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 and Martin Pule ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45854-3

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