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

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Zhang T, Song X, Xu L, Ma J, Zhang Y, Gong W, Zhang Y, Zhou X, Wang Z, Wang Y, Shi Y, Bai H, Liu N, Yang X, Cui X, Cao Y, Liu Q, Song J, Li Y, Tang Z, Guo M, Wang L, Li K

The binding of an anti-PD-1 antibody to FcgammaRIota 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.

PubMed ID
29687231 [ View in PubMed
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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 (FcgammaRs) 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 FcgammaRI with high affinity and mediates crosslinking between PD-1 and FcgammaRI. 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 FcgammaRI(+) 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 FcgammaRI(+) 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 FcgammaRI(+) binding and crosslinking had negative impact on the anti-PD-1 antibody-mediated anti-cancer activity.

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