Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies

Ferrari, Mathieu, Righi, Matteo, Baldan, Vania, Wawrzyniecka, Patrycja, Bulek, Anna, Kinna, Alexander, Ma, Biao, Bughda, Reyisa, Akbar, Zulaikha, Srivastava, Saket, Gannon, Isaac, Robson, Mathew, Sillibourne, James, Jha, Ram, El-Kholy, Mohamed, Amin, Oliver Muhammad, Kokalaki, Evangelia, Banani, Mohammed Amin, Hussain, Rehan, Day, William, Lim, Wen Chean, Ghongane, Priyanka, Hopkins, Jade R., Jungherz, Dennis, Herling, Marco, Welin, Martin, Surade, Sachin, Dyson, Michael, McCafferty, John, Logan, Derek, Cordoba, Shaun, Thomas, Simon, Sewell, Andrew ORCID: https://orcid.org/0000-0003-3194-3135, Maciocia, Paul, Onuoha, Shimobi and Pule, Martin 2024. Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies. Nature Communications 15 (1) , 1583. 10.1038/s41467-024-45854-3

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Abstract

Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	23 February 2024
Date of Acceptance:	5 February 2024
Last Modified:	23 Feb 2024 13:15
URI:	https://orca.cardiff.ac.uk/id/eprint/166521

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