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

Author

Listed:
  • Mathieu Ferrari

    (Autolus Therapeutics)

  • Matteo Righi

    (Autolus Therapeutics)

  • Vania Baldan

    (Autolus Therapeutics)

  • Patrycja Wawrzyniecka

    (Cardiff University School of Medicine; Heath Park)

  • Anna Bulek

    (Autolus Therapeutics)

  • Alexander Kinna

    (Autolus Therapeutics)

  • Biao Ma

    (Autolus Therapeutics)

  • Reyisa Bughda

    (Autolus Therapeutics)

  • Zulaikha Akbar

    (Autolus Therapeutics)

  • Saket Srivastava

    (Autolus Therapeutics)

  • Isaac Gannon

    (Autolus Therapeutics)

  • Mathew Robson

    (Autolus Therapeutics)

  • James Sillibourne

    (Autolus Therapeutics)

  • Ram Jha

    (Autolus Therapeutics)

  • Mohamed El-Kholy

    (Autolus Therapeutics)

  • Oliver Muhammad Amin

    (Autolus Therapeutics)

  • Evangelia Kokalaki

    (Autolus Therapeutics)

  • Mohammed Amin Banani

    (Autolus Therapeutics)

  • Rehan Hussain

    (Autolus Therapeutics)

  • William Day

    (Autolus Therapeutics)

  • Wen Chean Lim

    (Autolus Therapeutics)

  • Priyanka Ghongane

    (Autolus Therapeutics)

  • Jade R. Hopkins

    (Cardiff University School of Medicine; Heath Park)

  • Dennis Jungherz

    (University of Leipzig Medical Centre)

  • Marco Herling

    (University of Leipzig Medical Centre)

  • Martin Welin

    (Saromics Inc.)

  • Sachin Surade

    (Iontas Ltd., Pampisford)

  • Michael Dyson

    (Iontas Ltd., Pampisford)

  • John McCafferty

    (Iontas Ltd., Pampisford)

  • Derek Logan

    (Saromics Inc.)

  • Shaun Cordoba

    (Autolus Therapeutics)

  • Simon Thomas

    (Autolus Therapeutics)

  • Andrew Sewell

    (Cardiff University School of Medicine; Heath Park)

  • Paul Maciocia

    (Cancer Institute; University College London)

  • Shimobi Onuoha

    (Autolus Therapeutics)

  • Martin Pule

    (Autolus Therapeutics
    Cancer Institute; University College London)

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.

Suggested Citation

  • Mathieu Ferrari & Matteo Righi & Vania Baldan & Patrycja Wawrzyniecka & Anna Bulek & Alexander Kinna & Biao Ma & Reyisa Bughda & Zulaikha Akbar & Saket Srivastava & Isaac Gannon & Mathew Robson & Jame, 2024. "Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45854-3
    DOI: 10.1038/s41467-024-45854-3
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    References listed on IDEAS

    as
    1. De Dong & Lvqin Zheng & Jianquan Lin & Bailing Zhang & Yuwei Zhu & Ningning Li & Shuangyu Xie & Yuhang Wang & Ning Gao & Zhiwei Huang, 2019. "Structural basis of assembly of the human T cell receptor–CD3 complex," Nature, Nature, vol. 573(7775), pages 546-552, September.
    2. Hege Beard & Anuradha Cholleti & David Pearlman & Woody Sherman & Kathryn A Loving, 2013. "Applying Physics-Based Scoring to Calculate Free Energies of Binding for Single Amino Acid Mutations in Protein-Protein Complexes," PLOS ONE, Public Library of Science, vol. 8(12), pages 1-1, December.
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