In studies with mice, treatment with a new monoclonal antibody that targets immune system B cells has shown considerable promise for treating leukemias, autoimmune diseases and transplant rejection, according to immunologists at Duke University Medical Center.
B cells are the immune system's "arms factories," producing antibodies that target invading microbes for destruction. Abnormal B cell proliferation causes such leukemias as multiple myeloma and acute lymphoblastic leukemia, and such autoimmune diseases as rheumatoid arthritis and lupus.
The researchers, led by Professor and Chair of Immunology Thomas Tedder, Ph.D., reported their findings in the online Early Edition of the Proceedings of the National Academy of Sciences the week of Oct. 10, 2005. Other co-authors of the paper were Norhito Yazawa, Yasuhito Hamaguchi and Jonathan Poe in Tedder's laboratory. The research was sponsored by the National Institutes of Health.
Monoclonal antibodies (mAbs) are those created to target a specific protein. In their studies, the Duke researchers used mAbs targeting a protein called CD19 that is found on the surface of B cells. As their experimental animal models, they used mice that had been genetically altered to produce a human version of the CD19 protein on their B cells.
Their studies demonstrated that CD19 mAbs did tag B cells containing that protein, and that these B cells were then destroyed by the immune system.
When the researchers administered the CD19 mAbs to the mice, they found that it greatly depleted mature B cells, as well as precursor and immature B cells in the animals. The depletion of precursor and immature B cells is important because aberrant versions of such cells cause a number of leukemias and other malignancies where new therapies are needed, said Tedder.
And, they found that giving the mice CD19 mAbs, along with a mAb that targets another B cell protein, CD20, resulted in additive effects on B cell depletion. A CD20 mAb is now marketed as Rituximab.
Importantly, the researchers found that the CD19 mAb treatment dramatically depleted growth of malignant B cell tumors in the animals. In ten mice transplanted with malignant B cell lymphomas, the CD19 mAb treatment prevented the appearance of circulating and tissue tumor cells for up to seven weeks in all the animals. In contrast, all untreated mice died from their tumors by three weeks.
"We were actually quite shocked at how effectively CD19 mAb-treatments prevented malignant B cell expansion," said Tedder. "Treatment of such tumors in mouse models is extraordinarily difficult."
Finally, when the researchers measured the effects of CD19 mAb treatment on blood levels of antibodies produced by B cells, they found a significant reduction in circulating antibody levels as well as B cell mediated "humoral immune responses" in the animals, including reductions in autoantibodies of the type produced in autoimmune diseases and transplant rejection.