DGKζ

According to the recent announcement on the CDE (China's Center for Drug Evaluation) website, Bayer has successfully obtained clinical trial approvals for two of its novel Class 1 drugs, which are aimed at addressing the treatment needs of patients with late-stage solid tumors and acute ischemic stroke.   Based on Bayer's public information, one of the new drugs is a DGKα inhibitor, and the other is a protein-based drug targeting α2AP. These two candidates are currently in Phase 1 and Phase 2 clinical development stages, respectively, at the international level.   BAY 2862789 oral solution, a small-molecule DGKα inhibitor co-developed by Bayer and the German Cancer Research Center (DKFZ), is now undergoing the first-in-human Phase 1 clinical trial globally. Its research and development target is the treatment of solid tumors. The diacylglycerol kinase (DGK) family plays a crucial role in the development, differentiation, and functional regulation of T cells and NK cells, with DGKα and DGKζ being the predominant isoforms. Studies have shown that DGKα is significantly expressed in various refractory cancers, promoting cell proliferation and inhibiting apoptosis. Its high expression is closely related to T-cell exhaustion, which is a key factor in the evasion of immune surveillance by late-stage cancers. Therefore, the specific inhibition of DGKα holds great potential in the field of cancer therapy, as it can effectively suppress cancer cell proliferation and activate T-cell functions, achieving a dual anti-cancer effect. Furthermore, the synergistic effect of this inhibitor with PD-1/PD-L1 inhibitors offers new hope for the treatment of refractory cancers.   The other new drug, BAY 3018250, is a protein-based drug targeting α2AP, which is part of Bayer's cardiovascular disease research and development pipeline. It aims to treat acute ischemic stroke and pulmonary embolism. Currently, this drug has made significant progress in the international Phase 2 clinical trial for the treatment of deep vein thrombosis (DVT). DVT is a serious health issue that can lead to life-threatening blockage of blood flow in the lungs. BAY 3018250 exerts its therapeutic effect by dissolving blood clots. Thrombotic vascular occlusion is a key factor in the development of ischemic stroke, and α2-antiplasmin (α2AP), a member of the serine protease inhibitor family, is closely associated with an increased risk of ischemic stroke and the failure of recombinant tissue plasminogen activator (rt-PA) treatment. Research has shown that anti-α2AP therapy can significantly reduce the formation of microvascular thrombosis, ischemic brain injury, brain edema, intracerebral hemorrhage, and mortality after ischemic stroke, suggesting that the temporary inactivation of α2AP may have potential therapeutic value for ischemic stroke. With the approval for clinical trials in China, BAY 3018250 will now be evaluated for the specific indication of acute ischemic stroke, bringing new hope for the treatment of this condition.

中国国家药监局药品审评中心（CDE）官网公示，近日拜耳（Bayer）公司申报的两款1类新药获得临床试验默示许可，分别拟用于治疗晚期实体瘤和急性缺血性脑卒中患者。根据拜耳公开资料，这两款新药分别为DGKα抑制剂和抗a2AP的蛋白质药物，在国际上分别处于1期和2期临床阶段。 BAY 2862789口服溶液：DGKα抑制剂 适应症：晚期实体瘤 BAY 2862789口服溶液由拜耳与德国癌症研究中心（DKFZ）合作开发，为小分子DGKα抑制剂，目前在国际范围内处于1期首次人体研究阶段，拟开发治疗实体瘤。 甘油二酯激酶（DGKs）家族被认为是T细胞和NK细胞发育、分化和功能的生理调节剂，在多种细胞信号传导通路中起着重要的调节作用。DGKα和DGKζ均是DGKs主要的亚型，二者在T细胞中的上调均会导致T细胞沉默。 研究表明，DGKα在几种难治性肿瘤细胞中高表达，包括黑色素瘤、肝细胞癌、胶质母细胞瘤等，它能减缓细胞凋亡、促进细胞增殖。除癌细胞外，DGKα在T细胞中也非常丰富，并诱导T细胞沉默，这是晚期癌症逃过免疫作用的主要机制。因此，DGKα特异性抑制剂治疗癌症有望发挥抑制癌细胞增殖、同时激活T细胞功能的双重抗癌作用。此外，抑制DGKα可协同增强PD-1/L1的抗癌作用，为难治性癌症提供了一种有希望的新治疗策略。 值得一提的是，拜耳与德国癌症研究中心（DKFZ）还合作开发了一款DGKζ抑制剂BAY 2965501，该产品已经于今年4月在中国获批临床。研究表明，联合抑制/沉默DGKα和DGKζ可协同刺激黑色素瘤细胞凋亡和T细胞中白细胞介素-2的产生，二者有望产生协同抗癌作用。 BAY 3018250：抗a2AP的蛋白质药物 适应症：急性缺血性脑卒中 血栓性血管闭塞是缺血性卒中的主要原因。α2-抗纤溶酶（a2AP）是一种纤溶酶抑制剂，为丝氨酸蛋白酶抑制剂家族的一员，与缺血性卒中、组织纤溶酶原激活剂（rt-PA）治疗失败的风险增加有关。抗a2AP治疗可显著减少血栓栓塞性卒中后微血管血栓形成、缺血性脑损伤、脑肿胀、脑出血和死亡，这些研究提示暂时失活a2AP可能对缺血性脑卒中具有治疗价值。 BAY 3018250是拜耳心血管疾病研发管线中的一员，为抗a2AP的蛋白质类药物，拟开发治疗急性缺血性卒中和肺栓塞。该产品在国际范围内目前正处于治疗深静脉血栓（DVT）的2期临床研究阶段。DVT会导致严重的健康问题，包括血凝块卡在肺部，阻碍血液流向肺部等。BAY3018250可以通过溶解血凝块起到治疗作用。 本次BAY 3018250在中国获批临床，针对适应症为急性缺血性脑卒中。这意味着该产品即将在中国开展针对这种新适应症的临床研究。 参考资料： [1]中国国家药监局药品审评中心（CDE）官网. Retrieved June 20，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]拜耳研发管线. . Retrieved Apr 30，2024, From https://www.bayer.com/sites/default/files/ph-rd-pipeline-2024-05-final-1.pdf [3]Sakane F, et al. (2021)The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis. Cancers (Basel). doi: 10.3390/cancers13205190. [4]Reed GL, Houng AK, Singh S, Wang D. （2017）α2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke. Semin Thromb Hemost. doi: 10.1055/s-0036-1585077. 内容来源于网络，如有侵权，请联系删除。

2月6日，中国国家药监局药品审评中心（CDE）官网公示，拜耳（Bayer）公司申报了BAY 2965501片的临床试验申请并获得受理。公开资料显示，这是一款新型肿瘤免疫疗法，为一款DGKζ抑制剂。 公开资料显示，DGKζ是磷酸二酰甘油激酶家族的一员，其对多种细胞信号传导通路起着重要的调节作用。研究发现，DGKζ在多种肿瘤中的表达水平增高，与肿瘤的发病、发展和预后相关，因此DGKζ被认为是一个新的肿瘤免疫治疗靶点。 据文献报道，DGKζ抑制剂通过阻断DGKζ的活性，从而阻止肿瘤细胞的增殖和存活。具体来说，DGKζ可以催化生物膜上的二酰基甘油（DAG）转化为磷脂酸来下调T细胞的活化，从而作为一个不依赖配体的细胞内免疫检查点。抑制DGKζ已被证明可以增强T细胞对次优肿瘤抗原的启动，并以TCR参与依赖的方式克服肿瘤微环境中的多种免疫抑制机制。 根据拜耳公开资料，BAY 2965501由拜耳公司与德国癌症研究中心（DKFZ）合作开发，为一种高选择性的口服DGKζ抑制剂。在临床前研究中，该化合物可以增加自然杀伤细胞和T细胞介导的肿瘤细胞杀伤，增强白细胞介素2诱导的自然杀伤细胞活化，且能够克服T细胞中转化生长因子β、前列腺素E2和腺苷信号传递的抑制信号。体外研究还表明，与抗PD-1抗体单药相比，BAY 2965501联合抗PD-1抗体可降低肿瘤生长速度。临床前毒理学研究显示该产品只有低级别的胃肠道效应，表明临床可耐受。这项临床前研究数据此前已经在2023年美国癌症研究协会（AACR）年会上发表。 根据ClinicalTrials官网，拜耳于2024年初刚刚在美国、日本等地启动BAY 2965501的首次人体1期临床研究，评估该药单药或与抗PD-1单抗联用治疗晚期实体瘤的安全性、耐受性和初步有效性等。这项研究的重点是某些类型的皮肤癌、肾癌、胃癌和肺癌。 参考资料： [1]中国国家药监局药品审评中心（CDE）官网.Retrieved Feb 6，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]Bayer to present latest research across its advancing oncology portfolio at AACR 2023 Annual Meeting .Retrieved Apr 11 , 2023, From https://www.bayer.com/media/en-us/bayer-to-present-latest-research-across-its-advancing-oncology-portfolio-at-aacr-2023-annual-meeting/ 内容来源于网络，如有侵权，请联系删除。