Catumaxomab(Removab)是由单抗HO-3衍生的一种三功能抗体,能同时激活T细胞和辅助免疫细胞,从而破坏拥有表面抗原—上皮细胞黏附分子(Ep-CAM)的靶肿瘤细胞。该药在欧洲已获准用于治疗由Ep-CAM阳-性上皮源性转移瘤所引起的恶性腹水,目前其正处于治疗卵巢癌和胃癌的Ⅱ期临床治疗研究。

商品名

Removab

药品名

Catumaxomab

开发商：本品由德国Trion Pharrna公司开发，于2009年4月首次在德国上市

适应症

本品为一三功能大鼠/小鼠杂交单克隆抗体，特异性靶向上皮细胞粘附分子(EpCAM)和CD3抗原。大部分肿瘤EpCAM抗原过表达。CD3作为T细胞受体的一部分表达于成熟T细胞。本品Fc区段第三个功能结合点可通过Fcγ受体和免疫辅佐细胞相互作用。

由于本品的结合特性，肿瘤细胞、T细胞和免疫辅佐细胞得以近距离接触，因此，既定的针对肿瘤细胞的免疫反应得以发生，这些免疫反应包括T细胞活化、抗体依赖细胞介导细胞毒作用(ADCC)，补体依赖细胞毒作用和吞噬作用。结果导致肿瘤细胞瓦解。

本品适用于标准治疗无效或不可行的因EpCAM阳性肿瘤所致的恶性腹水的治疗。
临床评价

本品获准上市的依据是一项随机对照开放标示的Ⅱ／Ⅲ期临床研究(IP-REM-AC-01)结果。该项临床研究考察了本品对258例无法再进行化疗的伴有恶性腹水的EpCAM阳性癌症患者的疗效，其中129例为卵巢癌患者，其余分别为胃肠癌、乳腺癌、胰腺癌以及其他癌患者，受试者按2：l的比例随机分成两组，其中一组(n=l70)在穿刺术后第0、3、7和10天以剂量递增的方式腹腔注射本品(10、20、50、150μg)，另一组(n=88)穿刺术后不给药；有157例患者接受了至少1个剂量的本品，131例患者则接受了4个剂量。

该研究设定的主要指标为无穿刺中位生存期(即给药结束后至需再行穿刺抽取腹水或死亡的时间)，结果显示治疗组和对照组的无穿刺中位生存期分别为46天和11天；与对照组相比，治疗组的给药结束后至需再行穿刺抽取腹水的时间、疾病进展的中位时间以及接受4种剂量本品治疗的患者的中位生存期均更长(77、111、86天对13、35、68天)；此外，从医生和患者的问卷调查发现，本品治疗组患者的腹水症状也有所改善。在对各种癌症的治疗中，卵巢癌的疗效最显著，本品治疗组(n=88)和对照组(n=44)的无穿刺中位生存期分别为52天和11天，到给药结束后需再行穿刺抽取腹水的时问分别为71天和1l天，给药结束后第二次穿刺抽取腹水的时间分别为26天和13天，疾病进展的中位时间分别为111天和35天，接受4种剂量本品治疗的患者的中位生存期比对照组长29天。胃癌的疗效与之相似：本品治疗组和对照组的无穿刺中位生存期分别为44天和15天，给药结束后需再行穿刺抽取腹水的时间分别为118天和15天，接受4种剂量本品治疗的患者的中位生存期比对照组长27天。其他癌症患者中，本品治疗组和对照组的无穿刺中位生存期分别为30天和9天，给药结束后需再行穿刺抽取腹水的中位时间分别为69天和15天。给予本品治疗的卵巢癌患者的总生存期和无进展生存期均有所延长。

不良反应

在临床研究中，约90%的患者出现了不良反应。普遍发生的不良反应(发生率≥10％)有淋巴细胞减少症，腹痛，恶心，呕吐，腹泻，发热，疲劳，寒战和疼痛。常见的不良反应(发生率在1％～10％之间)包括白细胞增多症，贫血，中性白细胞增多症，血小板病，心动过速，眩晕，肠梗阻，便秘，消化不良，腹胀，肠胃胀气，胃病，胃食管返流，口腔炎，虚弱，流感样病，胸痛，水肿，口渴，高胆红素血症，细胞溶解性肝炎，感染，硬红斑，尿路感染，食欲减退，低钠血症，低钙血症，低钾血症，低蛋白质血症，脱水，高血糖症，关节痛，背痛，肌痛，头痛，头晕，焦虑，失眠，少尿，白细胞尿，蛋白尿，血尿，呼吸困难，胸腔积液，皮疹，过敏性皮炎，皮肤反应，红斑，多汗症，瘙痒症，荨麻疹，低血压，高血压，面红，热潮红。比较罕见(发生率≤l％)的不良反应包括胃出血，肠梗阻，注射部位炎症，渗漏，导管感染，皮肤感染，惊厥，急性肾衰竭，肺栓塞，严重胸腔积液，严重过敏性皮炎，严重皮疹，严重表皮脱落，严重皮肤反应等。

本品不可腹腔推注或应用其它非腹膜内给药方式。

细胞因子释放综合征：本品结合至免疫细胞和肿瘤细胞后将启动前炎性因子和细胞毒性细胞因子的释放，因此在本品治疗期间及之后，患者出现发热、恶心、呕吐和寒战等细胞因子释放综合征症状的情况非常普遍。呼吸困难和低／高血压也很常见。在临床研究中，为控制疼痛和发热，在本品给药之前静脉注射1000 mg对乙酰氨基酚是常规处理。但是，尽管进行了预防性用药，仍有患者出现了3级以上的上述不良反应。除对乙酰氨基酚外，其它止痛／退热／抗炎标准用药也推荐使用。系统性炎症反应综合征不太常见，但也有发生，多半在本品注射后24小时内出现，表现为发热、心动过速、白细胞增多等。以止痛／退热／非甾体抗炎药预先进行预防，可降低风险。

用法与用量

本品经由腹腔输注。使用前需以50 mL 0.9％氯化钠溶液稀释，再通过恒速输液泵腹腔内给药。

本品推荐的给药方案为：

第1剂：剂量为10 mg，给药时间为“第0天”；

第2剂：剂量为20 mg，给药时间为“第3天”；

第3剂：剂量为50 mg，给药时间为“第7天”；

第4剂：剂量为100 mg，给药时间为“第10天”。

给药间隔至少2天，可视不良反应情况适当延长。总治疗时间不超过20天。

制剂

本品为预填充注射剂，有两种规格，每支注射器分别装入0.1 mL(10μg)溶液
和0.5 mL(50μg)溶液。
 
规格

1针x10ug
1针x50ug

Novel Monoclonal Antibodies for Cancer Treatment: The Trifunctional Antibody Catumaxomab (Removab®)

Abstract
The trifunctional antibody (trAb) catumaxomab is characterized by a unique ability to bind three different cell types: tumor cells; T-cells; and accessory cells. It binds to epithelial cell adhesion molecule (EpCAM) on tumor cells, the CD3 antigen on T-cells, and to type I, IIa, and III Fcγ receptors (FcγRs) on accessory cells (e.g. natural killer cells, dendritic cells, and macrophages). Catumaxomab exerts its anti-tumor effects via T-cell-mediated lysis, antibody-dependent, cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory cells. Catumaxomab represents a self-supporting system, as no additional immune cell activation is required for tumor eradication. The efficacy and safety of catumaxomab have been demonstrated in a pivotal phase II/III study in malignant ascites (MA) and supporting phase I/II studies. It is administered as four intraperitoneal (i.p.) infusions of 10, 20, 50, and 150 µg on days 0, 3, 7, and 10, respectively. Catumaxomab was approved for the i.p. treatment of MA in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible in the European Union in April 2009. It is the first trAb and the first drug in the world approved specifically for the treatment of MA. Catumaxomab was awarded the Galen of Pergamon Prize, which recognizes pharmacological research for developing new and innovative drugs and diagnostics, in the specialist care category in 2010. The use of catumaxomab in other indications and additional routes of administration are currently being investigated to further exploit its therapeutic potential in EpCAM-positive carcinomas.

Keywords: catumaxomab, epithelial cell adhesion molecule (EpCAM), anti-EpCAM × anti-CD3, trifunctional antibody, targeted cancer immunotherapy, malignant ascites

Introduction
The development of monoclonal antibodies (mAbs), which act via antibody-dependent cell-mediated cytotoxicity (ADCC), represented a significant advance in cancer immunotherapy.1 Bispecific antibodies (bsAbs), which bind to tumor cells and T-cells, and act via T-cell-mediated lysis, are currently in clinical development.2,3 The trifunctional antibody (trAb) catumaxomab (Removab®, Fresenius Biotech GmbH, Munich, Germany) is characterized by a unique ability to bind three different cell types: tumor cells, T-cells, and accessory cells.4-6 It was approved in the European Union (EU) in April 2009 for the intraperitoneal (i.p.) treatment of malignant ascites (MA) in patients with epithelial cell adhesion molecule (EpCAM)-positive carcinomas where standard therapy is not available or no longer feasible. Catumaxomab is the first trAb and the first drug in the world approved specifically for the treatment of MA.

Catumaxomab
Catumaxomab has two different antigen-binding specificities: one for EpCAM on tumor cells and one for the CD3 antigen on T-cells. In addition, catumaxomab binds, via its intact Fc region, to type I, IIa, and III Fcγ receptors (FcγRs) on accessory cells, e.g. natural killer (NK) cells, dendritic cells (DCs), and macrophages. Catumaxomab exerts its anti-tumor effects via T-cell-mediated lysis,7 ADCC, and phagocytosis via activation of FcγR-positive accessory cells (Figure 1).5,6 Its anti-tumor activity is assisted by the induction of T-cell-secreted cytokines, such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α.8 An important aspect of catumaxomab's mode of action is that no additional activation of immune cells is required for effective tumor eradication, so it is a self-supporting system.

Malignant Ascites
MA is an increased accumulation of protein-containing fluid within the peritoneal cavity that is caused by i.p. spread of cancer. It is associated with advanced ovarian cancer, gastrointestinal malignancies, and other carcinomas, and leads to abdominal pain and swelling, dyspnea, nausea, vomiting, malnutrition, and anorexia.9,10 Patients with MA have a poor quality of life,9,11 and a poor prognosis, with median overall survival (OS) of approximately 1-6 months.9,12,13 The causes of MA are independent of the origin of the primary tumor (Figure 2).14-17 Tumor-secreted factors lead to tumor neovascularization and increased capillary permeability, resulting in increased plasma inflow into the peritoneal cavity. Tumor cells obstruct lymphatic drainage, leading to decreased fluid efflux from the peritoneal cavity.