Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer
The Notch-signaling ligand DLL1 has emerged as an important player and promising therapeutic target in breast cancer (BC). DLL1-induced Notch activation promotes tumor cell proliferation, survival, migration, angiogenesis and BC stem cell maintenance. In BC, DLL1 overexpression is associated with po...
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MDPI AG
2021-08-01
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Series: | Cancers |
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Online Access: | https://www.mdpi.com/2072-6694/13/16/4074 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gabriela Silva Joana Sales-Dias Diogo Casal Sara Alves Giacomo Domenici Clara Barreto Carolina Matos Ana R. Lemos Ana T. Matias Khrystyna Kucheryava Andreia Ferreira Maria Raquel Moita Sofia Braga Catarina Brito M. Guadalupe Cabral Cristina Casalou Duarte C. Barral Pedro M. F. Sousa Paula A. Videira Tiago M. Bandeiras Ana Barbas |
spellingShingle |
Gabriela Silva Joana Sales-Dias Diogo Casal Sara Alves Giacomo Domenici Clara Barreto Carolina Matos Ana R. Lemos Ana T. Matias Khrystyna Kucheryava Andreia Ferreira Maria Raquel Moita Sofia Braga Catarina Brito M. Guadalupe Cabral Cristina Casalou Duarte C. Barral Pedro M. F. Sousa Paula A. Videira Tiago M. Bandeiras Ana Barbas Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer Cancers ER<sup>+</sup> breast cancer Notch signaling DLL1 monoclonal antibody cell proliferation angiogenesis |
author_facet |
Gabriela Silva Joana Sales-Dias Diogo Casal Sara Alves Giacomo Domenici Clara Barreto Carolina Matos Ana R. Lemos Ana T. Matias Khrystyna Kucheryava Andreia Ferreira Maria Raquel Moita Sofia Braga Catarina Brito M. Guadalupe Cabral Cristina Casalou Duarte C. Barral Pedro M. F. Sousa Paula A. Videira Tiago M. Bandeiras Ana Barbas |
author_sort |
Gabriela Silva |
title |
Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer |
title_short |
Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer |
title_full |
Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer |
title_fullStr |
Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer |
title_full_unstemmed |
Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer |
title_sort |
development of dl1.72, a novel anti-dll1 antibody with anti-tumor efficacy against estrogen receptor-positive breast cancer |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-08-01 |
description |
The Notch-signaling ligand DLL1 has emerged as an important player and promising therapeutic target in breast cancer (BC). DLL1-induced Notch activation promotes tumor cell proliferation, survival, migration, angiogenesis and BC stem cell maintenance. In BC, DLL1 overexpression is associated with poor prognosis, particularly in estrogen receptor-positive (ER<sup>+</sup>) subtypes. Directed therapy in early and advanced BC has dramatically changed the natural course of ER<sup>+</sup> BC; however, relapse is a major clinical issue, and new therapeutic strategies are needed. Here, we report the development and characterization of a novel monoclonal antibody specific to DLL1. Using phage display technology, we selected an anti-DLL1 antibody fragment, which was converted into a full human IgG1 (Dl1.72). The Dl1.72 antibody exhibited DLL1 specificity and affinity in the low nanomolar range and significantly impaired DLL1-Notch signaling and expression of Notch target genes in ER<sup>+</sup> BC cells. Functionally, in vitro treatment with Dl1.72 reduced MCF-7 cell proliferation, migration, mammosphere formation and endothelial tube formation. In vivo, Dl1.72 significantly inhibited tumor growth, reducing both tumor cell proliferation and liver metastases in a xenograft mouse model, without apparent toxicity. These findings suggest that anti-DLL1 Dl1.72 could be an attractive agent against ER<sup>+</sup> BC, warranting further preclinical investigation. |
topic |
ER<sup>+</sup> breast cancer Notch signaling DLL1 monoclonal antibody cell proliferation angiogenesis |
url |
https://www.mdpi.com/2072-6694/13/16/4074 |
work_keys_str_mv |
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doaj-0771e7d40c8f4716bb580bc53bffb4182021-08-26T13:35:43ZengMDPI AGCancers2072-66942021-08-01134074407410.3390/cancers13164074Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast CancerGabriela Silva0Joana Sales-Dias1Diogo Casal2Sara Alves3Giacomo Domenici4Clara Barreto5Carolina Matos6Ana R. Lemos7Ana T. Matias8Khrystyna Kucheryava9Andreia Ferreira10Maria Raquel Moita11Sofia Braga12Catarina Brito13M. Guadalupe Cabral14Cristina Casalou15Duarte C. Barral16Pedro M. F. Sousa17Paula A. Videira18Tiago M. Bandeiras19Ana Barbas20iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugalDepartamento de Anatomia, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugalDepartamento de Anatomia, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugaliNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugaliNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugalUCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugaliBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, PortugalThe Notch-signaling ligand DLL1 has emerged as an important player and promising therapeutic target in breast cancer (BC). DLL1-induced Notch activation promotes tumor cell proliferation, survival, migration, angiogenesis and BC stem cell maintenance. In BC, DLL1 overexpression is associated with poor prognosis, particularly in estrogen receptor-positive (ER<sup>+</sup>) subtypes. Directed therapy in early and advanced BC has dramatically changed the natural course of ER<sup>+</sup> BC; however, relapse is a major clinical issue, and new therapeutic strategies are needed. Here, we report the development and characterization of a novel monoclonal antibody specific to DLL1. Using phage display technology, we selected an anti-DLL1 antibody fragment, which was converted into a full human IgG1 (Dl1.72). The Dl1.72 antibody exhibited DLL1 specificity and affinity in the low nanomolar range and significantly impaired DLL1-Notch signaling and expression of Notch target genes in ER<sup>+</sup> BC cells. Functionally, in vitro treatment with Dl1.72 reduced MCF-7 cell proliferation, migration, mammosphere formation and endothelial tube formation. In vivo, Dl1.72 significantly inhibited tumor growth, reducing both tumor cell proliferation and liver metastases in a xenograft mouse model, without apparent toxicity. These findings suggest that anti-DLL1 Dl1.72 could be an attractive agent against ER<sup>+</sup> BC, warranting further preclinical investigation.https://www.mdpi.com/2072-6694/13/16/4074ER<sup>+</sup> breast cancerNotch signalingDLL1monoclonal antibodycell proliferationangiogenesis |