Setrusumab

1  引言 NENs治疗现状 神经内分泌肿瘤（NENs）起源于弥漫神经内分泌系统的罕见恶性肿瘤，主要位于胃肠道、胰腺和支气管肺树。其诊断依赖实验室检查、临床检查、影像学和功能研究，组织学和免疫组化是金标准。治疗方法多样，但缺乏预测生物标志物，治疗方案依患者个体情况而定。 DLL3在NENs中的作用 DLL3在多种NENs中过表达，可作为潜在诊断靶点。分子成像研究显示，以DLL3为靶点的免疫PET扫描在检测SCLC和NEPC肿瘤及转移灶方面有潜力。 2  DLL3的结构概述 DLL3的结构 Delta-likeprotein3（DLL3）是结构特殊的DSL家族成员，和其他DSL配体不一样，它主要定位在高尔基体，只有在过表达时才会出现在细胞表面。这种独特的定位方式使其区别于其他配体，影响其与受体的作用模式和信号传导途径。         图1 DLL 和 Notch 受体的结构 DLL3是Notch信号通路的一部分，Notch信号通路是一个复杂的细胞调控途径。在正常细胞中，Notch受体与相邻细胞表面的配体结合，导致正常的细胞过程。而在肿瘤细胞的多种生命活动中Notch信号通路发挥关键作用，DLL3作为该通路的重要组成部分，与肿瘤的发生发展密切相关。  DLL3的氨基酸序列 Extracellular Helical Cytoplasmic 27-492 493-513 514-618 图2 DLL3的氨基酸序列 3  DLL3在癌症中的作用机制和角色 Notch 通路 Notch通路是一种高度保守的细胞信号通路，与恶性转化、细胞增殖、周期停滞和细胞凋亡、上皮到间充质转化以及神经内分泌分化抑制有关。Notch信号通路包含四个受体（Notch1-4）、五个来自DSL家族的配体（DLL1、3、4和Jag1、2）以及非经典配体DLL1同源物（DLK1）。DLL蛋白家族与细胞膜上Notch受体上的EGF重复序列相互作用，触发Notch信号传导。 在经典Notch信号传导中，配体结合导致受体被金属蛋白酶细胞内切割，然后Notch胞内结构域转位到细胞核并调节Notch反应基因的转录。这些基因在驱动肿瘤发生或抑制肿瘤中的特定作用取决于配体、细胞环境和肿瘤环境。 图3 DLL3 在 Notch 信号通路中的作用机制 DLL3是Notch通路的抑制性配体 DLL3作为Notch受体的抑制性配体发挥作用，已被证明与NEC/NET肿瘤发生有关。由于Notch激活与抑制的NE分化有关，因此通过DLL3的Notch沉默和降解似乎促进了各种肿瘤中的NE表型转换。在胸腺细胞中，DLL3对Notch信号的抑制作用有助于增强阳性选择过程。总体而言，DLL3被认为是Notch信号的抑制剂，这使得它成为治疗Notch活性异常相关癌症的重要靶点。 图4 DLL3 在恶性肿瘤中的表达和治疗潜力 4  DLL3 的表达和功能 DLL3 在NEN中的表达 图5 DLL3 在NEN中的表达 DLL3的功能 表1 DLL3 在肿瘤细胞中的分布和功能 DLL3作为Notch受体的抑制性配体，它不能直接结合Notch受体激活信号通路，而是通过顺式作用使Notch信号失活，当以反式形式存在时，它不会结合或激活Notch受体。具体来说，DLL3能够通过细胞内保留机制，阻止Notch和（或）DLL1在细胞表面定位，进而抑制Notch信号传导。 DLL3是转录因子ASCL1的直接下游靶点，而ASCL1与肺神经内分泌细胞的发育相关。这一关系提示DLL3可能和神经内分泌肿瘤的发生存在联系，特别是在肺癌方面。在SCLC中，DLL3过表达可促进肿瘤细胞增殖、迁移和侵袭，通过调节Snail信号通路发挥作用；在其他NENs中，如LCNEC、MTC、宫颈NECs、GEP-NENs、膀胱NENs、NEPC和MCC等，DLL3表达与肿瘤特征和预后相关。在非NENs中，DLL3也有不同作用，如在乳腺癌中与不良预后和免疫细胞浸润有关。 图6 Notch 信号通路在 SCLC 中的作用 5 DLL3在癌症免疫治疗中的应用 图7 靶向DLL3的免疫治疗策略 ADC（如Rova-T） Rova-T由人源化抗DLL3抗体与细胞毒性药物连接而成，是首个针对DLL3的ADC。在SCLC临床试验中，虽有一定疗效，但III期试验因疗效不佳和毒性问题终止，不过为后续研究提供了经验。其与免疫治疗药物联合使用可降低毒性并增强疗效。 图8 靶向 DLL3 的 ADC 的作用机制 BiTEs（如tarlatamab） BiTEs能连接T细胞和肿瘤细胞，激活T细胞杀伤肿瘤。BI764532和Tarlatamab在SCLC及其他DLL3阳性NENs的临床试验中展现出有前景的疗效和可接受的耐受性，HPN328在晚期DLL3表达肿瘤患者的试验中显示出初步的抗肿瘤活性和可管理的毒性。 图9 靶向 DLL3 的 BiTE CAR-T疗法（如AMG119） AMG119对DLL3阳性SCLC细胞有强大细胞毒性，在体外和体内研究中显示出疗效，I期研究评估了其安全性和抗肿瘤活性，显示出一定安全性和疗效。还有其他CAR-T候选疗法及CAR-NK细胞疗法处于研发阶段。 联合免疫检查点抑制剂 DLL3靶向疗法与免疫检查点抑制剂联合，理论上可形成正反馈增强疗效，但在SCLC中，CAR-T细胞与免疫检查点抑制剂联合的效果存在不一致，多模式联合治疗或为优化方向。 表2 目前正在进行的靶向DLL3的研发药物 近红外光免疫疗法（NIR-PIT） NIR-PIT利用抗体-光吸收剂偶联物，在近红外光照射下破坏肿瘤细胞并诱导免疫反应，针对DLL3的NIR-PIT在临床前研究中展现出抑制肿瘤生长的效果。但在人体中的可行性、安全性和耐受性尚待确定。 图10 DLL3 靶向近红外光免疫疗法的机制 放射性药物疗法（RPT） Lu-177标记的抗DLL3单克隆抗体在肿瘤异种移植模型中显示出疗效和较低毒性。将抗DLL3抗体与放射性同位素结合，对DLL3表达的SCLC细胞有选择性照射作用，临床前研究效果良好，未来需优化剂量等。 6  DLL3在不同癌症中的研究进展 根据肿瘤类型和细胞生长环境的不同，DLL3的激活可以发挥促癌或抑癌作用。有报道，DLL3在小细胞肺癌、乳腺癌、垂体瘤、急性髓系白血病中有促癌作用，但在肝癌、神经胶质瘤和恶性胶质瘤中却发挥了抑癌作用。 神经内分泌癌（NEC） 小细胞肺癌（SCLC）：它与肿瘤发生相关，通过调节SNAI1/Snail信号通路促进细胞增殖、迁移和侵袭，DLL3的表达与神经内分泌特征呈正相关，且与Notch家族基因的表达呈负相关。此外，它对患者预后的影响存在争议。 大细胞神经内分泌癌（LCNEC）：DLL3阳性与STK11/KEAP1突变相关，可作为预后不良和辅助化疗敏感性的标志物。 髓样甲状腺癌（MTC）：DLL3表达与间质纤维化、淋巴结转移相关，可用于识别侵袭性更强、易早期转移的肿瘤。 妇科癌症：在子宫内膜癌（EC）中，DLL3表达显著上调，其过表达、肿瘤分期以及淋巴结转移都是独立的预后预测因素。在卵巢癌（OC）中，DLL3等Notch信号通路相关基因的表达与不良总生存期相关，且随着癌症进展表达增加。宫颈NECs中，81%的患者有DLL3表达，转移灶中表达更高且与PIK3CA、PTEN突变呈负相关。 胃肠胰NECs（GEP-NENs）：DLL3在低分化NEC中高表达，且在ECC4、ECC10和ECC12细胞系中表达上调，与无进展生存期和总生存期较短相关。 膀胱NEC：DLL3的表达与神经内分泌标志物正相关，高表达的DLL3蛋白与患者较短的总生存期和无进展生存期相关，并且在患者来源的异种移植模型中，针对DLL3的药物展现出疗效，提示DLL3可作为预后不良的生物标志物和潜在治疗靶点。 神经内分泌前列腺癌（NEPC）：DLL3的表达与侵袭性临床行为相关，多数去势抵抗性小细胞神经内分泌前列腺癌（CRPC-NE）和部分去势抵抗性前列腺腺癌中存在DLL3表达，而局限性良性前列腺癌中则无。单剂量的抗DLL3人源化抗体SC16LD6.5可使表达DLL3的前列腺癌异种移植物产生完全且持久的反应，说明DLL3是神经内分泌前列腺癌的潜在治疗靶点。 Merkel细胞癌（MCC）：多数患者DLL3阳性，但与总生存期无显著关联，目前还需要大量研究来确定DLL3能否作为Merkel细胞癌的预后生物标志物以及ROVA-T的疗效。 非神经内分泌（NE）肿瘤 肝癌：DLL3过表达可诱导细胞凋亡，与在NENs中的作用不同，且其与乙肝病毒（HBV）相互作用，HBx蛋白可通过诱导表观遗传修饰沉默DLL3，进而促进癌变。 胰腺癌：DLL3在癌细胞系中的表达是正常胰腺上皮细胞的3倍，抑制其表达可抑制癌细胞生长，且它与Notch1等表达呈正相关。 胶质瘤：DLL3表达与IDH突变型胶质瘤相关，突变亚型中表达更高，不过其与患者生存期的关系存在争议，有的研究表明高表达与较好预后相关，有的则显示低表达患者生存期更短。 乳腺癌：高表达的DLL3与患者低总生存期及较多的肿瘤浸润免疫细胞（尤其是调节性T细胞）相关，提示其与不良预后有关，也为乳腺癌免疫治疗提供了新方向。 垂体腺瘤：生长激素分泌型垂体腺瘤中，EGFL7与DLL3相互作用并调节其信号传导。EGFL7高表达与肿瘤侵袭性相关，敲低EGFL7可下调DLL3，表明EGFL7可能通过抑制DLL3表达成为新的治疗靶点。 表3 DSL家族的配体在癌症中的作用 7  DLL3靶向疗法的未来展望 DLL3在肿瘤进展中作用关键，但目前对其临床应用的理解存在局限。DLL3靶向药物的疗效和耐受性存在问题，缺乏标准化的DLL3表达评估方法。未来需深入了解DLL3生物学特性，整合前沿技术构建全面的DLL3表达和功能模型。诱导多能干细胞来源的免疫细胞治疗具有标准化、功能增强等优势，是潜在发展方向。未来需优化ADC的有效载荷和连接子，开发创新药物，并明确DLL3作为预测生物标志物的作用。此外，还需重新设计临床试验范式，促进跨学科合作，以推动DLL3靶向疗法的发展。 关于仁域生物 成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。 公司核心技术平台包括全球最大的5000+天然驼源纳米抗体库(总库容＞3×10^12)、肿瘤细胞系免疫的骆驼免疫库、万亿级大容量全人源噬菌体展示scFv抗体库(总库容＞1×10^12)。 可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！ 科研专用—万亿级天然抗体库产品 （一步到位，轻松搭建基因工程抗体平台） 产品限量供应 protocol 获取 / 产品咨询 邮箱｜find@renyubio.com 电话｜19136178673 地址｜成都市经开区科技产业孵化园 参考文献 Das S, Samaddar S. Recent Advances in the Clinical Translation of Small-Cell Lung Cancer Therapeutics. Cancers (Basel). 2025 Jan 14;17(2):255.  Peddio A, Pietroluongo E, Lamia MR, Luciano A, Caltavituro A, Buonaiuto R, Pecoraro G, De Placido P, Palmieri G, Bianco R, Giuliano M, Servetto A. DLL3 as a potential diagnostic and therapeutic target in neuroendocrine neoplasms: A narrative review. Crit Rev Oncol Hematol. 2024 Dec;204:104524. Ding J, Yeong C. Advances in DLL3-targeted therapies for small cell lung cancer: challenges, opportunities, and future directions. Front Oncol. 2024 Dec 5;14:1504139.  Yang W, Wang W, Li Z, Wu J, Huang X, Li J, Zhang X, Ye X. Delta-like ligand 3 in small cell lung cancer: Potential mechanism and treatment progress. Crit Rev Oncol Hematol. 2023 Nov;191:104136.  Zhang H, Yang Y, Li X, Yuan X, Chu Q. Targeting the Notch signaling pathway and the Notch ligand, DLL3, in small cell lung cancer. Biomed Pharmacother. 2023 Mar;159:114248.  Cortinovis DL, Colonese F, Abbate MI, Sala L, Meazza Prina M, Cordani N, Sala E, Canova S. Harnessing DLL3 inhibition: From old promises to new therapeutic horizons. Front Med (Lausanne). 2022 Dec 1;9:989405. Yao J, Bergsland E, Aggarwal R, Aparicio A, Beltran H, Crabtree JS, Hann CL, Ibrahim T, Byers LA, Sasano H, Umejiego J, Pavel M. DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms. Oncologist. 2022 Nov 3;27(11):940-951.  Matsuo K, Taniguchi K, Hamamoto H, Inomata Y, Komura K, Tanaka T, Lee SW, Uchiyama K. Delta-like canonical Notch ligand 3 as a potential therapeutic target in malignancies: A brief overview. Cancer Sci. 2021 Aug;112(8):2984-2992.  Xiu MX, Liu YM, Kuang BH. The Role of DLLs in Cancer: A Novel Therapeutic Target. Onco Targets Ther. 2020 May 7;13:3881-3901.  Owen DH, Giffin MJ, Bailis JM, Smit MD, Carbone DP, He K. DLL3: an emerging target in small cell lung cancer. 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Orbit Phase 3 study of setrusumab in osteogenesis imperfecta continuing to planned second interim analysis, expected in mid-2025 Alvelestat, for Alpha-1 Antitrypsin Deficiency-associated Lung Disease, receives positive EMA opinion on European Orphan Designation Application; European Commission expected to issue final decision in first quarter 2025 LONDON, Jan. 12, 2025 (GLOBE NEWSWIRE) -- Mereo BioPharma Group plc (NASDAQ: MREO) (“Mereo” or the “Company”), a clinical-stage biopharmaceutical company focused on rare diseases, today provided an update on its lead clinical programs, setrusumab, a monoclonal antibody in Phase 3 clinical development for the treatment of Osteogenesis Imperfecta (OI) through a partnership with Ultragenyx Pharmaceutical, Inc. (Ultragenyx) and alvelestat, an oral neutrophil elastase inhibitor being studied for the treatment of alpha-1 antitrypsin deficiency-associated lung disease (AATD-LD). The Company also reiterated its previous cash runway guidance that its current cash and cash equivalents are expected to fund operations into 2027, through multiple key inflection points. “Based on the highly promising data from completed studies of setrusumab in OI, including the Phase 2 portion of the Orbit Study, we remain confident in the potential of setrusumab to become the standard-of-care in OI. We look forward to the second interim analysis expected mid-year as we continue our launch readiness activities in the key European markets,” said Dr. Denise Scots-Knight, Chief Executive Officer of Mereo BioPharma. “Additionally, EU Orphan Designation, which follows the granting of both Orphan Drug and Fast Track Designations from the FDA in the U.S., is another important milestone in our ongoing partnering process and our efforts to bring alvelestat to patients worldwide, including earlier stage patients who are not currently eligible for augmentation therapy in many countries. With our cash runway into 2027, we continue to be in a strong position to execute on our key milestones through 2025.” Setrusumab (UX143) As announced by the Company’s partner, Ultragenyx, the Phase 3 Orbit Study of setrusumab in OI is continuing to dose patients and progressing towards the planned second interim analysis expected in mid-2025, with a potential final analysis in the fourth quarter of 2025. Additionally, treatment is continuing in Cosmic, an open-label Phase 3 study evaluating setrusumab against intravenous bisphosphonate therapy in patients aged 2 to <7 years. Data from the Cosmic study will be evaluated in parallel with the Orbit interim and final analyses. Alvelestat (MPH-966) The European Medicines Agency (EMA)’s Committee for Orphan Medicinal Products (COMP) has issued a positive opinion on the Company’s application for Orphan Designation for alvelestat. The COMP recommendation has been provided to the European Commission, which is expected to issue a final decision on the Orphan Designation in the first quarter of 2025. Alvelestat previously received Orphan Drug Designation and Fast Track Designation from the U.S. FDA in 2021 and 2022, respectively. European Orphan Designation is awarded to therapeutic candidates targeting the treatment, prevention or diagnosis of life-threatening or chronically debilitating diseases with a prevalence of fewer than 5 in 10,000 people in the European Union which provide a significant benefit over available therapies, or for which no approved therapies exist. Therapeutics receiving EU Orphan Designation are eligible for ten years of marketing exclusivity upon approval, as well as fee reductions for various centralized activities including the Marketing Authorization Application, inspections and protocol assistance. Individual EU Member States also provide specific incentives to support the development, review and availability of Orphan Medicinal Products at the time of HTA evaluations and Pricing and Reimbursement negotiations. About Mereo BioPharma Mereo BioPharma is a biopharmaceutical company focused on the development of innovative therapeutics for rare diseases. The Company has two rare disease product candidates: setrusumab for the treatment of osteogenesis imperfecta (OI); and alvelestat, primarily for the treatment of severe alpha-1 antitrypsin deficiency-associated lung disease (AATD-LD). The Company’s partner, Ultragenyx Pharmaceutical, Inc., has completed enrollment in the Phase 3 portion of a pivotal Phase 2/3 study in pediatrics and young adults (5 to 25 years old) for setrusumab in OI and in the Phase 3 study in pediatric patients (2 to <7 years old) in the first half of 2024. The partnership with Ultragenyx includes potential additional milestone payments of up to $245 million and royalties to Mereo on commercial sales in Ultragenyx territories. Mereo has retained EU and UK commercial rights and will pay Ultragenyx royalties on commercial sales in those territories. Setrusumab has received orphan designation for osteogenesis imperfecta from the EMA and FDA, PRIME designation from the EMA, and Breakthrough Therapy designation and rare pediatric disease designation from the FDA. Alvelestat has received U.S. Orphan Drug Designation for the treatment of AATD and Fast Track designation from the FDA. Following results from ASTRAEUS and ATALANTa in AATD-lung disease, the Company has aligned with the FDA and the EMA on the primary endpoints for a Phase 3 pivotal study which, if successful, could enable full approval in both the U.S. and Europe. In addition to the rare disease programs, Mereo has two oncology product candidates, etigilimab, an anti-TIGIT; and navicixizumab for the potential treatment of late-line ovarian cancer. Navicixizumab has been partnered with Feng Biosciences, Inc. in a global licensing agreement that includes milestone payments and royalties. Mereo has also entered into an exclusive global license agreement with ReproNovo SA, a reproductive medicine company, for the development and commercialization of leflutrozole, a non-steroidal aromatase inhibitor. Forward-Looking Statements This press release contains “forward-looking statements” that involve substantial risks and uncertainties. All statements other than statements of historical fact contained herein are forward-looking statements within the meaning of Section 27A of the United States Securities Act of 1933, as amended, and Section 21E of the United States Securities Exchange Act of 1934, as amended. Forward-looking statements usually relate to future events and anticipated revenues, earnings, cash flows or other aspects of our operations or operating results. Forward-looking statements are often identified by the words “believe,” “expect,” “anticipate,” “plan,” “intend,” “foresee,” “should,” “would,” “could,” “may,” “estimate,” “outlook” and similar expressions, including the negative thereof. The absence of these words, however, does not mean that the statements are not forward-looking. These forward-looking statements are based on the Company’s current expectations, beliefs and assumptions concerning future developments and business conditions and their potential effect on the Company. While management believes that these forward-looking statements are reasonable as and when made, there can be no assurance that future developments affecting the Company will be those that it anticipates. All of the Company’s forward-looking statements involve known and unknown risks and uncertainties some of which are significant or beyond its control and assumptions that could cause actual results to differ materially from the Company’s historical experience and its present expectations or projections. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical development process; the Company’s reliance on third parties to conduct and provide funding for its clinical trials; the Company’s dependence on enrollment of patients in its clinical trials; and the Company’s dependence on its key executives. You should carefully consider the foregoing factors and the other risks and uncertainties that affect the Company’s business, including those described in the “Risk Factors” section of its Annual Report on Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the Securities and Exchange Commission. The Company wishes to caution you not to place undue reliance on any forward-looking statements, which speak only as of the date hereof. The Company undertakes no obligation to publicly update or revise any of our forward-looking statements after the date they are made, whether as a result of new information, future events or otherwise, except to the extent required by law. Mereo BioPharma Contacts: Mereo +44 (0)333 023 7300Denise Scots-Knight, Chief Executive Officer Christine Fox, Chief Financial Officer Burns McClellan (Investor Relations Adviser to Mereo) +01 646 930 4406Lee Roth Investors investors@mereobiopharma.com