Monoclonal Interleukin-2 Research Articles

Risankizumab efficacy and safety based on prior inadequate response or intolerance to advanced therapy: post hoc analysis of the INSPIRE and COMMAND phase 3 studies.

Treating ulcerative colitis (UC) in patients with prior advanced therapy (AT) exposure may be challenging. We report the efficacy and safety of risankizumab, a monoclonal interleukin 23p19 antibody, in patients with UC and prior inadequate response or intolerance to AT (AT-IR). In the 12-week phase 3 INSPIRE induction study, patients were randomized to intravenous risankizumab 1200mg or placebo. Clinical responders were randomized to subcutaneous risankizumab 180mg, risankizumab 360mg, or placebo (risankizumab withdrawal) in the 52-week phase 3 COMMAND maintenance study. This post hoc analysis assessed outcomes by AT-IR status, number, and mechanism of action. AT included biologics, Janus kinase inhibitors, and sphingosine-1-phosphate receptor modulators. Efficacy analyses included 472 non-AT-IR and 503 AT-IR patients (induction), and 137 non-AT-IR and 411 AT-IR patients (maintenance). More patients achieved clinical remission per Adapted Mayo score with risankizumab 1200mg versus placebo at induction week 12 (non-AT-IR, 29.7% versus 8.4%, nominal P < .0001; AT-IR, 11.4% versus 4.3%, nominal P = .0083); consistent with risankizumab 180mg or risankizumab 360mg versus placebo (withdrawal) at maintenance week 52 (non-AT-IR, 50.9% or 61.7% versus 31.1%, nominal P = .057 or P = .0033, respectively; AT-IR, 36.6% or 29.5% versus 23.2%, nominal P = .0159 or P = .2334, respectively). Risankizumab had increased efficacy over placebo, regardless of AT-IR number or mechanism of action, with higher efficacy rates for non-AT-IR compared to AT-IR. Safety results in non-AT-IR and AT-IR patients were generally comparable in both induction and maintenance. Risankizumab was effective and well tolerated, regardless of prior AT-IR status. INSPIRE [NCT03398148], COMMAND [NCT03398135].

Ziltivekimab for anemia and atherosclerosis in chronic kidney disease: a new hope?

Anemia of chronic kidney disease is a multifactorial condition secondary to various etiologies, including nutritional deficiencies, chronic inflammation, erythropoietin deficiency or resistance, bone marrow suppression, iron deficiency and adverse drug effects. The major therapeutic intervention for anemia among chronic kidney disease patients is erythropoiesis-stimulating agents. However, a limitation of erythropoiesis-stimulating agents is the risk for thromboembolic events, hypertension, seizures, solid organ malignancies and hyporesponsiveness. A novel interleukin-6 monoclonal antibody, ziltivekimab, has been evaluated for managing anemia in chronic kidney disease patients in pilot clinical trials with promising outcomes, including an improvement in hemoglobin levels and reduction of inflammatory parameters. These trials have shown that ziltivekimab does not increase the risk for cytopenia or infectious complications as has been described for other interleukin-6-targeting monoclonal antibodies, like tocilizumab. Furthermore, potentially beneficial effects on serum lipid profile have been reported, leading to the hypothesis of a favorable impact of the drug on atherosclerotic complications. In addition, ziltivekimab has shown efficacy in improving anemia parameters, including hemoglobin levels and iron studies. Ziltivekimab deserves full scale clinical development, and to this aim, large-scale clinical trials are under way.

Anti-IL-8 monoclonal antibodies inhibits the autophagic activity and cancer stem cells maintenance within breast cancer tumor microenvironment.

Breast cancer tumor microenvironment (TME) is a promising target for immunotherapy. Autophagy, and cancer stem cells (CSCs) maintenance are essential processes involved in tumorigenesis, tumor survival, invasion, and treatment resistance. Overexpression of angiogenic chemokine interleukin-8 (IL-8) in breast cancer TME is associated with oncogenic signaling pathways, increased tumor growth, metastasis, and poor prognosis. Thus, we aimed to investigate the possible anti-tumor effect of neutralizing antibodies against IL-8 by evaluating its efficacy on autophagic activity and breast CSC maintenance. IL-8 monoclonal antibody supplemented tumor tissue culture systems from 15 females undergoing mastectomy were used to evaluate the expression of LC3B as a specific biomarker of autophagy and CD44, CD24 as cell surface markers of breast CSCs using immunofluorescence technique. Our results revealed that anti-IL-8 mAb significantly decreased the level of LC3B in the cultured tumor tissues compared to its non-significant decrease in the normal breast tissues.Anti-IL-8 mAb also significantly decreased the CD44 expression in either breast tumors or normal cultured tissues. While it caused a non-significant decrease in CD24 expression in cultured breast tumor tissue and a significant decrease in its expression in the corresponding normal ones. Anti-IL-8 monoclonal antibody exhibits promising immunotherapeutic properties through targeting both autophagy and CSCs maintenance within breast cancer TME.

Targeted blockade of interleukin-8 negates metastasis and chemoresistance via Akt/Erk-NFκB axis in oral cancer

BackgroundThe tumor microenvironment plays a significant role in tumor growth, metastasis and chemoresistance via dysregulated signaling pathways. Toward this, an inflammatory chemokine, interleukin-8 (IL-8), is overexpressed in various cancers and is involved in tumor progression and chemoresistance. However, the mechanistic role of IL-8 in mediating metastasis and chemoresistance in oral squamous cell carcinoma (OSCC) is not known. Methods and resultsIn the present study, we evaluated the effect of IL-8 in regulating metastasis as well as chemoresistance in OSCC cell lines. For this, IL-8 was blocked exogenously using neutralizing IL-8 monoclonal antibody and IL-8 levels were enhanced by exogenous supply of recombinant human IL-8 (rhIL-8) to OSCC cells. The epithelial-to-mesenchymal transition (EMT) was evaluated using qPCR, migration by scratch/wound healing assay and invasion ability using transwell assay. rIL-8 induced chemoresistance was studied by apoptosis assay and the nuclear localization of NFκB using immunocytochemistry. IL-8 was significantly overexpressed in OSCC patients and cell lines. While exogenous blockade of IL-8 significantly reduced EMT, migration and invasion potential in OSCC cells, IL-8 overexpression upregulated these cellular traits thereby confirming the role of IL-8 in OSCC metastasis. Exogenous blockade of IL-8 also reversed chemoresistance in cisplatin resistant OSCC subline via NFκB signaling. ConclusionIL-8 plays a crucial role in OSCC metastasis and its targeted blockade can help in management of cisplatin resistance.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Gerilimzumab (GB224), a recombinant humanized interleukin-6 monoclonal antibody, in healthy Chinese adults: A randomized controlled dose–escalation study

ABSTRACT Objectives This study aimed to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of Gerilimzumab (GB224), a recombinant humanized IgG1λ monoclonal antibody against interleukin-6, in healthy Chinese adults. Methods Fifty-eight subjects were randomly assigned to receive a single subcutaneous dose of 2, 5, 10, 15, 20, 30 mg GB224 or placebo. Safety assessments were performed, and blood samples were collected for PK, PD, and immunogenicity analyses during a follow-up of 112 days. Results The most frequent adverse event was decreased fibrinogen (43.1%). GB224 was absorbed relatively fast with a median Tmax of 48 h (24–168 h) but eliminated slowly with a long mean half-life (839.38–981.63 h). Dose proportionality was shown to be in the dose range of 10–30 mg. A dose-dependent increase in serum interleukin-6 concentration from baseline was observed in the subjects receiving GB224. Only two subjects tested positive for antidrug antibodies after administration of GB224. Conclusion GB224 had a well-tolerated safety profile, desirable PK, and a low immunogenicity following a single-dose subcutaneous administration in healthy Chinese subjects. These findings warrant further investigation.

Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.

Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1β, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHY In the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.

Basiliximab vs. Antithymocyte Globulin as Initial Induction Therapy for Lung Transplantation: A National Two Years Review

Basiliximab (BAS) is an interleukin-2 monoclonal antibody initially used as induction therapy after liver and kidney transplantation. BAS use after lung transplantation (LTx) has supplanted antithymocyte globulin (ATG) as the main induction immunosuppression over the years, but few studies have compared them. In this study, we aimed to compare the efficacy and safety between BAS and ATG in LTx. We performed a retrospective analysis of all LTx done in Portugal between January 2016 and December 2019. Three groups were made according to the initial induction status: BAS, ATG or no induction (NI). The occurrences of cytomegalovirus (CMV) infection, pneumonia, side effects, primary graft dysfunction (PGD), acute rejection, chronic allograft disfunction (CLAD) and death episodes were assessed during two years after LTx. A total of 124 patients were divided in 3 groups: 61 (49.2%) BAS; 43 (34.7%) ATG; 20 (16.1%) NI. The incidences of pneumonia and CMV were similar between induction groups. Additionally, there was no difference between the induction groups in PGD, acute rejection, CLAD, deaths and two-year survival. Side effects were reported only in ATG group (n = 20; 46.5%). In our study, BAS had a better safety profile than ATG in LTx with a similar efficacy.

Microgravity-Related Changes in Bone Density and Treatment Options: A Systematic Review.

Space travelers are exposed to microgravity (µg), which induces enhanced bone loss compared to the age-related bone loss on Earth. Microgravity promotes an increased bone turnover, and this obstructs space exploration. This bone loss can be slowed down by exercise on treadmills or resistive apparatus. The objective of this systematic review is to provide a current overview of the state of the art of the field of bone loss in space and possible treatment options thereof. A total of 482 unique studies were searched through PubMed and Scopus, and 37 studies met the eligibility criteria. The studies showed that, despite increased bone formation during µg, the increase in bone resorption was greater. Different types of exercise and pharmacological treatments with bisphosphonates, RANKL antibody (receptor activator of nuclear factor κβ ligand antibody), proteasome inhibitor, pan-caspase inhibitor, and interleukin-6 monoclonal antibody decrease bone resorption and promote bone formation. Additionally, recombinant irisin, cell-free fat extract, cyclic mechanical stretch-treated bone mesenchymal stem cell-derived exosomes, and strontium-containing hydroxyapatite nanoparticles also show some positive effects on bone loss.

Clinical outcomes after IL-6 blockade in patients with COVID-19 and HIV: a case series

BackgroundIn hospitalized people with HIV (PWH) there is an increased risk of mortality from COVID-19 among hospitalized PWH as compared to HIV-negative individuals. Evidence suggests that tocilizumab—a humanized monoclonal interleukin (IL)-6 receptor inhibitor (IL-6ri) antibody—has a modest mortality benefit when combined with corticosteroids in select hospitalized COVID-19 patients who are severely ill. Data on clinical outcomes after tocilizumab use in PWH with severe COVID-19 are lacking.Case presentationWe present a multinational case series of 18 PWH with COVID-19 who were treated with IL-6ri’s during the period from April to June 2020. Four patients received tocilizumab, six sarilumab, and eight received an undocumented IL-6ri. Of the 18 patients in the series, 4 (22%) had CD4 counts < 200 cells/mm3; 14 (82%) had a suppressed HIV viral load. Eight patients (44%), all admitted to ICU, were treated for secondary infection; 5 had a confirmed organism. Of the four patients with CD4 counts < 200 cells/mm3, three were treated for secondary infection, with 2 confirmed organisms. Overall outcomes were poor—12 patients (67%) were admitted to the ICU, 11 (61%) required mechanical ventilation, and 7 (39%) died.ConclusionsIn this case series of hospitalized PWH with COVID-19 and given IL-6ri prior to the common use of corticosteroids, there are reports of secondary or co-infection in severely ill patients. Comprehensive studies in PWH, particularly with CD4 counts < 200 cells, are warranted to assess infectious and other outcomes after IL-6ri use, particularly in the context of co-administered corticosteroids.

Regulatory T Cell (Treg) Cytotoxic T Lymphocyte-associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA.

Biliary atresia (BA) entails an inflammatory injury of the biliary tree, leading to fibrosis of the extrahepatic and intrahepatic bile ducts. The chronic inflammatory biliary injury may be due to lack of appropriate regulatory T cell (Treg) suppression of inflammation. The aims of the study were to characterize Treg deficits in human BA and to determine if Treg augmentation therapy improved outcomes in the rhesus rotavirus (RRV)-induced mouse model of BA. Immunophenotyping of human peripheral blood and liver Tregs was performed with flow cytometry, Vectra-6 multicolor immunohistochemistry (IHC), and real-time polymerase chain reaction. Measured outcomes of Treg augmentation with the interleukin-2 monoclonal antibody JES6-1/interleukin-2 in the RRV-induced mouse model of BA included survival, direct bilirubin, IHC, and liver flow cytometry. Patients with BA had decreased peripheral blood Treg frequency and lack of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) upregulation despite a highly activated, effector Treg phenotype. IHC revealed decreased liver Treg frequency and Treg CTLA-4 expression. Treg augmentation in the murine model led to increased survival, decreased direct bilirubin levels and liver inflammation, and expansion of resident macrophages. In addition to the M2 phenotype of resident macrophages, these cells adopted an inflammatory M1 phenotype in response to RRV infection, which was inhibited with Treg augmentation. Patients with BA have Treg deficiencies associated with lack of sufficient CTLA-4 expression that is necessary for cell-cell contact inhibition of inflammatory responses. Treg augmentation therapy in murine BA protected from disease. Future treatment trials for BA should include agents that enhance Treg number or function, mimic CTLA-4 function, and promote anti-inflammatory M2 macrophage phenotypes.

562. Tocilizumab Use in the Second Trimester Pregnant Patients with Severe Covid-19 Pneumonia and their Maternal and Fetal Outcomes: Two Case Reports

BackgroundTocilizumab is an interleukin-6 monoclonal antibody with widespread use in rheumatologic conditions. Observational studies have shown a promising role of Tocilizumab in severe COVID-19 patients with cytokine storm syndrome. Data about tocilizumab use in pregnant patients is limited. We report two outcomes of two pregnant patients with COVID-19 in the second trimester who received tocilizumabMethodsA 24-year-old 20 weeks pregnant lady with a history of asthma and gestational diabetes mellitus presented with three days history of fever, cough and shortness of breath (Figure 1). She was clinically stable but later developed ARDS and developed increased oxygen demand up to 10 liters/min. She received Tocilizumab on. Patient was observed in a high dependency unit but did not require mechanical ventilation. Patient was discharged home with full recovery and later delivered a healthy baby. Timeline of medicines used during hospital (Figure 2). Case 2: 39-year-old 23 weeks pregnant lady presented with seven days history of fever cough and shortness of breath (Figure 1). On presentation, she had progressive worsening hypoxic respiratory failure and was intubated. Patient had her nasopharyngeal swab for CODI-19 RT PCR was positive. The patient had severe ARDS requiring ECMO (extracorporeal membrane oxygenation) for respiratory support. Tocilizumab 400 mg was given on the presentation, along with other medications (Figure 3). Patient had regular monitoring of fetus; however, she had intrauterine fetal demise on day 14. Patient It is unclear if IUFD was due to using of tocilizumab or severity of COVID19 itself. The patient stayed in ICU for 20 days and was discharged after full recovery. Figure 1. Case 1 treatment timeline. Abberviations: Azithro: Azithromycin, HCQ: Hydroxychloroquine, CQ: Chloroquine, LPV/r: lopinavir/Ritonavir, Osel: Oseltamivir, MP: Methylprednisolone, Ampi-sulb: Ampicillin-sulbactam, TCZ: tocilizumabFigure 2. Case 2 treatment timeline ResultsLearning points: Tocilizumab use in pregnant patients with severe COVID-19 pneumonia during the second trimester improved maternal outcomes in our cases. Tocilizumab use may be associated with worse fetal outcomes, including intrauterine fetal demise (IUFD). Figure 3. Table of clinical characteristics, pregnant outcomes. Abbreviations: LRTI: lower respiratory tract infection, HCQ: Hydroxychloroquine, CQ: chloroquine, Osel: Oseltamivir, Cef: Ceftrixone, Ampi-Sulb: ampicillin-sulbactam, Azithro: Azithromycin, TCZ: tocilizumab, MP: methylpredinisolone, H/O: History of, LSCS: C-section, NA: not available. Pip-tazo: Piperacillin-tazobactam, Mero: Meropenem, Sulfa-trim: Sulfamethoxazole-Trimethoprim, IUFD: Intrauterine fetal death.ConclusionThe pharmacological management of pregnant patients with severe COVID-19 pneumonia poses significant challenges. The use of Tocilizumab may improve maternal outcomes but may also increase the risk of worse fetal outcomes. Caution should be exercised in using this agent, and risks and benefits should be discussed with the patients.Disclosures All Authors: No reported disclosures

Prevention of IL-6 signaling ameliorates toluene diisocyanate-induced steroid-resistant asthma

BackgroundAccumulating evidence indicated the crucial role for interleukin 6 (IL-6) signaling in the development of allergic asthma. Yet, the role of IL-6 signaling in toluene diisocyanate (TDI)-induced mixed granulocytic airway inflammation still remains unclear. Thus, the aims of this study were to dissect the role of IL-6 signaling and to evaluate the effect of tocilizumab on TDI-induced steroid-resistant asthma. MethodsTDI-induced asthma model was prepared and asthmatic mice were respectively given IL-6 monoclonal antibody, IL-6R monoclonal antibody (tocilizumab, 5 mg/kg, i.p. after each challenge) for therapeutic purposes or isotype IgG as control. ResultsTDI exposure just elevated IL-6R expression in the infiltrated inflammatory cells around the airway, but increased glycoprotein 130 expression in the whole lung, especially in bronchial epithelium. Moreover, TDI inhalation increased airway hyperresponsiveness (AHR) to methacholine, coupled with mixed granulocytic inflammation, exaggerated epithelial denudation, airway smooth muscle thickening, goblet cell metaplasia, extensive submucosal collagen deposition, dysregulated Th2/Th17 responses, as well as innate immune responses and raised serum IgE. And almost all these responses except for raised serum IgE were markedly ameliorated by the administration of IL-6 neutralizing antibody or tocilizumab, but exhibited poor response to systemic steroid treatment. Also, TDI challenge induced nucleocytoplasm translocation of HMGB1 and promoted its release in the BALF, as well as elevated lung level of STAT3 phosphorylation, which were inhibited by anti-IL-6 and anti-IL-6R treatment. ConclusionsOur data suggested that IL-6 monoclonal antibody and tocilizumab might effectively abrogate TDI-induced airway inflammation and remodeling, which could be used as a clinical potential therapy for patients with severe asthma.

Tolerogenic anti–IL-2 mAb prevents graft-versus-host disease while preserving strong graft-versus-leukemia activity

AbstractDonor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti–interleukin-2 (IL-2) monoclonal antibody (JES6-1) forms anti–IL-2/IL-2 complexes that block IL-2 binding to IL-2Rβ and IL-2Rγ on conventional T cells that have low expression of IL-2Rα. Here, we show that administration of JES6 early after allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti–IL-2 treatment downregulated activation of the IL-2-Stat5 pathway and reduced production of granulocyte-macrophage colony-stimulating factor (GM-CSF). In GVHD target tissues, enhanced T-cell programmed cell death protein 1 (PD-1) interaction with tissue–programmed cell death-ligand 1 (PD-L1) led to reduced activation of protein kinase–mammalian target of rapamycin pathway and increased expression of eomesodermin and B-lymphocyte-induced maturation protein-1, increased T-cell anergy/exhaustion, expansion of Foxp3–IL-10–producing type 1 regulatory (Tr1) cells, and depletion of GM-CSF–producing T helper type 1 (Th1)/cytotoxic T cell type 1 (Tc1) cells. In recipient lymphoid tissues, lack of donor T-cell PD-1 interaction with tissue PD-L1 preserved donor PD-1+TCF-1+Ly108+CD8+ T memory progenitors and functional effectors that have strong GVL activity. Anti–IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8+ T memory progenitor cells are enriched with anti–IL-2 treatment compared with TAC treatment. We conclude that administration of tolerogenic anti–IL-2 monoclonal antibody early after allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.

International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease

AbstractCastleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Tocilizumab in the treatment of rapidly evolving COVID-19 pneumonia and multifaceted critical illness: A retrospective case series

BackgroundCOVID-19 associated critical illness characterized by rapidly evolving acute respiratory failure (ARF) can develop, especially on the grounds of hyperinflammation. Aim and methodsA case-series of 61 patients admitted to our intensive care unit (ICU) between August 12 and September 12, 2020 with confirmed COVID-19 pneumonia and rapidly evolving ARF requiring oxygen support therapy and/or mechanical ventilation was retrospectively analyzed. We examined whether intravenous administration of tocilizumab, a monoclonal interleukin-6 receptor antibody, was associated with improved outcome. All patients received empiric antivirals, dexamethasone 6 mg/day for 7 days, antibiotics, and prophylactic anticoagulation. Tocilizumab was administered at a dosage of 8 mg/kg [two consecutive intravenous infusions 12 h apart]. Outcome measures such as mortality on day-14, ICU length of stay, and rate of nosocomial acquired bacterial infections were also analyzed. Results: Patients were males (88.2%) aged 51 [interquartile range (IQR): 42.5–58.75)], with admission Acute Physiology and Chronic Health Evaluation (APACHE) 4 score of 53 (IQR: 37.75–72.5), and had more than one comorbidity (62.3%). On admission, twenty nine patients (47.5%) were mechanically ventilated, and thirty two patients (52.5%) were receiving oxygen therapy. No serious adverse effects due to tocilizumab therapy were recorded. However, twelve patients (19.6%) developed nosocomial acquired infections. ICU length of stay was 13 (IQR: 9–17) days, and mortality on day-14 was 24.6%. Six patients were shifted to other hospitals but were followed-up. The overall mortality on day-30 was 31.1%. Non-mechanically ventilated patients had higher survival rates compared to mechanically ventilated patients although results were not significant [hazards ratio = 2.6 (95% confidence intervals: 0.9–7.7), p = 0.08]. Tocilizumab did not affect the mortality of critically ill COVID-19 patients. ConclusionTocilizumab could be an adjunct safe therapy in rapidly evolving COVID-19 pneumonia and associated critical illness.

Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch

Interleukin-2 (IL-2) is a small α-helical cytokine that regulates immune cell homeostasis through its recruitment to a high-affinity heterotrimeric receptor complex (IL-2Rα/IL-2Rβ/γc). IL-2 has been shown to have therapeutic efficacy for immune diseases by preferentially expanding distinct T cell compartments, and several regulatory T cell (Treg)-biasing anti-IL-2 antibodies have been developed for combination therapies. The conformational plasticity of IL-2 plays an important role in its biological actions by modulating the strength of receptor and drug interactions. Through an NMR analysis of milliseconds-timescale dynamics of free mouse IL-2 (mIL-2), we identify a global transition to a sparse conformation which is regulated by an α-helical capping "switch" at the loop between the A and B helices (AB loop). Binding to either an anti-mouse IL-2 monoclonal antibody (mAb) or a small molecule inhibitor near the loop induces a measurable response at the core of the structure, while locking the switch to a single conformation through a designed point mutation leads to a global quenching of core dynamics accompanied by a pronounced effect in mAb binding. By elucidating key details of the long-range allosteric communication between the receptor binding surfaces and the core of the IL-2 structure, our results offer a direct blueprint for designing precision therapeutics targeting a continuum of conformational states.

IL-6 Trans-signaling Controls Liver Regeneration After Partial Hepatectomy.

Interleukin-6 (IL-6) is critically involved in liver regeneration after partial hepatectomy (PHX). Previous reports suggest that IL-6 trans-signaling through the soluble IL-6/IL-6R complex is involved in this process. However, the long-term contribution of IL-6 trans-signaling for liver regeneration after PHX is unknown. PHX-induced generation of the soluble IL-6R by ADAM (a disintegrin and metallo) proteases enables IL-6 trans-signaling, in which IL-6 forms an agonistic complex with the soluble IL-6 receptor (sIL-6R) to activate all cells expressing the signal-transducing receptor chain glycoprotein 130 (gp130). In contrast, without activation of ADAM proteases, IL-6 in complex with membrane-bound IL-6R and gp130 activates classic signaling. Here, we describe the generation of IL-6 trans-signaling mice, which exhibit boosted IL-6 trans-signaling and abrogated classic signaling by genetic conversion of all membrane-bound IL-6R into sIL-6R proteins phenocopying hyperactivation of ADAM-mediated shedding of IL-6R as single substrate. Importantly, although IL-6R deficient mice were strongly affected by PHX, survival and regeneration of IL-6 trans-signaling mice was indistinguishable from control mice, demonstrating that IL-6 trans-signaling fully compensates for disabled classic signaling in liver regeneration after PHX. Moreover, we monitored the long-term consequences of global IL-6 signaling inhibition versus IL-6 trans-signaling selective blockade after PHX by IL-6 monoclonal antibodies and soluble glycoprotein 130 as fragment crystallizable fusion, respectively. Both global IL-6 blockade and selective inhibition of IL-6 trans-signaling results in a strong decrease of overall survival after PHX, accompanied by decreased signal transducer and activator of transcription 3 phosphorylation and proliferation of hepatocytes. Mechanistically, IL-6 trans-signaling induces hepatocyte growth factor production by hepatic stellate cells. Conclusion: IL-6 trans-signaling, but not classic signaling, controls liver regeneration following PHX.

Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis

Neuroinflammation is increasingly recognized as an important mediator of disease progression in patients with amyotrophic lateral sclerosis (ALS), and is characterized by reactive central nervous system (CNS) microglia and astroglia as well as infiltrating peripheral monocytes and lymphocytes. Anti-inflammatory and neuroprotective factors sustain the early phase of the disease whereas inflammation becomes proinflammatory and neurotoxic as disease progression accelerates. Initially, motor neurons sustain injuries through multiple mechanisms resulting from harmful mutations causing disruptions of critical intracellular pathways. Injured motor neurons release distress signal(s), which induce inflammatory processes produced by surrounding glial cells in the CNS as well as peripheral innate and adaptive immune cells. This review will focus on mechanisms of neuroinflammation and their essential contributions in ALS pathogenesis. Regulatory T lymphocytes (Tregs) are a subpopulation of immunosuppressive T lymphocytes that become reduced and dysfunctional as the disease progresses in ALS patients. Their degree of dysfunction correlates with the extent and rapidity of the disease. Treg numbers are boosted in transgenic mutant SOD1 (mSOD1) mice through the passive transfer of Tregs or through treatment with an interleukin-2/ interleukin-2 monoclonal antibody complex and rapamycin. Treating the transgenic mice with either of these modalities delays disease progression and prolongs survival. In addition, Treg function is restored when dysfunctional Tregs are isolated from ALS patients and expanded ex vivo in the presence of interleukin-2 and rapamycin. Based on these findings, a first-in-human phase 1 trial has been completed in which expanded autologous Tregs were infused back into ALS patients as a potential treatment. The infusions were safe and shown to 'hit target' by enhancing both Treg numbers and suppressive functions. A delicate balance between anti-inflammatory and proinflammatory factors modulates the rates of disease progression and survival times in ALS. Tipping the balance toward the anti-inflammatory mediators shows promise in slowing the progression of this devastating disease.

The role of secukinumab in the treatment of psoriatic arthritis and ankylosing spondylitis.

Psoriatic arthritis and ankylosing spondylitis are chronic inflammatory diseases that can cause significant disability. The commercialization of the first tumour necrosis factor (TNF) inhibitors led to a radical improvement of the quality of life of people affected by these conditions; however, response was not universal, highlighting the need for alternative therapeutic targets. Secukinumab is a monoclonal interleukin (IL)-17A inhibitor which has been proven efficacious for psoriatic arthritis and ankylosing spondylitis in recent clinical trials. Dactylitis, enthesitis, skin and nails are some of the domains in which the inhibition of IL-17 has shown significant improvements apart from the joints. Its safety profile and satisfactory medium- to long-term outcome data are some of the aspects suggesting its potential impact in treatment protocols in the short term.

Phase 1b/2 study of nivolumab in combination with an anti–IL-8 monoclonal antibody, BMS-986253, in a biomarker-enriched population of patients with advanced cancer.

TPS3109Background: Interleukin 8 (IL-8) is a chemokine that has been suggested to play a predominant role in tumor immune escape by promoting an immunosuppressive tumor microenvironment (TME). High levels of serum IL-8 are associated with a poor prognosis in various tumors (Sanmamed, MF, et al. Clin Cancer Res. 2014;20:5697-5707), such as melanoma, non-squamous small cell lung cancer (NSCLC), and renal cell carcinoma, and decreases in serum IL-8 levels have been suggested to be associated with response to anti–PD-(L)1 therapy with nivolumab in a small cohort of pts with melanoma and NSCLC (Sanmamed, MF et al. Ann Oncol. 2017;28:1988-1995). Preclinical studies showed synergetic antitumor activity by combining anti-CXCR2 with anti–PD-1 vs either agent alone in mouse. BMS-986253 is a fully human-sequence IgG1κ anti–IL-8 monoclonal antibody that abrogates signaling through both IL-8 receptors (CXCR1 and CXCR2), resulting in a complete blocking of IL-8 mediated pathway, and as such, can be used to assess the m...