Drug Development

BioDrugs

, Volume 22, Issue 5, pp 331-337

A PEGylated Fab’ Fragment against Tumor Necrosis Factor for the Treatment of Crohn Disease

Exploring a New Mechanism of Action
  • Tim BourneAffiliated withInflammation Discovery, UCB Celltech
  • , Gianluca FossatiAffiliated withInflammation Discovery, UCB Celltech
  • , Andrew NesbittAffiliated withInflammation Discovery, UCB Celltech Email author 

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Abstract

Antibodies, having a high specificity for their particular target, are increasingly being used as therapeutic agents with functions including agonist, antagonist, and targeted drug delivery. The use of many biologic therapies, including antibody fragments, is generally limited by their rapid clearance from plasma. A commonly used approach to extend exposure to biologic therapies is the attachment of polyethylene glycol.

Tumor necrosis factor (TNF)-α is a multifunctional cytokine involved in the regulation of immune responses. Elevated levels of TNFα are found in a wide range of diseases, including the chronic inflammatory conditions rheumatoid arthritis, psoriasis, and Crohn disease (CD). Anti-TNFα antibodies have proved highly efficacious in the treatment of these conditions. In addition, they have proved invaluable for investigating the role of TNFα in disease etiology.

Based on evidence showing that neutralizing antibodies to TNFα were effective in animal models of CD, anti-TNFα antibody treatments were assessed in clinical trials. Interestingly, the anti-TNFα antibody etanercept proved ineffective at achieving remission in active CD despite potently neutralizing soluble TNFα. This indicated that an additional mode of action is also involved in the efficacy of the anti-TNFα agents adalimumab, certolizumab pegol, and infliximab in CD; one suggestion was apoptosis. However, etanercept, like adalimumab and infliximab, can induce apoptosis. Furthermore, certolizumab pegol (which has demonstrated efficacy in CD) does not cause complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, apoptosis, or necrosis of neutrophils, all measured in vitro. These functional differences observed with certolizumab pegol stem from its unique structure that does not include the crystallizable fragment (Fc) portion present in the other anti-TNFα agents, and the way in which it signals through membrane TNF.

It is well established that bacteria are a major part of the inflammatory process in CD. The property identified that reflected the efficacies of the anti-TNFα agents etanercept, adalimumab, certolizumab pegol, and infliximab in CD was the ability to inhibit the cytokine production by monocytes that is induced by bacterial lipopolysaccharide. It may therefore be the case that this mode of action is important for efficacy in CD.