M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model

Abstract

BACKGROUND:The transfer of pathogenic immunoglobulin G antibodies from mother to fetus is a critical step in the pathophysiology of alloimmune and autoimmune diseases of the fetus and neonate. Immunoglobulin G transfer across the human placenta to the fetus is mediated by the neonatal Fc receptor, and blockade of the neonatal Fc receptor may provide a therapeutic strategy to prevent or minimize pathological events associated with immune-mediated diseases of pregnancy. M281 is a fully human, aglycosylated monoclonal immunoglobulin G1 antineonatal Fc receptor antibody that has been shown to block the neonatal Fc receptor with high affinity in nonclinical studies and in a phase 1 study in healthy volunteers. OBJECTIVE: The objective of the study was to determine the transplacental transfer of M281 and its potential to inhibit transfer of immunoglobulin G from maternal to fetal circulation. STUDY DESIGN: To determine the concentration of M281 required for rapid cellular uptake and complete saturation of the neonatal Fc receptor in placental trophoblasts, primary human villous trophoblasts were incubated with various concentrations of M281 in a receptor occupancy assay. The placental transfer of M281, immunoglobulin G, and immunoglobulin G in the presence of M281 was studied using the dually perfused human placental lobule model. Immunoglobulin G transfer was established using a representative immunoglobulin G molecule, adalimumab, a human immunoglobulin G1 monoclonal antibody, at a concentration of 270 mg/ mL. Inhibition of immunoglobulin G transfer by M281 was determined by cotransfusing 270 mg/mL of adalimumab with 10 mg/mL or 300 mg/mL of M281. Concentrations of adalimumab and M281 in sample aliquots from maternal and fetal circuits were analyzed using a sandwich enzyme-linked immunosorbent assay and Meso Scale Discovery assay, respectively. RESULTS: In primary human villous trophoblasts, the saturation of the neonatal Fc receptor by M281 was observed within 30e60 minutes at 0.15e5.0 mg/mL, suggesting rapid blockade of neonatal Fc receptor in placental cells. The transfer rate of adalimumab (0.23% AE 0.21%) across dually perfused human placental lobule was significantly decreased by 10 mg/mL and 300 mg/mL of M281 to 0.07 AE 0.01% and 0.06 AE 0.01%, respectively. Furthermore, the transfer rate of M281 was 0.002% AE 0.02%, approximately 100-fold lower than that of adalimumab. CONCLUSION: The significant inhibition of immunoglobulin G transfer across the human placental lobule by M281 and the minimal transfer of M281 supports the development of M281 as a novel agent for the treatment of fetal and neonatal diseases caused by transplacental transfer of alloimmune and autoimmune pathogenic immunoglobulin G antibodies.

Antagonism of the Neonatal Fc Receptor as an Emerging Treatment for Myasthenia Gravis

“…Nipocalimab binds with picomolar affinity to FcRn at both endosomal pH 6.0 and extracellular pH 7.6 allowing occupancy of FcRn throughout the recycling pathway and has a specificity designed to minimize off target effects (22). It is not expected to cross the placenta and a clinical trial is underway in pregnant women at high risk for early onset severe hemolytic disease of the fetus and newborn (23,24). Phase 1 data supports infusion rates of 7.5 or 15 min for 30 and 60 mg/kg doses, respectively (25).…”

Monoclonal Antibody-Based Therapies for Myasthenia Gravis

“…Two other FcRn-directed antibodies have completed phase II testing for MG without published results but appear to be moving to phase III investigation. Nipocalimab is a human monoclonal antibody high-affinity binding to the FcRn in the picomolar range [65]. A phase II study in MG has been completed with positive results reported by the company (NCT03772587) [66].…”

Red cell alloimmunization: A 2020 update

“…M281 is a monoclonal antibody which binds to the neonatal Fc receptor to inhibit transplacental IgG transfer (Figure A and Figure B) . Early phase trials with M281 in healthy nonpregnant volunteers have shown that circulating IgG levels are reduced on average by 84%, perhaps by inhibiting the recycling of IgG in vascular endothelial cells which contributes to their usually long half‐life . Animal experiments prior to the phase 1 study yielded encouraging toxicology and efficacy data .…”

“…Early phase trials with M281 in healthy nonpregnant volunteers have shown that circulating IgG levels are reduced on average by 84%, perhaps by inhibiting the recycling of IgG in vascular endothelial cells which contributes to their usually long half‐life . Animal experiments prior to the phase 1 study yielded encouraging toxicology and efficacy data . If passage of pathogenic maternal IgG to a fetus can be blocked then immune‐mediated conditions could be prevented.…”

“…If passage of pathogenic maternal IgG to a fetus can be blocked then immune‐mediated conditions could be prevented. Recent ex vivo data using a dual (maternal and fetal) perfusion placental cotyledon model has demonstrated that when the maternal circulation is perfused with M281, there is significant inhibition of IgG maternal to fetal transmission whereas there is “insignificant” transmission of M281 into the fetal circulation (Figure ) . This property may be useful not only in reducing the development of HDFN, but also in blocking the antibodies which cause fetal neonatal autoimmune thrombocytopenia, autoimmune congenital heart block, and neonatal thyrotoxicosis.…”