The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Abstract

Antibodies targeting PD-1 have been demonstrated durable anti-cancer activity in certain cancer types. However, the anti-PD-1 antibodies are less or not efficacious in many situations, which might be attributed to co-expression of multiple inhibitory receptors or presence of immunosuppressive cells in the tumor microenvironment. Most of the anti-PD-1 antibodies used in clinical studies are of IgG4 isotype with the S228P mutation (IgG4 _S228P). The functional impact by the interaction of anti-PD-1 IgG4 _S228P antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4 _S228P and BGB-A317/IgG4-variant (abbreviated as BGB-A317), with the same variable regions but two different IgG4 Fc-hinge sequences. There was no significant difference between these two antibodies in binding to PD-1. However, BGB-A317/IgG4 _S228P binds to human FcγRI with high affinity and mediates crosslinking between PD-1 and FcγRI. In contrast, BGB-A317 does neither. Further cell-based assays showed that such crosslinking could reverse the function of an anti-PD-1 antibody from blocking to activating. More importantly, the crosslinking induces FcγRI ⁺ macrophages to phagocytose PD-1 ⁺ T cells. In a mouse model transplanted with allogeneic human cancer cells and PBMCs, BGB-A317 showed significant tumor growth inhibition, whereas BGB-A317/IgG4 _S228P had no such inhibition. Immunohistochemistry study revealed an inverse correlation between FcγRI ⁺ murine macrophage infiltration and the density of CD8 ⁺PD-1 ⁺ human T cells within tumors in the BGB-A317/IgG4 _S228P-treated group. These evidences suggested that FcγRI ⁺ binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity.

Electronic supplementary material

The online version of this article (10.1007/s00262-018-2160-x) contains supplementary material, which is available to authorized users.