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]
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Mouse |
| Target | CD20 |
| Clinical data | |
| Trade names | Bexxar |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a609013 |
| ATC code | |
| Identifiers | |
| CAS Number | |
| DrugBank | |
| ChemSpider |
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| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C6416H9874N1688O1987S44 |
| Molar mass | 143860.04 g·mol−1 |
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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
editA 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
editUnited States
editFollowing 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
editThe 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
edit- ^ a b c d e "BEXXAR drug label" (PDF). FDA. GlaxoSmithKline. August 2012. Retrieved 18 January 2016.
- ^ "Guide to Antibody structure and isotypes". Abcam. Retrieved 25 July 2020.
- ^ Mozee, Carla (29 April 2005). "Glaxo to acquire Corixa for $300 million". MarketWatch.
- ^ a b Srinivasan A, Mukherji SK (April 2011). "Tositumomab and iodine I 131 tositumomab (Bexaar)". AJNR. American Journal of Neuroradiology. 32 (4): 637–8. doi:10.3174/ajnr.A2593. PMC 7965875. PMID 21436340.
- ^ a b 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.
- ^ a b Timmerman, Luke (26 August 2013). "Why Good Drugs Sometimes Fail: The Bexxar Story". Xconomy.
- ^ "Corixa and Glaxo's Cancer Drug Wins F.D.A. Approval". The New York Times. 1 July 2003. ISSN 0362-4331.New York Times. July 1, 2003 Company News: Corixa and Glaxo's Cancer Drug Wins FDA Approval
- ^ a b "Tositumomab - Product Approval Information - Licensing Action". FDA/Center for Drug Evaluation and Research. 2 July 2003.
- ^ a b c "Tositumomab product description". Food and Drug Administration. Archived from the original on 27 January 2018. Retrieved 25 July 2020.
- ^ "Briefing Information Iodine I-131 Tositumomab". Food and Drug Administration. 17 December 2002. Archived from the original on 25 January 2018. Retrieved 25 July 2020.
- ^ "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". Federal Register. 23 October 2013. (78 FR 63226)
- ^ "EU/3/03/137". European Medicines Agency. 17 September 2018. Retrieved 25 July 2020.
- ^ "EU/3/03/136". European Medicines Agency. 17 September 2018. Retrieved 25 July 2020.