Acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, demonstrates efficacy in systemic sclerosis preclinical mouse models

Arthritis Research & Therapy

NingXin Wang¹  Michelle A. Seaberg¹  Stacey R. Dillon¹  Ly Tu²  Christophe Guignabert²  Raphaël Thuillet²  Mina Ottaviani²  Carole Nicco³  Fanny Duhalde³  Alexis Prudent³  Anne Cauvet³  Cindy Orvain³  Frédéric Batteux⁴  Yannick Allanore⁵  Jérôme Avouac⁵ 

[1] Alpine Immune Sciences, 98102, Seattle, WA, USA;INSERM UMR_S 999, Le Plessis-Robinson, France;Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France;Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France;Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France;Assistance Publique–Hôpitaux de Paris (AP–HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Service d’immunologie biologique (Professeur Batteux), Paris, France;Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France;Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital 27 rue du Faubourg Saint-Jacques, Cochin, 75014, Paris, France;

关键词: Systemic sclerosis;    Dermal fibrosis;    Pulmonary fibrosis;    Pulmonary hypertension;    Costimulation blockade;    ICOS;    CD28;   

DOI  :  10.1186/s13075-021-02709-2

来源: Springer

【 摘 要 】

BackgroundUncontrolled immune response with T cell activation has a key role in the pathogenesis of systemic sclerosis (SSc), a disorder that is characterized by generalized fibrosis affecting particularly the lungs and skin. Costimulatory molecules are key players during immune activation, and recent evidence supports a role of CD28 and ICOS in the development of fibrosis. We herein investigated the efficacy of acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, in two complementary SSc-related mouse models recapitulating skin fibrosis, interstitial lung disease, and pulmonary hypertension.MethodsExpression of circulating soluble ICOS and skin-expressed ICOS was investigated in SSc patients. Thereafter, acazicolcept was evaluated in the hypochlorous acid (HOCL)-induced dermal fibrosis mouse model and in the Fra-2 transgenic (Tg) mouse model. In each model, mice received 400 μg of acazicolcept or a molar-matched dose of an Fc control protein twice a week for 6 weeks. After 6 weeks, skin and lung were evaluated.ResultsICOS was significantly increased in the sera from SSc patients and in SSc skin biopsies as compared to samples from healthy controls. Similar body weight changes were observed between Fc control and acazicolcept groups in both HOCL and Fra-2 Tg mice suggesting a good tolerance of acazicolcept treatment. In mice challenged with HOCL, acazicolcept induced a significant decrease in dermal thickness, collagen content, myofibroblast number, and inflammatory infiltrates characterized by B cells, T cells, neutrophils, and macrophages. In the Fra-2 Tg mouse model, acazicolcept treatment reduced lung collagen content, fibrillar collagen, histological fibrosis score, and right ventricular systolic pressure (RVSP). A reduction in frequency of CD4+ and T effector memory cells and an increase in the percentage of CD4+ T naïve cells in spleen and lung of acazicolcept-treated Fra-2 Tg mice was observed as compared to Fc control-treated Fra-2 Tg mice. Moreover, acazicolcept reduced CD69 and PD-1 expression on CD4+ T cells from the spleen and the lung. Target engagement by acazicolcept was demonstrated by blockade of CD28 and ICOS detection by flow cytometry in treated mice.ConclusionsOur results confirm the importance of costimulatory molecules in inflammatory-driven fibrosis. Our data highlight a key role of ICOS and CD28 in SSc. Using complementary models, we demonstrated that dual ICOS/CD28 blockade by acazicolcept decreased dermal and pulmonary fibrosis and alleviated pulmonary hypertension. These results pave the way for subsequent research on ICOS/CD28-targeted therapies.

【 授权许可】

CC BY