Adalimumab

Adalimumab (Humira, Abbott Laboratories, Abbott Park, IL, USA) is the first fully human recombinant IgG1 monoclonal antibody that acts by inhibiting tumor necrosis factor-alpha (TNF-a or TNF) (Fig. 3.1) (Abbott Laboratories 2006). In contrast to infliximab, a chimeric antibody comprising both mouse and human domains that may elicit immune responses that potentially limit its long-term use in patients with chronic conditions such as rheumatoid arthritis, adalimumab is fully human, lowering the potential for immunoge-nicity (van de Putte et al. 2003).

Adalimumab is composed of human-derived heavy and light chain variable regions and human IgG1:k

Fig. 3.1. Three-dimensional structure of adalimumab

constant regions, engineered through phage display technology (Abbott Laboratories 2006). Phage display technology is designed to recapitulate the physiological antibody generation process in the laboratory. Comparable to the natural selection process for the B cell displaying the appropriate antibody, phage display allows for the selection of a fully human antibody specific for an antigen, in this case TNF, from a large repertoire of antibodies. If the desired antibody is felt to be rare in the repertoire, a variant of the technology allows for more rapid "guided selection" in a two-stage process. Therefore the first step in the generation of adalimu-mab was a guided selection approach using the murine anti-human TNF antibody MAK195 in order to isolate a human antibody that recognized the same neutralizing epitope as MAK195. MAK195 is a potent neutralizing monoclonal antibody, which has a high affinity and a low off-rate constant for human TNF. The MAK195 VH and VL were paired with human cognate repertoires and these phage antibody libraries underwent antigen binding selection using recombinant human TNF as the antigen. The selected human VH and VL genes were then combined to generate a fully human anti-TNF antibody.

Early human anti-TNF antibodies were optimized in a second phase mirroring the natural process for antibody optimization. The final antibody, adalimumab, is a full-length immunoglobulin (IgG1) molecule with optimized heavy and light chain characterized by high specificity, affinity, and potency (van de Putte et al. 2003). It is produced in a Chinese hamster ovary host cell that is transfected with a plasmid vector containing the expression cassettes for adalimumab heavy and light chains. Adalimumab is produced by a standard, well controlled fermentation and purification process. Each batch of adalimumab is characterized rigorously in a series of biochemical and biophysical characteriza tion assays in order to meet pre-specified release criteria.

Adalimumab is indistinguishable in structure and function from naturally occurring human IgG1 and has a comparable terminal half-life (approximately 2 weeks). Adalimumab was designed as a fully human anti-TNF monoclonal antibody to have the following characteristics:

High selectivity and affinity for TNF Suitability for long-term chronic administration with a low degree of immunogenicity, with or without concomitant use of methotrexate (MTX)

• A low incidence of allergic reactions

• A half-life comparable to that of human IgG1 resulting in infrequent dosing for patient convenience

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