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Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer

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 (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal
4
iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal
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Serviço de Anatomia Patológica, Centro Hospitalar de Lisboa Central-Hospital de São José, 1150-199 Lisbon, Portugal
6
Unidade de Mama, Instituto CUF de Oncologia, 1998-018 Lisbon, Portugal
7
UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
*
Author to whom correspondence should be addressed.
These authors share first authorship.
Current address: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
§
Current address: iNOVA4Health, CEDOC, NOVA Medical School (NMS), Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal.
Current address: Charles Institute of Dermatology, UCD School of Medicine, University College Dublin, Belfield, Dublin4, Eircode:D04 V1W8, Ireland.
Current address: Bayer Portugal, 2790-143 Carnaxide, Portugal.
Academic Editor: Balveen Kaur
Cancers 2021, 13(16), 4074; https://doi.org/10.3390/cancers13164074
Received: 30 June 2021 / Revised: 5 August 2021 / Accepted: 11 August 2021 / Published: 13 August 2021
(This article belongs to the Section Cancer Therapy)
Over 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. View Full-Text
Keywords: ER+ breast cancer; Notch signaling; DLL1; monoclonal antibody; cell proliferation; angiogenesis; tumor growth ER+ breast cancer; Notch signaling; DLL1; monoclonal antibody; cell proliferation; angiogenesis; tumor growth
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MDPI and ACS Style

Silva, G.; Sales-Dias, J.; Casal, D.; Alves, S.; Domenici, G.; Barreto, C.; Matos, C.; Lemos, A.R.; Matias, A.T.; Kucheryava, K.; Ferreira, A.; Moita, M.R.; Braga, S.; Brito, C.; Cabral, M.G.; Casalou, C.; Barral, D.C.; Sousa, P.M.F.; Videira, P.A.; Bandeiras, T.M.; Barbas, A. Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer. Cancers 2021, 13, 4074. https://doi.org/10.3390/cancers13164074

AMA Style

Silva G, Sales-Dias J, Casal D, Alves S, Domenici G, Barreto C, Matos C, Lemos AR, Matias AT, Kucheryava K, Ferreira A, Moita MR, Braga S, Brito C, Cabral MG, Casalou C, Barral DC, Sousa PMF, Videira PA, Bandeiras TM, Barbas A. Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer. Cancers. 2021; 13(16):4074. https://doi.org/10.3390/cancers13164074

Chicago/Turabian Style

Silva, Gabriela, Joana Sales-Dias, Diogo Casal, Sara Alves, Giacomo Domenici, Clara Barreto, Carolina Matos, Ana R. Lemos, Ana T. Matias, Khrystyna Kucheryava, Andreia Ferreira, Maria R. Moita, Sofia Braga, Catarina Brito, M. G. Cabral, Cristina Casalou, Duarte C. Barral, Pedro M.F. Sousa, Paula A. Videira, Tiago M. Bandeiras, and Ana Barbas. 2021. "Development of Dl1.72, a Novel Anti-DLL1 Antibody with Anti-Tumor Efficacy against Estrogen Receptor-Positive Breast Cancer" Cancers 13, no. 16: 4074. https://doi.org/10.3390/cancers13164074

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