Pre-clinical safety assessment of VB4-845, an EpCAM binding immunoconjugate
Notice bibliographique
Résumé
2136 VB4-845 is a recombinant fusion protein, consisting of a tumor-targeting antibody fragment fused to a truncated form of Pseudomonas exotoxin A (ETA252-608) that specifically targets the epithelial cell adhesion molecule (EpCAM). EpCAM is highly expressed in a wide variety of epithelial carcinomas including squamous cell carcinoma of the head and neck (SCCHN). VB4-845 is currently being evaluated for this indication in a phase II/III clinical trial using an intratumoural route of administration. In order to select an appropriate animal model for pre-clinical studies, the EpCAM amino acid sequence and epitope binding site of VB4-845 were compared among various species (mouse, rat, dog, rhesus monkey, chimpanzee) to that of humans. Amino acid identity varied from 81.6% (mouse) to 97.6% (chimpanzee) to that of humans. The EpCAM epitope amino acid identity varied from 66.7% (mouse) to 100% (rhesus monkey and chimpanzee) to that of humans. However, immunohistochemistry studies showed that VB4-845 did not cross-react with any species other than chimpanzee, a species in which end-point toxicology studies are not possible. Initial safety studies were conducted in Sprague-Dawley rats. As VB4-845 is in advanced clinical trials, additional toxicology and safety pharmacology studies were carried out in a second species, Cynomolgus monkey. Animals were dosed over a range of 0.015 to 3.5 mg/kg which corresponds to 0.03 to 70 mg in humans, up to 100 times greater than the highest clinical dose. The maximum tolerated dose was determined to be 1 mg/kg based on skin lesions at the injection site associated with other localized or systemic findings suggestive of inflammation (limited usage of affected limb, elevated body temperature, neutrophilia). Potential toxicity of repeated doses of VB4-845 was assessed in a four week repeated-dose study (0.035, 0.175, 0.350 mg/kg) which corresponds to the human clinical dose (0.7 mg) up to 10 times (7.0 mg) the proposed clinical dose. The once weekly subcutaneous (SC) administration did not result in any changes in ophthalmoscopy, neurological assessments, electrocardiography, hematology, urinalysis, organ weight data, or macroscopic findings. Clinical signs were limited to reduced appetite that was dose related but did not result in body weight changes. Localized skin lesions at the treatment sites were also dose related but resulted in inconsequential microscopic changes (foci of minimal-slight chronic inflammation and/or hemorrhage) with no evidence of systemic inflammation. The NOEL was determined to be 0.350 mg/kg. Pharmacokinetic analysis indicated that the maximum drug exposure occurred just less than four hours after SC administration. Safety studies continue to support the use of VB4-845 for the treatment of SCCHN and preparation for market registration.
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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 | 0,003 | 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 | 0,001 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».