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 ho...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45854-3 |
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| author | Mathieu Ferrari Matteo Righi Vania Baldan Patrycja Wawrzyniecka Anna Bulek Alexander Kinna Biao Ma Reyisa Bughda Zulaikha Akbar Saket Srivastava Isaac Gannon Mathew Robson James Sillibourne Ram Jha Mohamed El-Kholy Oliver Muhammad Amin Evangelia Kokalaki Mohammed Amin Banani Rehan Hussain William Day Wen Chean Lim Priyanka Ghongane Jade R. Hopkins Dennis Jungherz Marco Herling Martin Welin Sachin Surade Michael Dyson John McCafferty Derek Logan Shaun Cordoba Simon Thomas Andrew Sewell Paul Maciocia Shimobi Onuoha Martin Pule |
| author_facet | Mathieu Ferrari Matteo Righi Vania Baldan Patrycja Wawrzyniecka Anna Bulek Alexander Kinna Biao Ma Reyisa Bughda Zulaikha Akbar Saket Srivastava Isaac Gannon Mathew Robson James Sillibourne Ram Jha Mohamed El-Kholy Oliver Muhammad Amin Evangelia Kokalaki Mohammed Amin Banani Rehan Hussain William Day Wen Chean Lim Priyanka Ghongane Jade R. Hopkins Dennis Jungherz Marco Herling Martin Welin Sachin Surade Michael Dyson John McCafferty Derek Logan Shaun Cordoba Simon Thomas Andrew Sewell Paul Maciocia Shimobi Onuoha Martin Pule |
| author_sort | Mathieu Ferrari |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0a0cba1c19b24f4e8e75069f7a2b0924 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0a0cba1c19b24f4e8e75069f7a2b09242025-02-02T12:31:06ZengNature PortfolioNature Communications2041-17232024-02-0115111610.1038/s41467-024-45854-3Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignanciesMathieu Ferrari0Matteo Righi1Vania Baldan2Patrycja Wawrzyniecka3Anna Bulek4Alexander Kinna5Biao Ma6Reyisa Bughda7Zulaikha Akbar8Saket Srivastava9Isaac Gannon10Mathew Robson11James Sillibourne12Ram Jha13Mohamed El-Kholy14Oliver Muhammad Amin15Evangelia Kokalaki16Mohammed Amin Banani17Rehan Hussain18William Day19Wen Chean Lim20Priyanka Ghongane21Jade R. Hopkins22Dennis Jungherz23Marco Herling24Martin Welin25Sachin Surade26Michael Dyson27John McCafferty28Derek Logan29Shaun Cordoba30Simon Thomas31Andrew Sewell32Paul Maciocia33Shimobi Onuoha34Martin Pule35Autolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsCardiff University School of Medicine; Heath ParkAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsAutolus TherapeuticsCardiff University School of Medicine; Heath ParkDepartment of Hematology, Cell Therapy, Hemostaseology, and Infectious Diseases, University of Leipzig Medical CentreDepartment of Hematology, Cell Therapy, Hemostaseology, and Infectious Diseases, University of Leipzig Medical CentreSaromics Inc.Iontas Ltd., PampisfordIontas Ltd., PampisfordIontas Ltd., PampisfordSaromics Inc.Autolus TherapeuticsAutolus TherapeuticsCardiff University School of Medicine; Heath ParkCancer Institute; University College LondonAutolus TherapeuticsAutolus TherapeuticsAbstract 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.https://doi.org/10.1038/s41467-024-45854-3 |
| spellingShingle | Mathieu Ferrari Matteo Righi Vania Baldan Patrycja Wawrzyniecka Anna Bulek Alexander Kinna Biao Ma Reyisa Bughda Zulaikha Akbar Saket Srivastava Isaac Gannon Mathew Robson James Sillibourne Ram Jha Mohamed El-Kholy Oliver Muhammad Amin Evangelia Kokalaki Mohammed Amin Banani Rehan Hussain William Day Wen Chean Lim Priyanka Ghongane Jade R. Hopkins Dennis Jungherz Marco Herling Martin Welin Sachin Surade Michael Dyson John McCafferty Derek Logan Shaun Cordoba Simon Thomas Andrew Sewell Paul Maciocia Shimobi Onuoha Martin Pule Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies Nature Communications |
| title | Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies |
| title_full | Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies |
| title_fullStr | Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies |
| title_full_unstemmed | Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies |
| title_short | Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies |
| title_sort | structure guided engineering of immunotherapies targeting trbc1 and trbc2 in t cell malignancies |
| url | https://doi.org/10.1038/s41467-024-45854-3 |
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