Heidelberg, Germany, September19, 2019–Apogenix, a biopharmaceutical company developing nextgeneration immuno-oncology therapeutics, announced today thata new publication in Human Vaccines & Immunotherapeuticshighlights the advantages of hexavalent CD40 agonists, such as HERA-CD40L, inthe targeting of CD40 in immuno-oncology. Apogenix was invited to write this review paper of the various concepts for agonistic targeting of CD40 in immuno-oncology.
CD40 is expressed by antigen-presenting cells, endothelial cells, as well as numeroustumors. It is a key target in immuno-oncology because it has a fundamental role in initiating an antigen-specific immune response against tumors. The different strategies to induce CD40 signaling that were explored in the context of this review paper can bebroadly grouped into agonistic antibody-based and CD40L-based approaches. There are currently seven antibodies and one CD40L-based hexavalent fusion protein in active clinical trials.
The review reveals that anti-CD40 antibodies do not achieve the appropriate clustering capacity required for effective signaling into the target cell because of their bivalent nature. They typicallyrequire Fcγreceptor-mediated crosslinkingfor biological activity, which often causes serious side effects due to non-specific activation of the immune system. Recent data with CD40 and other receptors of the tumor necrosis factor superfamily (TNFSF) have shown that hexavalent agonists overcome the limitations of antibody-based approaches. These hexavalent TNFSF agonists specifically bind to their cognate receptors on target cells and induce clustering of six receptor chains in a spatially well-defined manner. Importantly, the agonistic activity of the TNFSF ligands is independent of additional crosslinking via Fcγreceptors.
Research Articles: “Concepts for agonistic targeting of CD40 in immuno-oncology”.