Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer

Retargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and sele...

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Detalhes bibliográficos
Autores: Tapia Galisteo, Antonio, Aguilar Sopeña, Óscar, Narbona Corral, Javier, Lacadena García-Gallo, Francisco Javier, Roda Navarro, Pedro, Sanz, Laura
Formato: artículo
Fecha de publicación:2022
País:España
Recursos:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/120124
Acesso em linha:https://hdl.handle.net/20.500.14352/120124
Access Level:acceso abierto
Palavra-chave:612.017
616-006.04
Trispecific antibodies
Cancer immunotherapy
Colorectal cancer
scFv
Single-domain antibodies
Tandem antibodies
Ciencias Biomédicas
Inmunología
Oncología
32 Ciencias Médicas
2412 Inmunología
3201.01 Oncología
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oai_identifier_str oai:docta.ucm.es:20.500.14352/120124
network_acronym_str ES
network_name_str España
repository_id_str
spelling Trispecific T-cell engagers for dual tumor-targeting of colorectal cancerTapia Galisteo, AntonioAguilar Sopeña, ÓscarNarbona Corral, JavierLacadena García-Gallo, Francisco JavierRoda Navarro, PedroSanz, Laura612.017616-006.04Trispecific antibodiesCancer immunotherapyColorectal cancerscFvSingle-domain antibodiesTandem antibodiesCiencias BiomédicasInmunologíaOncología32 Ciencias Médicas2412 Inmunología3201.01 OncologíaRetargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and anti-epithelial cell adhesion molecule (EpCAM) single-domain V antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR- and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFREpCAM) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved potency up to 100-fold compared to single-positive cells and significantly prolonged survival . In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity.Taylor and FrancisUniversidad Complutense de Madrid20222022-01-0120222022-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/120124reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F00132 RESISTENCIA A LA INMUNOTERAPIA EN CANCER COLORRECTAL: PAPEL DEL MICROAMBIENTE TUMORAL Y ESTRATEGIAS PARA REVERTIRLA.Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2020-117323RB-I00 CELULAS STAB-T TERAPEUTICAS CONTROLABLES FARMACOLOGICAMENTE PARA EL TRATAMIENTO SEGURO Y EFECTIVO DE TUMORES SOLIDOS Y HEMATOLOGICOSInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 PI16 00357Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available S2010- BMD-2312Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available SAF2017- 89437-Popen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1201242026-06-02T12:44:21Z
dc.title.none.fl_str_mv Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
title Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
spellingShingle Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
Tapia Galisteo, Antonio
612.017
616-006.04
Trispecific antibodies
Cancer immunotherapy
Colorectal cancer
scFv
Single-domain antibodies
Tandem antibodies
Ciencias Biomédicas
Inmunología
Oncología
32 Ciencias Médicas
2412 Inmunología
3201.01 Oncología
title_short Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
title_full Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
title_fullStr Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
title_full_unstemmed Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
title_sort Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
dc.creator.none.fl_str_mv Tapia Galisteo, Antonio
Aguilar Sopeña, Óscar
Narbona Corral, Javier
Lacadena García-Gallo, Francisco Javier
Roda Navarro, Pedro
Sanz, Laura
author Tapia Galisteo, Antonio
author_facet Tapia Galisteo, Antonio
Aguilar Sopeña, Óscar
Narbona Corral, Javier
Lacadena García-Gallo, Francisco Javier
Roda Navarro, Pedro
Sanz, Laura
author_role author
author2 Aguilar Sopeña, Óscar
Narbona Corral, Javier
Lacadena García-Gallo, Francisco Javier
Roda Navarro, Pedro
Sanz, Laura
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 612.017
616-006.04
Trispecific antibodies
Cancer immunotherapy
Colorectal cancer
scFv
Single-domain antibodies
Tandem antibodies
Ciencias Biomédicas
Inmunología
Oncología
32 Ciencias Médicas
2412 Inmunología
3201.01 Oncología
topic 612.017
616-006.04
Trispecific antibodies
Cancer immunotherapy
Colorectal cancer
scFv
Single-domain antibodies
Tandem antibodies
Ciencias Biomédicas
Inmunología
Oncología
32 Ciencias Médicas
2412 Inmunología
3201.01 Oncología
description Retargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and anti-epithelial cell adhesion molecule (EpCAM) single-domain V antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR- and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFREpCAM) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved potency up to 100-fold compared to single-positive cells and significantly prolonged survival . In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/120124
url https://hdl.handle.net/20.500.14352/120124
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F00132 RESISTENCIA A LA INMUNOTERAPIA EN CANCER COLORRECTAL: PAPEL DEL MICROAMBIENTE TUMORAL Y ESTRATEGIAS PARA REVERTIRLA.
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2020-117323RB-I00 CELULAS STAB-T TERAPEUTICAS CONTROLABLES FARMACOLOGICAMENTE PARA EL TRATAMIENTO SEGURO Y EFECTIVO DE TUMORES SOLIDOS Y HEMATOLOGICOS
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 PI16 00357
Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available S2010- BMD-2312
Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available SAF2017- 89437-P
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Taylor and Francis
publisher.none.fl_str_mv Taylor and Francis
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869413632385744896
score 15,812429

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