| Téléchargement | - Voir la version finale : Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22 (PDF, 7.1 Mio)
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| DOI | Trouver le DOI : https://doi.org/10.1016/j.omton.2024.200775 |
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| Auteur | Rechercher : McComb, Scott1Identifiant ORCID : https://orcid.org/0000-0002-4616-7864; Rechercher : Arbabi-Ghahroudi, Mehdi1; Rechercher : Hay, Kevin A.; Rechercher : Keller, Brian A.; Rechercher : Faulkes, Sharlene; Rechercher : Rutherford, Michael; Rechercher : Nguyen, Tina1; Rechercher : Shepherd, Alex1; Rechercher : Wu, Cunle1; Rechercher : Marcil, Anne1; Rechercher : Aubry, Annie1; Rechercher : Hussack, Greg1; Rechercher : Pinto, Devanand M.1Identifiant ORCID : https://orcid.org/0000-0002-0665-7041; Rechercher : Ryan, Shannon1; Rechercher : Raphael, Shalini1; Rechercher : van Faassen, Henk1; Rechercher : Zafer, Ahmed1; Rechercher : Zhu, Qin1; Rechercher : Maclean, Susanne1; Rechercher : Chattopadhyay, Anindita1; Rechercher : Gurnani, Komal1; Rechercher : Gilbert, Rénald1; Rechercher : Gadoury, Christine1; Rechercher : Iqbal, Umar1; Rechercher : Fatehi, Dorothy1; Rechercher : Jezierski, Anna1; Rechercher : Huang, Jez1; Rechercher : Pon, Robert A.1; Rechercher : Sigrist, Mhairi; Rechercher : Holt, Robert A.; Rechercher : Nelson, Brad H.; Rechercher : Atkins, Harold; Rechercher : Kekre, Natasha; Rechercher : Yung, Eric; Rechercher : Webb, John; Rechercher : Nielsen, Julie S.; Rechercher : Weeratna, Risini D.1 |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Bailleur de fonds | Rechercher : National Research Council Canada |
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| Format | Texte, Article |
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| Sujet | MT: Regular Issue; chimeric antigen receptors; CD22; CAR-T; nanobody; single-domain antibody; preclinical development; cell therapy; CAR optimization; leukemia and lymphoma; hematological malignancy |
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| Résumé | Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic. |
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| Date de publication | 2024-02-14 |
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| Maison d’édition | Cell Press |
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| Licence | |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | f2303280-cf0b-429e-8fa9-eb1be0475385 |
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| Enregistrement créé | 2024-06-18 |
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| Enregistrement modifié | 2024-06-18 |
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