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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Detalhes bibliográficos
Autor principal: Silva, G (author)
Outros Autores: Sales-Dias, J (author), Casal, D (author), Alves, S (author), Domenici, G (author), Barreto, C (author), Matos, C (author), Lemos, A (author), Matias, A (author), Kucheryava, K (author), Ferreira, A (author), Moita, MR (author), Braga, S (author), Brito, C (author), Cabral, MG (author), Casalou, C (author), Barral, D (author), Sousa, P (author), Videira, P (author), Bandeiras, T (author), Barbas, A (author)
Formato: article
Idioma:eng
Publicado em: 2021
Assuntos:
HSJ ANPAT
DLL1
ER+ Breast Cancer
Notch Signaling
Angiogenesis
Cell Proliferation
Monoclonal Antibody
Tumor Growth.
Texto completo:http://hdl.handle.net/10400.17/3881
País:Portugal
Oai:oai:repositorio.chlc.min-saude.pt:10400.17/3881
Descrição
Resumo: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+) subtypes. Directed therapy in early and advanced BC has dramatically changed the natural course of ER+ 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+ 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+ BC, warranting further preclinical investigation.

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