PAD4

JBI-802 is a first-in-class, orally administered, inhibitor of CoREST complex JBI-778 is a potential best-in-class, orally administered, brain penetrant inhibitor of PRMT5 MORRISVILLE, N.C., Oct. 25, 2024 /PRNewswire/ -- Jubilant Therapeutics Inc., a biopharmaceutical company advancing small molecule precision therapeutics to address unmet medical needs in oncology and autoimmune diseases, today announced the dosing of first patients in global clinical trials involving two pipeline programs: Phase I/II clinical trial of JBI-802 in heme-oncology and Phase I clinical trial for JBI-778 in solid tumors. "We are excited to take this significant step forward in our mission to transform the lives of patients through the development of easy to administer precision oral medicines with enhanced safety and therapeutic efficacy," said Hari S Bhartia, Chairman, Jubilant Therapeutics Inc. JBI-802 is a first-in-class, orally administered, small-molecule dual inhibitor of LSD1 (Lysine-specific histone demethylase 1A) and HDAC6 (Histone deacetylase 6) within the CoREST (Co-repressor of Repressor Element-1 Silencing Transcription) complex. In the earlier Phase I study conducted in advanced solid tumor patients, JBI-802 showed a dose-proportional increase in exposure across cohorts and a strong correlation between exposure and the on-target effect of platelet decrease. There were no reports of Dysgeusia and Anemia, typical adverse events seen with LSD1only inhibitors. The Phase I trial also showed anti-tumor activity in Non-Small Cell Lung Cancer (NSCLC) patients including a confirmed partial response. Overall, the study results provided human proof-of-principle for expanding the development of JBI-802 in Essential Thrombocythemia and Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPN) with thrombocytosis. Essential Thrombocythemia is a chronic disease of excessive platelets with over 100,000 patients in the United States for whom the primary treatment is hydroxyurea, a therapy that poses severe limitations for patients in terms of both safety and efficacy. The second clinical trial is to assess both safety and the recommended Phase II dose for JBI-778, an oral brain-penetrant inhibitor of PRMT5 (Protein arginine N-methyltransferase 5) in mEGFR Tyrosine Kinase Inhibitor (TKI) resistant NSCLC, IDH+ high-grade glioma (HGG) and Adenoid Cystic Carcinoma (ACC). PRMT5, although a proven pathway for multiple cancers, has produced mixed results in terms of drug development due to safety concerns surrounding SAM competitive approach to PRMT5 inhibition and patient segment limitations of MTAP null tumor-focused approach PRMT5 inhibition. JBI-778 is a unique substrate competitive brain penetrant PRMT5 inhibitor that has shown no adverse effects in preclinical setting and can address both MTAP null and wild type tumors as well as brain tumors, catering to a larger patient segment including those with brain metastases. "The two most advanced novel drug candidates at Jubilant Therapeutics Inc. were discovered in-house using our TIBEO (Therapeutic Index and Brain Exposure Optimization) Discovery Engine. It is our unique approach of structure-based drug design to generate novel pharmacophores with improved therapeutic index compared to existing agents. We are excited to advance both JBI-802 and JBI-778 in genetically-defined subsets of patients with select hematological and solid tumor indications with high unmet medical needs. Initial clinical data are expected to read out in 2025," said Syed Kazmi, Chief Executive officer, Jubilant Therapeutics Inc. About JBI-802 JBI-802 is novel, oral, potent and selective dual inhibitor of two epigenetic targets of the CoREST complex: LSD1 and HDAC6. It targets stem cell modulation by inhibiting LSD1 and modulates immune suppression with isoform selective HDAC6 inhibition. Preclinical research has demonstrated its synergistic anti-tumor activity, which is superior compared to either target alone and with a favorable safety profile. JBI-802 is under evaluation in both hematological cancers such as acute myeloid leukemia, myelodysplastic syndrome and other myeloproliferative cancers as well as solid tumors, such as non-small cell lung cancer and small cell lung cancer. About JBI-778 JBI-778 is novel, oral, potent and brain penetrant inhibitor of PRMT5. JBI-778 targets the substrate site and stabilizes SAM bound to PRMT5, providing high biological selectivity and has shown a superior safety profile as seen in animals. Preclinical research has demonstrated significant activity in Tyrokinase-Inhibitor resistant cell lines, brain tumor and NSCLC. JBI-778 is under evaluation in solid tumors such as NSCLC, High Grade Glioma and Adenoid Cystic Carcinoma. About Jubilant Therapeutics Inc. Jubilant Therapeutics Inc. is a clinical stage biopharmaceutical company developing precision oral medicines with enhanced therapeutic index to address unmet medical needs in oncology and autoimmune diseases for genetically defined patients. Its advanced structure-based discovery engine, TIBEO (Therapeutic Index and Brain Exposure Optimization), has been validated through successful partnerships. The Company's clinical pipeline consists of a first-in-class dual CoREST modifier, JBI-802, currently in a Phase I/II clinical trial in multiple tumors and a novel brain-penetrant modulator of PRMT5, currently in Phase I clinical trial. Additional pre-clinical programs include brain penetrant and gut restrictive PDL1 inhibitors, as well as PAD4 inhibitors for oncology and inflammatory indications. The Company is headquartered in Pennsylvania and guided by globally renowned scientific advisors. For more information, please visit or follow us on Twitter @JubilantTx and LinkedIn. Logo: SOURCE Jubilant Therapeutics Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

C4X Discovery Holdings Limited PatientSeek identifies a genetic signature that separates a4b7 integrin therapy responder and non-responder populations in inflammatory bowel disease Progresses precision method for patient selection - the right patient for the right medicine 16 September 2024 - C4X Discovery Holdings Limited (“C4XD”), the immuno-inflammation therapeutics company, today announces the discovery of a genetic response signature that identifies responder and non-responder groups amongst patients with ulcerative colitis, an inflammatory bowel disease (“IBD”), following treatment with the a4b7 integrin antibody vedolizumab. Clive Dix, Executive Chairman of C4XD, said: “Until now, no currently available biomarker has been robustly validated in predicting response to individual advanced therapies to guide clinical practice for IBD, leaving many patients underserved. Utilising our PatientSeek platform we have now identified a genetic response signature that separates responders and non-responders to vedolizumab, the a4b7 antibody therapy for ulcerative colitis. This is an incredibly exciting first for immuno-inflammation precision medicine as these data clearly demonstrate the power of PatientSeek’s analytical capabilities for patient selection based solely on genetic data. We will utilise the data’s predictive power for use in future clinical trials for our own small molecule a4b7 integrin programme and we will take this precision approach to progress our growing pipeline, including our TNFa and PAD4 programmes.” Precision medicine has the goal of identifying the right therapy that will be effective in the right patient at the right point in their disease progression. Championed originally in oncology, this approach is now gaining much attention from the scientific and medical community in the immuno-inflammation space. C4XD’s PatientSeek platform applies a unique mathematical approach to analyse datasets containing patients’ genetic records together with other information such as electronic health records. The resulting data can provide a statistically significant predictive ‘genetic response signature’. Genetic signatures, compared to clinical and omic biomarkers, have the significant advantage of not changing over time and are independent of disease progression. C4XD has accessed and analysed a large dataset which contains patients who have received vedolizumab and initial data have clearly demonstrated that, for the first time, responders and non-responders can be separated according to a genetic signature based on genetic variation in the non-coding regions of DNA. PatientSeek’s ability to identify genetic response signatures should lead to smaller, less expensive and more successful clinical trials targeting the right patient at the right time for the right drug. Contacts C4X Discovery HoldingsMo Noonan, Communications+44 (0)787 6444977 C4X Discovery Media – ICR ConsiliumMary-Jane Elliott, Chris Gardner, Angela Gray+44 (0)203 709 5700 Notes to Editors: About C4X DiscoveryC4X Discovery (C4XD) is a pioneering Drug Discovery company, combining scientific expertise with cutting-edge technologies to efficiently deliver world-leading medicines. We have a highly valuable and differentiated approach to Drug Discovery through our enhanced molecular design and patient stratification capabilities, generating small molecule drug candidates across multiple disease indications focused on immuno-inflammation. We are advancing our internal portfolio which ranges from early-stage target opportunities to late-stage Drug Discovery programmes and we have two commercially partnered programmes with Sanofi and AstraZeneca, and one clinical stage candidate which has been acquired by Indivior. For more information visit us at www.c4xdiscovery.com or follow us on twitter @C4XDiscovery.

引言 免疫系统需要控制免疫反应以在抑制感染和预防过量炎症对组织的损伤之间保持平衡【1】。作为循环系统中数量最多的免疫细胞类型，中性粒细胞对于一大部分的病原体具有重要的防御作用，同时为了维持免疫反应平衡，中性粒细胞的抗微生物反应必须被准确调控【2,3】。中性粒细胞被促炎信号激活，并依据表面受体组成和内源蛋白的不同开启不同的效应作用。比如，中性粒细胞吞噬微生物后会产生活性氧、发生脱颗粒或者释放NETs（Neutrophil extracellular traps，中性粒细胞胞外杀菌网络）【4】。NETs是一种细胞外结构，主要由DNA、颗粒蛋白、核蛋白等组成，这些物质组装在去凝集的染色质支架上。NETs能够包裹、中和并杀死微生物，包括真菌、细菌和寄生虫等。不过其它一些刺激信号如晶体和免疫复合物等也能诱导NETs的形成。值得注意的是，在一些自身免疫疾病中，中性粒细胞会被活化并释放NETs，如类风湿性关节炎（rheumatoid arthritis, RA）和系统性红斑狼疮（systemic lupus erythematosus, SLE）等【5,6】。NETs含有许多分子能够被免疫细胞的受体识别。例如，巨噬细胞和树突细胞吞噬NETs后，其胞内的cGAS（cyclic GMP-AMP synthase）能够识别NETs中的DNA骨架。另外，细胞表面受体TLR9也能够识别NET-DNA。一些研究也发现，NETs能够激活一些免疫细胞的膜受体，但是其作用机制还未研究清楚。 近日，来自英国埃克塞特大学的Gordon D. Brown团队在Nature发表了文章Recognition and control of neutrophil extracellular trap formation by MICL，他们发现受体MICL（myeloid inhibitory C-type lectin-like）缺失能够通过促进中性粒细胞NETs的形成进而促进类风湿性关节炎的进展。 研究人员利用Micl-/-小鼠构建了类风湿性关节炎的CAIA（collagen antibody-induced arthritis）模型，Micl敲除小鼠表现出了增强以及非缓解的关节炎表型。研究人员取野生小鼠疾病进展最明显的、造模第7天的小鼠关节组织进行分析。通过流式细胞检测发现，关节组织中浸润的中性粒细胞在Micl-/-小鼠中特异性增多。关节组织中其他细胞类型的数量没有发生改变，另外，骨髓以及血液中中性粒细胞的数量也没有发生改变。这一结果在RA的另一个K/BxN模型中也得到了类似的结果。 为了探究中性粒细胞在RA进展中的作用以及和MICL的关系，研究人员在CAIA模型中应用了anti-Ly6G以清除循环中性粒细胞，发现野生小鼠和Micl-/-小鼠的疾病进展下降到了同一层次，说明Micl敲除引起的RA进展是通过中性粒细胞来实现的。进一步的，研究人员分别从WT以及Micl-/-小鼠的骨髓中分离了中性粒细胞，然后在CAIA模型的第7天将这些中性粒细胞分别移植到RA模型小鼠中，研究人员观察到来自Micl-/-小鼠的中性粒细胞加重了关节炎症。这一结果更加证明了Micl-/-小鼠中中性粒细胞在RA进展中发挥了关键作用。 接下来，研究人员发现Micl-/-小鼠来源的中性粒细胞在尿酸钠（monosodium urate, MSU）或者A.fumigatus hyphae刺激下ROS水平提高，由于NET的形成与ROS水平相关，研究人员检测发现Micl缺失导致NET形成也相应增强。NADPH氧化酶抑制剂DPI（diphenyleneiodonium chloride）抑制了NET的形成，说明Micl缺失引起的NET形成依赖于NADPH氧化酶的活性。除了ROS之外，NET的形成也需要组蛋白的瓜氨酸化修饰，这种修饰依赖于PAD4蛋白的功能。而PAD4抑制剂能够在体外实验中抑制NET的形成，体内实验也显示PAD4抑制剂导致Micl-/-小鼠关节中NET的数量明显减少，但并没有影响关节中中性粒细胞的浸润。 研究人员之前的研究已经发现MICL的单克隆抗体能够加剧野生小鼠CAIA模型的病理程度，类似于Micl-/-小鼠的表型。体外实验也显示，MICL的单抗在中性粒细胞中引起了MSU介导的ROS产生增加。另外，MICL单抗对CAIA模型小鼠病理的刺激作用能够被PAD4抑制剂所抑制。这在RA的其他动物模型如CIA（collagen-induced arthritis）中得到了验证。研究人员进一步检测发现，人体MICL抗体能够促进中性粒细胞的活化以及NET的形成。来自RA病人的血清同样能够促进ROS的产生，说明RA病人血清中含有的MICL抗体抑制了MICL的功能，促进了中性粒细胞的活化以及NET的形成。 于是，研究人员进一步检测了RA病人血清中MICL抗体水平和RA病理程度的关系，发现RA病人中MICL抗体的整体水平比对照组高。另外，在与中性粒细胞NET相关的疾病如系统性红斑狼疮和COVID-19的病人血清中，MICL的抗体水平也同样比正常人高，说明MICL被抑制后，中性粒细胞的活化与这些免疫疾病的进展密切相关。 最后，研究人员发现MICL是一个PRR受体，能够识别NET中的基因组DNA，且这种识别作用能够被MICL的抗体打断。 模式图（Credit: Nature） 综上，本研究发现受体MICL能够调控自免疫疾病中中性粒细胞的活化，一些自免疫疾病病人体内产生过多的MICL抗体，抑制了MICL的功能，导致中性粒细胞持续活化，打破了机体的免疫平衡。本研究确认了自身免疫疾病中免疫平衡维持的关键分子机制，为相关疾病的治疗提供了新的思路和靶点。 参考文献 1. Kruger, P. et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathog. 11, e1004651 (2015). 2. Mantovani, A., Cassatella, M. A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011). 3. Wigerblad, G. & Kaplan, M. J. Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases. Nat. Rev. Immunol. 23, 274–288 (2023). 4. Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol. 18, 134–147 (2018). 5. Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl Med. 5, 178ra40 (2013). 6. Villanueva, E. et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538–552 (2011). https://doi.org/10.1038/s41586-024-07820-3 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述