Dinutuximab beta is a chimeric monoclonal IgG1 antibody that is specifically directed against the carbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells.
Dinutuximab beta has been shown in vitro to bind to neuroblastoma cell lines known to express GD2 and to induce both complement dependent cytoxicity (CDC) and antibody dependent cell-mediated cytoxicity (ADCC). In the presence of human effector cells, including peripheral blood nuclear cells and granulocytes from normal human donors, dinutuximab beta was found to mediate the lysis of human neuroblastoma and melanoma cell lines in a dose-dependent manner. Additionally, in vivo studies demonstrated that dinutuximab beta could suppress liver metastasis in a syngeneic liver metastasis mouse model.
Neurotoxicity associated to dinutuximab beta is likely due to the induction of mechanical allodynia that may be mediated by the reactivity of dinutuximab beta with the GD2 antigen located on the surface of peripheral nerve fibres and myelin.
Dinutuximab beta has been investigated using short-term infusions (STI – five days of eight-hour infusions at 20 mg/m²/day) and long-term infusions (LTI – ten days of continuous infusion at 100 mg/m²).
Dinutuximab beta is administered as an intravenous infusion. The maximum concentration (mean (± SD)) at the end of the long-term infusion was 11.2 (± 3.3) mg/L. Other routes of administration have not been investigated.
The population mean (±SD) estimate for the central volume of distribution was 2.04 (± 1.05) L and for the peripheral volume of distribution 2.65 (±1.01) L.
The metabolism of dinutuximab beta has not been investigated. As a protein, dinutuximab beta is expected to be metabolised to small peptides and individual amino acids by ubiquitous proteolytic enzymes.
The clearance after the LTI was 0.72 (± 0.24) L/d/m². The accumulation ratio for Cmax was 1.13 (± 0.54) after 5 LTI courses (mean (±SD)). The apparent terminal elimination t1/2 was 8.7 (± 2.6) days (mean (± SD)). The clearance of dinutuximab beta increased in the presence of high anti-drug antibody titres regardless of neutralising activity.
Variations in dose of the first infusion in Study 2 revealed a dose-proportional increase in exposure (AUC∞) up to the recommended dose of 100 mg/m² per course for 10 days.
The age of patients ranged from 1 to 27 years (median 6 years). Body weight ranged from 9 to 75 kg (median 18.5 kg) and body-surface area ranged from 0.44 to 1.94 m² (median 0.75 m²). A two-compartment population-PK model with first-order elimination from the central compartment was developed using the data from 224 patients in four studies (STI 30 patients, LTI 194 patients). Volume and clearance parameters increased across the ranges with increasing body size. Body weight and ADA titre were covariates for clearance while body weight, age and IL-2 co-administration were covariates for volume of distribution.
The population pharmacokinetic analyses showed comparable exposure to dinutuximab beta in patients of all ages studied when dosed at 100 mg/m².
The population pharmacokinetic analysis with 89 female (40%) and 135 male (60%) patients showed no clinically meaningful effect of gender on dinutuximab beta pharmacokinetics.
Since the PK analysis population was predominantly Caucasian (92.9%) race was not formally examined as a potential PK covariate.
Dosing on the basis of body surface area provides consistent exposure across populations.
No formal studies have been conducted in patients with renal impairment. Renal function was not a significant covariate in population pharmacokinetic analyses that included patients with normal renal function and mild renal impairment.
No formal studies have been conducted in patients with hepatic impairment. Subjects with ALT >3x ULN had comparable pharmacokinetics as subjects with ALT≤3x ULN.
Dinutuximab beta has been administered to male and female juvenile Guinea pigs, as well as male and female young cynomolgus monkeys, as repeat-dose regimens that exceeded the recommended clinical dose. Findings of note included changes (decrease) in thymus weight as well as bone marrow changes (atrophy affecting myeloid and erythroid precursor cell lines). The bone marrow changes were slight to severe and recovered after cessation of dosing. No effects on cardiovascular functions (ECG, blood pressure) were observed in monkeys.
No non-clinical studies to evaluate the potential of dinutuximab beta to cause carcinogenicity, genotoxicity or developmental and reproductive toxicity have been conducted. In the repeat-dose toxicity studies in Guinea pigs and cynomolgus monkeys, no adverse effects of dinutuximab beta were observed on reproductive organs at exposure levels above clinical levels.
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