Adalimumab Comparisons with Infliximab and Etanercept

A number of structural and functional features of ada-limumab distinguish this agent from the other registered TNF antagonists, infliximab and etanercept (Fig. 3.3). A hallmark of monoclonal antibodies is their exquisite specificity for a target antigen. Adalimumab is highly specific for TNF (in both soluble and membrane-bound forms), whereas etanercept binds and neutralizes LTa as well as TNF. Adalimumab binds to TNF with very high affinity (Kd ~85 pM) (Kaymakcalan et al. 2002), and potently neutralizes TNF in bioassays (IC50 ~130 pM) (Salfeld 1998). The kinetic binding parameters of adalimumab and infliximab are similar, but etanercept dissociates from TNF much more rapidly than adalimumab or infliximab (Kaymakcalan 2002). These differences may relate to the fundamental structural differences between antibodies and receptors, since adalimumab and infliximab are high-affinity antibodies and etanercept is a TNF receptor fusion protein.

Immunogenicity is another parameter that is directly related to the structure of protein therapeutics and can result in diminished efficacy as well as increased side effects. Adalimumab is a fully human monoclonal IgG1 antibody, indistinguishable from naturally occurring IgG1. Antibodies to adalimumab have been observed in a small proportion of patients (Abbott Laboratories 2006). This low level of immunogenicity is reflective of the natural process of anti-idiotypic antibody formation to endogenous antibodies characteristic of the natural immune network (Jerne 1974). Infliximab is a chimeric antibody, a recombinant fusion of murine and human antibody components, and is immunogenic in a high proportion of patients unless given in combination with immunosuppressive drugs (Anderson 2005; Baert 2003; Maini et al. 1998). Etanercept is comprised of human protein components, but in an artificial construct. Low levels of immunogenicity have been reported with eta-nercept in patients, but considerable variability was seen, depending on the assays used to detect anti-etaner-cept antibodies (Anderson 2005).

The pharmacokinetics of the three TNF antagonists also differ significantly, and these differences may

MOUSt variable

Chimeric Mor ocio nal Anb-TNF Antibody

Human Monoclonal Anil-TNF Anil body

Chimeric Mor ocio nal Anb-TNF Antibody

Human Monoclonal Anil-TNF Anil body

Human lgG1 Fc

* 100% human peptide sequence and structure

Solüble TNF Receptor - Fe Fusion Protein

Human lgG1 Fc

Solüble TNF Receptor - Fe Fusion Protein

Fig. 3.3. Adalimumab structure in comparison to other TNF-antagonists. IgG1 immunoglobulin G1, TNF tumor necrosis factor. (Adapted with permission from Anderson 2005)

Infliximab

• Variable region of a mouse monoclonal art!-TNF antibody coupled to trie constant region of a human IgGI

Adalimumab

* 100% human peptide sequence and structure

* Full-length human igGi

- Phage display technology result! ng in human derived variable regions and human lgG1:* constant regions

* Half-life of 10-20 days

Etanercept

• 100% human peptide sequences, but artificial construction

• Fusion protein made up of 2 soluble TNF receptor molecules (TNFRII) fused with the Fc fragment from human lgG1

•Half-life of 3 0-5.5 days relate to pharmacodynamic differences underlying the differential efficacy seen across indications. Adalimumab has a significantly longer plasma half-life than etanercept (10-20 days vs 3-5.5 days, respectively), which enables less frequent dosing of adalimumab to maintain efficacious steady state drug levels. In contrast to adalimumab and etanercept, infliximab is given by intravenous injection, resulting in maximal plasma concentrations of infliximab 10- to 30-fold higher than for adalimumab or etanercept, and trough concentrations of infliximab that fall below those of adalimumab or etanercept (Granneman et al. 2003; Maini et al. 1998; Zhou et al. 2004). The impact on efficacy or safety of the large range of plasma concentrations of infliximab during treatment is not known.

The comparative efficacy of the three TNF antagonists was evaluated in an animal model of rheumatoid arthritis driven by a human TNF transgene (Kaymak-calan 2002). Adalimumab was more potent than infliximab or etanercept in preventing the development of arthritis and in the suppression of histopathological evidence of synovial inflammation, vascularity, cartilage erosion, or bone erosion. Furthermore, the clearance of human TNF from serum was significantly slower after etanercept treatment than after adalimumab or infliximab treatment, suggesting that TNF-etanercept complexes persist longer in circulation. In human clinical studies, the efficacy of adalimumab is comparable to that of infliximab or etanercept in RA, but infliximab and adalimumab appear to be significantly more efficacious than etanercept in Crohn's disease and psoriasis. The mechanistic basis for these differences is unclear at the present time, but it is possible that antibodies have better tissue penetration and/or effector function than etanercept in these disease states. All three agents bind to membrane TNF on transfected cells, but there are conflicting in vitro data on binding and initiation of Fc-mediated effector functions such as complement activation or antibody-induced cellular cytotoxicity (ADCC) by normal human cells (Scallon 1995, van den Brande 2003). Other effector mechanisms, such as the induction of apoptosis in T cells, monocytes, or other cells, may be mediated by TNF antagonists by "reverse signaling" following binding to membrane TNF. However, several in vitro studies, particularly with infliximab and etanercept, have yielded conflicting results regarding the induction of apoptosis in T cells and monocytes by TNF antagonists (Catrina et al. 2005; Mitoma et al. 2005; Shen et al. 2005; van den Brande et al. 2003), and the relevance of these in vitro studies to the efficacy or safety of these agents in vivo remains to be determined.

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