Skip to main content

Advertisement

SpringerLink
Log in

Pharmaceutical aspects of anti-inflammatory TNF-blocking drugs

  • Review
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Tumor necrosis factor (TNF) is a key regulator of inflammatory processes in several immune-mediated inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriasis and psoriatic arthritis. Inactivating TNF has been found to be a plausible approach in treating these conditions. Two major strategies have been adopted by scientists to inactivate TNF: one is to use monoclonal antibodies (mAbs) that bind to TNF, and the other is to use fusion proteins that bind to TNF, both inactivate TNF and help to prevent TNF-mediated inflammatory processes. Monoclonal antibodies (mAbs) are biological products that selectively bind to specific antigen molecules, and fusion proteins are soluble receptors that bind to TNF. These types of drugs are generally known as biologics and there has been an explosion in the development and testing of biologics since the 1994 US approval and launch of abciximab, a mAb that binds to GPIIb/IIIa on platelets. Anti-TNF drugs that are currently approved by FDA for treating inflammatory conditions include adalimumab, certolizumab pegol, golimumab, infliximab and etanercept. Since these agents are complex protein molecules, the pharmacodynamics and pharmacokinetics of these drugs are different from small-molecule anti-inflammatory agents. This review focuses on the pharmaceutical aspects of these drugs such as mechanism of action, adverse effects, pharmacokinetics and drug interactions. An effort was also taken to compare the pharmacodynamics and pharmacokinetic properties of these drugs, with the available data at this time.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Aaltonen KJ, Virkki LM, Malmivaara A et al (2012) Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS ONE 7(1):e30275 pub 2012 Jan 17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Arend WP, Dayer JM (1990) Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 33:305–315

    Article  CAS  PubMed  Google Scholar 

  • Arenzana-Seisdedos F, Teyton L, Virelizier JL (1987) Immunoregulatory mediators in the pathogenesis of rheumatoid arthritis. Scand J Rheumatol Suppl 66:13–17

    Article  CAS  PubMed  Google Scholar 

  • Armuzzi A, Lionetti P, Blandizzi C et al (2014) Anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab. Int J Immunopathol Pharmacol 27(1 Suppl):11–32

    CAS  PubMed  Google Scholar 

  • Behrens F, Cañete JD, Olivieri I et al (2014) Tumour necrosis factor inhibitor monotherapy vs combination with MTX in the treatment of PsA: a systematic review of the literature. Rheumatology (Oxford). pii: keu415. [Epub ahead of print]

  • Boyce EG, Halilovic J, Stan-Ugbene O (2010) Golimumab: review of the efficacy and tolerability of a recently approved tumor necrosis factor-α inhibitor. Clin Ther 32:1681–1703

    Article  CAS  PubMed  Google Scholar 

  • Braun J, Sieper J (2003) Overview of the use of the anti-TNF agent infliximab in chronic inflammatory diseases. Expert Opin Biol Ther 3:141–168

    Article  CAS  PubMed  Google Scholar 

  • Brennan FM et al (1989) Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 29:244–247

    Article  Google Scholar 

  • Brennan FR, Morton LD, Sebastian Spindeldreher S et al (2010) Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs 2:233–255

    Article  PubMed Central  PubMed  Google Scholar 

  • Bringman TS, Aggarwal BB (1987) Monoclonal antibodies to human tumor necrosis factors alpha and beta: application for affinity purification, immunoassays, and as structural probes. Hybridoma 6:489–507

    Article  CAS  PubMed  Google Scholar 

  • Cassinotti A, Ardizzone S, Porro BG (2007) Certolizumab pegol: an evidence-based review of its place in the treatment of Crohn’s disease. Core Evid 2:209–229

    PubMed Central  Google Scholar 

  • Choi C, Kim T, Park H et al (2008) Safety and clinical responses in ankylosing spondylitis after three months of etanercept therapy. J Korean Med Sci 23:852–856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Descotes J (2009) Immunotoxicity of monoclonal antibodies. MAbs 1:104–111

    Article  PubMed Central  PubMed  Google Scholar 

  • Dostalek M, Gardner I, Gurbaxani BM et al (2013) Pharmacokinetics, pharmacodynamics and physiologically-based pharmacokinetic modelling of monoclonal antibodies. Clin Pharmacokinet 52:83–124

    Article  CAS  PubMed  Google Scholar 

  • Elliott MJ, Maini RN, Feldmann M et al (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 36:681–690

    Article  Google Scholar 

  • Elliott MJ, Maini RN, Feldmann M et al (1994) Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344:1105–1110

    Article  CAS  PubMed  Google Scholar 

  • Fallahi-Sichani M, Flynn JL, Linderman JJ et al (2012) Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability. J Immunol 188:3169–3178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • FDA (2009) Cancer warnings required for TNF blockers. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm175803.htm. Accessed on 19 Jan 2015

  • FDA Drug Safety Communication (2011) Drug labels for the tumor necrosis factor-alpha (TNFα) blockers now include warnings about infection with Legionella and Listeria bacteria. http://www.fda.gov/Drugs/DrugSafety/ucm270849.htm. Accessed on 19 Jan 2015

  • Ferrajoli A, Talpaz M, Kurzrock R et al (1993) Analysis of the effects of tumor necrosis factor inhibitors on human hematopoiesis. Stem Cells 11:112–119

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb AB (2007) Tumor necrosis factor blockade: mechanism of action. J Investig Dermatol Symp Proc 12:1–4

    Article  CAS  PubMed  Google Scholar 

  • Hirai M, Okamura N, Terano Y et al (1987) Production and characterization of monoclonal antibodies to human tumor necrosis factor. J Immunol Methods 96:57–62

    Article  CAS  PubMed  Google Scholar 

  • Hyrich KL, Watson KD, Silman AJ et al (2006) Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 12:1558–1565

    Article  Google Scholar 

  • Jackson JM (2007) TNF- alpha inhibitors. Dermatol Ther 20:251–264

    Article  PubMed  Google Scholar 

  • Keffer J et al (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10:4025–4031

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kievit W, Fransen J, Oerlemans AJ et al (2007) The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice. Ann Rheum Dis 66:1473–1478

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kirman I, Whelan RL, Nielsen OH (2004) Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease. Eur J Gastroenterol Hepatol 16:639–641

    Article  CAS  PubMed  Google Scholar 

  • Knight DM et al (1993) Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 30:1443–1453

    Article  CAS  PubMed  Google Scholar 

  • Köhler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497

    Article  PubMed  Google Scholar 

  • Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc. (2014)

  • Machado MA, Barbosa MM, Almeida AM et al (2013) Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis. Rheumatol Int 33:2199–2213

    Article  CAS  PubMed  Google Scholar 

  • Markham A, Lamb HM (2000) Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs 59:1341–1359

    Article  CAS  PubMed  Google Scholar 

  • Meager A, Parti S, Leung H et al (1987) Preparation and characterization of monoclonal antibodies directed against antigenic determinants of recombinant human tumour necrosis factor (rTNF). Hybridoma 6:305–311

    Article  CAS  PubMed  Google Scholar 

  • Mewar D, Wilson AG (2011) Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors. Br J Pharmacol 162:785–791

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Michaud TL, Rho YH, Shamliyan T et al (2014) The comparative safety of TNF Inhibitors in rheumatoid arthritis—a meta-analysis update of 44 randomized controlled trials. Am J Med. doi:10.1016/j.amjmed.2014.06.012 [Epub ahead of print]

    PubMed  Google Scholar 

  • Mohler KM, Torrance DS, Smith CA et al (1993) Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 151:1548–1561

    CAS  PubMed  Google Scholar 

  • Movat HZ, Cybulsky MI, Colditz IG et al (1987) Acute inflammation in gram-negative infection: endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc 46:97–104

    CAS  PubMed  Google Scholar 

  • Nam JL, Winthrop KL, van Vollenhoven RF et al (2010) Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis 69:976–986

    Article  CAS  PubMed  Google Scholar 

  • Neovius M, Arkema EV, Olsson H et al (2015) Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab. Ann Rheum Dis 74:354–360

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nestorov I (2005) Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum 34((5 Suppl1)):12–18

    Article  CAS  PubMed  Google Scholar 

  • Ordás I, Feagan BG, Sandborn WJ (2012) Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol 10:1079–1087

    Article  PubMed  Google Scholar 

  • Raja H, Matteson EL, Michet CJ et al (2012) Safety of tumor necrosis factor inhibitors during pregnancy and breastfeeding. Transl Vis Sci Technol 2012(1):6

    Article  Google Scholar 

  • Rau R (2010) Efficacy of methotrexate in comparison to biologics in rheumatoid arthritis. Clin Exp Rheumatol 28:S58–S64

    CAS  PubMed  Google Scholar 

  • Raza A (2000) Anti-TNF therapies in rheumatoid arthritis, Crohn’s disease, sepsis, and myelodysplastic syndromes. Microsc Res Tech 50:229–235

    Article  CAS  PubMed  Google Scholar 

  • Saag KG, Teng GG, Patkar NM et al (2008) American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 59:762–784

    Article  CAS  PubMed  Google Scholar 

  • Saklatvala J (1986) Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 322:547–549

    Article  CAS  PubMed  Google Scholar 

  • Saxne T et al (1988) Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 31:1041–1045

    Article  CAS  PubMed  Google Scholar 

  • Seckinger P, Isaaz S, Dayer JM (1988) A human inhibitor of tumor necrosis factor alpha. J Exp Med 167:1511–1516

    Article  CAS  PubMed  Google Scholar 

  • Spadiut O, Capone S, Krainer F et al (2013) Microbials for the production of monoclonal antibodies and antibody fragments. Trends Biotechnol 32:54–60

    Article  PubMed  Google Scholar 

  • Thorbecke GJ et al (1992) Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc Natl Acad Sci 89:7375–7379

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tracey D, Klareskog L, Eric H et al (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 117:244–279

    Article  CAS  PubMed  Google Scholar 

  • Trehu EG, Mier JW, Dubois JS et al (1996) Phase I trial of interleukin 2 in combination with the soluble tumor necrosis factor receptor p75 IgG chimera. Clin Cancer Res 2:1341–1351

    CAS  PubMed  Google Scholar 

  • Wallis RS (2007) Reactivation of latent tuberculosis by TNF blockade: the role of interferon gamma. J Investig Dermatol Symp Proc 12:16–21

    Article  CAS  PubMed  Google Scholar 

  • Williams RO, Feldmann M, Maini RN (1992) Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci 89:9784–9788

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wong M, Ziring D, Korin Y, Desai S et al (2009) TNFα blockade in human diseases: mechanisms and future directions. Clin Immunol 126:121–136

    Article  Google Scholar 

  • Xixi MA, Shengqian XU (2013) TNF inhibitor therapy for rheumatoid arthritis. Biomed Rep 1:177–184

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. West Haven Pharmacy, West Haven, CT, 06516, USA

    Sandhya Jinesh

Authors
  1. Sandhya Jinesh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandhya Jinesh.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jinesh, S. Pharmaceutical aspects of anti-inflammatory TNF-blocking drugs. Inflammopharmacol 23, 71–77 (2015). https://doi.org/10.1007/s10787-015-0229-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-015-0229-0

Keywords

Search

Navigation