Clinical strategies to prevent FIR in patients should focus on this pathway and may include transient depletion of neutrophils or blocking FcRIIIb with specific mAbs. == Electronic supplementary material == The online version of this article (10.1007/s11095-018-2448-8) contains supplementary material, which is available to authorized users. KEY WORDS:human FcRIIIb, humanized mouse model, immunotoxicology, infusion reactions, neutrophils == Introduction == Monoclonal antibodies (mAbs) constitute an impressively effective class of biological drugs in the treatment of a number of severe conditions, including cancer, immune disorders and infections (1). accompanied by an increase in inflammatory cytokines KC and MIP-2, and ROS. FIR were dependent on administration route and Fc-triggered effector functions mediated by neutrophils. Human neutrophils also Cinnarizine induced FIR in wild type mice infused with HamTfR. Specific knock-in mice demonstrated that human FcRIIIb on neutrophils was both necessary and sufficient to cause FIR. FcRIIIb-mediated FIR was abolished by depleting neutrophils or blocking FcRIIIb with CD11b antibodies. == Conclusions == Human FcRIIIb and neutrophils are primarily responsible for Cinnarizine triggering FIR. Clinical strategies to prevent FIR in patients should focus on this pathway and may include transient depletion of neutrophils or blocking FcRIIIb with specific mAbs. == Electronic supplementary material == The online version of this article (10.1007/s11095-018-2448-8) contains supplementary material, which is available to authorized users. KEY WORDS:human FcRIIIb, humanized mouse model, immunotoxicology, infusion reactions, neutrophils == Introduction == Monoclonal antibodies Cinnarizine (mAbs) constitute an impressively effective class of biological drugs in the treatment of a number of severe conditions, including cancer, immune disorders and infections (1). However, the broad use of mAbs during the last decades has revealed associated risks, primarily related to infusion reactions (24). While most infusion reactions are mild to moderate (e.g., skin rash, nausea, chill), in some patients these can be severe or life-threatening, e.g., anaphylactoid reactions or cytokine storm (24). Infusion reactions normally occur in the hours after first or second infusions (5) and the incidence varies considerably from less than 5% of treated patients affected (Omalizumab, Natalizumab, Cetuximab) to more than 20% (Infliximab, Rituximab, Trantuzumab) (6,7). Infusion reactions are normally a primary phenomenon, also known as first infusion reactions (FIR), and in most cases their incidence decreases significantly in subsequent infusions. Secondary infusion reactions (SIR) can result from accumulating anti-drug antibodies (ADAs) causing anaphylactoid reactions following repeated administrations of mAbs. SIRs resemble acute systemic anaphylaxis as mediated by immunoglobulin G (IgG) and are triggered mainly by neutrophils, but can also be induced by monocyte/macrophages in mice (8). In contrast, in the absence of preexisting ADAs the pathogenic factors contributing to FIR are largely unknown. Given the strong negative impact of FIR on the successful development of therapeutic mAbs, understanding the underlying mechanisms is of uppermost importance. For most therapeutic mAbs, preclinical studies in rodents and primates, even if highly reflective Cinnarizine of human pharmacodynamics, are poorly predictive of human infusion reactions and toxicology (9,10). The study of infusion reactions in mouse models is hampered by intrinsic differences between the human and mouse sets of Fc gamma receptors (FcRs). Humans display FcRIIa/c in monocytes/macrophages and granulocytes, FcRIIIa in monocytes and natural killer (NK) cells, and glycosylphosphatidylinositol (GPI)-anchored FcRIIIb exclusively in neutrophils (11). Mice express FcRIII on monocytes/macrophages, NK cells and neutrophils, FcRIV in monocyte/macrophages and neutrophils and they lack homologue receptors for human FcRIIa/c and FcRIIIb (11). In addition, human FcRIIIb is not bound by mouse IgG (12) and the affinities of different IgG subclasses for their FcRs are different in the two species (13). Human FcRIIIb lacks intracellular sequences and is anchored in the cell membrane via a GPI tail. Thus, intracellular signaling through FcRIIIb is not mediated by Cinnarizine the FcR common chain but has to be aided by other associated proteins. Blocking experiments have shown that the adhesion molecule macrophage-1 antigen (Mac-1, CD11b) mediates FcRIIIb signaling (14,15). Finally, polymorphic FcR variants exist in humans, Rabbit Polyclonal to SH2D2A which have no counterparts in mouse FcRs and result in strong differences in the affinity for IgG proteins (16). Here we describe the implementation of anin vivosystem apt to predict and assess risks associated with FIR. The system makes use of a humanized mouse model.