Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody

Rosenberger, Peter; Lindhofer, Horst

doi:10.1182/blood.v98.8.2526

Cited by 166 publications

(147 citation statements)

References 29 publications

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“…The therapeutic effectiveness of this novel trAb has not only been demonstrated in vitro and in different in vivo tumour models (Lindhofer et al, 1996;Ruf and Lindhofer, 2001;Schmitt et al, 2004). Catumaxomab's clinical benefit was recently verified when it was used to treat patients suffering from malignant ascites (Heiss et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer

Rosenberger¹,

Gires²,

Jäger³

et al. 2007

Br J Cancer

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Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein that is frequently overexpressed in a variety of carcinomas. This pan-carcinoma antigen has served as the target for a plethora of immunotherapies. Innovative therapeutic approaches include the use of trifunctional antibodies (trAbs) that recruit and activate different types of immune effector cells at the tumour site. The trAb catumaxomab has dual specificity for EpCAM and CD3. In patients with malignant ascites, catumaxomab significantly increased the paracentesis-free interval, corroborating the high efficacy of this therapeutic antibody. Here, we characterised the monoclonal antibody (mAb) HO-3, that is, the EpCAM-binding arm of catumaxomab. Peptide mapping indicated that HO-3 recognises a discontinuous epitope, having three binding sites in the extracellular region of EpCAM. Studies with glycosylation-deficient mutants showed that mAb HO-3 recognised EpCAM independently of its glycosylation status. High-affinity binding was not only detected for mAb HO-3, but also for the monovalent EpCAM-binding arm of catumaxomab with an excellent K D of 5.6 Â 10 À10 M. Furthermore, trAb catumaxomab was at least a 1000-fold more effective in eliciting the eradication of tumour cells by effector peripheral blood mononuclear cells compared with mAb HO-3. These findings suggest the great therapeutic potential of trAbs and clearly speak in favour of EpCAM-directed cancer immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer

Rosenberger¹,

Gires²,

Jäger³

et al. 2007

Br J Cancer

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“…5 In addition, recent studies indicate that this tri-cell complex, which induces also phagocytosis of tumor cells, 6 is an ideal mediator for the induction of a long-lasting antitumor immunity in a syngeneic mouse model. 28 Two studies have already reported encouraging results with bispecific antibodies in combination with pre-activated PBL in patients with ovarian cancer. 29,30 These approaches induced local inflammatory reactions and even tumor regression, but were lim- ited by the need for in vitro stimulation of effector cells.…”

Section: Discussionmentioning

confidence: 99%

“…Besides activation of T-lymphocytes and binding of tumor cells, these so-called trifunctional antibodies (trAb) are able to activate cell-mediated cytotoxicity leading to MHC-unrestricted but specific killing of targeted tumor cells without requirement for any pre-activation or co-stimulation. This new approach showed convincing results in vitro [5][6][7] and in mouse models, 8,9 requesting evaluation in a first clinical trial.…”

mentioning

confidence: 99%

Immunotherapy of malignant ascites with trifunctional antibodies

Heiss

Ströhlein

Jäger

et al. 2005

Intl Journal of Cancer

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109

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A new class of intact bispecific antibodies shows unmet effector qualities by activation of not only T cells but also simultaneous activation of Fcc receptor type I/III1 cells (macrophages, NKcells and DC). These trifunctional antibodies (trAb) lead to efficient specific killing of targeted tumor cells without any pre-or costimulation. This concept was investigated in vivo in patients with malignant ascites in a clinical situation that allowed monitoring of tumor cell elimination and correlation with clinical effects. In a prospective study, 8 patients with malignant ascites due to peritoneal carcinomatosis were treated with intraperitoneal application of trAb, which bound either the EpCAM-or Her2/neu-antigen on tumor cells. Treatment consisted of 4-6 applications within 9-23 days with a total amount of 145-940 lg. Seven of eight patients required no further paracentesis during follow-up or until death with a mean paracentesis-free interval of 38 weeks (median 5 21.5, range 5 4-136). Tumor cell monitoring showed a complete elimination of tumor cells in ascites already at total doses as low as 40-140 lg. Clinical response with disappearance of ascites accumulation was seen in all patients, which was correlated with elimination of tumor cells (p 5 0.0014). Severe adverse events were not observed. Clinically relevant side effects were fever, moderate abdominal pain and skin reactions. Intraperitoneal immunotherapy with trAb showed convincing efficacy in patients with malignant ascites. This treatment offers new therapeutic options for patients with peritoneal carcinomatosis. ' 2005 Wiley-Liss, Inc.

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“…Another bispecific antibody BiLu induces long-lasting antitumour immunity when administered intraperitoneally in a murine syngeneic model (Ruf and Lindhofer, 2001). It targets murine CD3 and human EpCAM.…”

Section: Prolonged Antitumour Immunity In Vivomentioning

confidence: 99%

EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges

Chaudry

Sales

Rosenberger³

et al. 2007

Br J Cancer

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Despite advances in surgery and adjuvant regimes, gastrointestinal malignancy remains a major cause of neoplastic mortality. Immunotherapy is an emerging and now successful treatment modality for numerous cancers that relies on the manipulation of the immune system and its effector functions to eradicate tumour cells. The discovery that the pan-epithelial homotypic cell adhesion molecule EpCAM is differentially expressed on gastrointestinal tumours has made this a viable target for immunotherapy. Clinical trials using naked anti EpCAM antibody, immunoconjugates, anti-idiotypic and dendritic cell vaccines have met variable success. The murine IgG2a Edrecolomab was shown to reduce mortality and morbidity at a level slightly lower than treatment with 5FU and Levamisole when administered to patients with advanced colorectal carcinoma in a large randomised controlled trial. Fully human and trifunctional antibodies that specifically recruit CD3-positive lymphocytes are now being tested clinically in the treatment of minimal residual disease and ascites. Although clinical trials are in their infancy, the future may bring forth an EpCAM mediated approach for the effective activation and harnessing of the immune system to destroy a pathological aberrance that has otherwise largely escaped its attention.

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Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody

Cited by 166 publications

References 29 publications

Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer

Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer

Immunotherapy of malignant ascites with trifunctional antibodies

EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges

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