Abstract 19805: Development of a Novel Human Anti-OPG Antibody That Attenuates Experimental Pulmonary Arterial Hypertension

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Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a fatal disease driven by a sustained pulmonary vasoconstriction and progressive vasculopathy leading to right heart failure. Current therapies for PAH relieve symptoms primarily through vasodilatory mechanisms but do not provide a cure. Osteoprotegerin (OPG) is increased within serum and pulmonary vascular lesions of patients with idiopathic PAH, and induces pulmonary artery smooth muscle cell proliferation and migration. Additionally, OPG-/- mice are protected from developing SuHx-induced PAH.

Hypothesis: Treatment with a novel human anti-OPG antibody will slow/stop disease progression, or regress established PAH.

Methods: High affinity anti-human OPG monoclonal antibodies were generated using the KyMouse™ system. Four novel anti-OPG antibodies with distinct profiles of TRAIL and RANKL binding inhibition, and cross-reactivity to rat were identified. Antibodies were tested (3 mg/kg/week, i.p.) for their ability to prevent PAH in the monocrotaline (mct) rat model (60 mg/kg). The lead candidate antibody was then tested for therapeutic efficacy (3 mg/kg/week, i.p. for 3 weeks) in the Sugen 5416 (20 mg/kg) plus 3 weeks hypobaric hypoxia (SuHx), followed by 6 weeks normobaric/normoxic room air model. PAH phenotype was assessed by echocardiography, closed chest right and left ventricular pressure volume catheter and histological assessment of pulmonary vascular remodelling.

Results: Analysis identified one antibody, Ky3, to significantly attenuate indices of PAH phenotype (RVSP, RVH, pulmonary vascular remodelling) compared to IgG4 treated mct-induced rats. The Ky3 antibody was then tested in comparison to both IgG4 and Sildenafil (50 mg/kg/day) treated rats exposed to SuHx. Although treatment with both Sildenafil and Ky3 resulted in a similar haemodynamic benefit (reduction in RVSP ~20-25 mmHg from 104 mmHg in IgG-treated rats), only Ky3 treatment significantly reduced pulmonary vascular remodelling as assessed by media/cross sectional area and percentage of remodelled small pulmonary arteries.

Conclusion: Targeting OPG represents a new treatment for clinical translation in PAH with a distinct mechanism of action to that of current vasodilator therapies.

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