Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM×anti-CD3) as a targeted cancer immunotherapy

Seimetz, Diane; Lindhofer, Horst; Bokemeyer, Carsten

doi:10.1016/j.ctrv.2010.03.001

Cited by 246 publications

(173 citation statements)

References 62 publications

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“…In a phase I trial of ertumaxomab in metastatic breast cancer, measurements of cytokines (IL-6, IL-2, TNF- and IFN-) suggest a strong T-helper cell type 1-associated immune response [35]. In addition, a randomised phase II/III trial of catumaxomab in malig- nant ascites has demonstrated that cytokine-release-related symptoms may be positively correlated with effi cacy and may serve as a predictive factor for the effi cacy of catumaxomab [8,36]. IFN- is an infl ammatory cytokine released from activated T cells and NK cells, and is known to exert anti-proliferative effects on neoplastic cells [37].…”

Section: Discussionmentioning

confidence: 99%

“…Trifunctional antibodies combine the characteristics of classical monospecifi c antibodies and bispecifi c molecules: In addition to the two specifi c antigen binding sites, trifunctional antibodies retain their intact Fc region, which mediates recruitment and activation of accessory cells (macrophages, dendritic cells, NK cells) [11]. Thus, the mode of action of these trifunctional antibodies is based on the simultaneous recruitment of T cells and accessory cells to the tumour site leading to improved tumour cell elimination by various immunologic killing mechanisms [8][9][10][11][12][13]. The trifunctional antibody catumaxomab (anti-EpCAManti-CD3, Removab ® ) has been approved recently in the European Union for the intraperitoneal treatment of malignant ascites due to EpCAM-positive carcinoma where standard therapy is not available or no longer feasible [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the mode of action of these trifunctional antibodies is based on the simultaneous recruitment of T cells and accessory cells to the tumour site leading to improved tumour cell elimination by various immunologic killing mechanisms [8][9][10][11][12][13]. The trifunctional antibody catumaxomab (anti-EpCAManti-CD3, Removab ® ) has been approved recently in the European Union for the intraperitoneal treatment of malignant ascites due to EpCAM-positive carcinoma where standard therapy is not available or no longer feasible [8,9]. The related trifunctional antibody ertumaxomab (anti-HER-2/neuanti-CD3) is in clinical development.…”

Section: Introductionmentioning

confidence: 99%

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Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

et al. 2011

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Background Trifunctional antibodies, such as catumaxomab (anti-EpCAManti-CD3) and ertumaxomab (anti-HER-2/neuanti-CD3), transiently link immune effector cells to tumour cells, which results in cellular cytotoxicity towards the tumour cells. A functional immune system is therefore essential for effective anti-tumour activity. However, the commonly observed haematotoxicity of chemotherapeutics and radiation therapy may be associated with some degree of immunosuppression. Combining chemotherapy and trifunctional antibodies in cancer treatment requires understanding of the impact of chemotherapeutics on immune cell function and, thus, on the activity of trifunctional antibodies. Methods The effect of chemotherapeutic treatment on trifunctional antibody-mediated anti-tumour activity was assessed in vitro. Blood samples were collected from 12 head and neck squamous cell carcinoma patients after chemotherapy (5-fl uorouracil, cisplatin) and radiotherapy, and from one healthy control donor. The immune cell status was analysed and mononuclear cells (MNC) were isolated. The potency of catumaxomab and ertumaxomab was assessed in a cytotoxicity assay using MNC isolated from each patient sample in co-culture with a tumour target cell line. The release of infl ammatory cytokines was also monitored in the cell culture supernatant. Results Most patients included in this study had decreased immune cell counts during the course of chemotherapy. Nonetheless, an effective and concentration-dependent anti-tumour activity mediated by trifunctional antibodies was demonstrated using these patient immune effector cells. The immune response activity of the patient immune cells was not impaired one week after cisplatin administration or even three days after the last 5-fl uorouracil treatment. Conclusion This study shows for the fi rst time that immune effector cells from cancer patients undergoing standard chemotherapy and radiotherapy can be activated by trifunctional antibodies for effi cient killing of tumour cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

et al. 2011

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“…The targeted immunotherapy catumaxomab [Removab Ò , Neovii (formerly Fresenius) Biotech GmbH, Munich, Germany] has been approved in the European Union since April 2009 for the intraperitoneal treatment of malignant ascites in patients with epithelial cell-adhesion molecule (EpCAM)-positive carcinomas for whom no further standard therapy is available or feasible [17,18]. Catumaxomab, a trifunctional antibody, has two different antigen-binding sites for EpCAM on tumour cells and CD3 receptors on T cells, respectively, plus a functional Fc domain that binds to type I, IIa and III Fcc receptors on accessory cells, e.g., natural killer cells, macrophages and dendritic cells [19].…”

Section: Introductionmentioning

confidence: 99%

A phase II study of catumaxomab administered intra- and postoperatively as part of a multimodal approach in primarily resectable gastric cancer

et al. 2014

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Background Postoperative relapse rate after gastrectomy and perioperative chemotherapy remain high in patients with advanced gastric cancer due to the spread of disseminated tumour cells in the peritoneal cavity. Perioperative administration of catumaxomab could potentially eliminate residual tumour cells after intended curative resection of the primary tumour. Methods This open-label, phase II study investigated the safety and efficacy of catumaxomab following neoadjuvant chemotherapy and subsequent surgery in patients with resectable (T2-4, N?, M0) gastric adenocarcinoma. Patients received catumaxomab intra-(single 10 lg dose) and postoperatively (10, 20, 50 and 150 lg on days 7, 10, 13 and 16, respectively). The primary endpoint was the postoperative complication rate (maximum rate defined as \62 %) within 30 days after surgery in patients who received at least the first catumaxomab dose.Results Of 64 patients treated with neoadjuvant chemotherapy, 58 underwent surgery and 54 received at least the first catumaxomab dose. Postoperative complications were reported in 18 of 54 evaluable patients (complication rate 33 %; 95 % confidence interval: 21-48 %); thus, the primary endpoint was met. The most frequent complications were pulmonary infection (17 %) and anastomosis insufficiency requiring surgery (11 %). The most common catumaxomab-related adverse events were pyrexia (67 %), leucocytosis (19 %), abdominal pain (17 %) and chills (17 %). The 4-year disease-free and overall survival rates were 38 and 50 %. Conclusion Intra-and postoperative administration of catumaxomab as part of a multimodal treatment approach was feasible and tolerable in patients with advanced gastric cancer and should be further investigated in a randomised trial.

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“…ADCC, and phagocytosis via activation of Fcγ-receptor-positive accessory cells. Importantly, no additional activation of immune cells is necessary for effective tumor elimination by catumaxomab, which therefore represents a self-supporting system [134,135]. In contrast to mAbs of the BiTE class, Triomabs exert a vaccination effect and induce long-lasting antitumor immunity, most likely due to their Fcmediated interaction with Fcγ-receptors expressed on dendritic cells and macrophages [136][137][138].…”

Section: Anti-epcammentioning

confidence: 99%

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

Naujokat¹

2012

J Clin Cell Immunol

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Cancer stem cells (CSCs) constitute a distinct subpopulation of tumor cells that exhibit self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs possess various intrinsic mechanisms of resistance to conventional chemotherapeutics, novel tumor-targeted drugs and radiation therapy, permitting them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, EpCAM (CD326), CD123, CD133, GD2, Lgr5, insulin-like growth factor receptor I (IGF-IR), and members of the Notch and Wnt signaling pathways, have been identified and mainly used for the characterization of CSCs in experimental settings. Recently, monoclonal antibodies and antibody constructs such as Triomabs and BiTEs raised against these CSC proteins have shown efficacy against CSCs in human xenograft mice, and some of them have been demonstrated to induce tumor regression in clinical trials.Since current cancer therapies fail to eliminate CSCs, ultimately leading to cancer recurrence and progression, selective targeting of CSCs with mAbs and antibody constructs reviewed herein may represent a novel and promising therapeutic strategy to eradicate cancer.

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Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM×anti-CD3) as a targeted cancer immunotherapy

Cited by 246 publications

References 62 publications

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

A phase II study of catumaxomab administered intra- and postoperatively as part of a multimodal approach in primarily resectable gastric cancer

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

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