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Therapeutic MAb Targeting Endothelin Receptor A for Pulmonary Arterial Hypertension

Cheng Zhang

Yanglin Guo

Kesuo Fan

Shuqian Jing

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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 07.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1013

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Background

Endothelin receptor A (ETa) is a G protein-coupled receptor and a major therapeutic target for pulmonary arterial hypertension (PAH). Approved small molecule endothelin receptor antagonists (ERAs) have been beneficial to PAH patients; however, low target specificity and chemical structure-based liver toxicity of the ERAs limited their ability to further improve patient’s quality of life and extend their survival.

Methods

To overcome the shortcomings of the existing drugs, we developed an antagonistic monoclonal antibody (Getagozumab) against ETa. Cell-based binding and calcium influx assays were set up for in vitro studies of Getagozumab. Both acute hypoxia-induced and MCT-induced PAH monkey models were also established to assess the pharmacodynamic and pharmacokinetic characteristics of Getagozumab.

Results

Getagozumab displayed a Kd of 8.7 nM in vitro and an IC50 of 37.9 nM in the cell-based functional assay. Getagozumab could significantly lower pulmonary artery pressure in both hypoxia-induced and MCT-induced monkey models and further attenuate the pulmonary arterial wall thickness and right ventricular hypertrophy in MCT-induced PAH monkeys. The preclinical studies demonstrated that Getagozumab is safe, long-lasting and significantly more efficacious than Ambrisentan. A phase I clinical trial of Getagozumab to study safety and PK in healthy volunteers is on-going in Australia.

Conclusions

Getagozumab could serve as a novel and best-in-class treatment option for PAH and may be able to further improve patient’s quality of life and extend their survival.