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Convalescent Plasma and Antibody Therapy in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Didem Rıfkı, Eymen Ü. Kılıç, Şükrü Tüzmen
Emapalumab is an anti-IFN-γ antibody that works by preventing IFN-γ from binding to cell surface receptors and activating inflammatory signals. Emapalumab combined with anakinra is being tested in COVID-19 patients currently in a Phase II/III multi-center randomized clinical trial (NCT04324021) [31] (Table 8.2).
Clinical Applications of Gene Therapy for Immuno-Deficiencies
Published in Yashwant Pathak, Gene Delivery, 2022
Khushboo Faldu, Sakshi Gurbani, Jigna Shah
Hemophagocytic lymphohistiocytosis (HLH) can be fatal. The symptoms include cytopenias, hyper inflammation, splenomegaly, and uncontrolled immune activation [63]. HLH can be caused due to various underlying conditions, like familial hemophagocytic lymphohistiocytosis (FHL), autoimmunity, infection, or malignancy. Defects in the functioning of cytotoxic T- and NK-cells, together with autosomal recessive alterations in syntaxin 11 (STX11), MUNC 13-4 [Protein unc-13 homolog D (UNC13D)], and perforin (PRF1) result in the development of FHL. The most common cause is PRF1 mutations. AlloHSCT is the preferred treatment modality for genetically mutated or relapsed refractory HLH patients [64, 65]. Etoposide, with or without cyclosporine and glucocorticoids, are a part of the standard of care, but lack adequate disease control in 40% of patients [66]. Emapalumab, an anti-interferon gamma (IFNγ) monoclonal antibody, has been approved as second-line therapy for primary HLH in the USA, as IFNγ plays a central role in pathogenesis in HLH, with levels correlating with active disease [67, 68]. Alemtuzumab and Janus kinase (JAK) inhibitors are being tested for improving remission and allowing progress to HSCT [69–74]. Alemtuzumab with corticosteroids and cyclosporine has provided favorable safety and efficacy in children suffering from primary HLH (91.6% survived to alloHSCT) [74]. HSC-GT and T-cell strategies are being developed for the treatment of FHL [75–79].
Treatment of inflammatory complications in common variable immunodeficiency (CVID): current concepts and future perspectives
Published in Expert Review of Clinical Immunology, 2023
The PI-3-kinase – mTOR pathway is upregulated in Th1-cells and treatment with everolimus/sirolimus or a PI-3K inhibitor like idelalisib or leniolisib might reduce the burden of the Th1-driven inflammation [112]. As previously mentioned, sirolimus has been reported effective in ITP and granulomatous disease in CVID, and for inflammatory complications of LRBA- and CTLA4-insufficiency [113–118]. Interferon-gamma is the signal cytokine of Th1-inflammation and can be targeted by the monoclonal antibody emapalumab [119]. Emapalumab is approved for treatment of HLH, but has been associated with a high risk of infections in that patient group. Interleukin-12 is another Th1-associated cytokine and can be targeted with ustekinumab that already is widely used for immune driven diseases, and that has a more favorable safety profile [120,121].
Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation
Published in Expert Review of Clinical Immunology, 2020
Isabelle Amigues, Alexander H Pearlman, Aarat Patel, Pankti Reid, Philip C. Robinson, Rashmi Sinha, Alfred Hj Kim, Taryn Youngstein, Arundathi Jayatilleke, Maximilian Konig
The involvement of IFN-γ in the pathogenesis of the hyperinflammatory syndrome is complex and potentially complicated by its antiviral role. Emapalumab, an interferon-γ neutralizing antibody, has been approved for the treatment of refractory HLH. Remarkably, in one case report of refractory HLH in the setting of multiple viremias, viral clearance was not negatively impacted [81]. Emapalumab was also used in a series of patients with rHLH/MAS related to sJIA who had not improved on high-dose glucocorticoids; patients had improvement in clinical and laboratory parameters [130]. Potential interference with antiviral host immune responses may be expected in early use of anti-INF-γ therapy, and the safety of this approach needs to be established. Emapulumab is currently being studied along with anakinra in reducing hyperinflammation in COVID-19 (NCT04324021). However, in light of conflicting data on levels of IFN-γ in severe COVID-19, emapalumab should not be used outside of clinical trials and controlled studies are needed to evaluate its efficacy, optimal timing of administration, and safety.
Immunotherapy for SARS-CoV-2: potential opportunities
Published in Expert Opinion on Biological Therapy, 2020
Mehrnoosh Pashaei, Nima Rezaei
Pathogenic IFN-ɣ+ GM-CSF+ TH1 cells secrete GM-CSF to promote inflammatory CD14+CD16+ monocyte responses with an increase of IL-6 level in COVID-19 patients [19]. Another inflammatory agent which can be a good target for the treatment of severe cases of COVID-19 is IFN-ɣ. Emapalumab, is an anti-IFN-ɣ monoclonal antibody that FDA approved for primary hemophagocytic lymphohistiocytosis (HLH) and may be effective in MAS. Emapalumab is under investigation in a phase II trial study (ClinicalTrials.gov Identifiers: NCT04324021), to evaluate the safety and efficacy of intravenous infusion every third day in severe COVID-19 patients [21]. Also, granulocyte–macrophage colony-stimulating factor (GM-CSF) is an attractive target as a therapeutic target in COVID-19. TJ003234 is an anti-GM-CSF monoclonal antibody and may be inhibited the infiltration of granulocytes and monocytes. The safety and efficacy of TJ003234 intravenous injection is currently being tested in a randomized, multicenter, double-blind, placebo-controlled, phase Ib/II trial study (ClinicalTrials.gov Identifiers: NCT04341116) in 144 patients with severe COVID-19 [21,22].