Skip to main content
SpringerLink
Log in

Toward Clinical use of the IgG Specific Enzymes IdeS and EndoS against Antibody-Mediated Diseases

  • Protocol
  • First Online:
Bacterial Pathogenesis

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1535))

Abstract

The endoglycosidase EndoS and the protease IdeS from the human pathogen Streptococcus pyogenes are immunomodulating enzymes hydrolyzing human IgG. IdeS cleaves IgG in the lower hinge region, while EndoS hydrolyzes the conserved N-linked glycan in the Fc region. Both enzymes are remarkably specific for human IgG that after hydrolysis loses most of its effector functions, such as binding to leukocytes and complement activation, all contributing to bacterial evasion of adaptive immunity. However, taken out of their infectious context, we and others have shown that IdeS and EndoS can alleviate autoimmune disease in a number of animal models of antibody-mediated disorders. In this chapter, we will briefly describe the discovery and characterization of these unique enzymes, present the findings from a number of animal models of autoimmunity where the enzymes have been tested, and outline the ongoing clinical testing of IdeS. Furthermore, we will discuss the rationale for further development of IdeS and EndoS into novel pharmaceuticals against diseases where IgG antibodies contribute to the pathology, including, but not restricted to, chronic and acute autoimmunity, transplant rejection, and antidrug antibody reactions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alcami A, Saraiva M (2009) Chemokine binding proteins encoded by pathogens. Adv Exp Med Biol 666:167–179. doi:10.1007/978-1-4419-1601-3_13

    Article  CAS  PubMed  Google Scholar 

  2. Donaldson DS, Williams NA (2009) Bacterial toxins as immunomodulators. Adv Exp Med Biol 666:1–18. doi:10.1007/978-1-4419-1601-3_1

    Article  CAS  PubMed  Google Scholar 

  3. Fallon PG, Alcami A (2006) Pathogen-derived immunomodulatory molecules: future immunotherapeutics? Trends Immunol 27:470–476. doi:10.1016/j.it.2006.08.002

    Article  CAS  PubMed  Google Scholar 

  4. Jongerius I, Ram S, Rooijakkers S (2009) Bacterial complement escape. Adv Exp Med Biol 666:32–48. doi:10.1007/978-1-4419-1601-3_3

    Article  CAS  PubMed  Google Scholar 

  5. Juncadella IJ, Anguita J (2009) The immunosuppressive tick salivary protein, Salp15. Adv Exp Med Biol 666:121–131. doi:10.1007/978-1-4419-1601-3_10

    Article  CAS  PubMed  Google Scholar 

  6. Elliott DE, Weinstock JV (2012) Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci 1247:83–96. doi:10.1111/j.1749-6632.2011.06292.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nizet V (2007) Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets. J Allergy Clin Immunol 120:13–22. doi:10.1016/j.jaci.2007.06.005

    Article  CAS  PubMed  Google Scholar 

  8. Navarre WW, Schneewind O (1999) Surface proteins of gram-positive bacteria and mechanisms of their targeting to the cell wall envelope. Microbiol Mol Biol Rev 63:174–229

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Collin M, Kilian M (2013) Bacterial modulation of Fc effector functions. In: Ackerman ME, Nimmerjahn F (eds) Antibody FC: linking adaptive and innate immunity, 1st edn. Academic Press (London), pp 317–332

    Google Scholar 

  10. Nelson DC, Garbe J, Collin M (2011) Cysteine proteinase SpeB from Streptococcus pyogenes - a potent modifier of immunologically important host and bacterial proteins. Biol Chem 392:1077–1088. doi:10.1515/BC.2011.208

    Article  CAS  PubMed  Google Scholar 

  11. Persson H, Vindebro R, von Pawel-Rammingen U (2013) The streptococcal cysteine protease SpeB is not a natural immunoglobulin cleaving enzyme. Infect Immun 81:2236–2241. doi:10.1128/IAI.00168-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. von Pawel-Rammingen U, Johansson BP, Björck L (2002) IdeS, a novel streptococcal cysteine proteinase with unique specificity for immunoglobulin G. EMBO J 21:1607–1615. doi:10.1093/emboj/21.7.1607

    Article  Google Scholar 

  13. Vincents B, Pawel-Rammingen von U, Björck L, Abrahamson M (2004) Enzymatic characterization of the streptococcal endopeptidase, IdeS, reveals that it is a cysteine protease with strict specificity for IgG cleavage due to exosite binding. Biochemistry 43:15540–15549. doi:10.1021/bi048284d

  14. von Pawel-Rammingen U, Johansson BP, Tapper H, Björck L (2002) Streptococcus pyogenes and phagocytic killing. Nat Med 8:1044–1045. doi:10.1038/nm1002-1044, author reply 1045–6

    Article  Google Scholar 

  15. Söderberg JJ, von Pawel-Rammingen U (2008) The streptococcal protease IdeS modulates bacterial IgGFc binding and generates 1/2Fc fragments with the ability to prime polymorphonuclear leucocytes. Mol Immunol 45:3347–3353. doi:10.1016/j.molimm.2008.04.013

    Article  PubMed  Google Scholar 

  16. Järnum S, Bockermann R, Runström A et al (2015) The bacterial enzyme IdeS cleaves the IgG-type of B cell receptor (BCR), abolishes BCR-mediated cell signaling, and inhibits memory B cell activation. J Immunol 195:5592–5601. doi:10.4049/jimmunol.1501929

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lannergård J, Guss B (2006) IdeE, an IgG-endopeptidase of Streptococcus equi ssp. equi. FEMS Microbiol Lett 262:230–235. doi:10.1111/j.1574-6968.2006.00404.x

    Article  PubMed  Google Scholar 

  18. Rudd P, Elliott T, Cresswell P et al (2001) Glycosylation and the immune system. Science 291:2370–2376

    Article  CAS  PubMed  Google Scholar 

  19. Tarentino AL, Quinones G, Schrader WP et al (1992) Multiple endoglycosidase (Endo) F activities expressed by Flavobacterium meningosepticum. Endo F1: molecular cloning, primary sequence, and structural relationship to Endo H. J Biol Chem 267:3868–3872

    CAS  PubMed  Google Scholar 

  20. Tarentino A, Quinones G, Changchien L, Plummer T (1993) Multiple endoglycosidase F activities expressed by Flavobacterium meningosepticum endoglycosidases F2 and F3. Molecular cloning, primary sequence, and enzyme expression. J Biol Chem 268:9702–9708

    CAS  PubMed  Google Scholar 

  21. Tarentino A, Gomez C, Plummer T (1985) Deglycosylation of asparagine-linked glycans by peptide:N-glycosidase F. Biochemistry 24:4665–4671

    Article  CAS  PubMed  Google Scholar 

  22. Collin M, Olsén A (2001) EndoS, a novel secreted protein from Streptococcus pyogenes with endoglycosidase activity on human IgG. EMBO J 20:3046–3055. doi:10.1093/emboj/20.12.3046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Collin M, Olsén A (2001) Effect of SpeB and EndoS from Streptococcus pyogenes on human immunoglobulins. Infect Immun 69:7187–7189. doi:10.1128/IAI.69.11.7187-7189.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dixon EV, Claridge JK, Harvey DJ et al (2014) Fragments of bacterial endoglycosidase s and immunoglobulin g reveal subdomains of each that contribute to deglycosylation. J Biol Chem 289:13876–13889. doi:10.1074/jbc.M113.532812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Flock M, Frykberg L, Sköld M et al (2012) Antiphagocytic function of an IgG glycosyl hydrolase from Streptococcus equi subsp. equi and its use as a vaccine component. Infect Immun 80:2914–2919. doi:10.1128/IAI.06083-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shadnezhad A, Naegeli A, Sjögren J et al (2016) EndoSd, an IgG glycan hydrolyzing enzyme in Streptococcus dysgalactiae subspecies dysgalactiae. Future Microbiol 11:721–736. doi:10.2217/FMB.16.14

    Article  CAS  PubMed  Google Scholar 

  27. Collin M, Svensson MD, Sjöholm AG et al (2002) EndoS and SpeB from Streptococcus pyogenes inhibit immunoglobulin-mediated opsonophagocytosis. Infect Immun 70:6646–6651. doi:10.1128/IAI.70.12.6646-6651.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sjögren J, Okumura CYM, Collin M et al (2011) Study of the IgG endoglycosidase EndoS in group A streptococcal phagocyte resistance and virulence. BMC Microbiol 11:120. doi:10.1186/1471-2180-11-120

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sjögren J, Collin M (2014) Bacterial glycosidases in pathogenesis and glycoengineering. Future Microbiol 9:1039–1051. doi:10.2217/fmb.14.71

    Article  PubMed  Google Scholar 

  30. Sjögren J, Cosgrave EFJ, Allhorn M et al (2015) EndoS and EndoS2 hydrolyze Fc-glycans on therapeutic antibodies with different glycoform selectivity and can be used for rapid quantification of high-mannose glycans. Glycobiology 25:1053–1063. doi:10.1093/glycob/cwv047

    Article  PubMed  PubMed Central  Google Scholar 

  31. Walsh SJ, Rau LM (2000) Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States. Am J Public Health 90:1463–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lim P-L, Zouali M (2006) Pathogenic autoantibodies: emerging insights into tissue injury. Immunol Lett 103:17–26. doi:10.1016/j.imlet.2005.10.023

    Article  CAS  PubMed  Google Scholar 

  33. Colvin RB, Smith RN (2005) Antibody-mediated organ-allograft rejection. Nat Rev Immunol 5:807–817. doi:10.1038/nri1702

    Article  CAS  PubMed  Google Scholar 

  34. Collin M, Shannon O, Björck L (2008) IgG glycan hydrolysis by a bacterial enzyme as a therapy against autoimmune conditions. Proc Natl Acad Sci U S A 105:4265–4270. doi:10.1073/pnas.0711271105

    Article  PubMed  PubMed Central  Google Scholar 

  35. Johansson BP, Shannon O, Björck L (2008) IdeS: a bacterial proteolytic enzyme with therapeutic potential. PLoS One 3:e1692. doi:10.1371/journal.pone.0001692

    Article  PubMed  PubMed Central  Google Scholar 

  36. Nandakumar KS, Collin M, Olsén A et al (2007) Endoglycosidase treatment abrogates IgG arthritogenicity: importance of IgG glycosylation in arthritis. Eur J Immunol 37:2973–2982. doi:10.1002/eji.200737581

    Article  CAS  PubMed  Google Scholar 

  37. Albert H, Collin M, Dudziak D et al (2008) In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. Proc Natl Acad Sci U S A 105:15005–15009. doi:10.1073/pnas.0808248105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nandakumar KS, Johansson BP, Björck L, Holmdahl R (2007) Blocking of experimental arthritis by cleavage of IgG antibodies in vivo. Arthritis Rheum 56:3253–3260. doi:10.1002/art.22930

    Article  CAS  PubMed  Google Scholar 

  39. Cines DB, Blanchette VS (2002) Immune thrombocytopenic purpura. N Engl J Med 346:995–1008. doi:10.1056/NEJMra010501

    Article  PubMed  Google Scholar 

  40. McMillan R (1997) Therapy for adults with refractory chronic immune thrombocytopenic purpura. Ann Intern Med 126:307–314

    Article  CAS  PubMed  Google Scholar 

  41. Voulgarelis M, Kokori SI, Ioannidis JP et al (2000) Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin. Ann Rheum Dis 59:217–222. doi:10.1136/ard.59.3.217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Allhorn M, Briceño JG, Baudino L et al (2010) The IgG-specific endoglycosidase EndoS inhibits both cellular and complement-mediated autoimmune hemolysis. Blood 115:5080–5088. doi:10.1182/blood-2009-08-239020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang R, Otten MA, Hellmark T et al (2010) Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes. Nephrol Dial Transplant 25:2479–2486. doi:10.1093/ndt/gfq115

    Article  CAS  PubMed  Google Scholar 

  44. van Timmeren MM, van der Veen BS, Stegeman CA et al (2010) IgG glycan hydrolysis attenuates ANCA-mediated glomerulonephritis. J Am Soc Nephrol 21:1103–1114. doi:10.1681/ASN.2009090984

    Article  PubMed  PubMed Central  Google Scholar 

  45. Andrews BS, Eisenberg RA, Theofilopoulos AN et al (1978) Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148:1198–1215

    Article  CAS  PubMed  Google Scholar 

  46. Lin Q, Xiu Y, Jiang Y et al (2006) Genetic dissection of the effects of stimulatory and inhibitory IgG Fc receptors on murine lupus. J Immunol 177:1646–1654. doi:10.4049/jimmunol.177.3.1646

    Article  CAS  PubMed  Google Scholar 

  47. Lood C, Allhorn M, Lood R et al (2012) IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: a possible new treatment? Arthritis Rheum 64:2698–2706. doi:10.1002/art.34454

    Article  CAS  PubMed  Google Scholar 

  48. Antel J, Baror A (2006) Roles of immunoglobulins and B cells in multiple sclerosis: from pathogenesis to treatment. J Neuroimmunol 180:3–8. doi:10.1016/j.jneuroim.2006.06.032

    Article  CAS  PubMed  Google Scholar 

  49. Humle Jorgensen S, Sorensen PS (2005) Intravenous immunoglobulin treatment of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. J Neurol Sci 233:61–65. doi:10.1016/j.jns.2005.03.005

    Article  CAS  PubMed  Google Scholar 

  50. Benkhoucha M, Molnarfi N, Santiago-Raber M-L et al (2012) IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis. J Neuroinflammation 9:209. doi:10.1186/1742-2094-9-209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Krumbholz M, Meinl E (2014) B cells in MS and NMO: pathogenesis and therapy. Semin Immunopathol 36:339–350. doi:10.1007/s00281-014-0424-x

    Article  CAS  PubMed  Google Scholar 

  52. Ratelade J, Verkman AS (2012) Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies. Int J Biochem Cell Biol 44:1519–1530. doi:10.1016/j.biocel.2012.06.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tradtrantip L, Ratelade J, Zhang H, Verkman AS (2013) Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody. Ann Neurol 73:77–85. doi:10.1002/ana.23741

    Article  CAS  PubMed  Google Scholar 

  54. Tradtrantip L, Asavapanumas N, Verkman AS (2013) Therapeutic cleavage of anti-aquaporin-4 autoantibody in neuromyelitis optica by an IgG-selective proteinase. Mol Pharmacol 83:1268–1275. doi:10.1124/mol.113.086470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kaida K, Ariga T, Yu RK (2009) Antiganglioside antibodies and their pathophysiological effects on Guillain-Barré syndrome and related disorders--a review. Glycobiology 19:676–692. doi:10.1093/glycob/cwp027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Takahashi R, Yuki N (2015) Streptococcal IdeS: therapeutic potential for Guillain-Barré syndrome. Sci Rep 5:10809. doi:10.1038/srep10809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schmidt E, Zillikens D (2013) Pemphigoid diseases. Lancet 381:320–332. doi:10.1016/S0140-6736(12)61140-4

    Article  PubMed  Google Scholar 

  58. Kasperkiewicz M, Sadik CD, Bieber K et al (2016) Epidermolysis bullosa acquisita: from pathophysiology to novel therapeutic options. J Invest Dermatol 136:24–33. doi:10.1038/JID.2015.356

    CAS  PubMed  Google Scholar 

  59. Hirose M, Vafia K, Kalies K et al (2012) Enzymatic autoantibody glycan hydrolysis alleviates autoimmunity against type VII collagen. J Autoimmun 39:304–314. doi:10.1016/j.jaut.2012.04.002

    Article  CAS  PubMed  Google Scholar 

  60. Yu X, Zheng J, Collin M et al (2014) EndoS reduces the pathogenicity of anti-mCOL7 IgG through reduced binding of immune complexes to neutrophils. PLoS One 9:e85317. doi:10.1371/journal.pone.0085317

    Article  PubMed  PubMed Central  Google Scholar 

  61. Winstedt L, Järnum S, Nordahl EA et al (2015) Complete removal of extracellular IgG antibodies in a randomized dose-escalation phase I study with the bacterial enzyme IdeS--a novel therapeutic opportunity. PLoS One 10:e0132011. doi:10.1371/journal.pone.0132011

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Swedish Research Council (projects 2012–1875 and 7480), the Royal Physiographic Society in Lund, the Foundations of Knut and Alice Wallenberg, Åke Wiberg, Alfred Österlund, Gyllenstierna-Krapperup, Torsten Söderberg, Greta and Johan Kock, King Gustaf V`s 80 years fund, the Swedish Society for Medicine, Swedish Governmental Funds for Clinical Research (ALF), and Hansa Medical AB. The funders had no role in the preparation of the manuscript or in the decision to publish.

Conflict of interests: Hansa Medical AB (HMAB) (www.hansamedical.com) holds patents for using EndoS and IdeS as treatment for antibody-mediated diseases. MC and LB are listed as inventors on the EndoS patents, and LB is listed as an inventor on the IdeS patents. MC and LB are scientific consultants for HMAB through their private companies GlycImmun (GI) (www.glycimmun.com) and AB Protiga, respectively. Genovis AB (GAB) (www.genovis.com) holds patents for the biotechnological use of IdeS, EndoS, and EndoS2 where MC is listed as an inventor on the EndoS/EndoS2 patents and LB on the IdeS patents.

Author information

Authors and Affiliations

  1. Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center B14, SE-221 84, Lund, Sweden

    Mattias Collin & Lars Björck

Authors
  1. Mattias Collin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lars Björck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mattias Collin .

Editor information

Editors and Affiliations

  1. Department of Clinical Sciences, Lund University, Division of Infection Medicine, Lund, Sweden

    Pontus Nordenfelt

  2. Department of Clinical Sciences, Lund University, Division of Infection Medicine, Lund, Sweden

    Mattias Collin

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this protocol

Cite this protocol

Collin, M., Björck, L. (2017). Toward Clinical use of the IgG Specific Enzymes IdeS and EndoS against Antibody-Mediated Diseases. In: Nordenfelt, P., Collin, M. (eds) Bacterial Pathogenesis. Methods in Molecular Biology, vol 1535. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6673-8_23

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6673-8_23

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6671-4

  • Online ISBN: 978-1-4939-6673-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation