Toxicology and pharmacokinetics of chimeric ARH460-16-2, a therapeutic monoclonal antibody targeting CD44
Notice bibliographique
Résumé
B41 CD44 is a widely distributed cancer-associated membrane glycoprotein, believed to play a critical role in cellular adhesion, migration, invasion and tumorigenicity. CD44 was recently shown to be expressed in cancer stem cells from several cancer types, including breast, colon, prostate, pancreas and AML. A monoclonal antibody targeting CD44, ARH460-16-2, was identified using the Arius’ FunctionFirst™ platform. The chimeric version of the antibody demonstrated potent dose-dependent tumor growth inhibition in an in vivo established subcutaneous model of breast cancer and in an established orthotopic model of metastatic liver cancer at all doses tested (20, 2 and 0.2 mg/kg). IHC staining of human cancers from breast, prostate, colon, and liver demonstrated that the epitope for ARH460-16-2 is present on the majority of human adenocarcinomas. Limited binding to normal human tissues was observed, predominantly in the bone marrow myeloid series with no binding to erythroid cells, megakaryocytes, endothelium, fibroblasts, smooth muscle, eye, heart, liver, ovary and colon epithelium. The binding pattern was not substantially different in cynomolgus monkey tissues, although some differences in intensity were seen. To enable the clinical development of ARH460-16-2, a dose-finding toxicology study was carried out in cynomolgus monkeys using the chimeric version of the antibody. In the first phase, monkeys (2 per group) were given a single 1 hr infusion of 10, 30 or 95 (high dose) mg/kg chARH460-16-2. A second cohort of 3 monkeys was infused with 25 mg/kg chARH460-16-2 once per week for 2 doses. Animals were observed daily, and clinical chemistry, hematology and coagulation parameters were assessed 24 hr after injection, and then twice more after 9 and 28 days for the first cohort. For the second cohort, analysis was similar except that the final blood collection was carried out at Day 15, at which point the repeat-dose animals were sacrificed for necropsy. In one of the high-dose treated monkeys, and all subjects in the repeat-dose group, there was a transient reddening of the skin which resolved after a few days. There were small decreases in the indicators of circulating erythrocyte mass which were attributable to blood sampling for clinical pathology and toxicokinetic assessments. These changes were accompanied by expected and appropriately increased reticulocyte counts. Other fluctuations in hematology, coagulation, body weight and clinical chemistry parameters were sporadic, transient, observed prestudy, and/or of a magnitude of change that is commonly observed in laboratory-housed cynomolgus monkeys undergoing similar study procedures. Together with the potent anti-tumor effect in models of human cancer, these results support the clinical development of a therapeutic monoclonal antibody targeting the cancer stem cell antigen CD44.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».