Abstract 4876: Avidity engineered multispecific antibodies that are highly efficacious in immune cell stimulation in patient tissue and in mice: significantly improved tumor control and turning cold tumors hot
Notice bibliographique
Résumé
Abstract Introduction: Antibodies and ADCs are mainstays in the treatment of cancer. However, given difficulties in achieving a deep and sustained response, significant improvements are desirable. We report on first in class “Booster” molecules, based on clinically validated ADCC-competent antibodies, equipped with two immunomodulatory domains that are affinity engineered to be functional only when in contact with a tumor cell. We see strong expansion and increased cytotoxicity of immune cells in the presence of cancer cells in vitro, activation of relevant immune cell types ex vivo, and reduction of tumor burden in vivo, with significantly better activity than adoptive cell therapy or control antibody without fusion domains. Methods: NRG mice were engrafted with luciferase expressing SKOV3 cells via intraperitoneal injection 7 days prior to treatment. Mice received 1 million NK cells isolated from healthy donors. Compounds were administered biweekly, and low dose IL2 thrice weekly. Blood was collected weekly, and tumor burden monitored weekly via bioluminescence. ex vivo: in situ activation of tumor infiltrating immune populations was evaluated by nanostring in freshly isolated tumor tissue. in vitro: cytotoxicity was measured by quantifying the number of alive tumor cells using automated microscopy. Expansion was performed by stimulating NK cells weekly with tumor cells that were opsonized with Booster or antibody, NK cells were counted weekly to determine expansion. Results: Mice treated with a HER2 targeting Booster demonstrated superior tumor control than trastuzumab treated mice, with near tumor remission by day 35. High NK counts were observed in the blood of Booster treated mice, and no NK cells were detected in that of trastuzumab treated mice. In the peritoneal cavity, NK counts were up to 600x higher in Booster treated mice than in trastuzumab treated mice. Our Booster reprograms the immune microenvironment ex vivo in freshly isolated tumor tissue, transforming a cold tumor into a hot tumor. It activates multiple cytotoxic and IFN-γ pathways, stimulates CD8+ T cell activation, downregulates pro-tumor pathways in Tregs and induces a phenotypic shift in macrophages from the immunosuppressive M2 to the pro-inflammatory M1 phenotype. In separate in vitro assays we saw sustained expansion and enhanced cytotoxicity of NK cells for at least 6 weeks. Cells stimulated with HER2 Booster showed prolonged tumor control, whereas trastuzumab stimulated cells failed to sustain tumor control beyond 21 days. Conclusion: In correlation with extensive in vitro and ex vivo data, we observe a prolonged and significant improvement in tumor control in mice treated with Boosters compared to mice treated with trastuzumab. Work is ongoing to develop these molecules, with the first clinical trial expected to start in 2026. Citation Format: Sophie Poznanski, Erik Slinger, Jarek Juraszek, Fatemeh Vahedi, Marcelo Pereira, Loreto Parga-Vidal, Dean Lee, Ali Ashkar, Robert Friesen. Avidity engineered multispecific antibodies that are highly efficacious in immune cell stimulation in patient tissue and in mice: significantly improved tumor control and turning cold tumors hot [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4876.
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 | 0,000 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».