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General Description:

Moxetumomab pasudotox, identified by CAS number 1020748-57-5, is a notable compound with significant therapeutic applications. 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. 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. 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.

Indications:

This drug is primarily indicated for: 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). 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Moxetumomab pasudotox undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Moxetumomab pasudotox are crucial for its therapeutic efficacy: 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Moxetumomab pasudotox is an important consideration for its dosing schedule: MxP presents a short half-life, which limits its efficacy against solid tumors. The half-life is reported to be of only 1.4 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Moxetumomab pasudotox exhibits a strong affinity for binding with plasma proteins: The main mechanism of action of MxP is done in the plasma and its cells. Thus, this property is not relevant for this drug. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Moxetumomab pasudotox from the body primarily occurs through: The main route of elimination is thought to be through the urine as it presents a very large clearance rate. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Moxetumomab pasudotox is distributed throughout the body with a volume of distribution of: The mean volume of distribution calculated based on population is 6.5 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Moxetumomab pasudotox is a critical factor in determining its safe and effective dosage: 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. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Moxetumomab pasudotox exerts its therapeutic effects through: 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. 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. Hence, the phase III clinical trial met the primary endpoint of durable complete response. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Moxetumomab pasudotox functions by: 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. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Moxetumomab pasudotox belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Moxetumomab pasudotox is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Blood Proteins, Cancer immunotherapy, CD22 (Clusters of Differentiation 22) inhibitors, CD22-Directed Cytotoxins, Globulins, Immunoconjugates, Immunoglobulins, Immunologic Factors, Immunotherapy, Immunotoxins, MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES, Narrow Therapeutic Index Drugs, Noxae, Proteins, Serum Globulins, Toxic Actions. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Moxetumomab pasudotox include:

• Molecular Weight: 63500.0
• Molecular Formula: C2804H4339N783O870S14