SUPERDIMERIC ANTIBODY-LIKE MOLECULE WITH DUAL FC DOMAINS PROVIDES POTENT B CELL DEPLETION WITH MINIMAL CYTOKINE INDUCTION VIA TARGETING OF CD19, CD20 AND FC GAMMA RECEPTORS
Notice bibliographique
Résumé
PV265 / #821 Poster Topic: AS24 - SLE-Treatment Background/Purpose Potent tissue B cell depletion using CD19-targeting CAR-T cells or T cell engagers in patients with autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) has led to durable clinical responses in early clinical studies and the results suggest the potential to reset the autoreactive immune system for long-term disease remission. However, there are limits to the safety and accessibility of CD19-targeting CAR-T cells or T cell engagers across large patient populations. While antibodies targeting CD20 have provided significant responses in several autoimmune diseases, they do not deplete CD19 + /CD20 - autoantibody-secreting plasmablasts or pro-B cells in bone marrow. Antibodies targeting CD19 have shown efficacy in Neuromyelitis optica spectrum disorder (NMOSD) and IgG4-related disease in clinical trials. Deep and broad depletion of B cells by targeting both CD19 plus CD20 with an antibody-based approach may provide additional clinical benefits by restoring immune homeostasis in autoimmune diseases with low risk of cytokine-mediated adverse events. Methods Here we describe HB2198 generated using the GEM-DIMER™ platform. HB2198 was designed for bivalent target binding to both CD20 (Fab domains derived from rituximab) and CD19 (Fab domains derived from humanized version of FMC63, the parental antibody used to generate approved CD19-targeting CAR-T cell therapies) and importantly, contains 2 Fc domains both with amino acid variants S239D and I332E, further increasing Fc gamma receptor binding and immune effector functions. We assessed the B cell depletion, T and NK cell activation, and inflammatory cytokine release in response to HB2198 by flow cytometry, ELISA, and functional assays in vitro using cell lines and primary immune cells from healthy individuals and patients. Pharmacodynamic effects in vivo were evaluated in non-human primates. Results HB2198 exhibited enhanced Antibody-Dependent Cellular Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP) immune effector functions over conventional antibodies targeting CD19 or CD20. HB2198 potently depleted B cells from healthy human whole blood after overnight culture. Further, HB2198 depleted memory B cells from healthy and SLE patient PBMCs ex vivo . Importantly, little or no induction of inflammatory cytokines IFN-γ, IL-6, TNF-α, or IL-2 was detected in vitro and in vivo . These findings contrasted with dose-dependent, potent in vitro cytokine induction observed in the presence of a CD20-CD3 T cell engager. Infusion of HB2198 into cynomolgus monkeys led to >99% depletion of circulating B cells within 1-3 days and durable depletion of memory B cells with minimal inflammatory cytokine response in vivo . Conclusions HB2198 demonstrated potent B cell depletion in vitro and long-term reduction in memory B cell depletion in vivo , suggesting the potential for broad and deep depletion of autoantibody producing cells. Importantly, minimal induction of proinflammatory cytokines was observed in vitro and in vivo . These data support the advancement of HB2198 in autoimmune indications where depletion of CD19 + and/or CD20 + cells would provide clinical benefit.
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 | 0,001 | 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 ».