Abstract 1467: AB-16B5, a therapeutic monoclonal antibody against human clusterin that blocks the epithelial-to-mesenchymal transition
Notice bibliographique
Résumé
Abstract Studies are increasingly implicating clusterin (CLU) as an important contributing factor in cancer promotion and invasion. Although there is evidence that secreted (s) CLU plays a pro-survival role in tumors, recently published results demonstrated that sCLU is also a potent stimulator of the epithelial-to-mesenchymal transition (EMT). A family of monoclonal antibodies (mAbs) specific for human sCLU was generated and a subset of these was found to inhibit the migration and invasion of several types of cancer cells. Importantly, this EMT-inhibiting subset of mAbs all bind to a specific amino acid sequence in sCLU and inhibit metastasis in vivo. The variable regions of the lead candidate mAb were modified using an in silico molecular modeling approach to generate a humanized IgG2, designated AB-16B5, which exhibited almost identical binding parameters compared to the original mouse antibody, with an apparent KD of 2 − 5 nM for recombinant human CLU. Treatment of 4T1 carcinoma cells with AB-16B5 inhibited TGFβ-induced EMT indicating that the biological activity in vitro was maintained in the humanized antibody. Moreover, AB-16B5 inhibited the motility of EMT6 cells in scratch assays and reduced the invasion of DU145 and PC-3 hormone-insensitive human prostate cancer cells when cultured in Matrigel. In animal studies, DU145 prostate cancer cells were implanted in SCID mice and treated with 5 mg/kg AB-16B5 twice per week as a monotherapy or in combination with the anti-mitotic drug, docetaxel (TxT). These experiments showed that the tumors in the AB-16B5 treated animals were 55% smaller than those in the control group. Furthermore, combining the AB-16B5 treatment with that of TxT caused a reduction of tumor size by 40% compared to the TxT-only group. PC-3-derived tumors in SCID mice treated with AB-16B5 showed a similar degree of tumor growth inhibition. Importantly, in both prostate cancer models, the mice exposed to AB-16B5 exhibited a marked increase in their overall survival. Furthermore, AB-16B5 treatment of Nude mice with intra-cardiac implantations of MDA-231 breast cancer cells resulted in a reduction of the number of metastatic bone lesions. The pharmacokinetic parameters of AB-16B5 are comparable to other IgG2 antibodies with its half-life being approximately 15 days following a bolus intravenous injection in mice. Finally, mice exposed to AB-16B5 at 10-times the therapeutic dose displayed no observable signs of toxicity and no major changes in serum biochemistry were detected. In conclusion, AB-16B5 is one of the rare therapeutic mAbs that directly targets EMT to reduce the invasion of tumors. Its therapeutic effects hold much promise to control metastasis from breast and prostate tumors, in addition to enhancing the response to chemotherapeutic drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1467.
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) | 0,000 | 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 | 0,002 |
| 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 ».