Beta interferon

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Beta interferon

Existing structure data : 1AU1

Properties of human protein
Mass / length primary structure 20.1 kDa / 166 AS
Identifier
Gene name IFNB1
External IDs
Drug information
ATC code L03 AB07 , L03 AB08
DrugBank DB00060
Drug class Interferons

Beta-interferon (also: interferon beta or IFN-β ) is a glycoprotein from the interferon family . Interferons are messenger substances that occur naturally in the body. They belong to the cytokine family and have antiviral , antiproliferative , antitumor and immunomodulating effects .

Interferons are divided into three main groups: alpha interferon, beta interferon, and gamma interferon. Interferon beta is physiological, e.g. B. in the human body from different cell types, e.g. B. fibroblasts and macrophages , are produced and secreted .

Recombinant , i.e. biotechnologically produced, human beta interferons are used as first-line drugs for the basic therapy of relapsing multiple sclerosis (MS) .

Chemical classification

Human beta interferon

Human, physiologically formed beta interferon consists of 166 amino acids and has a complex side chain of carbohydrates that is connected to the amino acid structure at position 80 ( asparagine ) via a nitrogen atom .

The amino acid sequence of natural human interferon beta is: 
MSYNLLGFLQ RSSNFQCQKL LWQLNGRLEY CLKDRMNFDI PEEIKQLQQF
QKEDAALTIY EMLQNIFAIF RQDSSSTGWN ETIVENLLAN VYHQINHLKT
VLEEKLEKED FTRGKLMSSL HLKRYYGRIL HYLKAKEYSH CAWTIVRVEI
LRNFYFINRL TGYLRN

The cysteine ​​residues in positions 31 and 141 (shown underlined) are connected to one another via a disulfide bridge. In position 17 the amino acid chain contains another cysteine (shown in red). The molar mass of the protein portion is approximately 20 kDa mathematically, the glycosylated molecule has a molecular weight of 22.5 kDa. Interferon-beta is a type I interferon that binds to the same receptors (IFNAR) on the cell surface as interferon-alpha. Its effect is similar to that of interferon-alpha. It is mainly produced by virus-infected fibroblasts and macrophages, but probably also by other cell types.

Recombinant Variants

A distinction is made between interferon beta-1a and interferon beta-1b. According to the recommendations of the Interferon Nomenclature Committee , variants that are produced by subunits of the human IFN-beta gene have a hyphen and a number in their name after beta, e.g. B. Interferon beta-1. The number is also specified by a letter that describes the peptide sequence at certain positions in the chain.

Interferon beta-1a is produced using mammalian cells (Chinese hamster ovary cells: CHO cells ), while genetically modified bacteria ( Escherichia coli ) are used to produce interferon beta-1b . The protein content of interferon beta-1a is identical to that of the human, physiologically produced beta interferon, the glycosylation pattern is very similar. In contrast, interferon beta-1b is not glycosylated and also differs structurally from natural human beta interferon in terms of protein content. In position 17 the amino acid chain contains the structurally almost identical but sulfur-free amino acid serine instead of cysteine , so that no false disulfide bridges can be formed. The N-terminal amino acid methionine is hydrolyzed.

Recombinant variant  Made of Amino acid sequence Glycosylation Relative molar mass CAS no. Drug bank
Interferon beta-1a CHO -K1 Position 1 = Met, Position 17 = Cys Yes About 22.5 k D 0145258-61-3 DB00060
Interferon beta-1b E. coli Position 1 is omitted, position 17 = Ser No 19.9 kD 0090598-63-3 DB00068

Interferon beta protein mixtures are referred to as interferon beta-n1, interferon beta-n2, etc.

Mechanism of action

The effect of beta interferons is primarily explained by their immunomodulatory properties: the binding to the receptor triggers a reaction cascade intracellularly, which leads to the expression of numerous interferon-dependent induced proteins. These proteins are considered to be mediators of the action of beta interferon, e.g. B. the enhancement of the suppressor activity of peripheral lymphocytes . According to current knowledge, MS is a T-lymphocyte-mediated autoimmune disease : activated T-lymphocytes, which are directed against various antigens of the nerve sheath protein myelin , cross the blood-brain barrier and penetrate the central nervous system. This activates an inflammatory cascade that ultimately leads to the appearance of the typical disease characteristics of MS.

Therapeutic use

Recombinant interferon beta is used as the drug of first choice for the basic therapy of relapsing multiple sclerosis (MS) . It slows the progression of the disease, reduces the frequency of the attacks and reduces their severity. Study results suggest using them as early as possible in the course of the disease. Treatment experience has shown that the more advanced the disease, the more difficult it is to influence the course of MS.

Rebif , Avonex and Betaferon are also approved for patients with a so-called clinically isolated syndrome typical of MS (CIS). These are patients who have had a one-time demyelinating event with an inflammatory process, when this demyelinating event warrants intravenous corticosteroid therapy, alternative diagnoses have been ruled out, and there is a high risk of developing clinically certain multiple sclerosis.

With beta interferons, drugs came onto the market for the first time, for which it has been proven beyond doubt that they have a beneficial effect on the long-term clinical course of relapsing MS, reduce the frequency and severity of relapses and slow the progression of the disease.

Research suggests that the benefit of treating interferon beta therapy in MS depends on dose and frequency of administration. This relationship has been shown in the relapse rate and severity of the relapses, the slowed progression of the disease, and especially the number of lesions in the brain and spinal cord.

Since autumn 2019, beta interferons (e.g. Betaferon, Rebif ) have also been approved for those who are pregnant or wanting to have children . If clinically necessary, therapy need not be interrupted or postponed because of pregnancy. Since no harmful effects are to be expected for the child, breastfeeding is possible without restriction under interferon beta.

Beta interferon is also designated as an orphan drug for the treatment of acute lung failure .

Chemically modified derivatives are PEGylated beta interferons ( peginterferon β ). PEGylation means binding of the active ingredient with polyethylene glycol (PEG), which enables a significantly slower release of the active ingredient ( retardation ). This form of modification is also used for alpha interferon ( peginterferon α ).

Since March 2020, beta-inferon, in combination with lopinavir and ritonavir , has been tested against SARS-CoV-2 as part of the World Health Organization's “Solidarity” study .

unwanted effects

As with all interferons, the most common side effects of interferon beta are flu-like symptoms such as muscle pain, fever, chills, asthenia, and headache. These are very common at the beginning of treatment, but decrease in most patients over the course of therapy. Other very common or common side effects are (depending on the preparation): liver problems (the increase in liver values ​​in the blood will be checked with regular blood tests during treatment), decrease in white or red blood cells, depression, sleep disorders, diarrhea, nausea, vomiting, pruritus , Numbness and tingling of the skin, increased body temperature, pain in the muscles and joints, muscle stiffness, confusion, ear pain, palpitations , tachycardia , blood changes that can lead to tiredness or decreased resistance to infection, runny nose, increased blood pressure and changes at the injection site. Occasionally, kidney problems, epileptic seizures, breathing problems, retinal disorders, mood swings, thyroid dysfunction, seizures, hair loss, changes in menstrual bleeding and severe allergic reactions can occur.

The rare side effects include cases of thrombotic-thrombocytopenic purpura and nephrotic syndrome . These rare life-threatening diseases can occur weeks to years after starting beta-interferon treatment. If these two diseases occur, the therapy must be stopped immediately. Despite these reported cases, there is no change in the positive benefit-risk assessment of beta-interferon preparations, the safety profile of which is well known from more than 20 years of widespread use in multiple sclerosis.

Commercial preparations

  • Interferon beta-1a: Avonex (EU, CH, USA, CND), Rebif (EU, CH, USA, CND), Plegridy
  • Interferon beta-1b: Betaferon (EU, CH), Betaseron (USA, CND), Extavia (EU, CND), Uribeta (MX)

Beta interferons are administered parenterally . They are available in the form of ready-made solutions for subcutaneous (e.g. Rebif ; standard dosage : 44 µg, three times a week using the RebiSmart injection aid ) or intramuscular injection (e.g. Avonex ; 30 µg, once a week) or as lyophilisates, which are made ready for use by dissolving shortly before use and administered intramuscularly (e.g. Avonex ; 30 µg, once a week) or subcutaneously (e.g. Betaferon, Extavia ; 250 µg, every other day). Plegridy contains a pegylated form of interferon beta-1a and only needs to be injected every two weeks.

Even if the beta interferons are the same, there are differences between the individual preparations. B. in relation to the speed of the onset of action, which is visible in the MRI: with 3 × weekly administration of Rebif , a reduction in the contrast agent-enhancing lesions compared to placebo was already evident after four weeks. A significantly greater reduction in relapse rates ((Panitch H, Goodin D, Francis G et al. J Neurol Sci. 2005 Dec 15; 239 (1): 67-74)) and fewer flu-like side effects can also be observed.

literature

Web links

  • Treat MS beta interferon on the website of the German Multiple Sclerosis Society (DMSG)
  • What to do? Therapy options for MS on "Living with MS" from Merck Serono GmbH

Individual evidence

  1. ↑ a b B. Wick, M. Schulz, WC Janzen: beta-interferons: new hope for MS patients . In: Pharmaceutical newspaper . No. 28/2000, 2000.
  2. ↑ Rieckmann et al .: Recombinant beta interferons: Immunomodulatory therapy of relapsing multiple sclerosis. Deutsches Ärzteblatt 93, issue 46 of November 15, 1996, page A-3022 full text
  3. ↑ Filippini et al .: Interferons in relapsing remitting multiple sclerosis: a systematic review. In: Lancet. Volume 361, Number 9357, February 2003, pp. 545-552, doi: 10.1016 / S0140-6736 (03) 12512-3 . PMID 12598138 . (Meta-analysis).
  4. ↑ a b c d Avonex ® Fachinformation , Rote Liste, Fachinfo-Service, accessed in February 2014
  5. ↑ a b Betaferon ® Fachinformation , Rote Liste, Fachinfo-Service, accessed in February 2014
  6. ↑ a b Extavia ® Fachinformation , Rote Liste, Fachinfo-Service, accessed in February 2014
  7. ↑ a b Rebif ® Fachinformation , Rote Liste, Fachinfo-Service, accessed in February 2014
  8. ↑ K. Hardtke et al. (Ed.): Commentary on the European Pharmacopoeia Ph. Eur. 7.6, Concentrated Interferon-beta-1a solution. Loose-leaf collection, 45th delivery 2013, Wissenschaftliche Verlagsgesellschaft Stuttgart
  9. ↑ European Pharmacopoeia, Edition 7, 6th supplement, p. 7262
  10. ↑ J. Vilcek in Archives of Virology, Volume 77, 1983, pp. 283-285.
  11. ↑ Leray et al .: Evidence for a two-stage disability progression in multiple sclerosis. In: Brain. Volume 133, Number 7, April 2010, pp. 1900-1913, doi: 10.1093 / brain / awq076 .
  12. ↑ S. Schwid, H. Panitch: Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: A multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high -frequency interferon β-1a for relapsing multiple sclerosis . In: Clinical Therapeutics . tape 29 , no. 9 , 2007, p. 2031-2048 , doi : 10.1016 / j.clinthera.2007.09.025 .
  13. ↑ L. Kappos, A. Traboulsee, C. Constantinescu, J.-P. Erälinna, F. Forrestal, P. Jongen, J. Pollard, M. Sandberg-Wollheim, C. Sindic, B. Stubinski, B. Uitdehaag, D. Li: Long-term subcutaneous interferon beta-1a therapy in patients with relapsing- remitting MS . In: Neurology . tape 67 , no. 6 , 2006, p. 944-953 , doi : 10.1212 / 01.wnl.0000237994.95410.ce .
  14. ↑ Betaferon approval change for use during pregnancy and breastfeeding. Retrieved January 20, 2020 .
  15. ↑ CHMP recommends amendment of the approval of Rebif® for the clinically necessary use during pregnancy and breastfeeding , PM Merck of September 23, 2019, accessed on October 28, 2019
  16. ↑ Summary of Product Characteristics EMA approval text using Rebif as an example, accessed on October 28, 2019
  17. ^ Community register of orphan medicinal products , EU / 3/07/505.
  18. ↑ Julia Koch: Insane speed . In: Der Spiegel . No. 14 , 2020, p. 106 ( online - March 28, 2020 ).
  19. ↑ Biogen: leaflet peginterferon beta-1a. Biogen, archived from the original on September 2, 2018 ; accessed on September 2, 2018 .
  20. ↑ Biogen: Instructions for use Avonex. Biogen, accessed September 2, 2018 .
  21. ↑ Merck: Rebif Package Leaflet: Information for the user. Merck, accessed September 2, 2018 .
  22. ↑ Bayer: Betaferon Package Leaflet: Information for the user. Bayer, accessed September 2, 2018 .
  23. ↑ Bayer Vital: Betaferon Instructions for Use for Users. Bayer Vital, accessed September 2, 2018 .
  24. ^ Medical advisory board of the German MS Society: Zipp F., Hartung HP, Flachenecker P, Opinion Medicine / Therapy No. 1 , August 2014.
  25. ↑ De Stefano N et al .: Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis ; In: Mult Scler. 2010; Volume 7, pages 888-892; doi: 10.1177 / 1352458510362442
  26. ↑ Sandberg-Wollheim M et al .: Comparative tolerance of IFN beta-1a regimens in patients with relapsing multiple sclerosis. The EVIDENCE study . In: J Neurol. 2005; Volume 252 (1), pages 8-13; doi: 10.1007 / s00415-005-0589-2