Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications

Yu-Tzu Tai, Laurence P Catley, Constantine S Mitsiades, Renate Burger, Klaus Podar, Reshma Shringpaure, Teru Hideshima, Dharminder Chauhan, Makoto Hamasaki, Kenji Ishitsuka, Paul Richardson, Steven P Treon, Nikhil C Munshi, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

122 Citations (Scopus)


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 languageEnglish
Pages (from-to)2846-2852
Number of pages7
JournalCancer Research
Issue number8
Publication statusPublished - 15 Apr 2004
Externally publishedYes


  • 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


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