The Human Chorionic Gonadotropin Derivate EA-230 Modulates the Immune Response and Exerts Renal Protective Properties: Therapeutic Potential in Humans

Abstract

The extent of the systemic inflammatory response following infectious or noninfectious insults is related to impaired patient outcome. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230 is a newly developed synthetic linear tetrapeptide derived from the "pregnancy hormone" human chorionic gonadotropin. In this review, we describe the immunomodulatory and renoprotective properties of EA-230 in preclinical animal models, phase 1 studies in humans and phase 2a studies performed during human experimental endotoxemia. In addition, details pertaining to the design of a recently completed phase 2b study in 180 patients who underwent cardiac surgery to investigate the safety and immunomodulatory and renoprotective properties of EA-230 are discussed.

Safety and Efficacy of Human Chorionic Gonadotropin Hormone-Derivative EA-230 in Cardiac Surgery Patients: A Randomized Double-Blind Placebo-Controlled Study

“…The absence of immunomodulatory effects of EA-230 in the present work is in contrast to results obtained in several animal studies (28–31, 33) and a previous experimental human endotoxemia study (38). In the latter study, treatment with EA-230 attenuated the endotoxin-induced increase of IL-6 and several other pro-inflammatory cytokines and resulted in significantly less pronounced fever and flu-like symptoms.…”

“…This favorable immune-tolerant phenotype and increase in GFR observed during pregnancy has been attributed to the human chorionic gonadotropin (hCG) hormone and has led to the discovery of EA-230, a hCG-derived linear tetrapeptide. Treatment with EA-230 attenuated pro-inflammatory cytokine release, prevented organ dysfunction and renal injury, and improved survival in several animal models of systemic inflammation (27)(28)(29)(30)(31)(32)(33). Furthermore, EA-230 mitigated renal injury and improved survival in murine models of renal transplantation and renal ischemia-reperfusion injury (34)(35)(36).…”

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

“…The SIRS pathology is caused by an upstream of pro-inflammatory agents (such as IL-6) and this dysregulated inflammatory response often results in tissue damage, failure of one or more organ systems, and high mortality. Even though the mechanism of action EA-230 is still unclear, biological evidence have demonstrated how changes of the hormonal milieu play a central role in the anti-inflammatory response ( van Groenendael et al, 2019 ).…”

How to Combat Gram-Negative Bacteria Using Antimicrobial Peptides: A Challenge or an Unattainable Goal?

“…However, this broad-spectrum peptide could be useful for treating Gram-negative bacteria infections such as P. aeruginosa and other multi-resistant bacteria [ 39 ]. WLBU2 has proven to be superior to natural peptides such as colistin and LL-37 due to it having less potential for inducing resistance and greater stability in in vivo conditions [ 36 , 37 ]. In spite of this, WLBU2′s poor selectivity continues to be a limiting factor [ 39 ].…”

“…Three peptides in clinical development (AB103 (p2TA), SGX942 (dusquetide) and EA-230) have immunomodulatory effects which could help resolve infections in in vivo conditions ( Table 1 and Figure 1 ). While these peptides lack direct activity against microorganisms, they can attenuate the inflammatory effect caused by bacteria and LPS and has been shown to reduce death in a murine model of sepsis affecting septic shock mechanisms [ 35 , 36 ]. Such an approach involving interaction with the immune system represents a field of research which has only just begun and will surely help in combating the development of Gram-negative bacteria resistance and that of other pathogens from a different perspective [ 34 ].…”