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

Cancer Immunol Immunother. 2018 Jul;67(7):1079-1090. doi: 10.1007/s00262-018-2160-x. Epub 2018 Apr 23.


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.

Keywords: Antibody; Cancer therapy; FcγRI; Macrophages; PD-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Apoptosis
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / metabolism
  • Cell Proliferation
  • Humans
  • Immunoglobulin G / drug effects
  • Immunoglobulin G / immunology*
  • Immunoglobulin G / metabolism
  • Lymphocyte Activation
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, IgG / metabolism*
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Immunoglobulin G
  • Programmed Cell Death 1 Receptor
  • Receptors, IgG