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Pdfs/EPAR/Remo Review and Guideline for Treatment

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Pdfs/EPAR/Remo Review and Guideline for Treatment Journal of Cancer 2011, 2 309 Ivyspring International Publisher Journal of Cancer 2011; 2:309-316 Review Novel Monoclonal Antibodies for Cancer Treatment: The Trifunctional An- tibody Catumaxomab (Removab®) Diane Seimetz Fresenius Biotech GmbH, Munich, Germany Corresponding author: Fresenius Biotech GmbH, Frankfurter Ring 193a, D-80807 München, Germany. Tel.: +49 89 306593 47; Fax: +49 89 306593 77; E-mail: [email protected] © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/ licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Received: 2011.04.29; Accepted: 2011.05.24; Published: 2011.05.25 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 epithe- lial 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, den- dritic 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 ad- ministered 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 pa- tients 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 cur- rently being investigated to further exploit its therapeutic potential in EpCAM-positive carcinomas. Key words: catumaxomab, epithelial cell adhesion molecule (EpCAM), anti-EpCAM × anti-CD3, trifunctional antibody; targeted cancer immunotherapy, malignant ascites Introduction The development of monoclonal antibodies Biotech GmbH, Munich, Germany) is characterized by (mAbs), which act via antibody-dependent a unique ability to bind three different cell types: tu- cell-mediated cytotoxicity (ADCC), represented a mor cells, T-cells, and accessory cells.4-6 It was ap- significant advance in cancer immunotherapy.1 proved in the European Union (EU) in April 2009 for Bispecific antibodies (bsAbs), which bind to tumor the intraperitoneal (i.p.) treatment of malignant asci- cells and T-cells, and act via T-cell-mediated lysis, are tes (MA) in patients with epithelial cell adhesion currently in clinical development.2,3 The trifunctional molecule (EpCAM)-positive carcinomas where antibody (trAb) catumaxomab (Removab®, Fresenius standard therapy is not available or no longer feasible. http://www.jcancer.org Journal of Cancer 2011, 2 310 Catumaxomab is the first trAb and the first drug in poor quality of life,9,11 and a poor prognosis, with the world approved specifically for the treatment of median overall survival (OS) of approximately 1–6 MA. months.9,12,13 The causes of MA are independent of the origin of the primary tumor (Figure 2).14-17 Tu- Catumaxomab mor-secreted factors lead to tumor neovascularization Catumaxomab has two different antigen-binding and increased capillary permeability, resulting in in- specificities: one for EpCAM on tumor cells and one creased plasma inflow into the peritoneal cavity. for the CD3 antigen on T-cells. In addition, ca- Tumor cells obstruct lymphatic drainage, leading to tumaxomab binds, via its intact Fc region, to type I, decreased fluid efflux from the peritoneal cavity. IIa, and III Fcγ receptors (FcγRs) on accessory cells, e.g. natural killer (NK) cells, dendritic cells (DCs), and Rationale for use of Catumaxomab in the macrophages. Catumaxomab exerts its anti-tumor Treatment of MA effects via T-cell-mediated lysis,7 ADCC, and phago- Prior to the approval of catumaxomab, no agents cytosis via activation of FcγR-positive accessory cells were specifically approved for the treatment of MA (Figure 1).5,6 Its anti-tumor activity is assisted by the and treatment options, such as peritoneovenous induction of T-cell-secreted cytokines, such as inter- shunts, paracentesis, and diuretics, are only pallia- feron (IFN)-γ and tumor necrosis factor (TNF)-α.8 An tive.11 There was thus a need for an effective treatment important aspect of catumaxomab’s mode of action is for MA. The rationale for the use of catumaxomab for that no additional activation of immune cells is re- the i.p. treatment of MA was four-fold: 1) epithelial quired for effective tumor eradication, so it is a tumors spreading into the peritoneal cavity play a self-supporting system. major role in the development of MA; 2) epithelial tumors frequently express EpCAM;18-21 3) in the peri- Malignant Ascites toneal cavity, EpCAM is a tumor-specific antigen; and MA is an increased accumulation of pro- 4) immune effector cells are present in MA.22,23 Tar- tein-containing fluid within the peritoneal cavity that geting EpCAM by i.p. administration of catumax- is caused by i.p. spread of cancer. It is associated with omab leads to a depletion of epithelial tumor cells in advanced ovarian cancer, gastrointestinal malignan- the peritoneal cavity and a sustained reduction of MA cies, and other carcinomas, and leads to abdominal production. pain and swelling, dyspnea, nausea, vomiting, mal- nutrition, and anorexia.9,10 Patients with MA have a Figure 1. Catumaxomab mechanism of action. ADCC = antibody-dependent cell-mediated cytotoxicity, CK = cyto- kine, DC = dendritic cell, EpCAM = epithelial cell adhesion molecule, Fcγ R = Fcγ receptor, GM-CSF = granulo- cyte–macrophage colony-stimulating factor, IL = interleukin, IFN = interferon, LFA = lymphocyte function-associated antigen, NK = natural killer, TNF = tumor necrosis factor. http://www.jcancer.org Journal of Cancer 2011, 2 311 Figure 2. Pathophysiology of malignant ascites. Table 1. Clinical development of catumaxomab in malignant ascites. Study number Indication Phase Study design Key results (No. of treated patients) STP-REM-0124 Malignant ascites due to I/II Multicenter, multinational, Recommended dose 10, 20, 50, 150 µg ovarian cancer (23) open label, uncontrolled, Efficacy: Reduction of ascites flow; no require- sequential dose escalation ment for puncture in 22 patients at study end IP-REM-PK-01-EU Malignant ascites due to II Multicenter, open label, i.p. catumaxomab measurable in plasma epithelial cancer (13) pharmacokinetic t1/2: geometric mean ~2 days High inter-subject variability IP-REM-AC-0125 Malignant ascites due to II/III Multicenter, multinational, Statistically significant and clinically relevant epithelial cancer (157) two arm, randomized, open superiority of catumaxomab plus paracentesis label versus paracentesis alone Clinical Development of Catumaxomab in current ascites due to treatment-refractory ovarian cancer.24 Patients received four or five 6-hour i.p. ca- MA tumaxomab infusions of 5–200 μg on days 0, 3, 6, and The clinical development of catumaxomab in 9 for the first four dose groups and a fifth infusion on MA consisted of three key studies: an open-label day 13 for the fifth dose group. Catumaxomab pro- phase I/II dose-finding study (STP-REM-01);24 a duced a significant and sustained reduction in ascites pharmacokinetic study (IP-REM-PK-01-EU); and a flow rate, and 22 patients did not require paracentesis pivotal phase II/III study (IP-REM-AC-01)25 (Table 1). between the last infusion and end of the study (day A phase II and two phase I studies in other indications 37). EpCAM-positive tumor cells in ascites were re- (ovarian cancer [AGO-OVAR-2.10],26 peritoneal car- duced by up to 5 logs and were eliminated to levels cinomatosis [IP-REM-PC-01-DE],27 and in- below the limit of detection. The MTD was deter- tra-abdominal epithelial cancers [IP-REM-GC-01]),28 mined to be 10, 20, 50, 200, and 200 μg. provided supporting efficacy and safety data. In total, Most adverse events were reversible and re- 270 patients received catumaxomab in these studies. solved without sequelae. Frequent adverse events were transient fever (83%), nausea (61%), and vomit- STP-REM-01 ing (57%), which were mostly grade 1/2. Although This study investigated the maximum tolerated there was no clear relationship between catumax- dose (MTD) of catumaxomab in 23 women with re- omab dose and the severity of adverse events, which http://www.jcancer.org Journal of Cancer 2011, 2 312 is similar to other cancer immunotherapies,29 a dose pooled, ovarian, and nonovarian cancer populations, schedule of 10, 20, 50, and 150 μg that is well below respectively (all p<0.0001). This corresponds to a the MTD was recommended for further studies. saving of about five punctures for catumaxomab, which is clinically relevant as there is continuous IP-REM-PK-01-EU protein loss with each puncture that leads to cachexia This was an open-label, multicenter, pharmaco- and a potential risk of infection and bowel perfora- kinetic study in 13 patients who received four i.p. tion. catumaxomab infusions of 10, 20, 50, and 150 μg. In Ascites signs and symptoms were analyzed 8 most patients, the catumaxomab concentration in- days after the last catumaxomab infusion or after day creased with the number of infusions and the doses 0 in the control group.25 Catumaxomab significantly applied.
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