Treatment of Autosomal Recessive Interleukin-7 Deficiency with NT-I7 (Efineptakin Alfa), Long-Acting Recombinant Human Interleukin-7: An Expanded Access Protocol
Notice bibliographique
Résumé
Background Interleukin-7 (IL-7) is a cytokine required for T cell development and homeostasis. IL-7 signal transduction is mediated by STAT5 phosphorylation and results in cell proliferation and anti-apoptotic effects. While genetic deficiencies in any of the components of IL-7 receptor (IL-7Rα or γ-chain) result in severe combined immunodeficiency, the recently discovered autosomal recessive IL-7 cytokine deficiency presents with a less severe phenotype characterized by T cell lymphopenia, recurrent HPV diseases complicated by cutaneous squamous cell carcinomas, and other opportunistic infections. NT-I7 is a long-acting human recombinant IL-7, and we hypothesize that treatment of patients with autosomal recessive IL-7 deficiency with NT-I7 will result in T cell expansion, regression of HPV-related diseases, and prevention of HPV-related cancers and opportunistic infections. Methods Peripheral blood mononuclear cells (PBMCs) from 2 patients with IL-7 deficiency were studied. Flow cytometric assays were used to evaluate the integrity of the IL-7 signaling axis and its downstream effect on T cell survival and proliferation by measuring the expression of CD127 (IL-7Rα), STAT5-phosphorylation, and BCL-2 and Ki-67 expression in response to IL-7 stimulation. Results Patients with IL-7 deficiency were found to have preserved expression of CD127 on CD4+ but not on CD8+ T cells. Accordingly, STAT5-phosphorylation in response to IL-7 stimulation was reduced in CD8+ T cells compared with healthy subjects. Nevertheless, prolonged ex vivo IL-7 stimulation increased BCL2 and Ki67 expression in both CD4+ and CD8+ T cells to a level comparable with that observed in healthy subjects. Furthermore, a preferential proliferation of CD31+ CD4+ naive T cells was noted. These ex vivo data supported the development of an investigational new drug expanded access clinical protocol using NT-I7, which was designed, approved, and launched. NT-I7 will be given up to 5 injections: 12 weeks apart for the first 3 doses, then every 24 weeks for the final 2 doses, allowing for dose escalation based on safety and clinical response. Conclusions The ex vivo anti-apoptotic and proliferative effect of IL-7 on T cells from patients with IL-7 deficiency raises the promising possibility that NT-I7 will have a similar effect in vivo in this as well as other inborn errors of immunity associated with impaired T cell homeostasis. Figure 1. Baseline CD127 expression, phosphorylated STAT5 and BCL2 signal transduction with IL-7 stimulation, and T cell proliferation assays in IL-7–deficient patients as compared with healthy controls. (a) Expression of CD127 on CD4+ and CD8+ T cells. (b) Phosphorylated STAT5 percent in response to stimulation with IL-7 (1 ng/ml). (c) BCL2 expression after incubation of CD4+ and CD8+ T cells with IL-7. (d) CD4+ and CD8 + T cell proliferation in response to IL-7 incubation as measured by Ki67 expression. (e) Proliferation of naive CD4+ T cells in response to IL-7 incubation as measured by Ki67 expression. Figure 2. Timeline of expanded access protocol screening, NT-I7 dosing, and laboratory monitoring. (a) Timeline of expanded access protocol screening, NT-I7 dosing, and laboratory monitoring. (b) Structure of NT-I7 demonstrating N terminus human IL-7 fused to a hyFc long-acting platform that combines the hinge flexibility of IgD and recycling of IgG4 to minimize protein–protein interactions and increase serum half-life. Table 1. Baseline clinical features of two patients with IL-7 deficiency.
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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».