1. Bispecific monoclonal antibodies for intravenous treatment of carcinoma patients: immunobiologic aspects.
- Author
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Kroesen BJ, Janssen RA, Buter J, Nieken J, Sleijfer DT, Mulder NH, and De Leij L
- Subjects
- Antibodies, Bispecific administration & dosage, Antibodies, Bispecific adverse effects, Antibodies, Bispecific immunology, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal immunology, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm adverse effects, Antibodies, Neoplasm immunology, Carcinoma, Renal Cell immunology, Combined Modality Therapy, Cytotoxicity, Immunologic, Dose-Response Relationship, Immunologic, Epithelial Cell Adhesion Molecule, Humans, Immunization, Passive adverse effects, Immunoglobulin Fab Fragments administration & dosage, Immunoglobulin Fab Fragments adverse effects, Immunoglobulin Fab Fragments immunology, Immunologic Factors administration & dosage, Immunologic Factors therapeutic use, Injections, Intravenous, Injections, Subcutaneous, Interferon-gamma blood, Interleukin-2 administration & dosage, Interleukin-2 adverse effects, Interleukin-2 therapeutic use, Kidney Neoplasms immunology, Leukopenia chemically induced, Muromonab-CD3 administration & dosage, Muromonab-CD3 adverse effects, Muromonab-CD3 immunology, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, Tumor Necrosis Factor-alpha analysis, Antibodies, Bispecific therapeutic use, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Antigens, Neoplasm immunology, Carcinoma, Renal Cell therapy, Cell Adhesion Molecules immunology, Immunoglobulin Fab Fragments therapeutic use, Kidney Neoplasms therapy, Muromonab-CD3 therapeutic use
- Abstract
Immunobiologic parameters measured during a phase I trial of intravenously (i.v.) administered bispecific monoclonal antibodies (BsmAb) in renal cell carcinoma (RCC) patients are described. The BsmAb used, BIS-1, is reactive with a pancarcinoma-associated 38 kDa transmembrane glycoprotein, EGP-2, as well with the CD3 complex. Patients received during a 2 h i.v. infusion F(ab')2 fragments of BIS-1 at doses of 1, 3, or 5 micrograms/kg body weight during concomitantly applied subcutaneous (s.c.) IL-2 treatment. Acute but transient BIS-1 F(ab')2-related toxicity was observed at the 3 and 5 micrograms/kg dose level, and the maximum tolerated dose (MTD) was set at 5 micrograms/kg. A dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes was found. The in vivo occupancy of CD3 molecules on T lymphocytes was highest at teh end of the infusion period and then rapidly decreased, as shown by flow cytometry. A much slower decrease of BIS-1 F(ab')2 binding was observed in vitro, suggesting migration of BIS-1 F(ab')2-loaded T lymphocytes from the circulation. A strong but transitory leukopenia was observed, in which LFA-1 alpha bright, CD3/CD8 double positive T cells left the circulation preferentially. This phenomenon was most likely induced by elevated TNF-alpha and IFN-gamma plasma levels, which were at a maximum shortly after the end of the infusion. Isolated peripheral blood mononuclear cells obtained from patients directly after treatment with BIS-1 F(ab')2 at the 3 and 5 micrograms/kg dose level showed increased EGP-2-directed antitumor activity.
- Published
- 1995
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