics‘

This dataset contains raw data contributing to the publication ‘Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics‘. This publication is about the discovery of nanobodies (variable domain of camelid heavy chain-only antibodies) binding both human and non-human primate transferrin receptor (TfR) that could serve as moieties to improve brain permeability of therapeutic antibodies. The blood-brain barrier (BBB), while being the gatekeeper of the central nervous system (CNS), is a bottleneck for the treatment of neurological diseases, as most of the biologicals do not reach their brain targets in sufficient quantities. Receptor-mediated transcytosis (RMT) is one physiological mechanism in which nutrients are recognized by specific receptors that are expressed on the surface of the endothelial cells, internalized in intracellular vesicles, and finally released in the brain parenchyma. Targeting such RMT receptors with antibodies or nanobodies is a strategy to increase the brain permeabilities of biologicals. Among these receptors, TfR is one of the most exploited RMT mechanisms for brain drug delivery. Here we report the discovery of two nanobodies that were able to bind human and cynomolgus TfRs, making these nanobodies more clinically relevant. Whereas nanobody BBB00515 bound cynomolgus TfR with 18 times more affinity than it did human TfR, nanobody BBB00533 bound human and cynomolgus TfR with similar affinities. When fused with an anti-beta-site amyloid precursor protein cleaving enzyme (BACE1) antibody (1A11AM), each of the nanobodies was able to increase its brain permeability after peripheral injection. A 40% reduction of brain Aβ1–40 levels could be observed in mice injected with anti-TfR/BACE1 bispecific antibodies when compared to vehicle-injected mice. In summary, we found two nanobodies that could bind both human and cynomolgus TfRs with the potential to be used clinically to increase the brain permeability of therapeutic biologicals.

本数据集包含支持论文《新型人/非人灵长类交叉反应性抗转铁蛋白受体纳米抗体用于生物制剂脑递送》的原始数据。该论文聚焦于纳米抗体（nanobodies，骆驼科动物重链仅抗体的可变域）的发现，此类纳米抗体可结合人类及非人灵长类转铁蛋白受体（transferrin receptor, TfR），并能作为靶向部分以提升治疗性抗体的脑通透性。血脑屏障（blood-brain barrier, BBB）作为中枢神经系统（central nervous system, CNS）的“守门人”，却是神经系统疾病治疗的瓶颈，因为多数生物制剂无法足量抵达其脑内靶点。受体介导的转胞吞作用（receptor-mediated transcytosis, RMT）是一种生理机制，即内皮细胞表面表达的特定受体识别营养物质后，将其内化至细胞内囊泡，最终释放到脑实质中。利用抗体或纳米抗体靶向此类RMT受体，是提升生物制剂脑通透性的一种策略。在这些受体中，转铁蛋白受体（TfR）是脑药物递送中最常利用的RMT相关受体之一。本研究报道了两种纳米抗体的发现，它们能够结合人类及食蟹猴转铁蛋白受体（cynomolgus TfR），从而具有更高的临床相关性。其中，纳米抗体BBB00515与食蟹猴TfR的亲和力是人类TfR的18倍，而纳米抗体BBB00533与人类及食蟹猴TfR的亲和力相近。当与抗β-分泌酶1（beta-site amyloid precursor protein cleaving enzyme 1, BACE1）抗体（1A11AM）融合后，这两种纳米抗体在经外周注射后均能提升其脑通透性。与注射溶媒的小鼠相比，注射抗TfR/BACE1双特异性抗体的小鼠脑内β淀粉样蛋白1-40（Aβ1-40）水平降低了40%。综上，我们发现了两种可结合人类及食蟹猴TfR的纳米抗体，它们具有临床应用潜力，可提升治疗性生物制剂的脑通透性。