Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies

With the use of a mouse model expressing human Fc-gamma receptors (Fc gamma Rs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8(+) to Treg cell ratio and promoting tumor rejection. Antibodies with improved Fc gamma R binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of Fc gamma R binding, whereas poorly infiltrated tumors will likely require combination approaches.