Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. With its dual binding sites, teclistamab is able to draw CD3+ T cells in close proximity to BCMA+ cells, resulting in T cell activation and subsequent lysis and death of BCMA+ cells, 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.
Within the first month of treatment, activation of T-cells, redistribution of T-cells, reduction of B-cells and induction of serum cytokines were observed.
Within one month of treatment with teclistamab, the majority of responders had reduction in soluble BCMA, and a greater reduction in soluble BCMA was observed in subjects with deeper responses to teclistamab.
Teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommended dose). The mean accumulation ratio following subcutaneous weekly dosing of teclistamab at steady state (based on the 7th weekly maintenance dose), was 2.71- and 3.05-fold for Cmax and AUCtau, respectively. The mean bioavailability following teclistamab subcutaneous administration was 69%, relative to intravenous dosing.
Pharmacokinetic parameters of teclistamab following the 1st and 7th recommended maintenance dose of 1.5 mg/kg are shown in the following table.
Pharmacokinetic parameters of teclistamab following the at first and seventh recommended maintenance dose (1.5 mg/kg) in patients with relapsed or refractory multiple myeloma in MajesTEC-1:
| Pharmacokinetic Parameters | 1st maintenance dose of 1.5 mg/kg | 7th maintenance dose of 1.5 mg/kg (steady-state) |
|---|---|---|
| Tmax (hours) | 72.0 (45.8–193) (n=40) | 48.9 (0.0–166) (n=15) |
| Cmax (µg/mL) | 8.74 ± 3.65 (n=40) | 25.3 ± 11.1 (n=15) |
| Ctrough (µg/mL) | 7.67 ± 3.52 (n=38) | 22.1 ± 10.9 (n=27) |
| AUCtau (µg·h/mL) | 1 169 ± 481 (n=38) | 3 905 ± 1 748 (n=13) |
Tmax = Time to reach the Cmax; Cmax = Maximum observed serum teclistamab concentration; Ctrough = Observed serum teclistamab concentration prior to next dose; AUCtau = Area under the concentration-time curve over the weekly dosing interval. Data are presented as mean ± standard deviation, except for Tmax which is presented as median (minimum, maximum).
Based on the population pharmacokinetic model, mean volume of distribution was 4.13 L (48.8% CV (coefficient of variation)) for the central compartment, and 1.34 L for the peripheral compartment.
Teclistamab exhibited both time-independent and time-dependent clearance. Based on the population pharmacokinetic model, the mean time-independent clearance of teclistamab is 0.449 L/day (53.6% CV), with the median of time-dependent clearance contributing approximately 43% of the total clearance at baseline and decreasing rapidly thereafter to less than 10% after Week 8.
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.
Population pharmacokinetic analysis (based on MajesTEC-1) showed that soluble BCMA did not impact teclistamab serum concentrations.
The pharmacokinetics of teclistamab in paediatric patients aged 17 years and younger have not been investigated.
Results of population pharmacokinetic analyses indicate that age (24 to 84 years) and sex did not influence the pharmacokinetics of teclistamab.
No formal studies of teclistamab in patients with renal impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m² ≤ estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m²) or moderate renal impairment (30 mL/min/1.73 m² ≤ eGFR <60 mL/min/1.73 m²) did not significantly influence the pharmacokinetics of teclistamab. Limited data are available from patients with severe renal impairment.
No formal studies of teclistamab in patients with hepatic impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin >1 to 1.5 times upper limit of normal (ULN) and any aspartate aminotransferase (AST), or total bilirubin ≤ULN and AST>ULN) did not significantly influence the pharmacokinetics of teclistamab. No data are available in patients with moderate and severe hepatic impairment.
No animal studies have been performed to assess the carcinogenic or genotoxic potential of teclistamab.
No animal studies have been conducted to evaluate the effects of teclistamab on reproduction and foetal development. In the 5-week repeat-dose toxicity study in cynomolgus monkeys, there were no notable effects in the male and female reproductive organs at doses up to 30 mg/kg/week (approximately 22 times the maximum recommended human dose, based on AUC exposure) intravenously for five weeks.
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