HBEGF

4月2日，石药集团宣布，公司开发的抗体药物偶联药物（Antibody-Drug Conjugate，ADC）CPO301的试验性新药申请（IND）已获得FDA批准，可在美国开展临床试验。该研究为一项多中心、剂量递增及剂量扩展的I期临床试验，以评估CPO301在EGFR基因突变或EGFR过表达的晚期肺癌的安全性、药物动力学及初步疗效。 原发性支气管肺癌，简称肺癌，是起源于气管、支气管黏膜或腺体，是最常见的肺部原发性恶性肿瘤。全球范围内，肺癌的发病率、死亡率都极高且呈上升趋势。2018年全球统计数据显示，男性肺癌发病率及死亡率均占恶性肿瘤的第1位。在女性人群中，肺痛的发病率位列恶性肿瘤的第3位，死亡率则仅次于乳腺癌位列第二。我国2015年统计数据显示，肺癌分别为男性和女性人群恶性肿瘤发病率的第一和第二位，而死亡率均居首位。 EGFR（epidermal growth factor receptor）是表皮生长因子受体（HER）家族成员之一。该家族包括HER1（erbB1，EGFR）、HER2（erbB2，NEU）、HER3（erbB3）及HER4（erbB4）。HER家族在细胞生理过程中发挥重要的调节作用。 目前发现的EGFR的配体，共6种，主要是表皮生长因子(EGF)和转化生长因子α(TGF-α)，另外还有双向调节蛋白（AR），β-细胞素（BTC），肝素结合EGF样生长因子（HBEGF）和表皮调节素（EPR）。由于EGF、TGF-α等配体与细胞外受体相结合，EGFR二聚体化引起胞内域形成酪氨酸激酶活化，即细胞内TK结构域与ATP产生生化反应，ATP变成ADP，TK磷酸化激活EGFR酶活性。活化的EGFR可将增殖信号和抗凋亡信号通过PI3K-AKT-mTOR、Ras-Raf-MEK-ERK1/2等多个下游信号传导途径，传递至细胞核，控制细胞生长和分裂等。 研究表明在许多实体肿瘤中存在EGFR的高表达或异常表达。EGFR与肿瘤细胞的增殖、血管生成、肿瘤侵袭、转移及细胞凋亡的抑制有关。此外，对EGFR与肿瘤的血管生成、高侵袭性及转移关系的研究发现EGFR可以通过Ang-1及VEGF等因子水平的调节而影响肿瘤血管生成。因此，EGFR是癌症治疗，尤其是肺癌治疗的热门靶点之一。 由于小分子抑制剂治疗常会引发突变，导致治疗抵抗，因此需要不断开发新一代针对抵抗突变的EGFR抑制剂；此外，针对EGFR开发的抗体药物，往往也需要与化疗联用以增强疗效。目前，全球唯一获批的靶向EGFR的ADC（抗体药物偶联物）药物为Rakuten Medical的cetuximab saratolacan（Akalux）。 CPO301是一款靶向表皮生长因子受体（EGFR）的ADC。临床前研究显示，CPO301呈剂量依赖性地抑制免疫缺陷小鼠中具有各种EGFR激活突变或野生型EGFR高表达模型的人类肿瘤的生长。CPO301尤其在含有针对三代EGFR-TKI奥希替尼耐药的EGFR三重突变（Exon19Del、T790M和C797S）的人源化非小细胞肺癌PDX模型中显示出很强的抗肿瘤效果。CPO301在临床前毒理学和安全药理学研究中并显示良好的安全性和耐受性。该等数据支持CPO301用于治疗晚期非小细胞肺癌的快速开发。本次批准，是石药研发肺癌ADC药物迈出的重要一步。 参考资料： https://mp.weixin.qq.com/s/3WLtAg_-mJox6dBvFTDXfw

Thanks to laboratory produced human mini-retinas, researchers were able to observe complex changes in the retina as they occur in macular degeneration. This enabled them to discover the so-called cell extrusion as a potential mechanism for neurodegenerative diseases. Visual cells in the human retina may not simply die in some diseases, but are mechanically transported out of the retina beforehand. Scientists from the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden have now discovered this. For their research, they used miniature human retinas produced in the laboratory, so-called organoids. In the new issue of the journal Nature Communications, they report on their discovery, which paves the way for completely new research approaches, especially in connection with age-related macular degeneration (AMD). "This principle, known as cell extrusion, has not yet been studied in neurodegenerative diseases," says Prof. Mike Karl, who heads the research group. AMD is the main cause of blindness and severe visual impairment in Germany. It is estimated that a quarter of people over the age of 60 suffer from AMD. The macula is a special region within the human retina that is needed, among other things, for high resolution color vision. In AMD, thousands of light-sensitive visual cells, the so-called photoreceptor cells, are lost in the macula. "This was the starting point for our research project: we observed that photoreceptors are lost, but we could not detect any cell death in the retina," explains Mike Karl, who conducts research at the Dresden site of the DZNE and the CRTD at TU Dresden. "Half of all photoreceptors disappeared from the retinal organoid within ten days, but obviously they did not die in the retina. That made us curious." For the researchers -- the DZNE and the CRTD were involved, as well as the Helmholtz Centre for Environmental Research (UFZ) -- an elaborate search for the causes began. This led them to a study from 2012 (doi: 10.1038/nature10999): Jody Rosenblatt from King's College in London was the first to describe the extrusion of living cells -- the mechanical ejection of cells from epithelia. The thereby extruded cells then only die in succession. She demonstrated this mechanism in simple epithelial cells of the kidney. Mike Karl and his team now showed in their pioneering work that this extrusion can also be triggered in the much more complex retina, consisting of several different cell types, and leads to neurodegeneration. Interestingly, this cell extrusion could explain the outlying cells that have been previously reported in the ageing and diseased retina of patients with AMD and other diseases, but have not been studied in detail until now. The researchers made use of a technique they had previously developed: They worked with so-called retinal organoids -- an organ-like, three-dimensional model of the human retina grown from human stem cells in the laboratory. These organoids provide some characteristics of the human macula. The team found that two substances previously described in various neurodegenerative diseases -- the proteins HBEGF and TNF -- are sufficient to trigger degeneration in the retinal organoid. During this process, the researchers filmed the organoids in real time by so-called live imaging, considered as the gold standard for cell tracking. "We were able to capture the degeneration of photoreceptors through cell extrusion in the lab," says Mike Karl. The scientists found that this extrusion is triggered by activation of the protein PIEZO1, a sensor for biomechanical forces. That biomechanics may play a larger role in retinal degeneration is a new finding. "The retina is not known to be a biomechanically active tissue such as a muscle. It was known that diseases of the nervous system are associated with changes in the shape of cells, but to which extent biomechanical regulators are involved has not yet been studied in detail," says Karl. Thanks to the organoids, he and his team were able to observe the processes in an accelerated manner, so to speak: While it takes several years or even decades for photoreceptors to disappear in patients, such a process could now be reproduced in the laboratory in just 40 days. In the next step, the researchers now want to find out whether this mechanism occurs in human patients in the same way as in organoids. Initial findings suggest that this might be the same mechanism, but proof is still lacking. In their study, the Dresden researchers also found that pharmacological agents could prevent extrusion in an experimental setting in their model. They used a special snake venom to block the mechanosensor PIEZO1 on the cells. As a result, not only were the photoreceptors not ejected, but further pathological changes in the retina were prevented. "This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD," Mike Karl sums up.