Two recombinant antibodies, Infliximab and Etanercept, that bind to and neutralize TNF-a have been approved by the FDA for the treatment of rheumatoid arthritis (RA) and disease.
2.3.1 Infliximab. Remicade (Infliximab) is a chimeric monoclonal antibody containing human constant and murine variable regions that inhibits TNF-a from binding to its receptor (53). It binds to TNF-a very strongly, with an association constant of 0.1 nAf. TNF-a is secreted as a trimer by macrophages, T-cells, and NK cells. Biological activities of TNF-a include induction of pro-inflammatory cytokines such as IL-1 and IL-6 and increased leukocyte migration through up-regulation of endothelium permeability and adhesion molecules by both endothelial cells and leukocytes. TNF-a also activates eosinophils and neutro-phils and induces acute phase proteins as well as enzymes such as matrix metalloproteinases involved in degradation of synoviocytes and chondrocytes in joint tissue. It is thought to play a major role in mediating tissue damage in RA and other autoimmune diseases. Infliximab has been shown to prevent RA in transgenic mice that develop polyarthritis caused by constitutive expression of TNF-a (54). When administered to mice after joint destruction had been established, damaged joints began to heal.
Infliximab in combination with methotrexate (MTX) is indicated for reducing the symptoms and inhibiting the progression of structural joint damage in patients with moderate-to-severe active rheumatoid arthritis who have had an inadequate response to methotrexate alone. It is also indicated for patients with Crohn's disease who have had inadequate responses to conventional therapy. Clinical studies with Infliximab in combination with MTX in 428 RA patients demonstrated serum half-lives of 8-9.5 days. In clinical trials, approximately 50% of patients receiving either 3 or 10 mg/kg of Infliximab every 4 weeks responded to treatment at a rate of approximately 50%, compared with placebo as measured by the American College of Rheumatology (ACR) response criteria (55). Treatment with Infliximab decreased inflammatory cell infiltration into inflamed areas in the joint, expression of adhesion molecules, E-se-lectin, intercellular adhesion molecule-1 and vascular cell adhesion mole-cule-1 (VCAM-1), chemoattractants such as IL-8 and monocyte chemotactic protein (MCP-1) and also inhibited expression of matrix metalloproteinases 1 and 3, which are involved injoint destruction (56). The treatment of Crohn's disease with Infliximab alone resulted in better than a 70% response rate compared with placebo within 4 weeks of receiving a single intravenous infusion according to the Crohn's Disease Activity Index (57).
Infliximab is provided as a sterile, lyophi-lized powder for reconstitution with 10 mL USP sterile water for injection such that the reconstituted material is 10 mg/mL followed by additional dilution into 250 mL of 0.9% sodium chloride. Recommended dose of Infliximab is 3 mg/kg given as an intravenous infusion between 0.4 and 4 mg/mL over a period of 2 h or more.
2.3.2 Etanercept. Enbrel (Etanercept),sim-ilar to Infliximab, binds to and neutralizes the biological activity of TNF-a. Etanercept is novel in that it was constructed by fusing cDNA from the extracellular ligand-binding portion of the TNF receptor to cDNAfrom the Fc portion of IgGland has the same approximate molecular weight (150 kDa) as an IgG molecule (58). Because Etanercept contains the TNF receptor, it binds and neutralizes both TNF-a! and TNF-J3 (lymphotoxin>(59), in contrast to Infliximab, which binds only TNF-a. However, Etanercept suppresses the same biologic and pathogenic mechanisms leading to RA as does Infliximab.
Like Infliximab, Etanercept is approved for use in adult patients with moderate-to-severe active RA. However, Etanercept was also approved to reduce the symptoms of moderate-to-severe polyarticular-course juvenile RA (JRA) in patients who have had inadequate responses to disease-modifying anti-rheumatic drugs (60) and for use in patients with psoriatic arthritis in combination with MTX who do not respond to MTX alone (61). Clinical evaluation of subcutaneous administration of Etanercept twice per week for 6 months demonstrated an overall 23% major clinical response, defined as maintenance of an ACR70 (70%)response over a 6-month period. Discontinuation of Etanercept generally resulted in return of symptoms within 1 month. If patients were retreated with Etanercept, they achieved the same response as the initial treatment.
Etanercept is supplied as 25 mg of lyophi-lized powder for reconstitution with 1 mL of USP bacteriostatic water for injection, resulting in a 25 mg/mL solution that may be self-injected by a patient or physician into the thigh, abdomen, or upper arm.
Risks associated with Infliximab and Etanercept treatment include increased risk of infections such as reactivation of latent tuberculosis, invasive fungal infections, and sepsis. Autoantibodies against DNA and other nuclear components were observed in 10% of patients treated with Infliximab or Etanercept, mimicking a lupus-like syndrome. Patients receiving placebo did not generate lupus-like antibodies. Infusion-related reactions to Inflix-imab included fever, chills, cardiopulmonary
reactions, urticaria, and pruritus. Because Et-anercept is injected subcutaneously, injection site reactions were limited to erythema, itching, pain, or swelling at the site of injection. Thirteen percent or fewer patients receiving Infliximab developed anti-Infliximab specific antibodies,while ll%of patientsreceivingEt-anercept generated anti-TNF receptor-specific antibodies. These antibodies were all non-neutralizing and did not inhibit TNF-a from binding to its cell surface receptor. Administration of Infliximab and Etanercept is associated with increased infections (62), therefore immune responses to vaccines may be affected. Although not studied in-depth, patients may be immunized if necessary, with the exception of live or attenuated vaccines.
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