Incidence of heart failure
Heart failure is a serious manifestation or latestage of various heart diseases, and the mortality and readmission rate remainhigh. The prevalence rate of heart failure in developed countries is 1.5%-2.0%,and the prevalence rate of people aged 70 and over is ≥ 10%. Theepidemiological survey in 2003 showed that the prevalence rate of heart failurein adults aged 35-74 in China was 0.9%. With the aging of the population inChina, the incidence of chronic diseases such as coronary heart disease,hypertension, diabetes and obesity is on the rise. The improvement of medical care prolongs the survival time of patients with heart diseases, which leadsto the continuous increase of the prevalence rate of heart failure in China. ①
Current treatment of heart failure
For the routine treatment of heart failure, first,diuretics, cardiotonic agents or vasodilators are used to reduce cardiacpreload and afterload and improve the hemodynamics during heart failure; second,angiotensin converting enzyme inhibitor (ACEI)/angiotensin II receptor blockers(ARB), β receptor blocker or mineralocorticoid receptor antagonist are used to inhibitover-activation of neuroendocrine system and improve ventricular remodeling, soas to eliminate the pathogenesis of chronic heart failure. Although theseconventional therapeutic drugs have played a good role in improving thesymptoms of heart failure, the overall prognosis of patients with heart failureis still poor, and their side effects are mainly manifested in drug tolerance,tachycardia and other arrhythmias, hypotension and activation ofneurohormone-angiotensin system related to the pathological process of heartfailure.
Therefore, in order to treat heart failure moreeffectively, reverse ventricular remodeling, improve the prognosis of patientsand prolong the survival time of patients, the effort of developing new medicineskeeps growing.
Recent research findings
In recent years, withthe continuous in-depth study of cardiovascular diseases, it has been foundthat Neuregulin (NRG) plays an important role in the regulation and maintenanceof embryonic heart development and adult heart function. NRG includes NRG-1, NRG-2,NRG-3 and NRG-4. Among them, NRG-1 protein mainly acts on cardiovascularsystem, lung, mammary gland and nervous system. In adult heart, NRG-1 isexpressed and released by cardiac endothelial cells and microvascularendothelial cells, but not expressed in large coronary artery, vein and aorta.Up to now, there are 15 isomers of NRG-1, which can be divided into α and βtypes according to the amino acid sequence difference of epidermal growthfactor (EGF)-like domain. Experiments show that NRG-1β has higher affinity thanNRG-1α, thus NRG-1β can activate receptor phosphorylation of myocardial cellsmore effectively, indicating that NRG-1β plays a major biological role inheart.
Erythroblastic leukemia viraloncogenehomologs (ErbB) includes ErbB1 (EGF), ErbB 2 (HER2),ErbB 3 (HER3) and ErbB4 (HER4). ErbB receptor protein contains an extracellulardomain binding to its ligand, a single transmembrane domain and anintracellular domain with tyrosine kinase functional activity. ErbB receptorprotein can activate downstream signaling pathways, promote cell proliferation,inhibit apoptosis and promote angiogenesis. ErbB receptors are widelydistributed in various tissues and organs of the three embryonal systems, amongwhich ErbB1 is mainly distributed on the surface of cells with division andproliferation potential, such as epithelial and endothelial cells; ErbB2, ErbB3and ErbB4 are mainly expressed in terminal differentiated cells. In heart, ErbB2and ErbB4 are mainly distributed in myocardial cells, while ErbB3 is mainlyexpressed in interstitial cells of endocardial cushion of fetal heart.
The extracellulardomain of NRG-1 produced by enzyme digestion combines with its receptor ErbB3or ErbB4 through paracrine to induce ErbB2/ErbB3 or ErbB2/ErbB4 heterodimer,respectively, thus activating phosphorylation of intracellular domain withtyrosine kinase functional activity and activating a series of downstreamsignal cascade systems. In heart, after the extracellular domain of NRG-1 bindsto ErbB4 expressed by myocardial cells, to induce ErbB2 and ErbB4 on myocardialcells to form ErbB2/ErbB4 heterodimer; by activating MEK/ERK 1/2 pathway toinduce protein synthesis and hypertrophic gene expression, the growth ofmyocardial cells is promoted; PI3K/AKT signaling pathway can play ananti-apoptosis role and promote the survival of myocardial cells, so as toprotect myocardial cells; Src/FAK signaling pathway promotes the orderlyarrangement of myocardial cells and strengthens the connection betweenmyocardium; in addition, NRG-1/ErbB signaling system can also interact with cardiac neurohormone regulatorysystem, activate muscarinic receptor M2 on myocardial cells by combiningacetylcholine, and interact with activated nitric oxide synthase (eNOs) ofmyocardial cells to induce myocardial contraction and inhibit over-activationof sympathetic nervous system, thus regulating homeostasis of cardiovascularsystem.
NRG-1/ErbB signalingsystem not only plays a key role in the development of heart and themaintenance of physiological function of adult heart, but also plays animportant role in the occurrence and development of heart failure. Theexpression of NRG-1/ErbB signaling system is constantly changing during thedevelopment of heart failure. In the early stage of heart failure, theexpression of NRG-1 in cardiac endothelial cells increases, but the expressionof ErbB2 and ErbB4 in myocardial cells does not change significantly, which maybe the adaptive change of myocardial cells against the over-activation ofadrenergic system by activating NRG-1/ErbB signaling pathway. However, with thegradual enlargement of ventricular chamber and the attenuation of cardiac pumpfunction, the expression of NRG-1, ErbB2 and ErbB4 decreases significantly, andthe NRG-1/ErbB signaling pathway is obviously inhibited, possibly in order toincrease the adaptive changes of myocardial tissue to the compensatory responseof adrenergic system. Reducing or inhibiting the expression of ErbB receptor inmyocardial cells will affect cardiac function, while increasing the expressionlevel of NRG-1 will delay the development of heart failure. Therefore, theadministration of exogenous NRG-1 will be beneficial to activate NRG-1/ErbBsignaling system in myocardial cells, thus improving cardiac function anddelaying the progression of heart failure. With unique pharmacological target,NRG-1 provides a new idea for the development of therapeutic drugs for heartfailure.
Endogenous NRG-1induces signal transduction by binding to ErbB3 (also known as HER3) and ErbB4(also known as HER4). Many preclinical and clinical studies have shown thatNRG-1 can interact with ErbB4 (HER4) expressed by myocardial cells, thus NRG-1has the potential to treat many cardiovascular diseases.
However,there are three factors that limit the clinical application of recombinanthuman NRG-1. First, the activation of HER3-mediated signaling pathway by NRG-1may promote the occurrence and/or progression of cancer, and present seriousside effect risk for any application process that needs long-termadministration or has no serious cardiovascular risk factors. Therefore, greatattention should be paid to the potential serious cardiovascular risk factorswhen NRG-1 drugs are used for long-term treatment. Second, over-activation ofHER3 by NRG-1 may destroy the integrity and homeostasis of gastrointestinalepithelial cells, resulting in serious gastrointestinal toxicity, and thuslosing the effective therapeutic window of NRG-1. Third, the clinical researchdata of rhNRG-1 active protein fragment show a short half-life, which indicatesthat rhNRG-1 drugs may need to be administered repeatedly to achieve therequired therapeutic level. Therefore, it is urgent to develop a new hNRG-1therapeutic agent, which can not only maintain the significant clinicaltherapeutic potential of NRG-1 in various cardiovascular indications, but alsohave lower carcinogenic risk or cancer progression risk, bettergastrointestinal tolerance and better pharmacokinetic characteristics.
JK07 features Characteristics of JK07
JK07 project is an international innovative antibodyfusion protein drug developed for the treatment of chronic heart failure basedon the above background, aiming at obtaining long-acting drugs with bettercurative effect and less side effects.
JK07 has a unique molecular design, which solvesthe limitations of recombinant NRG-1 protein therapy, blocks the function ofHER3 receptor without affecting the activation of HER4, and is expected toimprove the drugability and safety of the product.
References:
① Guidelines for Diagnosisand Treatment of Heart Failure in China 2018
