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Immunoglobulin G Is a Novel Substrate for the Endocytic Protein Megalin

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Abstract

Therapeutic immunoglobulin G (IgG) antibodies comprise the largest class of protein therapeutics. Several factors that influence their overall disposition have been well-characterized, including target-mediated mechanics and convective flow. What remains poorly defined is the potential for non-targeted entry into various tissues or cell types by means of uptake via cell surface receptors at those sites. Megalin and cubilin are large endocytic receptors whose cooperative function plays important physiological roles at the tissues in which they are expressed. One such example is the kidney, where loss of either results in significant declines in proximal tubule protein reabsorption. Due to their diverse ligand profile and broad tissue expression, megalin and cubilin represent potential candidates for receptor-mediated uptake of IgG into various epithelia. Therefore, the objective of the current work was to determine if IgG was a novel ligand of megalin and/or cubilin. Direct binding was measured for human IgG with both megalin and the cubilin/amnionless complex. Additional work focusing on the megalin-IgG interaction was then conducted to build upon these findings. Cell uptake studies using megalin ligands for competitive inhibition or proximal tubule cells stably transduced with megalin-targeted shRNA constructs supported a role for megalin in the endocytosis of human IgG. Furthermore, a pharmacokinetic study using transgenic mice with a kidney-specific mosaic knockout of megalin demonstrated increased urinary excretion of human IgG in megalin knockout mice when compared to wild-type controls. These findings indicate that megalin is capable of binding and internalizing IgG via a high affinity interaction.

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References

  1. Liu JK. The history of monoclonal antibody development - progress, remaining challenges and future innovations. Ann Med Surg (Lond). 2014;3:113–6. https://doi.org/10.1016/j.amsu.2014.09.001.

    Article  Google Scholar 

  2. FDA. Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed March 2020.

  3. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548–58. https://doi.org/10.1038/clpt.2008.170.

    Article  CAS  PubMed  Google Scholar 

  4. Ovacik M, Lin K. Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development. Clin Transl Sci. 2018;11:540–52. https://doi.org/10.1111/cts.12567.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mahadevappa R, Nielsen R, Christensen EI, Birn H. Megalin in acute kidney injury: foe and friend. Am J Physiol Ren Physiol. 2014;306:F147–54. https://doi.org/10.1152/ajprenal.00378.2013.

    Article  CAS  Google Scholar 

  6. Christensen EI, Birn H, Storm T, Weyer K, Nielsen R. Endocytic receptors in the renal proximal tubule. Physiology (Bethesda). 2012;27:223–36. https://doi.org/10.1152/physiol.00022.2012.

    Article  CAS  Google Scholar 

  7. Christensen EI, Verroust PJ, Nielsen R. Receptor-mediated endocytosis in renal proximal tubule. Pflugers Arch - Eur J Physiol. 2009;458:1039–48. https://doi.org/10.1007/s00424-009-0685-8.

    Article  CAS  Google Scholar 

  8. Kozyraki R, Fyfe J, Verroust PJ, Jacobsen C, Dautry-Varsat A, Gburek J, et al. Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc Natl Acad Sci U S A. 2001;98:12491–6. https://doi.org/10.1073/pnas.211291398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Coudroy G, et al. Contribution of cubilin and amnionless to processing and membrane targeting of cubilin-amnionless complex. J Am Soc Nephrol. 2005;16:2330–7. https://doi.org/10.1681/ASN.2004110925.

    Article  CAS  PubMed  Google Scholar 

  10. Fyfe JC, Madsen M, Højrup P, Christensen EI, Tanner SM, de la Chapelle A, et al. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood. 2004;103:1573–9. https://doi.org/10.1182/blood-2003-08-2852.

    Article  CAS  PubMed  Google Scholar 

  11. Maurer ME, Cooper JA. Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein. J Cell Sci. 2005;118:5345–55. https://doi.org/10.1242/jcs.02650.

    Article  CAS  PubMed  Google Scholar 

  12. Shah M, Baterina OY Jr, Taupin V, Farquhar MG. ARH directs megalin to the endocytic recycling compartment to regulate its proteolysis and gene expression. J Cell Biol. 2013;202:113–27. https://doi.org/10.1083/jcb.201211110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Christensen EI, Birn H. Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol. 2002;3:256–66. https://doi.org/10.1038/nrm778.

    Article  CAS  PubMed  Google Scholar 

  14. De S, Kuwahara S, Saito A. The endocytic receptor megalin and its associated proteins in proximal tubule epithelial cells. Membranes. 2014;4:333–55.

    Article  Google Scholar 

  15. Leheste JR, Rolinski B, Vorum H, Hilpert J, Nykjaer A, Jacobsen C, et al. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am J Pathol. 1999;155:1361–70. https://doi.org/10.1016/S0002-9440(10)65238-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Weyer K, Andersen PK, Schmidt K, Mollet G, Antignac C, Birn H, et al. Abolishment of proximal tubule albumin endocytosis does not affect plasma albumin during nephrotic syndrome in mice. Kidney Int. 2018;93:335–42. https://doi.org/10.1016/j.kint.2017.07.024.

    Article  CAS  PubMed  Google Scholar 

  17. Di L. Strategic approaches to optimizing peptide ADME properties. AAPS J. 2015;17:134–43. https://doi.org/10.1208/s12248-014-9687-3.

    Article  CAS  PubMed  Google Scholar 

  18. Tibbitts J, Canter D, Graff R, Smith A, Khawli LA. Key factors influencing ADME properties of therapeutic proteins: a need for ADME characterization in drug discovery and development. MAbs. 2016;8:229–45. https://doi.org/10.1080/19420862.2015.1115937.

    Article  CAS  PubMed  Google Scholar 

  19. Vegt E, Melis M, Eek A, de Visser M, Brom M, Oyen WJG, et al. Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice. Eur J Nucl Med Mol Imaging. 2011;38:623–32. https://doi.org/10.1007/s00259-010-1685-9.

    Article  CAS  PubMed  Google Scholar 

  20. Barone R, van der Smissen P, Devuyst O, Beaujean V, Pauwels S, Courtoy PJ, et al. Endocytosis of the somatostatin analogue, octreotide, by the proximal tubule-derived opossum kidney (OK) cell line. Kidney Int. 2005;67:969–76. https://doi.org/10.1111/j.1523-1755.2005.00160.x.

    Article  CAS  PubMed  Google Scholar 

  21. Melis M, Vegt E, Konijnenberg MW, de Visser M, Bijster M, Vermeij M, et al. Nephrotoxicity in mice after repeated imaging using 111In-labeled peptides. J Nucl Med. 2010;51:973–7. https://doi.org/10.2967/jnumed.109.074310.

    Article  CAS  PubMed  Google Scholar 

  22. Batuman V, Dreisbach AW, Cyran J. Light-chain binding sites on renal brush-border membranes. Am J Phys. 1990;258:F1259–65. https://doi.org/10.1152/ajprenal.1990.258.5.F1259.

    Article  CAS  Google Scholar 

  23. Batuman V, Verroust PJ, Navar GL, Kaysen JH, Goda FO, Campbell WC, et al. Myeloma light chains are ligands for cubilin (gp280). Am J Phys. 1998;275:F246–54. https://doi.org/10.1152/ajprenal.1998.275.2.F246.

    Article  CAS  Google Scholar 

  24. Klassen RB, Allen PL, Batuman V, Crenshaw K, Hammond TG. Light chains are a ligand for megalin. J Appl Physiol (1985). 2005;98:257–63. https://doi.org/10.1152/japplphysiol.01090.2003.

    Article  CAS  Google Scholar 

  25. Nagai J, Sato K, Yumoto R, Takano M. Megalin/cubilin-mediated uptake of FITC-labeled IgG by OK kidney epithelial cells. Drug Metab Pharmacokinet. 2011;26:474–85.

    Article  CAS  Google Scholar 

  26. Zhai XY, Nielsen R, Birn H, Drumm K, Mildenberger S, Freudinger R, et al. Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney. Kidney Int. 2000;58:1523–33. https://doi.org/10.1046/j.1523-1755.2000.00314.x.

    Article  CAS  PubMed  Google Scholar 

  27. Motoyoshi Y, et al. Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria. Kidney Int. 74:1262–9. https://doi.org/10.1038/ki.2008.405.

  28. Nielsen R, Christensen EI, Birn H. Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int. 2016;89:58–67. https://doi.org/10.1016/j.kint.2015.11.007.

    Article  CAS  PubMed  Google Scholar 

  29. Leheste JR, Melsen F, Wellner M, Jansen P, Schlichting U, Renner-Müller I, et al. Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J. 2003;17:247–9. https://doi.org/10.1096/fj.02-0578fje.

    Article  CAS  PubMed  Google Scholar 

  30. Birn H, Verroust PJ, Nexø E, Hager H, Jacobsen C, Christensen EI, et al. Characterization of an epithelial approximately 460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein. J Biol Chem. 1997;272:26497–504.

    Article  CAS  Google Scholar 

  31. Kozyraki R, Kristiansen M, Silahtaroglu A, Hansen C, Jacobsen C, Tommerup N, et al. The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Blood. 1998;91:3593–600.

    Article  CAS  Google Scholar 

  32. Girardi AC, Knauf F, Demuth HU, Aronson PS. Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells. Am J Phys Cell Phys. 2004;287:C1238–45. https://doi.org/10.1152/ajpcell.00186.2004.

    Article  CAS  Google Scholar 

  33. Cole JA, Forte LR, Krause WJ, Thorne PK. Clonal sublines that are morphologically and functionally distinct from parental OK cells. Am J Phys. 1989;256:F672–9.

    CAS  Google Scholar 

  34. Orlando RA, Farquhar MG. Identification of a cell-line that expresses a cell-surface and a soluble form of the Gp330 receptor-associated protein (Rap) Heymann nephritis antigenic complex. Proc Natl Acad Sci U S A. 1993;90:4082–6. https://doi.org/10.1073/pnas.90.9.4082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Petersen HH, et al. Functional interaction of megalin with the megalinbinding protein (MegBP), a novel tetratrico peptide repeat-containing adaptor molecule. J Cell Sci. 2003;116:453–61.

    Article  CAS  Google Scholar 

  36. Kounnas MZ, Argraves WS, Strickland DK. The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, alpha 2-macroglobulin receptor and glycoprotein 330. J Biol Chem. 1992;267:21162–6.

    Article  CAS  Google Scholar 

  37. Nagai M, Meerloo T, Takeda T, Farquhar MG. The adaptor protein ARH escorts megalin to and through endosomes. Mol Biol Cell. 2003;14:4984–96. https://doi.org/10.1091/mbc.E03-06-0385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bryniarski MA, Yee BM, Chaves LD, Stahura CM, Yacoub R, Morris ME. Megalin-mediated albumin endocytosis in cultured murine mesangial cells. Biochem Biophys Res Commun. 2020;529:740–6. https://doi.org/10.1016/j.bbrc.2020.05.166.

    Article  CAS  PubMed  Google Scholar 

  39. Zou Z, Chung B, Nguyen T, Mentone S, Thomson B, Biemesderfer D. Linking receptor-mediated endocytosis and cell signaling: evidence for regulated intramembrane proteolysis of megalin in proximal tubule. J Biol Chem. 2004;279:34302–10. https://doi.org/10.1074/jbc.M405608200.

    Article  CAS  PubMed  Google Scholar 

  40. Meerbrey KL, Hu G, Kessler JD, Roarty K, Li MZ, Fang JE, et al. The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. Proc Natl Acad Sci U S A. 2011;108:3665–70. https://doi.org/10.1073/pnas.1019736108.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Li X, et al. Nephrin preserves podocyte viability and glomerular structure and function in adult kidneys. J Am Soc Nephrol. 2015;26:2361–77. https://doi.org/10.1681/ASN.2014040405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gekle M, Mildenberger S, Freudinger R, Silbernagl S. Kinetics of receptor-mediated endocytosis of albumin in cells derived from the proximal tubule of the kidney (opossum kidney cells): influence of Ca2+ and cAMP. Pflugers Arch - Eur J Physiol. 1995;430:374–80.

    Article  CAS  Google Scholar 

  43. Gekle M, Mildenberger S, Freudinger R, Silbernagl S. Long-term protein exposure reduces albumin binding and uptake in proximal tubule-derived opossum kidney cells. J Am Soc Nephrol. 1998;9:960–8.

    CAS  PubMed  Google Scholar 

  44. Bryniarski MA, Yee BM, Jaffri I, Chaves LD, Yu JA, Guan X, et al. Increased megalin expression in early type 2 diabetes: role of insulin signaling pathways. Am J Physiol Ren Physiol. 2018;315:F1191–207. https://doi.org/10.1152/ajprenal.00210.2018.

    Article  Google Scholar 

  45. Gekle M, Mildenberger S, Freudinger R, Silbernagl S. Endosomal alkalinization reduces Jmax and km of albumin receptor-mediated endocytosis in OK cells. Am J Phys. 1995;268:F899–906.

    CAS  Google Scholar 

  46. McPherson RA, Pincus MR. Henry’s clinical diagnosis and management by laboratory methods. 23rd ed: Elsevier; 2017, Chapter 19, pp. 253–266.e2.

  47. Yousef MA, Datta R, Rodgers VGJ. Understanding nonidealities of the osmotic pressure of concentrated bovine serum albumin. J Colloid Interface Sci. 1998;207:273–82.

    Article  CAS  Google Scholar 

  48. Vilker VL, Colton CK, Smith KA. The osmotic pressure of concentrated protein solutions: effect of concentration and ph in saline solutions of bovine serum albumin. J Colloid Interface Sci. 1981;79:548–66. https://doi.org/10.1016/0021-9797(81)90106-5.

    Article  CAS  Google Scholar 

  49. Leheste JR, et al. Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J. 2002;16:247. https://doi.org/10.1096/fj.02-0578fje.

    Article  CAS  Google Scholar 

  50. Tu C, Mammen MJ, Li J, Shen X, Jiang X, Hu Q, et al. Large-scale, ion-current-based proteomics investigation of bronchoalveolar lavage fluid in chronic obstructive pulmonary disease patients. J Proteome Res. 2014;13:627–39.

    Article  CAS  Google Scholar 

  51. Tu C, Fiandalo MV, Pop E, Stocking JJ, Azabdaftari G, Li J, et al. Proteomic analysis of charcoal-stripped fetal bovine serum reveals changes in the insulin-like growth factor signaling pathway. J Proteome Res. 2018;17:2963–77. https://doi.org/10.1021/acs.jproteome.8b00135.

    Article  CAS  PubMed  Google Scholar 

  52. Shen S, An B, Wang X, Hilchey SP, Li J, Cao J, et al. Surfactant cocktail-aided extraction/precipitation/on-pellet digestion strategy enables efficient and reproducible sample preparation for large-scale quantitative proteomics. Anal Chem. 2018;90:10350–9. https://doi.org/10.1021/acs.analchem.8b02172.

    Article  CAS  PubMed  Google Scholar 

  53. Shen X, Shen S, Li J, Hu Q, Nie L, Tu C, et al. An IonStar experimental strategy for MS1 ion current-based quantification using ultrahigh-field Orbitrap: reproducible, in-depth, and accurate protein measurement in large cohorts. J Proteome Res. 2017;16:2445–56. https://doi.org/10.1021/acs.jproteome.7b00061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shen X, Shen S, Li J, Hu Q, Nie L, Tu C, et al. IonStar enables high-precision, low-missing-data proteomics quantification in large biological cohorts. Proc Natl Acad Sci. 2018;115:E4767–76. https://doi.org/10.1073/pnas.1800541115.

    Article  CAS  PubMed  Google Scholar 

  55. Orlando RA, Rader K, Authier F, Yamazaki H, Posner BI, Bergeron JJ, et al. Megalin is an endocytic receptor for insulin. J Am Soc Nephrol. 1998;9:1759–66.

    CAS  PubMed  Google Scholar 

  56. Lundstrom M, Orlando RA, Saedi MS, Woodward L, Kurihara H, Farquhar MG. Immunocytochemical and biochemical characterization of the Heymann nephritis antigenic complex in rat L2 yolk sac cells. Am J Pathol. 1993;143:1423–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Moestrup SK, Cui S, Vorum H, Bregengård C, Bjørn SE, Norris K, et al. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest. 1995;96:1404–13. https://doi.org/10.1172/JCI118176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kristiansen M, Kozyraki R, Jacobsen C, Nexø E, Verroust PJ, Moestrup SK. Molecular dissection of the intrinsic factor-vitamin B12 receptor, cubilin, discloses regions important for membrane association and ligand binding. J Biol Chem. 1999;274:20540–4. https://doi.org/10.1074/jbc.274.29.20540.

    Article  CAS  PubMed  Google Scholar 

  59. Dharmacon. shRNA - Applications. 2018. https://dharmacon.horizondiscovery.com/applications/rna-interference/shrna/.

  60. Moore CB, Guthrie EH, Huang MT, Taxman DJ. Short hairpin RNA (shRNA): design, delivery, and assessment of gene knockdown. Methods Mol Biol. 2010;629:141–58. https://doi.org/10.1007/978-1-60761-657-3_10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Koyama H, Goodpasture C, Miller MM, Teplitz RL, Riggs AD. Establishment and characterization of a cell line from the American opossum (Didelphys virginiana). In Vitro. 1978;14:239–46.

    Article  CAS  Google Scholar 

  62. Cui S, Verroust PJ, Moestrup SK, Christensen EI. Megalin/gp330 mediates uptake of albumin in renal proximal tubule. Am J Phys. 1996;271:F900–7.

    CAS  Google Scholar 

  63. Amsellem, S., Gburek J., Hamard G., Nielsen R., Willnow T. E., Devuyst O., Nexo E., Verroust P. J., Christensen E. I., Kozyraki R. Cubilin is essential for albumin reabsorption in the renal proximal tubule. J Am Soc Nephrol 21, 1859-1867, doi:https://doi.org/10.1681/ASN.2010050492 (2010), 1859, 1867.

  64. Nagai J, Christensen EI, Morris SM, Willnow TE, Cooper JA, Nielsen R. Mutually dependent localization of megalin and Dab2 in the renal proximal tubule. Am J Physiol Ren Physiol. 2005;289:F569–76. https://doi.org/10.1152/ajprenal.00292.2004.

    Article  CAS  Google Scholar 

  65. Birn H, Fyfe JC, Jacobsen C, Mounier F, Verroust PJ, Ørskov H, et al. Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest. 2000;105:1353–61. https://doi.org/10.1172/JCI8862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25. https://doi.org/10.1038/nri2155.

    Article  CAS  PubMed  Google Scholar 

  67. Mori KP, et al. Increase of total nephron albumin filtration and reabsorption in diabetic nephropathy. J Am Soc Nephrol. 2017;28:278–89. https://doi.org/10.1681/ASN.2015101168.

    Article  CAS  PubMed  Google Scholar 

  68. Jefferson JA, Shankland SJ, Pichler RH. Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int. 2008;74:22–36. https://doi.org/10.1038/ki.2008.128.

    Article  CAS  PubMed  Google Scholar 

  69. Engler FA, Zheng B, Balthasar JP. Investigation of the influence of nephropathy on monoclonal antibody disposition: a pharmacokinetic study in a mouse model of diabetic nephropathy. Pharm Res. 2014;31:1185–93. https://doi.org/10.1007/s11095-013-1241-y.

    Article  CAS  PubMed  Google Scholar 

  70. Chadha GS, Morris ME. Effect of type 2 diabetes mellitus and diabetic nephropathy on IgG pharmacokinetics and subcutaneous bioavailability in the rat. AAPS J. 2015;17:965–75. https://doi.org/10.1208/s12248-015-9771-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Storm T, Burgoyne T, Dunaief JL, Christensen EI, Futter C, Nielsen R. Selective ablation of megalin in the retinal pigment epithelium results in megaophthalmos, Macromelanosome Formation and Severe Retina Degeneration. Invest Ophthalmol Vis Sci. 2019;60:322–30. https://doi.org/10.1167/iovs.18-25667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Storm T, Heegaard S, Christensen EI, Nielsen R. Megalin-deficiency causes high myopia, retinal pigment epithelium-macromelanosomes and abnormal development of the ciliary body in mice. Cell Tissue Res. 2014;358:99–107. https://doi.org/10.1007/s00441-014-1919-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Powner MB, McKenzie JA, Christianson GJ, Roopenian DC, Fruttiger M. Expression of neonatal Fc receptor in the eye. Invest Ophthalmol Vis Sci. 2014;55:1607–15. https://doi.org/10.1167/iovs.13-12574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Boulton M, Dayhaw-Barker P. The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye (Lond). 2001;15:384–9. https://doi.org/10.1038/eye.2001.141.

    Article  CAS  Google Scholar 

  75. Raila J, Willnow TE, Schweigert FJ. Megalin-mediated reuptake of retinol in the kidneys of mice is essential for vitamin A homeostasis. J Nutr. 2005;135:2512–6. https://doi.org/10.1093/jn/135.11.2512.

    Article  CAS  PubMed  Google Scholar 

  76. Christensen EI, Moskaug JO, Vorum H, Jacobsen C, Gundersen TE, Nykjaer A, et al. Evidence for an essential role of megalin in transepithelial transport of retinol. J Am Soc Nephrol. 1999;10:685–95.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Technical assistance from technician Gitte Fynbo Biller is acknowledged.

Funding

This work was supported by funding from the Center for Protein Therapeutics (Buffalo, NY) and by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001412 to the University at Buffalo.

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  1. Mark A. Bryniarski and Bei Zhao contributed equally to this work.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 445 Pharmacy Building, Buffalo, New York, 14214-8033, USA

    Mark A. Bryniarski, Bei Zhao, Lee D. Chaves, Benjamin M. Yee, Shichen Shen & Marilyn E. Morris

  2. Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA

    Lee D. Chaves & Rabi Yacoub

  3. Department of Biomedicine, Aarhus University, 8000, Aarhus C., Denmark

    Jakob Hauge Mikkelsen & Mette Madsen

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Bryniarski, M.A., Zhao, B., Chaves, L.D. et al. Immunoglobulin G Is a Novel Substrate for the Endocytic Protein Megalin. AAPS J 23, 40 (2021). https://doi.org/10.1208/s12248-021-00557-1

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