Inotuzumab ozogamicin: Difference between revisions

{{Short description|Chemical compound}}

{{Use dmy dates|date=March 2024}}

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| verifiedrevid = 458271836

| image = Mab-ozogamicin.svg

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| tradename = Besponsa

| Drugs.com = {{Drugs.com|monograph|inotuzumab-ozogamicin}}

| MedlinePlus = a617041

| DailyMedID = Inotuzumab_ozogamicin

| pregnancy_AU = D

| pregnancy_category =

| routes_of_administration = [[Intravenous infusion|Intravenous]]

| ATC_prefix = L01

| ATC_suffix = FB01

| legal_AU = S4

| legal_CA = Rx-only

| legal_CA_comment = /{{nbsp}}Schedule D<ref>{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00349 | title=Search Page - Drug and Health Product Register | date=23 October 2014 }}</ref><ref>{{cite web | title=Drug and medical device highlights 2018: Helping you maintain and improve your health | website=[[Health Canada]] | date=14 October 2020 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2018.html| access-date=17 April 2024}}</ref>

| legal_UK = POM

| legal_UK_comment = <ref name=UKlabel />

| legal_US = Rx-only

| legal_US_comment = <ref name=USlabel />

| legal_EU = Rx-only

| legal_status =

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| bioavailability =

| protein_bound = 97% (cytotoxic agent)

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| elimination_half-life = 12.3 days

| excretion =

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| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 635715-01-4

| DrugBank = DB05889

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = none

| UNII = P93RUU11P7

| synonyms = CMC-544

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| C=6518 | H=10002 | N=1738 | O=2036 | S=42

'''Inotuzumab ozogamicin''', sold under the brand name '''Besponsa''', is an [[antibody-drug conjugate]] medication used to treat relapsed or refractory B-cell precursor [[acute lymphoblastic leukemia]].<ref name=UKlabel>{{cite web|title=Besponsa 1 mg powder for concentrate for solution for infusion|url=https://www.medicines.org.uk/emc/medicine/33679|publisher=UK Electronic Medicines Compendium|access-date=19 August 2017|date=June 2017}}</ref><ref name=USlabel>{{cite web | title=Besponsa- inotuzumab ozogamicin injection, powder, lyophilized, for solution | website=DailyMed | date=15 September 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cc7014b1-c775-411d-b374-8113248b4077 | access-date=16 November 2020}}</ref> It is administered by intravenous infusion.<ref name=UKlabel/><ref name=USlabel />

The medication consists of a [[humanized monoclonal antibody]] against [[CD22]] ([[inotuzumab]]), linked to a [[cytotoxic agent]] from the class of [[calicheamicin]]s called [[ozogamicin]].<ref name=Ricart2009>{{cite journal | vauthors = Ricart AD | title = Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin | journal = Clinical Cancer Research | volume = 17 | issue = 20 | pages = 6417–6427 | date = October 2011 | pmid = 22003069 | doi = 10.1158/1078-0432.ccr-11-0486 | doi-access = free }}</ref>

The US [[Food and Drug Administration]] (FDA) considers it to be a [[first-in-class medication]].<ref>{{cite report | title=New Drug Therapy Approvals 2017 | website=U.S. [[Food and Drug Administration]] (FDA) | date=January 2018 | url=https://www.fda.gov/media/110526/download | format=PDF | access-date=16 September 2020}}</ref>

==Medical use==

Inotuzumab ozogamicin is used to treat relapsed or refractory B-cell precursor [[acute lymphoblastic leukemia]].<ref name=UKlabel/><ref name=USlabel/>

In March 2024, the FDA approved inotuzumab ozogamicin for the treatment of children aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.<ref name="FDA 20240306">{{cite web | title=FDA approves inotuzumab ozogamicin for pediatric patients with acute lymphoblastic leukemia | website=U.S. Food and Drug Administration | date=6 March 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inotuzumab-ozogamicin-pediatric-patients-acute-lymphoblastic-leukemia | access-date=9 March 2024}} {{PD-notice}}</ref>

==Adverse effects==

The FDA label for the use of inotuzumab ozagamicin carries a [[boxed warning]] concerning the risk of [[liver toxicity]], in particular [[hepatic veno-occlusive disease]] (VOD), which has been fatal in some people.<ref>{{Cite web |last=Yang |first=Xiaochuan |date=13 May 2020 |title=Inotuzumab Ozogamicin is an Effective Salvage Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with High- Risk Molecular Features, Including Tp53 Loss |url=http://dx.doi.org/10.26226/morressier.5ebc261fffea6f735881a254 |access-date=21 August 2023 |doi=10.26226/morressier.5ebc261fffea6f735881a254 |s2cid=242875059 }}</ref> 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.<ref name=USlabel/>

The most common serious adverse reactions in people taking the drug in the clinical trial leading to approval were infections (23%), [[neutropenia|loss of neutrophils]] with fever (11%), hemorrhage (5%), stomach pain (3%), fever (3%), VOD (2%), and tiredness (2%).<ref name=UKlabel/>

More than 20% of people had the following adverse reactions: [[thrombocytopenia|loss of platelets]] (51%), [[neutropenia|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%).{{Citation needed|date=August 2023}}

Between 10% and 20% of people also had loss of appetite, vomiting, diarrhea, mouth sores, constipation, chills, and [[injection site reaction]]s.<ref name=UKlabel/>

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.<ref name=UKlabel/>

==Pharmacology==

The antibody component of inotuzumab ozogamicin binds to [[CD22]] receptors, which are expressed mostly on [[B cells]]. The whole conjugate is then [[Endocytosis|drawn into the cell]], where the ozogamicin is cleaved from the antibody by the acidic environment of the [[lysosome]].<ref>{{cite web|title=Inotuzumab ozogamicin (CMC-544)|url=https://adcreview.com/inotuzumab-ozogamicin-cmc-544-drug-description/|publisher=ADC Review|date=20 February 2016}}</ref> The ozogamicin eventually travels to the [[Cell nucleus|nucleus]] where it breaks up [[DNA]], causing the cell to die.<ref name=UKlabel/>

==Chemistry==

Inotuzumab ozogamicin consists of the [[humanized monoclonal antibody]] inotuzumab (against [[CD22]]), linked to a [[cytotoxic agent]] from the class of [[calicheamicin]]s called ozogamicin.<ref name=Ricart2009/><ref>{{cite journal|title=Recommended INN: List 54|journal=WHO Drug Information|date=2005|volume=19|issue=3|url=https://www.who.int/medicines/publications/druginformation/innlists/RL54.pdf}}</ref> Ozogamicin is N-acetyl-gamma-calicheamicin dimethylhydrazide.<ref name=UKlabel/> It includes the same linker, called "AcBut", and toxin, as [[gemtuzumab ozogamicin]], which arose from the same collaboration.<ref name=Damle2003>{{cite journal | vauthors = Damle NK, Frost P | title = Antibody-targeted chemotherapy with immunoconjugates of calicheamicin | journal = Current Opinion in Pharmacology | volume = 3 | issue = 4 | pages = 386–390 | date = August 2003 | pmid = 12901947 | doi = 10.1016/S1471-4892(03)00083-3 }}</ref> The linker is a carbonyl-containing carboxylic acid.<ref>{{cite journal | vauthors = Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, Hallett W, Tsou HR, Upeslacis J, Shochat D, Mountain A, Flowers DA, Bernstein I | title = Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia | journal = Bioconjugate Chemistry | volume = 13 | issue = 1 | pages = 47–58 | date = 2002 | pmid = 11792178 | doi = 10.1021/bc010021y }}</ref>

The antibody, originally called G5/44, was created by grafting the [[complementarity-determining region]]s and some [[Framework region|framework]] residues from the murine anti-CD22 mAb m5/44, onto human acceptor frameworks.<ref name=DiJoseph2004>{{cite journal | vauthors = DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, Kunz A, Hamann PR, Gorovits B, Udata C, Moran JK, Popplewell AG, Stephens S, Frost P, Damle NK | title = Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies | journal = Blood | volume = 103 | issue = 5 | pages = 1807–1814 | date = March 2004 | pmid = 14615373 | doi = 10.1182/blood-2003-07-2466 | doi-access = free }}</ref>

==History==

Inotuzumab ozogamicin was discovered by scientists collaborating at [[Celltech]] and [[Wyeth]], and it was [[drug development|developed]] by [[Pfizer]] which had acquired Wyeth. [[Celltech]] and [[Wyeth]] entered into a collaboration in 1991 to develop antibody-drug conjugates.<ref>{{cite web|title=Inotuzumab Ozogamicin|url=http://drugprofiles.informa.com/drug_profiles/638-inotuzumab-ozogamicin|publisher=Informa Biomedtracker|access-date=19 August 2017|archive-date=19 August 2017|archive-url=https://web.archive.org/web/20170819105511/http://drugprofiles.informa.com/drug_profiles/638-inotuzumab-ozogamicin|url-status=dead}}</ref>

The humanized antibody portion was generated at Celltech and the DNA encoding it was transfected into [[Chinese hamster ovary cell|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.<ref name=DiJoseph2004/> Celltech was acquired by [[UCB (company)|UCB]] in 2004<ref>{{cite news|title=Celltech sold to Belgian firm in £1.5bn deal|url=https://www.theguardian.com/business/2004/may/18/businessofresearch.money|work=The Guardian|date=18 May 2004}}</ref> and Wyeth was acquired by [[Pfizer]] in 2009.<ref>{{cite news| vauthors = Sorkin AR, Wilson D |title=Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth|url=https://www.nytimes.com/2009/01/26/business/26drug.html?mcubz=0|work=The New York Times|date=25 January 2009}}</ref>

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.<ref>{{Cite web |url=http://pfizer.newshq.businesswire.com/press-release/pfizer-discontinues-phase-3-study-inotuzumab-ozogamicin-relapsed-or-refractory-aggress |title=Pfizer Discontinues Phase 3 Study of Inotuzumab Ozogamicin in Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma (NHL) Due to Futility. May 2013 |access-date=20 July 2014 |archive-date=8 August 2014 |archive-url=https://web.archive.org/web/20140808054234/http://pfizer.newshq.businesswire.com/press-release/pfizer-discontinues-phase-3-study-inotuzumab-ozogamicin-relapsed-or-refractory-aggress |url-status=dead }}</ref>

In March 2024, the FDA approved inotuzumab ozogamicin for the treatment of children aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.<ref name="FDA 20240306" /> Efficacy was evaluated in a multicenter, single-arm, open-label study in 53 pediatric participants aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.<ref name="FDA 20240306" /> Two dose levels were evaluated--an initial dose of 1.4 mg/m2/cycle in 12 participants and 1.8 mg/m2/cycle in 41 participants.<ref name="FDA 20240306" /> Premedications included methylprednisolone 1 mg/kg (maximum of 50 mg), an antipyretic, and an antihistamine.<ref name="FDA 20240306" /> Participants received a median of 2 cycles of therapy (range: 1 to 4 cycles).<ref name="FDA 20240306" /> The application was granted [[priority review]] and [[orphan drug]] designations.<ref name="FDA 20240306" />

== Society and culture ==

=== Legal status ===

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 under the brand name Besponsa (Pfizer/Wyeth).<ref name=UKlabel/><ref name=USlabel/>

== References ==

{{reflist}}

== External links ==

* {{cite web | title=Inotuzumab Ozogamicin | website=National Cancer Institute | date=September 2017 | url=https://www.cancer.gov/about-cancer/treatment/drugs/inotuzumabozogamicin }}

* {{cite web | title=Inotuzumab Ozogamicin | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/inotuzumab-ozogamicin }}

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[[Category:Antibody-drug conjugates]]

[[Category:Monoclonal antibodies for tumors]]

[[Category:Drugs developed by Wyeth]]

[[Category:Drugs developed by Pfizer]]

[[Category:Orphan drugs]]