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General Description:

Teplizumab, identified by CAS number 876387-05-2, is a notable compound with significant therapeutic applications. Teplizumab (teplizumab-mzwv) is a humanized IgG1 kappa CD3-directed monoclonal antibody used to delay the onset of type 1 diabetes (T1D). T1D is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. Anti-CD3 therapy has traditionally been used to prevent graft-versus-host-disease in organ transplantation but more recently has been explored to prolong the onset of (T1D) in high-risk patients. Targeting T cells can be achieved through antibodies against the T cell receptor (TCR) component CD3. Although the mechanism of action of teplizumab has not been fully elucidated, it may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes. Fc-receptors can bind to the "tail-end" anti-CD3 antibodies in an antigen-non-specific manner and lead to severe adverse effects related to cytokine release syndrome (CRS). Teplizumab was designed as an Fc-non-binding antibody in order to reduce the incidence of CRS. On November 2022, teplizumab was approved by the FDA as the first drug that can delay the onset of type 1 diabetes.

Indications:

This drug is primarily indicated for: Teplizumab is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Teplizumab undergoes metabolic processing primarily in: As a monoclonal antibody, teplizumab is expected to be metabolized into small peptides by proteases throughout the body. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Teplizumab are crucial for its therapeutic efficacy: During the 14-day treatment course of teplizumab, steady-state concentrations are not expected to be achieved. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Teplizumab is an important consideration for its dosing schedule: In a 60 kg subject, teplizumab has a mean terminal elimination half-life of 4.5 days. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Teplizumab from the body primarily occurs through: Teplizumab showed saturable binding and elimination. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Teplizumab is distributed throughout the body with a volume of distribution of: In a 60 kg subject, teplizumab has a central volume of distribution (Vd) of 2.27 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Teplizumab is a critical factor in determining its safe and effective dosage: In a 60 kg subject, teplizumab has a clearance of 2.7 L/day. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Teplizumab exerts its therapeutic effects through: Teplizumab is a monoclonal antibody that binds to CD3 molecules on the surface of CD4+ and CD8+ T cells, both involved in the destruction of pancreatic β cells. Several studies have detected an increase in C-peptide levels in early-onset type 1 diabetes (T1D) patients treated with teplizumab, suggesting an improved β cell function. The exposure-response relationship and the safety and effectiveness pharmacodynamic time-response of teplizumab have not been fully elucidated. In the absence of T cell depletion, the use of teplizumab in a 14-day course of treatment can lead to the development of lymphopenia. Cytokine release syndrome (CRS) has also been detected in patients treated with teplizumab. The main manifestations of CRS include fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these manifestations occurred in the first 5 days of treatment. In addition, the use of teplizumab may lead to the development of serious infections and hypersensitivity reactions. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Teplizumab functions by: Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. T1D is a progressive disease with three recognizable stages and in which only Stage 3 is associated with clinically apparent symptoms. The earliest indication of T1D risk is the presence of at least two autoantibodies against relevant antigens, confirming an important role for B cells in what has traditionally been considered a T cell-dominated condition. Combined with other observations from animal and human studies, it is clear that T and B cells play a role in T1D; treatment has focussed on targeting each of them independently, as well as their interactions. The T cell receptor (TCR) comprises TCR α and β chains together with six CD3 molecules, including two CD3 ε chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response. Teplizumab, a humanized IgG1κ Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3γala-ala), is specific for the ε chain of CD3 and inhibits T cell activation through steric inhibition of antigen recognition. Recently, teplizumab has shown efficacy in delaying the time to diagnosis in patients at high risk of developing T1D. However, the exact mechanism underlying this effect remains clear. One hypothesis is that teplizumab acts as a partial agonist at the TCR, increasing the number of exhausted T cells positive for KLRG1, TIGIT, and CD8. These exhausted T cells persist but cannot perform effector functions and, therefore, would be unlikely to contribute to further β cell destruction. Other studies have noted changes in the T cell populations of clinical responders, including an increase in circulating CD8⁺ central memory (CD8CM) T cells. It is clear, however, that treatment is most effective in patients who have not yet progressed to Stage 3 and who have an active immune response. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Teplizumab 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:

Teplizumab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Blood Proteins, CD3-directed Antibody Interactions, Drugs Used in Diabetes, Globulins, Immunoglobulins, Immunoproteins, 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 Teplizumab include:

• Molecular Weight: 150000.0
• Molecular Formula: C6462H9938N1738O2022S46