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 M. Hussain, William Day, Wen Chean Lim, Priyanka Ghongane, Jade R. Hopkins, Dennis Jungherz, Marco Herling, M. Welin, Sachin Surade, Michael R. Dyson, John McCafferty, Derek Logan, Shaun Cordoba, Simon Thomas, Andrew K. Sewell, Paul Maciocia, Shimobi Onuoha, Martin Pulé
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.