1185 Optimization of purine-based TLR7 agonists as payloads for immune-stimulating antibody conjugates (ISACs)
Notice bibliographique
Résumé
<h3>Background</h3> Immune-stimulating antibody conjugates (ISACs) consist of antibodies conjugated to immune stimulants and are designed to induce antitumor immune response. Despite promising preclinical results, ISAC clinical development has been hampered by systemic toxicities or lack of efficacy. Substituted purines have previously been identified as a privileged scaffold to elicit TLR7 activation. Here, we demonstrate newly designed purine-based TLR7 agonists conjugated to trastuzumab which show significant tumor volume reduction in a HER2-high gastric cancer xenograft model without associated body weight loss (BWL) in healthy mice. <h3>Methods</h3> A library of TLR7 agonists was generated by varying substituents at C2- and N9-positions of a common 6-amino-8-hydroxy-purine scaffold, and the structure-activity relationship was studied <i>in vitro</i> using human and mouse TLR7 reporter gene assays (RGAs) as well as measuring cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and mouse splenocytes. Lead TLR7 agonists were conjugated to trastuzumab, and the resulting ISACs were evaluated <i>in vitro</i> for their abilities to induce the production of interleukin-6 (IL-6) from human PBMCs or mouse splenocytes co-cultured with NCI-N87 tumor cells. Selected ISACs were tested for efficacy (single iv injection at 2.5 mg/kg) in mice bearing NCI-N87 tumors (figure 1) and for tolerability (single iv injection at 3, 15, and 45 mg/kg) in healthy mice (figure 2). <h3>Results</h3> We prepared ~220 new TLR7 agonists with different substituents at C2- and N9-positions of the purine scaffold. Compounds with IC50 <100 nM in both human and mouse TLR7 RGAs were further screened for their abilities to induce production of cytokines in PBMCs and mouse splenocytes. Certain substituents were found to be highly immunostimulatory in both human and murine settings. Lead TLR7 agonists were conjugated to trastuzumab with a drug-to-antibody ratio of ~4 using cleavable or non-cleavable linkers. ISACs capable of inducing IL-6 production from PBMCs or splenocytes co-cultured with tumor cells were further tested in an NCI-N87 xenograft model in comparison to unconjugated trastuzumab and trastuzumab conjugated with the same linker-payload as NJH395, a clinical benchmark ISAC. Selected ISACs were tested for tolerability in healthy mice with a lead ISAC (Trastuzumab-MTvkPABC-P5) identified, capable of inducing tumor regression without causing BWL. <h3>Conclusions</h3> We demonstrated the potential of using novel purine-based TLR7 agonists as payloads for ISACs. In contrast to other TLR7-agonist conjugates, our lead ISAC appears to have a sufficiently wide therapeutic window displaying efficacy in an NCI-N87 xenograft model at 2.5 mg/kg without causing BWL in healthy mice at 45 mg/kg. <h3>Ethics Approval</h3> All animal studies were performed in accordance with Institutional Animal Care and Use Committee (IACUC)-approved protocols.
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 | 0,000 | 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) | 0,000 | 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 ».