Adalimumab

Adalimumab is the first fully human neutralizing IgG1 monoclonal antibody specific for TNF-alpha and is the third TNF sequestrant marketed. It was launched in US, UK and Germany for the treatment of rheumatoid arthritis. It prevents TNF binding to p55 and p75 cell surface TNF receptors thereby decreasing leukocyte migration and acute phase reactants such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and levels of serum IL-6, MMP-1 and MMP-3. Adalimumab was developed starting with a phage-display derived murine antibody, followed by replacement of both heavy and light chains with human forms and further optimization to yield the final humanized form. In receptor binding studies, adalimumab exhibits an IC50between 7.8×10-11and 15.6×10-11M with a Kdof 1×10-10M. It also binds to pro-TNFalpha on cell membranes mediating complement-dependent toxicity and to the Fc receptor mediating antibody-dependent cytotoxicity. In a human-TNF transgenic polyarthritis mouse model, adalimumab was efficacious based upon both clinical and histological readouts. Patients responding inadequately to methotrexate were co-administered methotrexate and adalimumab, which resulted in improved ACR scores in a 52-week study (ACR20: 59%; ACR50: 42%; ACR70; 23%). Radiographic analysis at six months showed decreased progression of structural joint damage (96%＞placebo) and that joint-space narrowing stabilizes after six months. Adalimumab has an ED50of 0.3 to 0.5 mg/kg and is dosed subcutaneously once every two weeks (0.8 mL containing 40 mg). The Vdss ranged from 0.063 to 0.76 L/kg consistent with being highly localized within the vasculature. It is slowly cleared with clearance values ranging from 0.18 to 0.27 mL/min and with a terminal half-life of about 12 days. As is the case with other TNF-alpha sequestrants, injection-site irritation is the most common side effect. The risk of developing opportunistic infection, especially tuberculosis, has been noted with TNF sequestrant biologics, which has led to screening of patients to identify those at risk.
Adalimumab was discovered by the collaboration between BASF Bioresearch Corporation and Cambridge Antibody Technology, U.K., itself a collaboration of the government-funded Medical Research Council and three academics, which began in 1993. Initially named D2E7, it was then further manufactured at BASF Bioresearch Corporation, developed by BASF Knoll (BASF Pharma), and ultimately manufactured and marketed by Abbott Laboratories after Abbott's acquisition of BASF Pharma. It is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. It is constructed from a fully human monoclonal antibody. Adalimumab was approved by the U.S. Food and Drug Administration in 2002 for the treatment of moderate to severe rheumatoid arthritis and was granted approval from the European Medicines Evaluation Agency (EMEA) in September 2003.
ChEBI: Sivelestat is a N-acylglycine and a pivalate ester. It is functionally related to a N-benzoylglycine.