Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments.

Autor:	Moreno-Vicente J; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK.; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Willoughby JE; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Taylor MC; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Booth SG; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., English VL; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Williams EL; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Penfold CA; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Mockridge CI; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Inzhelevskaya T; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Kim J; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Chan HTC; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Cragg MS; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Gray JC; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK., Beers SA; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK s.a.beers@soton.ac.uk.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jan; Vol. 10 (1).
DOI:	10.1136/jitc-2021-003735
Abstrakt:	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. Competing Interests: Competing interests: MC acts as a consultant to BioInvent and has received institutional support from BioInvent for grants and patents. JCG and SAB have received institutional support from BioInvent for grants. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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