Current state and potential applications of neonatal Fc receptor (FcRn) inhibitors in hematologic conditions

• Published in: American journal of hematology 2024-12, Vol.99 (12), p.2351-2366
• Main Authors: Jacobs, Jeremy W., Booth, Garrett S., Raza, Sheharyar, Clark, Landon M., Fasano, Ross M., Gavriilaki, Eleni, Abels, Elizabeth A., Binns, Thomas C., Duque, Miriam Andrea, McQuilten, Zoe K., Mingot‐Castellano, María Eva, Savani, Bipin N., Sharma, Deva, Tran, Minh‐Ha, Tormey, Christopher A., Moise, Kenneth J., Bloch, Evan M., Adkins, Brian D.
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune hemolytic anemia; Clinical trials; Erythrocytes; Fc receptors; Hematologic Diseases - drug therapy; Hematological diseases; Hemolytic anemia; Hemophilia; Histocompatibility Antigens Class I; Humans; Idiopathic thrombocytopenic purpura; Immunoglobulin G; Immunoglobulin G - therapeutic use; Immunomodulation; Immunosuppressive agents; Isoimmunization; Isotypes; Mucosal immunity; Neonates; Patients; Receptors, Fc - antagonists & inhibitors; Thrombotic thrombocytopenic purpura
• ISSN: 0361-8609; 1096-8652; 1096-8652
• DOI: 10.1002/ajh.27487

The neonatal fragment crystallizable (Fc) receptor (FcRn) transports IgG across mucosal surfaces and the placenta and protects IgG from degradation. Numerous clinical trials are investigating therapeutic FcRn inhibition for various immune‐mediated neuromuscular and rheumatologic conditions; however, FcRn inhibition also represents a potential therapy for IgG‐mediated hematologic conditions (e.g., immune thrombocytopenia, autoimmune hemolytic anemia, immune thrombotic thrombocytopenic purpura, acquired hemophilia, red blood cell/platelet alloimmunization). Current evidence derived from both in vitro and in vivo studies suggests that FcRn inhibitors effectively reduce total IgG levels without impacting its production or altering the levels of other immunoglobulin isotypes. Moreover, the risk of serious adverse events, including serious infections, appears to be lower than that seen with other commonly used immunomodulatory/immunosuppressive therapies, albeit in the setting of limited clinical trial data. Ultimately, additional clinical trials that include varied patient populations are required prior to incorporating these agents into standard treatment algorithms for most hematologic conditions. However, based on the pathophysiology of IgG‐mediated hematologic disorders and the mechanism of action of FcRn inhibitors, these agents may represent a future novel therapeutic strategy for patients with hematologic conditions caused by IgG antibodies. The neonatal fragment crystallizable (Fc) receptor (FcRn) transports IgG across mucosal surfaces and the placenta and protects IgG from degradation. Inhibition of this receptor results in both lysosomal degradation and prevention of cross‐placental transport, with a subsequent reduction in circulating IgG levels. FcRn inhibition does not impact the production of IgG, nor alter the levels of other immunoglobulin isotypes. Clinical trial data have thus far demonstrated that the risk of serious adverse events, including serious infections, appears to be lower than that seen with other commonly used immunomodulatory/immunosuppressive therapies. As such, FcRn inhibition represents a potential therapy for IgG‐mediated hematologic conditions (e.g., immune thrombocytopenia, autoimmune hemolytic anemia, immune thrombotic thrombocytopenic purpura, acquired hemophilia, red blood cell/platelet alloimmunization). This review summarizes the current evidence and highlights potential reasons why FcRn inhibitors may be a potential tr