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A team of scientists from Charité-Universitätsmedizin Berlin and the Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin, a Leibniz Institute, report that they have successfully treated two patients with the autoimmune disease systemic lupus erythematosus (SLE).
Using daratumumab, a monoclonal antibody (mAb) which targets specific immune cells known as plasma cells, the researchers were able to modulate the abnormal immunological memory processes found in these patients. Treatment induced sustainable clinical responses and resulted in a reduction in systemic inflammation.
The study “Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus” appears in the New England Journal of Medicine.
SLE is a prototypical autoimmune disease in which antibodies are produced against components of the body’s cellular nuclei. This autoimmune response is associated with inflammation that may affect the skin, joints, or internal organ systems such as the kidneys, heart or central nervous system. Traditionally, treatments have relied on the long-term suppression of the immune response. Until now, however, they have not been targeted at mature memory plasma cells.
Working alongside colleagues from the DRFZ, led by Andreas Radbruch, Dr rer nat, Charité researchers, led by Tobias Alexander, Dr med, have studied the effectiveness and tolerability of a plasma cell-specific treatment in two lupus patients who failed to respond to conventional therapies.
“In a certain proportion of patients, the disease cannot be controlled using currently available treatments. As a result, there is a desperate need for novel and targeted treatment approaches,” explains study lead Alexander, who is head of rheumatology outpatient services at Charité’s department of rheumatology and clinical immunology and also conducts research at the DRFZ.”
The researchers focused their efforts on the monoclonal anti-CD38 antibody daratumumab, which has been used for years to successfully treat patients with plasma cell cancer. The role of plasma cells in autoimmune diseases has been a major focus of the work conducted by the research group led by Alexander and his co-author, Falk Hiepe, Dr med.
“Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor,” write the investigators.
“Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented.”
“CD38 surface protein is considered a classic plasma cell marker. However, our preliminary investigations have shown that, in patients with lupus, increased levels of this marker can also be detected in other active immune cells such as memory T lymphocytes, as well as in the blood and urine,” explains Alexander.
This makes CD38 an ideal target for treatment, which aims to eliminate the pathologically altered immune cells.
The recipients of this new treatment were two female patients with life-threatening lupus, whose symptoms included inflammation of the heart and kidneys and antibody-induced anemia. Weekly administrations of daratumumab over four weeks resulted in a rapid and significant improvement in symptoms, which remained stable for several months. The patients also showed a marked decline in serum autoantibody levels.
Using advanced immunological techniques, including single-cell sequencing, the researchers were furthermore able to show that daratumumab has a positive effect on active T lymphocytes, which are thought to play an important role in disease development. No relevant side effects were recorded. Although testing revealed a decline in protective antibodies in the blood, this was not associated with increased susceptibility to infections.
“The promising results seen in SLE may be transferable to other autoimmune diseases in which autoantibodies play a role,” says first author Lennard Ostendorf, a doctoral student at the DRFZ.
The next step, however, will be to test the safety and efficacy of daratumumab in a larger group of lupus patients. For this, the researchers are planning to conduct a pilot clinical study, which will be led by Alexander and conducted at Charité.
