CD40 is a key activating receptor on professional antigen presenting cells and is also found on multiple tumor cells. It can trigger immune-mediated and direct antitumor effects. Vitale et al. describe the selection and in vitro and in vivo biochemical and biological attributes of CDX-1140, an agonist-CD40 antibody, which just entered clinical trials. Uniquely, CDX-1140 was selected for moderate, but not high, stimulatory activity to allow saturation of tissue CD40 with limited toxicity. CDX-1140 bound CD40 at a site distinct from CD40L, facilitating synergy. CDX-1140 showed properties expected for a CD40 agonist and was well tolerated in non-human primates.
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.