A Multi-Center Phase I Study of Codrituzumab in Pediatric Patients With Relapsed or Refractory Glypican 3 (GPC3) Expressing Extra-cranial Solid Tumors

The purpose of this study to find out whether codrituzumab is a safe treatment that causes few or mild side effects in children and young adults who have solid tumors that express the protein GPC3. The researchers also want to study the way codrituzumab is absorbed, distributed, and cleared from the body.

开始日期2021-06-09

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

JPRN-JapicCTI-163325

/ Completed临床1期

A PHASE I, OPEN-LABEL, MULTI-CENTER, DOSE-ESCALATION STUDY OF CODRITUZUMAB, AN ANTI-GLYPICAN-3 MONOCLONAL ANTIBODY, IN COMBINATION WITH ATEZOLIZUMAB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC HEPATOCELLULAR CARCINOMA

开始日期2016-08-01

申办/合作机构

Chugai Pharmaceutical Co., Ltd.

JPRN-jRCT2080221779

/ Unknown status临床2期

A Randomized, Placebo-controlled, Double-blind, Multicenter Phase II Trial of Intravenous GC33 at 1600 mg Q2W in Previously Treated Patients with Unresectable Advanced or Metastatic Hepatocellular Carcinoma (HCC)

开始日期2012-04-25

申办/合作机构

Chugai Pharmaceutical Co., Ltd.

100 项与 Codrituzumab 相关的临床结果

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100 项与 Codrituzumab 相关的转化医学

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100 项与 Codrituzumab 相关的专利（医药）

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项与 Codrituzumab 相关的文献（医药）

2025-01-01·Heliyon

Glypican-3 is a key tuner of the Hedgehog pathway in COPD

Article

作者: Ruaux, Christophe ; Mérol, Jean-Claude ; Polette, Myriam ; Hatoum, Sarah ; Petit, Laure M G ; Deslée, Gaëtan ; Dubernard, Xavier ; Saber Cherif, Lynda ; Dormoy, Valérian ; Delepine, Gonzague ; Ancel, Julien ; Devilliers, Maëva A ; Durlach, Anne ; Perotin, Jeanne-Marie

Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to fully decipher the complex machinery of airway HH pathway activation in health and COPD. The core elements and co-receptors of HH signalling were investigated in lung cell populations using single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC differentiation. We demonstrated that the core elements were not abundant in pulmonary cell populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental strategy to tune HH signalling in therapeutic perspectives.

2023-10-01·Molecular immunology

A novel bispecific antibody as an immunotherapeutic agent in hepatocellular carcinoma

Article

作者: Zhao, Liwen ; Liu, Qingxia ; Wang, Yong ; Song, Qifeng ; Wei, Jian ; Xu, Yao ; Luo, Cheng

Hepatocellular carcinoma (HCC) remains one of the most common and highly fatal malignancies in humans worldwide with increasing prevalence and limited therapeutic options. For many decades, many researchers have attempted to find effective curative methods for HCC and great strides have been made. GPC3 is overexpressed in HCC, but not in normal liver, making it a rational immunotherapeutic target for HCC. GC33, a humanized mAb directed against GPC3, is a safe and well-tolerated therapy choice for patients with HCC, which tested in a phase I trial in advanced HCC patients. Phase II trials of GC33 to evaluate its efficacy and safety in advanced or metastatic HCC, showed no significant differences in overall survival and progression-free survival compared with the placebo. Retrospective analysis indicates that high drug exposure and high CD16 expression may contribute to the clinical efficacy of GC33. Chugai Pharmaceutical has restarted its Phase I trial of GC33, continuing to explore its clinical value targeting GPC3 in solid tumors. To enhance the antitumor potency of GC33, we designed a GPC3/CD16A bispecific antibody (QDEB). In this study, we obtained QDEB at high purity and assessed its effectiveness in the therapy of HCC compared with GC33. In vitro cytotoxicity assays and in vivo experiments demonstrated that QDEB could enhance anti-tumor efficacy compared with GC33. CD16A activation and increased cytokines release were associated with higher anti-tumor activity. In conclusion, this bispecific antibody may possibly help develop new therapeutic strategies for HCC and develop new treatment options in the future.

2022-08-01·Hepatology (Baltimore, Md.)

Novel low‐avidity glypican‐3 specific CARTs resist exhaustion and mediate durable antitumor effects against HCC

Article

作者: Jiang, Xiaotao ; Brody, Pierce ; Sadek, Ramses ; Mao, Rui ; Hussein, Mohamed S. ; Zhang, Huajun ; Kehinde‐Ige, Mercy ; Shi, Huidong ; Qiu, Xiangguo ; Peng, Yibing ; He, Aiwu Ruth ; Caraballo Galva, Leidy D. ; He, Yukai

Abstract:

Background and Aims:

Chimeric antigen receptor engineered T cells (CARTs) for HCC and other solid tumors are not as effective as they are for blood cancers. CARTs may lose function inside tumors due to persistent antigen engagement. The aims of this study are to develop low‐affinity monoclonal antibodies (mAbs) and low‐avidity CARTs for HCC and to test the hypothesis that low‐avidity CARTs can resist exhaustion and maintain functions in solid tumors, generating durable antitumor effects.

Methods and Results:

New human glypican‐3 (hGPC3) mAbs were developed from immunized mice. We obtained three hGPC3‐specific mAbs that stained HCC tumors, but not the adjacent normal liver tissues. One of them, 8F8, bound an epitope close to that of GC33, the frequently used high‐affinity mAb, but with approximately 17‐fold lower affinity. We then compared the 8F8 CARTs to GC33 CARTs for their in vitro function and in vivo antitumor effects. In vitro, low‐avidity 8F8 CARTs killed both hGPC3high and hGPC3low HCC tumor cells to the same extent as high‐avidity GC33 CARTs. 8F8 CARTs expanded and persisted to a greater extent than GC33 CARTs, resulting in durable responses against HCC xenografts. Importantly, compared with GC33 CARTs, there were 5‐fold more of 8F8‐BBz CARTs in the tumor mass for a longer period of time. Remarkably, the tumor‐infiltrating 8F8 CARTs were less exhausted and apoptotic, and more functional than GC33 CARTs.

Conclusion:

The low‐avidity 8F8‐BBz CART resists exhaustion and apoptosis inside tumor lesions, demonstrating a greater therapeutic potential than high‐avidity CARTs.

项与 Codrituzumab 相关的新闻（医药）

2023-04-12

·药渡Daily

GPC3：肿瘤治疗潜力靶点，罗氏、武田、科济药业等企业积极布局

关键词GPC3；研究进展；肿瘤GPC3靶点GPC3，即Glypican-3，是硫酸乙酰肝素（HS）蛋白聚糖家族的成员。GPC3是一种相对分子量为66Kda的细胞外糖蛋白，通过磷脂酰肌醇锚定在细胞膜上，是细胞表面多功能的共同受体，在介导信号传递中发挥重要作用。同时，GPC3也属于分泌蛋白，可通过结合胞外基质、生长因子和蛋白酶等影响信号传递，在调节肿瘤的细胞增殖、分化、黏附和转移等过程中发挥重要作用。GPC3在健康胎儿的肝脏和肾脏中表达，但在成人中除了胎盘组织其它组织几乎不表达。此外，GPC3还在多种肿瘤中差异化表达，其中在肝细胞(HCC)、非小细胞肺癌、卵巢透明细胞癌(OCCA)、特殊型胃癌(GC)等肿瘤中特异性高表达，在子宫癌、恶性间皮癌、乳腺癌、胃癌等多种肿瘤中低表达或者不表达。研究发现，GPC3可参与多种信号通路，在肿瘤细胞生长中发挥重要生物学功能。然而，GPC3对癌细胞生长的作用机制尚不明确，目前主要有以下3种理论：1）Hedgehog（Hh）信号通路，GPC3可与Hh结合，导致Hh失去与其受体Ptc的结合能力。Ptc会抑制Smo蛋白活性，从而抑制下游通路；2）Wnt信号通路，GPC3过表可上调c-Myc的表达，c-Myc是经典的Wnt信号通路的蛋白，而c-Myc也可以在转录水平增加GPC3的表达。有研究表明，突变的GPC3可以阻断Wnt信号通路并且抑制Wnt信号通路依赖的肿瘤生长；3）FGF2信号通路，通过免疫共沉淀的方法，有研究发现，GPC3可与FGF2结合，并认为GPC3可抑制FGF2和BMP-7的活性，从而抑制肝癌的生长。GPC3相关的信号转导通路GPC3被认为是肿瘤药物开发的潜力靶点，目前全球药企围绕GPC3靶点开发出了多款在研药物，详见下表。在研GPC3靶向药最高处于2期临床，适应症主要为肝细胞癌，药物类型涉及单抗、双抗和CAR-T疗法。全球部分在研GPC3靶向药资料来源：公开资料罗氏在GPC3领域布局两款产品。CodrituzumabCodrituzumab是首个靶向GPC3的抗体，目前处于2期临床。不过，在治疗晚期转移性肝细胞癌的2期临床中，Codrituzumab与安慰剂作相比并未显著改善患者的总生存期和无进展生存期，不过临床试验的亚分析结果表明GC33可以改善GPC3过表达肝细胞癌患者的预后。2021年6月，罗氏旗下的中外制药重新启动了codrituzumab的1期临床试验，继续挖掘该药在实体瘤中的临床价值。ERY974ERY974是罗氏在Codrituzumab的基础上开发的CD3/GPC3靶向双抗。该药带有2个不同的可变区，其中一个识别肿瘤抗原GPC3，另一个用于结合表达CD3抗原的T细胞。剂量爬坡1期临床试验结果显示：20%以上的患者出现CRS反应和发热，0.81μg/kg剂量被证实不耐受。剂量低于0.81μg/kg时，ERY974耐受性良好，经过类固醇和抗IL-6R治疗后毒副作用可控。目前，ERY974联合阿替利珠单抗(PD-L1)和贝伐珠单抗(VEGF)治疗晚期肝细胞癌的1期临床正在招募中。此外，康诺亚也布局了GPC3/CD3靶向双抗，即CM350。CM350CM350基于康诺亚专有nTCE双特异性抗体平台开发，是国内首家、全球第二个进入临床研究的GPC3/CD3靶向双抗。临床前研究显示，CM350诱导T细胞介导的肿瘤细胞杀伤（TDCC）作用有效杀伤GPC3阳性肿瘤细胞，在小鼠肿瘤模型中显示出极高的肿瘤抑制效应。而且，基于nTCE双抗平台优点，CM350在高效杀伤肿瘤细胞的同时具有良好的安全特性，避免了对正常细胞的非特异性杀伤以及减少细胞因子的伴随释放，降低了临床治疗中潜在的毒副作用。目前，CM350正在国内开展一项针对晚期实体瘤的多中心、开放、单臂1/2期临床研究。GPC3靶向在研药物以CAR-T疗法为主，国内外多家企业布局。BOXR1030BOXR1030是基于SOTIOBiotech公司专有的BOXR™平台开发的CAR-T项目，用于治疗表达GPC3的各种实体瘤。BOXR™平台旨在提高T细胞在恶劣的肿瘤微环境中的适应性。临床前研究已确定了BOXR1030的“bolt-on”转基因的作用机制，并证明了其对抑制性肿瘤微环境具有抗性。与传统的GPC3 CAR-T细胞对比，BOXR1030在低氧和低葡萄糖条件下，均显示出T细胞增殖得到改善，具有更好的肿瘤杀伤能力。此外，在动物分离出的肿瘤浸润淋巴细胞中，对比对照细胞，BOXR1030对功能障碍的抵抗力更强，并且衰竭的标志物更少。B010-AB010-A是由上海医药集团股份有限公司中央研究院研发，拥有自主知识产权的GPC3靶向CAR-T疗法。该药物相比传统CAR-T疗法，创新性地加入SPH-Engine结构，促进CAR-T杀伤活性，同时可以促进CAR-T细胞体内循环，用于晚期实体瘤的治疗。临床前研究表明，B010-A具有更优的体内外抗肿瘤活性和更好的安全性。TAK-102TAK-102是武田与Noile-Immune Biotech合作开发的一款GPC3靶向CAR-T疗法。在SITC-2022年会上公布的中期临床数据显示：截至2022年3月25日，共有4名患者入组，这4名患者均未发生剂量限制性毒性、CRS和神经系统毒性。1名肝癌患者和1名脂肪肉瘤患者治疗后评估为病情稳定（SD），并且伴随肿瘤标志物如AFP、LDH的变化。检测患者外周血中TAK-102的拷贝数，存在剂量效应，与部分细胞因子IFN-γ、IL-12/-23 p40，IL-10的变化趋势相关。Ori-C101Ori-C101拥有独立知识产权的高特异性高亲和力的靶向GPC3全人源抗体序列和独特的信号激活元件Ori，拟用于治疗晚期肝细胞癌成人患者。信号激活域元件Ori能成倍提升记忆性免疫细胞的扩增效率，有效突破肿瘤微环境中的细胞外基质的物理屏障，抵御肿瘤微环境的免疫抑制，显著增强CAR-T在体内的抗肿瘤活性和持久性，具有更好的防止复发潜力。在过往的临床研究中，Ori-C101已经在GPC3阳性晚期肝癌患者中表现出良好安全性和有效性。2021 ASCO年会上公布的1期临床试验数据显示：截止至2021年3月31日，Ori-C101达到了44%的客观缓解率（ORR），78%疾病控制率（DCR）。除了上述药物，National Cancer Center Of Japan还研发出了GPC3靶向治疗肝细胞癌的肿瘤疫苗GPC-3298306，目前已进入2期临床。总结目前，越来越多的证据表明GPC3是肿瘤药物开发的一个潜力靶点，尤其是在肝细胞癌领域。作为生物标志物，GPC3在肝细胞癌的早期诊断、预后判断和免疫治疗中的价值已经逐步显现。然而，目前全球还没有GPC3靶向药获批上市，不过已有多款在研药物进入临床试验阶段。我国药企，如科济药业、原启生物、康诺亚等也积极布局GPC3靶点，尤其是科济药业，目前已有3款PC3靶向CAR-T疗法进入1期临床。总结目前，越来越多的证据表明GPC3是肿瘤药物开发的一个潜力靶点，尤其是在肝细胞癌领域。作为生物标志物，GPC3在肝细胞癌的早期诊断、预后判断和免疫治疗中的价值已经逐步显现。然而，目前全球还没有GPC3靶向药获批上市，不过已有多款在研药物进入临床试验阶段。我国药企，如科济药业、原启生物、康诺亚等也积极布局GPC3靶点，尤其是科济药业，目前已有3款PC3靶向CAR-T疗法进入1期临床。END👇关注药渡数据媒体矩阵

细胞疗法临床1期免疫疗法临床2期

100 项与 Codrituzumab 相关的药物交易

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外链

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研发状态

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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2期	美国	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	日本	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	比利时	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	法国	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	德国	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	中国香港	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	意大利	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	新西兰	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	新加坡	Hoffmann-La Roche, Inc.	2012-02-02
转移性肝细胞癌	临床2期	韩国	Hoffmann-La Roche, Inc.	2012-02-02

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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


JPRN-JapicCTI-163325 (ESMO2018)	临床1期	转移性肝细胞癌	20	Codrituzumab 1600mg	獵夢鹹鏇選範築網鑰窪(鏇艱廠醖齋齋網製衊壓) = 0% vs 15% vs 0% 顧廠淵膚餘蓋選壓襯夢 (鏇範繭窪蓋鑰壓獵衊顧 ) 更多	积极	2018-10-21
				Atezolizumab 1200mg
NCT01507168 (Pubmed \| J Hepatol) 人工标引	临床2期	晚期肝细胞癌	185	codrituzumab	觸廠築壓顧獵衊鬱艱繭(壓蓋鏇觸憲範積艱鏇網) = 繭膚膚廠範顧鹹蓋築餘糧衊鑰顧獵壓醖夢網艱 (蓋艱鑰顧選齋積獵築艱 ) 更多	不佳	2016-08-01
				Placebo	觸廠築壓顧獵衊鬱艱繭(壓蓋鏇觸憲範積艱鏇網) = 鏇願醖鏇鏇憲鏇繭壓餘糧衊鑰顧獵壓醖夢網艱 (蓋艱鑰顧選齋積獵築艱 ) 更多
NCT01507168 (ASCO2014)	临床2期	不可切除的肝细胞癌	185	GC33 1600 mg	蓋簾範齋獵觸遞襯鏇選(壓遞膚齋夢襯鏇繭糧選) = 壓餘膚範構膚衊觸繭糧夢築膚觸壓艱壓鹹膚繭 (壓願膚願憲夢壓膚蓋遞 ) 更多	-	2014-05-20
				Placebo	蓋簾範齋獵觸遞襯鏇選(壓遞膚齋夢襯鏇繭糧選) = 構觸築鬱願製糧鹽鏇網夢築膚觸壓艱壓鹹膚繭 (壓願膚願憲夢壓膚蓋遞 ) 更多