The CD40 Agonist Antibody CP-870,893 Enhances Dendritic Cell and B-cell Activity and Promotes Anti-Tumor Efficacy in SCID-hu Mice

Cancer Immunol Immunother. 2011 Jul;60(7):1009-17. doi: 10.1007/s00262-011-1014-6. Epub 2011 Apr 12.

Abstract

CD40 is a member of the TNF family of receptors that has been shown to play a crucial role in enhancing dendritic cell activity and fostering anti-tumor immune responses. In this study, we demonstrate the in vitro properties and in vivo efficacious activity of the CD40 agonist antibody, CP-870,893. CP-870,893 is a fully human, IgG2 antibody that selectively interacts with CD40 at a site distinct from its ligand-binding region with a KD of 0.4 nM. It enhances the expression of MHC class II, CD54, CD86, and CD23 on human B cells in vitro. CP-870,893 also enhances dendritic cell activity as evidenced by cytokine secretion (IL-12, IL-23, IL-8), the upregulation of CD86 and CD83, and the ability to prime T cells to secrete IFNγ. In SCID-beige mice, a single parenteral injection of CP-870,893 was therapeutically effective against several CD40(pos) human tumors (B-cell lymphoma, breast, colon, and prostate) indicating direct effects on tumor cell survival and/or growth. When mice were co-implanted with human T cells and dendritic cells, the activity of CP-870,893 against CD40(pos) tumors increased, and efficacy was also observed against CD40(neg) and CD40(low) tumors demonstrating the ability of CP-870,893 to enhance anti-tumor immune function in vivo. These studies suggest that CP-870,893 has the potential to be efficacious against a wide range of tumor types through both direct and immune-mediated effects.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / physiology*
  • Antibodies, Monoclonal, Humanized
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • CD40 Antigens / immunology*
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Flow Cytometry
  • Humans
  • Lymphocyte Activation
  • Mice
  • Mice, SCID
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / prevention & control*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • CD40 Antigens
  • Cytokines
  • selicrelumab