Retargeting of human lymphocytes against human ovarian carcinoma cells by bispecific antibodies: from laboratory to clinic.
We have selected a monoclonal antibody (MOv18) reactive with ovarian carcinoma, which exhibits a restricted tumor specificity, a high affinity constant and which recognizes a 38-kDa glycoprotein homogeneously expressed on the cell surface of 90% of human ovarian carcinomas. Localization studies with radiolabelled MOv18 showed that MOv18 could specifically reach ovarian carcinoma cells growing in the peritoneal cavity of nu/nu mice. MOv18 did not mediate antibody-dependent cellular cytotoxicity via Fc and could not be used as a carrier for toxins due to poor internalization of the antigen-antibody complex. Bispecific F(ab')2 antibodies made with MOv18 and an antibody reactive with CD3 were able to redirect the cytotoxicity of peripheral blood lymphocytes (PBL) against ovarian carcinoma cells both in vitro and in vivo in an animal model. The treatment of athymic mice bearing a human ovarian carcinoma intraperitoneally, with human PBL coated with the bispecific F(ab')2, significantly prolonged survival of the animals compared with tumour-bearing untreated and control mice treated with PBL alone. Four ovarian cancer patients have been treated with autologous lymphocytes coated with this bispecific F(ab')2 in a phase I clinical trial. No serious side-effects were observed but patients developed human anti-murine antibodies mainly directed against the idiotype of MOv18. We have now begun phase II clinical trials in ovarian cancer patients.
Mezzanzanica
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Division of Experimental Oncology E, Istituto Nazionale Tumori, Milan, Italy.
Canevari
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Colnaghi
M I
MI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000276:immunology* / Q000627:therapeutic use; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000276:immunology; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D016219:Immunotherapy, Adoptive; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins