Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma

Yu-Tzu Tai, Xianfeng Li, Xia Tong, Daniel Santos, Takemi Otsuki, Laurence Catley, Olivier Tournilhac, Klaus Podar, Teru Hideshima, Robert Schlossman, Paul Richardson, Nikhil C Munshi, Mohammad Luqman, Kenneth C Anderson

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

139 Citations (Scopus)


Monoclonal antibodies (mAb) directed against lineage-specific B-cell antigens have provided clinical benefit for patients with hematologic malignancies, but to date no antibody-mediated immunotherapy is available for multiple myeloma. In the present study, we assessed the efficacy of a fully human anti-CD40 mAb CHIR-12.12 against human multiple myeloma cells. CHIR-12.12, generated in XenoMouse mice, binds to CD 138-expressing multiple myeloma lines and freshly purified CD 138-expressing cells from >80% multiple myeloma patients, as assessed by flow cytometry. Importantly, CHIR-12.12 abrogates CD40L-induced growth and survival of CD40-expressing patient multiple myeloma cells in the presence or absence of bone marrow stromal cells (BMSC), without altering constitutive multiple myeloma cell proliferation. Immunoblotting analysis specifically showed that PI3-K/AKT, nuclear factor-κB (NF-κB), and extracellular signal-regulated kinase activation induced by CD40L (5 μg/mL) was inhibited by CHIR-12.12 (5 μg/mL). Because CD40 activation induces multiple myeloma cell adhesion to both fibronectin and BMSCs, we next determined whether CHIR-12.12 inhibits this process. CHIR-12.12 decreased CD40L-induced multiple myeloma cell adhesion to fibronectin and BMSCs, whereas control human IgG1 did not. Adhesion of multiple myeloma cells to BMSCs induces interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion, and treatment of multiple myeloma cells with CD40L further enhanced adhesion-induced cytokine secretion; conversely, CHIR-12.12 blocks CD40L-enhanced IL-6 and VEGF secretion in cocultures of multiple myeloma cells with BMSCs. Finally, CHIR-12.12 triggered lysis of multiple myeloma cells via antibody-dependent cellular cytotoxicity (ADCC) but did not induce ADCC against CD40-negative multiple myeloma cells, confirming specificity against CD40-expressing multiple myeloma cells. These results provide the preclinical rationale for clinical trials of CHIR-12.12 to improve patient outcome in multiple myeloma.

Original languageEnglish
Pages (from-to)5898-5906
Number of pages9
JournalCancer Research
Issue number13
Publication statusPublished - 01 Jul 2005
Externally publishedYes


  • Antibodies, Monoclonal/pharmacology
  • Antibody-Dependent Cell Cytotoxicity
  • Antigen-Antibody Reactions
  • CD40 Antigens/biosynthesis
  • CD40 Ligand/immunology
  • Cell Line, Tumor
  • Dose-Response Relationship, Immunologic
  • Humans
  • I-kappa B Proteins/metabolism
  • Immunization, Passive/methods
  • Interleukin-6/metabolism
  • Membrane Glycoproteins/immunology
  • Multiple Myeloma/immunology
  • NF-KappaB Inhibitor alpha
  • Phosphorylation
  • Protein Serine-Threonine Kinases/metabolism
  • Proteoglycans/immunology
  • Proto-Oncogene Proteins/metabolism
  • Proto-Oncogene Proteins c-akt
  • Syndecan-1
  • Syndecans
  • Vascular Endothelial Growth Factor A/metabolism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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