Simple SummaryOver 70% of breast cancers (BCs) are estrogen receptor-positive (ER+). The development of endocrine therapy has considerably improved patient outcomes. However, there is a clinical need for novel effective therapies against ER+ BCs, since many of these do not respond to standard therapy, and more than one-third of responders acquire resistance, experience relapse and metastasize. The Notch ligand Delta-like 1 (DLL1) is a key player in ER+ BC development and aggressiveness. Contrary to complete Notch pharmacological inhibitors, antibody-targeting of individual Notch components is expected to have superior therapeutic efficacy and be better tolerated. In this study, we developed and characterized a novel specific anti-DLL1 antibody with efficacy in inhibiting BC cell proliferation, mammosphere formation and angiogenesis, as well as anti-tumor and anti-metastatic efficacy in an ER+ BC mouse model without side effects. Thus, our data suggest that this anti-DLL1 antibody is a promising candidate for ER+ BC treatment.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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Sep 4, 2024
Debangshu Samanta + 5
Open Access