Preclinical development of an extracellular vesicle biotherapeutic for juvenile idiopathic arthritis

Mesenbio的目标是加速细胞外囊泡（EV）生物疗法的临床发展。我们已经设计了一种人类间充质干细胞系，以产生具有内在抗炎和组织再生特性的无限持续供应的ev。我们的目的是开发这些ev作为炎性关节炎的破坏性新疗法，以难治性幼年特发性关节炎（JIA）作为我们的初始目标适应症。电动汽车是纳米级的膜结合结构，含有生物材料，包括核酸和蛋白质。细胞释放ev，以传递其生物活性物质，并引起靶细胞的功能变化（如生长、分化、免疫抑制）。因此，电动汽车越来越被视为一种令人兴奋的新型生物治疗范例，它不受细胞治疗相关问题的影响，如免疫相容性、存活、储存、运输和成本。将EV疗法推向市场的关键挑战是一致性、有效性和扩大规模，这些都与产生EV的细胞的来源和供应有关，而不能依赖于不断取样质量和数量变化的未鉴定的捐赠人类细胞。2010年，我们启动了一项工作计划，在混合的人骨髓基质细胞群体中识别真正的间充质干细胞（MSCs）。异质基质细胞永生化扩增为单细胞衍生菌落。永生化状态使我们能够在数年内对许多克隆进行深入表征，我们成功地鉴定出克隆Y201，它具有真正的MSCs的标记谱、形态特征以及所有分化和免疫抑制特征（James S. et al, Stem Cell Reports, 2015; Kay AG et al, Front）。Immunol。（2022年6月6日）。我们已经证明，Y201间充质干细胞产生连续、一致的ev供应，具有免疫抑制和组织形成能力。我们于2021年成立了Mesenbio公司，以加速Y201 ev的开发，作为治疗炎症性关节疾病的生产平台，以难治性JIA为我们的第一个临床目标。该提案的目的是推进Y201 ev的临床前开发，以支持监管部门批准首次人体临床试验。我们将重点关注EV产品的上游加工、特征、安全性和有效性，目的是吸引更多资金，将治疗进展到临床试验应用。

Mesenbio's aim is to accelerate the clinical development of extracellular vesicle (EV) biotherapeutics. We have engineered a human mesenchymal stem cell line to produce a limitless, consistent supply EVs with intrinsic anti-inflammatory and tissue regenerating properties. Our intention is to develop these EVs as a disruptive new therapy for inflammatory arthritis, with refractory juvenile idiopathic arthritis (JIA) as our initial target indication.EVs are nano-sized, membrane-bound structures containing biological material, including nucleic acids and proteins. EVs are released by cells to deliver their bioactive cargoes and elicit functional change in target cells (e.g. growth, differentiation, immune suppression). Therefore EVs are increasingly viewed as an exciting new biotherapeutic paradigm, uncomplicated by the problems associated with cellular therapies, such as immune-compatibility, survival, storage, transport and costs. The key challenges for bringing EV therapies to market are consistency, efficacy and scale-up, which all link back to the source and supply of the EV-producing cells, which cannot rely on the constant sampling of uncharacterised donated human cells of variable quality and quantity.In 2010, we initiated a programme of work to identify authentic mesenchymal stem cells (MSCs) within a mixed population of human bone marrow stromal cells. Heterogeneous stromal cells were immortalised and expanded as single cell-derived colonies. The immortalised status enabled in-depth characterisation of many clones over several years and we succeeded in identifying clone Y201, which has the marker profile, morphological features and all the differentiation and immunosuppressive characteristics of true MSCs (James S. et al, Stem Cell Reports, 2015; Kay AG et al, Front. Immunol., 06 June 2022). We have demonstrated that Y201 MSCs produce a continuous, consistent supply of EVs that have both immunosuppressive and tissue-forming capabilities. In 2021 we founded the company, Mesenbio, to accelerate the development of Y201 EVs as a production platform to treat inflammatory joint disease, with refractory JIA as our first clinical target.The aim of this proposal is to advance the preclinical development of Y201 EVs to support regulatory approval for first-in-human clinical trials. We will focus here on upstream processing, characterisation and safety and efficacy of the EV product with the aim of attracting further funding to progress the therapy to clinical trial application.