A bispecific single-chain antibody fusion protein for targeted depletion of autoreactive B cells via unstimulated human T lymphocytes.

Autoantigen-specific B cells are culprits in the pathogenesis of many autoimmune diseases either through the production of autoreactive antibodies or as very effective antigen-presenting cells. A general depletion of B cells by a CD20-specific monoclonal IgG1 antibody has recently been validated as an effective strategy for treating rheumatoid arthritis. However, general elimination of B cells can lead to immunosuppression and increased risk of infection. In search for a more specific approach, we have generated a fusion protein for the antigen-specific targeting of autoreactive B cells for re-directed lysis by resting human T lymphocytes. We describe the design, purification and characterization of MOGxanti-CD3, a single-chain bispecific antibody fusion protein recognizing B cell receptors specific for the human myelin oligodendrocyte glycoprotein (MOG) and to CD3 on human T cells. MOGxAnti-CD3 induced selective and very efficient redirected lysis of MOG-reactive B cells through freshly isolated, unstimulated human T cells. Fusions between autoantigens and an anti-CD3 single-chain antibody may be suitable to develop very specific therapeutic approaches for the selective depletion of autoreactive B cells in autoimmune diseases.