Case Conversation: You don’t know IgG if you don’t know FcRn

July 31, 2024

Please join FWGBD on Wednesday, July 31st, 2024, at 12:00 PM ET for a journal club, Case Conversation: You don’t know IgG if you don’t know FcRn, with Dr. Doug Cines and Dr. Jim Bussel.

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IgG is central to many autoimmune and alloimmune diseases including many affecting women and girls. FcRn, the “neonatal” FcReceptor recycles and transports IgG which greatly impacts IgG effects. One important area is in primary immune thrombocytopenia (ITP),  an autoimmune disorder mediated by platelet autoantibodies, which is more common in women of childbearing age.  ITP results in thrombocytopenia, bleeding, and constitutional symptoms. The putative mechanism of effect of FcRn inhibitors is reduction of antiplatelet IgG levels by inhibition of “normal” IgG recycling. IgG levels fall to 20-40% of baseline with FcRn inhibition, and it is thought that the IgG anti-platelet antibody levels fall at least as much, resulting in less platelet destruction and greater platelet production. There are a number of FcRn inhibitors in clinical trial.

Another area in which FcRn inhibition appears to be important is in diseases like hemolytic disease of the fetus and newborn (HDFN). Maternal IgG antibodies, initiated by incompatibilities between maternal and fetal antigens on blood cells (red cells and platelets) are transported across the placenta from mother to fetus and these antibodies create fetal cytopenias and disease (e.g. anemia and thrombocytopenia). Using an FcRn inhibitor to block transfer of these IgG antibodies to the fetus is potentially an optimal mechanism to prevent fetal cytopenia.

Efgartigimod, a first-in-class novel human IgG1 Fc fragment, binds the neonatal Fc receptor with high affinity and has had a successful phase 3 trial of its IV form in ITP, but surprisingly its phase 3 subcutaneous trial failed to show efficacy compared to placebo. Nipocalimab, an intact IgG inhibitor of FcRn, completed a preliminary trial of HDFN in 13 mothers with early-onset severe HDFN. Seven of 13 fetuses had an outstanding response, but in the other 6 the effect was limited.

During this conversation, faculty will share the promising future of treatment for IgG-Mediated Blood Diseases of Women. The learning objectives include:

  1. Review the biology of FcRn
  2. Describe the pathophysiology of immunoglobulin G (IgG) mediated blood diseases in women.
  3. Discuss the mechanism and clinical effects of FcRn inhibitors in ITP.
  4. Discuss the mechanism and clinical effects of FcRn inhibitors in HDFN.

The production, accreditation, and archiving of this program were made possible through a sponsorship from Sobi.