Abatacept Might Be First-Ever Treatment for Rare Immune Deficiency

Janis C. Kelly

July 30, 2015

Enhanced understanding of immune system protein regulation led to the discovery of what might be the first effective treatment for a devastating genetic autoimmune disorder in children, and it involves a drug already approved for treating rheumatoid arthritis (RA).

Bernice Lo, PhD, from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, and colleagues report the findings in an article published in the July 24 issue of Science.

Senior author Michael B. Jordan, MD, from the Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Ohio, told Medscape Medical News that the researchers were both surprised and gratified to find that abatacept had "major positive impact" on three patients with common variable immune deficiency (CVID) who were treated for 5 or more years.

Treatment appeared particularly effective at reversing the devastating lymphocytic interstitial lung disease caused by CVID.

The researchers' key insight was that the CVID-associated deficiency in cytotoxic T lymphocyte antigen (CTLA4) was the result of a flaw in how CTLA4 is recycled between the cell surface and internal lysosomes in regulatory T cells (Treg). In the normal course of events, CTLA4 is expressed on the cell surface, where it blocks activation of responder T cells, and thus prevents autoimmune activation.

Periodically, CTLA4, along with other cell surface molecules, is removed from the Treg cell surface and swept into recycling endosomes, where lipopolysaccharide-responsive and beige-like anchor (LRBA) protein grabs it and recycles it to the cell surface.

However, as Dr Jordan's group discovered, patients with CVID are deficient in LRBA, and thus lack the mechanism for replacing CTLA4 on the cell surface.

CTLA4 dysfunction also plays a role in RA, which led to the development of the fusion protein abatacept as a treatment for RA. Abatacept comprises the Fc region of immunoglobulin G1 fused to the extracellular domain of CTLA4 and can substitute for CTLA4 in blocking one of the two signals needed for responder T-cell activation.

Therefore, Dr Lo and colleagues reasoned that abatacept might also be able to do an end-run around LRBA deficiency. This possibility was tested in six patients with CVID.

Dr Jordan said, "We were quite surprised that it worked as well as it did in terms of improving interstitial lung disease (clearing chest [computed tomography] scans, improving lung function). We were also surprised by the apparent decrease of infections in the three patients treated longer term. We fully expected that they might experience increased infections (this is still certainly possible in other patients), but these frequently ill patients had an overall decrease in common infections after being on this medication. We don't understand why, but perhaps this relates to the cessation of other medications, such as corticosteroids, that might have been contributing. Also, one patient looked as if she was developing hypogammaglobulinemia around the time we started this medication, but despite all indicators, she has not done so over the ensuing 4 to 5 years. Perhaps we averted the development of this complication seen in most (but not all) LRBA-deficient patients."

The authors write, "These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway." Dr Jordan stressed the need for a prospective clinical trial of abatacept, perhaps in comparison with other medications.

The study was supported by Merck Inc. Two coauthors are employees of Merck Inc. The other authors have disclosed no relevant financial relationships.

Science. 2015;349:436-440. Abstract


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