Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
(2024) In Nature Communications 15(1).- 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... (More)
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.
(Less)
- author
- Ferrari, Mathieu
; Righi, Matteo
; Baldan, Vania
; Wawrzyniecka, Patrycja
; Bulek, Anna
; Kinna, Alexander
; Ma, Biao
; Bughda, Reyisa
; Akbar, Zulaikha
; Srivastava, Saket
; Gannon, Isaac
; Robson, Mathew
; Sillibourne, James
; Jha, Ram
; El-Kholy, Mohamed
; Amin, Oliver Muhammad
; Kokalaki, Evangelia
; Banani, Mohammed Amin
; Hussain, Rehan
; Day, William
; Lim, Wen Chean
; Ghongane, Priyanka
; Hopkins, Jade R.
; Jungherz, Dennis
; Herling, Marco
; Welin, Martin
; Surade, Sachin
; Dyson, Michael
; McCafferty, John
; Logan, Derek
LU
; Cordoba, Shaun
; Thomas, Simon
; Sewell, Andrew
; Maciocia, Paul
; Onuoha, Shimobi
and Pule, Martin
(Less) - publishing date
- 2024-02-21
- type
- Contribution to journal
- publication status
- published
- keywords
- Humans, T-Lymphocytes, Immunotherapy, Receptors, Antigen, T-Cell, Neoplasms
- in
- Nature Communications
- volume
- 15
- issue
- 1
- article number
- 1583
- pages
- 16 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85185620850
- pmid:38383515
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-024-45854-3
- language
- English
- LU publication?
- no
- additional info
- © 2024. The Author(s).
- id
- 10859a00-f434-4897-ad0f-3dd210a5a7c2
- date added to LUP
- 2024-02-26 09:09:44
- date last changed
- 2024-04-13 06:04:22
@article{10859a00-f434-4897-ad0f-3dd210a5a7c2,
abstract = {{<p>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.</p>}},
author = {{Ferrari, Mathieu and Righi, Matteo and Baldan, Vania and Wawrzyniecka, Patrycja and Bulek, Anna and Kinna, Alexander and Ma, Biao and Bughda, Reyisa and Akbar, Zulaikha and Srivastava, Saket and Gannon, Isaac and Robson, Mathew and Sillibourne, James and Jha, Ram and El-Kholy, Mohamed and Amin, Oliver Muhammad and Kokalaki, Evangelia and Banani, Mohammed Amin and Hussain, Rehan and Day, William and Lim, Wen Chean and Ghongane, Priyanka and Hopkins, Jade R. and Jungherz, Dennis and Herling, Marco and Welin, Martin and Surade, Sachin and Dyson, Michael and McCafferty, John and Logan, Derek and Cordoba, Shaun and Thomas, Simon and Sewell, Andrew and Maciocia, Paul and Onuoha, Shimobi and Pule, Martin}},
issn = {{2041-1723}},
keywords = {{Humans; T-Lymphocytes; Immunotherapy; Receptors, Antigen, T-Cell; Neoplasms}},
language = {{eng}},
month = {{02}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies}},
url = {{http://dx.doi.org/10.1038/s41467-024-45854-3}},
doi = {{10.1038/s41467-024-45854-3}},
volume = {{15}},
year = {{2024}},
}