Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation.

Abstract

BACKGROUND:

CD40 activation of antigen presenting cells (APC) such as dendritic cells (DC) and B cells plays an important role in immunological licensing of T cell immunity. Agonist CD40 antibodies have been previously shown in murine models to activate APC and enhance tumor immunity; in humans, CD40-activated DC and B cells induce tumor-specific T cells in vitro. Although clinical translation of these findings for patients with cancer has been previously limited due to the lack of a suitable and available drug, promising clinical results are now emerging from phase I studies of the agonist CD40 monoclonal antibody CP-870,893. The most prominent pharmacodynamic effect of CP-870,893 infusion is peripheral B cell modulation, but direct evidence of CP-870,893-mediated B cell activation and the potential impact on T cell reactivity has not been reported, despite increasing evidence that B cells, like DC, regulate cellular immunity.

METHODS:

Purified total CD19+ B cells, CD19+ CD27+ memory, or CD19+ CD27(neg) subsets from peripheral blood were stimulated in vitro with CP-870,893, in the presence or absence of the toll like receptor 9 (TLR9) ligand CpG oligodeoxynucleotide (ODN). B cell surface molecule expression and cytokine secretion were evaluated using flow cytometry. Activated B cells were used as stimulators in mixed lymphocyte reactions to evaluate their ability to induce allogeneic T cell responses.

RESULTS:

Incubation with CP-870,893 activated B cells, including both memory and naïve B cells, as demonstrated by upregulation of CD86, CD70, CD40, and MHC class I and II. CP-870,893-activated B cells induced T cell proliferation and T cell secretion of effector cytokines including IFN-gamma and IL-2. These effects were increased by TLR9 co-stimulation via a CpG ODN identical in sequence to a well-studied clinical grade reagent.

CONCLUSION:

The CD40 mAb CP-870,893 activates both memory and naïve B cells and triggers their T cell stimulatory capacity. Simultaneous TLR9 ligation augments the effect of CP-870,893 alone. These results provide further rationale for combining CD40 and TLR9 activation using available clinical reagents in strategies of novel tumor immunotherapy.

• Authors: Erica L Carpenter, Rosemarie Mick, Jens Rüter, Robert H Vonderheide
• Journal: Journal of translational medicine (J Transl Med) Vol. 7 Pg. 93 (Nov 11 2009) ISSN: 1479-5876 [Electronic] England
• PMID: 19906293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CD40 Antigens
• Toll-Like Receptor 9
• selicrelumab

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antibodies, Monoclonal, Humanized
• B-Lymphocytes (drug effects, immunology)
• CD40 Antigens (agonists, immunology)
• Humans
• Immunologic Memory (drug effects, immunology)
• Lymphocyte Activation (drug effects, immunology)
• Mice
• Neoplasms (immunology)
• T-Lymphocytes (drug effects, immunology)
• Toll-Like Receptor 9 (immunology)