CCN4

*仅供医学专业人士阅读参考骨髓是人体的造血器官，在这里，造血干细胞处于由间充质干细胞等细胞构成的造血微环境之中，进行自我更新和多能性分化。造血干细胞分化为髓系祖细胞和淋巴系祖细胞，进而分化为髓系免疫细胞、血小板、红细胞等髓系细胞以及淋巴系细胞，此过程即为造血。骨髓造血活性增强是各种慢性病的标志，伴随的则是造血干细胞的自我更新能力逐渐耗尽。法国巴黎西岱大学的Julie Helft及其同事们的最新研究表明，乳腺癌能够在保留其自我更新能力的情况下，诱导全身的造血干细胞向髓系细胞的分化。他们使用转录组学分析和原位成像技术，发现乳腺癌能够远程重塑骨髓造血微环境，诱导造血干细胞和间充质干细胞在转录水平和空间定位上发生变化，从而影响造血微环境中细胞间的交流与互作，增加髓系细胞的浸润，但不会导致造血干细胞功能衰竭。论文首页截图髓系细胞浸润通常与实体瘤患者预后较差以及疾病严重性相关，因此了解患癌期间骨髓造血的情况和机制，对于抗肿瘤治疗至关重要。在这项研究中，先是利用乳腺癌小鼠模型的组织学切片和单细胞RNA测序分析，Julie Helft等人发现，局限发生于乳腺的肿瘤能够诱导小鼠发生全身性的变化。与正常小鼠相比，乳腺癌小鼠的骨髓造血活性增强，从基因表达特征来看，造血干细胞的髓系分化潜力增加。提取小鼠的造血干细胞，在体外实验中通过特定条件培养或者给其它小鼠进行移植，可以更直观地观察到，相比于正常小鼠，乳腺癌小鼠来源的造血干细胞确实更容易向髓系细胞分化。不过令人意外的是，尽管已表现出更高的髓系细胞分化潜能，乳腺癌小鼠造血干细胞的自我更新能力并没有减弱，体外培养7小时后，其造血干细胞数量是正常小鼠的2倍。乳腺癌小鼠的造血干细胞功能没有减弱此外，研究者们发现ANGPT2、WISP1和OPG等调控骨组织稳态的蛋白质在乳腺癌小鼠血液中水平提高。于是，他们使用荧光探针来检测小鼠体内的骨骼生长情况，发现乳腺癌小鼠比正常小鼠的骨骼形成增加。进一步的小鼠肱骨成像结果显示，乳腺癌小鼠肱骨的血管形态发生变化，血管内皮细胞的直径、体积和长度减少，且间充质干细胞的定位异常。具体而言，乳腺癌小鼠的间充质干细胞不再分布在血管内皮细胞周围，远离血管，而是与造血干细胞“贴紧”。与正常小鼠相比，乳腺癌小鼠的间充质干细胞与造血干细胞之间距离缩小、相互作用增强，造血干细胞则在骨髓中分布不均。造血干细胞和间充质干细胞的分布特点也就是说，乳腺癌小鼠造血干细胞所处的骨内膜生态位被重塑。对于乳腺癌小鼠的间充质干细胞来说，不仅是迷失了定位，基因表达也发生改变，表达更多与成骨细胞特征相关的基因（Mmp13、Col1a1），与脂肪细胞分化相关的基因（Apoe、Adipoq）表达下调。而且与成纤维细胞、成骨细胞和血管内皮等其它骨髓基质细胞相比，间充质干细胞在转录水平上受到最显著的影响。另外，体外实验验证表明，乳腺癌小鼠来源的间充质干细胞能够促进造血干细胞的扩增和向髓系细胞的分化。这些表明间充质干细胞有助于乳腺癌诱导骨髓造血活性增强。间充质干细胞促进造血干细胞向髓系细胞分化Julie Helft等人表示，这项研究结果暗示着癌症与慢性病以不同机制影响髓系造血，他们将在未来进一步探索乳腺癌条件下间充质干细胞和造血干细胞之间的互作关系，并找到乳腺癌远程操控骨髓的机制。参考文献：[1]https://www.nature.com/articles/s41556-023-01291-w本文作者丨张艾迪

Mediar's new partnerships follow an $85 million series A closed in March. Mediar Therapeutics is tapping the business development well early, teaming up with Pfizer and WuXi Biologics as two assets near the clinic.  The fibrosis-focused biotech will be lent Pfizer’s assistance on R&D work, test development and IND-enabling studies for its first two assets, MTX-463 and MTX-474, according to an announcement Wednesday. Though financial details weren’t disclosed, the biotech says it will retain full decision-making authority and rights to both programs. China's WuXi will assist with providing drug substance for the trials and bolstering manufacturing capabilities. Both partnerships are a function of Mediar’s nearing clinical arrival, with the two assets expected to reach phase 1 trials next year. The first candidate, MTX-463, is a monoclonal antibody targeting WISP-1, a kind of protein that often operates in the extracellular matrix and regulates cell function. Elevated levels of the protein have been associated with fibrosis progression. MTX-474 targets EphrinB2, which similarly impacts disease progression.  Mediar is not just bolstering external efforts to support its clinical progress, however. Jeffrey Bornstein, M.D., is joining as chief medical officer, moving across from Eledon Pharmaceuticals where he held the same role. Before that, he was a leader in Takeda’s gastroenterology unit, elevating from executive medical director to VP and head of clinical science over a four-year span. He also spent more than six years combined at Biogen and Gilead.  With the latest partnerships and a clinical leader on board, all systems appear ready to go. Mediar previously took care of the necessary fundraising to afford this stage of development, inking $85 million from a series A back in March. Novartis’ venture fund and Soffinova co-led the round, with help from Bristol Myers Squibb and Pfizer. 

Phase 1 studies planned for both WISP1 and EphrinB2 candidates in 2024 Company enters strategic collaborations with Pfizer Ignite and WuXi Biologics to accelerate IND-enabling studies and drug product manufacturing Jeffrey D. Bornstein, M.D. joins as Chief Medical Officer, bringing fibrosis expertise and more than 20 years of clinical development experience CAMBRIDGE, Mass., Oct. 25, 2023 /PRNewswire/ -- Mediar Therapeutics Inc., a biotechnology company advancing a portfolio of first-in-class therapies that halt fibrosis progression, today announced several milestones that support clinical advancement of its portfolio of novel antibodies: the nomination of two clinical candidates, key strategic collaborations with Pfizer Ignite and WuXi Biologics, and the appointment of Jeffrey D. Bornstein, M.D., as Chief Medical Officer. Mediar's first candidate, MTX-463, is a first-in-class monoclonal antibody designed to neutralize the WISP-1 signaling that is elevated in and contributes to fibrosis progression. Its second candidate, MTX-474, is a first-in-class monoclonal antibody designed to neutralize the EphrinB2 signaling that causes fibrosis advancement and may play a role in defining the fibrotic niche. Both candidates offer therapeutic potential across multiple indications, including fibrosing diseases of the lung and liver, and are supported by a compelling suite of preclinical in vivo and ex vivo data demonstrating specific anti-fibrotic effects and selective neutralization of their respective targets. Mediar plans to advance both MTX-463 and MTX-474 into Phase 1 clinical development in 2024. The company has also entered a strategic collaboration with Pfizer Ignite, a new end-to-end service for biotech companies with high potential science that leverages Pfizer Inc.'s significant R&D capabilities, scale and expertise to accelerate the development of breakthrough therapies. Research and development efforts, assay development, and IND-enabling studies for MTX-463 and MTX-474 will be conducted with support with Pfizer Ignite. Mediar will retain ongoing decision-making autonomy and rights to all programs throughout the collaboration. In addition, the company has entered a partnership with WuXi Biologics, wherein WuXi Biologics will provide fully integrated CMC development and cGMP manufacturing of clinical supply for drug substance and drug product to support IND-enabling and initial clinical studies for MTX-463 and MTX-474. The appointment of Jeffrey D. Bornstein, M.D., as Chief Medical Officer further supports Mediar's focus on moving its novel pipeline of biologics towards the clinic. "We are excited by this progress and believe that approaches that pinpoint fibrosis progression may be the key step in improving outcomes for patients," said Mediar's Chief Executive Officer Rahul Ballal, Ph.D. "In addition, Jeff's wealth of experience in driving clinical development of fibrosis treatments will be instrumental as we continue to advance our portfolio of first-in-class antibody treatments. We look forward to leveraging his deep insight and KOL connections across a variety of indications to design effective and efficient studies." "Fibrosis is the final common pathway for chronic diseases in multiple organ systems, contributing to a significant number of deaths each year, and creating a large global unmet need that must be addressed," said Dr. Bornstein. "Mediar's novel approach of targeting of fibrotic mediators holds exciting potential offering opportunities to address fibrosis at the later stages of progression either on its own or added to therapies that do not target fibrosis directly or sufficiently. I'm thrilled to join this talented team and advance these candidates into clinical studies." Dr. Bornstein joins Mediar with more than 20 years of clinical development expertise in the biopharmaceutical industry, with deep experience overseeing clinical studies of fibrosis treatments across multiple indications, including idiopathic pulmonary fibrosis (IPF), primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH). Dr. Bornstein previously served as Chief Medical Officer of Eledon Pharmaceuticals and Vice President, Head of Clinical Sciences, Gastroenterology at Takeda Pharmaceuticals. In addition, he directed development programs, including those focused on fibrosis, at Biogen, Gilead Sciences, Elan Pharmaceuticals and other early-stage biotechnology companies. After earning his M.D. and completing a residency in internal medicine at McGill University, Dr. Bornstein completed a fellowship in gastroenterology at Duke Medical Center, where he joined the faculty, conducting clinical research in hepatitis C and providing clinical care in gastroenterology and hepatology as a practicing physician. About Mediar Therapeutics Mediar Therapeutics is a biotechnology company pioneering a new approach to fibrosis treatment that halts the disease at a different source – the fibrotic mediators that drive disease progression. Mediar was founded based on a deep understanding of the complex science underlying fibrosis onset and progression. By combining novel targets with reliable, easily detectable blood biomarkers and familiar modalities, Mediar is derisking the path forward for fibrosis therapies in clinical development. For more information, contact [email protected] or follow us on LinkedIn. SOURCE Mediar Therapeutics