TNFα blockade in human diseases: An overview of efficacy and safety

Lin, Joyce; Ziring, David; Desai, Sheetal; Kim, Sungjin; Wong, Maurice; Korin, Yael; Braun, Jonathan; Reed, Elaine F.; Gjertson, David W.; Singh, Ram Raj

doi:10.1016/j.clim.2007.08.012

Cited by 233 publications

(210 citation statements)

References 116 publications

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“…28 The need for repeated systemic injections of these anti-TNF drugs for long periods of time enhances the rate of undesirable side effects of anti-TNF therapies. 28,29 Therefore, simple local administration would have indisputable advantages especially for a 'closed' organ as the eye. Moreover, the induction of self-continuous and sustained production of therapeutic anti-TNF-a proteins by the eye tissues was a most appealing possibility.…”

Section: Discussionmentioning

confidence: 99%

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

et al. 2009

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Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-a (TNF-a) enhances intraocular cytotoxic events, systemic anti-TNF therapies have been introduced in the treatment of severe intraocular inflammation, but frequent re-injections are needed and are associated with severe side effects. We have devised a local intraocular nonviral gene therapy to deliver effective and sustained anti-TNF therapy in inflamed eyes. In this study, we show that transfection of the ciliary muscle by plasmids encoding for three different variants of the p55 TNF-a soluble receptor, using electrotransfer, resulted in sustained intraocular secretion of the encoded proteins, without any detection in the serum. In the eye, even the shorter monomeric variant resulted in efficient neutralization of TNF-a in a rat experimental model of endotoxininduced uveitis, as long as 3 months after transfection. A subsequent downregulation of interleukin (IL)-6 and iNOS and upregulation of IL-10 expression was observed together with a decreased rolling of inflammatory cells in anterior segment vessels and reduced infiltration within the ocular tissues. Our results indicate that using a nonviral gene therapy strategy, the local self-production of monomeric TNF-a soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation.

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Section: Discussionmentioning

confidence: 99%

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

et al. 2009

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“…Two monoclonal antibodies (mAb) and a soluble receptor, which bind to soluble and membrane forms of TNFα and can neutralize the pathological effects of TNFα in IMIDs, are licensed for clinical use (reviewed in [116]). …”

Section: Tnfα Antagonistsmentioning

confidence: 99%

“…Although anti-TNFα therapy is safe and well tolerated, some of the adverse events reported in patients treated with TNFα blockading agents include immunogenicity, infections, delayed hypersensitivity-type reactions and autoimmune diseases such as drug-induced lupus and demyelination (reviewed in [116]). …”

Section: Mechanism Of Treatment-limiting Adverse Responsesmentioning

confidence: 99%

“…Since their first license for clinical use in 1998, the three approved TNFα antagonists have shown clear benefits in a series of randomized, controlled trials enrolling over 8000 patients with inflammatory diseases. Efficacy and safety profiles of these agents in IMIDs have been reviewed in a recently published article in the Journal [116].…”

Section: Introductionmentioning

confidence: 99%

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TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

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256

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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“…Imbalances in this system can lead to the development of chronic inflammatory conditions, autoimmune diseases and increased susceptibility and/or non-resolution of infections (Hanada, Yoshimura, 2002). In immune-mediated inflammatory disorders (IMIDs), the immune system becomes imbalanced thereby preventing healing of inflammation, which consequently evolves and promotes tissue damage (Lin et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic approaches for tumor necrosis factor inhibition

Barbosa

Fumian

Miranda

et al. 2011

Braz. J. Pharm. Sci.

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Tumor necrosis factor (TNF) consists of an inflammatory cytokine essential for homeostasis and organism defense. Despite its physiological relevance, both increased biosynthesis and release of TNF lead to the exacerbation of inflammatory and oxidative responses, which are related to the pathogenesis of a host of diseases of an inflammatory, autoimmune and/or infectious nature. In this context, effective therapeutic approaches for the modulation of TNF have been the focus of research efforts. Approximately one million individuals worldwide have been treated with biotechnological inhibitors of this cytokine, the so-called anti-TNF biopharmaceuticals. However, given the high risk of infection and the limitations related to cost and administration routes, new therapeutic approaches aimed at biological targets that directly or indirectly modulate the production and/or activation of TNF appear promising alternatives for the discovery of new anti-inflammatory and immunomodulatory orally active drugs and are therefore discussed in this paper.Uniterms: Tumor necrosis factor. TACE. p38 MAPK. NF-kB. cAMP. Phosphodiesterase. Adenosine receptor.O fator de necrose tumoral (do inglês, tumor necrosis factor -TNF) consiste em uma citocina inflamatória essencial para a homeostase e defesa do organismo. A despeito de sua relevância fisiológica, o aumento da biossíntese e liberação do TNF conduzem à exacerbação das respostas inflamatória e oxidativa, as quais estão relacionadas à patogênese de várias doenças de natureza inflamatória, auto-imune e/ou infecciosa. A busca por abordagens terapêuticas eficientes na modulação do TNF tem sido alvo de diversos esforços de pesquisa. Aproximadamente um milhão de pessoas ao redor do mundo já foi tratado com inibidores biotecnológicos desta citocina, os chamados biofármacos anti-TNF. Entretanto, em face ao elevado risco de infecções e as limitações relacionadas ao custo e a via de administração, novas abordagens terapêuticas com foco em alvos que modulem, de forma direta ou indireta, a produção e/ou ativação do TNF surgem como alternativas promissoras para a descoberta de novos fármacos antiinflamatórios e imunomoduladores ativos por via oral e serão discutidas neste trabalho. Unitermos: Fator de necrose tumoral. TACE. MAPK p38. NF-kB. AMPc. Fosfodiesterase. Receptor de adenosina.

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TNFα blockade in human diseases: An overview of efficacy and safety

Abstract: Tumor necrosis factor-alpha (TNFα) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess

Cited by 233 publications

References 116 publications

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

TNFα blockade in human diseases: Mechanisms and future directions

Therapeutic approaches for tumor necrosis factor inhibition

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