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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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Autores principales: Tapia-Galisteo, Antonio, Sánchez Rodríguez, Íñigo, Aguilar-Sopeña, Oscar, Harwood, Seandean Lykke, Narbona, Javier, Ferreras Gutierrez, Mariola, Navarro, Rocío, Martín-García, Laura, Corbacho, Cesáreo, Compte, Marta, Lacadena, Javier, Blanco, Francisco J., Chames, Patrick, Roda-Navarro, Pedro, Álvarez-Vallina, Luis, Sanz, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837253/
https://www.ncbi.nlm.nih.gov/pubmed/35154908
http://dx.doi.org/10.1080/2162402X.2022.2034355
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author Tapia-Galisteo, Antonio
Sánchez Rodríguez, Íñigo
Aguilar-Sopeña, Oscar
Harwood, Seandean Lykke
Narbona, Javier
Ferreras Gutierrez, Mariola
Navarro, Rocío
Martín-García, Laura
Corbacho, Cesáreo
Compte, Marta
Lacadena, Javier
Blanco, Francisco J.
Chames, Patrick
Roda-Navarro, Pedro
Álvarez-Vallina, Luis
Sanz, Laura
author_facet Tapia-Galisteo, Antonio
Sánchez Rodríguez, Íñigo
Aguilar-Sopeña, Oscar
Harwood, Seandean Lykke
Narbona, Javier
Ferreras Gutierrez, Mariola
Navarro, Rocío
Martín-García, Laura
Corbacho, Cesáreo
Compte, Marta
Lacadena, Javier
Blanco, Francisco J.
Chames, Patrick
Roda-Navarro, Pedro
Álvarez-Vallina, Luis
Sanz, Laura
author_sort Tapia-Galisteo, Antonio
collection PubMed
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(HH) 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 (EGFR(−)EpCAM(−)) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. 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.
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spelling pubmed-88372532022-02-12 Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer Tapia-Galisteo, Antonio Sánchez Rodríguez, Íñigo Aguilar-Sopeña, Oscar Harwood, Seandean Lykke Narbona, Javier Ferreras Gutierrez, Mariola Navarro, Rocío Martín-García, Laura Corbacho, Cesáreo Compte, Marta Lacadena, Javier Blanco, Francisco J. Chames, Patrick Roda-Navarro, Pedro Álvarez-Vallina, Luis Sanz, Laura Oncoimmunology Original Research 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(HH) 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 (EGFR(−)EpCAM(−)) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. 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 & Francis 2022-02-07 /pmc/articles/PMC8837253/ /pubmed/35154908 http://dx.doi.org/10.1080/2162402X.2022.2034355 Text en © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Tapia-Galisteo, Antonio
Sánchez Rodríguez, Íñigo
Aguilar-Sopeña, Oscar
Harwood, Seandean Lykke
Narbona, Javier
Ferreras Gutierrez, Mariola
Navarro, Rocío
Martín-García, Laura
Corbacho, Cesáreo
Compte, Marta
Lacadena, Javier
Blanco, Francisco J.
Chames, Patrick
Roda-Navarro, Pedro
Álvarez-Vallina, Luis
Sanz, Laura
Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
title 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_short Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer
title_sort trispecific t-cell engagers for dual tumor-targeting of colorectal cancer
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837253/
https://www.ncbi.nlm.nih.gov/pubmed/35154908
http://dx.doi.org/10.1080/2162402X.2022.2034355
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