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{{Short description|Pharmaceutical drug}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
| verifiedrevid = 470611959
| verifiedrevid = 470611959
⚫
<!-- Monoclonal antibody data -->

⚫
<!--Monoclonal antibody data-->
| type = mab
| type = mab
| mab_type = mab
| mab_type = mab
| source = o
| source = o
| target = [[CD20]]
| target = [[CD20]]
⚫
<!-- Clinical data -->

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<!--Clinical data-->
| tradename = Bexxar
| tradename = Bexxar
| Drugs.com = {{drugs.com|monograph|tositumomab}}
| Drugs.com = {{drugs.com|monograph|tositumomab}}
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| legal_UK = <!-- GSL / P / POM / CD -->
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = <!-- OTC / Rx-only -->
| legal_US = <!-- OTC / Rx-only -->
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<!-- Identifiers -->

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<!--Identifiers-->
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| ChemSpiderID = none
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| CAS_number_Ref = {{cascite|changed|CAS}}
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| ChemSpiderID = NA
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| CAS_number = 208921-02-2
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| CAS_number_Ref = {{cascite|correct|??}}
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| CAS_number = 192391-48-3
| ATC_prefix = V10
| ATC_prefix = V10
| ATC_suffix = XA53
| ATC_suffix = XA53
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| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201604
| ChEMBL = 1201604
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<!-- Chemical data -->

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| C=6416 | H=9874 | N=1688 | O=1987 | S=44
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<!--Chemical data-->
⚫
| C=6416 | H=9874 | N=1688 | O=1987 | S=44
| molecular_weight = 143859.7 g/mol
}}
}}
'''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>
'''Tositumomab''' is a drug for the treatment of [[follicular lymphoma]]. It is an [[IgG]]2a anti-[[CD20]] [[monoclonal antibody]] derived from immortalized mouse cells.


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>
Tositumomab is applied in a sequential infusion followed by '''iodine (<sup>131</sup>I) tositumomab''', which is the same antibody covalently bound to the [[radionuclide]] [[iodine-131]] (<sup>131</sup>I).<ref>[http://us.gsk.com/products/assets/us_bexxar.pdf Bexxar Prescribing Information]</ref> <sup>131</sup>I emits both [[beta radiation|beta]] and [[gamma radiation]] and decays with a [[half-life]] of 8 days.


==Clinical use==
Clinical trials have established the efficacy of the tositumomab/iodine (<sup>131</sup>I) tositumomab regimen in patients with relapsed or [[chemotherapy]]/[[rituxan]] [[refractory]] follicular lymphoma.


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>
This drug combination is manufactured by [[Corixa (company)|Corixa]] (now [[GlaxoSmithKline]]). It sells in the U.S. under the trade name '''Bexxar'''. Sale of the drug will be discontinued in February 2014.<ref>{{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>


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}}
Bexxar was developed by Mark Kaminski and Richard Wahl.{{cn|date=August 2013}}{{clarify|reason=drug discovery and development are universally the work of large, diverse teams|date=August 2013}}


==Availability==
There is some evidence that it may cause a smaller decrease in [[platelet]] counts than [[ibritumomab tiuxetan]] does.<ref name="pmid17942813">{{Cite journal|author=Jacene HA, Filice R, Kasecamp W, Wahl RL |title=Comparison of 90Y-ibritumomab tiuxetan and 131I-tositumomab in clinical practice |journal=[[J. Nucl. Med.]] |volume=48 |issue=11 |pages=1767–76 |year=2007 |pmid=17942813 |doi=10.2967/jnumed.107.043489 |url=http://jnm.snmjournals.org/cgi/pmidlookup?view=long&pmid=17942813}}</ref>
===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==
{{Reflist}}
{{Reflist}}

==External links==
* [http://www.cancer.gov/dictionary?CdrID=367411 Bexxar regimen] entry in the public domain NCI Dictionary of Cancer Terms


{{Extracellular chemotherapeutic agents}}
{{Extracellular chemotherapeutic agents}}
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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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