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.

Author Info: (1) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (2) Celldex Therapeutics, Inc, Needham, MA, USA. (3) Celldex Therapeutics, Inc, 5

Author Info: (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. (4) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (5) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (6) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (7) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (8) Celldex Therapeutics, Inc, Needham, MA, USA. (9) Celldex Therapeutics, Inc, Needham, MA, USA. (10) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (11) Celldex Therapeutics, Inc, Needham, MA, USA. (12) Celldex Therapeutics, Inc, Needham, MA, USA. (13) Celldex Therapeutics, Inc, Needham, MA, USA. (14) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (15) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. (16) Celldex Therapeutics, Inc, Needham, MA, USA. (17) Celldex Therapeutics, Inc, 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA. tkeler@celldex.com.

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