Bispecific monoclonal antibodies for intravenous treatment of carcinoma patients: immunobiologic aspects
| Autor: | Judith Nieken, Richard A.J. Janssen, Dirk Sleijfer, Bart-Jan Kroesen, Jan Buter, Nanno Mulder, Lou F. M. H. de Leij |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 1995 |
| Předmět: |
Cytotoxicity
Immunologic medicine.drug_class Antibodies Neoplasm CD3 Injections Subcutaneous Immunology Dose-Response Relationship Immunologic Pharmacology CD3 Complex Monoclonal antibody Flow cytometry Immunoglobulin Fab Fragments Interferon-gamma In vivo Antigens Neoplasm T-Lymphocyte Subsets Antibodies Bispecific medicine Carcinoma Humans Immunologic Factors Carcinoma Renal Cell medicine.diagnostic_test biology Chemistry Tumor Necrosis Factor-alpha Immunization Passive Antibodies Monoclonal Hematology Leukopenia medicine.disease Epithelial Cell Adhesion Molecule Combined Modality Therapy In vitro Kidney Neoplasms Toxicity Injections Intravenous biology.protein Interleukin-2 Cell Adhesion Molecules Muromonab-CD3 |
| Zdroj: | Journal of hematotherapy & stem cell research, 4(5):8581377, 409-414 |
| ISSN: | 1525-8165 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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