An international collaboration of scientists evaluated literature concerning the mechanism of action of epratuzumab, a monoclonal antibody currently in two Phase 3 clinical trials for systemic lupus erythematosus (SLE), and proposed a reason for the efficacy of treatment. The antibody targets CD22 receptors on B-cells, depleting the population through signaling events within the B-cells. Understanding the mechanisms of action of epratuzumab is important when defining the safety and efficacy of the treatment in SLE patients before it is used clinically.
In an earlier clinical trial, “Epratuzumab produced sustained improvements in disease activity in patients with active SLE,” according to the research team led by Dr. Thomas Dörner at Charité Berlin. “Thus, understanding the impact of epratuzumab on B-cell function should provide insights into the specific actions of B cells involved in SLE pathogenesis and rational approaches to target and modulate them effectively.” The review, “The Mechanistic Impact of CD22 Engagement with Epratuzumab on B Cell Function: Implications for the Treatment of Systemic Lupus Erythematosus,” was published in Autoimmunity Reviews.
B-cells perform various roles aside from secreting antibodies, and a B-cell’s unique function in the body is controlled by the B-cell receptor (BCR) that is dictated by distinct genes in the B-cell. Another receptor on the B-cell surface, CD22, acts to inhibit BCRs and control the level of B-cell activation. “In a broader context, CD22 is considered to be one of several B-cell surface receptors that have been called ‘response regulators’ and which are responsible for fine-tuning BCR signals,” stated Dr. Dörner.
Epratuzumab is an antibody targeted against CD22 and causes CD22 loss on the B-cell surface by inducing internalization of the receptor within 45 minutes of binding. When CD22 is internalized by the B-cell, additional components necessary to activate the BCR response are internalized, dampening B-cell activation.
Reduced B-cell activity comes in a variety of flavors. As one example, the proliferative capacity of SLE patient-derived B-cells is reduced by epratuzumab. As another example, cytokine production by B-cells is reduced. After treatment with epratuzumab, B-cells secrete fewer pro-inflammatory cytokines that are often increased in SLE patients (TNF and IL-6).
It is evident that epratuzumab is unique in activity when compared to other antibodies directed toward B-cells. “Overall, these data suggest that epratuzumab is not a B-cell-depleting antibody like rituximab, which targets CD20 on B cells and is capable of causing an almost complete removal of at least blood B cells in a matter of days,” wrote Dr. Dörner. Instead, the activity and proliferation of B-cells is reduced, effectively depleting the number of B-cells that would otherwise be elevated in SLE patients.
Despite these insights in epratuzumab action, researchers are continuing to understand the roadmap to B-cell depletion by epratuzumab. Precise checkpoints in cell signaling events have yet to be defined, as well as which organs are the “real sites of action.” Regardless, knowing that B-cell activity is reduced upon epratuzumab administration is key to understanding how SLE patients will respond to therapy.
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