Preclinical Development of an Actinium-225-Labeled Antibody Radio-Conjugate Directed Against CD45 for Targeted Conditioning and Radioimmunotherapy
Notice bibliographique
Résumé
Introduction: Radiolabeled CD45 antibodies have demonstrated clinical promise as targeted conditioning treatments prior to bone marrow transplant (BMT) as a better tolerated and potentially more effective alternative to harsh chemotherapy and/or total body irradiation regimens for myeloablative conditioning. CD45 is expressed on all immune cells, including hematopoietic stem cells and both precursor and mature lymphoid and myeloid cells, with an average copy number up to 200,000 molecules per cell, making it an ideal antigen for directing targeted radiation for conditioning. It is also highly expressed on most lymphomas and leukemias, and approximately 50% of multiple myeloma, further offering the potential for mediating a substantial anti-tumor effect in treated patients. We describe the preclinical development of a novel anti-CD45 antibody radio-conjugate (ARC) that harnesses the power of alpha radiation by arming the pan-CD45 antibody BC8 with Actinium-225 (225Ac). 225Ac is a potent radionuclide with high linear energy transfer (80-100 keV/μm) yet short path length (50-80 μm) to deliver significantly more lethal double strand DNA breaks per alpha track than beta particles. In addition, the use of 225Ac for targeted conditioning has advantages of safe handling and ease of use and a long 10 day half-life that enables flexibility in preparation and use. Methods and Results: To generate 225Ac-BC8, the monoclonal antibody was first conjugated with the DOTA chelator, then labeled with 225Ac, achieving a labeling efficiency typically greater than 80%. 225Ac-BC8 was subsequently purified to high radiochemical purity by column chromatography. Using human CD45+ Ramos lymphoma cell line and EL4 as negative control, 225Ac-BC8 was shown to be stable and retain selective immunoreactivity following conjugation and labeling. To evaluate the anti-tumor potency of 225Ac-BC8, two CD45+ human multiple myeloma (MM) cell lines with high or low relative CD45 antigen density, U266 and H929, respectively, (Collette, et al. 2007) were tested by cell cytotoxicity assay. Following transient exposure (4 or 12 hours) to 225Ac-BC8, the ARC demonstrated potent dose-dependent MM cell killing 72 hours post-treatment, achieving greater than 90% cytotoxicity of both cell lines. To further assess the therapeutic potential of 225Ac-BC8, its anti-tumor activity was tested in subcutaneous (s.c.) xenograft models of H929 and U266. NOD-SCID mice bearing established s.c. tumors were randomized to receive a single dose of 300 nCi of 225Ac-BC8, 300 nCi of an irrelevant radio-conjugate 225Ac-18B7, naked BC8 antibody, or no treatment control. In both models, 225Ac-BC8 exerted complete and durable tumor control for the duration of study. None of the control groups exhibited any anti-tumor effect. Studies to evaluate 225Ac-BC8 in models of CD45+ lymphoma are ongoing. Since BC8 does not cross-react with mouse CD45 and only weakly with macaque CD45, biodistribution, dosimetry and imaging analysis was performed in mice using radio-labeled anti-mouse pan-CD45 surrogate antibody 30F11. SPECT/CT imaging and biodistribution was performed with 111In-labeled 30F11. Following IV administration, 111In-CD45 (30F11) rapidly cleared from the blood and accumulated in immune system organs including spleen, bone marrow, and lymph node. Dosimetry calculations for 225Ac-CD45 (30F11) were determined for absorbed dose to target organs. Only modest uptake was noted in the kidney, but significant uptake occurred in liver, the major site for catabolism of full-length antibodies. 225Ac-CD45 (30F11) is a useful molecule to study the tolerability and myeloablative properties of 225Ac-CD45 antibody for targeted conditioning prior to donor BMT, using B6-Ly5b donor cells in B6-Ly5a mice. Results of ongoing studies will also be presented. Conclusions: The pan-CD45 antibody BC8 was shown to be efficiently conjugated and labeled with the potent alpha emitter 225Ac to mediate robust and selective killing of CD45+ MM cells and xenografts. Biodistribution analysis confirmed selective uptake into organs of the immune system including homing to BM. Supported by ongoing myeloablative/BM reconstitution studies, these preclinical data support the development of 225Ac-BC8 as a novel potent and safe targeted conditioning approach for BMT. Reference: Collette, et al., (2007). Eur. Cytokine Netw. 18:120-126. Disclosures Ludwig: Actinium Pharmaceuticals: Employment, Equity Ownership. Dawicki:Actinium Pharmaceuticals: Research Funding. Geoghegan:Actinium Pharmaceuticals: Employment. Liang:Actinium Pharmaceuticals: Employment. Seth:Actinium Pharmaceuticals: Employment, Equity Ownership. Gokhale:Actinium Pharmaceuticals: Employment. Berger:Actinium Pharmaceuticals, Inc: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment. Dadachova:Actinium Pharmaceuticals: Consultancy, Research Funding; RadImmune Therapeutics: Consultancy, Research Funding.
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 | 0,001 |
| 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 ».