Cancer Immunol Immunother. 2018 Oct 31. doi: 10.1007/s00262-018-2267-0. [Epub ahead of print]
Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy.
Vitale LA1, Thomas LJ2, He LZ1, O'Neill T1, Widger J1, Crocker A1, Sundarapandiyan K1, Storey JR2, Forsberg EM2, Weidlick J1, Baronas AR2, Gergel LE2, Boyer JM2, Sisson C1, Goldstein J1, Marsh HC Jr2, Keler T3.
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.
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. |
