Display options
Cite
Sharp JA, Whitley PH, Cunnion KM, et al. Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential. Front Immunol. 2014;5:406doi: 10.3389/fimmu.2014.00406.
Sharp, J. A., Whitley, P. H., Cunnion, K. M., & Krishna, N. K. (2014). Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential. Frontiers in immunology, 5406. https://doi.org/10.3389/fimmu.2014.00406
Sharp, Julia A, et al. "Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential." Frontiers in immunology vol. 5 (2014): 406. doi: https://doi.org/10.3389/fimmu.2014.00406
Sharp JA, Whitley PH, Cunnion KM, Krishna NK. Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential. Front Immunol. 2014 Aug 22;5:406. doi: 10.3389/fimmu.2014.00406. eCollection 2014. PMID: 25202312; PMCID: PMC4141160.
Copy Download .nbib Format: NLM
Share it on

Front Immunol. 2014 Aug 22;5:406. doi: 10.3389/fimmu.2014.00406. eCollection 2014.

Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential.

Frontiers in immunology

Julia A Sharp, Pamela H Whitley, Kenji M Cunnion, Neel K Krishna

Affiliations

  1. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School , Norfolk, VA , USA.
  2. American Red Cross, Mid-Atlantic Region , Norfolk, VA , USA.
  3. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School , Norfolk, VA , USA ; Department of Pediatrics, Eastern Virginia Medical School , Norfolk, VA , USA ; Children's Specialty Group, Division of Infectious Diseases , Norfolk, VA , USA.
  4. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School , Norfolk, VA , USA ; Department of Pediatrics, Eastern Virginia Medical School , Norfolk, VA , USA.

PMID: 25202312 PMCID: PMC4141160 DOI: 10.3389/fimmu.2014.00406

Abstract

The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses and an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease, acute intravascular hemolytic transfusion reaction (AIHTR), and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH), is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema, which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibits complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these peptide inhibitors of complement C1 (PIC1) bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s-C1r-C1r-C1s) and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of 15 amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro and inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR.

Keywords: ABO incompatibility; AIHTR; C1q; MBL; classical pathway; complement; inhibitor; peptide

References

  1. J Immunol. 1979 Aug;123(2):788-92 - PubMed
  2. J Immunol. 2009 Jun 15;182(12):7708-17 - PubMed
  3. Arch Dis Child Fetal Neonatal Ed. 2007 Mar;92(2):F83-8 - PubMed
  4. Am J Clin Pathol. 2008 Feb;129(2):276-81 - PubMed
  5. N Engl J Med. 2006 Sep 21;355(12):1233-43 - PubMed
  6. Biochem J. 1979 Jun 1;179(3):449-57 - PubMed
  7. Nat Med. 2001 Apr;7(4):488-92 - PubMed
  8. J Clin Microbiol. 1998 Sep;36(9):2571-4 - PubMed
  9. J Clin Invest. 1976 Oct;58(4):942-9 - PubMed
  10. Immunol Lett. 2004 Sep;95(2):113-28 - PubMed
  11. Transfusion. 2001 Mar;41(3):323-8 - PubMed
  12. Immunobiology. 2002 Sep;205(4-5):395-406 - PubMed
  13. Nat Biotechnol. 2007 Nov;25(11):1265-75 - PubMed
  14. Drugs. 2013 Dec;73(18):2053-66 - PubMed
  15. J Immunol. 2013 Apr 15;190(8):3831-8 - PubMed
  16. Int J Artif Organs. 2011 Jul;34(7):571-6 - PubMed
  17. Mol Immunol. 2013 Jan;53(1-2):132-9 - PubMed
  18. Vox Sang. 2010 Aug 1;99(2):99-111 - PubMed
  19. Cell Immunol. 2007 Jul;248(1):18-30 - PubMed
  20. Blood. 2003 Jun 15;101(12):5046-52 - PubMed
  21. J Immunol Methods. 1986 Feb 12;86(2):161-70 - PubMed
  22. Cancer Res. 1956 Mar;16(3):216-21 - PubMed
  23. Transpl Int. 2011 Aug;24(8):e61-6 - PubMed
  24. Transfus Med. 1992 Mar;2(1):1-6 - PubMed
  25. Semin Thromb Hemost. 2011 Jun;37(4):362-74 - PubMed
  26. Blood. 2014 Mar 27;123(13):2094-101 - PubMed
  27. Transfusion. 2014 Nov;54(11):2892-900 - PubMed
  28. Nat Med. 2001 Apr;7(4):485-7 - PubMed
  29. Blood. 2014 Jun 26;123(26):4015-22 - PubMed
  30. Mol Immunol. 2007 Jul;44(14):3608-14 - PubMed
  31. J Immunol. 2013 Apr 15;190(8):3839-47 - PubMed
  32. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8650-5 - PubMed
  33. J Immunol. 2001 Dec 1;167(11):6374-81 - PubMed
  34. Transplant Proc. 2012 Dec;44(10):3033-6 - PubMed
  35. Transfus Med Rev. 2010 Jan;24(1):64-7 - PubMed
  36. J Virol. 2003 Nov;77(21):11798-808 - PubMed
  37. Bioorg Med Chem Lett. 2008 Mar 1;18(5):1603-6 - PubMed
  38. Adv Exp Med Biol. 2008;632:273-92 - PubMed
  39. Adv Immunol. 1985;37:151-216 - PubMed
  40. Transfusion. 2005 Aug;45(2 Suppl):122S-9S - PubMed
  41. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10016-20 - PubMed
  42. Expert Rev Hematol. 2008 Dec;1(2):189-204 - PubMed
  43. Biochem Biophys Res Commun. 2007 Feb 9;353(2):363-368 - PubMed
  44. J Virol. 2008 Jan;82(2):817-27 - PubMed
  45. Curr Opin Hematol. 2005 Mar;12(2):117-22 - PubMed
  46. Transfus Med Hemother. 2008;35(5):346-353 - PubMed
  47. Best Pract Res Clin Anaesthesiol. 2013 Mar;27(1):17-35 - PubMed
  48. Mol Immunol. 2010 Jan;47(4):792-8 - PubMed
  49. Clin Dev Immunol. 2012;2012:307093 - PubMed
  50. Mol Immunol. 2010 Nov-Dec;48(1-3):305-13 - PubMed
  51. Haematologica. 2013 Mar;98(3):464-72 - PubMed
  52. Transfusion. 2005 Feb;45(2):234-44 - PubMed
  53. Blood. 1998 Nov 15;92(10):3898-903 - PubMed
  54. Blood. 2013 Feb 14;121(7):1242-4 - PubMed

Publication Types