PD-1 is an inhibitory receptor induced on activated T cells; engagement by PD-L1/PD-L2 suppresses TCR signaling and effector function, enabling tumor immune escape.¹ Separately, antibody Fc-FcɣR interactions can influence the activity of checkpoint antibodies through effects on myeloid cells and antibody disposition in the tumor microenvironment.^2,3

Tislelizumab blocks PD-1 interactions with PD-L1 and PD-L2, restoring T-cell effector function. Its distinct PD-1 epitope and very slow dissociation support tight, durable PD-1 engagement, while FcɣR minimization is intended to reduce Fc-mediated myeloid interactions that could otherwise diminish an effective PD-1 blockade.^3-5 FcɣR minimization matters mechanistically as preclinical studies have shown that FcɣR engagement can modulate checkpoint antibody activity and that tumor-associated macrophages can remove anti-PD-1 from T cells via FcɣR-dependent processes.^3,6

Fc, fragment crystallizable (antibody tail region); FcɣR, Fcɣ receptor; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; TCR, T-cell receptor.

References

1. Pardoll DM. Nat Rev Cancer. 2012;12:252-264
2. Dahan R, et al. Cancer Cell. 2015;28:285-295
3. Arlauckas SP, et al. Sci Transl Med. 2017;9(389):eaal3604.
4. Hong Y, et al. FEBS Open Bio. 2021;11:782-792
5. Lee SH, et al. Biochem Biophys Res Commun. 2020;527(1):226-231
6. Dahan R, et al. Cancer Cell. 2015;28:285-295