Abstract
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.
Highlights
Systemic sclerosis (SSc) is a rare autoimmune rheumatic disease characterized by vasculopathy and dysregulation of the immune response, and extensive fibrosis of skin and internal organs [1]
CD28 blockade by acazicolcept decreased dermal and pulmonary fibrosis and alleviated pulmonary hypertension. These results pave the way for subsequent research on inducible T cell costimulator (ICOS)/CD28-targeted therapies
The blockade of CD28 and ICOS in an acute Graft-versus host disease (GvHD) mouse model by the novel dual CD28/ICOS antagonist led to improved survival in acazicolcept-treated mice compared to mice receiving a CD28-CD80/CD86 pathway antagonist only [31]. These results suggest that co-targeting ICOS and CD28 is a relevant strategy to suppress autoimmune responses and a Phase II clinical trial (NCT04835441) is ongoing to investigate the efficacy of the drug in systemic lupus erythematosus (SLE)
Summary
Systemic sclerosis (SSc) is a rare autoimmune rheumatic disease characterized by vasculopathy and dysregulation of the immune response, and extensive fibrosis of skin and internal organs [1]. This leads to increased morbidity and mortality of SSc patients mainly due to cardiovascular and pulmonary complications [2]. Costimulation blockade in several SSc murine models has shown to mitigate fibrosis, linking T cell activation, and fibrosis/remodelling development [6]. Uncontrolled 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 the lungs and skin. We 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
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