TY - JOUR
T1 - M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model
AU - Roy, Sucharita
AU - Nanovskaya, Tatiana
AU - Patrikeeva, Svetlana
AU - Cochran, Edward
AU - Parge, Viraj
AU - Guess, Jamey
AU - Schaeck, John
AU - Choudhury, Amit
AU - Ahmed, Mahmoud
AU - Ling, Leona E.
N1 - Funding Information:
This work was supported by Momenta Pharmaceuticals, Inc.Authors Nanovskaya and Ahmed have received grant/research support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Authors Roy, Cochran, Parge, Guess, Schaeck, Choudhury, and Ling are or were full-time employees of Momenta Pharmaceuticals, Inc and may own company stock and/or stock options. S. Patrikeeva reports no conflict of interest. We thank Dr Victor Farutin for guidance in statistical analysis, Drs Anthony M. Manning and Santiago Arroyo for their review and helpful discussion and guidance for this study, and Agnes Costello for help in preparation of this manuscript. Momenta Pharmaceuticals contributed to the study design, research, data interpretation, and the writing, review, and approval of the manuscript. We also thank Stephanie E. Tedford, PhD, and Lamara D. Shrode, PhD, ISMPP, CMPP™, of J. B. Ashtin, who provided editorial support during the preparation of the manuscript. Drs Roy and Nanovskaya were involved in the concept/design of the study and the data acquisition and interpretation. S. Patrikeeva and Dr Schaeck were involved in the data acquisition. Dr Choudhury, E. Cochran, and V. Parge were involved in the data acquisition and interpretation. J. Guess was involved in the statistical analysis. Drs Ahmed and Ling were involved in the concept/design of the study and data interpretation. All authors critically reviewed the manuscript and provided final approval for submission. All authors agree to be accountable for all aspects of the work, ensuring the accuracy and integrity of the publication. Data requests from any qualified researchers who engage in rigorous, independent scientific research will be considered if the trials are not part of an ongoing or planned regulatory submission (this includes requests for data on unlicensed products and indications). Data will be provided following review and approval of a research proposal, statistical analysis plan, confirmation that the requested data can be shared under applicable privacy laws, and execution of a data-sharing agreement. Data requests can be submitted at any time, and the data will be accessible for 12 months, with possible extensions considered. Requests can be sent to MedInfo@momentapharma.com.
Publisher Copyright:
© 2019 The Author(s)
PY - 2019/5
Y1 - 2019/5
N2 - 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 μg/mL. Inhibition of immunoglobulin G transfer by M281 was determined by cotransfusing 270 μg/mL of adalimumab with 10 μg/mL or 300 μg/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 30–60 minutes at 0.15–5.0 μg/mL, suggesting rapid blockade of neonatal Fc receptor in placental cells. The transfer rate of adalimumab (0.23% ± 0.21%)across dually perfused human placental lobule was significantly decreased by 10 μg/mL and 300 μg/mL of M281 to 0.07 ± 0.01% and 0.06 ± 0.01%, respectively. Furthermore, the transfer rate of M281 was 0.002% ± 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.
AB - 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 μg/mL. Inhibition of immunoglobulin G transfer by M281 was determined by cotransfusing 270 μg/mL of adalimumab with 10 μg/mL or 300 μg/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 30–60 minutes at 0.15–5.0 μg/mL, suggesting rapid blockade of neonatal Fc receptor in placental cells. The transfer rate of adalimumab (0.23% ± 0.21%)across dually perfused human placental lobule was significantly decreased by 10 μg/mL and 300 μg/mL of M281 to 0.07 ± 0.01% and 0.06 ± 0.01%, respectively. Furthermore, the transfer rate of M281 was 0.002% ± 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.
KW - M281
KW - autoimmune disease
KW - fetal transfer
KW - monoclonal antibodies
KW - neonate
KW - placental perfusion model
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U2 - 10.1016/j.ajog.2019.02.058
DO - 10.1016/j.ajog.2019.02.058
M3 - Article
C2 - 30849355
AN - SCOPUS:85065192610
VL - 220
SP - 498.e1-498.e9
JO - American Journal of Obstetrics and Gynecology
JF - American Journal of Obstetrics and Gynecology
SN - 0002-9378
IS - 5
ER -