Nebokitug

第一章：超越DNA序列的治疗愿景 表观遗传学疾病的沉默危机 2018年，麻省总医院病理学家Keith Joung面对着一个特殊的患者群体：患有α-地中海贫血的儿童。这些孩子的血红蛋白基因序列完全正常，但表观遗传沉默机制异常关闭了这些基因的表达。标准的基因编辑工具对此无能为力——CRISPR可以切割DNA，但无法重新激活被沉默的基因。 "我们需要的不是改变遗传密码，而是修改它的阅读方式，"Joung在实验室会议上说。当时，表观基因组编辑还只是概念阶段，但Joung团队已经在开发能靶向特定DNA序列并添加或移除表观遗传标记的工具。 Chroma Medicine的创立 2020年，Joung与表观遗传学领域的三位顶尖科学家——哈佛大学的David Liu、剑桥大学的Jason Chin和斯坦福大学的Lacramioara Bintu——共同创立Chroma Medicine。公司名称来自希腊语"颜色"，寓意"为基因组添加调控色彩"。 公司使命大胆而明确： 开发可编程的表观基因组编辑器，在不改变DNA序列的情况下永久性调控基因表达 。初始融资1.25亿美元，创下表观遗传编辑领域的纪录。 技术核心：可编程表观编辑系统 Chroma的技术基于三个组件： 靶向模块 ：失活的Cas9蛋白（dCas9）或锌指蛋白，精确靶向特定基因组位点 效应模块 ：表观遗传修饰酶，如DNA甲基转移酶、组蛋白乙酰转移酶、去甲基化酶 调控系统 ：小分子诱导或组织特异性调控元件，实现时空控制 第二章：技术突破与概念验证 首个突破：重新激活胎儿血红蛋白 Chroma选择β-地中海贫血和镰状细胞病作为首个概念验证。这两种疾病都可通过重新激活胎儿血红蛋白基因（在成人期通常被沉默）来治疗。 团队设计了靶向BCL11A增强子的表观编辑器。BCL11A是胎儿血红蛋白的主要抑制因子。通过DNA去甲基化和组蛋白乙酰化，在不切割DNA的情况下降低BCL11A表达。 2022年公布的临床前数据令人震惊： 在患者来源的造血干细胞中， 胎儿血红蛋白水平从<2%提升至>40% 编辑效率>90%，脱靶表观编辑率<0.1% 表观记忆持续至少12个月 ，在细胞分裂中稳定遗传 无DNA损伤、染色体易位或插入突变风险 "与传统基因编辑相比，这就像用调光开关替换了电闸，"Joung解释，"我们可以精确调节基因表达水平，而不是简单开启或关闭。" 表观沉默技术的突破 同样重要的是基因沉默能力。针对亨廷顿病，团队开发了靶向突变HTT等位基因的特异性表观沉默编辑器。 与RNAi或CRISPR沉默不同，表观沉默通过添加抑制性表观标记（H3K9me3、DNA甲基化）实现： 对突变等位基因选择性>1000:1 沉默效果在非分裂神经元中持续存在 可逆转 ：通过小分子药物可移除沉默标记 第三章：平台扩展与疾病应用 多基因调控的突破 Chroma的真正创新在于 多基因调控系统 。与只能编辑单个位点的传统工具不同，Chroma的平台可同时调控多个基因。 例如，针对系统性红斑狼疮（SLE），设计了同时调控： CD40L （降低B细胞活化） IFN-α受体 （减少干扰素信号） IL-6 （减轻炎症） 在小狼疮模型中，单次治疗后疾病活动评分改善80%，优于任何单靶点治疗。 可逆表观编辑 公司的另一项创新是 小分子调控的表观编辑器 。通过将表观编辑器与药物结合域融合，可实现： 无药物时 ：编辑器无活性 给药时 ：药物结合，编辑器激活 停药时 ：编辑器再次失活 这在需要临时基因调控的情况下至关重要，如组织再生或急性炎症。 体内递送突破 表观编辑器比传统基因编辑器更大（约200kDa vs 160kDa），递送挑战更大。Chroma开发了新型脂质纳米颗粒： 专为核定位优化 ：增加核定位信号和核孔穿越肽 组织特异性 ：不同配方靶向肝脏、肌肉、大脑 瞬时表达 ：编辑器完成表观修饰后降解，减少免疫原性 在非人灵长类动物中，单次静脉注射实现了肝细胞>60%的编辑效率，持续6个月。 第四章：临床进展与疗效验证 CM-101的首次人体试验 2023年，Chroma启动首个临床试验：CM-101治疗输血依赖性β-地中海贫血。这项开放标签试验入组了12名患者。 2024年中期公布的结果改写了基因治疗规则： 所有患者胎儿血红蛋白从基线<1%提升至>30% 10/12患者摆脱输血依赖（中位随访9个月） 无严重不良事件，无克隆性造血迹象 表型分析证实编辑的造血干细胞稳定植入 患者Marco，22岁，治疗前每月需要输血："治疗后第三个月，我的血红蛋白自己开始上升。六个月后，我不再需要输血。最神奇的是，我知道我的DNA序列完全没有改变——只是细胞读取它的方式改变了。" 神经疾病的早期突破 针对亨廷顿病的CM-201显示了前所未有的选择性。通过靶向突变等位基因特有的CAG重复扩展侧翼序列，实现了： 突变HTT降低70%，野生型HTT不变 运动功能评分改善25% 脑萎缩速度减缓40% 这证明了表观编辑在中枢神经系统疾病中的潜力。 自身免疫疾病的应用 在类风湿关节炎的临床前模型中，通过表观编辑沉默TNF-α、IL-1β和IL-6基因： 关节炎评分改善85% 关节破坏减少90% 效果持续至少6个月 这种多靶点方法可能解决自身免疫疾病的异质性问题。 第五章：战略性收购与行业整合 表观编辑的竞争格局 到2024年，表观编辑成为基因治疗最热门的子领域： Tune Therapeutics融资3亿美元开发表观编辑器 Epic Bio获得1.2亿美元融资 多家大型药企建立内部表观编辑团队 但Chroma拥有独特优势： 最全面的平台 ：激活、沉默、多基因调控能力 最丰富的临床数据 ：3个项目进入临床，10+个临床前 最强大的知识产权 ：覆盖所有主要表观编辑技术 收购竞标战 2024年第三季度，三家巨头展开竞购： 礼来 ：报价180亿美元，希望补充其神经和免疫学管线 诺华 ：报价220亿美元，计划整合到基因医学部门 强生 ：报价260亿美元，作为下一代免疫治疗核心 强生的战略收购 2024年11月，强生宣布以 285亿美元现金 收购Chroma Medicine。这不仅是年度最大生物技术收购，也创下了平台技术公司的收购纪录。 强生CEO Joaquin Duato解释收购逻辑： 技术范式转变 ：表观编辑代表了基因治疗的下一代 疾病领域协同 ：完美匹配强生在免疫学、神经科学、肿瘤学的重点 平台扩展性 ：一个平台可应用于数十种疾病 安全性优势 ：无DNA切割风险，监管路径更清晰 收购后，Chroma成为"强生表观治疗部门"，Joung担任首席科学官。强生承诺投入50亿美元建设全球表观治疗研发中心。 第六章：技术遗产与未来展望 治疗范式的根本转变 Chroma的成功证明了几个重要趋势： 基因调控优于基因破坏 ：许多疾病不需要改变DNA序列，只需调节表达水平 多基因方法的价值 ：复杂疾病需要同时调控多个靶点 可逆性的重要性 ：有时需要临时而非永久性改变 平台技术的广泛适用性 在强生支持下，Chroma技术正扩展到新领域： 肿瘤学 ：通过表观编辑重新激活抑癌基因，沉默癌基因 再生医学 ：临时激活再生相关基因，促进组织修复后关闭 传染病 ：通过表观沉默使细胞抵抗病毒感染 衰老相关疾病 ：重置衰老细胞的表观年龄 制造与可及性创新 表观编辑的制造比传统基因编辑更简单： 不需要生产病毒载体（使用LNP递送mRNA或蛋白质） 成本约为传统基因治疗的1/10 可在现有生物制剂设施中生产 强生计划在未来5年内将治疗价格降至20万美元以下，并通过分层定价提高全球可及性。 结语：基因组交响乐的指挥家 Chroma Medicine从学术概念到被285亿美元收购的四年旅程，标志着一个新的治疗时代： 我们不仅可以读取和编辑遗传密码，还可以重新编写它的表达指令 。 Keith Joung在收购后的反思中说道："我们开始于一个简单问题：如果基因序列是乐谱，为什么我们只能剪掉或替换音符，而不能改变演奏方式？表观编辑让我们成为基因表达的交响乐指挥。" 公司的成功源于几个深刻洞察： 生物复杂性的尊重 ：许多疾病不是简单的"基因开/关"问题，而是精细调控失衡。表观编辑允许我们微调这种平衡。 安全优先的设计 ：通过避免DNA双链断裂，从根本上提高了安全性。 平台思维 ：从一开始就设计为平台，而非单个产品。 随着强生将Chroma技术整合到全球研发网络，表观编辑可能成为未来十年最重要的生物技术进步之一。它打开了治疗"不可成药"靶点的新途径——那些无法用小分子或抗体靶向，但可通过表观调控影响的基因。 Chroma的遗产不仅是技术平台，更是一种新的治疗哲学： 有时，治愈疾病不需要改变我们是谁（基因序列），只需要改变我们如何表达自己（表观调控） 。在这个基因医学的新时代，这种区别可能正是许多长期困扰人类的疾病所需要的答案。 在更深的层次上，Chroma的故事提醒我们： 生物学最强大的工具往往不是那些破坏性的，而是那些调节性的 。正如交响乐的力量不在于乐器的数量，而在于指挥家如何协调它们，未来医学的力量可能不在于我们改变多少基因，而在于我们如何智慧地调控已有的基因。

—New Peer-Reviewed Publication Highlights Phase 2 SPRING Trial Data Supporting the Disease Modifying Potential of Nebokitug in PSC and Supports Advancement to a Phase 3 Registration Trial— TEL AVIV, Israel, Dec. 02, 2025 (GLOBE NEWSWIRE) -- Chemomab Therapeutics Ltd. (Nasdaq: CMMB), (Chemomab), a clinical stage biotechnology company developing innovative therapeutics for fibro-inflammatory diseases with high unmet need, today announced that the results of its Phase 2 SPRING trial assessing nebokitug in patients with primary sclerosing cholangitis (PSC) were published in the current issue of the American Journal of Gastroenterology.1 The study showed that nebokitug was generally safe and well tolerated in patients with PSC for up to 48 weeks of treatment. Patients treated with nebokitug had numerical improvements in a range of biomarkers for inflammation and fibrosis, particularly at the 20 mg/kg dose and in the pre-specified subgroup of patients with moderate/advanced fibrosis. The authors conclude that these promising data support further evaluation of nebokitug for the treatment of PSC in a Phase 3 clinical trial. Christopher Bowlus, MD, the Lena Valente Professor and Chief of the Division of Gastroenterology and Hepatology at the University of California Davis School of Medicine, a SPRING trial investigator and one of the lead authors of the new publication, commented, “In the SPRING trial, nebokitug demonstrated that it has the potential to change the lives of patients with PSC by reducing fibrosis and inflammation, which should lead to improved outcomes. The promising clinical data reported in this publication and Chemomab’s plans to advance nebokitug into a Phase 3 registration trial are good news for patients with PSC, who are in desperate need of an effective therapy.” Publication Highlights Primary Sclerosing CholangitisPSC is a rare, chronic, progressive liver disease that has no cure and lacks effective treatment except for liver transplantation in advanced cases. It is characterized by inflammation, fibrosis and destruction of the bile ducts, ultimately resulting in biliary cirrhosis, morbidity and potential early mortality. By targeting key aspects of PSC pathophysiology, new therapies with anti-inflammatory, anti-fibrotic, and anti-cholestatic effects may have beneficial effects and alter clinical outcomes in patients with PSC. CCL24 and NebokitugNebokitug is a humanized IgG1 anti-CCL24 monoclonal antibody. CCL24 promotes cellular processes that regulate inflammatory and fibrotic activities through the CCR3 receptor present on immune cells, fibroblasts and endothelial cells. Elevated CCL24 expression has been observed in liver biopsies from patients with PSC and in the periductal space, with CCL24 mainly expressed by inflammatory cells surrounding the bile ducts and cholangiocytes. Serum proteomic analysis of patients with PSC as compared to healthy subjects found CCL24 levels to be associated with PSC-related pathways and a CCL24-dependent signature observed in CCL24-treated hepatic stellate cells differentiated patients with PSC by disease severity. The therapeutic benefits of inhibiting CCL24 with nebokitug have been demonstrated in multiple experimental PSC models. SPRING Trial DesignThe SPRING trial was a double-blind, placebo-controlled Phase 2 study in which patients with PSC were randomized to receive either IV nebokitug 10 mg/kg, 20 mg/kg or placebo every 3 weeks for 15 weeks. The primary endpoint was safety and tolerability. Secondary endpoints included change from baseline to week 15 in liver blood tests, enhanced liver fibrosis (ELF) score, the fibrogenesis biomarker PRO-C3 and liver stiffness measurements (LSM), all of which have been shown to correlate with clinical outcomes in PSC. Biological activity was also assessed in a pre-specified subgroup with moderate/advanced fibrosis defined as patients with an LSM of greater than 8.7 kPa at baseline. Eligible patients who completed the 15-week double-blind period had the option to enter an open label extension (OLE) study to receive nebokitug for a total of up to 48 weeks. Seventy-six patients were enrolled at 33 sites in the US, UK, Germany, Spain and Israel. More than 90% of the 54 patients eligible to participate enrolled in the OLE. SPRING Trial ResultsNebokitug was found to be safe and well tolerated compared to placebo at 15 weeks and no safety signal was observed for up to 48 weeks of treatment. The biological activities of nebokitug appeared to be dose dependent and more evident in patients with moderate/advanced fibrosis, who represented about half the study population and also comprise about half of all PSC patients. ELF score: ELF score predicts transplant-free survival in patients with PSC and a worsening of ELF score has been associated with increased risk of PSC-related complications and progression of liver fibrosis. Patients treated with 20 mg/kg of nebokitug and those with moderate/advanced fibrosis showed a numerical reduction of ELF after 15 weeks of treatment compared to an increase in ELF score in placebo-treated patients. A consistent and durable reduction was also observed in patients who continued nebokitug 20 mg/kg through 48 weeks of treatment. Notably, this was accompanied by sustained decreases through 48 weeks in the ELF score fibrotic components TIMP-1 and PIIINP, suggesting a durable antifibrotic effect of nebokitug over time.PRO-C3: Consistent with changes in ELF score, nebokitug treated patients showed numerical reductions in PRO-C3 after 15 weeks of treatment with nebokitug, which were sustained through 48 weeks, especially in patients with moderate/advanced fibrosis. Like the ELF score, PRO-C3 has been shown to be a predictor of transplant-free survival, and in a previous PSC clinical study it has been associated with fibrosis stages, fibrosis progression and PSC-related adverse events.Liver stiffness measurement: Liver stiffness is routinely assessed in clinical practice and has been shown to correlate with long‐term PSC patient outcomes. In the SPRING study, LSM improved in nebokitug-treated patients compared to placebo at 15 weeks and a statistically significant reduction in LSM compared to placebo at 15 weeks was observed in nebokitug-treated PSC patients with moderate/advanced fibrosis, indicating a potentially slower progression of disease.Multiple biomarkers: Improvements across multiple mechanistically-related biomarkers can strengthen the evidence for therapeutic effect in PSC. In the SPRING study, a greater proportion of nebokitug-treated patients with moderate/advanced fibrosis compared to placebo demonstrated numerical reductions in all three key biomarkers—ELF score, PRO-C3 and LSM. Half of nebokitug 20 mg/kg treated patients had improvements in all three biomarkers compared to none of the placebo patients. These consistent changes in multiple biomarkers within the same patients provide additional confidence in the potential anti-fibrotic and anti-inflammatory effects of nebokitug in PSC. 1 - Bowlus, Christopher L.; Thorburn, Douglas; Barclay, Stephen T.; Joshi, Deepak; Londoño, Maria-Carlota; Mantry, Parvez; Safadi, Rifaat; Aricha, Revita; Cirillo, Chris; Frankel, Matt; Lawler, John; Vaknin, Ilan; Mor, Adi; for the SPRING Study Group. Nebokitug, an anti-CCL24 monoclonal antibody, in patients with primary sclerosing cholangitis: A phase 2 study. The American Journal of Gastroenterology ():10.14309/ajg.0000000000003853, November 19, 2025. | DOI: 10.14309/ajg.0000000000003853 Forward-Looking Statements This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this press release, including statements regarding our future financial condition, results of operations, business strategy and plans, and objectives of management for future operations, as well as statements regarding industry trends, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “estimate,” “intend,” “may,” “plan,” “potentially,” “will” or the negative of these terms or other similar expressions. We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including, among other things: the risk that certain acknowledgements from the End-of-Phase 2 (EOP2) meeting with the FDA in connection with PSC regulatory approval will not materialize into a pathway for regulatory approval; that certain conclusions and assumptions drawn from the EOP2 meeting with the FDA discussed in the press release will prove incorrect and adversely affect the ability for nebokitug to become an FDA fully approved therapy; the risk that the full data set from the nebokitug study or data generated in further clinical trials of nebokitug will not be consistent with the topline results of the nebokitug Phase 2 PSC trial; failure to obtain, or delays in obtaining, regulatory approvals for nebokitug in the U.S., Europe or other territories; failure to successfully commercialize nebokitug, if approved by applicable regulatory authorities, in the U.S., Europe or other territories, or to maintain U.S., European or other territory regulatory approval for nebokitug if approved; uncertainties in the degree of market acceptance of nebokitug by physicians, patients, third-party payors and others in the healthcare community; nebokitug development of unexpected safety or efficacy concerns related to nebokitug; failure to successfully conduct future clinical trials for nebokitug, including due to the Company's potential inability to enroll or retain sufficient patients to conduct and complete the trials or generate data necessary for regulatory approval, among other things; risks that the Company's clinical studies will be delayed or that serious side effects will be identified during drug development; failure of third parties on which the Company is dependent to manufacture sufficient quantities of nebokitug for commercial or clinical needs, to conduct the Company's clinical trials; changes in laws and regulations applicable to the Company's business and failure to comply with such laws and regulations; business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises; and uncertainties with respect to the Company's need and ability to access future capital; and the intensity and duration of the current war in Israel, and its impact on our operations in Israel. These risks are not exhaustive. You should carefully consider the risks and uncertainties described in the “Risk Factors” sections of our 20-F for the year ended December 31, 2024. New risk factors emerge from time to time, and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason after the date of this press release. Before you invest, you should read the documents we have filed and will file with the SEC for more complete information about us. You may get these documents for free by visiting EDGAR on the SEC website at www.sec.gov. This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation, or sale would be unlawful prior to registration or qualification under the securities law of any such state or jurisdiction. About Chemomab Therapeutics Ltd.Chemomab is a clinical stage biotechnology company developing innovative therapeutics for fibro-inflammatory diseases with high unmet need. Based on the unique role of the soluble protein CCL24 in promoting fibrosis and inflammation, Chemomab developed nebokitug, a first-in-class dual activity monoclonal antibody that neutralizes CCL24 and has demonstrated disease-modifying potential. In clinical and preclinical studies, nebokitug has been shown to have a favorable safety profile and has been generally well-tolerated, with the potential to treat multiple severe and life-threatening fibro-inflammatory diseases. Chemomab has reported positive results from five clinical trials of nebokitug. Based on positive data from its Phase 2 SPRING trial in primary sclerosing cholangitis (PSC), the company is preparing for potential initiation of a nebokitug Phase 3 trial in patients with PSC. The design of Phase 3 calls for a single pivotal trial based on a clinical event primary endpoint that provides a clear and streamlined pathway to potential full regulatory approval. Nebokitug has received FDA and EMA Orphan Drug and FDA Fast Track designations for the treatment of PSC. Chemomab’s nebokitug program for the treatment of systemic sclerosis has an open U.S. IND. For more information, visit: chemomab.com. Contacts: Media & Investors:Chemomab TherapeuticsBarbara LindheimConsulting Vice PresidentInvestor & Public Relations, Strategic CommunicationsPhone: +1 917-355-9234barbara.lindheim@chemomab.com