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Recent Developments in Therapies and Strategies Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Misbah Hameed, M. Zia-Ul-Haq, Marius Moga
Interferon treatment presented inadequate activity against SARS-CoV and MERS-CoV. IFNß1 controls CD73 levels in the pulmonary endothelium resulting in subsequent adenosine secretion. Adenosine has a strong anti-inflammatory effect that provide the endothelial barrier. Interferon treatment could thus reduce vascular escape in ARDS but is not sufficient for patients showing ARDS [66].
Role of regulatory T cells in mucosal immunity
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Treg cells also suppress immune responses through passive or competitive mechanisms. In vitro, Treg cells can outcompete conventional T cells in aggregating around DCs due to high-level expression of the adhesion molecule LFA-1, which binds to ICAM on DCs. Treg cells are also capable of depriving activated conventional T cells of IL-2, which is a critical T-cell growth factor. Treg cells constitutively express the Il2ra (encoding CD25) and Il2rb (CD122) genes and express the high-affinity IL-2R complex at much higher levels than conventional T cells. In contrast to conventional T cells, Treg cells do not secrete IL-2 upon activation and are thus “anergic” because Foxp3 actively represses IL-2 transcription. Thus, Treg cells efficiently consume IL-2, thereby limiting clonal expansion of activated T cells. This “IL-2 consumption” mechanism plays an important role in the regulation of CD8 T-cell responses. For example, Treg cells that cannot bind IL-2 (due to CD122 deficiency) but can transduce IL-2 signals (due to transgenic expression of a constitutively active STAT5 mutant) are impaired in their ability to inhibit the activation of CD8+ T cells but not CD4+ T cells. Treg cells also express CD39 and CD73, both of which are positively regulated by Foxp3 and sequentially degrade immune-stimulatory ATP into immune-regulatory adenosine. It remains unclear, however, whether IL-2 and ATP deprivation are essential for mucosal immune regulation.
Tolerance and autoimmunity
Published in Gabriel Virella, Medical Immunology, 2019
George C. Tsokos, Gabriel Virella
Functional heterogeneity of Tregs: Multiple mechanisms have been ascribed to mouse and human Treg cells that suppress autoreactive T cells: Secretion of immunomodulatory proteins by Treg cells, such as IL-10 and TGFβ, which suppress pro-inflammatory responses. A functional group of Tregs is known as effector (e)Tregs, which produce IL-10, are found in sites of inflammation and are probably responsible for the control of inflammation.Expression of CD80 and CD86 and increased release of the immunosuppressive enzyme, indoleamine-2,3-dioxygenase (IDO) can result in the conversion of dendritic cells to tolerogenic cells.High expression of the ectoenzymes CD39 and CD73 converts ATP to AMP (CD39) and AMP to adenosine (CD73), which is a strong suppressor molecule after it binds to cells expressing adenosine receptors.
A patent review of adenosine A2B receptor antagonists (2016-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Beatrice Francucci, Diego Dal Ben, Catia Lambertucci, Andrea Spinaci, Rosaria Volpini, Gabriella Marucci, Michela Buccioni
Since 2019 Incyte Corporation focused its research on development of new compounds belonging to imidazopyrimidines and triazolopyrimidines, pyrazolopyridines and triazolopyridines, fused pyrimidine and pyrazine, and pyrrole tricyclic derivatives generating six patents. The biological activity of compounds reported was determined by Ki at A2AAR and EC50 at A2BAR using the A2A Tag-Lite HTRF assay and the cAMP GS assay, respectively. One example of the most active compounds of each series is reported in Figure 2. Some of the molecules discussed in these patents were tested in a combined therapy together with various PD-L1/PD-1 inhibitors in the treatment of several tumors [104]. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor proliferation. The antitumor effects using various combinations of an A2A/A2BAR inhibitor and a PD-1/PD-L1 inhibitor were reported. This combined therapy could be helpful when the patient does not respond to classic anticancer therapies. In addition, some molecules were tested in combination with CD73 inhibitors obtaining good anticancer results [105]. CD73 is a glycosyl-phosphatidylinositol (GPI)-anchored adhesion protein that catalyses the dephosphorylation of extracellular Ado monophosphate (AMP) to Ado. Many tumors have high CD73 levels, which contribute to tumor growth and immune-suppressive effects. A combined therapy of an A2A/A2B antagonist and a CD73 inhibitor would be useful to counteract synergistically the growth of the tumor.
Small-molecule CD73 inhibitors for the immunotherapy of cancer: a patent and literature review (2017–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Alessio Nocentini, Clemente Capasso, Claudiu T. Supuran
As mentioned throughout this review, much of the current research on CD73 inhibitors is in the inflammation and cancer fields. Here, we did not review the developments in the anti-inflammatory action of CD73 inhibitors here, but only dealt with the oncological aspect. Indeed, several clinical trials involving anti-CD73 monoclonal antibodies are currently being conducted to treat solid tumors, among which the ones involving Oleclumab (MEDI9447) which is the most advanced Mab targeting CD73, with several ongoing trials for the treatment of pancreatic, breast, prostate, NSLCC, and other types of tumors, alone or in combination with other anticancer drugs (see ref [19,20,75,76]). Several other anti-CD73 mAbs, such as BMS986179, SRF373/NZV930, CPI-006/CPX-006, IPH5301, TJ004309, are also being tested in early phase I clinical trials [20,75].
Evaluation of WO2017098421: GSK’s benzothiazine compounds as CD73 inhibitor filings
Published in Expert Opinion on Therapeutic Patents, 2018
Ya-Ping Gong, Ren-Zhong Wan, Zhao-Peng Liu
Inhibition of CD73 enzyme activity was tested using human CD73 enzyme, which catalyzes the conversion of AMP to adenosine. The adenosine formed is then detected using a RapidFire/Sciex 4000 Q-Trap RF-MS. In this assay, human flag-CD73 (1-552, Thr376Ala) is used. The final concentrations of CD73 and AMP in this test are 50 pM and 20 mM, respectively. The generated adenosine is normalized to the C13-adenosine internal standard. The inhibition of the tested compounds is expressed as percent inhibition of internal assay controls and a four-parameter curve fit is applied in Activity Base XE to determine the potency of each tested compound. All the 187 compounds of formula (2) were tested in at least one experimental run, and they exhibited pIC50 values from 5 to 8.4 against CD73. The reported pIC50 values for the representative compounds are shown in Figure 4.