Monoclonal antibodies in cancer therapy

Gruber, Rudolf; Holz, E; Riethmüller, Gert

doi:10.1007/bf00820669

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…Recently, several mAbs that predominantly act by ADCC and CDC have been approved for the treatment of cancer patients. These include chimaeric IgG1 mAb rituximab (Rituxan s ) binding to the B-cell differentiation antigen CD20 for the treatment of Bcell lymphomas (Grillo-Lopez et al, 1999;Smith, 2003), humanised IgG1 mAb trastuzumab (Herceptin s ) targeting HER-2 (human epithelial growth factor receptor type 2) overexpressed in a subgroup of breast cancers (Vogel et al, 2001), humanised IgG1 alemtuzumab (Campath s ) targeting the differentiation antigen CD52 for the treatment of B-cell chronic lymphocytic leukaemia (Hale et al, 1998;Kottaridis et al, 2000;Faulkner et al, 2004) and edrecolomab (Panorex s ), a murine IgG2a mAb targeting Ep-CAM (epithelial cell adhesion molecule), which gained temporary approval in Germany for the treatment of colorectal carcinoma (Riethmuller et al, 1994;Gruber et al, 1996;Schwartzberg, 2001;White et al, 2001). Several other mAbs are currently at advanced stages of clinical development.…”

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confidence: 99%

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Prang¹,

Preithner²,

Brischwein³

et al. 2005

Br J Cancer

131

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MT201 is a fully human monoclonal IgG1 antibody with moderate affinity for epithelial cell adhesion molecule (Ep-CAM) being clinically developed for the treatment of carcinomas. Like many other clinically validated IgG1 monoclonal antibodies, MT201 primarily acts by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Here, we analysed ADCC and CDC induced by MT201 and, as reference, trastuzumab against a panel of nine human breast cancer cell lines expressing distinct surface levels of Ep-CAM and human epithelial growth factor receptor type 2 antigen. Maximal cell lysis by ADCC by MT201 and trastuzumab in the presence of peripheral mononuclear cells did not significantly differ when averaged over the nine cell lines, but showed marked differences with respect to individual cell lines. The extent of cell lysis at intermediate surface target density was highly variable, suggesting a dominant influence of other susceptibility factors. Only one breast cancer cell line was eliminated via CDC, but only by MT201. Resistance to CDC appeared to correlate with high expression levels of complement resistance factors. Our present data as well as recent data on the prevalence and prognostic relevance of Ep-CAM expression in metastatic breast cancer suggest that Ep-CAM-specific monoclonal IgG1 antibodies may have a significant therapeutic potential in the treatment of breast cancer.

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confidence: 99%

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Prang¹,

Preithner²,

Brischwein³

et al. 2005

Br J Cancer

131

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“…Although C may become activated on tumour cells by tumour-binding antibodies (Magyarlaki et al, 1996), immune complexes (Lucas et al, 1996) or as a consequence of apoptosis (Matsumoto et al, 1997) or proteolytic processes (Niculescu et al, 1992;Yamakawa et al, 1994;Bjrge L et al, 1997a), the cytotoxic activity of C is insufficient as an effective immunological surveillance mechanism against tumours (Gorter and Meri, 1999;Jurianz et al, 1999). Immunotherapy with C-activating mAbs in the treatment of solid tumours has so far shown only limited success (Dillman, 1994;Gruber et al, 1996). The 'humanised' anti-CD20 mAb, rituximab has shown an overall response rate of over 50% (Maloney et al, 1997) in the treatment of non-Hodgkin's lymphomas.…”

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confidence: 99%

Ascitic complement system in ovarian cancer

et al. 2005

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Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity. The levels of C3 and C4 were similar to or in the lower normal range when compared to values in normal sera, respectively. However, elevated levels of C3a and soluble C5b-9 suggested C activation in vivo. Malignant cells isolated from the AF samples had surface deposits of C1q and C3 activation products, but not of C5b-9 (the membrane attack complex; MAC). Activation could have become initiated by anti-tumour cell antibodies that were detected in the AFs and/or by changes on tumour cell surfaces. The lack of MAC was probably due to the expression of C membrane regulators CD46, CD55 and CD59 on the tumour cells. Soluble forms of C1 inhibitor, CD59 and CD46, and the alternative pathway inhibitors factor H and FHL-1 were present in the AF at concentrations higher than in serum samples. Despite the presence of soluble C inhibitors it was possible to use AF as a C source in antibody-initiated killing of ovarian carcinoma cells. These results demonstrate that although the ovarian ascitic C system fails as an effective immunological surveillance mechanism, it could be utilised as an effector mechanism in therapy with intraperitoneally administrated mAbs, especially if the intrinsic C regulators are neutralised.

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“…The interest in therapeutic and diagnostic in vivo applications of MABs has clearly increased during the past years [27]. An important aspect of the application of unmodified mouse-MAB is the induction of human anti-mouse antibodies (HAMA).…”

Section: Monoclonal Antibodies and Antibody Constructsmentioning

confidence: 99%

Monoclonal Antibodies for the Immunotherapy of Solid Tumours

Mauerer¹,

Gruber

2012

CPB

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More than 80% of all cancers are caused by solid malignancies. More than 90% of these tumours are of epithelial origin. The main principles in tumour treatment are surgery, radiotherapy, chemotherapy or combinations of these. Complete surgical removal of the tumour is the most effective therapy for solid malignancies. Recent advances in early cancer detection led to a higher rate of resectable primary tumours and therefore prognosis will be determined especially by metastasis. Even in early stages some tumour cells may disseminate for example into the bone marrow. If these occult metastasis get evident they are mostly incurable by surgery and often highly resistant to chemotherapy. Developing new therapeutic agents to destroy these resting cells is a major challenge for the improvement of cancer therapy in the future. Advances to reach these goals were made in immunological therapies with monoclonal antibodies (MABs). These MABs are for example directed against tumor-associated antigens (TAAs). By binding selectively on tumor cells they can activate immunological effector mechanisms, e.g. antibody dependent cell cytotoxicity (ADCC) or complement mediated lysis. Other mechanisms are the blocking of inhibiting molecules to re-activate anergic tumor infiltrating lymphocytes (TILs). Furthermore growing tumours depend on oxygen supply, i.e. on effective neovascularisation. Antibodies against VEGF are able to inhibit neovascularisation and are therefore used successfully in tumour therapy.

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Monoclonal antibodies in cancer therapy

Cited by 8 publications

References 42 publications

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Cellular and complement-dependent cytotoxicity of Ep-CAM-specific monoclonal antibody MT201 against breast cancer cell lines

Ascitic complement system in ovarian cancer

Monoclonal Antibodies for the Immunotherapy of Solid Tumours

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