PAD2 and PAD4 (peptidyl arginine deiminase 2/4)

Class

Bispecific antibody (dual PAD2/PAD4 inhibitor)

Pathway

Blocks extracellular protein citrullination that drives production of pathogenic anti-citrullinated peptide antibodies (ACPA) in RA

PAD2 and PAD4 belong to a family of calcium-dependent enzymes called peptidyl arginine deiminases, which chemically convert the amino acid arginine within proteins into citrulline, a process called citrullination. This modification happens normally inside cells, but it also occurs outside cells when neutrophils, a type of white blood cell, die and release their enzymes, including PAD2 and PAD4, into surrounding tissue. In genetically susceptible individuals, citrullinated proteins can be recognized as foreign, triggering production of anti-citrullinated peptide antibodies (ACPA). These autoantibodies are a hallmark of rheumatoid arthritis and are believed to worsen joint inflammation by forming immune complexes that activate other immune cells. Because both PAD2 and PAD4 are released by dying neutrophils in inflamed joints and both can generate citrullinated antigens, blocking both isoforms at once offers a more complete way to interrupt this process than targeting either enzyme alone. Agents designed to neutralize PAD2 and PAD4 outside cells aim to reduce ongoing citrullination and, in turn, the antibody response that appears to drive tissue damage, addressing a proposed underlying mechanism in rheumatoid arthritis and related autoimmune conditions.