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

Summary

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), 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 FcγR 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 FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

Graphical Abstract

Highlights

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  Anti-CTLA-4 of hIgG1 and hIgG2 isotypes promote depletion of intra-tumoral Treg cells

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  hIgG2 antibodies mediate in vivo depletion of intra-tumoral Treg cells via CD32a

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  Anti-CTLA-4 with enhanced Fc effector function improves therapeutic outcomes

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  The CD16-V158F SNP is associated with response to ipilimumab in inflamed tumors

Abstract

Arce Vargas et al. use a mouse model expressing human FcγRs to show that antibodies with isotypes equivalent to ipilimumab increase the CD8 ⁺ to Treg ratio by depleting intra-tumoral Tregs to promote tumor rejection. In melanoma patients, response to ipilimumab is associated with a high affinity FcγR polymorphism.