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: 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 transient change, and within three weeks, these cells re-entered the bloodstream at levels comparable to the baseline but enriched in class-switched memory B cells.
 
Typically memory B cells are immune antibody-producing cells where immunoglobulins have been rearranged in order to generate antibodies with a high affinity to specific antigens. In some patients, 2-40 novel B cell clones were found to emerge, at frequencies up to 1 in 100 B cells, indicating an antigen-specific substantial clonal expansion. It has been shown that this is consistent with unchanged antigen-specific IgG responses to five common viruses, such as measles and mumps viruses, in the third week after treatment.
 
Hence this response is not; therefore, merely a polyclonal activation of B cells but rather a specific response to an antigen.
 
The study findings of this trial of different doses of CPI-006 in patients with a median age of 64, with other illnesses including diabetes and obesity, show no adverse effects. Universal recovery was observed, with discharge at a median of 4 days after hospitalization.
 
Significantly the addition of CPI-006 led to a threefold rise in IgM and IgG1 levels compared to a control, indicating both increased antibody formation and perhaps class switching as well. Cytokines such as CCL3, CCL4, CCL2, and CCL22 are also found to be at higher levels following CPI-006 treatment. But this did not increase the levels of the pro-inflammatory cytokines IFNg, IL-2, IL-6, IL-10, or TNFa. This is an important consideration in COVID-19, whose severity is thought to be linked to a hyper-inflammatory state.
 
Also an accompanying steep surge in the titer of IgM and IgG antibodies against either SARS-CoV-2 or the RBD or both was seen to occur within a week of a single low dose of CPI-006. While the duration since the first symptom is not related to the antibody levels at the study baseline, CPI-006 induced a rise in IgM to over 100,000 in one patient, which persisted until 28 days later. This correlated with an increase in neutralizing antibody levels and is expected, from the results of earlier studies, to correspond to those of plaque reduction neutralization tests.
 
Interestingly IgM and IgG levels continue to rise, even at 56 days in one patient. And these exceeded antibody titers in convalescent sera even when these came from patients who would have been expected to have better antibody responses.
 
Further detailed examination of PBMCs shows that memory B cells are increased and memory and effector CD4POS and CD8POS T cells. The cytokine profile indicates it is skewed towards a Th1 response.
 
The study team stressed, “CPI-006 induces the expression of CD69, an activation marker, resulting in the prolonged retention of activated B cells in lymphoid organs. This increased lymphoid residence time provides time to complete B cell activation and interact with CD4POS T follicular helper cells to shape downstream immune responses.”
 
Importantly neutralizing anti-TS and anti-RBD antibody titers rise within a week of administration of one low dose of CPI-006. This dose is above the 1 μg/ml threshold at which B cells activation is highest, but is low enough to permit it to leave the body rapidly. In addition to the intravenous route used here, subcutaneous and intramuscular administration also becomes potential realities in this case.
 
The study team said that further research will be needed to understand how these B and T cells perform against the virus and whether they can help regulate both types of immunity in a balanced manner.
 
Should indeed CPI-006 achieves long-term sustained elevations of the antibody response, it could be useful not only in treating COVID-19 but also in adjuvanted vaccines for increased titer, diversity, and duration of antibody production as well as its effect on memory cells.
 
Significantly the diversification of the BCR could mean that the virus cannot easily escape the effects of the resulting immune activation by escape mutations. It would also help with developing more mAbs from the isolation and sequencing of specific cells.
 
The study team notes the need for a randomized controlled trial to prove that/ if these antibody enhancing effects are truly due to CPI-006. Yet, they say, “These encouraging early results are in line with our hypothesized biological mechanism and we remain cautiously optimistic.”
 
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