Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases

Tumor necrosis factor-alpha (TNF) has been unequivocally validated as a therapeutic target in a number of immune-mediated inflammatory disorders (IMIDs). There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF. But approaches to TNF inhibition differ and currently include mAbs (infliximab, adalimumab, and golimumab), either chimeric or human in sequence, a PEGylated Fab′ fragment (certolizumab), and an IgG1–TNFR2 fusion protein (etanercept). It is emerging that the pharmacological properties of these three anti-TNF subtypes differ with respect to Fc function, binding of tmTNF and the possible consequences of this, as well as the ability to form complexes. The mode of administration of each agent, clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety.

Introduction

Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine with both proinflammatory and immunoregulatory functions. The diverse activities are mediated via ligand interaction with two distinct receptors, p55/TNFRI and p75/TNFRII expressed on most human cells, which activate separate transduction pathways resulting in distinct biologic effects. TNF is a validated therapeutic target in a number of chronic immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), inflammatory bowel disease (IBD), and psoriasis with or without complicating arthritis. It was the first cytokine to be fully validated as a therapeutic target for the treatment of RA through a series of preclinical studies of the immunobiology of synovial tissue harvested from patients with active disease, preclinical animal model studies, and human trials [1]. TNF is expressed as a transmembrane precursor (tmTNF) that undergoes proteolytic processing to form a soluble homotrimer. The binding of both the membrane-bound and soluble forms of TNF (sTNF) to its receptors induces production of several other proinflammatory cytokines, cell adhesion molecules, and other inflammatory molecules.

Three TNF-specific monoclonal antibodies, infliximab (Remicade^®), adalimumab (Humira^®), and golimumab (Simponi^®) have been approved for patient use (Figure 1). In addition, the TNF-specific, PEGylated Fab′ antibody fragment certolizumab pegol (Cimzia^®) has also been approved for clinical use (Figure 1). The Fab′ fragment was engineered with a single hinge region free-cysteine residue which enables site-specific attachment of polyethylene glycol (PEG) without affecting the ability of the Fab′ fragment to bind and neutralize TNF. The attachment of a 40 kDa PEG moiety to the Fab′ fragment markedly increases the half-life of certolizumab to one comparable with that of a whole antibody product. Another anti-TNF biologic therapy, etanercept (Enbrel^®), is a fusion protein of two TNFR2 receptor extracellular domains and the Fc portion of human IgG (Figure 1), and this agent has also been approved for the treatment of several IMIDs.

Although all these biologics have TNF as a defined target, some differences in clinical effectiveness of the agents across the range of IMIDs in which TNF is implicated has been noted, etanercept, for example, lacking efficacy in IBD. Such observations suggest that neutralization of soluble TNF may not be the only mechanism of action of these agents and have led to questions regarding differences in the pharmacology and mechanisms of action of these biologic approaches to TNF inhibition.