Monoclonal antibodies in cancer therapy

Riethmüller, Gert; Schneider-Gädicke, E.; Johnson, Judith P.

doi:10.1016/0952-7915(93)90129-g

Cited by 69 publications

(26 citation statements)

References 42 publications

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“…Lack of antibody penetration into the core of TMSs probably reflects the existence of tight intercellular junctions between the cells (Jain, 1988). In addition, cells in the spheroids may have synthesized a glycocalyx (Riethmuller et al, 1993) or a basement membrane-like structure (Zeuthen et al, 1980) that also restrict the access of antibodies into the deeper layers of the TMSs.…”

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

“…The approach of using MAbs and the C system as an effector to kill tumour cells may be an attractive adjuvant immunotherapeutic alternative (Chapman et al, 1992;Riethmuller et al, 1993). Attempts to use unconjugated C-activating MAbs in the therapy of solid tumours have therefore been tried (Houghton et al, 1985;Goodman et al, 1990;Riethmuller et al, 1993;Rubin, 1993).…”

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

“…Attempts to use unconjugated C-activating MAbs in the therapy of solid tumours have therefore been tried (Houghton et al, 1985;Goodman et al, 1990;Riethmuller et al, 1993;Rubin, 1993). Although the MAbs bind to the tumour cells in vivo (Houghton et al, 1985;Rubin, 1993) and mediate local C deposition (Houghton et al, 1985), the therapeutic efficiency is limited (Houghton et al, 1985;Riethmuller and Johnson, 1992;Riethmuller et al, 1993;Rubin, 1993) and correlates negatively with the volume of the tumour mass (Riethmuller et al, 1993). Barriers for free access of MAbs and C to the tumour cells and the existence of C resistance mechanisms may limit the success rate (Riethmuller et al, 1993).…”

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

“…Although the MAbs bind to the tumour cells in vivo (Houghton et al, 1985;Rubin, 1993) and mediate local C deposition (Houghton et al, 1985), the therapeutic efficiency is limited (Houghton et al, 1985;Riethmuller and Johnson, 1992;Riethmuller et al, 1993;Rubin, 1993) and correlates negatively with the volume of the tumour mass (Riethmuller et al, 1993). Barriers for free access of MAbs and C to the tumour cells and the existence of C resistance mechanisms may limit the success rate (Riethmuller et al, 1993). However, in vitro tests have shown that it is possible to kill tumour cells in suspension using appropriate MAbs and C in combination with targeted neutralization of membrane regulators of complement (Cheung et al, 1988;Bj0rge et al, 1994;Hakulinen and Meri, 1994;Junnikkala et al, 1994;Brasoveanu et al, 1995;Maenpaa et al, 1996).…”

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

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Resistance of ovarian teratocarcinoma cell spheroids to complement-mediated lysis

Bjørge

Junnikkala²,

Kristoffersen³

et al. 1997

Br J Cancer

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Summary We have shown previously that it is possible to target complement-mediated killing against cultured ovarian tumour cells in vitro. As malignant ovarian cells usually grow in solid nodules in vivo, we have in the present study examined the effectiveness of complement killing against ovarian teratocarcinoma cells (PA-1) growing in three-dimensional tumour microspheroids (TMSs). Our study shows that PA-1 cells growing in TMSs are less susceptible to complement-mediated killing than cells growing in monolayer cultures, even after neutralization of protectin (CD59), the main inhibitor of complement lysis. Cells in suspension and cells growing in TMSs showed a similar expression of membrane co-factor protein (MCP, CD46) and CD59. Decay-accelerating factor (DAF, CD55) was not detected on the surface of cells in suspension, but appeared focally on the outermost cell layers of the TMSs. Complement-activating antibodies bound to all PA-1 cells in suspension but only to the most peripherally located cells in TMSs, even though the target antigens were similarly expressed in the two systems. Antibody-induced complement activation on PA-1 cells in suspension led to C3 and C5b-9 deposition on most cells, while C3 and C5b-9 were only found on the outermost layers of the TMSs. The increased complement resistance of tumour cells growing in threedimensional spheroids is partly because of an insufficient penetration of antibodies and complement into the TMSs. TMSs are a useful model for the development of more efficient ways to kill malignant cells in micrometastases with monoclonal antibodies and complement.

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Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

Section: Sensitivity Of Pa-1 Cells and Spheroids To C-mediated Cytotomentioning

confidence: 99%

See 2 more Smart Citations

Resistance of ovarian teratocarcinoma cell spheroids to complement-mediated lysis

Bjørge

Junnikkala²,

Kristoffersen³

et al. 1997

Br J Cancer

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“…Recent technological improvements have made it possible to clone and produce large amounts of intact recombinant monoclonal antibodies or antibody fragments with unique specificities (reviewed by Winter and Milstein, 1991;Dall'Acqua and Carter, 1998;Hudson, 1998). Several tumour-associated antigens have been identified and are currently being investigated as therapeutic targets for haematological and solid tumours (Riethmüller et al, 1993). non-small-cell lung cancer (NSCLC) is an aggressive solid tumour associated with a poor prognosis since surgery or chemotherapy is only beneficial in a fraction of all cases.…”

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confidence: 99%

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

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Summary Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA D227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a K d of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA D227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA D227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10 -10 M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA D227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA D227A . Thus, 5T4FabV13-SEA D227A has highly attractive properties for therapy of human NSCLC.

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