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Source: COVID-19 Immunotherapy  Sep 17, 2020  3 years, 6 months, 4 weeks, 14 hours, 34 minutes ago

COVID-19 Immunotherapy: CPI-006 -Inhibitor Of CD73 Enzymatic Activity Activates Effective B Cell And Humoral Responses To SARS-CoV-2 In Phase 1 Trial

COVID-19 Immunotherapy: CPI-006 -Inhibitor Of CD73 Enzymatic Activity Activates Effective B Cell And Humoral Responses To SARS-CoV-2 In Phase 1 Trial
Source: COVID-19 Immunotherapy  Sep 17, 2020  3 years, 6 months, 4 weeks, 14 hours, 34 minutes ago
COVID-19 Immunotherapy: Researchers from Corvus Pharmaceuticals Inc-California, Temple University-Philadelphia and Icahn School of Medicine at Mount Sinai-New York in a phase 1 clinical trial have demonstrated that using a Inhibitor Of CD73 Enzymatic Activity called CPI-006, the researchers were able to induce the effective B Cell and Humoral response to SARS-CoV-2 infection in COVID-19 patients exhibiting mild to moderate symptoms.


 
The study team initiated a Phase 1, single-dose, dose-escalation trial in hospitalized patients with mild to moderate COVID-19. The objectives of the trial are to evaluate the safety of CPI-006 in COVID-19 patients and to determine effects of CPI-006 on anti-SARS-CoV-2 antibody responses and the development of memory B cell and T cells.
 
Ten patients were enrolled in the trial receiving doses of 0.3 mg/kg or 1.0 mg/kg. All evaluable patients had low pre-treatment serum levels of anti-viral antibodies to the SARSCoV-2 trimeric spike protein and its receptor binding domain, independent of the duration of their COVID-19 related symptoms prior to enrollment.
 
Anti-viral antibody responses were induced 7 days after CPI-006 treatment and titers continued to rise past Day 56. Increases in the frequency of memory B cells and effector/memory T cells were observed 28 days after treatment.
 
The preliminary clinical trial results suggest that CPI-006 activates B cells and may enhance and prolong anti-SARS-CoV-2 antibody responses in patients with COVID-19. This approach may be useful for treating COVID-19 or as an adjuvant to enhance the efficacy of vaccines.
 
The study findings were published on a preprint server and are currently being peer-reviewed. https://www.medrxiv.org/content/10.1101/2020.09.10.20191486v1
 
Past studies have shown that the neutralizing power of antibodies in COVID-19 is related to their ability to inhibit virus attachment to the host cells at the angiotensin-converting enzyme 2 (ACE2) receptor. The higher the titer of neutralizing antibody, therefore, the more effective they are at clearing the virus and promoting clinical recovery, as well as containing viral spread.
 
The cell surface enzyme CD73 has been studied as a target for cancer immunotherapy. It has been found earlier to be involved in the trafficking of lymphocytes and the activation of T cells. However, CD73 may also play a part in the maturation of B cells, based on studies in patients with common variable immunodeficiency (CVID), who cannot produce Immunoglobulin G (IgG).
 
Typically, most human B cells display the CD73 receptor involved in the activation of lymphocytes and their subsequent migration to a site of inflammation or infection. So does a subset of T cells.
 
This CD73 molecule also has an enzyme function, catalyzing the conversion of AMP to adenosine. This change can modulate the immune response, in contrast to its other pro-inflammatory effects.
 
The research shows that CPI-006, an anti-CD73 monoclonal IgG1 antibody (mAb) that does not bind FcgR. It inhibits the enzymatic function of CD73 but activates B cells that express it.
 
Lead and corresponding author of the study from Corvus Ph armaceuticals, Dr Stephen B. Willingham told Thailand Medical News, “These immune effects suggested that CPI-006 may be effective at enhancing the magnitude, diversity, and duration of humoral and cellular responses to viruses such as SARS-CoV-2.”
 
In past cancer studies, detailed examination of the B cell receptor (BCR) at the molecular level in patients treated with CPI-006 indicates that novel B cell clones are both produced and expanded by this molecule.
 
Hence the study team sought to find out if this could be developed as a drug for COVID-19 immunotherapy, resulting in higher antiviral immune responses.
 
Significantly, preliminary findings from the trial show that it can be useful in treating COVID-19 as well as used in combination with vaccines to induce immunity to the virus.  
 
The study team found that this molecule suppresses/inhibits the enzyme-mediated immunosuppressive function of CD73.
 
Utilizing human peripheral blood mononuclear cells (PBMCs), cultured in conditions that favor T cell activation, they found that when AMP was added, T cells did not proliferate as vigorously as before, and cytokine secretion was also reduced. In the presence of CPI-006, this reverted to normal, by preventing the AMP-to-adenosine conversion.
 
Interestingly, the same results were seen with interferon-gamma (IFNg) production, which reflected the T cell response to this molecule.
 
It is known that many human blood cell lineages in the body express CD73, which is thought to promote the activation and adhesion of lymphocytes.
 
The study team screened the immune cells for surface markers that were differentially expressed after treating with CPI-006, using flow cytometry.
 
The team found that CPI-006 dramatically induces B cell activation in a dose-dependent manner. In fact, at concentrations of 1 μg/mL, the activation marker CD69 was expressed at near-maximum levels.
 
Also B cell antibody production increased antigen presentation markers such as CD86 and MHC-II, and B cell maturation was also observed. These activated B cells also transform into plasmablasts, or antibody-secreting cells. Another mechanism of B cell activation is via the canonical signaling pathways in the body.
 
However such phenomena have not been described by earlier researchers concerning the CD73 signaling pathway and may be seen only with CPI-006. Moreover, CD69 expression is enhanced only by the bivalent binding of CPI-006.
 
Currently a phase I trial is underway in advanced cancer patients in evaluating the role of CPI-006 for immunotherapy. The results indicate that at all doses of CPI-006, the circulating CD73POS B cell frequency drops steeply, within half an hour of treatment. On the other hand, this molecule does not cause B cell death or antibody-dependent cytotoxicity, which indicates the drop in B cells is due to their redistribution after activation, into lymphoid tissues. This is a transien