Preferential HER4 stimulation preserves neuregulin-induced improvement of myocardial function

Neuregulin-1 (NRG-1), the natural ligand for HER3 and HER4, has been established as an essential growth factor for heart function. Prior studies have demonstrated the therapeutic potential of NRG-1 in the treatment of heart failure, but HER3 receptor activation has been a concern given its cancer association. Here, we describe the novel antibody fusion protein JK07, consisting of an antagonistic HER3 antibody and the EGF-binding domain of NRG-1. We confirm the HER3 antibody and the NRG-1 domains both retain functional activity in vitro and in vivo. Importantly, we demonstrate here for the first time that preserving HER4 stimulation by NRG1 in the presence of attenuated HER3 stimulation is sufficient to realize the therapeutic effects of NRG-1 in treatment of heart failure. Comparing JK07 to a control NRG-1 antibody fusion which does not recognize HER3, we show that JK07 can achieve equivalent recovery of ejection fraction in a rodent model of chronic heart failure. Finally, JK07 exhibited therapeutic potential in heart failure in rhesus macaques. In conclusion, this work demonstrates selective HER4 activation is sufficient for NRG-1 to improve myocardial function in multiple pre-clinical heart failure models and that JK07 holds promise as a potential therapeutic intervention for heart failure.