Nature Communications (Feb 2024)

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

  • 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

DOI
https://doi.org/10.1038/s41467-024-45854-3
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 16

Abstract

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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.