B cell modulation in rheumatology

Abstract

While evidence of dysregulation of the B cell compartment was first demonstrated with the identification of autoantibodies, other functional roles of B lymphocytes in autoimmune pathogenesis have generally been underappreciated or completely overlooked. With the recent approval of the first B cell targeting agent in rheumatoid arthritis, new strategies are being developed to target B cells through a range of membrane-associated lineage-specific molecules and also by interfering with B-cell-specific pro-survival signals. B-cell-directed agents therefore provide an effective new mechanistic approach to treatment and also enable new perspectives from the dissection of the contributions of B cells in physiologic and pathologic immune responses.

Figure 1. Survival factors for B-lineage cells

There are several cytokine and chemokine factors that can enhance survival of B -lineage cells, as primarily demonstrated from in vitro studies, but are believed to potentially also act in physiologic lymphocyte development, and dysregulated expression may contribute to autoimmune pathogenesis. Stem cells in the bone marrow can replace peripheral B cells. These factors have different levels of activity for B-lineage cells at different stages of differentiation. These factors may also affect certain non-B cells as well. Il-7 is primarily made by mesenchymal stromal cells in the bone marrow, while other factors may be made by a range of cells that differ in health and disease. Adapted from G. Silverman Arthritis Rheum. 2006

Figure 2. Potential Targets on B-lineage cells

Throughout life, B cells pass through sequential stages of differentiation that can be distinguished based on the expression of diagnostic patterns of surface molecules. CD20, which is expressed during intermediate stages of differentiation, has been used as a B-cell–specific target or new therapeutic agents. Other membrane-associated molecules, which may provide alternative targets for new therapies, are differentially expressed during B cell maturation and differentiation. While CD19, CD20 and CD22 are B-lineage specific, CD27 is also expressed on some T cells. Adapted from Silverman G. Arthritis Rheum. 2006. 54:2356–2367.

Figure 3. Construction of B-cell targeting therapeutic agents

The range of types of recombinant protein–based agents that target B cells. The first antibody in the series was rituximab. It was originally all mouse (red). It was engineered to replace both light-chain and heavy-chain constant regions with human constant regions (green). The variable regions involved in antigen recognition are all mouse (red). Several human monoclonal antibodies are now available. It is believed that ocrelizumab was an engineered version of rituximab that attempted to remove any residual mouse amino acids in the variable regions. Ofatumumab were made by immunization of mice that had been given large transgenes of human Ig variable regions, so that the mouse made a human antibody that was then cloned and expressed as a recombinant human antibody. Belimumab is a human antibody. TRU-015 is somewhat smaller than a natural IgG because two constant region domains were omitted. To hold the variable regions of the heavy and light chains together, a small linking peptide is included. Atacicept is the two human binding domains on TACI fused to human heavy-chain constant region domains. It binds/blocks both APRIL and BAFF/BLyS. The natural ligands are different homotrimers or heterotrimers of these molecules. BR3-Fc is similar except only one binding region was required. It binds/blocks only BAFF/BLyS. The natural ligand forms a trimer that is required for interactions. The IgG heavy chain constant regions greatly improve circulating half-life of the molecule by interacting with FcRn. Any engineered protein with an unnatural protein sequence may still be recognized by the human immune system.