Immune Therapy Could Treat Leukemias, Autoimmune Diseases, Transplant Rejection

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 myelomaand acute lymphoblastic leukemia, and such autoimmune diseases asrheumatoid arthritis and lupus.

The researchers, led by Professorand Chair of Immunology Thomas Tedder, Ph.D., reported their findingsin the online Early Edition of the Proceedings of the National Academyof Sciences the week of Oct. 10, 2005. Other co-authors of the paperwere Norhito Yazawa, Yasuhito Hamaguchi and Jonathan Poe in Tedder'slaboratory. The research was sponsored by the National Institutes ofHealth.

Monoclonal antibodies (mAbs) are those created to targeta specific protein. In their studies, the Duke researchers used mAbstargeting a protein called CD19 that is found on the surface of Bcells. As their experimental animal models, they used mice that hadbeen genetically altered to produce a human version of the CD19 proteinon their B cells.

Their studies demonstrated that CD19 mAbs didtag B cells containing that protein, and that these B cells were thendestroyed by the immune system.

When the researchers administeredthe CD19 mAbs to the mice, they found that it greatly depleted mature Bcells, as well as precursor and immature B cells in the animals. Thedepletion of precursor and immature B cells is important becauseaberrant versions of such cells cause a number of leukemias and othermalignancies where new therapies are needed, said Tedder.

And,they found that giving the mice CD19 mAbs, along with a mAb thattargets another B cell protein, CD20, resulted in additive effects on Bcell depletion. A CD20 mAb is now marketed as Rituximab.

Importantly,the researchers found that the CD19 mAb treatment dramatically depletedgrowth of malignant B cell tumors in the animals. In ten micetransplanted with malignant B cell lymphomas, the CD19 mAb treatmentprevented the appearance of circulating and tissue tumor cells for upto seven weeks in all the animals. In contrast, all untreated mice diedfrom their tumors by three weeks.

"We were actually quite shockedat how effectively CD19 mAb-treatments prevented malignant B cellexpansion," said Tedder. "Treatment of such tumors in mouse models isextraordinarily difficult."

Finally, when the researchersmeasured the effects of CD19 mAb treatment on blood levels ofantibodies produced by B cells, they found a significant reduction incirculating antibody levels as well as B cell mediated "humoral immuneresponses" in the animals, including reductions in autoantibodies ofthe type produced in autoimmune diseases and transplant rejection.

Accordingto Tedder, the results of the CD19 mAb animal studies warrant rapidadvance to clinical trials for treatment of B cell leukemias and othermalignancies that derive from early B cell precursors and perhapsantibody-producing B cells.

The CD19 mAbs may show broadereffectiveness than Rituximab, he said, because CD20 is expressed onlyby mature B cells, in contrast to CD19, which is expressed by bothmature and immature B cells and by antibody-producing cells.

Teddernoted that in general such immunotherapies are likely to produce farfewer side effects than current chemotherapies -- which can producesecondary malignancies, sterility and growth retardation in childrenwho 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 makeit an effective treatment for autoimmune diseases such as lupus, saidTedder.

"In addition, this treatment could greatly aid transplantpatients who require multiple organ transplants because they develop ahumoral antibody response to their transplanted organs, or they alreadyhave preformed antibodies that prevent them from accepting some donorgrafts." In contrast to the potentially benign nature of the CD19 mAbtreatment for such patients, current therapy involves removing thespleen and giving such patients chemotherapeutic treatment andplasmapheresis to remove antibodies from the blood.

Tedder andhis Duke colleagues are now developing plans for clinical trials atDuke of the CD19 mAbs in leukemias as well as autoimmune diseases.Also, a company that he founded, Cellective Therapeutics, Inc., will befurther developing the therapy.