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The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.

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

Open access
Zhang, Tong, Song, Xiaomin, Xu, Lanlan, Ma, Jie, Zhang, Yanjuan, Gong, Wenfeng, Zhang, Yilu, Zhou, Xiaosui, Wang, Zuobai, Wang, Yali, Shi, Yingdi, Bai, Huichen, Liu, Ning, Yang, Xiaolong, Cui, Xinxin, Cao, Yanping, Liu, Qi, Song, Jing, Li, Yucheng, Tang, Zhiyu, Guo, Mingming, Wang, Lai, Li, Kang·2018·Cancer Immunology, Immunotherapy
DOI 10.1007/s00262-018-2160-x
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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 (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.

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Metadata

Authors
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.
Venue
Cancer Immunology, Immunotherapy
Publisher
Springer Science and Business Media LLC
Published
2018-04-23
Volume
67
Issue
7
Pages
1079-1090
ISSN
  • 0340-7004 (ISSN-L)
  • 1432-0851
DOI
10.1007/s00262-018-2160-x
OpenAlex
W2799565954
Cited by
290
References
9
FWCI
11.97
Type
journal article
Language
en
Open access
hybrid

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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., . . . Li, K. (2018). The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-018-2160-x

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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