Inotuzumab ozogamicin

Inotuzumab ozogamicin (trade name Besponsa) is an antibody-drug conjugate used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).[1][2]

Inotuzumab ozogamicin
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD22
Clinical data
Trade namesBesponsa
Other namesCMC-544
AHFS/Drugs.comConsumer Drug Information
Routes of
administration		Intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding97% (cytotoxic agent)
Elimination half-life12.3 days
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6518H10002N1738O2036S42
Molar mass150,000 g/mol g·mol−1
 NY (what is this?)  (verify)

The medication consists of the humanized monoclonal antibody against CD22 (inotuzumab), linked to a cytotoxic agent from the class of calicheamicins called ozogamicin.[3]

This drug was discovered by scientists collaborating at Celltech and Wyeth, and it was developed by Pfizer which had acquired Wyeth.

Medical use

Inotuzumab ozogamicin is used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia.[1][2]

It is administered by intravenous infusion in a doctor's office or clinic.[1]

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.[1]

The drug prolongs the QT interval in some people, so it should be used with caution in people with heart arrhythmias.[1]

Adverse effects

The US label for the use of inotuzumab ozagamicin 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.[2]

The most common serious adverse reactions in people taking the drug in the clinical trial leading to approval were infections (23%), loss of neutrophils with fever (11%), hemorrhage (5%), stomach pain (3%), fever (3%), VOD (2%), and tiredness (2%).[1]

More than 20% of people had the following adverse reactions: 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.[1]

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.[4] The ozogamicin eventually travels to the nucleus where it breaks up DNA, causing the cell to die.[1]

Chemistry

Inotuzumab ozogamicin consists of the humanized monoclonal antibody inotuzumab (against CD22), linked to a cytotoxic agent from the class of calicheamicins called ozogamicin.[3][5] Ozogamicin is N-acetyl-gamma-calicheamicin dimethylhydrazide.[1] It includes the same linker, called "AcBut", and toxin, as gemtuzumab ozogamicin, which arose from the same collaboration.[6] The linker is a carbonyl-containing carboxylic acid.[7]

Structure of AcBut linker used in inotuzumab ozogamicin and gemtuzumab ozogamicin

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.[8]

History

Celltech and Wyeth entered into a collaboration in 1991 to develop antibody-drug conjugates.[9]

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.[8] Celltech was acquired by UCB in 2004[10] and Wyeth was acquired by Pfizer in 2009.[11]

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.[12]

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).[1][2]

References
  1. "BESPONSA 1 mg powder for concentrate for solution for infusion". UK Electronic Medicines Compendium. June 2017. Retrieved 19 August 2017.
  2. "US (notuzumab ozogamicin label" (PDF). FDA. August 2017. Retrieved 19 August 2017. For label updates, see FDA index page for BLA 761040
  3. Ricart, AD (15 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.
  4. "Inotuzumab ozogamicin (CMC-544)". ADC Review. February 20, 2016.
  5. "Recommended INN: List 54" (PDF). WHO Drug Information. 19 (3). 2005.
  6. 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.
  7. 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 (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.
  8. 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 (1 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.
  9. "Inotuzumab Ozogamicin". Informa Biomedtracker. Retrieved 19 August 2017.
  10. "Celltech sold to Belgian firm in £1.5bn deal". The Guardian. 18 May 2004.
  11. Sorkin, Andrew Ross; Wilson, Duff (25 January 2009). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times.
  12. Pfizer Discontinues Phase 3 Study of Inotuzumab Ozogamicin in Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma (NHL) Due to Futility. May 2013
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