Chemistry:Tositumomab

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Short description: Pharmaceutical drug
Tositumomab
Monoclonal antibody
TypeWhole antibody
SourceMouse
TargetCD20
Clinical data
Trade namesBexxar
AHFS/Drugs.comMonograph
MedlinePlusa609013
ATC code
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6416H9874N1688O1987S44
Molar mass143860.04 g·mol−1
 ☒N☑Y (what is this?)  (verify)

Tositumomab is a murine monoclonal antibody which targets the CD20 antigen produced in mammalian cell.[1] It was combined with iodine-131 to produce a radiopharmaceutical for unsealed source radiotherapy, Iodine-131 Tositumomab (branded as Bexxar), for the treatment of non-Hodgkins lymphoma.[1] It is classified as a IgG2a lambda antibody.[1][2]

The drug combination was developed by Corixa which was purchased by GlaxoSmithKline in 2005.[3] It was sold for about $25,000 for one round of treatment.[4] Bexxar competed with Zevalin,[5] until the former's discontinuation in 2014.[6]

Clinical use

A personalized regimen using Bexxar was approved for the treatment of relapsed or chemotherapy/rituxan-refractory Non-Hodgkin lymphoma in 2003.[4][7][8]

The radioactive dose was adjusted for each patient in order to maximize the radiation delivered to the tumor and minimize the exposure of other organs.[1][9]:14–15 Bexxar combined separate administration of unlabelled and iodine-labelled (i.e. covalently bonded to 131I) tositumomab. A first dose of labelled antibody was given once, and whole-body radiation was measured with a gamma camera over seven days. Analysis of that imaging data allowed an optimal dose of labelled antibody to be calculated, which was then administered once a day, for up to seven days.[1][9]:14–15 Each time the labelled antibody was administered, it was always preceded by unlabelled (non-radioactive) antibody. Early clinical trials had shown that total body residence times of radioactivity were longer in people who first received unlabelled antibody, so that a lower dose of labelled antibody was needed to deliver the required total dose of radiation; additionally labelled antibody targeted tumors better in people pre-treated with unlabelled antibody.[9]:21

Availability

United States

Following a first investigational new drug application in 1989 and biologics license application in 2000, Bexxar was approved by the FDA in 2003.[10][8] Sale of Bexxar was discontinued and marketing approval was withdrawn in February 2014 due to a decline in usage (fewer than 75 patients in 2012). One possible explanation for the lack of demand, despite a claimed 70% response rate, was that oncologists could not sell it directly to patients but had to refer patients to third party specialist centers, however a "muddled clinical trials strategy", supply chain issues, reimbursement problems, and emergence of non-radioactive competitors has also been blamed.[6][5][11]

Europe

The European Medicines Agency granted tositumomab and 131I-tositumomab orphan drug status, for the treatment of follicular lymphoma, to Amersham plc in 2003. This was withdrawn in October 2015 at the request of the new owner, GlaxoSmithKline.[12][13]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "BEXXAR drug label". GlaxoSmithKline. August 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125011s0126lbl.pdf. 
  2. ↑ "Guide to Antibody structure and isotypes". https://www.abcam.com/protocols/antibody-structure-and-isotypes. 
  3. ↑ Mozee, Carla (29 April 2005). "Glaxo to acquire Corixa for $300 million" (in en-US). MarketWatch. https://www.marketwatch.com/story/corixa-agrees-to-glaxo-acquisition-for-300-million. 
  4. ↑ 4.0 4.1 "Tositumomab and iodine I 131 tositumomab (Bexaar)". AJNR. American Journal of Neuroradiology 32 (4): 637–8. April 2011. doi:10.3174/ajnr.A2593. PMID 21436340. 
  5. ↑ 5.0 5.1 Davies, A J (28 May 2007). "Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I131 tositumomab". Oncogene 26 (25): 3614–3628. doi:10.1038/sj.onc.1210378. PMID 17530015. 
  6. ↑ 6.0 6.1 Timmerman, Luke (26 August 2013). "Why Good Drugs Sometimes Fail: The Bexxar Story". Xconomy. http://www.xconomy.com/national/2013/08/26/why-good-drugs-sometimes-fail-in-the-market-the-bexxar-story/. 
  7. ↑ "Corixa and Glaxo's Cancer Drug Wins F.D.A. Approval" (in en-US). The New York Times. 1 July 2003. ISSN 0362-4331. https://www.nytimes.com/2003/07/01/business/company-news-corixa-and-glaxo-s-cancer-drug-wins-fda-approval.html. New York Times. July 1, 2003 Company News: Corixa and Glaxo's Cancer Drug Wins FDA Approval
  8. ↑ 8.0 8.1 "Tositumomab - Product Approval Information - Licensing Action". 2 July 2003. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2003/tosicor062703L.htm. 
  9. ↑ 9.0 9.1 9.2 "Tositumomab product description". https://www.fda.gov/ohrms/dockets/ac/02/briefing/3916B1_02_D-FDA%20-%20Product%20Description.htm. 
  10. ↑ "Briefing Information Iodine I-131 Tositumomab". 17 December 2002. https://www.fda.gov/ohrms/dockets/ac/02/briefing/3916b1.htm. 
  11. ↑ "GlaxoSmithKline LLC; Withdrawal of Approval of the Indication for Treatment of Patients With Relapsed or Refractory, Low Grade, Follicular, or Transformed CD20 Positive Non-Hodgkin's Lymphoma Who Have Not Received Prior Rituximab; BEXXAR". 23 October 2013. https://www.federalregister.gov/documents/2013/10/23/2013-24840/glaxosmithkline-llc-withdrawal-of-approval-of-the-indication-for-treatment-of-patients-with-relapsed.  (78 FR 63226)
  12. ↑ "EU/3/03/137" (in en). 17 September 2018. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu303137. 
  13. ↑ "EU/3/03/136" (in en). 17 September 2018. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu303136. 



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