Abstract LBA018: Discovery of novel functional TROP2 antibodies for treatment of epithelial cancers
Notice bibliographique
Résumé
Abstract Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein with an extracellular domain highly expressed in a wide range of late-stage epithelial cancers. TROP2 upregulation in solid cancers is associated with increased tumor aggressiveness, metastasis, and an overall decreased survival in large groups of difficult-to-treat cancers, making it an attractive target for cancer therapy. TROP2 positive cancers have been successfully targeted by antibody-drug conjugates (ADC) but not naked functional antibodies. ADC’s have associated drug toxicity in healthy tissues, off-target effects, and payload delivery issues. Given ADC dose-limiting side effects, narrow therapeutic windows, and efficacy limitations, there is a pressing need to improve anti-TROP2 therapeutics for patients who are poorly served by current therapies, if at all. Understanding these needs, we applied our proprietary heavy chain-only antibody (HCAb) transgenic mouse platform to the creation of therapeutic anti-TROP2 antibodies. After immunization, anti-TROP2 antibodies were selected using VHH (variable region of HCAbs)-phage-display. Due to their size and shape, VHH antibodies target a broader spectrum of epitopes compared to full size VH/VL antibodies. Further, VHH antibodies are associated with high affinity, stability, and robustness. In this abstract, we describe five novel anti-TROP2 HCAbs without ADC payloads that induce in vivo tumor regression in murine xenograft models of human cancers. When tested in an in vitro viability assay with the MDA-MB-453 triple negative breast cancer (TNBC) cell line, a novel anti-TROP2 HCAb significantly reduced cancer cell numbers compared to other anti-TROP2 antibodies in the absence of complement or effector cells. In the in vivo MDA-MB-453 TNBC established xenograft model, tumor regression was achieved with five different TROP2 HCAbs at 8mg/kg administered once per week, and in the in vivo established model of MDA-MB-231 strong anti-tumor efficacy was also achieved. In binding cross-reactivity experiments, anti-TROP2 HCAbs showed similar binding to human and cynomolgus TROP2 and low binding to the mouse or rat orthologs. Anti-TROP2 HCAbs bind to a panel of TROP2-expressing human cancer cell lines, including a wide range of human epithelial tumours, such as breast, colon, lung and pancreatic cancers. Epitope binding by competitive ELISA showed that binding to TROP2 by these HCAbs could not be competed by hRS7 or other anti-TROP2 antibodies demonstrating that they target epitopes different from known TROP2 antibodies. Our preclinical data demonstrates the potent anti-tumor activity on TROP2-positive cancers by novel anti-TROP2 HCAbs without the need for cytotoxic payloads. These results and additional data highlight the feasibility of developing functional anti-TROP2 antibodies for clinical use which avoid the challenges of ADCs. Citation Format: Israel Matos, Hiba Zahreddine, Yahya Ashraf, Aditya Pandey, Emily Chen, Liying Gong, Alex Zhou, Claire Bonfils, Aniel Moya, Yun Cui, Xiaowei Wang, Elijus Undzyz, Shugang Yao, Jacynthe Toulouse, Dominic Hou, Gordon Ngan, Luis da Cruz, David Young. Discovery of novel functional TROP2 antibodies for treatment of epithelial cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA018.
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) | 0,002 | 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 ».