Tumor necrosis factor (TNF)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

Source: Macrophages, T cells

TNF effects

- Endothelial cells: activation (inflammation, coagulation)
- Neutrophils: activation
- Hypothalamus: fever
- Liver: synthesis of acute phase proteins
- Muscle, fat: catabolism (cachexia)
- Many cell types: apoptosis

Proof of Concept

The success of TNF-α inhibitors in RA was "proof-of-concept" that inhibition of a single cytokine can be effective in treating a disease in which multiple cytokines are expressed, if that cytokine serves a central role. Inhibition of TNF in patients with asthma does not have the same effect seen in RA, has risks, and has taken a back seat in drug development.

Inhibitors of TNF-α

Most established clinical application of TNF inhibitors is in RA.

The anti-TNF-α strategies involve:

- anti-TNF-α antibody
- soluble TNF receptor

Five TNF inhibitors are used in clinical practice:

- Etanercept (Enbrel) - 2 TNF-alpha receptors coupled to the constant region of human IgG1 – a fusion protein.

- Infliximab (Remicade) - human constant region of IgG1 coupled to the variable regions of mouse anti-TNF-alpha – a chimeric (mouse/human) anti-TNF-alpha antibody (mAb).

- Adalimumab (Humira) - human mAb comprised of the human constant region of IgG1 attached to human variable regions - a fully human monoclonal anti-TNF-alpha antibody (mAb).

- Certolizumab (Cimzia) - antigen-binding fragement (Fab) of a humanized mAb coupled to polyethylene glycol.

- Golimumab (Simponi) -

Human IgG1κ

monoclonal

antibody specific

for human TNF-α.

Warnings

There is a risk of reactivation of TB or new infections with TNF inhibition. Tuberculin (TB) skin test with purified protein derivative (PPD) should be performed prior to initiation of therapy and annually.

Monitor for increase in liver function tests.

Vaccination with live vaccines is not recommended while patients are receiving TNF inhibitors.

Inhibitors of TNF-α for treatment of asthma

Inhibition of TNF in patients with asthma does not have the same dramatic effect seen in RA. Results of large-scale clinical trials with blockers of TNF-a have been disappointing. There was an increase in cancer risk.

It is possible that only a subset of severe asthmatics respond to anti-TNF therapy. Levels of expression of membrane-bound TNF-α by peripheral blood monocytes in such subjects with asthma may predict responses.

References

Berry M, Brightling C, Pavord I, Wardlaw AJ. TNF-alpha in asthma. Curr Opin Pharmacol 2007;7:279-82.

Brightling C, Berry M, Amrani Y. Targeting TNF-a a novel therapeutic approach for asthma. J Allergy Clin Immunol 2008;121:5-10.

mAb: If it ends in -mumab, it's a fully human protein, -zumab is humanized (10% mouse), -ximab is chimeric (33% mouse). ACP blog, 2012.

Published: 04/09/2010
Updated: 04/09/2012