Anti-CD40 agonistic antibodies with enhanced FcgRIIB binding mediate superior tumor protection

CD40 molecule was an immunology superstar of 90s. Scientists thought they found a mechanism that controlled robust CD8 T cell and antibody responses. However, 20 years later, nothing much came out of those studies. In fact, scientists are still figuring out what is the best way to activate human CD40 molecule. 

For example, in new study published in Cancer Cell, Jeffrey Ravetch's group showed that in mouse model expressing transgenic human CD40, effectiveness of anti-hCD40 antibody correlated with enhanced binding to inhibitory FcγRIIB.  

The authors developed several variants of anti-hCD40 (clone CP-870,893, a fully human IgG2, one of the most potent agonistic CD40 mAb) with higher affinity and selectivity to human FcγRIIB (and minimal change in binding to FcγRIIA). Protein immunization confirmed that improved affinity to FcγRIIB correlated with effectiveness of CD8 T cell priming.

Moreover, enhanced affinity of anti-hCD40 antibody to FcγRIIB (V11 clone, for example) correlated with improved anti-cancer effect of anti-hCD40 agonistic antibody (in MC38 and B16 cancer models).

In summary, this study indicates that in mouse model of hCD40 / hFcγRIIB expression selective binding to hFcγRIIB is important for enhanced anti-cancer effect of anti-hCD40 antibodies.

David Usharauli