Abstract 2931: Functional characterization of KJ-103, a novel therapeutic anti-TROP2 heavy chain-only antibody
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. In many solid tumors TROP2 upregulation is associated with increased tumor aggressiveness, metastasis, and decreased survival in difficult-to-treat cancers, making it an attractive target for cancer therapy. TROP2 ADCs have been developed and one has been approved in breast cancer and advanced bladder cancer. The toxicity associated with the toxin payload and the development of resistance to the payload limits their use. We previously described an anti-TROP2 heavy chain-only antibody (HCAb), KJ-103. KJ-103 has demonstrated high potency in in vivo preclinical human models, including breast cancer, colon cancer, esophageal carcinoma and pancreatic cancer. In vivo efficacy of KJ-103 was strongly diminished by use of a IgG4-FALA variant which has negligible interaction with Fc gamma receptors indicating that effector function is the primary mechanism of action. Activity in mouse strains with deficiency in different immune cell types showed that macrophages were the predominant effector cell responsible for in vivo activity. Analysis of the xenograft microenvironment from different cancer models established a clear correlation between the in vivo efficacy and the degree of macrophage infiltration that was independent of the CD47 IHC score. In vitro, KJ-103 induces the phagocytosis by human macrophages of M0, M1 and M2 subtypes. KJ-103 also induced phagocytosis by mouse macrophages, that reflected human CD47 (huCD47)/mouse SIRPα (mSIRPα) affinity. Importantly, in vivo tumor regression was observed in NCG mouse models where there is nM huCD47/mSIRPα alpha affinity. In vivo dose response in SCID and NCG mice which have different huCD47/mSIRPα affinity showed tumor regression at doses levels of 2-10mg/kg in both strains. The huCD47/mSIRPα affinity effect was only obvious at low dose levels (0.5mg/kg). In a dose range finding study in cynomolgus monkeys KJ-103 was very well tolerated with no abnormal observations in clinical parameters and blood clinical chemistry and hematology. KJ-103 has been humanized and has the same degree of activity as the parental antibody. Immunohistochemistry showed that the KJ-103 epitope was expressed across many tumor types, including breast, colon, ovarian, and head and neck among others. KJ-103 is a HCAB that has demonstrated high levels of preclinical potency and safety making it suitable for clinical development for TROP2 positive tumors. Citation Format: Shugang Yao, Hiba Zahreddine, Amit Subedi, Liying Gong, Amogh Nair, Alex Zhou, Tiffany Cheng, Elijus Undzys, Dominic Hou, Lucy Lai, Luis A. Da Cruz, David Young. Functional characterization of KJ-103, a novel therapeutic anti-TROP2 heavy chain-only antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2931.
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 ».