Identification

Summary

Gemtuzumab ozogamicin is a monoclonal anti-CD33 antibody used to treat CD33-positive acute myeloid leukemia.

Brand Names
Mylotarg
Generic Name
Gemtuzumab ozogamicin
DrugBank Accession Number
DB00056
Background

Gemtuzumab ozogamicin is a recombinant humanized IgG4 kappa antibody which is conjugated with calicheamicin derivative, a cytotoxic antitumor antibiotic isolated from fermentation of Micromonospora echinospora ssp. calichensis. Gemtuzumab ozogamicin has approximately 50% of the antibody loaded with 4-6 moles calicheamicin per mole of antibody Label. The antibody is specifically directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML). By binding to the CD33 antigen on tumors, the cytotoxic agent blocks the growth of cancerous cells and causes cell death.

Marketing approval of gemtuzumab ozogamicin was granted on May 17, 2000 by FDA as a treatment for patients with CD33-positive AML in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy 1. However, it was voluntarily withdrawn from the market in 2010 due to safety concerns, increased patient deaths and insufficient evidence of clinical benefit during confirmatory trials 5. On September 1 2017, gemtuzumab ozogamicin was again approved for the treatment of adults with newly diagnosed CD33-positive acute myeloid leukemia but with a lower dosing regimen and a different schedule in combination with chemotherapy or on its own 5. It is also indicated for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory) 5.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db00056
Protein Chemical Formula
Not Available
Protein Average Weight
151500.0 Da (range)
Sequences
>Light Chain
DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQGS
GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVKRTVAAPSVF
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Heavy Chain
EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGGTDY
NQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK
Download FASTA Format
Synonyms
  • Gemtuzumab ozogamicin

Pharmacology

Indication

Indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. Indicated for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory).

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Used for the treatment of acute myeloid leukemia (AML), mylotarg binds to the CD33 antigen, which is expressed on the surface of leukemic cells in more than 80% of patients with AML. The CD33 antigen is not expressed on pluripotent hematopoietic stem cells or nonhematopoietic cells. This gives mylotarg the selectivity needed to target leukemic cells.

Mechanism of action

Mylotarg is directed against the CD33 antigen expressed by hematopoietic cells. Binding of the anti-CD33 antibody portion of Mylotarg with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivative binds to DNA in the minor groove resulting in site-specific DNA double strand breaks via formation of a p-benzene diradical 4. Eventually, cell death is induced.

TargetActionsOrganism
AMyeloid cell surface antigen CD33
antibody
Humans
ULow affinity immunoglobulin gamma Fc region receptor III-BNot AvailableHumans
ULow affinity immunoglobulin gamma Fc region receptor III-ANot AvailableHumans
UHigh affinity immunoglobulin gamma Fc receptor INot AvailableHumans
Absorption

In pediatric patients receiving a dose level of 9mg/m^2, the peak plasma concentration (Cmax) was approximately 3.47±1.04 mg/L with the AUC of 136 ±107 mg * h/L 4.

Volume of distribution

The volume of distribution at steady state (Vss) was approximately 6.5 ± 5.5 L in pediatric patients receiving a dose level of 9mg/m^2 4.

Protein binding

Not Available

Metabolism

Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin. The drug is most likely removed by opsonization via the reticuloendothelial system.

Route of elimination

Not Available

Half-life

In pediatric patients receiving a dose level of 9mg/m^2, the half life was approximately 64±44 h after the first dose 4.

Clearance

The mean clearance rate was approximately 0.12±0.15 L/h/m^2 in pediatric patients receiving a dose level of 9mg/m^2 4.

Adverse Effects
Adverseeffects
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Toxicity

The most frequently reported toxicities are myelosuppression and hepatic veno-occlusive disorder.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Gemtuzumab ozogamicin.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Gemtuzumab ozogamicin.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Gemtuzumab ozogamicin.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Gemtuzumab ozogamicin.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Gemtuzumab ozogamicin.
AducanumabThe risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Aducanumab.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Gemtuzumab ozogamicin.
AlefaceptThe risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Alefacept.
AlemtuzumabThe risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Alemtuzumab.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MylotargInjection, powder, lyophilized, for solution5 mg/5mLIntravenousWyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc.2017-09-07Not applicableUS flag
MylotargInjection, powder, for solution5 mgIntravenousPfizer Europe Ma Eeig2020-12-22Not applicableEU flag
MylotargPowder, for solution4.5 mg / vialIntravenousPfizer Canada Ulc2020-03-11Not applicableCanada flag

Categories

ATC Codes
L01XC05 — Gemtuzumab ozogamicin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
8GZG754X6M
CAS number
220578-59-6

References

General References
  1. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R: Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001 Jun;7(6):1490-6. [Article]
  2. Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA, David CL, Phan AT, Colburn DE, Rashid A, Estey EH: Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer. 2001 Jul 15;92(2):406-13. [Article]
  3. Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, Antin JH, Stone RM, Soiffer RJ, DeAngelo DJ: Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood. 2003 Sep 1;102(5):1578-82. Epub 2003 May 8. [Article]
  4. Buckwalter M, Dowell JA, Korth-Bradley J, Gorovits B, Mayer PR: Pharmacokinetics of gemtuzumab ozogamicin as a single-agent treatment of pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Pharmacol. 2004 Aug;44(8):873-80. [Article]
  5. FDA Press Announcements: FDA approves Mylotarg for treatment of acute myeloid leukemia [Link]
PubChem Substance
46505767
RxNav
1294580
ChEMBL
CHEMBL1201506
Therapeutic Targets Database
DAP000390
PharmGKB
PA164749431
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Gemtuzumab_ozogamicin
FDA label
Download (160 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentECG / Pharmacokinetics / Safety1
4CompletedTreatmentIntravenous Infusions / Leukemia, Myelocytic, Acute1
4CompletedTreatmentLeukemia, Myeloblastic, Acute1
3CompletedTreatmentAcute Myeloid Leukemia (AML)4
3CompletedTreatmentLeukemia, Myelocytic, Acute2
3CompletedTreatmentLeukemias4
3CompletedTreatmentLeukemias / Myelodysplastic Syndromes (MDS)1
3RecruitingTreatmentAcute Myeloid Leukemia (AML)4
2Active Not RecruitingTreatmentAcute Myeloid Leukemia (AML) / Adult Acute Megakaryoblastic Leukemia (M7) / Adult Acute Monoblastic Leukemia / Adult Acute Monocytic Leukemia / Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 / Adult Acute Myeloid Leukemia With Maturation / Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 / Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1 / Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL / Adult Acute Myeloid Leukemia Without Maturation / Adult Acute Myelomonocytic Leukemia / Adult Erythroleukemia / Adult Pure Erythroid Leukemia / Secondary Acute Myeloid Leukemia (Secondary AML, sAML)1
2Active Not RecruitingTreatmentAcute Myeloid Leukemia (AML) / Myelodysplastic Syndromes (MDS)2

Pharmacoeconomics

Manufacturers
  • Wyeth pharmaceuticals inc
Packagers
  • Ben Venue Laboratories Inc.
  • Wyeth Pharmaceuticals
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous5 MG
Injection, powder, lyophilized, for solutionIntravenous5 mg/5mL
Powder, for solutionIntravenous4.5 mg / vial
Powder, for solutionIntravenous5.0 mg
Prices
Unit descriptionCostUnit
Mylotarg 5 mg vial3104.82USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5773001No1998-06-302015-06-30US flag
US5585089No1996-12-172013-12-17US flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)61 °C (FAB fragment), 71 °C (whole mAb)Vermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000)

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Receptor activity
Specific Function
Putative adhesion molecule of myelomonocytic-derived cells that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,6-linked sialic acid. The sialic acid recognition si...
Gene Name
CD33
Uniprot ID
P20138
Uniprot Name
Myeloid cell surface antigen CD33
Molecular Weight
39824.885 Da
References
  1. Naito K, Takeshita A, Shigeno K, Nakamura S, Fujisawa S, Shinjo K, Yoshida H, Ohnishi K, Mori M, Terakawa S, Ohno R: Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines. Leukemia. 2000 Aug;14(8):1436-43. [Article]
  2. Niculescu-Duvaz I: Technology evaluation: gemtuzumab ozogamicin, Celltech Group. Curr Opin Mol Ther. 2000 Dec;2(6):691-6. [Article]
  3. van Der Velden VH, te Marvelde JG, Hoogeveen PG, Bernstein ID, Houtsmuller AB, Berger MS, van Dongen JJ: Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood. 2001 May 15;97(10):3197-204. [Article]
  4. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R: Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001 Jun;7(6):1490-6. [Article]
  5. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR: Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 Jul 1;19(13):3244-54. [Article]
  6. McHayleh W, Foon K, Redner R, Sehgal R, Raptis A, Agha M, Luong TM, Schlesselman JJ, Boyiadzis M: Gemtuzumab ozogamicin as first-line treatment in patients aged 70 years or older with acute myeloid leukemia. Cancer. 2010 Jun 15;116(12):3001-5. doi: 10.1002/cncr.25078. [Article]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Receptor for the Fc region of immunoglobulins gamma. Low affinity receptor. Binds complexed or aggregated IgG and also monomeric IgG. Contrary to III-A, is not capable to mediate antibody-dependent...
Gene Name
FCGR3B
Uniprot ID
O75015
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor III-B
Molecular Weight
26215.64 Da
References
  1. Caron PC, Lai LT, Scheinberg DA: Interleukin-2 enhancement of cytotoxicity by humanized monoclonal antibody M195 (anti-CD33) in myelogenous leukemia. Clin Cancer Res. 1995 Jan;1(1):63-70. [Article]
  2. Rogler G, Hausmann M, Vogl D, Aschenbrenner E, Andus T, Falk W, Andreesen R, Scholmerich J, Gross V: Isolation and phenotypic characterization of colonic macrophages. Clin Exp Immunol. 1998 May;112(2):205-15. [Article]
  3. Ericson SG, Benoit NE, Mills LE, Fanger MW: The effect of recombinant human interleukin-3 and recombinant human granulocyte-macrophage colony-stimulating factor on Fc gamma receptor expression and antibody-dependent cellular cytotoxicity of hematopoietic progenitor cells during in vitro myeloid maturation. Exp Hematol. 1994 Mar;22(3):283-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as...
Gene Name
FCGR3A
Uniprot ID
P08637
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor III-A
Molecular Weight
29088.895 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Ericson SG, Benoit NE, Mills LE, Fanger MW: The effect of recombinant human interleukin-3 and recombinant human granulocyte-macrophage colony-stimulating factor on Fc gamma receptor expression and antibody-dependent cellular cytotoxicity of hematopoietic progenitor cells during in vitro myeloid maturation. Exp Hematol. 1994 Mar;22(3):283-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Receptor signaling protein activity
Specific Function
High affinity receptor for the Fc region of immunoglobulins gamma. Functions in both innate and adaptive immune responses.
Gene Name
FCGR1A
Uniprot ID
P12314
Uniprot Name
High affinity immunoglobulin gamma Fc receptor I
Molecular Weight
42631.525 Da
References
  1. Ericson SG, Benoit NE, Mills LE, Fanger MW: The effect of recombinant human interleukin-3 and recombinant human granulocyte-macrophage colony-stimulating factor on Fc gamma receptor expression and antibody-dependent cellular cytotoxicity of hematopoietic progenitor cells during in vitro myeloid maturation. Exp Hematol. 1994 Mar;22(3):283-9. [Article]

Drug created at June 13, 2005 13:24 / Updated at December 08, 2021 01:57