Alpine’s Dual Inhibitor ALPN-101 Reduces Immune Cell Activation in Preclinical Models of Sjögren’s Syndrome
Alpine Immune Sciences‘ ALPN-101, a treatment for inflammatory and autoimmune diseases that works by inhibiting two key pathways — ICOS and CD38 — is better at reducing immune cell activity than a combination of treatments targeting these molecules individually, suggests a study in cells and animal models of Sjögren’s syndrome.
The findings were presented at the 2019 American College of Rheumatology (ACR) Annual Meeting in a poster, titled “ALPN-101, a First-in-Class Dual ICOS/CD28 Antagonist, Suppresses Key Effector Mechanisms Associated with Sjögren’s Syndrome.”
Sjögren’s syndrome is an autoimmune disease where immune cells attack and damage certain glands in the body, particularly those producing tears and saliva. As a result, the most distinctive feature of the condition is dryness of the eyes and mouth.
The key immune participants in Sjögren’s and other autoimmune conditions are T-cells, which attack the tissues directly and cause damage, and B-cells, which produce autoantibodies. As such, treatment strategies that limit the activation of these cells could be beneficial for people with Sjögren’s syndrome.
ALPN-101 was designed to do just that. It works by simultaneously binding to, and blocking the activity of, two different molecules that are important for the activation of T-cells and B-cells: CD28 and ICOS.
In the study, researchers from Alpine tested the drug on circulating immune cells taken from the blood of Sjögren’s patients and healthy subjects. The cells were given stimuli that would normally cause them to activate and produce inflammatory molecules, called cytokines, and the researchers examined the extent to which ALPN-101 reduced cytokine production.
For comparison, the researchers also treated these cells with individual inhibitors of CD28 and ICOS — abatacept and prezalumab. Abatacept (approved as Orencia for certain kinds of autoimmune arthritis) binds and blocks CD28, while prezalumab specifically binds and blocks ICOS.
Neither is approved for the treatment of Sjögren’s syndrome, and prezalumab has never gained regulatory approval due to lackluster clinical trial results.
The researchers found that ALPN-101 treatment reduced immune cell activation more than abatacept, prezalumab, or both combined, as evidenced by significantly lower levels of pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, and IL-1β) being produced by the cells. This was true for both cells from healthy donors and from Sjögren’s patients.
Similar results, presented separately at the ACR, were found for cells from individuals with rheumatoid or psoriatic arthritis, which suggests that ALPN-101 may work as an immunosuppressive agent in multiple inflammatory conditions.
The researchers also tested ALPN-101 in mice; again, they discovered that ALPN-101 reduced immune activation to a greater extent than abatacept, prezalumab, or their combination. All of this suggests that inhibiting both activators simultaneously could lead to a greater effect than combining treatments to target them separately.
“Particularly intriguing are the unique inflammatory pathways that appear to be affected by ALPN-101, distinct from the other biologic therapies studied, as well as its potent efficacy in the animal models,” Stanford Peng, MD, PhD, president and head of research and development at Alpine, said in a press release.
In a recently completed Phase 1 trial (NCT03748836), researchers tested ALPN-101’s safety in healthy volunteers. The treatment was found to be well-tolerated by participants, either as an into-the-vein (intravenous) or an under-the-skin (subcutaneous) injection. It also showed dose-dependent activity, with higher doses corresponding to stronger inhibition of T-cell activation.
An upcoming Phase 1/2 trial, called BALANCE, will continue studying ALPN-101 in people with graft-versus-host disease — a complication of stem cell transplants where the donor’s immune cells recognize the patient’s cells and tissues as foreign and attack them.
That trial’s findings and trial protocol were shared at the recent American Society of Hematology 2019 Annual Meeting, in Orlando, Florida.