Two new trifunctional antibodies for the therapy of human malignant melanoma

Rosenberger, Peter; Jäger, Michael; Ellwart, Joachim W.; Wosch, Susanne; Kusterer, Elisabeth; Lindhofer, Horst

doi:10.1002/ijc.11630

Cited by 45 publications

(28 citation statements)

References 46 publications

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“…Trifunctional antibody constructs against specific antigens like HER2/neu and the recently developed trAb against melanoma-associated proteoglycans or gangliosides (GD2/GD3) may overcome these limitations. 34 The clinical strategy we carried out demonstrated a safe and feasible use of trAb. However, a first dose effect was seen in sev- Interval starting from the first day of trAb infusion.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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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“…26,27 Interestingly, a significant release of IL-10 was already observed in context with in vitro studies using the trifunctional antibodies catumaxomab (antiEpCAM Â anti-CD3), TRBs02/07 (anti-GD2/GD3 Â anti-CD3) and Bi20. 14,28 However, so far, the therapeutic consequences are not well understood and need to be investigated further.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy of recurrent B-cell malignancies after allo-SCT with Bi20 (FBTA05), a trifunctional anti-CD3 × anti-CD20 antibody and donor lymphocyte infusion

Buhmann

Simões

Stanglmaier³

et al. 2008

Bone Marrow Transplant

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Donor lymphocyte infusions (DLIs) after allo-SCT displayed limited use in CLL and highly malignant nonHodgkin's lymphoma (NHL). Here we studied whether Bi20 (FBTA05), a novel trifunctional bispecific antibody targeting CD20 on lymphoma cells and CD3 on T cells, could induce GVL responses in combination with DLI or mobilized PBSCT after allogeneic transplantation in these diseases. Six patients (three cases with p53-mutated CLL and three with high-grade NHL (HG-NHL)) refractory to standard therapy were treated with escalating doses of Bi20 (range 10-2000 lg) followed by DLI or SCT. Thereby, all CLL patients showed a prompt but transient clinical and hematological response. In one patient with HG-NHL, we observed a halt in progression for almost 4 months. Side effects (fever, chills and bone pain) were tolerable and appeared at antibody dose levels between 40 and 200 lg. The cytokine profile was characterized by transient increases of IL-6, IL-8 and IL-10. Neither human anti-mouse antibodies nor GVHD developed, allowing repeated treatment courses. In summary, the trifunctional antibody Bi20 induced prompt antitumor responses in extensively pretreated, p53-mutated alemtuzumab and rituximab refractory patients indicating its therapeutic potential.

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“…However, combination of ch14.18 with interleukin-2 [207] and GM-CSF plus IL-2 plus isotretinoin [208] results in enhancement of antitumor activity of ch14.18 in melanoma and neuroblastoma patients, respectively. TRBs07 (Ektomun, Ektomab) is a bispecific, trifunctional antibody construct (Triomab) comparable to catumaxomab that originate from parental mouse anti-GD2 and anti-GD3 IgG2a mAb Me361 and rat anti-CD3 IgG2b mAb 26II6 [209]. This Triomab binds human CD3 as well as the gangliosides GD2 and GD3 with a preference for GD2, thereby redirecting and activating CD3-positive T-lymphocytes, which induce specific lysis of target cells expressing GD2, such as human melanoma cells and other neuroectodermal tumor cells [209].…”

Section: Anti-gd2mentioning

confidence: 99%

“…TRBs07 (Ektomun, Ektomab) is a bispecific, trifunctional antibody construct (Triomab) comparable to catumaxomab that originate from parental mouse anti-GD2 and anti-GD3 IgG2a mAb Me361 and rat anti-CD3 IgG2b mAb 26II6 [209]. This Triomab binds human CD3 as well as the gangliosides GD2 and GD3 with a preference for GD2, thereby redirecting and activating CD3-positive T-lymphocytes, which induce specific lysis of target cells expressing GD2, such as human melanoma cells and other neuroectodermal tumor cells [209]. Similar to catumaxomab, TRBs07 additionally binds via its Fc fragment to Fcγ-receptors on dendritic cells, macrophages and natural killer cells, and induces the secretion of cytokines such as IFN-γ, TNF-α, IL-2, IL-6 and IL-10 by peripheral blood mononuclear cells in vitro [209].…”

Section: Anti-gd2mentioning

confidence: 99%

“…This Triomab binds human CD3 as well as the gangliosides GD2 and GD3 with a preference for GD2, thereby redirecting and activating CD3-positive T-lymphocytes, which induce specific lysis of target cells expressing GD2, such as human melanoma cells and other neuroectodermal tumor cells [209]. Similar to catumaxomab, TRBs07 additionally binds via its Fc fragment to Fcγ-receptors on dendritic cells, macrophages and natural killer cells, and induces the secretion of cytokines such as IFN-γ, TNF-α, IL-2, IL-6 and IL-10 by peripheral blood mononuclear cells in vitro [209]. The Triomab Surek, which possesses the identical anti-GD2 binding arm as TRBs07, but binds to mouse CD3 instead of human CD3, has recently been shown to induce tumor eradication and protection against a second tumor challenge in a mouse melanoma model.…”

Section: Anti-gd2mentioning

confidence: 99%

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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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Two new trifunctional antibodies for the therapy of human malignant melanoma

Cited by 45 publications

References 46 publications

Immunotherapy of malignant ascites with trifunctional antibodies

Immunotherapy of malignant ascites with trifunctional antibodies

Immunotherapy of recurrent B-cell malignancies after allo-SCT with Bi20 (FBTA05), a trifunctional anti-CD3 × anti-CD20 antibody and donor lymphocyte infusion

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

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