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July 2021; 8 (4) ArticleOpen Access

Inhibition of Maternal-to-Fetal Transfer of IgG Antibodies by FcRn Blockade in a Mouse Model of Arthrogryposis Multiplex Congenita

Ester Coutinho, Leslie Jacobson, Anthony Shock, Bryan Smith, View ORCID ProfileAnthony Vernon, Angela Vincent
First published May 27, 2021, DOI: https://doi.org/10.1212/NXI.0000000000001011
Ester Coutinho
From the Department of Basic and Clinical Neuroscience (E.C., A. Vernon), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute; Medical Research Council Centre for Neurodevelopmental Disorders (E.C., A. Vernon), King's College London; Nuffield Department of Clinical Neurosciences (L.J., A. Vincent), University of Oxford; and UCB Pharma (A.S., B.S.), Slough, United Kingdom.
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  • For correspondence: estercoutinho@gmail.com
Leslie Jacobson
From the Department of Basic and Clinical Neuroscience (E.C., A. Vernon), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute; Medical Research Council Centre for Neurodevelopmental Disorders (E.C., A. Vernon), King's College London; Nuffield Department of Clinical Neurosciences (L.J., A. Vincent), University of Oxford; and UCB Pharma (A.S., B.S.), Slough, United Kingdom.
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  • For correspondence: leslie.jacobson@ndcn.ox.ac.uk
Anthony Shock
From the Department of Basic and Clinical Neuroscience (E.C., A. Vernon), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute; Medical Research Council Centre for Neurodevelopmental Disorders (E.C., A. Vernon), King's College London; Nuffield Department of Clinical Neurosciences (L.J., A. Vincent), University of Oxford; and UCB Pharma (A.S., B.S.), Slough, United Kingdom.
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  • For correspondence: tony.shock@ucb.com
Bryan Smith
From the Department of Basic and Clinical Neuroscience (E.C., A. Vernon), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute; Medical Research Council Centre for Neurodevelopmental Disorders (E.C., A. Vernon), King's College London; Nuffield Department of Clinical Neurosciences (L.J., A. Vincent), University of Oxford; and UCB Pharma (A.S., B.S.), Slough, United Kingdom.
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  • For correspondence: bryan.smith@ucb.com
Anthony Vernon
From the Department of Basic and Clinical Neuroscience (E.C., A. Vernon), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute; Medical Research Council Centre for Neurodevelopmental Disorders (E.C., A. Vernon), King's College London; Nuffield Department of Clinical Neurosciences (L.J., A. Vincent), University of Oxford; and UCB Pharma (A.S., B.S.), Slough, United Kingdom.
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  • ORCID record for Anthony Vernon
  • For correspondence: anthony.vernon@kcl.ac.uk
Angela Vincent
From the Department of Basic and Clinical Neuroscience (E.C., A. Vernon), Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute; Medical Research Council Centre for Neurodevelopmental Disorders (E.C., A. Vernon), King's College London; Nuffield Department of Clinical Neurosciences (L.J., A. Vincent), University of Oxford; and UCB Pharma (A.S., B.S.), Slough, United Kingdom.
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Citation
Inhibition of Maternal-to-Fetal Transfer of IgG Antibodies by FcRn Blockade in a Mouse Model of Arthrogryposis Multiplex Congenita
Ester Coutinho, Leslie Jacobson, Anthony Shock, Bryan Smith, Anthony Vernon, Angela Vincent
Neurol Neuroimmunol Neuroinflamm Jul 2021, 8 (4) e1011; DOI: 10.1212/NXI.0000000000001011

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    Figure 1 Experimental Overview and Human Material Used

    (A) Experimental design: CD-1 dams were injected intraperitoneally (IP) with human purified IgG or plasma containing AChR antibodies from E12.5 to E17.5 or E18.5. Dams in the treatment group were further injected intraperitoneally with 4470, an anti-FcRn monoclonal antibody (mAb) murinized (from UCB Pharma) at doses between 0 and 40 mg/kg at days E12.5 and 15.5. The control group received a mouse IgG1 isotype mAb control. Dams and offspring were killed at the end of gestation (E18.5) and sera collected for human IgG and AChR antibody testing, or to assess neonatal outcomes, dams were allowed to deliver, and at P1, litters were reduced to 5–6 pups. Neonatal assessments were conducted from P1 to P21. (B) Human material used: patient's clinical history, IgG concentration, and number of injected dams for each experiment. (C) Titration of the patient plasmas against human AChR. Compared with the typical AChR-IgG, the 2 AMC-IgG preparations are relatively specific for the fetal isoform (approximately 40% of the total 10,000 cpm), but AMC1 serum (and IgG, not shown) displaces one of the 125I-a-bungarotoxins from the fetal AChR explaining the low plateau values shown. AChR = acetylcholine receptor; AMC = arthrogryposis multiplex congenita; cpm = counts per minute; IgG = immunoglobulin G.

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    Figure 2 Effects of FcRn Blockade on Antibody Transfer and Fetal Outcomes

    (A) Effect of different concentrations of 4470 on the transfer of typical AChR antibodies measured by radioimmunoassay, showing reduction of transfer to the fetal sera at 40 mg/kg (dam serum, red; fetal sera, green). *1 dam/litter pair excluded in the 20 and 40 mg/kg groups due to blood contamination. (B and C) Effect of 4470 (green) vs mAb control (red) at 40 mg/kg on the levels of total human IgG (B) and AChR antibodies (C). (D) Effect of 4470 (green) vs mAb control (red) at 40 mg/kg on the presence of deformities; representative microphotograph showing deformities in the limbs (black arrow) and spinal curve (red). (E) Effect of 4470 (green) vs mAb control (red) at 40 mg/kg on the presence of spontaneous movement. (F) Effect of 4470 (green) vs mAb control (red) at 40 mg/kg on the presence of empty placentas and embryos undergoing resorption. AChR = acetylcholine receptor; AMC = arthrogryposis multiplex congenita; cpm = counts per minute; FcRn = neonatal Fc receptor; IgG = immunoglobulin G; mAb = monoclonal antibody.

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    Figure 3 Effect of FcRn Blockade on Neonatal Weight and Neonatal Milestones in Male and Female Pups

    (A) Male and (B) female pups' neonatal weight increase from P1 to P21. Days to reach criterion on ear twitching (C), eye opening (D), negative geotaxis (E), and open field (F) testing. AMC = arthrogryposis multiplex congenita; FcRn = neonatal Fc receptor; IgG = immunoglobulin G.

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