Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy

Cancer Immunol Immunother. 2019 Feb;68(2):233-245. doi: 10.1007/s00262-018-2267-0. Epub 2018 Oct 31.


Limitations of immunotherapy include poorly functioning events early in the immune response cycle, such as efficient antigen presentation and T cell priming. CD40 signaling in dendritic cells leads to upregulation of cell surface costimulatory and MHC molecules and the generation of cytokines, which promotes effective priming of CD8+ effector T cells while minimizing T cell anergy and the generation of regulatory T cells. This naturally occurs through interaction with CD40 ligand (CD40L) expressed on CD4+ T-helper cells. CD40 signaling can also be achieved using specific antibodies, leading to several agonist CD40 antibodies entering clinical development. Our approach to select a CD40 agonist antibody was to define a balanced profile between sufficiently strong immune stimulation and the untoward effects of systemic immune activation. CDX-1140 is a human IgG2 antibody that activates DCs and B cells and drives NFkB stimulation in a CD40-expressing reporter cell line. These activities are Fc-independent and are maintained using an F(ab')2 fragment of the antibody. CDX-1140 binds outside of the CD40L binding site, and addition of recombinant CD40L greatly enhances DC and B activation by CDX-1140, suggesting that CDX-1140 may act synergistically with naturally expressed CD40L. CDX-1140 also has both direct and immune-mediated anti-tumor activity in xenograft models. CDX-1140 does not promote cytokine production in whole blood assays and has good pharmacodynamic and safety profiles in cynomolgus macaques. These data support the potential of CDX-1140 as part of a cancer therapy regimen, and a phase 1 trial has recently commenced.

Keywords: Agonist antibody; Antigen presenting cells; CD40; Immunotherapy.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • CD40 Antigens / agonists*
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • CHO Cells
  • Cell Line, Tumor
  • Cricetinae
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Immunotherapy / methods*
  • Macaca fascicularis
  • Mice, SCID
  • Mice, Transgenic
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • CD40 Antigens
  • CD40 Ligand