Preclinical antilymphoma activity of a humanized anti-CD40 monoclonal antibody, SGN-40.

Abstract

SGN-40 is a humanized IgG1 antihuman CD40 that is currently in a phase I clinical trial for the treatment of multiple myeloma. As surface CD40 expression on B-lineage cells is maintained from pro-B cells to plasma cells, SGN-40 may be applicable to treatment of other B-cell neoplasias, including non-Hodgkin's lymphoma. In this study, we examined potential in vitro and in vivo anti-B-lineage lymphoma activity of SGN-40. Recombinant SGN-40 was expressed and purified from Chinese hamster ovary cells and characterized based on binding affinity, specificity, and normal B-cell stimulation. The ability of SGN-40 to target neoplastic B cells was examined in vitro by proliferation inhibition, cytotoxicity, and antibody-dependent cell cytotoxicity assays and in vivo by human lymphoma xenograft models. Recombinant SGN-40 showed high affinity, Kd of approximately 1 nmol/L, and specific binding to CD40. Whereas SGN-40 was a weak agonist in stimulating normal B-cell proliferation in the absence of IL-4 and CD40L, it delivered potent proliferation inhibitory and apoptotic signals to, and mediated antibody-dependent cytotoxicity against, a panel of high-grade B-lymphoma lines. These in vitro antilymphoma effects were extended to disseminated and s.c. xenograft CD40 tumor models. In these xenograft models, the antitumor activity of SGN-40 was comparable with that of rituximab. The preclinical in vitro and in vivo antilymphoma activity of SGN-40 observed in this study provides a rationale for the clinical testing of SGN-40 in the treatment of CD40+ B-lineage lymphomas.

• Authors: Che-Leung Law, Kristine A Gordon, John Collier, Kerry Klussman, Julie A McEarchern, Charles G Cerveny, Bruce J Mixan, Wyne P Lee, Zhonghau Lin, Patricia Valdez, Alan F Wahl, Iqbal S Grewal
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 18 Pg. 8331-8 (Sep 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16166310 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• CD40 Antigens
• Immunoglobulin G
• CASP3 protein, human
• Casp3 protein, mouse
• Caspase 3
• Caspases

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antibody-Dependent Cell Cytotoxicity
• Apoptosis (drug effects, immunology)
• B-Lymphocytes (cytology, drug effects, immunology)
• CD40 Antigens (immunology)
• Caspase 3
• Caspases (metabolism)
• Cell Growth Processes (drug effects, immunology)
• Cell Line, Tumor
• Enzyme Activation
• Humans
• Immunoglobulin G (immunology, pharmacology)
• Lymphoma, B-Cell (immunology, pathology, therapy)
• Mice
• Mice, SCID
• Xenograft Model Antitumor Assays