SYNB-1891

The cGAS-STING signaling pathway is a cytoplasmic DNA sensing pathway that plays a critical role in innate immune responses. Understanding this signaling pathway is extremely important for studying drug targets and treatment strategies. When tumor DNA is sensed by cGAS in the cytoplasm, cGAS catalyses the linkage of nucleotides to form CDNs, which then binds to and activates STING. This process triggers a series of immune responses, including the activation of interferon pathways and mobilization of other important signaling pathways. The activated STING translocates to various locations within the cell, recruiting other key molecules such as TBK1 and IRF3, further activating interferon pathways and other vital immune response pathways. These responses assist the body in resisting the invasion of pathogens such as viruses and tumors. In addition to tumor DNA, STING can also sense cyclic dinucleotide natural ligands produced by bacteria to activate downstream signaling pathways. This reveals the essential role of the cGAS-STING pathway in immune surveillance of the organism. As of now, 87 drugs targeting STING have been discovered, covering 35 different indications. There are 72 organizations involved in the development of these drugs. Clinical trial data shows that there have been 53 clinical trials related to drugs targeting STING. Furthermore, the development of drugs targeting STING has received widespread attention and protection, with 12,480 patent applications related to drugs targeting STING. To support the progress of research on drugs targeting STING, 5,586 papers have been published. This reflects the scientific activity and knowledge accumulation in this field. Key DrugsThe first generation of STING agonists are derivatives of CDNs. However, their range of actions is limited due to their rapid clearance in vivo, poor membrane permeability, and their requirement for administration directly into tumors. In order to address these issues, the focus of research and development for a new generation of STING agonists is to achieve systemic administration, increase drug concentration distribution within tumors, and thus improve the drug treatment window. F-star Therapeutics' SB11285 is a new generation of STING agonists, which can specifically target the hard-to-reach tumor cells and induce the activated immune cells to migrate from the periphery to the tumor lesions. In a phase I clinical trial of treatment for advanced solid tumors with SB11285 either alone or in combination with the PD-L1 antibody Atezolizumab (trade name: Tecentriq), SB11285 demonstrated good tolerability and efficacy. Merck's MSA-2 is a stable type of STING agonist, which binds to STING in a non-covalent dimeric form, inducing it to assume a closed conformation. Efficacy studies showed that MSA-2, administered intratumorally, subcutaneously or orally, demonstrated good tolerability in a mouse model of colorectal cancer and resulted in complete tumor regression in 80% to 100% of the treated mice. Furthermore, MSA-2 only interacts with STING when it forms a dimer, and the acidic conditions of the tumor microenvironment are more conducive to the dimerization of MSA-2. Therefore, despite MSA-2 being administered systemically, it has potential tumor specificity, showing good safety and tolerability. Takeda's TAK-676 is a novel synthetic STING agonist optimized to reduce serum degradation and enhance permeability compared to intratumoral STING agonists. It can be utilized through systemic venous administration. Furthermore, the addition of TAK-676 post-radiation therapy can intensify immune response by increasing STING mediated IFN inhibitor release and further stimulating T-cell mediated anti-tumor immune responses. Ongoing studies are aimed at evaluating the safety and preliminary anti-tumor activity of TAK-676 combined with pembrolizumab post-radiation. Eisai's E7766 is a macrocyclic bridged STING agonist. In a mouse model of hepatic tumors, a single injection of E7766 caused 90% of tumors to regress with no relapses over eight months. Currently, E7766 is undergoing phase I/Ib clinical trials aiming to evaluate its efficacy as a monotherapy in patients with advanced solid tumors and lymphomas. Scripps Research Institute's SR-717 is a non-nucleotide small molecule STING agonist that can be orally or systemically administered. In an aggressive melanoma animal model, SR-717 significantly inhibited the growth and metastasis of tumors and promoted tumor antigen presentation to the immune system, substantially increasing the levels of peritumoral CD8+ T cells and natural killer (NK) cells. GSK's GSK37417, a non-CDN small molecule STING agonist with a diamino-benzimidazole scaffold, is currently in phase I dose-escalation study, examining GSK37417 as a monotherapy or in combination with dostarlimab (trade name: Jemperli) for treating refractory/recurrent solid cancer patients. GSK37417 is administered via an intravenous injection, with the study expected to conclude in 2025. Synlogic's SYNB1891 represents an E.coli strain expressing the dacA protein, which catalyzes the conversion of two ATP molecules into a cyclic AMP dimer, thereby activating STING protein to trigger type I interferon responses and enhance tumor-specific T Cell responses. Roche has partnered with Synlogic to explore the efficacy of its PD-L1 inhibitor atezolizumab in combination with SYNB1891 in treating patients with advanced solid tumors.

近日，Mersana Therapeutics, Inc.宣布，其免疫合成STING-激动剂ADC候选药物XMT-2056的I期临床试验被FDA临床搁置。原因是XMT-2056在剂量爬坡的第一个剂量组中就出现了5级(致死性)严重不良事件(SAE)，目前具体死亡原因仍在调查中。在临床暂停期间，将不会再有患者入组或在试验中给药。 XMT-2056是Mersana公司首个进入临床的免疫合成STING激动剂ADC候选产品，其将STING激动剂作为毒性载荷与HER2抗体进行偶联，实现STING激动剂在肿瘤中的靶向递送。 这一临床试验的搁置，直接导致Mersana股价大跌。事实上，尽管STING激动剂已成为国内外抗肿瘤药物研发的新热点，但是其研发过程充满了曲折。那么当前阶段，STING激动剂研发进展如何呢？ cGAS-STING通路作用机制 环状GMP-AMP合成酶（cGAS）-干扰素基因刺激因子（STING）信号通路是一种胞质DNA传感通路，在先天免疫反应中起着关键作用。当肿瘤来源的DNA被胞质中的DNA感受器——cGAS识别时，cGAS会催化连接两个核苷酸，形成环状二核苷酸（CDNs），随后CDNs作为第二信使与STING结合并将其激活。激活STING后，导致STING从内质网向高尔基体及溶酶体转运，招募TBK1及IRF3，激活I型干扰素通路，以及激活NF-kB及STAT6等多条通路，调动机体的抗病毒及抗肿瘤的免疫反应。另外，STING也可感受细菌产生的环二核苷类天然配体，进而激活下游信号通路。因此，cGAS-STING通路在机体的抗肿瘤和抗病原体免疫监视中起重要作用。 近年来，靶向STING的激动剂成为国内外抗肿瘤药物研发的新热点。不过由于STING激动剂CDNs是一类不稳定的分子，无法在血液中长时间存在，因此，这给基于CDNs来开发合成STING激动剂带来了很大困难。 第一代STING激动剂 第一代进入药物开发的STING激动剂是CDNs。其中，Aduro Biotech的ADU-S100是典型代表。2015年，诺华与Aduro就ADU-S100达成合作协议；不过2019年，由于ADU-S100与诺华的PD-1抗体斯巴达珠单抗（spartalizumab）联用的I期临床数据不乐观，诺华终止了ADU-S100的合作开发，Aduro公司后续也停止了II期临床试验。 MK-1454由默沙东开发，在2018年ESMO年会上公布的Ⅰ期剂量递增研究数据显示，研究者在MK-1454单药治疗组中未观察到完全或部分反应。但在MK-1454与默沙东旗下的PD-1单抗帕博利珠单抗（Pembrolizumab，商品名Keytruda）联合治疗组中，有24%的患者（6/25）表现出持续超过6个月的部分反应。目前，MK-1454正在Ⅱ期临床研究中，旨在评估MK-1454与帕博利珠单抗联合治疗头颈部鳞状细胞癌（HNSCC）的疗效和安全性。 第一代STING激动剂由于是CDNs的衍生物，在体内清除快、膜通透性差、只能瘤内给药，导致作用范围受限。因此，新一代STING激动剂的研发方向便是实现系统给药，提高化合物的肿瘤分布浓度，提升药物治疗窗口。 新一代STING激动剂研发概况 F-star Therapeutics的SB11285是新一代STING激动剂。它能够被特异性地送达难于触达的肿瘤细胞，且可促进被激活的免疫细胞从外周向肿瘤病灶迁移。在与PD-L1抗体阿替利珠单抗（Atezolizumab，商品名：Tecentriq）联用或者单药治疗晚期实体瘤的I期临床试验中，结果显示，SB11285无论是单药治疗还是与阿替利珠单抗联用，均表现出了良好的耐受性。另外，SB11285的活性等级高，在较低剂量下不会过度活跃，并且能够被淋巴细胞摄取，因此不会有太大的器官毒性。 默沙东的MSA-2是一种稳定型STING激动剂，其以非共价二聚体的形式与STING结合，诱导出封闭构象。疗效研究显示，在结直肠癌小鼠模型中，通过瘤内、皮下或口服途径给药，MSA-2耐受性良好，可诱导80%至100%接受治疗的小鼠肿瘤完全消退。另外，由于MSA-2只有在形成二聚体的情况下才能够与STING结合，而肿瘤微环境的酸性条件更有利于MSA-2的二聚化。这意味着，虽然MSA-2是全身性给药，但是具有潜在的肿瘤特异性。也就是说，MSA-2具有较好的安全性和耐受性。 武田的TAK-676是一种新型合成STING激动剂。与瘤内注射STING激动剂相比，TAK-676的最佳设计是降低血清降解并增强渗透性，允许全身性静脉给药。另外，在放疗后加入TAK-676可通过增加STING介导的IFN抑制剂释放来增强免疫应答，并进一步刺激T细胞介导的抗肿瘤免疫反应。目前正在进行的研究旨在探索放疗后TAK-676联合帕博利珠单抗的安全性和初步抗肿瘤活性。 卫材的E7766是一种大环桥联STING激动剂，在肝脏肿瘤小鼠模型中，单次注射E7766可使90%的肿瘤消退，8个月以上无复发。目前，E7766正在进行I/Ib期临床试验，旨在评估E7766单一疗法对晚期实体瘤和淋巴瘤患者的疗效。 Scripps研究所的SR-717是一种可口服或系统性给药的非核苷酸小分子STING激动剂，在侵袭性黑色素瘤动物模型中，SR-717显著抑制了肿瘤生长，阻止了肿瘤转移，诱导肿瘤分子呈现给免疫系统，极大提高了肿瘤周围CD8+ T细胞和自然杀伤（NK）细胞的水平。 GSK的GSK37417是一种含有二聚氨基苯并咪唑支架的非CDN小分子，目前正在进行I期剂量递增研究，在该研究中，GSK37417作为单一疗法或与多司他利单抗（Jemperli）联用治疗复发/难治性实体瘤患者。GSK37417通过静脉注射给药，研究预计在2025年完成。 Synlogic公司的SYNB1891是一种表达dacA蛋白的大肠杆菌，它能将2个ATP分子催化生成环状的AMP二聚体，激活STING蛋白，进而产生1型干扰素反应，并且激发和促进肿瘤特异性T细胞反应。2019年5月，罗氏与Synlogic公司达成合作，以探索其PD-L1抑制剂阿替利珠单抗与SYNB1891联用治疗晚期实体瘤患者的效果。 国内STING激动剂研发布局 在国内进行STING激动剂开发的公司中，成都先导、嘉和生物进度靠前。其中成都先导的HG381是首个在中国获批开展临床试验的STING激动剂，其基于公司特有的DNA编码化合物库（DEL）技术自主研发。临床前研究表明，在结肠癌、肝癌、乳腺癌等多种小鼠肿瘤模型中，HG381可显著抑制肿瘤生长并引起肿瘤消退，同时能够诱导机体产生抗肿瘤免疫记忆，抑制肿瘤的重新生长。在与PD-1抗体联用时，HG381展现出了更加优异的疗效。 嘉和生物的GB492（IMSA-101）最初由ImmuneSensor开发，2020年6月，嘉和生物获得GB492在大中华区的开发权。目前，GB-492正在国内开展I期临床研究，旨在评价GB-492在成年难治性或不适合接受标准治疗的晚期恶性肿瘤受试者中的安全性和初步有效性，并确定GB-492单药治疗以及联合抗PD-1/L1单抗治疗的II期推荐给药剂量。此外，嘉和生物还计划将GB-492与旗下抗PD-1抗体杰洛利单抗（GB-226）联合开发用于治疗实体瘤。 不同于多数大分子免疫检查点抑制剂，STING激动剂是一类具有开创意义的小分子固有免疫激动剂。一方面，其分子量小，可通过系统给药实现较高肿瘤分布；此外，STING激动剂能够克服免疫检查点抑制剂的不足，通过促进瘤内肿瘤特异性CD8+ T细胞的启动和招募，对“冷肿瘤”也有着良好的抗肿瘤效应，弥补了免疫检查点抑制剂的不足。因此，STING激动剂可能是继PD-(L)1抗体后，肿瘤免疫疗法领域的重磅炸弹。开发新型STING激动剂，挖掘其抗肿瘤作用机制，具有十分重要的价值。 参考资料： 1.Mersana therapeutics announces clinical hold on XMT-2056 phase 1 clinical trial; Mersana Therapeutics,Inc. 2.Motwani,M.,et al. DNA sensing by the cGAS-STING pathway in health and disease.Nature Reviews Genetics.doi:10.1038/s41576-019-0151-1. 3.Galon,J.,et al. Approaches to treat immune hot, altered and coldtumours with combination immunotherapies. Nature reviews Drug discovery. DOI:10.1038/s41573-018-0007-y. 4.常佳佳,侯石,闫心林.干扰素基因刺激因子(STING)及其激动剂的研究进展.药学学报,2021,56(7): 1880-1892. 5.《STING激动剂HG381获批临床 成都先导新药研发实力稳步提升》，成都先导，2021-04-12； 6.《嘉和生物宣布GB492临床试验申请获得国家药品监督管理局受理》，嘉和生物，2021-03-12.