Table 3.

Novel therapeutic molecules, targeted mechanism, and their clinical impact in sepsis

Therapeutic molecules	Targeted mechanism	Therapeutic strategies	Model used	Special features	Clinical impact	Source
Kukoamine B (KB)	LPS- and CpG-DNA-induced pro-inflammatory responses	Traditional Chinese herbs	Heat-killed E. coli challenged sepsis models	As a dual inhibitor of LPS and CpG-DNA, KB directly neutralize and prevent them from interacting with macrophages	Inhibit expression of pro-inflammatory mediators without interfering with signal pathways or cell viability of macrophages. Protect mice from E. coli challenged and reduced circulatory LPS and TNF-α	444
Ceria–zirconia nanoparticles (7 CZ NPS)	Regeneration of anti-oxidants	Nanotherapeutic approach	CLP-/LPS-induced sepsis models	Ceria nanoparticles are potential regenerative antioxidants that could overcome the constantly produced ROS in a single dose. Zr4+ facilitate regeneration of Ce3+ and higher Ce3+/Ce4+ ratio so as to exhibit best ROS scavenging performance during sepsis	7CZ NPS block aberrant inflammatory responses via ROS scavenging and have additional effects on inflammatory pathway. Expected to be internalized by macrophages and neutrophils, these strongly phagocytic immune cells infiltrate to damaged tissues and act directly with intracellular ROS at infection focus. Overall, it demonstrated reduced mortality and systemic inflammation in sepsis models	395
Nucleic acid–scavenging nanoparticles (NABNs)	Inhibit cfDNA-TLR9-MyD88-NF-κB pathway	Nanotherapeutic approach	CLP-induced sepsis models	Biodegradable mesoporous silica nanoparticles with different charge density serve as cfDNA scavengers and are also known as nucleic acid–scavenging nanoparticles (NABNs). High cfDNA is strongly associated with sepsis mortality	With favorable accumulation and retention behavior in inflammatory tissues, NABNs inhibit cfDNA-induced inflammation and improve multiple-organ injury and mortality caused by sepsis	396
Xuebijing	HMGB1-mediated inflammatory pathway	Traditional Chinese medicine	CLP-induced lung injury model	Xuebijing downregulate HMGB1 and RAGE expression and interaction, thereby reduce cytokine-mediated inflammation (TNF-α, IL-1β, IL-6) and neutrophil infiltration in the alveolar space	Inhibit HMGB-mediated inflammation and improve survival	445
TN domain-specific mAb	HMGB1-mediated inflammatory pathway	Monoclonal antibody	CLP-induced sepsis models	TN, an endogenous protein, is capable to capture HMGB1 to trigger several conflicting events during sepsis: endocytotic degradation of HMGB1, macrophage pyroptosis, attenuated release of HMGB1, and induction of beneficial chemokine secretion. Sepsis-induced TN depletion showed pathogenic consequences while supplement of subphysiological TN confers protection	TN-specific protective monoclonal antibody bind and inhibit TN/HMGB1 interaction, prevent endocytosis of HMGB1, and attenuate sepsis-induced TN depletion and tissue injury, rescuing animals from lethal sepsis	393
CD28 T-lymphocyte receptor mimetic (Reltecimod, AB103)	Interaction between superantigen and costimulatory receptor CD28 dimer expressed on T cells, which function to mediate T helper type 1 cytokine responses	Monoclonal antibody	E. coli LPS-induced, CLP-induced sepsis models	Receipt of AB103 attenuated inflammatory cytokine responses (TNF-α, IL-6) and neutrophil influx into tissues and promoted bacterial clearance	AB103 resulted in higher survival rate and reduces mortality in experimental models of polymicrobial and Gram-negative bacterial infection and sepsis	446
			Surgical confirmation of necrotizing soft tissue infections (NSTI) and organ dysfunction (mSOFA)	Early administration of reltecimod resulted in improvements of 28-day survival, day 14 mSOFA, and avoidance of surgical procedures	Improve resolution of organ dysfunction and hospital discharge status	447
ALK inhibitor (LDK378)	A novel ALK-EGFR-AKT pathway responsible for regulation of STING-dependent inflammatory responses	FDA-approved anticancer drug	CLP-/LPS-induced sepsis models	ALK pathway was upregulated in sepsis patients. ALK-EGFR-AKT pathway is a critical driver of STING activation. Pharmacologically blocking the ALK-dependent STING signaling pathway could modulate the DNA-induced excessive inflammation response in sepsis, particularly referring to bacterial CDN or host DNA released by injured cells	LD378 confers protection against lethal sepsis by alleviating tissue injuries and pro-inflammatory cytokines. LD378 also improve micro-circulation and macro-circulation and reduce organ injuries	359
Sialic acid–binding immunoglobulin-like lectin-E nanoparticles decorated with natural Siglec ligand	Siglec-E induction pathway provide inhibitory signal for TLR-mediated response in macrophages and neutrophils	Nanotherapeutic approach	CLP-induced sepsis models	Siglec system have important roles in homeostasis and restoration of normal immune cell function. In inflammatory settings, LPS enhance IL-10 production, which induce Siglec-E expression that forms a positive feedback loop for IL-10 expression	Sialylated nanoparticle promote oligomerization and activation of Siglecs on macrophages, reduce inflammatory cytokine production in models of systemic inflammation and localized lung injury	448
Magnetic nanobeads coated with an engineered human opsonin	Extracorporeal removal of pathogen and endotoxin from bloodstream	Nanotherapeutic approach	Staphylococcus aureus or E. coli-infected rats	Blood flow from an infectious patient was mixed with nanobeads incorporated in this extracorporeal blood cleansing device coated with an engineered human opsonin, the magnetic nanobeads capture and remove opsonin-bound pathogen and toxin from the blood, while cleansed blood is then returned back to individuals	In models of endotoxemic shock, this biospleen device cleared >90% bacterial from blood, reduced pathogen and immune cell infiltration in multiple organs, and decreased inflammatory cytokine levels	394
pH/enzyme-responsive bioresponsive nanocarrier targeted for drug delivery to infectious microenvironments (IME)	Vascular cell adhesion interfere with leukocyte recruitment responses and various inflammatory signaling pathway at the infectious microenvironments (IME)	Nanotherapeutic approach	P. aeruginosa challenged acute peritonitis model	Biotin–avidin system facilitate conjugation of ICAM antibody to nanoparticles. Together with pH and enzyme-responsive properties, these facilitate co-delivery of antibiotics and anti-inflammatory agent to IME, thus effectively control both bacterial burden and host inflammatory response	Co-delivery of antibiotics and anti-inflammatory agent to IME improved survival rate in animal models, observed with marked reduction in leukocyte counts, inflammatory cytokines (TNF-α, IL-1β, and IL-6), and CFU detected in peritoneal fluids and blood. Proteins content were also reduced in peritoneal fluids, suggesting leaky vasculature repairing	397
An ANG2-binding antibody (ABTAA)	Angiopoietin-TIE2 system	Monoclonal antibody	CLP-/LPS-induced sepsis model	Ang2, a Tie2 antagonist, is often elevated in severe sepsis patients. By inducing Ang2 oligomerization and clustering at Tie2 receptor molecule, ABTAA covert the deleterious antagonist into a novel Tie-2 activator and induce downstream endothelial protective signaling. Converting existing Ang2 into agonist of Tie2 is a more effective approach than blocking with an Ang2 inhibitory antibody or supplement of Tie2 agonist Ang1	ABTAA augment survival by strengthening endothelial glycocalyx, reducing cytokine storms, preventing vascular leakage, and mitigating organ damage via barrier defense effect of TIE2 activation	377
Adrenomedullin-binding antibody (Adrecizumab, ADZ)	Inhibition of sepsis-induced ADM to stimulate protective effect by restoring endothelial function	Monoclonal antibody, biomarker-guided therapy	Early septic shock with high concentration of circulating ADM (recruiting)	ADM is a vasoactive peptide expressed within endothelial cells. Described as a double-edged sword, ADM could not only induce vasodilation and hypotension but also reinforce endothelial barrier. During sepsis, high plasma concentrations of ADM were correlated with worse clinical outcomes	Experimentally, AZM shift distribution of ADM away from interstitium toward blood and facilitate interaction with endothelial cell receptors to prevent vascular leakage and hypotension. In preclinical studies, ADZ improved vascular barrier function, reduced vasopressor demand and organ dysfunction, and improved survival. Phase II study was completed and pre-results will be published shortly	449
Human recombinant alkaline phosphatase	Dephosphorylation of endotoxin and adenosine triphosphate by alkaline phosphatase resulted in an attenuated inflammatory response	Monoclonal antibody	Sepsis patients with acute kidney injury (AKI)	As an endogenous enzyme, alkaline phosphatase exhibits detoxifying effects through dephosphorylation of endotoxins and pro-inflammatory mediators, such as extracellular adenosine triphosphate	In critically ill sepsis-associated AKI patients, alkaline phosphatase improves endogenous creatinine clearance but did not have significant effect on short-term kidney function (first week)	450