Development of Dl1.72, a novel anti-DLL1 antibody with anti-tumor efficacy against estrogen receptor-positive breast cancer

Gabriela Silva, Joana Sales-Dias, Diogo B. 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. BandeirasAna Barbas

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number4074
JournalCancers
Volume13
Issue number16
DOIs
Publication statusPublished - 2 Aug 2021

Keywords

  • Angiogenesis
  • Cell proliferation
  • DLL1
  • ER breast cancer
  • Monoclonal antibody
  • Notch signaling
  • Tumor growth

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