Immunoglobulin G4,anti-(human integrin R4) (human-mouse monoclonal AN100226 c4-chain),disulfide with human-mouse monoclonal AN100226 light chain,dimer

Description

The a4 family of integrins expressed on the surface of leukocytes are involved in cell adhesion processes. The α4 integrin can pair with either of two b subunits to generate a heterodimeric cell surface receptor known as α4β1 (VLA4) or α4β7. Ligands for VLA4 include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, while α4β7 interacts predominantly with mucosal addressin cell adhesion molecule-1 (MadCAM-1) existing on vascular endothelial cells of the gastrointestinal tract. By virtue of this α4–mediated interaction between leukocytes and vascular endothelial cells that leads to trans-endothelial infiltration of various leukocytes (lymphocytes, monocytes, T-cells, etc.) at the site of inflammation, interference with the adhesion of the α4 integrin has been deemed a viable approach for disrupting the inflammatory cascade. As an antibody that binds to the α4 integrin subunit, natalizumab has been developed and launched for the treatment of multiple sclerosis, a chronic inflammatory disorder of the central nervous system. It is also being developed for other chronic inflammatory diseases, such as, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome (IBS). Natalizumab is a recombinant humanized monoclonal antibody produced in murine myeloma cells. It contains human framework regions and the complementarity-determining regions of an antibody that is targeted to the α4 integrin. For the treatment of irritable bowel diseases (Crohn’s disease, ulcerative colitis, and IBS), the target is the α4β7 glycoprotein while efficacy in treating MS is attributed to binding to the α4 subunit of α4β1. For MS, the binding of natalizumab prevents docking of VCAM-1 to its receptor on leukocytes, thereby, effectively inhibiting leukocyte trafficking across the blood brain-barrier (BBB). A reduction in migration across the BBB translates into a reduction in lesions and relapses. In a two-year, placebo-controlled, double blind phase III study, a oncemonthly, 300 mg i.v. infusion of natalizumab reduced relapses by 66% compared to placebo. All of the secondary endpoints, such as, the number of new or newly enlarging T2-hyperintense lesions, the number of gadolinium-enhancing lesions, and the proportion of relapse-free patients, were all met. Regarding side effects, headache, fatigue, and arthralgia were reported in 5% of natalizumab patients, 2% more common than observed with placebo. Serious hypersensitivity-like reactions were experienced in 1% of the natalizumab group. In these cases, adverse effects usually developed within two hours of the onset of the infusion. The symptoms included urticaria, fever, rash, rigors, dizziness, pruritus, nausea, flushing, dyspnea, hypotension, and chest pain. Antibodies to natalizumab are believed to be responsible, and any patient experiencing hypersensitivity should discontinue further treatment. Since adequate studies have not been performed in the pregnant, pediatric, and elderly, natalizumab is currently contraindicated in these patient populations. In addition, this drug should not be taken concurrent with medications that suppress the immune system, such as, corticosteroids; the combination increases the risk for serious infections. With a dose of 300 mg to MS patients, the long half-life of 11±4 days results in a once-a-month trip to the physician for the one-hour infusion. Natalizumab is cleared at a rate of 16 mL/h with a C_max of 98 μg/ mL and a mean steady-state concentration of approximately 30 μg/mL.

Originator

Elan (UK)

brand name

Tysabri