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

被引：13

作者：

Ferrari, Mathieu ^{[1
]}

Righi, Matteo ^{[1
]}

Baldan, Vania ^{[1
]}

Wawrzyniecka, Patrycja ^{[2
]}

Bulek, Anna ^{[1
]}

Kinna, Alexander ^{[1
]}

Ma, Biao ^{[1
]}

Bughda, Reyisa ^{[1
]}

Akbar, Zulaikha ^{[1
]}

Srivastava, Saket ^{[1
]}

Gannon, Isaac ^{[1
]}

Robson, Mathew ^{[1
]}

Sillibourne, James ^{[1
]}

Jha, Ram ^{[1
]}

El-Kholy, Mohamed ^{[1
]}

Amin, Oliver Muhammad ^{[1
]}

Kokalaki, Evangelia ^{[1
]}

Banani, Mohammed Amin ^{[1
]}

Hussain, Rehan ^{[1
]}

Day, William ^{[1
]}

Lim, Wen Chean ^{[1
]}

Ghongane, Priyanka ^{[1
]}

Hopkins, Jade R. ^{[2
]}

Jungherz, Dennis ^{[3
]}

Herling, Marco ^{[3
]}

Welin, Martin ^{[4
]}

Surade, Sachin ^{[5
]}

Dyson, Michael ^{[5
]}

Mccafferty, John ^{[5
]}

Logan, Derek ^{[4
]}

Cordoba, Shaun ^{[1
]}

Thomas, Simon ^{[1
]}

Sewell, Andrew ^{[2
]}

Maciocia, Paul ^{[6
]}

Onuoha, Shimobi ^{[1
]}

Pule, Martin ^{[1
,6
]}

机构：

[1] Autolus Therapeut, London, England

[2] Cardiff Univ, Sch Med, Heath Pk, Cardiff, Wales

[3] Univ Leipzig, Dept Hematol Cellular Therapy Hemostaseol & Infect, Med Ctr, Leipzig, Germany

[4] Saromics Inc, Lund, Sweden

[5] Iontas Ltd, Cambridge, England

[6] UCL, Canc Inst, London, England

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

英国生物技术与生命科学研究理事会;

关键词：

CHIMERIC ANTIGEN RECEPTOR; CHAIN CONSTANT-REGION; MONOCLONAL-ANTIBODIES; VARIABLE REGIONS; SPECIFICITY; EXPRESSION; GENERATION; LYMPHOMA; CAR;

D O I：

10.1038/s41467-024-45854-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta-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. The T cell receptor beta-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.

引用

页数：16

共 42 条

[1] Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains [J].