Background: IW-601 is a first-in-class monoclonal antibody targeting MOSPD2, a novel adhesion checkpoint protein expressed on the surface of monocytes and neutrophils. IW-601 binding to MOSPD2 increases Integrin β2 adhesion and leads to reduced cell motility, blocking the ability to reach inflamed tissue [1,2]. Pre-clinical studies have demonstrated the efficacy of IW-601 in models of MS, RA, IBD and NASH [3]. In human ex-vivo studies, IW-601 profoundly inhibited the migration of monocytes isolated from patients with MS, RA and IBD regardless of disease severity, gender, or patient’s concomitant medication.

Objectives: To assess and characterize the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses (SAD) of IW-601 in humans.

Methods: IW-601-001 is a randomized, blinded, placebo-controlled, dose-ranging study evaluating single and multiple ascending doses of IW-601 in healthy subjects. In the SAD part subjects are randomized on a 2:1 ratio to receive subcutaneous IW-601 at doses of 0.5, 1.5, 4.5 and 10 mg/kg or a matching volume of placebo. Following dosing, subjects are confined to the unit for 48 hours to monitor safety and sample PK. Dose escalation between the cohorts depends on review and approval of an independent Data Safety Monitoring Committee (DSMC).

Results: 32 subjects were enrolled in 4 sequential single dose cohorts. There were 17 males and 15 females. Median age was 22 (range 19-50), and median weight was 65.4 kg (range 50-80). All subjects completed the study according to the protocol. DSMC approved advancing dose escalation per protocol up to the maximal planned dose of 10 mg/kg. No signs of significant safety issues with IW-601 were reported in any of the cohorts. There were no serious adverse events, and no dose limiting toxicities. All adverse events were CTCAE Grade 1. No clinically significant abnormalities were reported post treatment in vital signs, physical examination, ECG and safety laboratory assessments. There were no noteworthy post treatment changes in the above assessments in any of the treatment groups and no noteworthy differences between the treatment and placebo groups. Some participants reported mild transient injection site reactions of erythema and edema in the first hour post dosing mostly resolving completely by 24 hours. The PK of IW-601 was dose-proportional with a relatively long half-life of ~30 days. PD analyses show specific and dose-dependent in-vivo binding of IW-601 to monocytes and neutrophils, and specific reduction in monocyte migration ex-vivo, supporting the mechanism of action.

Conclusion: Single ascending doses of subcutaneous IW-601 up to a dose of 10 mg/kg were safe and well tolerated in healthy subjects. The PK profile shows dose-proportionality and long half-life which is expected to allow subcutaneous dosing once every 3-4 weeks. In vivo PD data provide mechanistic validation for IW-601. Collectively, SAD data demonstrates druggability of IW-601 and supports continued development of this novel drug candidate in indications where monocytes and neutrophils have a predominant role.

REFERENCES: [1] Mendel I., et al, Identification of Motile Sperm Domain–Containing Protein 2 as Regulator of Human Monocyte Migration. J Immunol. (2017) 198 (5): 2125–2132.

[2] Mendel I., et al, MOSPD2 regulates the activation state of αLβ2 integrin to control monocyte migration. J Immunol. (2022) 208 (1_Supplement): 105.39.

[3] Yacov N., et al, Anti-MOSPD2 Antibodies as A Novel Therapy for Rheumatoid Arthritis. Ann of Rheum Dis. (2020) Volume 79, Issue Suppl 1. P.574.

Acknowledgements: NIL.

Disclosure of Interests: Tamar Rachmilewitz Minei ImmuneWalk Therapeutics, Yoseph Caraco: None declared, Oshrat Propheta-Meiran ImmuneWalk Therapeutics, Erez Feige ImmuneWalk Therapeutics, Itay Perlstein Immunewalk Therapeutics, Niva Yacov ImmuneWalk Therapeutics, Itzhak Mendel ImmuneWalk Therapeutics.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.