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{{Short description|Pharmaceutical drug}}
{{Drugbox
{{Drugbox
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| legal_US = <!-- OTC / Rx-only -->
| legal_US = <!-- OTC / Rx-only -->
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = none
| ChemSpiderID = none
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|changed|CAS}}
| CAS_number = 192391-48-3
| CAS_number = 208921-02-2
| ATC_prefix = V10
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| ATC_suffix = XA53
| ATC_suffix = XA53
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<!-- Chemical data -->
<!-- Chemical data -->
| C=6416 | H=9874 | N=1688 | O=1987 | S=44
| C=6416 | H=9874 | N=1688 | O=1987 | S=44
| molecular_weight = 143859.7 g/mol
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}}
'''Tositumomab''' is a murine IgG2a lambda monoclonal antibody directed against the [[CD20]] antigen, produced in mammalian cells.<ref name=Label> GlaxoSmithKline and FDA> [http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125011s0126lbl.pdf Bexxar label. Last updated August 2012. Page accessed January 18, 2016</ref> Combined with [[radioisotope]] [[iodine 131]]<ref name=Timmerman2013/> it was called '''Iodine I 131 Tositumomab'''. Unlabelled tositumomab together with iodine-labelled tositumomab was called '''Bexxar'' and a regimen using Bexxar was approved for the treatment of relapsed or [[chemotherapy]]/[[rituxan]]-[[refractory]] [[Non-Hodgkin lymphoma]] in 2003.<ref>New York Times. July 1, 2003 [http://www.nytimes.com/2003/07/01/business/company-news-corixa-and-glaxo-s-cancer-drug-wins-fda-approval.html Company News: Corixa and Glaxo's Cancer Drug Wins FDA Approval]</ref><ref>[http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2003/tosicor062703L.htm Product Approval Information - Licensing Action]</ref>
'''Tositumomab''' is a [[murine]] [[monoclonal antibody]] which targets the [[CD20]] antigen produced in mammalian cell.<ref name="GSK_FDA_Label">{{cite web |title=BEXXAR drug label |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125011s0126lbl.pdf |website=FDA |publisher=GlaxoSmithKline |access-date=18 January 2016 |date=August 2012}}</ref> 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]].<ref name="GSK_FDA_Label" /> It is classified as a [[IgG]]2a lambda antibody.<ref name="GSK_FDA_Label" /><ref>{{cite web |title=Guide to Antibody structure and isotypes |url=https://www.abcam.com/protocols/antibody-structure-and-isotypes |website=Abcam |access-date=25 July 2020}}</ref>


The drug combination was developed by [[Corixa (company)|Corixa]] which was purchased by [[GlaxoSmithKline]] in 2005.<ref>{{Cite news |last=Mozee |first=Carla |date=29 April 2005 |title=Glaxo to acquire Corixa for $300 million |language=en-US |work=MarketWatch |url=https://www.marketwatch.com/story/corixa-agrees-to-glaxo-acquisition-for-300-million}}</ref> It was sold for about $25,000 for one round of treatment.<ref name=Srinivasan2011rev>{{cite journal | vauthors = Srinivasan A, Mukherji SK | title = Tositumomab and iodine I 131 tositumomab (Bexaar) | journal = AJNR. American Journal of Neuroradiology | volume = 32 | issue = 4 | pages = 637–8 | date = April 2011 | pmid = 21436340 | doi = 10.3174/ajnr.A2593 | pmc = 7965875 | doi-access = free }}</ref> Bexxar competed with [[Zevalin]],<ref name="Davies07">{{cite journal |last1=Davies |first1=A J |title=Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I131 tositumomab |journal=Oncogene |date=28 May 2007 |volume=26 |issue=25 |pages=3614–3628 |doi=10.1038/sj.onc.1210378 |pmid=17530015|doi-access=free}}</ref> until the former's discontinuation in 2014.<ref name="Timmerman2013">{{Cite news |last=Timmerman |first=Luke |date=26 August 2013 |title=Why Good Drugs Sometimes Fail: The Bexxar Story |work=Xconomy |url=http://www.xconomy.com/national/2013/08/26/why-good-drugs-sometimes-fail-in-the-market-the-bexxar-story/}}</ref>
It was sold in the U.S. and Canada under the trade name '''Bexxar'''.


==Clinical use==
This drug combination was developed by [[Corixa (company)|Corixa]] which was purchased by [[GlaxoSmithKline]]) in 2005.<ref>Carla Mozee for MarketWatch. April 29, 2005 [http://www.marketwatch.com/story/corixa-agrees-to-glaxo-acquisition-for-300-million Glaxo to acquire Corixa for $300 million]</ref>


A personalized regimen using Bexxar was approved for the treatment of relapsed or [[chemotherapy]]/[[rituxan]]-[[refractory]] [[Non-Hodgkin lymphoma]] in 2003.<ref name=Srinivasan2011rev /><ref>{{Cite news |date=1 July 2003 |title=Corixa and Glaxo's Cancer Drug Wins F.D.A. Approval |language=en-US |work=The New York Times |url=https://www.nytimes.com/2003/07/01/business/company-news-corixa-and-glaxo-s-cancer-drug-wins-fda-approval.html |issn=0362-4331}}New York Times. July 1, 2003 [https://www.nytimes.com/2003/07/01/business/company-news-corixa-and-glaxo-s-cancer-drug-wins-fda-approval.html Company News: Corixa and Glaxo's Cancer Drug Wins FDA Approval]</ref><ref name="FDAapproval">{{Cite web |date=2 July 2003 |title=Tositumomab - Product Approval Information - Licensing Action |url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2003/tosicor062703L.htm |website=FDA/Center for Drug Evaluation and Research}}</ref>
Sale of Bexxar was discontinued and marketing approval was withdrawn in February 2014 due to the decline in usage (fewer than 75 patients in 2012) and the existence of other similar drugs.<ref name=Timmerman2013>{{cite web | url = http://www.xconomy.com/national/2013/08/26/why-good-drugs-sometimes-fail-in-the-market-the-bexxar-story/ | title = Why Good Drugs Sometimes Fail: The Bexxar Story}}</ref><ref>Notice by the Food and Drug Administration on October 23, 2013. [https://www.federalregister.gov/articles/2013/10/23/2013-24840/glaxosmithkline-llc-withdrawal-of-approval-of-the-indication-for-treatment-of-patients-with-relapsed 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]</ref>

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.<ref name="GSK_FDA_Label" /><ref name="2002Descrip">{{Cite web |title=Tositumomab product description |url=https://www.fda.gov/ohrms/dockets/ac/02/briefing/3916B1_02_D-FDA%20-%20Product%20Description.htm |archive-url=https://web.archive.org/web/20180127032045/https://www.fda.gov/ohrms/dockets/ac/02/briefing/3916B1_02_D-FDA%20-%20Product%20Description.htm |archive-date=27 January 2018 |access-date=25 July 2020 |website=[[Food and Drug Administration]]}}</ref>{{rp|14–15}} Bexxar combined separate administration of unlabelled and iodine-labelled (i.e. [[covalently bonded]] to <sup>131</sup>I) 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.<ref name="GSK_FDA_Label" /><ref name=2002Descrip/>{{rp|14–15}} Each time the labelled antibody was administered, it was always preceded by unlabelled (non-radioactive) antibody. Early [[clinical trial]]s 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.<ref name=2002Descrip/>{{rp|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.<ref>{{cite web |title=Briefing Information Iodine I-131 Tositumomab |url=https://www.fda.gov/ohrms/dockets/ac/02/briefing/3916b1.htm |website=[[Food and Drug Administration]] |access-date=25 July 2020 |archive-url=https://web.archive.org/web/20180125201355/https://www.fda.gov/ohrms/dockets/ac/02/briefing/3916b1.htm |archive-date=25 January 2018 |date=17 December 2002}}</ref><ref name="FDAapproval" /> 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 [[oncologist]]s 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.<ref name="Timmerman2013" /><ref name="Davies07"/><ref>{{Cite web |date=23 October 2013 |title=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 |url=https://www.federalregister.gov/documents/2013/10/23/2013-24840/glaxosmithkline-llc-withdrawal-of-approval-of-the-indication-for-treatment-of-patients-with-relapsed |website=Federal Register}} ({{Federal Register|78|63226}})</ref>

===Europe===
The [[European Medicines Agency]] granted tositumomab and <sup>131</sup>I-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.<ref>{{cite web |title=EU/3/03/137 |url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu303137 |website=European Medicines Agency |access-date=25 July 2020 |language=en |date=17 September 2018}}</ref><ref>{{cite web |title=EU/3/03/136 |url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu303136 |website=European Medicines Agency |access-date=25 July 2020 |language=en |date=17 September 2018}}</ref>


==References==
==References==
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[[Category:Monoclonal antibodies]]
[[Category:Monoclonal antibodies]]
[[Category:Drugs developed by GSK plc]]


{{antineoplastic-drug-stub}}
{{monoclonal-antibody-stub}}

Latest revision as of 21:41, 20 December 2023

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
 ☒NcheckY (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[edit]

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[edit]

United States[edit]

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[edit]

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[edit]

  1. ^ a b c d e "BEXXAR drug label" (PDF). FDA. GlaxoSmithKline. August 2012. Retrieved 18 January 2016.
  2. ^ "Guide to Antibody structure and isotypes". Abcam. Retrieved 25 July 2020.
  3. ^ Mozee, Carla (29 April 2005). "Glaxo to acquire Corixa for $300 million". MarketWatch.
  4. ^ 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.
  5. ^ 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.
  6. ^ a b Timmerman, Luke (26 August 2013). "Why Good Drugs Sometimes Fail: The Bexxar Story". Xconomy.
  7. ^ "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
  8. ^ a b "Tositumomab - Product Approval Information - Licensing Action". FDA/Center for Drug Evaluation and Research. 2 July 2003.
  9. ^ a b c "Tositumomab product description". Food and Drug Administration. Archived from the original on 27 January 2018. Retrieved 25 July 2020.
  10. ^ "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.
  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". Federal Register. 23 October 2013. (78 FR 63226)
  12. ^ "EU/3/03/137". European Medicines Agency. 17 September 2018. Retrieved 25 July 2020.
  13. ^ "EU/3/03/136". European Medicines Agency. 17 September 2018. Retrieved 25 July 2020.
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