A team of researchers have successfully treated two patients with the autoimmune disease systemic lupus erythematosus for the first time.
The team from Charité – Universitätsmedizin Berlin and the Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin, a Leibniz Institute, used daratumumab, a monoclonal antibody which targets specific immune cells known as plasma cells, to modulate the abnormal immunological memory processes found in these patients.
The treatment induced sustainable clinical responses and resulted in a reduction in systemic inflammation. “The promising results seen in Systemic lupus erythematosus (SLE) may be transferable to other autoimmune diseases in which autoantibodies play a role,” said first author Lennard Ostendorf, a doctoral student at the DRFZ.
The research has been published in the New England Journal of Medicine.
Immunological memory
The body’s immunological memory enables the immune system to respond more rapidly and effectively to pathogens that have been encountered before – a response which is mediated by both memory T lymphocytes and antibodies. These are produced by cells known as ‘plasma cells’.
Mature memory plasma cells reside in special niches in the bone marrow and are able to produce large amounts of antibodies for decades or even a lifetime. In autoimmune diseases, the immune system mistakes part of the body as foreign and considers it a danger. This initiates a process, assisted by the body’s immunological memory, whereby the immune system mounts a response using ‘autoantibodies’.
Systemic lupus erythematosus is a prototypical autoimmune disease in which antibodies are produced against components of the body’s cellular nuclei. Traditionally, treatments for Lupus have relied on the long-term suppression of the immune response, and, until now have not been targeted at mature memory plasma cells.
For the first time the researchers have studied the effectiveness and tolerability of a plasma cell-specific treatment in two lupus patients who failed to respond to conventional therapies.
Dr Alexander, who is Head of Rheumatology Outpatient Services at Charité’s Department of Rheumatology and Clinical Immunology and also conducts research at the DRFZ, said: “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.”
Novel treatment
The researchers focussed their efforts on the monoclonal anti-CD38 antibody daratumumab, which has been used for years to successfully treat patients with plasma cell cancer.
Dr Alexander said: “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,” explaining that 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 anaemia.
The patients were given weekly administrations of daratumumab over four weeks, which resulted in a rapid and significant improvement in their symptoms. The symptoms remained stable for several months and the patients also showed a decline in serum autoantibody levels.
Using state-of-the-art immunological techniques – including single-cell sequencing – the researchers demonstrated that daratumumab has a positive effect on active T lymphocytes, which are thought to play an important role in disease development.
The researchers note that no relevant side effects were recorded, and although testing revealed a decline in protective antibodies in the blood, this was not associated with increased susceptibility to infections.
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 Dr Alexander and conducted at Charité.
