This is an open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with sorafenib. OMP-54F28 will be administered IV on Day 1 of each 21-day cycle. The planned dose levels of OMP-54F28 are 5 and 10 mg/kg. Depending on safety in this study, additional lower or intermediate dose levels may be evaluated.

开始日期2014-01-01

申办/合作机构-

NCT02092363

/ Completed临床1期

A Phase 1b Dose Escalation Study of OMP-54F28 in Combination With Paclitaxel and Carboplatin in Patients With Recurrent Platinum-Sensitive Ovarian Cancer

This is an open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with paclitaxel and carboplatin. OMP-54F28 will be administered IV on Days 1 of each 21-day cycle. Paclitaxel (175 mg/m2) and carboplatin (AUC = 5 mg/mL • min) will be administered IV on Day 1 of each cycle. A total of 6 cycles of paclitaxel and carboplatin will be given. Additional cycles may be given as per institutional standard of care after discussion with the Medical Monitor. Treatment with OMP-54F28 will continue after completion of treatment with paclitaxel and carboplatin. The planned dose levels of OMP-54F28 are 5 and 10 mg/kg.

开始日期2014-01-01

申办/合作机构-

NCT02050178

/ Completed临床1期

A Phase 1b Dose Escalation Study of OMP-54F28 in Combination With Nab-Paclitaxel and Gemcitabine in Patients With Previously Untreated Stage IV Pancreatic Cancer

This is an open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with nab-paclitaxel and gemcitabine. OMP-54F28 will be administered IV on Days 1 and 15 of each 28-day cycle. Nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered IV on Days 1, 8, and 15 of each cycle. The planned dose levels of OMP-54F28 are 3.5 mg/kg and 7.0 mg/kg.

开始日期2013-11-01

申办/合作机构

Mereo BioPharma 5, Inc.

100 项与 Ipafricept 相关的临床结果

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100 项与 Ipafricept 相关的转化医学

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100 项与 Ipafricept 相关的专利（医药）

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项与 Ipafricept 相关的文献（医药）

2026-12-01·JOURNAL OF MOLECULAR MEDICINE-JMM

Beyond the target: implications of Wnt pathway inhibitors on bone health

Review

作者: Haÿ, Eric ; Nachef, Clement ; Cohen-Solal, Martine ; Vanjak, Arnaud ; Funck-Brentano, Thomas

Abstract:

Wnt signaling inhibitors are under investigation as potential therapies for conditions characterized by upregulated Wnt signaling, such as cancers, hematological disorders, and organ fibrosis. However, because the Wnt pathway is essential for bone homeostasis, its inhibition can adversely affect skeletal health. This review focuses on the bone-related off-target effects of Wnt inhibitors currently in clinical development, specifically those evaluated in Phase I and II trials with available published data. We found that inhibitors targeting upstream components of the pathway—such as Wnt ligands or receptors (e.g., porcupine inhibitors, Ipafricept, or Vantictumab)—frequently lead to bone-related adverse effects, including fractures and early trial termination. Co-administration of bisphosphonates may help mitigate these effects. In contrast, downstream inhibitors (e.g., PRI-724, niclosamide) have not been linked to bone toxicity, although this may reflect either underreporting or a genuinely lower skeletal impact. Further preclinical studies are warranted to better understand these differential effects. A thorough understanding of bone-specific risks is critical as Wnt signaling inhibitors continue to advance in clinical development.

2025-11-01·Iranian biomedical journal

Regulatory Signaling Pathways in Ovarian Cancer Stem Cells: Their Role in Tumor Progression and Therapeutic Strategies.

Review

作者: Amalia, Dini ; Febriani, Febriani ; Arfianti, Arfianti

In ovarian cancer, ovarian cancer stem cells (OCSCs) not only contribute to tumor formation but also drive the progression, metastasis, and chemoresistance. The defining properties of OCSCs are sustained through the Wnt/β-catenin, Notch, and Hedgehog signaling pathways, which can synergize rather than act independently to form a triad that enhances key functional capabilities of OCSCs. Various therapeutic agents have been studied to target these pathways in OCSCs, including γ-secretase inhibitors (nirogacestat), smoothened inhibitors (vismodegib and sonidegib), and Wnt/β-catenin inhibitors (PRI-724 and ipafricept). While these agents have demonstrated antitumor activity in preclinical and early clinical studies, their clinical use remains challenging due to compensatory interactions among signaling pathways, which diminish the efficacy of single-agent treatments. To improve treatment outcomes, strategies involving combination approaches and personalized treatments need to be explored. This review aims to summarize current evidence on the role of Wnt/β-catenin, Notch, and Hedgehog signaling pathways in OCSCs and their therapeutic implications in ovarian cancer.

2020-10-15·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer

1区 · 医学

Article

作者: Weekes, Colin ; Cohen, Steven J. ; Cardin, Dana B. ; Brachmann, Rainer K. ; Shahda, Safi ; Dotan, Efrat ; Messersmith, Wells ; Denlinger, Crystal S. ; Kapoun, Ann M. ; Astsaturov, Igor ; Stagg, Robert J. ; Lenz, Heinz-Josef ; O'Neil, Bert ; Uttamsingh, Shailaja

Abstract:

Purpose::

The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).

Patients and Methods::

Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.

Results::

A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2–4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4–18.4], median overall survival was 9.7 m (95% CI, 7.0–14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.

Conclusions::

Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.

项与 Ipafricept 相关的新闻（医药）

2026-07-08

·GMP药政咨询

抗体药物与信号通路：全景解析与竞争格局

从分子机制到临床管线：9大通路 × 100+靶点 × 200+在研药物的系统盘点抗体药物是现代生物医药最重要的支柱之一。截至2025年，全球已有超过130款抗体类药物获批上市，在研后期管线超过200款。然而，这些药物并非无序开发——它们的靶点选择、作用机制和临床策略，几乎都锚定在人体细胞内的信号通路上。核心问题：人体有多少条信号通路？哪些通路已被抗体药物"占领"？哪些仍是一片蓝海？本文将从分子机制出发，系统梳理九大核心信号通路的抗体开发现状，为药物开发人员提供一份"靶点地图"。一、信号通路分类与数量：数字背后的全景 1.1 信号通路数据库统计要回答"人体有多少条信号通路"，需要从主流通路数据库入手：数据库通路总数信号转导通路人类特异通路更新时间 KEGG587~30（信号转导子类）~340（含疾病/代谢）2026.07 Reactome~2,600~400（信号相关）~1,8002026 NCI-Nature PID~300~128~3002024 但"通路总数"和"可成药通路数"是两回事。根据FDA和EMA已批准药物的靶点统计，真正被药物成功干预的信号通路不超过30条，其中抗体药物涉及的通路约15-20条。大量通路虽然已被科学文献描述，但尚未产生获批药物。信号通路"漏斗"：从数据库到成药 Reactome: ~2,600 通路（含代谢、疾病、信号等所有类别）信号转导通路: ~400 条（有文献支持的信号传递级联）药物可干预通路: ~60 条（有小分子或抗体在研）已获批药物通路: ~30 条抗体药物通路: ~15-20 条图1. 信号通路的"成药漏斗"：从理论通路到实际成药的逐级筛选 1.2 九大核心信号通路分类框架基于FDA/EMA已批准抗体药物和后期临床管线数据，我们将抗体药物涉及的信号通路归纳为九大核心通路：类别通路核心特征代表性靶点受体酪氨酸激酶(RTK)EGFR/ErbB家族细胞增殖/分化EGFR, HER2, HER3 VEGFR家族血管生成VEGF, VEGFR2 MET/IGF1R等侵袭/代谢c-MET, IGF1R 免疫检查点PD-1/PD-L1, CTLA-4T细胞免疫调控PD-1, PD-L1, CTLA-4, LAG-3 细胞因子通路JAK-STAT免疫/炎症IL-6R, IL-5, IL-17, IL-23 代谢/增殖PI3K/AKT/mTOR细胞存活/代谢PI3Kα, mTOR, AKT 增殖/分化MAPK/ERK (RAS-RAF-MEK-ERK)细胞增殖KRAS, BRAF, MEK 发育通路Wnt/β-catenin干细胞/分化FZD, LRP5/6, Wnt 发育通路Notch旁侧抑制/分化DLL4, Notch1-4 发育通路Hedgehog胚胎发育SHH, SMO, GLI 炎症通路NF-κB炎症/免疫TNF-α, BAFF, RANKL, CD40 二、主要信号通路详解与抗体开发策略 2.1 RTK家族：抗体药物的"黄金矿脉" 受体酪氨酸激酶（RTK）是抗体药物最成功的靶点家族。RTK家族包含20个亚家族、58个成员，其中EGFR家族和VEGFR家族贡献了最多的获批抗体。 EGFR/ErbB家族 EGFR家族信号通路与抗体作用机制细胞膜 EGFR (HER1) EGF HER2 (无配体) × HER3 (弱激酶) NRG PI3K/AKT MAPK/ERK 西妥昔单抗 EGFR/KRAS野生曲妥珠单抗 HER2+乳腺癌帕妥珠单抗 HER2二聚化 VEGFR 血管生成贝伐珠单抗雷莫西尤 c-MET 侵袭/转移 Teliso-V (ADC) 图2. RTK家族主要靶点与已上市/在研抗体药物 Rochetd> 靶点已上市抗体机制适应症开发公司 EGFR西妥昔单抗 (Cetuximab)阻断配体结合mCRC, SCCHNImClone/BMS 帕尼单抗 (Panitumumab)全人源IgG2mCRCAmgen 尼妥珠单抗 (Nimotuzumab)低亲和力/低毒性鼻咽癌百泰生物 HER2曲妥珠单抗 (Trastuzumab)阻断二聚化+ADCC乳腺癌/胃癌Genentech/Roche 帕妥珠单抗 (Pertuzumab)阻断HER2-HER3二聚化乳腺癌Genentech/Roche 玛格妥昔单抗 (Margetuximab)优化Fc/增强ADCC乳腺癌MacroGenics 恩美曲妥珠单抗 (T-DM1)ADC/微管抑制剂乳腺癌德曲妥珠单抗 (T-DXd)ADC/拓扑异构酶I抑制剂乳腺癌/胃癌/肺癌第一三共/AZ VEGF/VEGFR贝伐珠单抗 (Bevacizumab)中和游离VEGFmCRC/NSCLC/卵巢Genentech/Roche 雷莫西尤单抗 (Ramucirumab)靶向VEGFR2胃癌/NSCLCEli Lilly 阿柏西普 (Aflibercept)VEGF Trap/融合蛋白眼科/结直肠癌Regeneron c-METTelisotuzumab vedotin (Teliso-V)ADC/MMAEMET+ NSCLCAbbVie (2025 FDA加速批准) RTK通路的抗体开发策略核心在于：阻断配体-受体结合（如西妥昔单抗阻断EGF-EGFR）、阻止受体二聚化（如帕妥珠单抗阻断HER2-HER3）、通过ADC递送细胞毒素（如T-DXd）和增强免疫效应（如玛格妥昔单抗的Fc优化）。 2.2 JAK-STAT通路：从免疫调节到自身免疫 JAK-STAT信号通路与抗体干预策略 IL-6R IL-6信号 IL-5R 嗜酸粒细胞 IL-17R 银屑病 IL-23R IBD/银屑病 IL-4Rα 哮喘 JAK1 / JAK2 / JAK3 / TYK2（激酶域） STAT1-7 → 核转位 → 基因转录托珠单抗 (IL-6R) 美泊利单抗 (IL-5) 司库奇尤单抗(IL-17) 乌司奴单抗(IL-23) 度普利尤单抗(IL-4Rα) JAK抑制剂（小分子）: 托法替布/巴瑞替尼/乌帕替尼/非戈替尼图3. JAK-STAT通路：抗体在上游（配体/受体），小分子在下游（激酶） JAK-STAT通路是连接细胞外细胞因子信号与基因表达的核心枢纽。该通路的特点是"一条通路，多个入口"——不同细胞因子通过不同受体-JAK组合激活不同STAT，产生截然不同的生物学效应。抗体开发策略：由于JAK激酶的催化口袋高度保守，小分子JAK抑制剂面临选择性挑战（如托法替布的广谱JAK抑制导致感染风险）。因此，抗体药物选择在上游（配体或受体层面）进行更精准的干预——靶向特定细胞因子或其受体，实现对特定STAT通路的精准调控。 Rochetd> 靶点抗体适应症开发公司 IL-6R托珠单抗 (Tocilizumab)RA/巨细胞动脉炎/COVID-19 沙利鲁单抗 (Sarilumab)RASanofi/Regeneron IL-5美泊利单抗 (Mepolizumab)严重嗜酸性粒细胞哮喘GSK 瑞利珠单抗 (Reslizumab)嗜酸性粒细胞哮喘Teva IL-5Rα贝纳利珠单抗 (Benralizumab)嗜酸性粒细胞哮喘AstraZeneca IL-17A司库奇尤单抗 (Secukinumab)银屑病/ASNovartis 依奇珠单抗 (Ixekizumab)银屑病Eli Lilly IL-23 p19乌司奴单抗 (Ustekinumab)银屑病/IBDJanssen 古塞奇尤单抗 (Guselkumab)银屑病Janssen IL-4Rα度普利尤单抗 (Dupilumab)哮喘/特应性皮炎/CRSwNPSanofi/Regeneron 2.3 NF-κB通路：炎症性疾病的"主控开关" NF-κB是连接炎症信号与基因表达的核心转录因子。该通路分为经典通路（由TNF-α、IL-1β、LPS激活，快速响应炎症）和非经典通路（由BAFF、CD40L、RANKL激活，调控免疫细胞发育）。 NF-κB通路：经典与非经典双臂及抗体干预点经典 NF-κB 通路 TNF-α TNFR1 IKKα/β/NEMO IκBα降解 p50/p65核转位英夫利昔单抗阿达木单抗依那西普非经典 NF-κB 通路 BAFF CD40L RANKL TRAF3降解 → NIK稳定化 IKKα → p100→p52 p52/RelB 核转位贝利尤单抗地舒单抗 CD40抗体(在研) 图4. NF-κB双臂通路：经典臂由TNF-α驱动（抗体阻断），非经典臂由BAFF/RANKL/CD40L驱动 NF-κB通路的抗体策略精髓：抗TNF-α抗体（英夫利昔/阿达木/依那西普）是自身免疫领域最成功的药物之一，全球年销售额合计超过400亿美元峰值。抗BAFF抗体（贝利尤单抗）靶向B细胞存活信号用于SLE，抗RANKL抗体（地舒单抗）靶向骨吸收通路用于骨质疏松和骨转移。这些药物的共同点是：不在NF-κB通路内部干预，而是在上游配体-受体层面进行阻断，因为直接抑制NF-κB会导致广泛的免疫抑制。 2.4 PI3K/AKT/mTOR通路：代谢与增殖的交汇点 PI3K/AKT/mTOR是细胞代谢和增殖的核心调控网络。该通路在RTK激活后启动，与MAPK通路平行存在但功能互补——MAPK主要驱动增殖，PI3K/AKT/mTOR主要驱动存活和代谢。 PI3K/AKT/mTOR通路：抗体与小分子的协同定位 RTK (EGFR/HER2等) PI3K α/β/δ/γ AKT (PKB) mTOR C1/C2 细胞存活 /代谢/蛋白合成抗体: 曲妥珠单抗等 Alpelisib (PI3Kα) Capivasertib (AKT) 依维莫司 (mTOR) ↑ 抗体在上游 ↑ 小分子在下游 PI3K通路药物开发现状已上市小分子: Alpelisib(PI3Kα), Idelalisib(PI3Kδ), Copanlisib(PI3Kα/δ), 依维莫司/替西罗莫司(mTOR) 抗体策略: 主要通过上游RTK抗体(HER2/EGFR)间接抑制PI3K/AKT通路图5. PI3K/AKT/mTOR通路：抗体在上游RTK层面，小分子在下游激酶层面 PI3K/AKT/mTOR通路的抗体开发面临一个特殊挑战：该通路与胰岛素信号高度重叠，直接抑制会导致血糖升高。因此，目前的策略主要是通过上游RTK抗体（如抗HER2）间接抑制PI3K通路，或使用小分子选择性抑制剂（如PI3Kα选择性抑制剂alpelisib）直接干预。直接靶向PI3K/AKT/mTOR通路组分的抗体药物几乎空白。 2.5 MAPK/ERK通路：从KRAS到ERK的级联传递 RAS-RAF-MEK-ERK级联是细胞增殖信号的经典通路。KRAS突变存在于约30%的人类癌症中，长期以来被认为是"不可成药"靶点。直到2021年sotorasib（KRAS G12C共价抑制剂）获批，这一局面才被打破。抗体在MAPK通路中的角色：由于RAS-RAF-MEK-ERK是胞内级联，抗体无法直接进入细胞。因此，抗体药物通过上游RTK阻断（如抗EGFR/HER2）来间接抑制MAPK通路激活。这也是为什么EGFR抗体在KRAS野生型结直肠癌中有效，而在KRAS突变型中无效——KRAS突变绕过了上游RTK，直接激活下游级联。 2.6 Wnt通路：发育信号与肿瘤干细胞 Wnt通路在胚胎发育中至关重要，在成人中主要维持干细胞自我更新。Wnt通路异常激活与结直肠癌（APC突变）、肝癌和多种实体瘤干细胞特性密切相关。 Wnt通路抗体开发的核心挑战：Wnt通路高度冗余（19种Wnt配体、10种Fzd受体），单一靶点阻断难以完全抑制通路活性。此外，Wnt信号对正常肠道干细胞维持至关重要，系统性阻断可能导致严重胃肠道毒性。靶点药物类型阶段开发公司 FZD1/2/5/7/8Vantictumab (OMP-18R5)抗体I/II期（暂停）OncoMed FZD7Ipafricert (OMP-54F28)Fc融合蛋白I期（暂停）OncoMed RSPO3Omp-131R10抗体临床前/I期OncoMed DLL4 (Notch)Demcizumab抗体I/II期OncoMed LGR5Anti-LGR5抗体抗体临床前多家目前Wnt通路的抗体开发整体处于早期阶段，OncoMed公司的多项临床因疗效不佳或毒性问题已暂停。但新的策略正在涌现——如靶向LGR4的单抗通过调节Wnt信号诱导铁死亡，在结直肠癌中克服获得性耐药（Nature Cancer, 2024），以及靶向RSPO融合的ADC药物。 2.7 Notch通路：旁侧抑制与细胞命运决定 Notch通路通过细胞间直接接触（juxtacrine）传递信号，调控细胞分化命运。Notch信号在T细胞分化（αβ/γδ分化）和肿瘤血管生成中发挥关键作用。靶点药物类型阶段适应症 DLL4Demcizumab (OMP-21M18)抗体I/II期（暂停）NSCLC/胰腺癌 Notch2/3Tarextumab (OMP-59R5)抗体I/II期（暂停）SCLC/胰腺癌 Notch1Brontictuzumab抗体I期肿瘤 Notch1Crenezumab抗体暂停— Notch通路抗体的开发同样面临"on-target off-tumor"毒性挑战——Notch信号在肠道分泌细胞分化中至关重要，系统性阻断会导致分泌细胞化生和胃肠道毒性。 2.8 Hedgehog通路：胚胎发育信号的再激活 Hedgehog通路在胚胎发育中决定细胞命运和组织极性，在成人中异常激活与基底细胞癌（BCC）、髓母细胞瘤密切相关。 Hedgehog通路的药物开发以小分子为主导——vismodegib和sonidegib（SMO抑制剂）已获批用于BCC。抗体药物在该通路开发较少，主要因为通路组分（SHH、SMO、GLI）位于细胞表面或胞内，抗体的最佳干预点不明确。 2.9 免疫检查点通路：肿瘤免疫治疗的核心严格来说，免疫检查点（PD-1/PD-L1、CTLA-4、LAG-3、TIGIT等）并非传统信号通路，但它们通过调控T细胞受体下游信号（包括PI3K/AKT、MAPK、NF-κB等）发挥免疫调节作用，因此在此一并讨论。 Rochetd>Rochetd> 靶点已上市抗体开发公司适应症 PD-1纳武利尤单抗 (Nivolumab)BMS黑色素瘤/NSCLC/肾癌等帕博利珠单抗 (Pembrolizumab)MerckNSCLC/黑色素瘤等（20+适应症）信迪利单抗 (Sintilimab)信达生物淋巴瘤/胃癌等特瑞普利单抗 (Toripalimab)君实生物鼻咽癌/黑色素瘤替雷利珠单抗 (Tislelizumab)百济神州淋巴瘤/NSCLC/食管癌等卡瑞利珠单抗 (Camrelizumab)恒瑞医药肝癌/NSCLC/食管癌等多斯塔利单抗 (Dostarlimab)GSKdMMR实体瘤西达本胺+信迪利 (联合)—— PD-L1阿替利珠单抗 (Atezolizumab) 度伐利尤单抗 (Durvalumab)AstraZenecaNSCLC/膀胱癌等阿维鲁单抗 (Avelumab)Merck KGaA/Pfizer默克尔细胞癌 CTLA-4伊匹木单抗 (Ipilimumab)BMS黑色素瘤卡度尼利单抗 (Cadonilimab, PD-1/CTLA-4)康方生物宫颈癌（双抗） LAG-3瑞拉替单抗 (Relatlimab)BMS黑色素瘤（联合Nivo） TIGIT多家在研三、产品开发现状：全景管线盘点 3.1 已上市抗体药物按通路分布通路已上市抗体数代表药物主要适应症领域免疫检查点12+Keytruda, Opdivo, Tecentriq肿瘤 RTK-EGFR/HER28+Herceptin, Erbitux, Enhertu肿瘤 RTK-VEGF3+Avastin, Cyramza, Eylea肿瘤/眼科 JAK-STAT(细胞因子)15+Actemra, Dupixent, Cosentyx, Stelara自免/炎症 NF-κB(TNF/BAFF/RANKL)8+Humira, Remicade, Benlysta, Prolia自免/骨质疏松其他(CD20/CD19等)10+Rituxan, Gazyva, Darzalex血液肿瘤 Wnt/Notch/Hedgehog0—— 3.2 2026年在研后期管线统计 2026年后期临床抗体管线分布（n=209） 80 PD-1/PD-L1 55 HER2/EGFR 40 VEGF/血管 35 JAK-STAT 30 NF-κB相关 25 BCMA/TAA 15 CTLA-4/LAG-3 8 TIGIT 5 Wnt/Notch 靶点/通路管线关键数据 • 2025年全球新批准抗体: 19款（53%中国首次获批） • 2026年预计进入注册申报: 209款（76%非肿瘤） • 当前在审上市申请: 26款（69%在中国审评） • ADC和双抗占新型分子管线的 ~40% 图6. 2026年全球后期临床抗体管线按通路/靶点分布（数据来源: Antibodies to Watch 2026）四、竞争格局评估：哪些靶点已"红海化"？通路/靶点已上市在研后期竞争热度饱和度评估 PD-1/PD-L112+80+极高已严重红海化，差异化空间极小 HER26+55+极高ADC+双抗仍在创新，但靶点本身极度拥挤 VEGF/VEGFR3+40+高贝伐珠单抗生物类似药众多，差异化困难 EGFR3+30+高单抗竞争激烈，ADC提供新方向 TNF-α5+15+中高生物类似药竞争为主，创新空间有限 IL-6R/IL-17/IL-238+35+中高自免领域竞争激烈，但长效化/选择性仍有空间 CTLA-42+15+中伊匹木单抗后继者多以双抗形式出现 LAG-3115+中首个上市后竞争加剧，多数为联合用药 TIGIT08+低中多项III期失败，开发风险高但竞争少 BCMA2+25+中双抗+ADC+CART多线并进 c-MET1(ADC)10+低中首个ADC刚获批，竞争尚不激烈 Wnt (FZD/RSPO)05低临床失败多，需突破性策略 Notch (DLL4/Notch)05低毒性挑战大，多数暂停 Hedgehog0抗体0-2极低小分子主导，抗体策略不明确 PI3K/AKT/mTOR0抗体0-3极低小分子主导，抗体策略空白 RAS-RAF-MAPK0抗体0-2极低胞内靶点，抗体无直接干预空间竞争格局关键洞察：红海靶点（PD-1/PD-L1, HER2, VEGF, EGFR）：已上市+在研合计超过200个项目，差异化几乎只能依赖新型分子格式（双抗、ADC、偶联药物）或适应症拓展蓝海靶点（Wnt, Notch, Hedgehog, PI3K直接靶向）：在研项目个位数，但技术挑战大，需要突破性策略（如靶向通路调控因子而非核心组分）中间地带（TIGIT, c-MET, LAG-3, BCMA）：竞争尚可，且已有概念验证数据支持，是相对理想的开发方向五、未来趋势预测：下一个十年的新兴方向 5.1 双特异性抗体：通路协同干预的新范式双抗的核心价值在于同时干预两条信号通路，实现协同效应。代表性的双抗策略包括： PD-1/VEGF双抗（依沃西单抗，ivonescimab）：同时阻断免疫检查点和血管生成通路，在EGFR突变NSCLC中显示优于帕博利珠单抗的PFS PD-1/CTLA-4双抗（卡度尼利单抗）：同时靶向两个免疫检查点，减少联合用药的毒性管理复杂性 HER2×HER3双抗ADC（Izalontamab brengitecan）：同时靶向两个ErbB家族成员，克服单靶点耐药 PD-1/IL-2双抗：在解除免疫抑制的同时激活T细胞增殖信号 5.2 新兴通路与靶点预测新兴方向通路/靶点科学依据开发潜力评估 cGAS-STING通路STING激动剂/抗体先天免疫激活，抗肿瘤免疫★★★★★（多家在I/II期） NLRP3炎症小体NLRP3/ASC炎症性疾病新机制★★★★（小分子先行，抗体探索中） YTE/长效化改造已上市靶点Fc优化延长半衰期，降低给药频率★★★★★（多个产品已验证） CLDN18.2 ADCClaudin18.2胃癌/胰腺癌高表达★★★★★（中国市场最热靶点之一） B7-H3 ADCB7-H3 (CD276)多瘤种高表达，免疫调节★★★★（多个ADC在I/II期）免疫条件性ADC多种TAA肿瘤微环境激活★★★★（前药设计突破） LGR4/LGR5抗体Wnt辅助受体克服传统Wnt靶向困境★★★（早期概念验证） RSPO融合靶向RSPO2/3融合特定患者亚群精准治疗★★★（伴随诊断依赖） 5.3 中国原研的崛起：全球管线的新引擎 2025年获批的19款抗体中，53%在中国首次获批。在ADC领域，中国原研产品占全球在研ADC管线的超过60%。中国Biotech的平均临床开发周期（4.2年）显著短于欧美（5.6年），尤其在免疫调节类抗体领域。全球抗体药物获批地域分布趋势 3 2020 5 2022 7 2024 10 2025 5 2020 6 2025 中国原研获批欧美原研获批趋势预测：到2028年，中国原研抗体有望占全球新增获批的50%以上核心驱动力: 研发效率优势(5.4年 vs 6.6年) + ADC/双抗技术突破 + 临床试验优势图7. 2020-2025年全球抗体获批地域分布趋势（数据: Antibodies to Watch 2026）六、总结与展望抗体药物开发与信号通路的关系，本质上是"靶点选择"与"作用机制"的匹配问题。回顾本文的九大通路分析，我们可以提炼出几个核心判断：六大战略判断： RTK和免疫检查点仍是"主战场"，但已进入红海竞争阶段，差异化必须依赖新型分子格式（ADC、双抗）或适应症拓展细胞因子通路（JAK-STAT上游）持续产出，自免/炎症领域的新靶点（APRIL, IL-36R, MASP-2等）正在商业化落地 NF-κB通路的间接策略已验证成功（TNF/BAFF/RANKL），但直接干预NF-κB仍面临选择性挑战发育通路（Wnt/Notch/Hedgehog）的抗体开发整体处于早期，需要突破传统"单靶点阻断"思路，考虑通路调控因子、辅助受体或条件性激活策略 PI3K/AKT/mTOR和MAPK通路的抗体策略以"上游间接调控"为主，直接靶向胞内激酶的抗体药物在可预见的未来仍难以实现双抗和ADC是突破通路冗余的关键技术——双抗实现通路协同干预，ADC实现"靶向递送"绕过信号冗余对于药物开发人员而言，靶点选择不应仅看"热度"，更要看通路生物学理解的深度和差异化策略的可行性。在PD-1红海中寻找新方向，不如在TIGIT、c-MET、B7-H3、CLDN18.2等中间地带深耕；在传统单抗赛道内卷，不如在双抗ADC、免疫条件性激活等新型分子格式上布局。信号通路不是靶点的集合，而是药物设计的逻辑框架。理解通路，就是理解药物为什么有效、为什么失败、以及如何在下一个靶点上取得突破。参考文献： ICH Q8(R2). Pharmaceutical Development, 2009. Reichert JM. Antibodies to watch in 2026. MAbs. 2026;18(1). Nature Signal Transduction and Targeted Therapy. Therapeutic advances of targeting RTKs in cancer, 2024. Nature Reviews Drug Discovery. Pharmacological targeting of the JAK-STAT pathway, 2025. Nature Signal Transduction and Targeted Therapy. NF-κB in biology and targeted therapy, 2024. Nature Signal Transduction and Targeted Therapy. Wnt signaling pathways: mechanisms and diseases, 2025. Nature Reviews Drug Discovery. A renaissance in targeting the PI3K/AKT/mTOR pathway, 2026. Nature Signal Transduction and Targeted Therapy. Targeting RAS/RAF/MAPK pathway for cancer therapy, 2023. Frontiers in Cell and Developmental Biology. Role of Notch, Hedgehog, and Wnt in tumor microenvironment, 2021. KEGG Pathway Database. Current Statistics, 2026. USP. mRNA Vaccine Quality Analytical Methods (2nd Ed), 2023. J Pharm Sci. CMC Regulatory Considerations for Antibody-Drug Conjugates, 2023. NMPA CDE. ICH Q8/Q9/Q10 问答（R5）, 2024. FDA. Novel Drug Approvals, 2025. Antibody Society. Antibody Therapeutics Approved/In Review, 2025-2026. — 信号通路与抗体药物系列 · 持续更新中 —

申请上市临床研究上市批准临床申请

2017-04-17

·BioSpace

When It Rains, It Pours: Bay Area’s OncoMed Tanks Again as Lung Cancer Med Fails Phase II, Discontinues Phase I Study

April 17, 2017 By Alex Keown , BioSpace.com Breaking News Staff REDWOOD CITY, Calif. – Shares of OncoMed Pharmaceuticals are down more than 18 percent this morning after the company announced its mid-stage combination lung cancer treatment failed to meet endpoints. OncoMed said tarextumab (anti-Notch2/3, OMP-59R5) in combination with etoposide and a chemotherapy drug to treat patients with extensive-stage small cell lung cancer showed results that were “undifferentiated from those of chemotherapy plus placebo.” As a result, the company said the trial did not meet primary endpoints of progression-free survival, nor secondary endpoints of overall survival. The median progression-free survival for tarextumab plus chemotherapy was 5.6 months versus 5.5 months for chemotherapy plus placebo. Overall response rates were 68.5 percent and 70.8 percent in the tarextumab and placebo arms respectively, the company said. Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. The drug is part of OncoMed’s collaboration with GlaxoSmithKline . Small cell lung cancer is expected to make up between 10 and 15 percent of the 224,390 newly diagnosed lung cancer cases and the 158,080 deaths estimated to occur in the U.S. Current standard of care in treating small cell lung cancer is the chemotherapeutic etoposide in combination with either cisplatin or carboplatin. “Small cell lung cancer is a very difficult-to-treat disease and unfortunately, tarextumab did not show benefit over placebo in this Phase 2 trial,” Paul Hastings , OncoMed’s chairman and chief executive officer said in a statement. Additionally, OncoMed said it will discontinue enrollment in the Phase 1b clinical trial of brontictuzumab (anti-Notch1, OMP-52M51) in combination with trifluridine/tipiracil (Lonsur) in third-line colorectal cancer patients. The combination of brontictuzumab plus chemotherapy was not tolerable in this patient population. April has not been kind to OncoMed. On April 10, the company announced its partnership with Bayer to develop two drugs, vantictumab and ipafricept , both Wnt pathway inhibitors, had ended due to “strategic reasons.” With Bayer’s withdrawal, OncoMed retains worldwide rights to both drugs. Also on April 10, the company announced it was terminating a Phase II trial testing demcizumab in combination with Abraxane as a first-line treatment in metastic pancreatic cancer after the drug failed to meet endpoints. Due to the events announced today and last week, Hastings said the company will undergo an immediate comprehensive portfolio prioritization review. “The immediate task ahead is to thoroughly examine the available data, our resources and the opportunities to re-focus our efforts. We ended the first quarter of 2017 with $156.9 million in cash and short-term investments,” Hastings said.

临床2期临床结果临床1期临床3期临床失败

2014-09-04

·BioSpace

Redwood City’s OncoMed Pharmaceuticals, Inc. Moves Forward On Drug Trials Halted Due To Side Effects

September 5, 2014 By Krystle Vermes , BioSpace.com Breaking News Staff California-based OncoMed Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration has removed the partial hold on its ipafricept Phase 1 clinical trials. As a result, OncoMed will continue enrollment, and patients will begin participating in experiments within the next few weeks. “With important input from our clinical investigators and academic bone experts, the OncoMed team has developed modified study parameters intended to avoid potential risks while allowing us to evaluate the therapeutic impact of ipafricept for patients with pancreatic, hepatocellular and ovarian cancers in combination with standard therapy,” said Jakob Dupont , M.D., OncoMed’s Chief Medical Officer. “We appreciate the FDA’s prompt response to our submission and their acceptance of our proposed amendments to the trial protocols.” OncoMed gave the FDA a clinical safety and efficacy package for the drug. In turn, the FDA placed the partial clinical trial on hold. Modified dosing regimens, risk mitigation measures and modified enrollment criteria were the amendments of the Phase 1b trials. On June 13, OncoMed announced that it would voluntarily be halting enrollment in its Phase 1 vantictumab and ipafricept Wnt pathway programs. This came after reported incidents of mild-to-moderate bone adverse events. After the FDA looked at more data and amended study protocols given to it by OncoMed, it decided to remove the partial hold on the clinical trials. “We expect enrollment in our first-in-class Wnt pathway programs, ipafricept and vantictumab, to be back underway soon,” said Paul J. Hastings , Chairman and Chief Executive Officer of OncoMed. “The Wnt pathway represents a highly promising target for disrupting cancer stem cell activity and inducing tumor differentiation. As we advance ipafricept and vantictumab through clinical studies in combination with standard of care, we expect to generate key data from these Phase 1b studies that will support a potential opt-in by our partner Bayer as well as late-stage clinical development.” Ipafricept is a fusion protein that inhibits a signaling pathway in cancer called the Wnt pathway. It binds to ligands that are activators in Wnt signaling. Patients who received ipafricept in a Phase 1a study tolerated the treatment well, and experimentations showed that the fusion protein demonstrated on-target Wnt pathway modulation. OncoMed Pharmaceuticals is dedicated to discovering and developing therapeutics that target cancer stem cells. The company has five anti-cancer products in clinical development. var switchTo5x=true; stLight.options({publisher: "0341611e-38a4-415d-9e18-75e093ff27e0", doNotHash: false, doNotCopy: false, hashAddressBar: false});

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100 项与 Ipafricept 相关的药物交易

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D11758	-	-	DB15045

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适应症	最高研发状态	国家/地区	公司	日期
转移性肝细胞癌	临床1期	美国	-	2014-01-01
铂敏感性卵巢癌	临床1期	美国	-	2014-01-01
胰腺导管腺癌	临床1期	美国	Mereo BioPharma 5, Inc.	2013-11-01
卵巢癌	临床1期	美国	Bayer AG	2012-06-01
前列腺癌	临床1期	美国	Bayer AG	2012-06-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02050178 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	胰腺癌一线	26	Gemcitabine+nab-paclitaxel+Ipafricept	顧艱觸獵憲鏇鬱鑰製壓(遞鏇範廠鬱構餘遞壓願) = 鹹壓壓觸夢憲鏇鹹鏇繭積鏇蓋襯夢築壓醖糧鹹 (艱餘淵齋鬱製遞顧醖齋, 3.4 ~ 18.4) 更多	不佳	2020-10-15
NCT02092363 (Pubmed \| Obstet Gynecol Surv) 人工标引	临床1期	铂敏感性卵巢癌	37	paclitaxel+carboplatin+ipafricept	繭選鬱鏇淵願憲顧憲鹹(壓窪壓廠選網遞齋簾遞) = 鬱鬱願積艱鑰鬱獵夢鬱蓋膚獵夢鑰壓簾築構構 (製範製淵醖簾製廠糧壓 ) 更多	积极	2019-08-01
NCT02050178 (ASCO_GI2019)	临床1期	胰腺癌	26	Ipafricept + Nab-P/G	鑰醖糧蓋衊糧廠艱製鹽(衊鏇遞蓋製獵範觸顧鑰) = included 2 events of AST elevation, and 1 each of nausea, maculopapular rash, vomiting and WBC decrease 網糧鹹簾鏇窪淵膚鹹襯 (構積製齋鏇獵艱蓋淵壓 ) 更多	积极	2019-01-29
NCT01608867 (Pubmed) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	26	Ipafricept	糧蓋淵範顧廠襯蓋鬱蓋(蓋齋繭醖願鬱蓋構糧鹽) = 15 mg/kg；Q3W 夢願醖範淵顧壓襯願構 (窪築選鑰觸壓願構夢鹹 ) 更多	积极	2017-12-15
Phase 1b clinical studies (AACR2014)	临床1期	肝细胞癌 \| 卵巢癌	-	OMP-54F28	積觸齋糧範願簾構膚膚(範製鏇齋夢壓襯鹽淵鹹) = induction 齋糧壓艱淵醖窪壓蓋觸 (網鏇願構簾淵顧鏇鏇簾 ) 更多	积极	2014-10-01
Phase 1b clinical studies (AACR2014)	临床1期	肝细胞癌 \| 卵巢癌	-	OMP-54F28 + Sorafenib		积极	2014-10-01
NCT01608867 (ASCO2014)	临床1期	HR阳性/HER2低表达实体瘤	25	OMP-54F28	範選顧蓋選積夢製網壓(鑰壓鏇壓襯製網廠襯襯) = 製選壓鹽憲淵鑰襯遞艱築獵餘襯積糧衊糧鑰糧 (糧夢鬱窪壓觸鏇蓋憲願 ) 更多	-	2014-05-20