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

Abstract

Background 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 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. Methods Expression 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. Results ICOS 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. Conclusions Our 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.

Effects of B Cell Depletion by CD19‐Targeted Chimeric Antigen Receptor T Cells in a Murine Model of Systemic Sclerosis

“…21 An important difference between these two conditions is the prominent lung involvement in the Fra-2 mouse model, characterized by dense and diffuse inflammatory infiltrates mostly composed of T cells, B cells, and macrophages. 29,31,33 Our data show the persistence and accumulation of CD19-targeted CAR-T cells in the lesional lung tissue that may be promoted by prominent lung inflammatory lesions.…”

“…The sample size was determined according to our previous experiments using this model. 31,32 Each cage contained mice from all three groups. Investigators were blinded of group allocation during the conduct of the experiments and data analysis.…”

Non‐Redundant Roles of T Cell Costimulation Pathways in Inflammatory Arthritis Revealed by Dual Blockade of ICOS and CD28 with Acazicolcept (ALPN‐101)

“…The therapeutic candidate acazicolcept (ALPN‐101; ICOSL vIgD‐Fc) is a selected dimer of an engineered ICOSL variant immunoglobulin domain fused to an IgG1‐Fc lacking effector function (Figure 1A), and was designed to potently inhibit CD28 and ICOS costimulation (Figure 1B) (33). Acazicolcept has demonstrated promising efficacy in multiple inflammatory disease models including acute GVHD (31) and systemic sclerosis (32). Because the CD28 pathway has been clinically validated in RA and PsA, we examined the potential therapeutic advantage of dual CD28/ICOS inhibition in inflammatory arthritis.…”

“…Despite structural similarities and engagement of common downstream pathways, it is clear that ICOS and CD28 have non-redundant roles in T cell activation (18), which may in part explain the disappointing results observed with therapeutic agents targeting either of these pathways separately. In preclinical models, combined blockade and/or deficiency of both CD28 and ICOS is advantageous for islet allograft survival (28), inflammatory bowel disease (7), delayed-type hypersensitivity (29), GVHD (30,31), and systemic sclerosis (32).…”

“…A platform utilizing directed evolution of Ig superfamily proteins to produce variant immunoglobulin domains with increased affinity for cognate counter-structure ligands has been previously described (32). Using this engineering platform, we derived ICOSL domains with enhanced binding to ICOS and increased high-affinity binding to CD28.…”