Ifn-gamma Enhances the Antimyeloma Activity of the Fully Human Anti-human Leukocyte Antigen-dr Monoclonal Antibody 1d09c3.
From: “Cristina Gandini” Medical Oncology Unit, Medical Oncology, University of Milano, Milan, Italy.
Cancer research
- Publish Date: Apr 2007
- ISSN: 0008-5472
- Volume: 67
- Issue: 7
- Pages: 3269-75
- Medium: Print
- Language: English
- Citation (JAMA): Carlo-Stella Carmelo, Guidetti Anna, Di Nicola Massimo, et al. Ifn-gamma Enhances the Antimyeloma Activity of the Fully Human Anti-human Leukocyte Antigen-dr Monoclonal Antibody 1d09c3.. Cancer Res. Apr 2007;67:3269-75
Abstract
To investigate the therapeutic activity of the fully human anti-HLA-DR antibody 1D09C3 in multiple myeloma (MM), we reevaluated HLA-DR expression on CD138(+) cells, analyzed the capacity of IFN-gamma to up-regulate HLA-DR expression on MM cell lines, and tested the in vitro and in vivo activity of 1D09C3 alone or in combination with IFN-gamma. CD138(+)HLA-DR(+) cells were detected in 31 of 60 patients, with 15 of 60 patients having >/=20% CD138(+)HLA-DR(+) cells (median, 50%; range, 23-100). Because primary plasma cells cannot be efficiently cultured in vitro, we used a panel of MM cell lines with a dim/negative to bright HLA-DR expression to evaluate 1D09C3-induced cell death. Annexin V/propidium iodide (PI) staining showed that 1D09C3-induced cell death correlated with constitutive HLA-DR expression. Induction of HLA-DR by IFN-gamma restored the sensitivity of HLA-DR dim cell lines to 1D09C3. In vivo, the combined IFN-gamma/1D09C3 treatment significantly increased the median survival of nonobese diabetic/severe combined immunodeficient mice xenografted with KMS-11 cell line, compared with controls (147 versus 48 days, P 1D09C3 alone (147 versus 92 days, P IFN-gamma/1D09C3 treatment over 1D09C3 alone was further shown by a 2-fold increase of mice being disease-free at 150 days after xenograft (47% versus 25%). No mice experienced any apparent treatment-related toxicity. Our data show that (a) one fourth of MM patients express HLA-DR on CD138(+) cells and (b) IFN-gamma-induced up-regulation of HLA-DR results in a potent enhancement of the in vivo antimyeloma activity of 1D09C3.
Mesh Headings (Keywords): Adult, Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal, Drug Synergism, Female, HLA-DR Antigens, Humans, Interferon-gamma, Recombinant, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged, Multiple Myeloma, Plasma Cells, Syndecan-1, Up-Regulation, Xenograft Model Antitumor Assays
Check for Full Text / PubMed Unique Identifier (PMID): 17409435
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