Abstract
CD40 is expressed on B-cell malignancies, including human multiple myeloma (MM) and a variety of carcinomas. We examined the potential therapeutic utility of SGN-40, the humanized anti-CD40 monoclonal antibody, for treating human MM using MM cell lines and patient MM cells (CD138(++), CD40(+)). SGN-40 (0.01-100 micro g/ml) induces modest cytotoxicity in MM cell lines and patient MM cells. In the presence of de novo protein synthesis inhibitor cycloheximide, SGN-40 significantly induced apoptosis in Dexamethasone (Dex)-sensitive MM.1S and Dex-resistant MM.1R cells and in patient MM cells. SGN-40-mediated cytotoxicity is associated with up-regulation of cytotoxic ligands of the tumor necrosis factor family (Fas/FasL, tumor necrosis factor-related apoptosis-inducing ligand, and tumor necrosis factor alpha). SGN-40 treatment also induces a down-regulation of CD40 dependent on an endocytic pathway. Consequently, pretreatment of MM cells with SGN-40 blocked sCD40L-mediated phosphatidylinositol 3'-kinase/AKT and nuclear factor kappaB activation. Importantly, pretreatment of MM.1S and MM.1R cells with SGN-40 inhibited proliferation triggered by interleukin 6 (IL-6) but not by insulin-like growth factor-I. In addition, SGN-40 pretreatment of MM.1S cells blocked the ability of IL-6 to protect against Dex-induced inhibition of DNA synthesis. This was associated with a 2-4-fold reduction of IL-6 receptor at protein and mRNA levels in SGN-40-treated MM.1S cells and patient MM cells. Taken together, these results provide the preclinical rationale for the evaluation of SGN-40 as a potential new therapy to improve patient outcome in MM.
Original language | English |
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Pages (from-to) | 2846-2852 |
Number of pages | 7 |
Journal | Cancer Research |
Volume | 64 |
Issue number | 8 |
DOIs | |
Publication status | Published - 15 Apr 2004 |
Externally published | Yes |
Keywords
- Antibodies, Monoclonal/immunology
- CD40 Antigens/biosynthesis
- CD40 Ligand/immunology
- Cell Line, Tumor
- Cytotoxicity, Immunologic
- Humans
- I-kappa B Proteins/metabolism
- Immunization, Passive/methods
- Insulin-Like Growth Factor I/pharmacology
- Interleukin-6/pharmacology
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinases/metabolism
- Multiple Myeloma/immunology
- NF-KappaB Inhibitor alpha
- Phosphorylation
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins c-akt
- RNA, Messenger/biosynthesis
- Receptors, Interleukin-6/antagonists & inhibitors