CD19: a promising B cell target for rheumatoid arthritis

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Abstract

B-cell depletion with unconjugated CD20 monoclonal antibody (mAb) is used to treat rheumatoid arthritis and other autoimmune diseases. CD20-targeted immunotherapy depletes mature B cells through monocyte-mediated antibody-dependent cellular cytotoxicity, but does not effectively deplete pre-B or immature B cells, certain peripheral B cell subpopulations, most antibody-producing cells, or their malignant counterparts. As immature B cells expressing autoreactive antigen receptors are not depleted by anti-CD20 mAb, a new strategy for eliminating autoantigen-selected B cells and for treating early lymphoblastic leukemias and/or lymphomas was developed using CD19-specific mAbs that induce Fcγ receptor-dependent and monocyte-dependent B-cell depletion. Preclinical studies using transgenic mice expressing human CD19 have shown that pre-B cells and their malignant counterparts, as well as pre-existing antibody-producing and autoantibody-producing cells, are depleted. Therefore, CD19-directed immunotherapy is expected to treat diverse pre-B-cell-related and plasmablast-related malignancies, and humoral transplant rejection. Moreover, in contrast to CD20-directed immunotherapies, CD19 mAbs could purge the B cell repertoire of autoreactive clones and reset the developmental clock to a point that curtails the extent of emerging self-reactivity, in addition to reducing autoreactive T-cell activation through the elimination of mature B cells. Humanized CD19 mAbs are expected to enter clinical trials in 2009, offering a new approach for the treatment of autoimmune disease that removes both immature B cells and antibodies with autoreactive specificities. CD19-directed immunotherapy could, therefore, offer a new horizon in B-cell depletion for the treatment of multiple autoimmune diseases.

Key Points

  • Autoreactive B cells have important pathogenic roles in autoimmune disorders beyond autoantibody production

  • B cells exclusively express CD19, with continuous cell surface expression from the early pre-B cell stage of development through to the early stages of plasma cell differentiation

  • B-cell depletion with unconjugated CD19 monoclonal antibody (mAb) removes the majority of bone marrow, circulating and tissue B cells in human CD19 transgenic mice and primates, including pre-B cells and immature B cells

  • In human CD19 transgenic mice, CD19 mAb treatment substantially reduces serum autoantibody levels and autoantibody responses during pathogenic immune responses

  • Preclinical studies in mice and monkeys provide optimism for the future success of CD19 mAb therapy in patients with autoimmune diseases

  • Unconjugated CD19 mAbs will be entering phase I clinical trials for the treatment of autoimmune diseases in 2009

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Figure 1: Cell surface CD19 and CD20 expression during B-cell development.1
Figure 2: Human CD19 expression by hematopoietic cells within the spleen and lymphoid tissues.
Figure 3: The structure of human CD19.
Figure 4: CD19 monoclonal antibodies deplete B cells in vivo through macrophage-mediated antibody-dependent cellular cytotoxicity in animal models and in vitro.

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Acknowledgements

The author thanks Cynthia Magro, William St. Clair, Jonathan Poe, David Pisetsky, Karen Haas, Damian Maseda, and Takashi Matsushita for their assistance and suggestions. This work was supported by grants from the National Institutes of Health (AI56363, CA105001, CA96547, and AI057157).

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Correspondence to Thomas F. Tedder.

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Competing interests

T. F. Tedder's research has centered on the development, activation, and functions of B cells with a specific focus on the identification of B cell-restricted cell surface molecules, their structural and biochemical features, and how these molecules regulate function in vivo. He obtained his PhD at the University of Alabama, Birmingham with Dr. Max Cooper, and was a postdoctoral fellow with Dr. Stuart Schlossman at Dana-Farber Cancer Institute/Harvard, before joining the faculty. He joined Duke University Medical Center as their first Chairman of a new Department of Immunology, where he remains as a Professor in the Department of Immunology.

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