Pharmacodynamic, Biodistribution and Toxicology Results for SNS01-T, a Nanoparticle That Targets eIF5A for the Treatment of Multiple Myeloma
Notice bibliographique
Résumé
Abstract Abstract 2051 Eukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, inflammation, differentiation, and apoptosis and is the only known protein to be post-translationally modified with a hypusine residue. Both hypusinated eIF5A and deoxyhypusine synthase, the enzyme that mediates eIF5A hypusination, have been identified as markers of neoplastic growth and metastasis. Accumulation of unmodified eIF5A is generally only observed during apoptosis and mutants of eIF5A that cannot be hypusinated (eIF5AK50R) are pro-apoptotic. In vitro cell studies and in vivo xenograft models have demonstrated that simultaneous small interfering RNA (siRNA)–mediated suppression of native eIF5A expression and over-expression of eIF5AK50R potently induces apoptosis in multiple cancer cell types, including myeloma, and inhibits human myeloma tumor growth in murine xenograft models. SNS01-T is a nanoparticle comprising: 1) a plasmid encoding the pro-apoptotic eIF5AK50R driven by a B cell specific promoter; 2) an siRNA that inhibits pro-survival hypusine-eIF5A expression; and 3) a polymer that assembles the nucleic acids into a nanoparticle. Pharmacokinetic, pharmacodynamic, biodistribution, and toxicology studies have been conducted with SNS01-T to support studies in multiple myeloma patients. The pharmacokinetics and biodistribution of SNS01-T were evaluated in mice using RT-qPCR to assess the distribution and persistence of plasmid DNA and siRNA. Toxicology includes acute and 6-week studies with twice weekly administration of SNS01-T in male and female mice and dogs. Clinical signs, hematology, histopathology, clinical pathology, pharmacokinetics, and serum cytokines were measured. SNS01-T reached all tissues examined including the bone marrow. No evidence of accumulation of the plasmid or siRNA was observed and levels declined rapidly after the end of treatment. Toxicological findings of SNS01-T administration in mice at 0.25 and 0.5 mg/kg for 6 weeks included clinical signs limited to the injection site, increases in organ weight, increases in IFN-g and GRO, and hematological changes, that could not be attributed solely to the test article. Toxicological findings of SNS01-T administration in beagles at 0.375 and 0.75 mg/kg for 6 weeks included a dose-dependent increase in incidences of clinical signs, resulting in a NOAEL of 0.375 mg/kg. A multiple ascending dose Phase 1b/2a open-label study has been initiated to evaluate the safety and tolerability of six weeks of twice-weekly administration of SNS01-T by intravenous infusion in patients with relapsed or refractory multiple myeloma. Approximately 12–15 patients are being enrolled and administered escalating doses of SNS01-T (Table 1). The patient starting dose is based upon the lower dose evaluated in the mouse toxicology study (0.25 mg/kg). The initial dosage in the clinical study was selected by reducing by a factor of 20 to 0.0125 mg/kg. The primary safety endpoints are the frequency, severity, and duration of treatment-related adverse events in patients following treatment with SNS01-T. Although safety is the primary endpoint of this study, efficacy is being evaluated by time to progression and by changes in values of the following biomarkers: monoclonal (M) protein, hemoglobin, bone marrow plasma cell percentage, plasma cell labeling index, C-reactive protein, and free light chain. Pharmacokinetics of SNS01-T are being assessed by monitoring levels of pExp5A pDNA and eIF5A siRNA in the blood and bone marrow by RT-qPCR. Immunogenicity of SNS01-T is also being assessed in patient samples by monitoring induction of pro-inflammatory cytokines and antibodies to SNS01-T. It is expected that results from the first group of patients will be presented.Table 1:Dose Escalation Schedule by GroupGroupNumber of PatientspExp5A pDNA DoseeIF5A siRNA DoseTotal Nucleic Acid Dose (SNS01-T)130.0083 mg/kg0.0042 mg/kg0.0125 mg/kg230.0333 mg/kg0.0167 mg/kg0.05 mg/kg330.1333 mg/kg0.0667 mg/kg0.2 mg/kg43–60.25 mg/kg0.125 mg/kg0.375 mg/kg Disclosures: Dondero: Senesco Technologies Inc.: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Thompson:Senesco Technologies Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».