Targeting the treatment of autoimmune diseases
Plasma cells at the center of a novel treatment approach

Date:
September 22, 2020
Source:
Charite' - Universita"tsmedizin Berlin
Summary:
Researchers have successfully treated two patients with the
autoimmune disease systemic lupus erythematosus. Using daratumumab,
a monoclonal antibody 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.



FULL STORY ========================================================================== Researchers from Charite' -- Universita"tsmedizin Berlin and the
Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin, a Leibniz Institute,
have successfully treated two patients with the autoimmune disease
systemic lupus erythematosus.

Using daratumumab, a monoclonal antibody 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 results of this research have been published
in the New England Journal of Medicine.


==========================================================================
The body's immunological memory enables the immune system to respond
more rapidly and effectively to pathogens that have been encountered
before. This immune response is mediated by both memory T lymphocytes and antibodies, which 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
life-time. In autoimmune diseases, the immune system mistakes part of
the body as foreign and considers it a danger. In a process that is
assisted by the body's immunological memory, the immune system mounts a response using 'autoantibodies'. Systemic lupus erythematosus (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.

For the first time -- and working alongside colleagues from the DRFZ (led
by Prof. Dr. Andreas Radbruch) -- Charite' researchers, led by Dr. Tobias Alexander, 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 Dr. Alexander, who is Head of Rheumatology Outpatient Services at Charite''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 Dr. Alexander and his co-author, Prof. Dr. Falk Hiepe. "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 Dr. 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 state-of-the-art 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 Dr. Alexander and conducted
at Charite'.


========================================================================== Story Source: Materials provided by
Charite'_-_Universita"tsmedizin_Berlin. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Lennard Ostendorf, Marie Burns, Pawel Durek, Gitta Anne Heinz,
Frederik
Heinrich, Panagiotis Garantziotis, Philipp Enghard, Ulrich Richter,
Robert Biesen, Udo Schneider, Fabian Knebel, Gerd Burmester,
Andreas Radbruch, Henrik E. Mei, Mir-Farzin Mashreghi, Falk Hiepe,
Tobias Alexander. Targeting CD38 with Daratumumab in Refractory
Systemic Lupus Erythematosus. New England Journal of Medicine,
2020; 383 (12): 1149 DOI: 10.1056/NEJMoa2023325 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200922102422.htm

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