Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus, Arthritis Research & Therapy, 2006, 8:R74, T. Dörner, J. Kaufmann, W. Wegener, et. al.

In a small preliminary study, a new treatment called epratuzumab that targets one protein in the immune system seemed to be well-tolerated by patients with mild to moderate active lupus.

The role of B-cells in autoimmune diseases such as lupus, in particular their role in stimulating the production of inflammatory antibodies, has sparked interest in developing treatments that can reduce the number of B-cells in the bloodstream or interrupt their functioning. One such compound, epratuzumab, was originally developed by the biotech firm Immunomedics as an anti-cancer therapy, and is now being tested in lupus patients.

Epratuzumab itself is an antibody, designed to target a unique protein (called CD22) that is found on a particular kind of immune cell called a B cell. Binding to CD22 by an antibody is likely to lead to the elimination of the B cell. Structurally, epratuzumab is a combination protein that includes building blocks from mice and humans.

CD22, the protein that the developers wanted to target, was put into mice so they would make an immune response against it. The part of the mouse antibodies that bound to the CD22 was grafted onto a human antibody. Therefore, 95 percent of the compound is of human origin, which makes it a “humanized” antibody.

When most of the protein comes from humans, this makes it better tolerated and longer lasting when given to humans as a treatment. If an antibody had more percent of mouse (or foreign) protein in it, it would be less likely to be safe or to last very long when put into the human bloodstream.

Giving epratuzumab to people results in fewer B-cells in the circulation. In addition, some research has suggested that some of the functions of the CD22 protein may be related to lupus, so this treatment could have other effects unrelated to B-cell depletion, by interfering with some of the activities of CD22.

In the preliminary clinical trial described in this report, 14 patients with moderately active lupus received four doses of epratuzumab, each given two weeks apart. Disease activity was measured in each patient using a scoring system called the BILAG (British Isles Lupus Assessment Group) Index. The patients were evaluated at the start of the study and at visits which took place at weeks 6, 10, 18, and 32.

Virtually every patient with moderate disease activity (total BILAG score of 6 to 12) had improvement in their overall BILAG scores. This improvement lasted at least 18 weeks for the majority of the patients (92 percent). Even at 32 weeks more than one-third (38 percent) of the patients still had at least 50% reduction in BILAG scores compared to the beginning of the study. The patients with more severe symptoms at the start of the study also seemed to have improvement.

Lab tests indicated B cell levels decreased by 35 percent at the initial evaluation, and this lasted for six months after the treatment. Another white blood cell called the T cell was not affected by the treatment. No changes in antibodies (including ANA and anti-DNA) were found. It was possible to detect the persistence of the treatment agent, eratuzumab in all of the blood samples taken from the patients through at least 10 weeks. In five of seven samples tested after 18 weeks, eratuzumab was still detectable.

Ten patients reported side events. Six had mild, temporary adverse reactions when the drug was being administered, and one patient experienced drowsiness owing to the antihistamine medication that each patient was given prior to the epratuzumab infusions. Five patients had one or more infections, none of which was serious and all of which resolved with appropriate treatment.

Since there was no group of patients who got a placebo (inert) treatment in this study, it is not known whether the study drug increased the risks of getting infections in these patients. A larger study would be needed for this.
This drug did not deplete their B cells as much as some other similar drugs do. This raises the possibility that it might be safer to use. However, this very small, early study is only a preliminary assessment. Although epratuzumab seemed to benefit most of the patients, it is not known whether some or all of these patients might have gotten better without any treatment. And while there were no serious side effects seen, the study was stopped only 6-months after the treatment, so long-term effects have not yet been studied. Also some serious side effects might still be revealed if this treatment is tested in larger groups of patients.

The answers to these questions can only be addressed with a double blind, placebo-controlled trial. Placebo-controlled means that some of the participating patients will receive only an inert treatment (not the real treatment). Double-blind means that neither the study team nor the participants know whether any individual is getting the real treatment or the placebo during the course of the study. In this way the placebo group can be compared to the people getting epratuzumab to see whether the drug is actually better than an inert treatment and whether or not it causes significantly more side effects.

The results of this trial are encouraging enough to warrant further study, but longer, more rigorous studies with many more patients are required to determine epratuzumab’s role as a medical therapy for lupus.