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


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.

SUBMITTER: Ferrari M 

PROVIDER: S-EPMC10881500 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Ferrari Mathieu M   Righi Matteo M   Baldan Vania V   Wawrzyniecka Patrycja P   Bulek Anna A   Kinna Alexander A   Ma Biao B   Bughda Reyisa R   Akbar Zulaikha Z   Srivastava Saket S   Gannon Isaac I   Robson Mathew M   Sillibourne James J   Jha Ram R   El-Kholy Mohamed M   Amin Oliver Muhammad OM   Kokalaki Evangelia E   Banani Mohammed Amin MA   Hussain Rehan R   Day William W   Lim Wen Chean WC   Ghongane Priyanka P   Hopkins Jade R JR   Jungherz Dennis D   Herling Marco M   Welin Martin M   Surade Sachin S   Dyson Michael M   McCafferty John J   Logan Derek D   Cordoba Shaun S   Thomas Simon S   Sewell Andrew A   Maciocia Paul P   Onuoha Shimobi S   Pule Martin M  

Nature communications 20240221 1


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 stru  ...[more]

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