Immune therapy discovery
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.
According to Tedder, the results of the CD19 mAb animal studies warrant rapid advance to clinical trials for treatment of B cell leukemias and other malignancies that derive from early B cell precursors and perhaps antibody-producing B cells.
The CD19 mAbs may show broader effectiveness than Rituximab, he said, because CD20 is expressed only by mature B cells, in contrast to CD19, which is expressed by both mature and immature B cells and by antibody-producing cells.
Tedder noted that in general such immunotherapies are likely to produce far fewer side effects than current chemotherapies -- which can produce secondary malignancies, sterility and growth retardation in children who take them for leukemias.
In particular, the researchers' finding that the treatment greatly depletes B cells in the peritoneum -- a major source of autoantibody-producing cells in mice -- could make it an effective treatment for autoimmune diseases such as lupus, said Tedder.
"In addition, this treatment could greatly aid transplant patients who require multiple organ transplants because they develop a humoral antibody response to their transplanted organs, or they already have preformed antibodies that prevent them from accepting some donor grafts." In contrast to the potentially benign nature of the CD19 mAb treatment for such patients, current therapy involves removing the spleen and giving such patients chemotherapeutic treatment and plasmapheresis to remove antibodies from the blood.
Tedder and his Duke colleagues are now developing plans for clinical trials at Duke of the CD19 mAbs in leukemias as well as autoimmune diseases. Also, a company that he founded, Cellective Therapeutics, Inc., will be further developing the therapy.
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.
According to Tedder, the results of the CD19 mAb animal studies warrant rapid advance to clinical trials for treatment of B cell leukemias and other malignancies that derive from early B cell precursors and perhaps antibody-producing B cells.
The CD19 mAbs may show broader effectiveness than Rituximab, he said, because CD20 is expressed only by mature B cells, in contrast to CD19, which is expressed by both mature and immature B cells and by antibody-producing cells.
Tedder noted that in general such immunotherapies are likely to produce far fewer side effects than current chemotherapies -- which can produce secondary malignancies, sterility and growth retardation in children who take them for leukemias.
In particular, the researchers' finding that the treatment greatly depletes B cells in the peritoneum -- a major source of autoantibody-producing cells in mice -- could make it an effective treatment for autoimmune diseases such as lupus, said Tedder.
"In addition, this treatment could greatly aid transplant patients who require multiple organ transplants because they develop a humoral antibody response to their transplanted organs, or they already have preformed antibodies that prevent them from accepting some donor grafts." In contrast to the potentially benign nature of the CD19 mAb treatment for such patients, current therapy involves removing the spleen and giving such patients chemotherapeutic treatment and plasmapheresis to remove antibodies from the blood.
Tedder and his Duke colleagues are now developing plans for clinical trials at Duke of the CD19 mAbs in leukemias as well as autoimmune diseases. Also, a company that he founded, Cellective Therapeutics, Inc., will be further developing the therapy.
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