TNFα as Therapeutic Target: New Drugs, More Applications

Abstract

TNFalpha is a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune diseases. With the introduction of infliximab and etanercept, two injectable biologic TNFalpha blocking drugs are now available. Both are effective in the treatment of rheumatoid arthritis, reducing clinical inflammation and damage to bones. In addition, infliximab is FDA-approved for the treatment of Crohn's disease. More recent controlled trials have shown effectiveness for TNFalpha blockers in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Further trials are underway in diverse inflammatory conditions including including uveitis, sarcoidosis, Behcet's syndrome, and graft versus host disease. Although the safety profile has been generally excellent, the rare development of reactivation tuberculosis, anti double-stranded DNA antibodies, or a demyelination syndrome point out the need for further close follow-up of treated patients. New formulations of recombinant anti-TNFalpha biologics undergoing clinical trials use modifications to reduce antigenicity, increase the half-life, and maintain or extend the efficacy of these agents. Future development of TNFalpha antagonists is turning to small molecule inhibitors. The inhibition of the TNFalpha signaling cascade is under study using blockers of the p38, JNK, and ERK kinases, and by antagonists of transcription factor NF-kappaB activation. The goal of this approach is to develop compounds that are orally available, have increased selectivity compared to generalized blockade of TNFalpha, yet are therapeutically useful for a range of chronic inflammatory diseases.

In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes

“…35 Conjugation to IgG-Fc can markedly increase the half-life of small protein drugs, and in some cases has provided an effective treatment option allowing weekly injections. 39,40 GLP-1 receptors are GPCRs mostly pre-existing at the cell membrane in the form of dimers and oligomers 41,42 and, therefore, dimeric GLP-1 peptides are expected to possess substantially increased avidity. [43][44][45][46] We previously showed that in vivo expression of GLP-1/IgGFc via gene transfer significantly prevented onset of diabetes in db/db mice, 35 which is a severe T2D mouse model.…”

Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases

“…Biochemical characterization and genetic analysis reveal that JNK plays a central role in regulation of many cellular activities, such as proliferation, differentiation, migration, transformation and programmed cell death (apoptosis and necrosis; cell death for the simplicity hereinafter) (Lin, 2006). Deregulation of the JNK activity has been implicated in many human diseases including certain types of cancer (Antonyak et al, 2002;Cripe et al, 2002;She et al, 2002), cardiac hypertrophy and ischemia (He et al, 1999;Nemoto et al, 1998;Sadoshima et al, 2002), immune disorders (Reimold, 2002), liver injury (Uehara et al, 2005), obesity (Hirosumi et al, 2002) and neurodegenerative diseases like Alzheimer's and Parkinson's disease (Xia et al, 2001;Okazawa and Estus, 2002). Not surprisingly, JNK activation is tightly regulated by many cellular regulators or modulators, such as scaffold proteins (Whitmarsh et al, 1998;Ito et al, 1999;McDonald et al, 2000) and MAP phosphatases (Karin, 1995).…”

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

“…The potentially increased circulating t 1/2 of such IgG-'carrier' drugs has been shown to be an effective treatment option by weekly injections. [31][32][33] Also, given that most of the GPCRs are pre-formed in the cell membrane in the form of dimers and oligomers, dimeric ligands are expected to possess substantially increased affinity. 34,35 In order to study the biological properties and effectiveness of the recombinant human chimeric GLP-1 fusion protein, GLP-1/Fc, we have examined the peptidergic actions of GLP-1-Fc using a combination of in vitro cell line studies and by intramuscular gene transfer and expression in a type 2 diabetic mouse model in vivo.…”