Characterization and Phase 1 Trial of a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19

Abstract

COVID-19 is a global pandemic that has resulted in over 800,000 deaths. Robust humoral anti-viral immune responses have the potential to generate a diverse set of neutralizing antibodies to eliminate viruses and protect against re-infection, transmission, and the evolution of mutations that escape targeted therapeutics. CD73 is present on the majority of human B cells and a subset of T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into adenosine, which can be immunosuppressive. Here we report on CPI-006, a humanized FcγR binding-deficient IgG1 anti-CD73 antibody that blocks CD73 enzymatic activity and directly activates CD73+ B cells, inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of adenosine. Immunophenotypic analysis of peripheral blood from advanced cancer patients receiving CPI-006 revealed evidence of B cell activation, clonal expansion, and development of memory B cells. 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. We have therefore initiated a Phase 1, single-dose, dose-escalation trial in hospitalized patients with mild to moderate COVID-19. The objectives of this 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 have been 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 SARS-CoV-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. These preliminary 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.

Clinical Results with a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19

“…CD73 was originally characterized as a costimulatory molecule for T cells, but our previously reported results presented demonstrated that mupadolimab predominantly activates CD73 POS B cells. [17] CD73 is most highly expressed on human IgD POS IgM DIM/NEG naïve B cells, and CD27 POS memory B cells expressing IgG or IgA. [11] Mupadolimab induces the expression of CD69, an activation marker that negatively regulates S1PR1 function, resulting in the prolonged retention of activated B cells in lymphoid organs and thymus.…”

“…Serum concentrations of mupadolimab achieved levels exceeding 1 µg/ml for greater than 24 hours for doses of 1 mg/kg and higher; concentrations known to activate B cells in vitro. [17] IgG titers were sustained without decrement up to 6 months after POS (Figure 2C). Antibody levels reached higher titers compared to convalescent sera from recovered patients (convalescent sera collected at 4-6 weeks POS, no comorbidities, and median age of 40) (Figure 2A-B, 2D-E).…”

“…[15] Mupadolimab is an IgG1κ humanized FcγR binding-deficient anti-CD73 monoclonal antibody (mAb) that activates CD73 POS B cells. [16,17] In vitro, mupadolimab induces the increased expression of markers associated with B cell maturation and antigen presentation, morphologic transformation to plasmablasts, and increased secretion of IgM and IgG. The unique immunologic properties of mupadolimab provided the rationale to examine its use as an immunotherapy for COVID-19 with the aim of boosting anti-viral immune responses and improving clinical outcome.…”

The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

“…Many similar agents are in early-stage discovery and preclinical development [95,[97][98][99][100][101][102]. Somewhat surprisingly, some anti-CD73 antibodies are already being tested for coronavirus disease 2019 (COVID-19) therapy [103,104], despite evidence of clinical benefits of CD73 and adenosine in lung injury [105], and benefit of adenosine in pneumonia associated with COVID-19 [106]. CD73 activity on immune cells versus other types of cells (endothelial, epithelial) need to be carefully considered to advance safe and effective treatments for COVID-19.…”

CD73 Maintains Hepatocyte Metabolic Integrity and Mouse Liver Homeostasis in a Sex-Dependent Manner

“…Importantly, these findings have translational implications for human liver diseases, as well as anti-CD73 antibodies and inhibitors, which currently are undergoing clinical development for cancer 26 and COVID-19 immunotherapy. 27 …”