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.
Publication types
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Clinical Trial
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Clinical Trial, Phase I
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Controlled Clinical Trial
MeSH terms
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Antibodies, Bispecific / administration & dosage
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Antibodies, Bispecific / adverse effects
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Antibodies, Bispecific / immunology
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Antibodies, Bispecific / therapeutic use*
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / adverse effects
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / therapeutic use*
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Antibodies, Neoplasm / administration & dosage
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Antibodies, Neoplasm / adverse effects
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Antibodies, Neoplasm / immunology
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Antibodies, Neoplasm / therapeutic use*
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Antigens, Neoplasm / immunology*
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Carcinoma, Renal Cell / immunology
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Carcinoma, Renal Cell / therapy*
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Cell Adhesion Molecules / immunology*
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Combined Modality Therapy
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Cytotoxicity, Immunologic
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Dose-Response Relationship, Immunologic
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Epithelial Cell Adhesion Molecule
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Humans
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Immunization, Passive / adverse effects
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Immunoglobulin Fab Fragments / administration & dosage
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Immunoglobulin Fab Fragments / adverse effects
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Immunoglobulin Fab Fragments / immunology
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Immunoglobulin Fab Fragments / therapeutic use*
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Immunologic Factors / administration & dosage
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Immunologic Factors / therapeutic use
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Injections, Intravenous
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Injections, Subcutaneous
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Interferon-gamma / blood
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Interleukin-2 / administration & dosage
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Interleukin-2 / adverse effects
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Interleukin-2 / therapeutic use
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Kidney Neoplasms / immunology
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Kidney Neoplasms / therapy*
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Leukopenia / chemically induced
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Muromonab-CD3 / administration & dosage
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Muromonab-CD3 / adverse effects
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Muromonab-CD3 / immunology
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Muromonab-CD3 / therapeutic use*
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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Tumor Necrosis Factor-alpha / analysis
Substances
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Antibodies, Bispecific
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Antibodies, Monoclonal
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Antibodies, Neoplasm
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Antigens, Neoplasm
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Cell Adhesion Molecules
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Epithelial Cell Adhesion Molecule
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Immunoglobulin Fab Fragments
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Immunologic Factors
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Interleukin-2
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Muromonab-CD3
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Tumor Necrosis Factor-alpha
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Interferon-gamma