Development of bispecific antibodies that drive selective targeted local complement inhibition on rheumatoid arthritis-related antigens.

Abstract

In rheumatoid arthritis (RA) autoantibodies can trigger complement activation in the joint, contributing to tissue damage. Complement inhibitory drugs have shown important benefit in other clinical conditions. However, their use is limited because these drugs act systemically, not only requiring high doses but also rendering patients more susceptible to infections. Therefore, we designed a strategy to only inhibit complement locally, while leaving the systemic complement system intact to fight infections. We designed bispecific antibodies (bsAbs) using controlled Fab-arm exchange. In these bsAbs, one antibody arm binds to a specific disease-relevant antigen, like carbamylated proteins, while the other arm recruits endogenous complement regulators, like factor H (FH) or C4b-binding protein (C4BP). These bsAbs were subsequently evaluated for their specificity and complement regulator recruiting capacity. We generated anti-carbamylated protein antibody (anti-CarP)-based bsAbs and confirmed specificity for carbamylated proteins. The bsAbs efficiently recruited FH or C4BP to surfaces containing carbamylated proteins. The bsAbs inhibited complement activation induced by immunoglobulin G immune complexes and more importantly, the bsAbs were able to inhibit complement activation triggered by anti-CarP antibodies from RA patients to background levels. This study shows that bsAbs that bind carbamylated proteins and FH or C4BP can specifically recruit the endogenous complement regulatory proteins from plasma to achieve selective local targeted complement inhibition, providing a new therapeutic approach for the local treatment of autoimmune diseases.