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General Description:

Teclistamab, identified by CAS number 2119595-80-9, is a notable compound with significant therapeutic applications. Teclistamab is an IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells and B cell maturation antigen (BCMA) expressed on malignant multiple myeloma cells. Teclistamab consists of an anti-BCMA arm and an anti-CD3 arm connected via two interchain disulfide bonds, allowing the drug to recruit CD3-expressing T cells to BCMA-expressing cells to promote T cell–mediated cytotoxicity. On August 24, 2022, the European Commission (EC) granted conditional marketing authorization of teclistamab as first-in-class bispecific antibody for the treatment of multiple myeloma, marking its first global approval. Teclistamab was later granted accelerated approval by the FDA on October 25, 2022.

Indications:

This drug is primarily indicated for: Teclistamab is indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy. Teclistamab is approved by the EC and FDA under conditional marketing authorization and accelerated approval, respectively. New evidence for this drug will be continuously monitored and reviewed, which will affect continued approval for the drug's indication. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Absorption:

The absorption characteristics of Teclistamab are crucial for its therapeutic efficacy: The mean bioavailability following subcutaneous administration ranges from 69% to 72%. A study involved patients with multiple myeloma who received step-up doses of 0.06 mg/kg and 0.3 mg/kg followed by a subcutaneous dose of 1.5 mg/kg teclistamab once weekly. The mean accumulation ratio between the first and thirteenth weekly treatment dose of 1.5 mg/kg teclistamab was 4.2-fold for C_max, 4.1-fold for C_trough, and 5.3-fold for AUC_tau. The mean (CV%) C_max after administration of 1.5 mg/kg teclistamab was 23.8 mcg/mL (55%). The median (range) T_max of teclistamab after the first and thirteenth treatment doses were 139 (19 to 168) hours and 72 (24 to 168) hours, respectively. Most subjects who received a dosage range of 0.08 mg/kg to 3 mg/kg teclistamab reached steady-state exposure after 12 weekly treatment doses. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Teclistamab is an important consideration for its dosing schedule: Based on non-compartmental analysis, the mean half-life (SD) was 3.8 (1.7) days (individual values ranging up to 8.8 days) following the first treatment intravenous dose of teclistamab. This determines the duration of action and helps in formulating effective dosing regimens.

Volume of Distribution:

Teclistamab is distributed throughout the body with a volume of distribution of: The mean (CV%) volume of distribution of teclistamab was 5.63 L (29%). The volume of distribution of teclistamab increases with increasing body weight. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Teclistamab is a critical factor in determining its safe and effective dosage: Teclistamab exhibits both time-independent and time-dependent clearance. The clearance of teclistamab increases with increasing body weight. In a study involving patients receiving step-up doses of 0.06 mg/kg and 0.3 mg/kg followed by a subcutaneous dose of 1.5 mg/kg teclistamab once weekly, the geometric mean (CV%) clearance is 0.472 L/day (64%) at the thirteenth dose. The mean (CV%) maximal reduction from baseline to the thirteenth treatment dose was 40.8% (56%). Patients who discontinue teclistamab-cqyv after the 13th treatment dose are expected to have a 50% reduction from Cmax in teclistamab-cqyv concentration at a median (5th to 95th percentile) time of 15 (7 to 33) days after Tmax and a 97% reduction from Cmax in teclistamab-cqyv concentration at a median time of 69 (32 to 163) days after Tmax. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Teclistamab exerts its therapeutic effects through: Teclistamab promotes T cell-mediated cytotoxicity against BCMA-expressing myeloma cells. It works to activate and redistribute T cells. Teclistamab treatment was associated with reduced B-cells and increased concentrations of serum cytokines, including IL-6, IL-10, and IL-2R. The soluble form of BCMA, which is produced through cleavage at the transmembrane domain by γ-secretase, in patients with multiple myeloma often correlates with disease progression and shorter overall survival rate. The majority of patients who received teclistamab had a reduction in soluble BCMA within one month of drug treatment. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Teclistamab functions by: B-cell maturation antigen (BCMA) is a member of the tumour necrosis factor family of receptors expressed on the surface of B-lineage cells, as well as late-stage B cells and plasma cells. BCMA interacts with its ligands to activate survival signalling pathways such as NF-kappa B, STAT3, ERK1/2, and AKT/PI3K, and upregulates anti-apoptotic proteins to regulate B-cell maturation, proliferation, and survival. Besides B cells, BCMA is also widely expressed on multiple myeloma (MM) cells and supports the survival of MM cells, making it a promising therapeutic target for therapeutic agents for MM. Teclistamab is a bispecific T cell engaging antibody that targets the CD3 receptor, which is expressed on the surface of T cells, and BCMA, which is expressed on malignant cells. Due to its dual binding sites, teclistamab is able to draw CD3⁺ T cells in close proximity to BCMA⁺ cells, resulting in T cell activation and T cell-mediated cytotoxicity, which is mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. This effect occurs without regard to T cell receptor specificity or reliance on major histocompatibility complex (MHC) Class 1 molecules on the surface of antigen presenting cells. Ultimately, teclistamab promotes the lysis and death of BCMA⁺ cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Teclistamab 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:

Teclistamab is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Monoclonal, Bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, Bispecific Monoclonal Antibodies, Blood Proteins, Immunoglobulins, 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 Teclistamab include:

• Molecular Weight: 146000.0
• Molecular Formula: C6383H9847N1695O2003S40