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The Targeted Delivery of Interleukin 4 Inhibits Development of Endometriotic Lesions in a Mouse Model

Federica Quattrone 1, Ana Maria Sanchez 1, Maria Pannese 1, Teresa Hemmerle 2, Paola Viganò 3, Massimo Candiani 3, Felice Petraglia 4, Dario Neri 2, and Paola Panina-Bordignon, PhD1

1 Division of Genetics and Cell Biology, Reproductive Sciences Laboratory, IRCCS Ospedale San Raffaele, Milan, Italy
2 Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland
3 Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy
4 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy

 

"The Targeted Delivery of Interleukin 4 Inhibits Development of Endometriotic Lesions in a Mouse Model"

 Uno studio appena pubblicato su Reproductive Sciences riporta i sorprendenti risultati sull’efficacia farmacologica di un nuovo bio-farmaceutico in un modello animale di endometriosi. La molecola, sviluppata dal gruppo di Dario Neri, Professore al Politecnico di Zurigo e fondatore dell’azienda biotecnologica senese Philogen S.p.A., è una immunocitochina, F8-IL4, che svolge la propria azione tramite la veicolazione selettiva di interleuchina 4 sulle lesioni endometriosiche in via di formazione.

I risultati dimostrano che il trattamento con F8-IL4 di topi con endometriosi, riduce sia il numero che il volume delle lesioni endometriosiche. A supporto del dato macroscopico, anche l’espressione di geni coinvolti nell’adesione, invasione tissutale e vascolarizzazione delle lesioni endometriosiche risulta significativamente diminuita.

Questi dati forniscono un forte razionale per lo sviluppo clinico di F8-IL4 quale nuovo approccio terapeutico in donne con endometriosi. Attualmente, sono in corso studi di tossicologia in femmine di primati.

La tecnologia di sviluppo di immunocitochine simili a F8-IL4, ha generato bio-farmaceutici attualmente in fase di sperimentazione clinica di Fase I/II nel campo dell’oncologia.

Abstract

Endometriosis is caused by the displacement of endometrium outside the uterus contributing heavily to infertility and debilitating pelvic pain. Ectopic adhesion and growth are believed to occur under the influence of a favorable hormonal environment and immunological factors. The objective of this study is to analyze the effect of a targeted therapy with an antibody-based pharmacodelivery of interleukin 4 (F8-IL4) in a mouse model of experimentally induced endometriosis. Endometriosis-like lesions were induced in Balb/c mice. The animals were treated intravenously with F8-IL4 or with untargeted IL4 (KSF-IL4). Twelve days after disease induction, the lesions were isolated. A significant reduction in the number of total lesions/mouse and in the total volume of lesions/mouse was observed in mice treated with F8-IL4 compared to controls (P = .029 and P = .006, respectively), while no difference was found between KSF-IL4-treated mice and their controls. Gene expression was evaluated by quantitative real-time polymerase chain reaction. Expression of genes involved in cell adhesion, extracellular matrix invasion, and neovascularization was significantly downregulated in F8-IL4-treated mice compared to their controls (integrin β1: P = .02; metalloproteinase [MMP] 3: P = .02; MMP9: P = .04; vascular endothelial growth factor: P = .04). Gene expression of inflammatory cytokines (tumor necrosis factor α, IL1β, IL1α, and IL6) did not vary in the ectopic lesions isolated from F8-IL4-treated mice compared to their controls. Immunohistochemistry demonstrated a significantly reduced expression of E-cadherin and β-catenin in the lesions of mice treated with F8-IL4. Our results show that the antibody-mediated targeted delivery of IL4 inhibits the development of endometriosis in a syngeneic mouse model by likely impairing adhesion, invasion, and vascularization of the ectopic endometrium.

Vai alla pubblicazione

https://www.ncbi.nlm.nih.gov/pubmed/25850899

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