Moxetumomab Pasudotox

Identification

Name
Moxetumomab Pasudotox
Accession Number
DB12688
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

CD22 is a lineage-restricted B-cell antigen that is expressed solely in on B-chronic lymphocytic leukemia, hairy cell leukemia, acute lymphocytic leukemiathe and Burkitt's lymphoma. The predecessor of Moxetumab pasudotox (MxP), named BL22, was first created based on the antibody RFB4 which specifically binds to CD22. This antibody was used to generate a recombinant immunotoxin in which a stabilized Fv segment by a disulfide bond is fused to the Pseudomonas exotoxin A (PE38) which does not have the cell-binding portion.[1]

MxP appears as an improved form of BL22 by the mutation of the Fv region and the antibody phage-displayed. As well the residues SSY in the heavy chain are mutated to THW.[1] It was developed by Astra Zeneca and FDA approved on September 13, 2018, after being granted the status of Fast Track, Priority Review and Orphan Drug designations.[8]

Protein structure
Db12688
Protein chemical formula
C2804H4339N783O870S14
Protein average weight
63500.0 Da
Sequences
>>VH-P38 subunit<<<
MEVQLVESGGGLVKPGGSLKLSCAASGFAFSIYDMSWVRQTPEKCLEWVAYISSGGGTTY
YPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARHSGYGTHWGVLFAYWGQGTLV
SAKASGGPEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVALYIAARL
SWNQVDQVIRALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAAN
GPADSGDALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERLLQAHRQLEERGYVFVGYH
GTFLEAAQSIVFGGVRARSQDLDAIWRGFYIAGDPALAYGYAQDQEPDARGRIRNGALLR
VYVPRSSLPGFYRTSLTLAAPEAAGEVERLIGHPLPLRLDAITGPEEEGGRLETILGWPL
AERTWIPSAIPTDPRNVGGDLDPSSIPDKEQAISALPDYASQPGKPPREDLK
>>VL subunit<<<
MDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILHSGVP
SRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPWTFGCGTKLEIK
>>PE-38 of Moxetumomab pasudotox<<<
PEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVALYLAARLSWNQVDQ
VIRNALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAANGPADSG
DALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERLLQAHRQLEERGYVFVGYHGTFLEA
AQSIVFGGVRARSQDLDAIWRGFYIAGDPALAYGYAQDQEPDARGRIRNGALLRVYVPRS
SLPGFYRTSLTLAAPEAAGEVERLIGHPLPLRLDAITGPEEEGGRLETILGWPLAERTVV
IPSAIPTDPRNVGGDLDPSSIPDKEQAISALPDYASQPGKPPREDLK
References:
  1. World Health Organization (2009). WHO Drug Information (23rd ed.). WHO.
  2. Patent WO20141002243A2 [Link]
Download FASTA Format
Synonyms
  • moxetumomab pasudotox-tdfk
External IDs
CAT-8015
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LumoxitiInjection, powder, lyophilized, for solution1 mg/1mLIntravenousAstraZeneca Pharmaceuticals LP2018-10-24Not applicableUs
Categories
UNII
2NDX4B6N8F
CAS number
1020748-57-5

Pharmacology

Indication

MxP is indicated for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies including treatment with a purine nucleoside analog. The use of this drug is not recommended in patients with severe renal impairment (CrCl < 29 ml/min).[8]

HCL is an uncommon type of lymphocytic leukemia that starts in B cells or B lymphocytes. It is characterized by an accumulation of abnormal B lymphocytes. HCL is called "hairy" as it produces hair-like projections in the surface of the cancer cells. A usual symptom in people having HCL is the presence of splenomegaly and less often hepatomegaly.[2]

Associated Conditions
Pharmacodynamics

Compared with its predecessor, MxP is even 50-fold more active on lymphoma cell lines and leukemic cells. In phase I clinical trial, MxP showed no dose-limiting toxicity and the overall response rate was of 79%. From pediatric patients with acute lymphoblastic leukemia, the complete response was observed in 12 individuals which is a result that has never been seen before.[4]

In an open-label clinical trial, MxP showed a complete response, defined as the maintenance of hematologic remission, of more than 180 days in 30% of the patients and 75% of the patients achieved at least partial response.[8] Hence, the phase III clinical trial met the primary endpoint of durable complete response.[10]

Mechanism of action

MxP is a CD22-directed cytotoxin. It is stated as an immunotoxin which is defined as the class of agents that combine the selectivity of antibodies towards the target and the potency of toxins to perform the pharmacological anticancer function. CD22 is a B-lymphocyte restricted transmembrane protein with a high density in HCL cells when compared with normal B cells. After binding to CD22, MxP is internalized and processed, which allows the release of the modified toxin. This toxin inhibits protein translation which induces an apoptotic state of the high CD22-expressed cancer cell.[3]

The toxin included in MxP is the Pseudomonas exotoxin A which, after internalization, undergoes conformational changes and in the cytosol, the ribosylation activity of the domain III of the toxin inactivates the eukaryotic translation elongation factor (eEF-2) by transferring ADP (adenosine di-phosphate-ribose) from NAD to a modified histidine at position 715 in eEF-2. This action produces the inactivation of eEF-2 which leads to protein synthesis inhibition and programmed cell death.[5]

TargetActionsOrganism
AB-cell receptor CD22
binder
Human
AElongation factor 2
inactivator
Human
Absorption

MxP serum concentration increases in a dose-proportional manner and reaches a mean steady state of 379 ng/ml with a Cmax of 626 ng.h/ml. There are no reports of systemic accumulation.[7]

Volume of distribution

The mean volume of distribution calculated based on population is 6.5 L.[7]

Protein binding

The main mechanism of action of MxP is done in the plasma and its cells. Thus, this property is not relevant for this drug.

Metabolism

The metabolism of MxP has not been well established but due to the nature of the drug, it is thought to be degraded into small peptides and individual amino acids.[7]

Route of elimination

The main route of elimination is thought to be through the urine as it presents a very large clearance rate.[7]

Half life

MxP presents a short half-life, which limits its efficacy against solid tumors.[6] The half-life is reported to be of only 1.4 hours.[7]

Clearance

The mean systemic clearance is very fast and it is reported to be of 25 L/h. This clearance rate is decreased after subsequent dosing to 4 L/h.[7]

Toxicity

No studies have been performed regarding the carcinogenic potential and/or effect on fertility of MxP. It has been observed that the administration of MxP in a dose > 3 times the recommended can produce the degeneration of heart tissue and a dose > 10 times the recommended there are reports of gliosis, axonal degeneration in the spinal cord and body tremors.[Label]

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Bang S, Nagata S, Onda M, Kreitman RJ, Pastan I: HA22 (R490A) is a recombinant immunotoxin with increased antitumor activity without an increase in animal toxicity. Clin Cancer Res. 2005 Feb 15;11(4):1545-50. doi: 10.1158/1078-0432.CCR-04-1939. [PubMed:15746059]
  2. Getta BM, Park JH, Tallman MS: Hairy cell leukemia: Past, present and future. Best Pract Res Clin Haematol. 2015 Dec;28(4):269-72. doi: 10.1016/j.beha.2015.10.015. Epub 2015 Oct 21. [PubMed:26614906]
  3. Park JH, Levine RL: Targeted immunotherapy for hairy cell leukemia. J Clin Oncol. 2012 May 20;30(15):1888-90. doi: 10.1200/JCO.2011.39.8313. Epub 2012 Feb 21. [PubMed:22355051]
  4. Kreitman RJ, Pastan I: Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011 Oct 15;17(20):6398-405. doi: 10.1158/1078-0432.CCR-11-0487. [PubMed:22003067]
  5. Shapira A, Benhar I: Toxin-based therapeutic approaches. Toxins (Basel). 2010 Nov;2(11):2519-83. doi: 10.3390/toxins2112519. Epub 2010 Oct 28. [PubMed:22069564]
  6. Wei J, Bera TK, Liu XF, Zhou Q, Onda M, Ho M, Tai CH, Pastan I: Recombinant immunotoxins with albumin-binding domains have long half-lives and high antitumor activity. Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):E3501-E3508. doi: 10.1073/pnas.1721780115. Epub 2018 Mar 26. [PubMed:29581296]
  7. Wayne AS, Shah NN, Bhojwani D, Silverman LB, Whitlock JA, Stetler-Stevenson M, Sun W, Liang M, Yang J, Kreitman RJ, Lanasa MC, Pastan I: Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia. Blood. 2017 Oct 5;130(14):1620-1627. doi: 10.1182/blood-2017-02-749101. Epub 2017 Aug 9. [PubMed:28983018]
  8. FDA news [Link]
  9. Patent WO20141002243A2 [Link]
  10. AstraZeneca news [Link]
External Links
PubChem Substance
347911362
FDA label
Download (811 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL) / Non-Hodgkin's Lymphoma (NHL)1
1CompletedTreatmentHairy Cell Leukemia (HCL)1
1SuspendedTreatmentLeukemia, Lymphoma1
1TerminatedTreatmentLeukemias1
1TerminatedTreatmentMalignant Lymphomas1
1, 2CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Non-Hodgkin's Lymphoma (NHL)1
2TerminatedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2TerminatedTreatmentB-Cell Pediatric ALL1
3Active Not RecruitingTreatmentHairy Cell Leukemia (HCL)1
Not AvailableAvailableNot AvailableRelapsed/Refractory Hairy Cell Leukemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous1 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Binder
Curator comments
This target is used to direct the drug to the correct cell line.
General Function
Carbohydrate binding
Specific Function
Mediates B-cell B-cell interactions. May be involved in the localization of B-cells in lymphoid tissues. Binds sialylated glycoproteins; one of which is CD45. Preferentially binds to alpha-2,6-link...
Gene Name
CD22
Uniprot ID
P20273
Uniprot Name
B-cell receptor CD22
Molecular Weight
95347.07 Da
References
  1. Park JH, Levine RL: Targeted immunotherapy for hairy cell leukemia. J Clin Oncol. 2012 May 20;30(15):1888-90. doi: 10.1200/JCO.2011.39.8313. Epub 2012 Feb 21. [PubMed:22355051]
  2. Kreitman RJ, Pastan I: Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011 Oct 15;17(20):6398-405. doi: 10.1158/1078-0432.CCR-11-0487. [PubMed:22003067]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inactivator
Curator comments
This target is part of the intracellular effect of the toxin part of MxP
General Function
Translation elongation factor activity
Specific Function
Catalyzes the GTP-dependent ribosomal translocation step during translation elongation. During this step, the ribosome changes from the pre-translocational (PRE) to the post-translocational (POST) ...
Gene Name
EEF2
Uniprot ID
P13639
Uniprot Name
Elongation factor 2
Molecular Weight
95337.385 Da
References
  1. Shapira A, Benhar I: Toxin-based therapeutic approaches. Toxins (Basel). 2010 Nov;2(11):2519-83. doi: 10.3390/toxins2112519. Epub 2010 Oct 28. [PubMed:22069564]

Drug created on October 20, 2016 17:38 / Updated on November 02, 2018 07:28