Complement Inhibitor Research Articles

Sutimlimab for Cold Agglutinin Disease.

Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia (AIHA) distinct from warm antibody AIHA. One of the ways it is distinct is that CAD is usually not responsive to corticosteroids compared with warm antibody AIHA. Historically, CAD therapy has been limited to immunotherapy or chemoimmunotherapy with varying responses. Cold agglutinin disease also poses a risk for thrombosis and mortality. For patients, fatigue tends to be a common symptom of CAD. The hallmark of CAD is complement-mediated hemolysis, which makes complement inhibitors a critical therapeutic option for patients. Previously, eculizumab, a C5 inhibitor, had limited therapeutic effect for CAD. More recently, sutimlimab, a C1s inhibitor, was shown in two phase III studies to be an efficacious treatment for CAD, improving hemoglobin, hemolysis, and fatigue. However, there is a paucity of medical literature on CAD and on sutimlimab in particular that is geared toward advanced practice providers (APPs). This article aims to provide APPs with a background in CAD and a focus on sutimlimab, assisting these providers in caring for patients with CAD receiving this therapy.

Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3/C3b-targeted therapy, pegcetacoplan.

Haemophilus influenzae Endophthalmitis Associated With Intravitreal Pegcetacoplan Injection

Purpose: To describe a case of endophthalmitis caused by Haemophilus influenzae, an encapsulated bacterium, after intravitreal (IVT) injection of pegcetacoplan. Methods: A single retrospective case was evaluated. Results: An 88-year-old woman with a history of diabetes mellitus, on dialysis for chronic kidney disease, hypertension, hypothyroidism, diffuse large B-cell lymphoma, and geographic atrophy in both eyes received an IVT injection of pegcetacoplan in both eyes. She subsequently developed endophthalmitis in the right eye caused by H influenzae. Further bloodwork showed Proteus mirabilis bacteremia. Conclusions: Pegcetacoplan, a complement inhibitor, may be associated with intraocular infections with encapsulated organisms, especially in immunocompromised patients.

Epidemiological estimates of paroxysmal nocturnal hemoglobinuria in Bulgaria.

Paroxysmal nocturnal hemoglobinuria is a rare clonal hematopoietic stem cell disorder with debilitating health consequences if untreated. Although cases have been described globally, precise epidemiological distribution is difficult to assess due to geographical underrepresentation in disease reporting. Evaluation of the burden of paroxysmal nocturnal hemoglobinuria in Bulgaria is currently missing. To provide epidemiological estimates, a systematic literature search for publications in the Bulgarian language or by Bulgarian authors was performed for a ten-year period (2013-2022), and clinically relevant information on case presentation was collected. Additionally, data was retrieved from the National Health Insurance Fund and National Statistical Institute on the count of registered cases with ICD-10 code "D59.5" and census for the same period. The estimated prevalence of paroxysmal nocturnal hemoglobinuria is relatively lower in the Bulgarian population than in other countries, and it is estimated to be 2.77 cases per 1,000,000 patient years. The treatment pattern mainly shows conventional blood product support use and is consistent with the pre-complement inhibition era. Underdiagnosis, lack of a reliable disease reporting system, and, until recently, restricted access to complement inhibitor therapy are significant impediments to the management of paroxysmal nocturnal hemoglobinuria in Bulgaria.

Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model.

Complement activation is implicated in driving brain inflammation, self-cell damage and progression of injury in Alzheimer's disease and other neurodegenerative diseases. Here, we investigate the impact of brain delivery of a complement-blocking antibody on neurodegeneration in an Alzheimer's mouse model. We engineered a brain-penetrant recombinant antibody targeting the pro-inflammatory membrane attack complex. Systemic administration of this antibody in APPNL-G-F mice reduced brain levels of complement activation products, demonstrating successful brain entry and target engagement. Prolonged treatment decreased synapse loss, amyloid burden and brain inflammatory cytokine levels, concomitant with cognitive improvement compared to controls. These results underscore the potential of brain-penetrant complement-inhibiting drugs as promising therapeutics, targeting downstream of amyloid plaques in Alzheimer's disease.

Real-World Clinical Outcomes Among Patients Untreated With Complement Inhibitors (CIs) in Paroxysmal Nocturnal Hemoglobinuria (PNH) – A Retrospective Claims Database Analysis in the United States

Real-World Clinical Outcomes Among Patients Untreated With Complement Inhibitors (CIs) in Paroxysmal Nocturnal Hemoglobinuria (PNH) – A Retrospective Claims Database Analysis in the United States

MDS-658 Real-World Clinical Outcomes Among Patients Untreated With Complement Inhibitors (CIs) in Paroxysmal Nocturnal Hemoglobinuria (PNH) – A Retrospective Claims Database Analysis in the United States

MDS-658 Real-World Clinical Outcomes Among Patients Untreated With Complement Inhibitors (CIs) in Paroxysmal Nocturnal Hemoglobinuria (PNH) – A Retrospective Claims Database Analysis in the United States

Superiority of Avacopan and Mepolizumab to Glucocorticoid Tapering in the Treatment of Anti-neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: A Systematic Review.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a spectrum of autoimmune diseases, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Studies have shown that avacopan and mepolizumab are promising therapeutics for partial or complete replacement of glucocorticoids (GC), with sustained remission while completely weaning off GC. Avacopan inhibits C5aR in the complement pathway, preventing neutrophil migration, while mepolizumab targets IL-5R, reducing eosinophil activity. Additionally, complement inhibition has not only contributed to the recovery of renal function and alleviation of physical symptoms but has also enhanced patients' overall quality of life and mental well-being. This systematic review explores the pathogenesis of AAV, traditional treatments, and the potential of emerging complement and interleukin antagonist therapies such as avacopan and mepolizumab in revolutionizing AAV management.

Targeting complement dysregulation: eculizumab in scleroderma renal crisis management-a case-based review.

Systemic sclerosis (SSc) poses significant challenges in clinical management, especially when complicated by scleroderma renal crisis (SRC), a rare but life-threatening manifestation. Here, we report a 41-year-old female patient with SSc who presented with SRC and concurrent thrombotic microangiopathy. Her condition persisted despite conventional treatments such as plasma exchange and renin-angiotensin-aldosterone system blockade. In particular, treatment with eculizumab, a C5 complement inhibitor, led to a rapid improvement in platelet count, reduction in lactate dehydrogenase levels, and complete recovery of renal function. Genetic testing revealed a variant of unknown significance in the thrombomodulin (THBD) gene, which is associated with the complement system. This case highlights the complex interplay between complement dysregulation and SRC, and highlights the promising role of eculizumab in refractory cases. Further investigation of complement involvement and the efficacy of eculizumab in SRC warrants attention to improving therapeutic outcomes in this challenging condition.

Contemporary review of IgA nephropathy.

IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide with a predilection for Asian-Pacific populations and relative rarity in those of African descent. Perhaps 20%-50% of patients progress to kidney failure. The pathogenesis is incompletely understood. Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage. Diagnosis requires a biopsy interpreted by the Oxford criteria. Additional pathologic features include podocytopathy, thrombotic microangiopathy, and C4d staining. Biomarkers predicting adverse outcomes include proteinuria, reduced GFR, hypertension, and pathology. Acceptable surrogate endpoints for therapeutic trials include ongoing proteinuria and rate of eGFR decline. The significance of persisting hematuria remains uncertain. The mainstay of therapy is supportive, consisting of lifestyle modifications, renin-angiotensin inhibition (if hypertensive or proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or proteinuric), and endothelin-receptor antagonism (if proteinuric). Immunosuppression should be considered for those at high risk after maximal supportive care. Corticosteroids are controversial with the most positive results observed in Chinese. They carry a high risk of serious side effects. Similarly, mycophenolate may be most effective in Chinese. Other immunosuppressants are of uncertain benefit. Tonsillectomy appears efficacious in Japanese. Active areas of investigation include B-cell inhibition with agents targeting the survival factors BAFF and APRIL and complement inhibition with agents targeting the alternate pathway (Factors B and D), the lectin pathway (MASP-2), and the common pathway (C3 and C5). Hopefully soon, the who and the how of immunosuppression will be clarified, and kidney failure can be forestalled.

Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients' quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.

Systematic Review of Individual Patient Data COVID-19 Infection and Vaccination–Associated Thrombotic Microangiopathy

Sporadic cases of atypical hemolytic uremic syndrome (aHUS) have been described in the literature in association with COVID-19 infection and vaccination in adults and pediatric patients. The exact mechanisms underlying COVID-19-associated thrombotic microangiopathies (TMAs) remain incompletely understood. Herein, we present a detailed meta-analysis of the clinical characteristics, outcomes, and management strategies of COVID-19-associated aHUS and thrombotic thrombocytopenic purpura (TTP). This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses updated guidelines. PubMed was utilized for searching for case reports and series. Adverse outcome at last follow-up was defined as estimated glomerular filtration rate< 30 ml/min per 1.73 m2 (patients with aHUS), no remission with therapy, or patient death. Data were analyzed using Wilcoxon rank and Chi-square tests. Our analysis cohort included 118 studies reporting on 170 patients. These included 84 cases of aHUS and 86 cases of TTP resulting from COVID-19 infection (n= 92) or vaccination (n= 78). Significantly more cases of aHUS were reported after infection (n= 65) than immunization (n= 19), compared to TTP, where the reverse was true (n= 27 and n= 59, respectively; P< 0.001). In patients with aHUS with stage 3 acute kidney injury (AKI), requirement of kidney replacement therapy (KRT) was seen in three-fourths of the cohort for a median of 15. In patients with TTP, severe COVID-19 infection (P= 0.04) predicted nonremission or death at last follow-up. Administration of i.v., rituximab and caplacizumab were protective (P= 0.03 and P= 0.06, respectively). Immune TTP (iTTP) was reported more often than HUS following mRNA vaccines (81% vs. 58%; P= 0.06). COVID-19 infection and vaccination are a potential trigger for onset or relapse of aHUS and TTP, especially in patients who are not on maintenance complement inhibitors or immunosuppression.

The complement model disease paroxysmal nocturnal hemoglobinuria.

We describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement-mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement-mediated pathophysiology ultimately led to regulatory approval of the first-in-class complement inhibitor, eculizumab, in 2007. This anti-complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant-resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti-C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low-level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.

Genomic analysis of foodborne Staphylococcus aureus obtained from unannounced food inspections between 2012 and 2021 in East China.

Staphylococcus aureus is a significant cause of foodborne illness in China. Our investigation concentrated on the genetic characterization of foodborne S. aureus identified during unannounced inspections conducted in Suzhou from 2012 to 2021. Dominant clones included clonal complex (CC) 1, CC398, CC188, and CC7, with CC398 notably increasing in 2020-2021. The isolates commonly contained 1-3 plasmids, with rep5a (48.55%) and rep16 (44.51%) predominating. A concerning 24.3% showed multidrug resistance, particularly to penam (blaZ and mecA) and fosfomycin (fosB), with resistance rates rising from 32.7% to 53.3%, potentially linked to the increase in CC types like CC5, CC20, and CC25. Most isolates carried genes for virulence factors such as aureolysin, hemolysin, staphylokinase, and staphylococcal complement inhibitor. A significant increase in virulence genes, especially the enterotoxin gene sea, was observed, possibly associated with shifts in CC1 and CC7 prevalence. This underscores the necessity for ongoing surveillance to understand the genomic traits of S. aureus in ensuring food safety.

A review of progress on complement and primary membranous nephropathy.

Primary membranous nephropathy (PMN) is a predominant cause of adult nephrotic syndrome, with its incidence witnessing a progressive surge over time. Approximately 35% to 47% of patients progress to renal failure within 10 years, causing a huge social burden. Within China, the proportion of PMN in primary glomerular disease exhibits a gradual ascension. Recent studies have shown that the 3 activation pathways of complement: the classical pathway, mannose-binding lectin pathway, and alternative pathway, are all involved in the pathogenesis of PMN. Despite historical limitations in detecting C1q deposits on the glomeruli of PMN in the past, recent studies have confirmed the classical pathway is implicated in patients with PMN. Considering the dysregulation of the complement system has been observed in PMN, complement inhibitors become increasingly promising. Several clinical trials are presently underway to evaluate the efficacy of complement inhibitors, such as MASP2 antagonists (OMS721), C3 and C3b antagonists (APL2), FD inhibitors (BCX9930), C3aR antagonists (SB290157 and JR14a), FB inhibitors (LNP023). This article reviews the recent research progress on the role of the complement pathway in the pathogenesis of PMN, and underscores the importance of continued research into the complement pathway and its inhibitors, which may pave the way for groundbreaking advancements in the management of PMN.

New Therapies for Highly Sensitized Patients on the Waiting List.

Exposure to HLA alloantigens through pregnancy, blood products, and previous transplantations induce powerful immunologic responses that create an immunologic barrier to successful transplantation. This is commonly detected through screening for HLA antibodies using Luminex beads coated with HLA antigens at transplant evaluation. Currently accepted approaches to desensitization include plasmapheresis/low-dose or high-dose intravenous Ig plus anti-CD20. However, these approaches are often unsuccessful because of the inability to remove high titer circulating HLA antibodies and limit rebound responses by long-lived anti-HLA antibody secreting plasma cells (PCs) and memory B cells (B MEM ). This is especially significant for patients with a calculated panel reactive antibody of 99%-100%. Newer desensitization approaches, such as imlifidase (IgG endopeptidase), rapidly inactivate IgG molecules and create an antibody-free zone by cleaving IgG into F(ab'2) and Fc fragments, thus eliminating complement and cell-mediated injury to the graft. This represents an important advancement in desensitization. However, the efficacy of imlifidase is limited by pathogenic antibody rebound, increasing the potential for antibody-mediated rejection. Controlling antibody rebound requires new strategies that address the issues of antibody depletion and inhibition of B MEM and PC responses. This will likely require a combination of agents that effectively and rapidly deplete pathogenic antibodies and prevent immune cell activation pathways responsible for antibody rebound. Here, using anti-IL-6 receptor (tocilizumab) or anti-IL-6 (clazakizumab) could offer long-term control of B MEM and PC donor-specific HLA antibody responses. Agents aimed at eliminating long-lived PCs (anti-CD38 and anti-B-cell maturation antigen×CD3) are likely to benefit highly HLA sensitized patients. Complement inhibitors and novel agents aimed at inhibiting Fc neonatal receptor IgG recycling will be important in desensitization. Administering these agents alone or in combination will advance our ability to effectively desensitize patients and maintain durable suppression post-transplant. After many years of limited options, advanced therapeutics will likely improve efficacy of desensitization and improve access to kidney transplantation for highly HLA sensitized patients.

Complement Factor B Inhibition or Deletion Is Not Sufficient to Prevent Neurodegeneration in a Murine Model of Glaucoma.

Purpose: Activation of the classical complement pathway is thought to contribute to the development and progression of glaucoma. The role of alternative complement or amplification pathways in glaucoma is not well understood. We evaluated complement factor B (FB) expression in postmortem human ocular tissues with or without glaucoma and the effect of FB inhibition and deletion in a mouse ocular hypertensive model of glaucoma induced by photopolymerized hyaluronic acid glycidyl methacrylate (HAGM). Methods: Human CFB mRNA in human eyes was assessed by RNAscope and TaqMan. HAGM model was performed on C57BL6/J mice. The effect of FB in HAGM model was evaluated with an oral FB inhibitor and Cfb-/- mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. Results: CFB mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. Cfb mRNA is also upregulated in the HAGM model. Oral FB inhibitor, ED-79-GX17, dosed daily at 200 mg/kg for 3 days after intraocular pressure (IOP) induction in wild-type mice showed complement inhibition in ocular tissues and significantly inhibited systemic complement levels. Daily dosing of ED-79-GX17 for 30 days or Cfb deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. Conclusion: The alternative complement component FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of Cfb expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.

Identification of disease phenotypes in acetylcholine receptor-antibody myasthenia gravis using proteomics-based consensus clustering

The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a challenge for patient stratification and treatment decision making. Novel strategies are needed to classify patients based on their biological phenotypes aiming to improve patient selection and treatment outcomes. For this purpose, we assessed the serum proteome of a cohort of 140 patients with anti-acetylcholine receptor-Ab-positive MG and utilised consensus clustering as an unsupervised tool to assign patients to biological profiles. For in-depth analysis, we used immunogenomic sequencing to study the B cell repertoire of a subgroup of patients and an invitro assay using primary human muscle cells to interrogate serum-induced complement formation. This strategy identified four distinct patient phenotypes based on their proteomic patterns in their serum. Notably, one patient phenotype, here named PS3, was characterised by high disease severity and complement activation as defining features. Assessing a subgroup of patients, hyperexpanded antibody clones were present in the B cell repertoire of the PS3 group and effectively activated complement as compared to other patients. In line with their disease phenotype, PS3 patients were more likely to benefit from complement-inhibiting therapies. These findings were validated in a prospective cohort of 18 patients using a cell-based assay. Collectively, this study suggests proteomics-based clustering as a gateway to assign patients to a biological signature likely to benefit from complement inhibition and provides a stratification strategy for clinical practice. CN and CBS were supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf. CN was supported by the Else Kröner-Fresenius-Stiftung (EKEA.38). CBS was supported by the Deutsche Forschungsgemeinschaft (DFG-German Research Foundation) with a Walter Benjamin fellowship (project 539363086). The project was supported by the Ministry of Culture and Science of North Rhine-Westphalia (MODS, "Profilbildung 2020" [grant no. PROFILNRW-2020-107-A]).

Resolution of extravascular hemolysis with oral iptacopan monotherapy in apatient with treatment experienced paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder characterized by aloss of glycosyl-phosphatidyl-inositol-linked (GPI) proteins on various hematopoietic cells. Some GPI proteins are involved in the regulation of the complement system, and their absence renders erythrocytes susceptible to complement-mediated lysis. Current standard of care in PNH is to block the complement system at the level of C5 using ravulizumab or eculizumab; however, some patients with PNH may develop extravascular hemolysis (EVH) during treatment with C5 inhibitors. The proximal complement inhibitor iptacopan has recently been shown to be efficacious in patients with PNH. This article reports on a43-year-old female patient with PNH who was successfully treated with iptacopan. The patient had received ravulizumab for several years and developed aclinically relevant EVH. After obtaining informed consent, the patient received oral iptacopan 200 mg twice daily and ravulizumab was discontinued. Over the next few weeks hemoglobin levels and reticulocyte counts normalized. The patient reported mild flushes with erythema, chills, and mild muscle pain, all of which resolved during follow-up. No breakthrough hemolysis occurred, and no severe adverse events were recorded.

Reciprocal Interaction with Neutrophils Facilitates Cutaneous Accumulation of Liposomes.

Liposomes are versatile drug delivery systems in clinical use for cancer and many other diseases. Unfortunately, PEGylated liposomal doxorubicin (sLip/DOX) exhibits serious dose-limiting cutaneous toxicities, which are closely related to the extravascular accumulation of sLip/DOX in the dermis. No clinical interventions have been proposed for cutaneous toxicities due to the elusive transport pathways. Herein, we showed that the reciprocal interaction between liposomes and neutrophils played pivotal roles in liposome extravasation into the dermis. Neutrophils captured liposomes via the complement receptor 3 (CD11b/CD18) recognizing the fragment of complement component C3 (iC3b) deposited on the liposomal surface. Uptake of liposomes also activated neutrophils to induce CD11b upregulation and enhanced the ability of neutrophils to migrate outside the capillaries. Furthermore, inhibition of complement activation either by CRIg-L-FH (a C3b/iC3b targeted complement inhibitor) or blocking the phosphate negative charge in mPEG-DSPE could significantly reduce liposome uptake by neutrophils and alleviate the cutaneous accumulation of liposomes. These results validated the liposome extravasation pathway mediated by neutrophils and provided potential solutions to the devastating cutaneous toxicities occurring during sLip/DOX treatment.