POTENT AND SPECIFIC KILLING OF SLE B CELLS WITH ALLONK <sup>®</sup> (AB-101), AN ALLOGENEIC CORD BLOOD-NK CELL THERAPY, IN COMBINATION WITH ANTI-CD19 OR ANTI-CD20 MONOCLONAL ANTIBODIES
Notice bibliographique
Résumé
PV250 / #419 Poster Topic: AS24 - SLE-Treatment Background/Purpose Systemic lupus erythematosus (SLE) is a systemic inflammatory disorder involving loss of tolerance and development of autoantibodies. B cells play a crucial role in the pathogenesis of SLE by producing autoantibodies that target self-antigens, leading to tissue damage and inflammation. In individuals with SLE, Natural Killer (NK) cells are often found to be fewer in number and functionally impaired, including defective antibody-dependent cellular cytotoxicity (ADCC), altered differentiation and abnormal cytokine production. Given the reported defects in NK cells from SLE patient samples, we hypothesize that administration of an NK cell therapy, in combination with B cell-depleting monoclonal antibodies (mAbs), will have the potential to induce deeper B cell depletion and improve efficacy, over the mAb alone. Here we demonstrate proof of concept for the use of an NK cell therapy to enhance the depletion of SLE donor B cells in the presence of anti-CD19 or anti-CD20 mAbs by an ADCC mechanism. AlloNK ® is a non-genetically modified, allogeneic, off-the-shelf, cryopreserved NK cell product, currently being evaluated in a Phase 1 clinical trial in combination with rituximab or obinutuzumab in subjects with SLE or lupus nephritis ( NCT06265220 ). Methods Comprehensive immunophenotypic analysis of B and NK cell subsets from SLE (n=9) and healthy donor (n=6) peripheral blood mononuclear cells (PBMC) was conducted by flow cytometry. In addition, PBMC were isolated from SLE donors (n=9) and co-cultured with AlloNK at various effector to target (E:T) ratios and mAbs concentrations to assess ADCC. Results To further investigate these findings, B and NK cell subsets from both SLE patients and healthy individuals were assessed. In SLE patient samples, there was an observed increase in transitional B and a decrease in activated memory B cells compared to healthy individuals. Additionally, SLE patient samples had a reduction in total NK, CD16 and NKG2D but an increase in CD56 bright CD16 neg NK cells compared to healthy donors. AlloNK, which has been optimized for ADCC through the preselection of cord blood units for the natural high-affinity variant of CD16 (158V/V), was tested in combination with anti-CD20 (rituximab, obinutuzumab) or anti-CD19 (tafasitamab) mAbs in a short-term ADCC assay to show specific killing of SLE donor B cells. After 4h, the percentage of caspase 3/7 + B and T cells was determined by flow cytometry. At a 1:1 E:T ratio, AlloNK mediated killing of B cells in the presence of obinutuzumab (range 79-95%), rituximab (range 19-62%), and tafasitamab (range 24-77%) in a dose-dependent manner. Killing was specific as no off-target apoptosis of T cells was observed. Conclusions Taken together, these data suggest that AlloNK has the potential to be effective in combination with mAbs to induce deeper B cell depletion and improved efficacy, over the mAbs alone, in SLE and LN.
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 | 0,000 |
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 ».