Kiessling and B. and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential contamination risk associated with FcRn inhibition, in addition to highlighting areas for MAC glucuronide α-hydroxy lactone-linked SN-38 future research. Key words: FcRn, neonatal Fc receptor, immunoglobulin, IgG, albumin, hypogammaglobulinemia, autoantibody, antibody-mediated autoimmunity, FcRn inhibitors, contamination risk Abbreviations used: B2M, 2 microglobulin, COVID-19, Coronavirus disease 2019, Fc, Fragment crystallizable, FcRn, Neonatal Fc receptor, FcR, Fc-gamma receptor, FIH, First-in-human, GI, Gastrointestinal, Gm, Gamma marker, HBV, Hepatitis B computer virus, IA, Immunoadsorption, IC, Immune complex, IgRT, IgG replacement therapy, ITP, Immune thrombocytopenia, IV, Intravenous, IVIg, Intravenous immunoglobulin, MG, Myasthenia gravis, PLE, Protein-losing enteropathy, PLEX, Plasma exchange, QMG, Quantitative MG, QW, Once-weekly, SARS-CoV-2, Severe acute respiratory syndrome coronavirus-2, SC, Subcutaneous, SID, Secondary immunodeficiency, TEAE, Treatment-emergent adverse event, VL, Viral load, WBC, White blood cell Autoantibody-mediated autoimmune diseases can result in tissue damage through IgG (IC) deposition1 , 2 or via monomeric pathogenic activation and/or recruitment of inflammatory phagocytes.2, 3, 4, 5, 6, 7 MAC glucuronide α-hydroxy lactone-linked SN-38 Current therapeutic strategies for the treatment of chronic autoantibody-mediated MAC glucuronide α-hydroxy lactone-linked SN-38 diseases consist of reducing antibody production by immunosuppression or B-cellCtargeting drugs, and removal of autoantibodies and IC via (PLEX) or (IA).8, 9, 10 Alternatively, for monomeric IgG-mediated diseases, immunomodulatory high-dose intravenous immunoglobulin (IVIg) therapy acts via a number of mechanisms including increased catabolism of autoantibodies via the neonatal fragment crystallizable (Fc) receptor (FcRn), cytokine neutralization, blockade of activating Fc-gamma receptors (FcRs), or inhibition of autoantibodies by binding of natural anti-idiotypes11 , 12 (see review by Shock et?al13 in this issue). In many regions, supply and cost of IVIg are important factors. It can be challenging for health care systems to meet the demand for IVIg, which is usually increasing due to growth in the number of patients requiring IgG replacement therapy (IgRT) for treatment of antibody deficiencies, and the expanding use of immunomodulatory high-dose IVIg (on- and off-label) in the context of a worldwide plasma shortage.14, 15, 16 IgG has one of the longest half-lives of serum proteins, sustained by a specialized recycling pathway involving FcRn (see Patel and Bussel17 review in this issue). FcRn is usually predominantly expressed around the endothelium, but has also been detected in a diverse range of tissues and cell types.2 Because recycling is the principal mechanism for maintaining a high serum level of IgG (and albumin), modulation of this pathway by blocking FcRn is an attractive mechanism for the reduction of pathogenic IgG autoantibodies. Inhibition of FcRn accelerates destruction of IgG via of IgG1, thus manipulating the FcRn-IgG1 conversation on Fc effector function.26 All 4 recombinant human IgG1 variants, one of which (MST/HN) carried the same 5 point mutations as efgartigimod (M252Y, S254T, T256E, H433K, N434F23), markedly reduced binding to classical FcRs. Three of the 4 variants (including MST/HN) exhibited significantly reduced binding to complement factor C1q. MAC glucuronide α-hydroxy lactone-linked SN-38 Reductions in FcRs and C1q binding limited the ability of these human IgG1 variants to activate antibody-dependent mechanisms such KLF4 antibody as cell-mediated cytotoxicity, cellular phagocytosis, and complement-mediated cell lysis. Interestingly, previous successful attempts to treat acute childhood ITP with infusions of unmutated Fc fragments suggested a predominant blocking action on classical FcRs on mononuclear phagocytes.27 To our knowledge, the effects of efgartigimod on classical FcRs- and C1q-mediated functions have not been published and more information is needed MAC glucuronide α-hydroxy lactone-linked SN-38 to determine whether efgartigimod, besides inhibiting FcRn, has a significant effect on FcRs and C1q binding. (M281), a high-affinity, fully human monoclonal IgG1 anti-FcRn.