Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments.
Authors
Taylor, Martin C
Booth, Steven G
English, Vikki L
Williams, Emily L
Penfold, Christine A
Mockridge, C Ian
Inzhelevskaya, Tatyana
Kim, Jinny
Chan, HT Claude
Cragg, Mark S
Gray, Juliet C
Beers, Stephen A
Publication Date
2022-01Journal Title
J Immunother Cancer
ISSN
2051-1426
Publisher
BMJ
Volume
10
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Moreno-Vicente, J., Willoughby, J. E., Taylor, M. C., Booth, S. G., English, V. L., Williams, E. L., Penfold, C. A., et al. (2022). Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments.. J Immunother Cancer, 10 (1) https://doi.org/10.1136/jitc-2021-003735
Abstract
BACKGROUND: Despite extensive clinical use, the mechanisms that lead to therapeutic resistance to anti-programmed cell-death (PD)-1 monoclonal antibodies (mAbs) remain elusive. Here, we sought to determine how interactions between the Fc region of anti-PD-1 mAbs and Fcγ receptors (FcγRs) affect therapeutic activity and how these are impacted by the immune environment. METHODS: Mouse and human anti-PD-1 mAbs with different Fc binding profiles were generated and characterized in vitro. The ability of these mAbs to elicit T-cell responses in vivo was first assessed in a vaccination setting using the model antigen ovalbumin. The antitumor activity of anti-PD-1 mAbs was investigated in the context of immune 'hot' MC38 versus 'cold' neuroblastoma tumor models, and flow cytometry performed to assess immune infiltration. RESULTS: Engagement of activating FcγRs by anti-PD-1 mAbs led to depletion of activated CD8 T cells in vitro and in vivo, abrogating therapeutic activity. Importantly, the extent of this Fc-mediated modulation was determined by the surrounding immune environment. Low FcγR-engaging mouse anti-PD-1 isotypes, which are frequently used as surrogates for human mAbs, were unable to expand ovalbumin-reactive CD8 T cells, in contrast to Fc-null mAbs. These results were recapitulated in mice expressing human FcγRs, in which clinically relevant hIgG4 anti-PD-1 led to reduced endogenous expansion of CD8 T cells compared with its engineered Fc-null counterpart. In the context of an immunologically 'hot' tumor however, both low-engaging and Fc-null mAbs induced long-term antitumor immunity in MC38-bearing mice. Finally, a similar anti-PD-1 isotype hierarchy was demonstrated in the less responsive 'cold' 9464D neuroblastoma model, where the most effective mAbs were able to delay tumor growth but could not induce long-term protection. CONCLUSIONS: Our data collectively support a critical role for Fc:FcγR interactions in inhibiting immune responses to both mouse and human anti-PD-1 mAbs, and highlight the context-dependent effect that anti-PD-1 mAb isotypes can have on T-cell responses. We propose that engineering of Fc-null anti-PD-1 mAbs would prevent FcγR-mediated resistance in vivo and allow maximal T-cell stimulation independent of the immunological environment.
Keywords
Basic tumor immunology, 1506, 2434, immunotherapy, programmed cell death 1 receptor, antibodies, neoplasm
Sponsorship
Cancer Research UK (A20537, A24721, A25139, A29286)
Identifiers
jitc-2021-003735
External DOI: https://doi.org/10.1136/jitc-2021-003735
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333138
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
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