Published in:
Open Access
01-07-2018 | Original Article
The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions
Authors:
Tong Zhang, Xiaomin Song, Lanlan Xu, Jie Ma, Yanjuan Zhang, Wenfeng Gong, Yilu Zhang, Xiaosui Zhou, Zuobai Wang, Yali Wang, Yingdi Shi, Huichen Bai, Ning Liu, Xiaolong Yang, Xinxin Cui, Yanping Cao, Qi Liu, Jing Song, Yucheng Li, Zhiyu Tang, Mingming Guo, Lai Wang, Kang Li
Published in:
Cancer Immunology, Immunotherapy
|
Issue 7/2018
Login to get access
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 (IgG4S228P). The functional impact by the interaction of anti-PD-1 IgG4S228P antibody with Fc gamma receptors (FcγRs) is poorly understood. To assess the effects, we generated a pair of anti-PD-1 antibodies: BGB-A317/IgG4S228P 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/IgG4S228P 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/IgG4S228P 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/IgG4S228P-treated group. These evidences suggested that FcγRI+ binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity.