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Immunomodulating Agents in Gastrointestinal Disease
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Samir A. Shah, Athos Bousvaros, A. Christopher Stevens
Advances in molecular biology have spawned the generation of fusion toxin proteins that can be designed to target specific cellular subpopulations. One component of the molecule is the toxin (e.g., diphtheria, ricin, pseudomonas) that is joined to the receptor binding portion of a targeted ligand. The interleukin 2 diphtheria toxin (DAB389IL-2) contains the cytotoxic portion of the diphtheria toxin catalytic domain, and the transmembrane domain is fused to the receptor binding portion of IL-2 [216]. Therefore, this agent targets IL-2 receptor bearing cells, which are mostly activated T cells. Endocytosis of the fusion protein and subsequent delivery of the catalytic domain to the target cell cytosol arrests translation, resulting in cell death of activated T cells [217].
Interleukin-1 Inhibitors and Their Significance in Rheumatoid Arthritis
Published in Thomas F. Kresina, Monoclonal Antibodies, Cytokines, and Arthritis, 2020
Gloria C. Higgins, Arnold E. Postlethwaite
Symons and coworkers have detected significantly higher levels of soluble IL-2 receptor (sIL-2R) in synovial fluids and sera from rheumatoid arthritis patients than in control sera (174). Receptor was detected by an ELISA using monoclonal antibodies to the α chain of the IL-2 receptor. The level of sIL-2R correlated with the level of IL-1 β, measured by radioimmunoassay (RIA), in synovial fluids. Levels also correlated with the ability of synovial fluids to inhibit the IL-2-induced proliferation of CTLL-2 cells. The proposed mechanism of this inhibition was competition by sIL-2. Synovial fluid mononuclear cells spontaneously released high levels of sIL-2R into serum-free culture fluids. On gel filtration, the sIL-2R produced in vitro migrated at approximately 40 kD, which corresponds to the molecular weight of the released α chain. However, both sIL-2R and functional IL-2 inhibitor from synovial fluid comigrated at approximately 100 kD. The hypothesis that sIL-2R was forming aggregates or binding to another protein in synovial fluid was tested by incubating synovial fluid mononuclear cell (SFMC) culture supernatant and synovial fluid together before gel filtration. There was a decrease in the amount of sIL-2R migrating at 40 kD, which could be accounted for by an increase in sIL-2R migrating in the 50-200 kD range. These results suggest that soluble IL-2 receptor in synovial fluid may bind IL-2 and modulate its activity in vivo.
Signal Transduction Mechanisms Regulating Cytokine-Mediated Induction of Acute Phase Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Several cytokine receptors function as multicomponent systems, consisting primarily of a binding component(s) and a signal transducing component(s). The binding subunit often represents the low-affinity receptor, which can interact with the signal transducing subunit, following ligand binding, to form the high-affinity receptor complex capable of initiating signal transduction. In the case of the IL-2 receptor, both subunits, α and β, individually bind IL-2 with low and intermediate affinities, respectively, whereas the αβ complex binds IL-2 with high affinity.
The treatment of advanced melanoma: a review of systemic and local therapies in combination with immune checkpoint inhibitors in phase 1 and 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Danielle K. DePalo, Ahmad Tarhini, Jonathan S. Zager
Cytokines, including interferon (IFN)-α, interleukin (IL)-2, −12, −18, and −21, have long been used in the treatment of melanoma and are the original immunotherapies [26,27]. While effective in carefully selected patients, their application is limited due to significant autoimmune toxicities. IL-2 acts by binding the IL-2 receptor to activate multiple pathways affecting lymphocyte function, proliferation, and survival [28]. High-dose IL-2 in particular was the first immunotherapy approved for metastatic melanoma due to durable response and survival in a small proportion of patients [29,30]. However, high-dose IL-2 administration requires intensive monitoring and vasopressor administration due to the frequent SIRS-like response to treatment [31]. IL-12 controls natural killer (NK) and T cell production, stimulates IFN-γ production, promotes Th-1 differentiation, and bridges the innate and adaptive immune systems [26,32]. While systemic IL-12 administration has had little traction in the treatment of melanoma due to poor efficacy and high toxicity, its immunomodulatory effects are still relevant to the treatment of the disease [26,33–35]. Broadly, cytokines stimulate and increase populations of tumor-specific T-cells, while ICIs antagonize immune regulatory pathways, in theory allowing the two mechanisms to act synergistically [28].
Monitoring immunomodulation in patients with sepsis
Published in Expert Review of Molecular Diagnostics, 2021
Evdoxia Kyriazopoulou, Evangelos J. Giamarellos-Bourboulis
The soluble IL-2 receptor (sIL-2 r) also known as CD25 is one well-established biomarker of MAS. The IL-2 receptor has three subunits: α, β, and γ. While the β and γ subunits are constitutively active, the α subunit is expressed only after cell activation. sIL-2 r is cleaved from the IL-2 rα protein upon T-cell activation. Except from T cells sIL-2 r is also released from dendritic cells, activated B cells, monocytes, and malignant cells [31]. In one analysis of 775 adults with MAS, sIL-2 r was increased more than 2400 IU/mL in 79% and more than 10,000 IU/mL in 38%. In contrast, hyperferritinemia was found in 90% [35]. In one single-center retrospective study of 78 adults with suspected MAS, receiver operating characteristic curve analysis demonstrated that sIL-2 r is a very good diagnostic test with area under the curve (AUC) 0.90 (95% confidence interval, 0.83–0.97) compared with AUC 0.78 (95% confidence interval, 0.67–0.88) for ferritin. The optimal threshold for sIL-2 r was 2515 IU/mL (sensitivity, 100%; specificity, 72.5%). Levels above 10,000 IU/mL were associated with worse prognosis [36,37]. It seems that sIL-2r is unable to distinguish subtypes of MAS [38], whereas Tsuji et al. suggested that high sIL-2 R/ferritin ratio may be useful to distinguish MAS associated with lymphoma [39]. No specific study in sepsis so far has focused on this biomarker.
Bempegaldesleukin (NKTR-214): a CD-122-biased IL-2 receptor agonist for cancer immunotherapy
Published in Expert Opinion on Biological Therapy, 2019
Cytokine-signaling pathways, specifically involving interleukin-2 (IL-2), were the focus of some of the earliest research in cancer immunology, and human recombinant IL-2, aldesleukin, was the first cytokine to be approved for the treatment of cancer. Unfortunately, the severe toxicities and unfavorable pharmacokinetic profile of aldesleukin along with its pleiotropic effects on both effector T cells, which identify and kill tumor cells, and regulatory T cells (Tregs), which act to suppress effector T-cell function, have limited its use. However, now that we have a better understanding of the critical nature of the IL-2 pathway in balancing immune activation and suppression, we are revisiting the development of engineered proteins that activate the IL-2 receptor pathway in more pharmacologically productive ways as therapeutic agents with the potential to activate the immune system to eliminate tumor cells.