T-cell Blocker Acazicolept Helps Reduce Scarring in Preclinical Study
Acazicolcept (ALPN-101), an experimental therapy that blocks T-cell activation and is being developed by Alpine Immune Sciences, was found effective at decreasing scarring in mouse models of systemic sclerosis (SSc).
A team of scientists at Alpine and other institutions published their findings in a study, “Acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, demonstrates efficacy in systemic sclerosis preclinical mouse models,” in the journal Arthritis Research & Therapy. The study was funded by Alpine.
SSc, also called scleroderma, is an autoimmune disease characterized by excessive scarring in body tissues. The disease is driven by the abnormal activity of certain immune cells, such as T-cells.
When a T-cell encounters a cell infected with a potential threat (e.g. a virus), it can become activated, releasing so-called cytotoxic factors to kill the infected cell. It can also send signals to other cells to boost the immune response. In autoimmune diseases like SSc, T-cells become activated even when there is no threat, resulting in an attack on healthy tissue.
The activation of T-cells is dependent on the activity of certain proteins that help the cell to sense threats. Of particular relevance are two proteins called CD28 and ICOS, both of which play key roles in T-cell activation.
Acazicolcept is an experimental medicine designed to block the activity of both CD28 and ICOS, thus preventing T-cell activation. In the study, scientists tested acazicolcept in two mouse models of SSc — one characterized mainly by skin scarring, and one by lung scarring, body-wide inflammation, and structural changes in pulmonary blood vessels. The mice were injected twice weekly with acazicolcept or a control protein.
Results showed that the treatment significantly reduced scarring in both models. In the skin model, treated mice had thinner (less scarred) skin, and in the lung model, mice had less scar tissue in their lungs. They also scored significantly better in clinical measures of mouse health (weight loss, coat appearance, etc.).
Additional experiments indicated that the treatment reduced the activity of T-cells and lowered right ventricular systolic pressure, a measure of the pressure inside the artery that supplies blood to the lungs.
“Our study demonstrated that the concomitant blockade of both ICOS and CD28 pathways with acazicolcept leads to a significant decrease in dermal and pulmonary fibrosis in two complementary mouse models of SSc,” the researchers concluded.
The team also looked at ICOS levels in the blood of 161 SSc patients and 35 people without the disease. Levels of this protein were significantly higher in the SSc patients (20.10 vs. 7.97 nanograms per milliliter). Skin samples were taken from three patients in each group, and analyses indicated that those with SSc had more ICOS-expressing T-cells in disease lesions.
“We have demonstrated evidence of activation of the ICOS pathway both in serum [blood] and skin from SSc patients,” the researchers wrote.
“Our results open the door to follow-up studies where clinical data will be required to establish the translation of our findings to patients and to support potential future innovative therapies, especially in the early/inflammatory phase of SSc,” they concluded.
Alpine is currently sponsoring a Phase 2 clinical trial called SYNERGY (NCT04835441) that is testing acazicolcept in people with another autoimmune disease, systemic lupus erythematosus.
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