| Download | - View final version: Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22 (PDF, 7.1 MiB)
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| DOI | Resolve DOI: https://doi.org/10.1016/j.omton.2024.200775 |
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| Author | Search for: McComb, Scott1ORCID identifier: https://orcid.org/0000-0002-4616-7864; Search for: Arbabi-Ghahroudi, Mehdi1; Search for: Hay, Kevin A.; Search for: Keller, Brian A.; Search for: Faulkes, Sharlene; Search for: Rutherford, Michael; Search for: Nguyen, Tina1; Search for: Shepherd, Alex1; Search for: Wu, Cunle1; Search for: Marcil, Anne1; Search for: Aubry, Annie1; Search for: Hussack, Greg1; Search for: Pinto, Devanand M.1ORCID identifier: https://orcid.org/0000-0002-0665-7041; Search for: Ryan, Shannon1; Search for: Raphael, Shalini1; Search for: van Faassen, Henk1; Search for: Zafer, Ahmed1; Search for: Zhu, Qin1; Search for: Maclean, Susanne1; Search for: Chattopadhyay, Anindita1; Search for: Gurnani, Komal1; Search for: Gilbert, Rénald1; Search for: Gadoury, Christine1; Search for: Iqbal, Umar1; Search for: Fatehi, Dorothy1; Search for: Jezierski, Anna1; Search for: Huang, Jez1; Search for: Pon, Robert A.1; Search for: Sigrist, Mhairi; Search for: Holt, Robert A.; Search for: Nelson, Brad H.; Search for: Atkins, Harold; Search for: Kekre, Natasha; Search for: Yung, Eric; Search for: Webb, John; Search for: Nielsen, Julie S.; Search for: Weeratna, Risini D.1 |
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| Affiliation | - National Research Council of Canada. Human Health Therapeutics
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| Funder | Search for: National Research Council Canada |
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| Format | Text, Article |
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| Subject | 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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| Abstract | 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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| Publication date | 2024-02-14 |
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| Publisher | Cell Press |
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| Licence | |
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| In | |
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| Language | English |
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| Peer reviewed | Yes |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | f2303280-cf0b-429e-8fa9-eb1be0475385 |
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| Record created | 2024-06-18 |
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| Record modified | 2024-06-18 |
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