Abstract 567: Effectiveness of [225Ac]Ac-labeled anti-MUC-16 radioimmunconjugate against CA125 expressing pancreatic and ovarian cancer xenografts
Notice bibliographique
Résumé
Purpose: Cancer biomarkers like CA125 (MUC-16) are targets for the selective delivery of toxic radiation and/or cytotoxic molecules to tumor loci. MUC-16 is overexpressed in 80% of epithelial ovarian cancer (EOC) and 65% of pancreatic ductal adenocarcinomas (PDAC). Prognosis of EOC and PDAC has remained poor with 5-year survival rate of between 30-50% and 15-20% for EOC & PDAC respectively, hence, the need for new treatment approaches. Our lab has developed a fully human monoclonal antibody (mAb) that binds specifically to MUC-16 and demonstrated the effectiveness of [89Zr]Zr-DFO-MUC-16 as a PET imaging agent. Here, we have developed [225Ac]Ac-Macropa-MUC-16 and investigated its effectiveness against CA125 expressing EOC and PDAC cell derived xenografts (CDX) and patient derived xenografts (PDX). Method: The anti-MUC-16 mAb was conjugated to macrocyclic bifunctional chelator Macropa-NCS and radiolabeled with [225Ac]AcNO3 to produce [225Ac]Ac-Macropa-MUC-16 radioimmunoconjugate (RIC). Quality control assays were conducted to evaluate the integrity of the antibody, stability of the RIC and binding to MUC-16. We developed MUC-16 positive PDAC CDX (SW1990) and PDX (medium MUC-16 expression) and EOC PDXs (high and low MUC-16 expression).Biodistribution studies of [225Ac]Ac-Macropa-MUC-16 was performed in non-tumor bearing mice at different timepoints and used to project organ doses using OLINDA. Groups of tumor-bearing mice were treated using 2 x of 13 kBq of the RIC at day 0 and 10 and tumor growth was monitored. [225Ac]Ac-Macropa-Rituximab was used as a control RIC.Additionally, safety of the RIC was assessed after administration of 1 or 2 doses of the agent to healthy mice followed by clinical chemistry, CBC and histopathology. Results: 16.67% of CDX (SW1990) treated with 2 x 13 kBq of the RIC had complete remission (CR). The remaining 83.33 % in this group had tumor growth suppression for ≥ 50 days post treatment and never reached endpoint (≥ 1500 mm3), while saline and control RIC groups reached end point by day 33.[225Ac]Ac-Macropa-MUC-16 was very effective against high and medium MUC16 expressing PDAC and EOC PDXs, respectively heading to 100% CRs while median survival for control groups was 36 (PDAC) and 47 (EOC) days. The RIC was less effective at inhibiting EOC PDX with low MUC-16 expression. For this, the % tumor growth inhibition (% TGI) was 94.5±6.8% and 84.7±11% at the day 12 and 21, respectively. Although CBC & clinical chemistry show no safety issues, histopathological studies showed mild to moderate pathologies in the liver and spleen for mice exposed to 2 doses of 15 kBq of the RIC. . Conclusion: [225Ac]Ac-Macropa-MUC-16 is effective against MUC-16 expressing EOC and PDAC xenografts. The exciting therapeutic potential is however dependent on the expression level of MUC-16 and points to the significance of heterogeneity within and between tumor types in cancers. Citation Format: Emmanuel Nwangele,Hanan Babeker,Alyssar Monzer,Fabrice Ngoh Njotu,Jessica Pougoue Ketchemen,Alireza Doroudi,Florence-Anjong Tikum,Nikita Henning,Emina Torlakovic,Maruti Uppalapati,Humphrey Fonge. Effectiveness of [225Ac]Ac-labeled anti-MUC-16 radioimmunconjugate against CA125 expressing pancreatic and ovarian cancer xenografts [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 567.
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) | 0,001 | 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 ».