Abstract P6-17-13: ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers
Notice bibliographique
Résumé
Abstract Background: HER2-targeted therapies have transformed the treatment of patients with HER2-expressing breast and gastric cancers. Despite this, there remains a need for new treatments that are well tolerated and effective not only for cancers with high HER2 expression levels but also those with lower levels of expression. ZW49 is an antibody drug conjugate (ADC) that combines a novel auristatin payload (potent anti-cancer agent) with the unique mechanisms of action of the anti-HER2 biparatopic antibody, ZW25, which binds to the same domains as trastuzumab and pertuzumab. In preclinical studies in cancer cell lines with low to high levels of HER2 expression, ZW25 is associated with increased binding and internalization compared to trastuzumab, while the novel N-acyl sulfonamide auristatin payload has demonstrated increased in vivo tolerability compared to other microtubule inhibitors. ZW49 therefore has the potential to address unmet medical need across a range of HER2-expressing cancers. Methods: Multiple in vitro and in vivo experiments were performed to characterize ZW49 as a potential therapeutic candidate. Internalization and cell growth inhibition of ZW49 were evaluated in HER2-expressing cell lines. Anti-tumor activity was assessed in patient-derived xenograft (PDX) tumor models of HER2 low and high expressing breast cancers. Tolerability was assessed in a 6-week repeat-dose non-GLP toxicology study in non-human primates (NHP) with intravenous administration of ZW49 at either 9 mg/kg or 12 mg/kg once every two weeks. Results: In vitro, ZW49 was more rapidly internalized into HER2-expressing cells compared to a monospecific trastuzumab-ADC. ZW49 also displayed potent in vitro cell growth inhibition in several breast cancer cell lines with a range of HER2 expression. This activity was confirmed in multiple in vivo PDX models, including a HER2 IHC 3+ HBCx-13b xenograft where two doses of ZW49 at 3 mg/kg or higher generated tumor regressions, and a HER2 IHC 1+ ST-910 xenograft where a single dose of ZW49 at 6 mg/kg or higher generated regressions. In both models, regressions occurred at exposures that were well tolerated in NHP. In a repeat dose pilot non-GLP study the highest dose tested (12 mg/kg) was considered to be the no observed adverse effect level (NOAEL) and a GLP repeat-dose toxicology study was ongoing at the time of abstract submission. Conclusions: ZW49 is a novel biparatopic HER2-targeted ADC that demonstrated anti-tumor activity in low and high HER2-expressing breast cancer cell lines and PDX models. Notably, tumor regressions were observed at exposure levels that were well tolerated in NHP. These results support the potential of ZW49 as a novel therapeutic agent that may help address unmet medical need in patients with high and low HER2-expressing cancers. Citation Format: Hamblett KJ, Barnscher SD, Davies RH, Hammond PW, Hernandez A, Wickman GR, Fung VK, Ding T, Garnett G, Galey AS, Zwierzchowski P, Clavette BC, Winters GC, Rich JR, Rowse GJ, Babcook JS, Hausman D. ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-13.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».