307 Interaction of anti-PD-1/PD-1 immunocomplexes with human FcRs: binding properties and functional implication

Background Rescue of exhausted T cell immunity through the inhibition PD-1/PD-L1 interaction is a pillar immunotherapeutic anti-PD-1 monoclonal antibodies (mAbs), as Nivolumab and Pembrolizumab. Despite IgG4 subclass, mAbs can bind different FcγRs trigger immunosuppressive activity in FcR-expressing myeloid cells. This effect evident when engage soluble PD-1 (sPD-1) forming stable sPD-1-antiPD-1mAb immune complex (PD-1 IC). In present study we dissect process by investigating which displays highest affinity for monomeric or complexed Nivolumab. addition, methods detecting quantifying ICs plasma patients treated with blockers are under development clinical application. Methods By surface plasmon resonance (SRP) (BiacoreTM T200, Cytiva), FcγRI/CD64, FcγRIIa/CD32a, FcγRIIb/CD32b, FcγRIIIa/CD16a FcγRIIIb/CD16b anti-PD1 corresponding PD-1-IC has been evaluated, their cellular localization assessed confocal microscopy. Further, sPD-1 IC determined customized ELISAs western blot approaches mAb-treated patients. Results The binding occurred all tested, albeit sensorgrams revealed diverse degrees affinity. No major difference overall versus observed FcγRIIb/CD32b. Instead, dissociation phase was clearly slowest respect to mAb studies. Nevertheless, only undergoes internalization interacting human FcγR+ cells vitro, pathways that does not appear lead lysosomal co-localization. Customized ELISA quantification developed detect after enrichment specific matrix. Data concerning evaluation concentration cancer Nivolumab, will be presented. Conclusions subclass expected display lowest Fcγs, report here therapeutic significantly CD16, CD32 CD64, particularly if stabilized form engaging PD-1. evidence, occurring vivo, could introduce novel functional properties these agents, potential detrimental effects on efficacy. Our findings imply tools antagonize PD-1-related exhaustion Fc-null non-mAb-based strategies preferred full-fledged antitumor responses without unwanted related FcR triggering.