Product pipeline: CD40 Agonist

Human CD40 is a member of the tumor necrosis factor (TNF) receptor family and is present on many normal leukocytes, particularly on B-cells, Dendritic Cells (DC) and monocytes. CD40 is also expressed on endothelial cells and (kidney tubular) epithelial cells. It plays a general role in inflammation and a key role in antibody production and CD8+ CTL induction. In addition, CD40 triggering of DC is a crucial signal to drive expansion, migration and (anti-tumor/viral) effector function of CD8+ cytotoxic T lymphocytes (CTL).

These findings form the basis of two patents of ISA Pharmaceuticals and create the rationale for development of cancer immunotherapy by local or systemic application of CD40 agonistic ligands. Incubation of B-cells and DC with agonistic anti-CD40 antibody causes marked activation, associated with upregulation of expression of a variety of costimulatory molecules including CD80, CD86, MHC class I and II as well as of CD40 itself. Agonistic anti-CD40 treatment can be applied for both CD40 positive and CD40 negative cancers, because the anti-CD40 agonism acts at the level of DC activation and not by direct tumor targeting. Local delivery of the CD40 agonist helps to reduce toxicity while maintaining systemic immunotherapeutic effects.

The company has started the development of a human CD40-agonistic compound.