Novel anti-DLL1 antibody with anti-tumor efficacy against breast cancer

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Novel anti-DLL1 antibody with anti-tumor efficacy against breast cancer

Tuesday, 17.08.2021

Over 70% of breast cancers (BC) are estrogen receptor-positive (ER+). The Notch ligand Delta-like 1 (DLL1) is a key player in ER+ BCs development and aggressiveness and its overexpression are associated with poor prognosis. In this study, Portuguese researchers developed a novel anti-DLL1 antibody that inhibited tumor growth and liver metastases in a xenograft mouse model. The data suggests that anti-DLL1 immunotherapy can be a promising strategy for ER+ BC treatment.

 

Authors and Affiliations:

Gabriela Silva1, Joana Sales-Dias1,2, Diogo Casal3,4, Sara Alves3,5, Giacomo Domenici1,2, Clara Barreto1,6, Carolina Matos1, Ana R. Lemos1,2, Ana T. Matias4, Khrystyna Kucheryava1, Andreia Ferreira1,4, Maria Raquel Moita1,2, Sofia Braga4,7, Catarina Brito1,2, M. Guadalupe Cabral4, Cristina Casalou4,8, Duarte C. Barral4, Pedro M. F. Sousa1,2, Paula A. Videira9, Tiago M. Bandeiras1,2, Ana Barbas1,10

1 iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal

2 Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal

3 Departamento de Anatomia, NOVA Medical School, Universidade NOVA de Lisboa, 1150-82 Lisboa, Portugal;

4 iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1150-82 Lisboa, Portugal;

5 Serviço de Anatomia Patológica, Centro Hospitalar de Lisboa Central-Hospital de São José, 1150-199 Lisboa , Portugal

6 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;

7 Instituto CUF de Oncologia, Lisbon, Portugal.

8 Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland;

9 UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;

10 Bayer Portugal, 2790-143 Carnaxide, Portugal

 

Abstract:

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 changed dramatically the natural course of ER+ BC, but 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 that was converted into a full human IgG1 (Dl1.72). The Dl1.72 antibody exhibits DLL1 specificity and affinity in the low nanomolar range and significantly impairs 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. Altogether, these findings suggest that anti-DLL1 Dl1.72 could be an attractive agent against ER+ BC, warranting further preclinical investigation.

 

Journal: MDPI Cancers 

 

Linkhttps://www.mdpi.com/2072-6694/13/16/4074