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A PEGylated Fab’ Fragment against Tumor Necrosis Factor for the Treatment of Crohn Disease

Exploring a New Mechanism of Action

  • Drug Development
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Abstract

Antibodies, having a high specificity for their particular target, are increasingly being used as therapeutic agents with functions including agonist, antagonist, and targeted drug delivery. The use of many biologic therapies, including antibody fragments, is generally limited by their rapid clearance from plasma. A commonly used approach to extend exposure to biologic therapies is the attachment of polyethylene glycol.

Tumor necrosis factor (TNF)-α is a multifunctional cytokine involved in the regulation of immune responses. Elevated levels of TNFα are found in a wide range of diseases, including the chronic inflammatory conditions rheumatoid arthritis, psoriasis, and Crohn disease (CD). Anti-TNFα antibodies have proved highly efficacious in the treatment of these conditions. In addition, they have proved invaluable for investigating the role of TNFα in disease etiology.

Based on evidence showing that neutralizing antibodies to TNFα were effective in animal models of CD, anti-TNFα antibody treatments were assessed in clinical trials. Interestingly, the anti-TNFα antibody etanercept proved ineffective at achieving remission in active CD despite potently neutralizing soluble TNFα. This indicated that an additional mode of action is also involved in the efficacy of the anti-TNFα agents adalimumab, certolizumab pegol, and infliximab in CD; one suggestion was apoptosis. However, etanercept, like adalimumab and infliximab, can induce apoptosis. Furthermore, certolizumab pegol (which has demonstrated efficacy in CD) does not cause complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, apoptosis, or necrosis of neutrophils, all measured in vitro. These functional differences observed with certolizumab pegol stem from its unique structure that does not include the crystallizable fragment (Fc) portion present in the other anti-TNFα agents, and the way in which it signals through membrane TNF.

It is well established that bacteria are a major part of the inflammatory process in CD. The property identified that reflected the efficacies of the anti-TNFα agents etanercept, adalimumab, certolizumab pegol, and infliximab in CD was the ability to inhibit the cytokine production by monocytes that is induced by bacterial lipopolysaccharide. It may therefore be the case that this mode of action is important for efficacy in CD.

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References

  1. Stockwin LH, Holmes S. Antibodies as therapeutic agents: vive la renaissance! Expert Opin Biol Ther 2003 Oct; 3(7): 1133–52

    Article  PubMed  CAS  Google Scholar 

  2. Lobato MN, Rabbitts TH. Intracellular antibodies and challenges facing their use as therapeutic agents. Trends Mol Med 2003 Sep; 9(9): 390–6

    Article  PubMed  CAS  Google Scholar 

  3. Clark IA. How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev 2007 Jun–Aug; 18(3–4): 335–43

    Article  PubMed  CAS  Google Scholar 

  4. Holliger P, Hudson PJ. Engineered antibody fragments and the rise of single domains. Nat Biotechnol 2005 Sep; 23(9): 1126–36

    Article  PubMed  CAS  Google Scholar 

  5. Weir AN, Nesbitt A, Chapman AP, et al. Formatting antibody fragments to mediate specific therapeutic functions. Biochem Soc Trans 2002 Aug; 30(4): 512–6

    Article  PubMed  CAS  Google Scholar 

  6. Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 2003 Sep 26; 55(10): 1261–77

    Article  PubMed  CAS  Google Scholar 

  7. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003 Sep; 3(9): 745–56

    Article  PubMed  CAS  Google Scholar 

  8. Watts AD, Hunt NH, Wanigasekara Y, et al. A casein kinase I motif present in the cytoplasmic domain of the tumour necrosis factor ligand family is implicated in ‘reverse signaling’. EMBO J 1999 Apr; 18(8): 2119–26

    Article  PubMed  CAS  Google Scholar 

  9. Loftus EV, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn’s disease in population-based patient cohorts from North America: a systematic review. Aliment Pharmacol Ther 2002 Jan; 16(1): 51–60

    Article  PubMed  Google Scholar 

  10. Bernstein CN. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am J Gastroenterol 2006 Jan; 101(7): 1559–68

    Article  PubMed  Google Scholar 

  11. Sands BE. Inflammatory bowel disease: past, present, and future. J Gastroenterol 2007 Jan; 42: 16–25

    Article  PubMed  Google Scholar 

  12. Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997 Apr; 40: 443–8

    PubMed  Google Scholar 

  13. Van Dullemen HM, van Deventer SJ, Hommes DW, et al. Treatment of Crohn’s disease with anti-tumour necrosis factor chimeric antibody (cA2). Gastroenterology 1995 Jul; 109(1): 129–35

    Article  PubMed  Google Scholar 

  14. Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. N Engl J Med 1997 Oct; 337(15): 1029–35

    Article  PubMed  CAS  Google Scholar 

  15. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999 May; 340: 1398–405

    Article  PubMed  CAS  Google Scholar 

  16. Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumour necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999; 117: 761–9

    Article  PubMed  CAS  Google Scholar 

  17. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: a randomised, double-blind, placebo-controlled trial. Gastroenterology 2001 Nov; 121: 1088–94

    Article  PubMed  CAS  Google Scholar 

  18. Baker M, Stringer F, Stephens S. Pharmacokinetic properties of the anti-TNF agent certolizumab pegol [abstract]. Gut 2006; 55Suppl. V: A122

    Google Scholar 

  19. Sandborn WJ, Feagan BG, Stoinov S, et al., for the PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007; 357: 228–38

    Article  PubMed  CAS  Google Scholar 

  20. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al., for the PRECISE 2 Study Investigators. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007; 357: 239–50

    Article  PubMed  CAS  Google Scholar 

  21. Chapman AP. PEGylated antibodies and antibody fragments for improved therapy: a review. Adv Drug Deliv Rev 2002; 54: 531–45

    Article  PubMed  CAS  Google Scholar 

  22. Smith B, Ceska T, Henry A, et al. Detailing the novel structure of the biopharma-ceutical certolizumab pegol [abstract]. J Crohn’s Colitis 2008; 2(1): 50

    Google Scholar 

  23. Lugering A, Schmidt M, Lugering N, et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 2001 Nov; 121: 1145–57

    Article  PubMed  CAS  Google Scholar 

  24. Shen C, Assche GV, Colpaert S, et al. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 2005 Feb; 21: 251–8

    Article  PubMed  CAS  Google Scholar 

  25. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induced apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 2003 Jun; 124: 1774–85

    Article  PubMed  Google Scholar 

  26. ten Hove T, van Montfrans C, Peppelenbosch MP, et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 2002 Feb; 50: 206–11

    Article  PubMed  Google Scholar 

  27. Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNFα monoclonal antibody cA2 binds recombinant transmembrane TNFα and activates immune effector functions. Cytokine 1995 Apr; 7: 251–9

    Article  PubMed  CAS  Google Scholar 

  28. Kirchner S, Holler E, Haffner S, et al. Effect of different tumor necrosis factor (TNF) reactive agents on reverse signaling of membrane integrated TNF in monocytes. Cytokine 2004 Oct; 28: 67–74

    Article  PubMed  CAS  Google Scholar 

  29. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis 2007; 13: 1323–32

    Article  PubMed  Google Scholar 

  30. Mpofu S, Fatima F, Moots RJ. Anti-TNF-α therapies: they are all the same (aren’t they?). Rheumatology 2005 Mar; 44: 271–3

    Article  PubMed  CAS  Google Scholar 

  31. Mitoma H, Horiuchi T, Hatta N, et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-α. Gastroenterology 2005 Feb; 128: 376–92

    Article  PubMed  CAS  Google Scholar 

  32. Eissner G, Kirchner S, Lindner H, et al. Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and macrophages. J Immunol 2000 Jun; 164: 6193–8

    PubMed  CAS  Google Scholar 

  33. Ringheanu M, Daum F, Markowitz J, et al. Effects of infliximab on apoptosis and reverse signaling of monocytes from healthy individuals and patients with Crohn’s disease. Inflam Bowel Dis 2004 Nov; 10(6): 801–10

    Article  Google Scholar 

  34. Xin L, Wang J, Zhang H, et al. Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signalling’. Int J Mol Med 2006 Nov; 18: 885–92

    PubMed  CAS  Google Scholar 

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Acknowledgments

T. Bourne, A. Nesbitt, and G. Fossati are employees of UCB. The work described was also funded by UCB.

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Authors and Affiliations

  1. Inflammation Discovery, UCB Celltech, Slough, UK

    Tim Bourne, Gianluca Fossati &  Andrew Nesbitt

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  1. Tim Bourne
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  2. Gianluca Fossati
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  3. Andrew Nesbitt
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Correspondence to Andrew Nesbitt.

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Bourne, T., Fossati, G. & Nesbitt, A. A PEGylated Fab’ Fragment against Tumor Necrosis Factor for the Treatment of Crohn Disease. BioDrugs 22, 331–337 (2008). https://doi.org/10.2165/00063030-200822050-00005

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