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General Description:

Loncastuximab tesirine, identified by CAS number 1879918-31-6, is a notable compound with significant therapeutic applications. Relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL) are a therapeutic challenge for patients who have undergone prior systemic therapies with limited success. Prognosis is poor and more effective therapies are needed to treat relapsed/refractory cases and improve survival. On April 23 2021, the Food and Drug Administration granted accelerated approval for the antibody-drug conjugate, loncastuximab tesirine-lpyl, also known as Zynlonta. This therapy was developed by ADC Therapeutics and its accelerated approval for relapsed or refractory B-cell lymphoma is based on promising results from the LOTIS-2 clinical trial.

Indications:

This drug is primarily indicated for: Loncastuximab tesirine is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma who have undergone two or more prior lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. The above indication is approved under accelerated FDA approval following the results of clinical studies. Continued approval is dependant upon the results of confirmatory clinical trials. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Loncastuximab tesirine undergoes metabolic processing primarily in: The monoclonal antibody portion of loncastuximab tesirine-lpyl is catabolized into small peptides. In vitro studies show that the small molecule cytotoxin portion, SG3199, is metabolized by CYP3A4/5. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Loncastuximab tesirine are crucial for its therapeutic efficacy: Due to its intravenous route of administration, loncastuximab tesirine is readily absorbed into the circulation. Cmax during Cycle 1 of therapy was 2995 μg/L and 3155 μg/L in Cycle 2. AUC was 15,245 - 22,823 μg*day/L during pharmacokinetic studies. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Loncastuximab tesirine is an important consideration for its dosing schedule: The half-life of loncastuximab tesirine-lpyl was 7.06-12.5 days at steady-state. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Loncastuximab tesirine from the body primarily occurs through: The main excretion pathways of SG3199 have not been formally studied in humans. SG3199 is thought to be minimally excreted by the kidneys. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Loncastuximab tesirine is distributed throughout the body with a volume of distribution of: In clinical studies, the average loncastuximab tesirine-lpyl volume of distribution was 7.11 liters, with a range between 7.19-8.43 liters. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Loncastuximab tesirine is a critical factor in determining its safe and effective dosage: In pharmacokinetic studies, the mean clearance of loncastuximab tesirine-lpyl decreased with time from 0.499 L/day after a single dose to 0.275 L/day at steady-state. One pharmacokinetic study measured a clearance ranging from 0.5-0.64 L/day. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Loncastuximab tesirine exerts its therapeutic effects through: Loncastuximab tesirine exhibits antitumour activity against malignant B-cells, treating lymphomas. Higher exposure in Cycle 1 of therapy in clinical trials was associated with an increased incidence of Grade ≥2 adverse reactions, including liver function test abnormalities, skin and nail reactions, and liver function test abnormalities. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Loncastuximab tesirine functions by: Human CD19 antigen is a membrane glycoprotein in the immunoglobulin superfamily expressed in the various stages of B-cell development; it is detected in most malignancies of B-cell origin. Additionally, CD19 has rapid internalization kinetics and does not shed into the general circulation, rendering it a useful therapeutic target for antibody-drug conjugates (ADCs) in the treatment of B-cell malignancies. Loncastuximab tesirine is an antibody-drug conjugate designed to target human CD19. It is a humanized monoclonal antibody and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin by a protease enzyme cleavable valine-alanine linker. The monoclonal IgG1 kappa antibody component binds to CD19, a transmembrane protein located on B-cell surfaces. The small molecule component, SG3199, functions as a PBD dimer and alkylating agent. Following binding to CD19, loncastuximab tesirine becomes internalized into the cell and subsequently proteolytic cleavage releases the SG3199 component. SG3199 binds to the DNA minor groove, forming cytotoxic DNA interstrand crosslinks, leading to B-cell cell death. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Loncastuximab tesirine 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:

Loncastuximab tesirine is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibody-drug Conjugates, Antineoplastic Agents, Antineoplastic Agents, Immunological, Benzazepines, Blood Proteins, CD19-Directed Monoclonal Antibodies, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Substrates, Globulins, Heterocyclic Compounds, Fused-Ring, Immunoglobulins, Immunoproteins, P-glycoprotein substrates, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Loncastuximab tesirine include:

• Molecular Weight: 151000.0