Infliximab Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
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.
History
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Beh?et's disease.
It was developed by Junming Le (b. 1940) and Jan Vil?ek (b. 1933) at New York University School of Medicine and in collaboration with Centocor (now Janssen Biotech, Inc.).
Infliximab was approved for medical use in the United States in 1998, and in the European Union in August 1999. Infliximab biosimilars have been approved in the EU (2013), in Japan (2014), and in the United States (2016, 2017, 2019).
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 IgG
1 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.
Biologische Funktion
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.
Allgemeine Beschreibung
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.
Biologische Aktivit?t
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).
Nebenwirkungen
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.
Vorsichtsma?nahmen
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.
Infliximab Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
