Anti-citrullinated autoantigens are produced by Peptidyl Arginine Deiminase (PAD) enzymes, which are mainly expressed and released by neutrophils. Inhibiting PAD enzymatic activity is believed to offer clinical benefits, leading to the development of a PAD2/4 bispecific antibody. Levels of PAD2 and PAD4, along with PAD enzymic activity, are elevated in the serum of rheumatoid arthritis patients compared to healthy individuals. 

AstraZeneca’s novel anti-PAD2/4 bispecific antibody, AZD1163, is being developed using phage display and demonstrated high affinity binding to recombinant human PAD2 and PAD4. AZD1163 effectively inhibited endogenous PAD activity in the serum and synovial fluid of rheumatoid arthritis patients without inducing proinflammatory responses or affecting normal neutrophil functions. 

In non-human primate studies, a single 5 mg/kg dose of AZD1163 led to sustained suppression of PAD activity for eight weeks, even in samples with elevated PAD4 levels mimicking those in some rheumatoid arthritis patients' serum. 

At present, AstraZeneca is investigating this bispecific antibody in Phase I study (NCT06103877; Recruiting) and the first data read out is anticipated in 2025. The aim of this study is to demonstrate the safety and tolerability of AZD1163 when administered intravenously and subcutaneously in healthy participants.

Conclusion

At present, cancer indications account for the majority of bispecific antibody development. The US FDA has approved bispecific antibodies for cancer indications in addition to hemophilia A, diabetic macular edema, and neovascular (wet) age-related macular degeneration (AMD).

Rheumatoid arthritis is a condition that affects approximately 1% of the population and, therefore, undoubtedly brings in the big bucks. While still in early stages of development, this antibody has shown promising results in inhibiting PAD activity in rheumatoid arthritis patients' serum and synovial fluid, marking a significant step forward in potential rheumatoid arthritis treatments. This compound's proof of concept suggests it could be a valuable addition to the rheumatoid arthritis therapeutic landscape, warranting further attention as it progresses through preclinical development.

In addition to AstraZeneca, IGM Biosciences is conducting a Phase Ib clinical study (NCT06087406; Recruiting) to evaluate their bispecific antibody, Imvotamab (CD20 x CD3 bispecific antibody T cell engager [TCE]) for the treatment of Rheumatoid arthritis. The purpose of this study is to determine the safety and tolerability of imvotamab in adult participants with active Rheumatoid arthritis who are refractory or intolerant to 2 previous biologic disease-modifying anti-rheumatic drugs (bDMARD) or targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARD) therapies.