Preclinical development of an extracellular vesicle biotherapeutic for juvenile idiopathic arthritis

Mesenbio的目标是加速细胞外囊泡（EV）生物治疗药物的临床开发。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，难治性幼年特发性关节炎（JIA）作为我们的初始目标适应症。EV是纳米尺寸的膜结合结构，含有生物材料，包括核酸和蛋白质。EV由细胞释放以递送其生物活性货物并引起靶细胞的功能变化（例如生长、分化、免疫抑制）。因此，EV越来越被视为一种令人兴奋的新生物医学范式，不受与细胞疗法相关的问题的影响，例如免疫相容性，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、有效性和规模扩大，这些都与EV生产细胞的来源和供应有关，而这些来源和供应不能依赖于对质量和数量可变的未经表征的捐赠人类细胞的持续采样。我们启动了一项工作计划，以在人骨髓基质细胞的混合群体中鉴定真正的间充质干细胞（MSC）。将异质基质细胞永生化并扩增为单细胞衍生的集落。永生化状态使得能够在几年内深入表征许多克隆，并且我们成功地鉴定了克隆Y201，其具有真正MSC的标记物谱、形态学特征和所有分化和免疫抑制特征（James S.等人，Stem Cell Reports，2015; Kay AG等人，Front.免疫学，二零二二年六月六日）。我们已经证明，Y201 MSC产生了持续、一致的EV供应，这些EV具有免疫抑制和组织形成能力。2021年，我们成立了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，难治性JIA是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，以支持首次人体临床试验的监管批准。我们将重点关注EV产品的上游加工、表征以及安全性和有效性，旨在吸引更多资金，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.