Abstract 324: 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 expressed during development and at lower levels in normal adult tissues. TROP2 has pleiotropic functions including formation of cell-cell junctions by mediating interactions with extracellular and intracellular proteins. In situations of TROP2 deficiency its role in normal tissues appears to be compensated by expression of EpCAM, a highly related family member. In cancer, the levels of TROP2 are increased in many epithelial tumor types. Overexpression of TROP2 confer oncogenic behavior in several in vitro and in vivo models. Both its extracellular and intracellular domains play a role in modulating interactions with ligands and/or receptors and with intracellular signaling partners to result in an oncogenic phenotype. In many solid tumors TROP2 upregulation is associated with increased tumor aggressiveness, metastasis, and decreased survival in large groups of difficult-to-treat cancers, making it an attractive target for cancer therapy. TROP2-based ADCs have been developed and one has been approved for therapeutic use in triple negative breast cancer and advanced bladder cancer. The toxicity associated with the toxin payload limits their use including in combination with chemotherapy in the earlier lines of treatment, and by the development of resistance to the payload. We isolated several anti-TROP2 heavy chain-only antibodies (HCAb) by immunization of a proprietary transgenic HCAb mouse. In this abstract, we describe the properties and activity of several of these antibodies. These antibodies are characterized by potent in vivo antitumor activity in established tumor models in NCG mice in the absence of ADCC, and by the inhibition of tumor cell viability in vitro, directly and in the absence of any effector cells. In NCG mice, which are characterized by a short antibody half-life, anti-TROP2 HCAbs displayed a T1/2 of approximately 3.5 days. These antibodies displayed very potent anti-tumor activity in established tumor xenograft models, causing tumor regression at 2 mg/kg and 80% TGI at 0.5 mg/kg in NCG mice when administered once per week. They also caused tumor regression when dosed once every three weeks in NCG mice and in tumors of very large sizes. Therefore, these antibodies directly target one or more aspects of TROP2 tumor biology that have a profound and long-lasting effect on the cancer cells. Upon glycoengineering, the afucosylated version of the antibodies displayed a strongly enhanced ADCC activity. In vitro they are characterized by different internalization rates which define several non-overlapping epitopes on TROP2. They are characterized by picomolar binding affinity to recombinant human TROP2 as determined by SPR. These antibodies bind with greater affinity to human and cyno but bind poorly to mouse, rat and rabbit. These potent naked TROP2 antibodies represent new opportunities to address TROP2 expressing cancers. Citation Format: Israel Matos, Yahya Ashraf, Hiba Zahreddine, Liying Gong, Amanda Baumholtz, Alex Zhou, Claire Bonfils, Aniel Moya-Torres, Yun Cui, Xiaowei Wang, Richard Wargachuk, Tiffany Cheng, Elijus Undzys, Shugang Yao, Jacynthe Linda Tolouse, Dominic Hou, Gordon Ngan, Luis daCruz, David Young. Discovery of novel functional TROP2 antibodies for treatment of epithelial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 324.
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 ».