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| Primary information |
|---|
| ID | 14607 |
| Therapeutic ID | Th1521 |
| Protein Name | Moxetumomab pasudotox |
| Sequence | >Th1521_Moxetumomab_pasudotox
MEVQLVESGGGLVKPGGSLKLSCAASGFAFSIYDMSWVRQTPEKCLEWVAYISSGGGTTYYPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARHSGYGTHWGVLFAYWGQGTLVSAKASGGPEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVALYIAARLSWNQVDQVIRALASPGSGGDLGEAIREQPEQARLALTLAAAESERFVRQGTGNDEAGAANGPADSGDALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERLLQAHRQLEERGYVFVGYHGTFLEAAQSIVFGGVRARSQDLDAIWRGFYIAGDPALAYGYAQDQEPDARGRIRNGALLRVYVPRSSLPGFYRTSLTLAAPEAAGEVERLIGHPLPLRLDAITGPEEEGGRLETILGWPLAERTWIPSAIPTDPRNVGGDLDPSSIPDKEQAISALPDYASQPGKPPREDLK
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| Molecular Weight | 63500 |
| Chemical Formula | C2804H4339N783O870S14 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | MxP presents a short half-life, which limits its efficacy against solid tumors.[A38882] The half-life is reported to be of only 1.4 hours.[A38883] |
| 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.[A38864] 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.[A38864] 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.[L4568] |
| Indication/Disease | 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).[L4568] 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.[A38877] |
| 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.[A38880] 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.[L4568] Hence, the phase III clinical trial met the primary endpoint of durable complete response.[L4572] |
| 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.[A38879] 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.[A38881] |
| 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.[FDA label] |
| 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.[A38883] |
| 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.[A38883] |
| The mean volume of distribution calculated based on population is 6.5 L.[A38883] |
| 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.[A38883] |
| Categories | Immunotherapy |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | B-cell receptor CD22,Elongation factor 2 |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |