Dramatically Enhanced Immunopotency and Anti-Tumor Activity of Liposome-Encapsulated CpG Oligonucleotides (ODN) in Mice Is Paralleled by Vigorous and Broad-Based Immune Responses in Cynomolgus Monkeys after Both Intravenous (IV) and Subcutaneous (SC) Administration.
Notice bibliographique
Résumé
Abstract Immunostimulatory CpG ODN have shown great promise in preclinical studies as an immunotherapeutic agent for treatment of a variety of malignant diseases. They are currently being evaluated in a number of clinical trials, the most advanced being Phase III trials for ProMune® (CpG7909; Coley Pharmaceuticals Group Inc/Pfizer Inc) in NSCLC. We have previously shown that encapsulation in liposomal nanoparticles dramatically enhances the immune activity of CpG ODN (LN-CpG ODN) in murine models and show here that this increased activity translates to enhanced anti-tumor activity when administered iv with monoclonal antibodies (mAbs) to enhance antibody-dependent cellular cytotoxicity. Co-administration of the anti-CD20 mAb Rituxan® with LN-CpG ODN, results in a synergistic increase in life span in excess of 500% in a xenogeneic murine model of B-cell lymphoma compared to ≤100% for either Rituxan or LN-CpG ODN individually. To validate the potential of LN-CpG ODN as an immunotherapeutic for treatment of human disease, we have compared the immune activity of LN-CpG ODN and CpG7909 administered sc and iv in non-human primates. We demonstrate that LN-CpG ODN exhibits significant immunostimulatory activity in cynomologus monkey (Macaca facicularis) with the activation of immune cell populations including NK cells, T-lymphocytes and antigen presenting cells as judged by rapid upregulation of CD69 or CD86 to levels 2–4 fold above control. Consistent with these observations, LN-CpG ODN also induces significant elevation in plasma levels of a number of cytokines and chemokines including IL-1ra and IL-6 and MCP-1 and MIP-1α respectively. Compared to CpG7909, a CpG ODN that has been optimized for human/primate reactivity, LN-CpG ODN is equal or superior in almost all of the immune parameters monitored in these studies including up to 3 fold higher levels of cell activation and plasma cytokines/chemokines than seen with equivalent doses of CpG7909. Moreover, LN-CpG ODN is extremely well tolerated at the doses tested in these studies, with no signs of toxicity based on clinical observations or blood (hematology, chemistry) parameters. Currently, sc represents the preferred route of administration for CpG ODN in the clinic as little to no immune stimulation has been observed when given iv. We believe that iv administered, encapsulated CpG ODN will induce enhanced immune stimulation by targeting CpG ODN to phagocytic immune effector cells. Potential therapeutic advantages include systemic activation of NK cells to enhance the ADCC mechanism of action for mAb drugs and the activation of immune cells at tumor sites. In conclusion, these data demonstrate that encapsulation within liposomal nanoparticles is an effective and feasible strategy by which to enhance the immune activity of CpG ODN in non-human primates and support the potential application of LN-CpG ODN as an effective immunotherapeutic for treatment of human disease.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 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) | 0,002 | 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 ».