title: The CD40 agonist antibody CP-870,893 enhances dendritic cell and B-cell activity and promotes anti-tumor efficacy in SCID-hu mice.
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.
authors.affiliation: Department of Immunology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. Ronald.P.Gladue@Pfizer.com
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Gladue
authors.forename: Timothy
authors.initials: T
authors.lastname: Paradis
authors.forename: Susan H
authors.initials: SH
authors.lastname: Cole
authors.forename: Carol
authors.initials: C
authors.lastname: Donovan
authors.forename: Robin
authors.initials: R
authors.lastname: Nelson
authors.forename: Robbin
authors.initials: R
authors.lastname: Alpert
authors.forename: Joe
authors.initials: J
authors.lastname: Gardner
authors.forename: Ed
authors.initials: E
authors.lastname: Natoli
authors.forename: Eileen
authors.initials: E
authors.lastname: Elliott
authors.forename: Richard
authors.initials: R
authors.lastname: Shepard
authors.forename: Vahe
authors.initials: V
authors.lastname: Bedian
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; D016207:Cytokines; C518149:selicrelumab