Anti-citrullinated protein autoantibodies promote inflammation and joint tissue injury and define a poor prognostic group of patients with rheumatoid arthritis (RA). Citrullinated autoantigens that drive this autoimmune response are generated by peptidylarginine deiminase (PAD) enzymes, which are predominately expressed and released by neutrophils and monocytes. Accordingly, blocking the enzymatic activity of PADs to curb the generation of citrullinated autoantigens that drive autoimmunity and tissue injury may provide therapeutic benefit. Herein, we developed a high affinity, bispecific, anti-PAD2/4, effector-null antibody, AZD1163, which potently inhibits recombinant PAD2 and PAD4 activity in both histone H3 and fibrinogen citrullination assays. AZD1163 inhibited all endogenous PAD activity in the serum of patients with RA irrespective of the presence of anti-PAD4 autoantibodies, and neutralized PAD activity in synovial fluid. AZD1163 also bound and internalized PADs expressed on cell membranes into low pH endosomes for degradation, reducing the surface expression and catalytic potential. Binding of AZD1163 to neutrophils and monocytes did not trigger complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, or the production of proinflammatory cytokines, or otherwise impact neutrophil phagocytosis, production of reactive oxygen species, or NETosis. In a non-human primate study of pharmacokinetics (PK) and pharmacodynamics, a single dose of AZD1163 exhibited PK consistent with a half-life extended antibody and a rapid and durable suppression of endogenous PAD activity. AZD1163 has a favorable preclinical safety profile. Collectively, these in vitro and in vivo pharmacology and safety data support the clinical development of AZD1163 as a novel therapeutic strategy for RA by reducing autoantigen load.
Sims et al. (Wed,) studied this question.