A Multi-center Phase 2 Study of Neoadjuvant Immunotherapy in Combination With the Anti-GDF-15 Antibody Visugromab (CTL-002) for the Treatment of Muscle Invasive Bladder

This is a multi-center, stratified and single-blinded Phase 2 study of neoadjuvant immunotherapy in combination with the antiGDF15 antibody visugromab (CTL-002) for the treatment of subjects with MIBC set to undergo radical Cystectomy (RC)/Re-TURBT who cannot receive or refuse to receive cisplatin-based chemotherapy.

开始日期2023-09-06

申办/合作机构

CatalYm GmbH

NCT04725474

/ Active, not recruiting临床1/2期

A Phase 1/2, FIH, Two-part, Open-label Clinical Trial of Intravenous (IV) Administration of CTL-002 Given as Monotherapy and/or in Combination With an Anti-PD-1 Checkpoint Inhibitor in Subjects With Advanced-stage, Relapsed/Refractory Solid Tumors (The "GDFATHER"-Trial: GDF-15 Antibody-mediaTed Human Effector Cell Relocation).

The Phase 1 part (Part A) is a dose escalation study of IV visugromab (CTL-002, a monoclonal antibody neutralizing GDF-15) as monotherapy and in combination with an approved checkpoint inhibitor (CPI) in patients with advanced solid tumors.
Enrolment into the Ph 1 part is completed.
The Phase 2 parts (Part B) are cohort expansions with visugromab (CTL-002) in combination with a defined CPI at a fixed dose into seven different solid tumor indications.

开始日期2020-12-09

申办/合作机构

CatalYm GmbH

100 项与维苏格罗单抗相关的临床结果

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100 项与维苏格罗单抗相关的转化医学

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100 项与维苏格罗单抗相关的专利（医药）

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项与维苏格罗单抗相关的文献（医药）

2025-01-30·Nature

Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours

Article

作者: Trojan, Jörg ; Vilalta-Lacarra, Anna ; Fettes, Petra ; Richly, Heike ; Akdemir, Julia ; Chun, Felix Kyoung Hwan ; Gajewski, Thomas F ; Hackl, Hubert ; Racca, Fabricio ; Esteban-Villarrubia, Jorge ; Rössler, Bernhard ; Reis, Henning ; Torres-Jiménez, Javier ; Bargou, Ralf ; Lloyd, Peter ; Wild, Peter ; Trajanoski, Zlatko ; Alonso, Guzman ; Landa-Magdalena, Ana ; Auckenthaler, Alexandra ; Hermann, Frank ; Schuler, Martin ; Schuberth-Wagner, Christine ; Gjorgjioska, Ana ; Rodriguez Ruiz, Maria-Esperanza ; König, David ; Koster, Kira-Lee ; Foerster, Friedrich ; Melero, Ignacio ; Goebeler, Maria-Elisabeth ; Auer, Marlene ; Saavedra, Omar ; Koll, Florestan J ; Machacek, Matthias ; Dutta, Aradhana ; Gromke, Tanja ; Fridman, Wolf H ; Galle, Peter R ; de Miguel Luken, Maria ; Soto-Castillo, Juan José ; Eggenschwiler, Corinne ; Liebig, Mara ; Sanduzzi-Zamparelli, Marco ; Dummer, Reinhard ; Garralda, Elena ; Hess, Dagmar ; Läubli, Heinz ; Rüschoff, Josef ; da Silva, Antonio ; Tereshchenko, Anastasiia ; Rüdiger, Manfred ; Eggermont, Alexander M M ; Calvo, Emiliano ; L'Huillier, Phil ; Haake, Markus ; Fortuny, Marta ; Koch, Christine ; Klar, Kathrin ; Gogolla, Falk ; Moreno, Irene ; Sayehli, Cyrus ; Joerger, Markus ; Sabat, Paula ; Oberoi, Arjun ; Hernando-Calvo, Alberto ; Schmitt, Andreas M ; Reichhardt, Daniela ; Schöniger, Sandra ; Lichtenegger, Felix S ; Ramelyte, Egle ; Zink, Carina ; de Velasco, Guillermo ; Martín-Liberal, Juan ; Reig, Maria ; Wischhusen, Jörg ; Leo, Eugen

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment¹. Yet, response rates are still limited, and tumour progression commonly occurs². Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition³. In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

2015-07-01·Arteriosclerosis, thrombosis, and vascular biology1区 · 医学

Choline Transporter-Like Protein-2

1区 · 医学

Article

作者: Santoso, Sentot ; Werth, Silke ; De Meyer, Simon F. ; Tjahjono, Yudy ; Bayat, Behnaz ; Berghöfer, Heike ; Deckmyn, Hans ; Sachs, Ulrich J.

Objective—:

In contrast to other antibodies involved in transfusion-related acute lung injury, anti–HNA-3a antibodies are incapable of inducing direct neutrophil activation and seem to interact with endothelial cells (ECs) primarily. In animal studies, anti–HNA-3a-mediated transfusion-related acute lung injury could be precipitated in the absence of neutrophils, but was stronger when neutrophils were present. In a different context the target protein of these antibodies, choline transporter-like protein-2 (CTL-2), was reported to interact with a protein of the inner ear carrying 2 von Willebrand factor (VWF) A-domains. These observations prompted us to investigate whether VWF might be involved in anti–HNA-3a-mediated neutrophil activation, and whether signaling via CD11b/CD18 is involved, as in various other experimental settings.

Approach and Results—:

Cell adhesion demonstrated specific binding of CTL-2 to VWF. Immunoprecipitation analysis of CTL-2/CD11b/CD18 coexpressing cells indicated that anti–HNA-3a colocalizes CTL-2 and CD11b/CD18 when VWF is present. Functional studies revealed that anti–HNA-3a-mediated neutrophil agglutination is an active, protein kinase C-dependent and partially Fc-dependent process. Agglutination and the production of reactive oxygen species seem to require the formation of a trimolecular complex between the target antigen (CTL-2), CD11b/CD18 and VWF. In line with these observations, anti–HNA-3a induced less severe transfusion-related acute lung injury and less neutrophil recruitment to the alveolar space in VWF knockout mice.

Conclusions—:

We introduce CTL-2 as a new binding partner for VWF. Interaction of neutrophils with VWF via CTL-2 allows anti–HNA-3a to induce signal transduction via CD11b/CD18, which leads to neutrophil activation and agglutination. In transfusion-related acute lung injury, this mechanism may further aggravate endothelial leakage.

项与维苏格罗单抗相关的新闻（医药）

2025-05-13

·CPHI制药在线

金笔奖|冉冉升起的新兴靶点——GDF15

关注并星标CPHI制药在线在2024 ESMO大会上发布、同步发表于《新英格兰医学杂志》（The New England Journal of Medicine）的一项重要研究结果显示，辉瑞的创新疗法ponsegromab 的II 期临床研究达到了主要终点，即与安慰剂相比，接受ponsegromab治疗的癌症恶液质和GDF-15水平升高患者的体重与基线相比发生了显著变化。在较高用药剂量下可使癌症恶病质患者在12周内恢复约5.6%的体重，食欲、身体活动量和骨骼肌质量均有所改善。Ponsegromab是一种针对GDF15（生长分化因子-15）的单克隆抗体。GDF15是一种蛋白质，研究发现它在恶病质等病症中起到了关键作用。辉瑞在此领域的研究并非首次亮相，但此次的进展令人瞩目。根据辉瑞的计划，将推进Ponsegromab进入三期临床试验，这意味着这款药物可能会成为一种能够治疗癌症恶病质的突破性疗法。早在2022年，Ponsegromab注射液就获CDE临床实验默示许可，适应症为癌症相关恶液质，以及成人患者心力衰竭。这是国内首款获批IND的GDF15单抗。免疫耐药及恶病质潜力靶点：GDF-15癌症相关厌食/恶病质综合征(cancer-related anorexia/cachexia syndrome, CACS)是指癌症患者在患病过程中不可控制的体重减轻，其症状包括厌食，肌肉量和脂肪组织减少引起的体重减轻。每年全球癌症死亡人数的一半（约820万人）归因于最常与恶病质相关的癌症，如胰腺癌（33万人死亡），食道癌（40万），胃癌（72万），肺癌（159万），肝（75万）和结肠直肠癌（69万）。研究表明，没有体重减轻的癌症患者有更好的预后推估，有效的治疗手段能够大大增加癌症患者的存活几率。根据FortuneBusinessInsights，2019年全球癌症恶病质市场规模为20.2亿美元，预计到2032年将达到37.6亿美元，预测期内复合年增长率为5.0%。此外，全球范围内恶性肿瘤患者患病率不断上升，恶病质患病率也不断增加，对其有效治疗需求激增，推动市场增长。肿瘤恶病质的临床治疗主要为营养干预和药物干预。共识仅推荐改善患者食欲的孕激素类似物、糖皮质激素以及中医药辅助治疗。截至目前，FDA尚未批准任何药物用于肿瘤恶病质的治疗。研发端，全球首个治疗肿瘤恶病质药物阿那莫林anamorelin（日本小野制药）已于2021年在日本上市，是一种选择性GHS-R1a（促生长激素释放激素受体）激动剂，目前仍为肿瘤恶病质靶向治疗的研究热点。除阿那莫林外，治疗肿瘤恶病质的创新药管线主要聚焦被称为“厌食激素”的生长分化因子15（GDF15）。GDF-15是一种应激诱导细胞因子，可与后脑中的神经胶质细胞衍生的神经营养因子家族受体α样蛋白（GFRAL）结合。GDF-15-GFRAL通路已成为厌食症和体重调节的主要调节因子，并与恶病质的发病机制有关。研究表明GDF-15水平升高与体重和骨骼肌质量下降以及癌症患者的力量和生存率下降有关，以上这些因素凸显了GDF-15是潜在的治疗靶点。另外，GDF15也被认为是抗肿瘤T细胞活性的负调节因子，与抑制免疫反应有关，并阻止了T细胞被招募到肿瘤微环境中。同时，肿瘤在其微环境中表达并释放大量的GDF-15，这使它能够避免被循环免疫细胞识别并产生抗肿瘤免疫反应。因此，抑制GDF15也是克服癌症标准治疗和免疫治疗（如检查点抑制剂）耐药的重要靶点。GDF-15靶点相关的药物可以通过以下途径治疗肿瘤：减少癌症相关恶病质的发生和发展，提高癌症生存期和生活质量；干扰DC的激活和成熟；减少树突状细胞对T细胞的诱导和激活作用；阻断有效的免疫细胞外渗和肿瘤浸润；抑制T细胞和NK细胞对肿瘤细胞的杀伤作用；通过产生和增强调节性T细胞的功能，在肿瘤组织中诱发免疫抑制。初见曙光截至目前，全球范围内尚未有GDF15靶点相关药物获批上市，处于临床阶段的药物数量也较少。除Ponsegromab外，开发用于克服免疫耐药及恶病质处于临床活跃阶段的仅有CatalYm的Visugromab和AVEO的Rilogrotug两款药物。值得一提的是，国内劲方医药研发的GDF15/IL-6双抗GFS202A IND也于近日获批，不久将开展1期临床，首选适应症为肿瘤恶病质（恶性肿瘤）。GFS202A有望通过双靶点协同机制提升疗效，并同时缓解炎症反应、降低抗癌治疗相关副作用。CatalYm公司VisugromabVisugromab是一款人源化的单克隆抗体，旨在中和肿瘤产生的GDF15来抵消免疫抑制机制，增强免疫细胞对肿瘤的浸润，改善DC细胞对T细胞的激活，增强T细胞和NK细胞的肿瘤杀伤作用。目前已进入到2期临床研究当中。在2024年ASCO年会上，CatalYm报告了其正在进行的“GDFATHER”1/2a期试验的随访结果。数据显示，Visugromab与抗PD-1抗体nivolumab联合治疗，在非小细胞肺癌（NSCLC）、尿路上皮癌（UC）或肝细胞癌（HCC）的抗PD-1/PD-L1复发/难治性患者中，获得了深度和持久的抗肿瘤活性，包括几个完全反应。AVEO的RilogrotugAV-380是AVEO 首款靶向GDF15 的高效人源化抑制性 IgG1 抗体，用于治疗癌症恶病质。临床前数据显示，恶病质作为一种复杂的代谢综合征，抑制GDF15可诱导分解代谢转向合成代谢，这表明AV-380抑制GDF15可能逆转恶病质的影响。目前正在进行针对癌症患者的 1b 期临床试验。在2023年9月底于爱丁堡召开的第七届癌症恶病质会议（7th Cancer Cachexia Conference）上，AVEO公布了Rilogrotug临床1b期剂量递增研究的方案，拟探索在标准治疗（SOC）中加入Rilogrotug是否会为转移性恶病质患者带来额外的临床获益。参考来源 1.Groarke JD, Crawford J, Collins SM, Lubaczewski S, Roeland EJ, Naito T, Hendifar AE, Fallon M, Takayama K, Asmis T, Dunne RF, Karahanoglu I, Northcott CA, Harrington MA, Rossulek M, Qiu R, Saxena AR.Ponsegromab?for the Treatment of Cancer Cachexia.N Engl J Med. 2024 Sep 14. doi: 10.1056/NEJMoa24095152.Groarke JD, Crawford J, Collins SM, Lubaczewski SL, Breen DM, Harrington MA, Jacobs I, Qiu R, Revkin J, Rossulek MI, Saxena AR.Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.J Cachexia Sarcopenia Muscle. 2024 Jun;15(3):1054-1061 作者简介：@江湖之远，男，暨南大学药物化学专业硕士，曾在多家国内药企从事肿瘤新药学术推广工作，关注国内外肿瘤新药研发动态，专注于肿瘤新药领域耕耘。END【企业推荐】领取CPHI & PMEC China 2025展会门票来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床申请临床2期临床3期临床1期

2025-04-25

·Business Wire

CatalYm to Present New Data Demonstrating GDF-15 Blockade Enhances Efficacy of Antibody-Drug Conjugates at AACR 2025

MUNICH--(BUSINESS WIRE)--CatalYm today announced the presentation of the first preclinical data demonstrating that the company’s clinical-stage antibody visugromab can improve the anti-tumor activity of antibody-drug conjugates (ADCs). The data will be presented at the American Association for Cancer Research (AACR) Annual Meeting, taking place in Chicago, IL, April 25-30, 2025. The poster will highlight the potential of targeting Growth Differentiation Factor 15 (GDF-15) to enhance the activity and overcome resistance to ADC therapies, which are increasingly used as frontline treatments in several solid tumor indications. The full abstract is available on the AACR Annual Meeting website. The study showed that several clinically validated ADCs, including topoisomerase I and microtubule inhibitor-based regimens, consistently triggered GDF-15 expression, suggesting a potential resistance mechanism to ADC therapy. Across in vitro and in vivo models of multiple solid tumor types, ADC treatment induced GDF-15 release from tumor cells, leading to elevated serum levels and reduced ADC efficacy. Combining ADC treatment with GDF-15 neutralization improved anti-tumor responses, resulting in reduced tumor growth and enhanced infiltration and activation of T cells and myeloid cells in the tumor microenvironment. “We are building a broader understanding of GDF-15 as a key resistance mechanism activated by targeted approaches like ADCs as well as the leading immunotherapies like PD-1 inhibitors,” said Christine Schuberth-Wagner, PhD, Chief Scientific Officer at CatalYm. “By blocking GDF-15, visugromab restores anti-tumor immune activity and enhances treatment efficacy, underscoring its potential as a versatile combination partner across a broad spectrum of cancer therapies beyond immunotherapies.” “ADCs continue to demonstrate potent and specific therapeutic impact, nevertheless resistance is a significant challenge for long-term patient benefit. In addition to our Phase 2 clinical development program, CatalYm will continue to investigate how our GDF-15 neutralizing antibody visugromab can create a novel path to address cancer resistance effectively,” added Scott Clarke, Chief Executive Officer at CatalYm. The preclinical findings build on clinical evidence from the GDFATHER-1/2a trial (GDF-15 Antibody-mediaTed Human Effector T Cell Relocation Phase 1/2a Trial; NCT04725474), that was recently published in Nature. The data show that visugromab induces deep and durable responses in patients with relapsed or refractory solid tumors who had progressed on prior anti-PD-1/PD-L1 therapies. In addition to restoring anti-tumor immune responses, visugromab also demonstrated the potential to mitigate cancer-associated cachexia. CatalYm is currently conducting a broad, global Phase 2b clinical development program for visugromab, evaluating its effectiveness in earlier treatment lines of non-squamous non-small-cell lung cancer and hepatocellular carcinoma, as well as neoadjuvant treatment in urothelial cancer in combination with standard of care. Poster details Session title: “PO.IM01.03 - Antibodies and Antibody-Drug Conjugates” Abstract title: “GDF-15 neutralization enhances the therapeutic activity of antibody-drug conjugates” Abstract number: 4777/13 Location: Section 36 Date and time: April 29, 2025, 9:00 AM – 12 PM CT/ 4:00 PM – 7:00 PM CEST About Visugromab Visugromab is a monoclonal antibody that neutralizes the tumor-derived Growth Differentiation Factor-15 (GDF-15), a locally acting immunosuppressant fostering immunotherapy resistance. Neutralizing GDF-15 with visugromab reverses key cancer resistance mechanisms to reinstate an efficient anti-tumor response by re-enabling immune cell activation, proliferation and induction of interferon-γ. About CatalYm CatalYm is developing visugromab, a first-in-class anti-GDF-15 antibody, in solid tumors and other indications. In its first-in-human Phase 1/2a study, visugromab demonstrated durable anti-tumor efficacy with long-lasting objective responses in relapsed and refractory metastatic solid tumor patients in combination with anti-PD-1 treatment. In addition, data from the same study demonstrated that visugromab can significantly counteract the effects of cachexia in these patients. This data was recently published in Nature and presented at the International Conference on Sarcopenia, Cachexia & Wasting Disorders. CatalYm is now advancing visugromab into multiple Phase 2b studies. Founded in 2016 and based in Munich, Germany and San Francisco, USA, CatalYm is backed by leading international investors including Canaan Partners, Bioqube Ventures, Forbion, Omega Funds, Gilde Healthcare, Jeito Capital, Novartis Venture Fund, Vesalius, Brandon Capital, Bayern Kapital, BioGeneration Ventures, and Coparion.

临床2期免疫疗法临床结果AACR会议抗体药物偶联物

2025-02-25

·靶点圈

研究进展 | 肥胖与肿瘤治疗新星靶点—GDF15

01 GDF15 结构概述 GDF15的结构与家族关系 GDF15属于转化生长因子-β（TGF-β）超家族，曾被称为MIC-1、PDF、PLAB、PTGF-β和NAG-1等。基因位于染色体19p12-13.1，由两个外显子组成，被一个2.9kb的内含子隔开。图1 GDF15 的基因（A）和蛋白质（B）结构示意图 GDF15合成时为前体蛋白，经蛋白水解切割后分泌成熟形式和前肽，前肽可自主发挥功能，其成熟域形成稳定二聚体二硫键结构，且存在多种翻译后修饰，影响其稳定性和功能。图2 GDF-15的合成、成熟和分泌 GDF15的氨基酸序列 Signal Propeptide Chain 1-29 30-194 195-308 GDF15的表达 GDF15在胎盘滋养细胞、前列腺、尿路上皮和胃肠道细胞中的细胞质表达，多种细胞在应激时也可分泌。图3 器官间和细胞器间连接调节 GDF15 的表达和功能 GDF15的调节因子多种转录因子可诱导其表达，如p53、TFEB等，共同维持机体的生理平衡。图4 GDF15 的调节因子和效应器 GDF15的受体 2017年确定GFRAL是GDF15的特异性受体，属于TGF-β超家族中GDNF家族受体α组。GFRAL是一种44kDa的蛋白质，具有单个跨膜结构域和短的胞质结构域，其基因位于人类6号染色体p12.1，主要在脑内特定区域高度表达。当GDF15与GFRAL结合后，形成的GDF15-GFRAL复合物会进一步结合并磷酸化共受体酪氨酸激酶RET。此外，GDF-15还可与ErbB2受体结合。 GDF15的靶细胞 GDF-15的靶细胞众多，涵盖成纤维细胞、红细胞、肿瘤细胞等，对不同靶细胞产生不同的生物学效应，如促进成纤维细胞活化、影响红细胞生成和肿瘤细胞增殖转移等。 GDF15相关信号通路 GDF15能通过与GFRAL结合，激活MAPK、PI3K/AKT、STAT3、RET、Wnt等通路，影响肿瘤生长、代谢等。此前认为其可激活SMAD通路，后证实可能是TGFβ污染所致。图5 GDF15 相关信号通路 GDF15的生理状态基础血浆水平在337-1060pg/mL，随年龄增长，在某些生理变化时升高。与红细胞成熟、Treg细胞调节等相关。 GDF15的病理状态 ①在多种疾病中血浆水平升高，如代谢、心血管疾病、癌症等。 ②作用具有多样性，如在肥胖中调节食欲和体重，在癌症中具有抑制早期肿瘤生长、促进晚期进展和转移的双重作用，在心血管疾病中可作为生物标志物和发挥保护功能。 ③与多种癌症（如结直肠癌、卵巢癌和肝细胞癌）的进展密切相关。图6 GDF-15 在不同生理和病理背景下状态 GDF15的检测方法血清GDF-15常用免疫分析法检测，如酶联免疫吸附测定（ELISA）、细胞计数微球阵列和电化学发光免疫分析（ECLIA）。这些方法灵敏度高、特异性强，能精确定量。健康人血清GDF-15水平在200-1200pg/mL，老年人和女性略高。图7 导致细胞内生长和 GDF-15 增加的主要途径及其临床意义 02 GDF-15在疾病中的作用图8 GDF-15在不同疾病中的作用 GDF-15的生理作用生理状态下，GDF15参与代谢调节、炎症反应和生物应答，如调节食物摄入、改善胰岛素分泌等。 GDF-15 炎症和血血症 GDF-15可作为败血症严重程度的生物标志物，血清GDF-15水平在败血症时会升高，与降钙素原、IL-6和IL-10呈正相关，并且与败血症的预后、严重程度以及患者的生存情况相关。体外实验表明，它可降低TNF-α、IL-6、MCP-1和IL-10等促炎细胞因子的表达，抑制巨噬细胞炎症反应，改善吞噬和杀菌功能，但全身效应存在争议。 GDF-15介导衰老 GDF-15水平随年龄增长，与衰老相关疾病密切相关，影响细胞衰老、线粒体功能和细胞间通讯。在细胞衰老过程中，GDF-15是衰老相关分泌表型（SASP）的重要组成部分；线粒体功能障碍会诱导其表达。 GDF-15介导纤维化 GDF-15与肝、肺等器官纤维化相关，在不同研究中对纤维化的影响存在差异，可能通过调节巨噬细胞功能发挥作用。 GDF-15影响再生过程在植入材料相关研究中，巨噬细胞接触钛纳米颗粒会增加GDF-15表达，影响植入物骨整合，导致无菌性松动；在前列腺癌骨转移中，GDF-15可激活破骨细胞生成并招募巨噬细胞。 GDF-15在心血管疾病中的作用 GDF-15可作为心血管疾病的生物标志物，与心血管死亡率和全因死亡率呈正相关。它可以影响心肌梗死后免疫细胞募集、减少心脏纤维化、促进受损心肌的血管生成和心脏修复，也能预测患者的死亡风险和复发情况。 GDF-15在代谢疾病中的作用图9 GDF15 抑制能量摄入和肥胖的机制 ①调节食欲，影响食物偏好：GDF-15具有调节食欲的作用，能通过与GFRAL结合减少能量摄入，进而减轻体重。缺乏GDF15或GFRAL会导致代谢变化。 ②导致恶心、呕吐和味觉厌恶：GDF15-GFRAL信号可引发恶心、呕吐和味觉厌恶等反应，机制可能与激活相关神经通路和5-HT3R有关。 ③延迟胃排空：通过与GFRAL相互作用延缓胃排空，但这并非GDF15诱导厌食的必要条件。 ④增加能量消耗，促进脂肪分解：研究表明GDF15存在非饮食依赖的减重途径，维持骨骼肌能量消耗，促进能量代谢，可激活脂肪组织中与脂质代谢相关的基因，促进脂肪组织的分解代谢，减少白色脂肪含量。 ⑤影响糖代谢：GDF15对维持正常血糖水平和胰岛素敏感性至关重要，高血浆GDF-15水平与葡萄糖耐量受损、胰岛素抵抗、糖尿病及糖尿病相关并发症有关，但在葡萄糖稳态中的具体作用尚不明确。表1 靶向GDF15及受体的治疗肥胖药物 GDF15在癌症中的作用 ①作为诊断和预后生物标志物 GDF-15在多种胃肠道肿瘤（如肝癌、胰腺癌、胃癌、结直肠癌、食管癌等）以及其他多种癌症（如乳腺癌、肺癌等）中呈现高表达，可作为诊断和预后生物标志物，其水平变化与肿瘤的发展和患者预后相关。 ②GDF-15在肿瘤发展中的双重作用在肿瘤发生早期，GDF-15对肿瘤生长有抑制作用。在肿瘤晚期，GDF-15可促进肿瘤的进展和转移。 ③与巨噬细胞的相互作用巨噬细胞通过分泌GDF-15影响肿瘤微环境。同时，肿瘤细胞也可诱导巨噬细胞分泌GDF-15，二者相互作用，共同促进肿瘤发展。在肿瘤发展过程中，GDF-15可促使巨噬细胞表型发生改变。早期，GDF-15可能减少M1型巨噬细胞，降低免疫监视，有利于肿瘤生长；晚期，高浓度的GDF-15增加M2型巨噬细胞浸润，促进肿瘤血管生成、转移和化疗耐药。图10 GDF-15 的致癌作用 03 靶向GDF15的癌症治疗图11 GDF15 用于癌症治疗的人源化免疫球蛋白抗体的机制癌症免疫治疗肿瘤来源的GDF15抑制T细胞功能，阻断GDF15可逆转免疫抑制，激活T细胞杀伤癌细胞，相关人源化抗体已开展临床试验。在临床试验中，CTL-002能促进实体瘤患者CD4/CD8阳性和细胞毒性T细胞的浸润，发挥抗肿瘤活性；AZD8853可抑制晚期癌症患者的肿瘤进展，相关临床试验正在进行中。抑制癌症耐药性 GDF15与多种癌症的耐药性相关，抑制其分泌有望克服耐药，提高癌症治疗效果。例如，化疗刺激会促使人类胰腺星状细胞分泌GDF15，导致胰腺癌产生化疗耐药性；GDF15还可通过ForkheadboxproteinM1途径诱导乳腺癌耐药。抑制GDF15的分泌有望克服癌症治疗中的耐药问题，增强癌症治疗效果。研究发现，联合使用依立布林与GDF15抑制剂可提高乳腺癌治疗效果；中和GDF15能显著逆转食管癌的化疗耐药性，提升化疗疗效。缓解癌症恶病质中和GDF15可改善癌症恶病质症状，相关药物在临床前和临床试验中显示出一定疗效。研究表明，GDF15能改善顺铂诱导的体内副作用，使用GDF15抗体（如mAB2、3P10）治疗可恢复恶病质小鼠的肌肉功能，增强其体力活动能力。在临床试验中，Ponsegnomab作为高特异性GDF15抑制剂，可使癌症患者体重安全增加；新型GDF15阻断剂KA1641-ZY1在抗恶病质方面表现更优。表2 靶向GDF15的药物进展 04 GDF15在不同肿瘤中的作用图12 GDF-15在不同疾病中的蛋白质浓度肝细胞癌（HCC）在HCC中，GDF15不仅参与肿瘤细胞的增殖、迁移、侵袭和血管生成等过程，还在肿瘤免疫微环境中发挥重要作用，影响免疫细胞的功能，促进肿瘤的免疫逃逸。血清GDF15水平可用于HCC诊断和预后判断，与AFP、PIVKA-II联合检测可提高诊断敏感性和特异性，其表达水平与HCC病理分级相关，与患者生存期有关，但需更多临床数据验证。抑制GDF15功能或表达可能成为HCC有效治疗策略。图13 GDF15 对肝癌免疫微环境中免疫细胞的影响胰腺癌 GDF15可区分良恶性胰腺疾病，且对早期胰腺导管腺癌具有较好的诊断准确性，在恶性胰腺疾病患者中的水平显著高于良性疾病或健康对照者。GDF15蛋白可与GFRAL结合，触发胰腺导管腺癌细胞的进展和迁移。其表达通过胰腺腺癌微环境中激活的Akt/CREB1途径上调，促进胰腺癌细胞转移。高GDF15组患者中磷酸化JunN-末端激酶和Akt水平增加，表明GDF15及其调节靶点与胰腺癌发展有关。胃癌研究表明GDF15可能是胃癌的潜在诊断生物标志物，其mRNA和蛋白在胃癌患者中均过度表达，在转移性胃癌中表达水平尤其升高。GDF15过表达可激活STAT3信号，触发胃癌细胞增殖和迁移。顺铂是晚期胃癌的优化疗法，但GDF15-GFRAL-GCN2通路的激活会诱导谷胱甘肽产生，导致顺铂耐药。此外，细胞衰老常伴随顺铂耐药癌细胞出现，而GDF15会因线粒体应激而分泌，可能弥合线粒体功能障碍、细胞衰老和胃癌进展之间的差距。结直肠癌（CRC） CRC患者血清和肿瘤组织中的GDF15水平均高于健康个体和肿瘤无组织的同一CRC患者，提示其可作为诊断标志物指示CRC肿瘤发生。GDF15高表达与不良预后相关，可诱导CRC细胞向间充质表型转变，加速细胞生长、迁移和侵袭。缺氧可通过激活PERK-GDF15级联反应引发CRC扩散。食管癌（OC） GDF15在OC发生中过度表达，并在促进OC进展中起调节作用。回顾性人类队列研究显示，OC患者的血浆GDF15水平相对高于正常人群。GDF15可激活TGFβ-RII和Akt-Erk1/2通路，从而调节食管鳞状细胞的增殖和迁移，可能作为诊断和预后标志物，也是个性化治疗的有希望的靶点。乳腺癌 GDF15在乳腺癌发展中具有促进作用，可通过多种途径影响乳腺癌进程，与乳腺癌的耐药性相关。它能通过p-AKT/FOXM1和IGF-1R-FOXM1途径，促进乳腺癌的发展。此外，GDF15还可介导HER2磷酸化，降低HER2过表达乳腺癌细胞对曲妥珠单抗的敏感性，影响乳腺癌的治疗效果。表3 GDF-15 血清和肿瘤水平与不同癌症类型临床结果的相关性仁域生物参考文献 Tigu AB, Munteanu R, Moldovan C, Rares D, Kegyes D, Tomai R, Moisoiu V, Ghiaur G, Tomuleasa C, Einsele H, Gulei D, Croce CM. Therapeutic advances in the targeting of ROR1 in hematological cancers. Cell Death Discov. 2024 Nov 17;10(1):471. Li L, Huang W, Ren X, Wang Z, Ding K, Zhao L, Zhang J. Unlocking the potential: advancements and future horizons in ROR1-targeted cancer therapies. Sci China Life Sci. 2024 Dec;67(12):2603-2616. Tomuleasa C, Tigu AB, Munteanu R, Moldovan CS, Kegyes D, Onaciu A, Gulei D, Ghiaur G, Einsele H, Croce CM. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduct Target Ther. 2024 Aug 14;9(1):201. Quezada MJ, Lopez-Bergami P. The signaling pathways activated by ROR1 in cancer. Cell Signal. 2023 Apr;104:110588. Osorio-Rodríguez DA, Camacho BA, Ramírez-Segura C. Anti-ROR1 CAR-T cells: Architecture and performance. Front Med (Lausanne). 2023 Feb 17;10:1121020. Kipps TJ. ROR1: an orphan becomes apparent. Blood. 2022 Oct 6;140(14):1583-1591. Zhao Y, Zhang D, Guo Y, Lu B, Zhao ZJ, Xu X, Chen Y. Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies. Front Oncol. 2021 May 28;11:680834. Peng H. Perspectives on the development of antibody-drug conjugates targeting ROR1 for hematological and solid cancers. Antib Ther. 2021 Oct 15;4(4):222-227. Kamrani A, Mehdizadeh A, Ahmadi M, Aghebati-Maleki L, Yousefi M. Therapeutic approaches for targeting receptor tyrosine kinase like orphan receptor-1 in cancer cells. Expert Opin Ther Targets. 2019 May;23(5):447-456. 关注我们，持续更新相关内容

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适应症	最高研发状态	国家/地区	公司	日期
肌层浸润性膀胱癌	临床2期	意大利	CatalYm GmbH	2023-09-06
实体瘤	临床2期	-	CatalYm GmbH	2022-03-01
晚期癌症	临床2期	德国	CatalYm GmbH	2020-12-09
晚期癌症	临床2期	西班牙	CatalYm GmbH	2020-12-09
晚期癌症	临床2期	瑞士	CatalYm GmbH	2020-12-09
晚期恶性实体瘤	临床2期	德国	CatalYm GmbH	2020-12-09
晚期恶性实体瘤	临床2期	西班牙	CatalYm GmbH	2020-12-09
晚期恶性实体瘤	临床2期	瑞士	CatalYm GmbH	2020-12-09
膀胱癌	临床2期	德国	CatalYm GmbH	-
恶病质	临床2期	德国	CatalYm GmbH	-

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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


NCT04725474 (GDFATHER, BusinessWire) 人工标引	临床1/2期	肝细胞癌 \| 实体瘤 \| 非鳞状非小细胞肺癌 ... 更多	-	visugromab (non-squamous NSCLC)	鹽夢膚選憲顧築夢糧醖(蓋蓋遞築遞鬱窪鬱鑰選) = 鏇憲齋繭築顧獵襯艱選製製鬱餘衊網壓獵鏇淵 (衊鏇憲鏇築廠窪艱衊膚 ) 更多	积极	2024-12-11
NCT04725474 (GDFATHER, BusinessWire) 人工标引	临床1/2期	肝细胞癌 \| 实体瘤 \| 非鳞状非小细胞肺癌 ... 更多	-	visugromab (UC)	鹽夢膚選憲顧築夢糧醖(蓋蓋遞築遞鬱窪鬱鑰選) = 餘廠廠範繭積膚鹽糧築製製鬱餘衊網壓獵鏇淵 (衊鏇憲鏇築廠窪艱衊膚 ) 更多	积极	2024-12-11
NCT04725474 (GDFATHER, Biospace) 人工标引	临床1/2期	肝细胞癌 \| 非小细胞肺癌 \| 尿路上皮癌	-	Visugromab + Nivolumab	遞膚簾簾構選範齋製選(鏇構鹹醖膚簾衊觸鬱壓) = 製壓構築積鑰網築淵醖製鹹衊醖觸齋壓鹹襯憲 (繭醖範齋襯簾膚蓋觸願 )	积极	2024-06-02
NCT04725474 (GDFATHER, Biospace) 人工标引	临床1/2期	肝细胞癌 \| 非小细胞肺癌 \| 尿路上皮癌	-	Visugromab + Nivolumab (NSCLC)	夢簾艱遞餘壓餘願憲淵(衊簾積廠蓋襯膚蓋構繭) = 鏇壓觸繭醖遞積遞糧築獵簾鹹窪網憲餘築鹽網 (窪觸鏇糧廠夢廠醖簾膚 )	积极	2024-06-02
NCT04725474 (GDFather, ASCO2024) 人工标引	临床2期	肝细胞癌 \| 非小细胞肺癌 \| 尿路上皮癌	87	Visugromab 10 mg/kg + Nivolumab 240 mg Q2W	廠簾鹽窪淵範餘夢窪鏇(醖範夢糧範鏇鬱鹽衊窪) = 鹽蓋餘壓顧獵獵積積壓餘艱範窪壓製觸襯觸製 (觸遞醖夢廠齋鏇獵壓壓 ) 更多	积极	2024-05-24
NCT04725474 (GDFather, ASCO2024) 人工标引	临床2期	肝细胞癌 \| 非小细胞肺癌 \| 尿路上皮癌	87	Visugromab 10 mg/kg + Nivolumab 240 mg Q2W (NSCLC)	-	积极	2024-05-24
NCT04725474 (GDFATHER-2, Biospace) 人工标引	临床2期	晚期非小细胞肺癌 \| 尿路上皮癌 PD-L1 Positive	27	Visugromab+nivolumab (NSCLC)	齋鹹窪獵糧獵蓋獵鑰築(範淵淵鑰鬱鏇艱積鬱範) = 膚壓餘淵衊選衊積觸齋鬱壓壓選選鹽積鹽簾網 (構鹹簾憲餘觸廠壓網壓 )	积极	2023-12-06
NCT04725474 (ESMO_IO2023)	临床2期	实体瘤 \| 非小细胞肺癌 \| 膀胱癌 PD-L1+	114	Visugromab 10 mg/kg + Nivolumab 240 mg	艱積繭蓋鏇齋膚繭鹹願(鹹構襯淵築餘餘襯繭範) = 簾範鹹鬱鹹醖壓衊遞齋願鏇顧鏇獵製憲範遞鏇 (願鹹鑰餘鹹鏇簾觸鏇積 )	积极	2023-12-06
NCT04725474 (GDFATHER, ASCO 12023 \| ASCO 22023) 人工标引	临床2期	实体瘤	79	Nivolumab 240 mg+visugromab 10 mg/kg	衊顧簾窪艱醖選齋築齋(襯範構憲襯齋壓夢築築) = 齋獵構鏇積願獵繭窪網選繭壓鹽構鬱憲齋艱醖 (選遞膚製糧壓遞構獵獵 ) 更多	积极	2023-05-31
NCT04725474 (GDFATHER-1, ESMO2022) 人工标引	临床1期	复发性实体肿瘤	25	CTL-002 0.3-20 mg/kg+Nivolumab	顧壓簾願蓋鹹壓廠網積(願製蓋淵鑰醖淵廠齋鑰) = 範顧餘選觸齋壓鑰蓋鹽壓夢顧膚糧製鹽遞網構 (遞蓋鹹願積願鏇夢構襯 ) 更多	积极	2022-09-10