Background/Purpose: Neutrophil extracellular traps (NETs) contribute to the pathophysiology of many immune-mediated inflammatory diseases (IMIDs). Though NETosis-targeting therapeutics have shown potential as effective treatments, currently there are no NET-specific therapies available. We have developed CIT-013, a first-in-class monoclonal antibody specifically targeting citrullinated histones H2A and H4 in NETs, having a unique dual mode of action by inhibiting NET release and enhancing macrophage-mediated NET clearance. CIT-013 has shown safety and tolerability in phase 1 clinical trials.

The aims of the study described here were to investigate CIT-013’s target engagement in a mouse model of collagen-induced arthritis (CIA), and in a human model of low-grade LPS induced inflammation. Furthermore, we provide evidence for CIT-013’s potential application in rheumatoid arthritis (RA) patients by showing presence of its target in human RA serum and inflamed synovial tissue.

Methods: To assess the efficacy of CIT-013 in the CIA mouse model, a mouse variant of CIT-013 was used (mCIT-013). Disease progression was monitored by visual arthritis scoring, and paw sections were used to study the histological features of bone and cartilage erosion. In a separate CIA study, radiolabeled mCIT-013 was administered to study the biodistribution of the antibody. CIT-013’s target was determined in human RA synovial tissue and serum samples with the use of standard histological staining techniques and an in-house CIT-013 epitope detection ELISA. Inhibition of NET release was investigated in LPS-challenged healthy human volunteers with the use af a citrullinated histone 3 detection ELISA.

Results: Therapeutic treatment of CIA mice with mCIT-013 halted progression of pannus formation, cartilage damage and bone resorption. In fact, when using radiolabeled mACHA we found that it specifically localizes to the inflamed joints in CIA mice where we have previously shown NETs to accumulate and disappear upon therapeutic CIT-013 treatment (Chirivi et al, 2021). In human RA synovial tissue CIT-013 epitope levels correlate with the observed histological inflammation grade, whereas in human RA serum CIT-013’s target was significantly enhanced compared to healthy volunteer samples. LPS nano-dosing in healthy volunteers induced an increase in circulating NETs which was completely inhibited by CIT-013 treatment at two dose levels.

Conclusion: Together, this demonstrates that CIT-013 can target its epitopes in inflamed joints, suppresses the proinflammatory properties of NETs, and thereby has therapeutic potential for IMIDs like RA. This strengthens further the potential of CIT-013 as a unique therapeutic approach for NET-associated diseases with unmet therapeutic needs.

CIT-013 is expected to enter phase 2 proof-of-concept clinical trials in RA and Hidradenitis suppurativa during 2024.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-citrullinated-histone-antibody-cit-013-targets-nets-in-inflamed-joints-and-halts-net-mediated-joint-deterioration/