A carregar...
Publicação
Development of Dl1.72, a novel anti-DLL1 antibody with anti-tumor efficacy against estrogen receptor-positive breast cancer
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 4.03 MB | Adobe PDF |
Orientador(es)
Resumo(s)
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.
Descrição
Funding Information: Funding: This research was funded by Fundação para a Ciência e Tecnologia, Portugal, grants PTDC/BBB-BMD/4497/2014 (to A.B.) and PD/BD/113987/2015 (to J.S.-D.), iBETXplore grants 3D-ABC-PI-717 (to G.D.) and BiACaT-HER2:JAG1 (to G.S.). iNOVA4Health—UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by Fundação para a Ciência e Tecnolo-gia/Ministério da Ciência, Tecnologia e Ensino Superior, through national funds is acknowledged. Funding from the INTERFACE Programme, through the Innovation, Technology and Circular Economy Fund (FITEC), is gratefully acknowledged. Support was also provided by the Applied Molecular Biosciences Unit—UCIBIO, which is financed by national funds from Fundação para a Ciência e Tecnologia (UIDP/04378/2020 and UIDB/04378/2020). Funding Information: This research was funded by Funda??o para a Ci?ncia e Tecnologia, Portugal, grants PTDC/BBB-BMD/4497/20141 (to A.B.) and PD/BD/113987/2015 (to J.S.-D.), iBETXplore grants 3D-ABC-PI-717 (to G.D.) and BiACaT-HER2:JAG1 (to G.S.). iNOVA4Health?UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by Funda??o para a Ci?ncia e Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior, through national funds is acknowledged. Funding from the INTERFACE Programme, through the Innovation, Technology and Circular Economy Fund (FITEC), is gratefully acknowledged. Support was also provided by the Applied Molecular Biosciences Unit?UCIBIO, which is financed by national funds from Funda??o para a Ci?ncia e Tecnologia (UIDP/04378/2020 and UIDB/04378/2020). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Palavras-chave
Angiogenesis Cell proliferation DLL1 ER breast cancer Monoclonal antibody Notch signaling Tumor growth Oncology Cancer Research SDG 3 - Good Health and Well-being