Infliximab

Description

Infliximab is a chimeric (“humanized”) IgG1κ monoclonal antibody to human TNFα. By combining the Fv domain of the mouse antibody responsible for recognizing TNFα with parts of the human Fc domain of IgG1 (IgG1κ), the fused protein looks more like normal human IgG1 molecule (“humanized”), so there is a better chance the fused protein will not be destroyed by the patient's own immune system.

Uses

Infliximab targets the transcription factor NF-κB with harmine and related compounds for treatment of cancers and inflammatory diseases and combination with other agents

Indications

TNF-α is an inflammatory cytokine thought to have a contributory role in producing chronic inflammation in various diseases, including Crohn’s disease and rheumatoid arthritis. Infliximab (Remicade) is a mouse–human chimeric monoclonal neutralizing antibody to human TNF- and is considered a biological drug.

Indications

Infliximab (Remicade), a chimeric anti-TNF monoclonal antibody, and adalimumab (Humira), a fully humanized anti-TNF monoclonal antibody, are both promising therapies under investigation for psoriasis.

Infliximab is a chimeric monoclonal antibody targeted against TNF-α. It consists of a human IgG₁ Fc heavy chain and partial κ-light chain fused to a murine hypervariable region. Infliximab binds to both soluble and transmembrane forms of TNF-αand inhibits their ability to bind to TNF receptors. It does not inhibit TNF-β, which binds to the same receptors as TNF-α. Infliximab is administered intravenously, usually at 4 to 8-week intervals.

Biological Functions

Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses. Cells expressing transmembrane TNFα bound by infliximab can be lysed. The TNFα antibodies decrease synovitis and joint erosions in a murine model of collagen-induced arthritis and, when administered after disease onset, allows eroded joints to heal.

General Description

The MAb infliximab (Remicade, chimeric) is produced fromcells that have been sensitized with human TNFα. The MAbis a chimeric human–mouse immunoglobulin. The constantregions are of human peptide sequence and the variable regionsare murine. The MAb is of type IgG1 κ.
Infliximab is indicated for the treatment of moderately toseverely active Crohn disease to decrease signs and symptomsin patients who had an inadequate response to conventionaltreatments. Infliximab binds specifically to TNFα. Itneutralizes the biological activity of TNFα by binding withhigh affinity to soluble and transmembrane forms of theTNF. Infliximab destroys TNFα-producing cells. An additionalmechanism by which infliximab could work is asfollows: by inhibiting TNFα, pathways leading to IL-1 andIL-6 are inhibited. These interleukins are inflammatory cytokines.Inhibiting their production blocks some of theinflammation common to Crohn disease.

Biological Activity

Infliximab has an approximate molecular weight of 149,100 daltons and binds specifically, with high affinity, to both the transmembrane and soluble forms of TNFα in the blood, thus neutralizing its biological activity. It does not bind to TNFβ (lymphotoxin A), a related cytokine that uses the same receptors as TNFα.

Clinical Use

Infliximab (Remicade) is a mouse–human chimeric monoclonal neutralizing antibody to human TNF-αand is considered a biological drug. Specific indications are for the reduction of signs and symptoms in patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapies (single infusion) and for reduction of the number of draining enterocutaneous fistulas in patients with fistulizing Crohn’s disease (three-infusion regimen).

Side effects

Infliximab produces an acute infusion-related reaction consisting of fever and chills in approximately 20% of patients. Other common side effects include headache, nausea, and diarrhea. Persons given infliximab with methotrexate may have a greater elevation of hepatic enzyme levels than those given methotrexate alone. Because it is a human–mouse fusion protein, infliximab seems to be more immunogenic than etanercept. During infliximab treatment, autoantibodies (anti-dsDNA, ANA) and antibodies to the drug itself (human antichimeric antibodies) can develop. Concomitant therapy with methotrexate or immunosuppressive drugs decreases this risk somewhat. It is possible that infliximab may increase the incidence of autoimmune diseases and malignancies; however, longterm data are needed to determine whether this is the case.As with etanercept, a low risk of serious infection was seen in clinical trials of infliximab; however, sepsis, disseminated tuberculosis, and other potentially fatal infections have been reported in patients taking this drug.

Side effects

This antibody is being studied as maintenance therapy for Crohn’s disease and to determine the best induction regimen to achieve remission. The most common side effects, which are related to the intravenous infusion itself, include rash, low blood pressure, chills, and chest pain. These symptoms are generally temporary and often respond to a decrease in infusion rate. In addition, some patients develop antibodies, which have been associated in rare cases with symptoms similar to those of patients with systemic lupus erythematosus. These symptoms were also temporary. Another side effect is increased risk of infections. Fatal cases of tuberculosis have been reported following infliximab therapy. Another potential side effect is an increased risk of lymphoma. Its occurrence remains controversial.

Drug interactions

Potentially hazardous interactions with other drugs
Anakinra and abatacept: avoid concomitant use.
Live vaccines: avoid concomitant use.

Metabolism

Most likely removed by opsonisation via the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production.

Precautions

Infliximab should not be given to individuals withknown hypersensitivity to murine proteins. As withetanercept, precautions for the prevention of serious infectionsmust be taken, and live virus vaccines are contraindicated.