KN060-a humanized dual-domain antibody simultaneously targeting FXI-A2/A3 epitopes: Pioneering the anti-coagulation factor XI strategy for Aterial hypertension – Evidence from preclinical models

Abstract

Growing evidence positions Factor XI (FXI) as a promising anticoagulation target, where its role in pathological thrombus formation significantly outweighs its contribution to physiological hemostasis. This distinctive pathophysiological profile has propelled FXI inhibition as a transformative therapeutic paradigm, with multiple candidates in Phase I-III trials spanning venous thromboembolism prophylaxis to arterial thrombosis prevention. Building on emerging insights into FXI-mediated vascular inflammation and remodeling, we herein unveil the first preclinical evidence supporting KN060—a humanized dual-domain antibody simultaneously targeting FXI-A2/A3 epitopes—as a novel antihypertensive agent. In angiotensin II-challenged mice, 5-week KN060 monotherapy (10 mg/kg triweekly) elicited sustained systolic blood pressure (SBP) reduction of 27.8 mmHg (120.7 mmHg in KN060 group vs 148.5 mmHg in vehicle control group). Furthermore, in spontaneously hypertensive rats, 9-week KN060 monotherapy (15 mg/kg twice weekly) achieved sustained SBP reduction of 34.7 mmHg (172.2 mmHg in KN060 group vs 206.9 mmHg in vehicle control group), concomitantly reducing left ventricular mass (0.67 g vs 0.773 g) and aortic relative media thickness (28.74 vs 31.59). Notably, co-administration of KN060 (3 mg/kg) with losartan (5 mg/kg) in SHRs demonstrated synergistic efficacy, achieving greater SBP reduction than losartan monotherapy (ΔSBP: −23.7 mmHg vs −15.9 mmHg). These findings establish KN060 as a first-in-class therapeutic bridging anticoagulation and vascular protection. Its unique bispecific architecture enables near-complete FXI activity inhibition while preserving hemostatic capacity, addressing critical limitations of conventional RAAS blockers in resistant hypertension. With an ongoing Phase Ib trial in primary hypertension patients (NMPA approval No CXSL2400827), KN060 emerges as a transformative candidate for precision management of hypertension.