Inotuzumab ozogamicin

Inotuzumab ozogamicin
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD22
Names
Trade namesBesponsa
Other namesCMC-544
Clinical data
Drug classAntibody-drug conjugate
Main usesB-cell precursor acute lymphoblastic leukemia (ALL)[1]
Side effectsLow platelets, low white blood cells, infection, low red blood cells, tiredness, bleeding, fever, nausea, headache, liver problems[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa617041
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only) [3]
    • US: ℞-only [1]
    • EU: Rx-only
    Pharmacokinetics
    Protein binding97% (cytotoxic agent)
    Elimination half-life12.3 days
    Chemical and physical data
    FormulaC6518H10002N1738O2036S42
    Molar mass146634.36 g·mol−1

    Inotuzumab ozogamicin, sold under the brand name Besponsa, is a medication used to treat B-cell precursor acute lymphoblastic leukemia (ALL).[1] It is used when the cancer cells are CD22 positive and other treatments have failed.[1][2] It is given by gradual injection into a vein.[4]

    Common side effects include low platelets, low white blood cells, infection, low red blood cells, tiredness, bleeding, fever, nausea, headache, and liver problems.[2] Liver problems may include hepatic veno-occlusive disease.[2] Other side effects may include QT prolongation and infertility.[5] Use in pregnancy may harm the baby.[5] It is a monoclonal antibody linked to N-acetyl-γ-calicheamicin.[5] The antibody attaches to cells that express CD22 which brings about their death.[4]

    Inotuzumab ozogamicin was approved for medical use in the United States and Europe in 2017.[5][2] In the United Kingdom it costs the NHS about £8,000 per 1 mg dose as of 2021.[4] This amount in the United States costs about 24,000 USD.[6]

    Medical use

    Inotuzumab ozogamicin is used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia.[3][1]

    It is administered by intravenous infusion in a doctor's office or clinic.[3]

    Side effects

    The most common serious side effects are infections (23%), loss of neutrophils with fever (11%), hemorrhage (5%), stomach pain (3%), fever (3%), VOD (2%), and tiredness (2%).[3] More than 20% of people had the following: loss of platelets (51%), loss of neutrophils (49%), infections (48%), anemia (36%), leukopenia (35%), tiredness (35%), hemorrhage (33%), fever (32%), nausea (31%), headache (28%), loss of neutrophils with fever (26%), elevated transaminases (26%), stomach pain (23%), and jaundice (21%). Between 10% and 20% of people also had loss of appetite, vomiting, diarrhea, mouth sores, constipation, chills, and injection site reactions.[3]

    It carries an FDA black box warning concerning the risk of liver toxicity, in particular hepatic veno-occlusive disease (VOD), which has been fatal in some people. The risk of this is higher in people who take the drug before having hematopoietic stem cell transplantation (HSCT) and more people die who have HSCT following treatment with this drug, than people who have HSCT taking other chemotherapies. The risk gets higher as more rounds of treatment with inotuzumab ozogamicin are administered.[1]

    The drug prolongs the QT interval in some people, so it should be used with caution in people with heart arrhythmias.[3]

    Pregnancy and breastfeeding

    In studies in pregnant animals, the drug caused harm to the fetus at doses less than those used clinically, and so the drug has not been tested in pregnant women. Pregnant women should not take inotuzumab ozogamicin and must not become pregnant while taking it. It is unknown if the drug or its metabolites are secreted in breast milk, but women should not breastfeed while taking it, and should wait two months after the last dose to start breastfeeding.[3]

    Pharmacology

    The antibody component of inotuzumab ozogamicin binds to CD22 receptors, which are expressed mostly on B cells. The whole conjugate is then drawn into the cell, where the ozogamicin is cleaved from the antibody by the acidic environment of the lysosome.[7] The ozogamicin eventually travels to the nucleus where it breaks up DNA, causing the cell to die.[3]

    Chemistry

    Inotuzumab ozogamicin consists of the humanized monoclonal antibody inotuzumab (against CD22), linked to a cytotoxic agent from the class of calicheamicins called ozogamicin.[8][9] Ozogamicin is N-acetyl-gamma-calicheamicin dimethylhydrazide.[3] It includes the same linker, called "AcBut", and toxin, as gemtuzumab ozogamicin, which arose from the same collaboration.[10] The linker is a carbonyl-containing carboxylic acid.[11] The antibody, originally called G5/44, was created by grafting the complementarity-determining regions and some framework residues from the murine anti-CD22 mAb m5/44, onto human acceptor frameworks.[12]

    History

    Celltech and Wyeth entered into a collaboration in 1991 to develop antibody-drug conjugates.[13] It was discovered by scientists collaborating at Celltech and Wyeth, and it was developed by Pfizer which had acquired Wyeth.

    The humanized antibody portion was generated at Celltech and the DNA encoding it was transfected into CHO cells, which were sent to Wyeth, where chemists expressed and purified the antibodies and conjugated them with the linker to the cytotoxin; the work was published in 2004.[12] Celltech was acquired by UCB in 2004[14] and Wyeth was acquired by Pfizer in 2009.[15]

    In May 2013, a phase III trial in patients with relapsed or refractory CD22+ aggressive non-Hodgkin lymphoma (NHL) who were not candidates for intensive high-dose chemotherapy was terminated for futility.[16]

    In 2017, inotuzumab ozogamicin was approved by the European Commission and the FDA for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in 2017 under the trade name Besponsa (Pfizer/Wyeth).[3][1]

    The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[17]

    References

    1. 1 2 3 4 5 6 7 "Besponsa- inotuzumab ozogamicin injection, powder, lyophilized, for solution". DailyMed. 15 September 2020. Archived from the original on 26 November 2020. Retrieved 16 November 2020.
    2. 1 2 3 4 5 "Besponsa". Archived from the original on 4 March 2021. Retrieved 26 November 2021.
    3. 1 2 3 4 5 6 7 8 9 10 "Besponsa 1 mg powder for concentrate for solution for infusion". UK Electronic Medicines Compendium. June 2017. Archived from the original on 19 August 2017. Retrieved 19 August 2017.
    4. 1 2 3 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 917. ISBN 978-0857114105.
    5. 1 2 3 4 "Inotuzumab Monograph for Professionals". Drugs.com. Archived from the original on 24 January 2021. Retrieved 26 November 2021.
    6. ↑ "Besponsa Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 26 November 2021.
    7. ↑ "Inotuzumab ozogamicin (CMC-544)". ADC Review. February 20, 2016. Archived from the original on November 29, 2020. Retrieved September 23, 2021.
    8. ↑ Ricart AD (October 2011). "Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin". Clinical Cancer Research. 17 (20): 6417–27. doi:10.1158/1078-0432.ccr-11-0486. PMID 22003069. Archived from the original on 2018-07-04. Retrieved 2021-09-23.
    9. ↑ "Recommended INN: List 54" (PDF). WHO Drug Information. 19 (3). 2005. Archived (PDF) from the original on 2020-08-10. Retrieved 2021-09-23.
    10. ↑ Damle NK, Frost P (August 2003). "Antibody-targeted chemotherapy with immunoconjugates of calicheamicin". Current Opinion in Pharmacology. 3 (4): 386–90. doi:10.1016/S1471-4892(03)00083-3. PMID 12901947.
    11. ↑ Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, et al. (2002). "Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia". Bioconjugate Chemistry. 13 (1): 47–58. doi:10.1021/bc010021y. PMID 11792178.
    12. 1 2 DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, et al. (March 2004). "Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies". Blood. 103 (5): 1807–14. doi:10.1182/blood-2003-07-2466. PMID 14615373. Archived from the original on 2017-10-18. Retrieved 2021-09-23.
    13. ↑ "Inotuzumab Ozogamicin". Informa Biomedtracker. Archived from the original on 19 August 2017. Retrieved 19 August 2017.
    14. ↑ "Celltech sold to Belgian firm in £1.5bn deal". The Guardian. 18 May 2004. Archived from the original on 19 August 2017. Retrieved 23 September 2021.
    15. ↑ Sorkin AR, Wilson D (25 January 2009). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times. Archived from the original on 19 August 2017. Retrieved 23 September 2021.
    16. ↑ "Pfizer Discontinues Phase 3 Study of Inotuzumab Ozogamicin in Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma (NHL) Due to Futility. May 2013". Archived from the original on 2014-08-08. Retrieved 2021-09-23.
    17. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Archived from the original on 23 October 2020. Retrieved 16 September 2020.
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