Agents modulating B cell activation through the CD81-CD19 co-receptor complex

B cell activation and antibody production are essential in the immune response to infection and for the development of lasting protective immunity. Inappropriate B cell activation, however, contributes to a wide variety of autoimmune diseases, including rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Moreover, aberrant, sustained B cell receptor activation plays an important pathogenic role in chronic lymphocytic leukemia (CLL). Current therapies for these diseases have undesirable toxicities because they target all B cells (e.g. CAR-T cells for B cell leukemias), leading to immunosuppression. The B cell co-receptor, which includes the tetraspanin protein CD81, the signaling subunit CD19, and the complement-binding component CD21, lowers the threshold for B cell activation by approximately 1000-fold. Thus, agents blocking B cell co-receptor function will be powerful modulators of B cell activation. Here, we will develop agents targeting the B cell co-receptor subcomplex consisting of CD19 and CD81and assess their ability to modulate the activation threshold in primary human B cells, and their effect on the B cell signaling response, with the goal of identifying therapeutic candidates for treatment of B cell-driven autoimmune diseases and BCR-driven leukemias. These agents should be preferable to therapies targeting all B cells because they will suppress chronic signaling activity without depleting normal B cells.