Abstract 1387: Development of novel antiangiogenic biologics: multifunctional VEGF traps
Notice bibliographique
Résumé
Abstract Current anti-VEGF biologics have been successfully used as therapeutic agents for cancer and age-related macular degeneration (AMD). Since these strategies target VEGF systemically, side effects, long-term toxicities, such as proteinuria and thromboembolic events, and need for frequent eye injections in AMD treatment, prevail. Therefore, the aim of this study was to generate novel anti-VEGF biologics that inhibit VEGF activity specifically at the desired target site. Two classes of antibody-based recombinant proteins were engineered that simultaneously bind VEGF and either: 1) the extracellular matrix (ECM) or 2) target-site specific antigens. The first subgroup of proteins, “shV-H traps”, is comprised of a Fc domain shortened form of VEGF-trap linked to a sequence of hydrophobic amino acids, with various affinities for heparin sulfate proteoglycans of the ECM, designed to have a short systemic half-life. The second subgroup of molecules, “V-lassos”, is composed of a C-terminus positioned form of VEGF-trap linked to single-chain variable domain antibodies specific for either HER-2 or fibronectin extra domain B (EDB), expressed on tumour cell surfaces or in the vascular bed of solid tumours, respectively. Recombinant proteins were expressed in transgenic cancer cell lines in a doxycycline inducible manner and were shown to inhibit VEGF activity and also retain the native function of their constituent domains. Specifically, the shV-H traps adhered to the ECM and the HER-2 V-lasso inhibited the proliferation of HER-2 positive cancer cell lines. Xenograft studies were performed using the aforementioned transgenic cancer cell lines in order to determine the efficacy of shV-H traps and Vlasso. shV-H traps were able to inhibit or delay tumour growth of A-673, Pc-3 and HT-29 xenografts. In contrast to soluble VEGF-trap, sh-VH traps were retained at the tumour site and were undetectable in the circulation. Moreover, sh-VH traps did not cause any of the side-effects observed with soluble VEGF-trap, such as delay of wound healing and regression of trachea blood vessels. Both Vlassos were able to inhibit or delay the tumour growth of SKOV-3 and A-673 xenografts. Furthermore, the transgenic approach for inducible expression indicated that HER-2 Vlasso is more effective compared to anti-HER-2 Ab and VEGF-trap used alone or in combination. Preliminary results suggest that high recombinant protein levels can be generated via large-scale production in 293F cells, indicating that the new multifunctional VEGF-traps can be produced in large amounts for clinical studies. These novel classes of anti-angiogenic molecules could potentially be advantageous in a clinical setting. Furthermore, they can be useful in order to further study and understand the mechanisms involved in VEGF inhibition. Finally, similar dual function proteins can be designed for inhibition of other molecules with disease relevance. 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 1387.
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 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) | 0,000 | 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) | 0,001 | 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 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 ».