1. Academic Validation
  2. Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy

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.
Laura A Vitale 1 Lawrence J Thomas 2 Li-Zhen He 1 Thomas O'Neill 1 Jenifer Widger 1 Andrea Crocker 1 Karuna Sundarapandiyan 1 James R Storey 2 Eric M Forsberg 2 Jeffrey Weidlick 1 April R Baronas 2 Lauren E Gergel 2 James M Boyer 2 Crystal Sisson 1 Joel Goldstein 1 Henry C Marsh Jr 2 Tibor Keler 3
Affiliations

Affiliations

  • 1 Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA.
  • 2 Celldex Therapeutics, Inc, Needham, MA, USA.
  • 3 Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. tkeler@celldex.com.
Abstract

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.

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