key: cord-0965573-hyovucjs
authors: Willingham, S. B.; Criner, G.; Hill, C.; Hu, S.; Rudnick, J. A.; Daine-Matsuoka, B.; Hsieh, J.; Mashhedi, H.; Hotson, A. N.; Brody, J.; Marron, T.; Piccione, E.; Buggy, J. J.; Mahabhashyam, S.; Jones, W. B.; Mobasher, M.; Miller, R. A.
title: Characterization and Phase 1 Trial of a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19
date: 2020-09-15
journal: nan
DOI: 10.1101/2020.09.10.20191486
sha: b45e2adb5690b605b39ec9fd042094d67178abec
doc_id: 965573
cord_uid: hyovucjs

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 Fc{gamma}R 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.

Since its emergence in Hubei province, China, in December of 2019, the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 has become a global health crisis. [1] [2] [3] There is an urgent need for therapies that can improve survival, clinical outcomes, and reduce the requirements for intensive supportive care and prolonged hospitalization. [4] A growing understanding of the viral/host interactions required for viral entry and replication has also informed the development of multiple vaccines. [5] The SARS-CoV-2 trimeric spike protein (TS) is a viral envelop glycoprotein which contains a receptor binding domain (RBD) in the spike 1 (S1) subunit. [6] This RBD directly interacts with N-terminal domain of angiotensin converting enzyme 2 (ACE2) on host cells to initiate a sequence of events leading to efficient viral infection. [3, 7] Multiple recent publications have demonstrated that antibodies that disrupt this interaction are effective at preventing viral infection. [6, 8] This provides evidence that neutralizing antibody responses to SARS-CoV-2 are possible and may provide clinical benefit in patients with COVID-19 and protection from disease in healthy subjects. Indeed, the U.S. Food and Drug Administration (FDA) has given emergency use authorization for the use of COVID-19 Convalescent Plasma (CCP) for the treatment of COVID-19. Clinical studies with CCP suggest that higher titers of neutralizing antibody provide superior clinical benefit to recipients. [9, 10] These findings support the value of anti-viral antibodies in eradicating viral infection in patients, lessening disease severity, and potentially reducing transmission.

CD73 is an emerging cancer immunotherapy target that was initially found to be important for lymphocyte trafficking and T cell activation. [11, 12] CD73 is expressed on subsets of human CD4 POS and CD8 POS T cells, germinal center follicular dendritic cells, and both naïve and class switched memory B cells. [12] [13] [14] A role for CD73 in B cell maturation has been proposed as reduced CD73 expression on B cells from patients with common variable immunodeficiency (CVID) correlates with an inability to produce IgG. [15, 16] Like many glycosyl phosphatidylinositol (GPI)-anchored molecules, CD73 has been shown to transmit activation signals when ligated by antibodies, although a physiologic ligand for CD73 has not been identified. [11, 12] CD73 also functions as an ectonucleotidase that hydrolyzes adenosine monophosphate (AMP) into adenosine. [17] . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09. 10.20191486 doi: medRxiv preprint Here, we describe the generation and characterization of CPI-006, an IgG1k humanized FcgR binding-deficient anti-CD73 monoclonal antibody (mAb) that activates CD73 POS B cells. In vitro, CPI-006 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. Biomarker studies in an ongoing Phase 1 cancer clinical trial revealed that CPI-006 causes a rapid and transient redistribution of circulating B cells that return to circulation enriched in a memory B cell phenotype. [18] Molecular studies of the B cell receptor (BCR) repertoire in treated patients suggests that CPI-006 stimulates the generation and expansion of novel B cell clones. These findings provided the rationale to examine CPI-006 as an immunotherapy for COVID-19 with the aim of enhancing anti-viral immune responses. The results of this trial to date suggest that the immunomodulatory properties of CPI-006 may be applied for the treatment of COVID-19 and also potentially utilized in combination with vaccines to induce immunity in healthy subjects. RESULTS 

CPI-006 is a humanized anti-CD73 IgG1k antibody engineered with an N297Q mutation in CH2 of the heavy chain to eliminate Fc effector functions such as the ability to fix complement and initiate antibody dependent cellular cytotoxicity (ADCC, Supplemental Figure 1A ). CPI-006 binds human CD73 with a KD of 200 pM measured using bio-layer interferometry (Supplemental Figure 1B ). The ability of this antibody to inhibit the enzymatic activity of cellular CD73 was evaluated by directly measuring free phosphate levels generated upon conversion of AMP to adenosine. CPI-006 inhibited CD73 activity to baseline levels that were established using the CRISPR CD73 knockout cell line and comparison to treatment with saturating amounts of APCP (adenosine 5'-(a,b-methylene) diphosphate), a small molecule inhibitor of CD73 enzymatic activity ( Figure 1A ). In contrast, MEDI9447, another anti-CD73 antibody that binds a nonoverlapping epitope, only partially reduced CD73 activity. [19] CPI-006 also eliminated the enzymatic activity of CD73 expressed on primary human peripheral blood mononuclear cells (PBMCs) while MEDI9447 demonstrated a partial effect on enzymatic activity ( Figure 1B) .

Collectively, these data show that CPI-006 and MEDI9447 inhibit catalytic activity of cellular CD73 expressed by tumor cells and lymphocytes, but only CPI-006 completely abolishes CD73 enzymatic activity.

To model the immunosuppressive effects of adenosine on T cells, human PBMCs were obtained from healthy donors and cultured under T cell activating conditions. Addition of AMP resulted in decreased T cell proliferation and cytokine secretion. Addition of CPI-006 restored T cell proliferation in all donors tested, consistent with the antibody preventing conversion of AMP into immunosuppressive adenosine ( Figures 1C) . MEDI9447 restored T cell proliferation in a subset of donors but did not reach the magnitude of the CPI-006 response (Figures 1C).

Interferon-gamma (IFNg) production was evaluated as an additional readout for T cell response and similar results were observed ( Figures 1D) . These data demonstrate that antibodymediated inhibition of CD73 activity blocks the suppressive effects of adenosine on T cell proliferation and cytokine secretion.

CD73 is expressed on subsets of human hematopoietic cells and had previously been implicated to play a role in lymphocyte activation and adhesion [12, 13, 20, 21] . We performed a flow cytometry-based screen to identify differentially expressed cell surface markers on immune cells following in vitro treatment with CPI-006. CPI-006 strikingly activated B lymphocytes, resulting in the upregulation of activation markers (CD69 and CD83) and antigen presentation machinery (CD86 and MHC-II) to similar levels achieved with the positive control of BCR crosslinking via anti-IgM ( Figure 2A ). CPI-006 mediated B cell activation also resulted in increased cell surface expression of CD27, IgG, CD38, and CD138, all markers consistent with induction of B cell maturation ( Figure 2B ). CPI-006 induced activation was dose-dependent with concentrations of 1 µg/mL achieving near maximal induction of CD69 in vitro ( Figure 2C ). B cell activation has not previously been described in relation to CD73 signaling and is seemingly unique to CPI-006, as both MEDI9447 and clone AD2, two anti-CD73 antibodies that do not cross-block CPI-006, fail to induce activation ( Figure 2C ). Naïve B cells stimulated with CPI-006 in vitro underwent morphological changes consistent with differentiation into plasmablasts ( Figure 2D ). CPI-006 mediated B cell activation was restricted to CD73 POS B cells and required bivalent binding as CPI-006 immunoglobulin Fab fragments had minimal effect on expression levels of CD69 ( Figure 2E ). CPI-006 induction of CD69 was blocked with ibrutinib, a covalent BTK inhibitor ( Figure 2F ), demonstrating that CPI-006 directly activates B lymphocytes by invoking canonical B cell signaling pathways. B cell activation was not a consequence of the concentration of extracellular adenosine as addition of NECA (5′-(N-Ethylcarboxamido)

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.10.20191486 doi: medRxiv preprint adenosine), a potent and stable analogue of adenosine, did not block the induction of activation markers by CPI-006 ( Figure 2G ). [22] To assess functional consequences of B cell activation with CPI-006, we first measured the concentration of IgG and IgM secreted by healthy donor PBMCs into the culture supernatant six days after in vitro treatment. Addition of CPI-006 resulted in a 3-fold increase in IgM and IgGl levels (IgGk not measured) relative to an isotype control, demonstrating that CPI-006 stimulates antibody secretion and possibly class switching to IgG ( Figure 3A ). CPI-006 also induced production of B cell cytokines such as CCL3, CCL4, CCL2, and CCL22 ( Figure 3B -3E), but did not induce IFNg, IL-2, IL-6, IL-10, or TNFa from healthy donor PBMCs (data not shown).

CPI-006 would therefore not be expected to increase the potential for inflammatory cytokine release reported in some COVID-19 patients. [23] [24] [25] Collectively, these experiments demonstrate that CPI-006 activates B lymphocytes, resulting in morphological and immunological changes consistent with B cell differentiation and antibody production.

Furthermore, this property is unique to CPI-006 and is independent of adenosine-modulatory activity.

Immunologic Effects of CPI-006 in a Phase 1 Trial in Advanced Cancer Patients CPI-006 is being evaluated as an immunotherapy for cancer in an ongoing phase 1 study (NCT03454451). In this dose escalation, repeat dose (21-day cycle) study, we observed dramatic decreases in circulating CD73 POS B cells at all CPI-006 dose levels (1-24 mg/kg), 30 minutes after antibody infusion ( Figure 4A ). CPI-006 does not induce B cell death or initiate ADCC (Supplemental Figure 1A ) so this result is most likely due to the redistribution of activated B cells into lymphoid tissues. B cells returned to circulation at levels similar to baseline by day 21. Returning B cells were enriched in CD27 POS IgD NEG class switched memory B cells in the majority of subjects receiving ≥ 3 mg/kg CPI-006 ( Figure 4B ). Memory B cells are essential for both acute and long-term immunity as they have undergone immunoglobulin rearrangement and somatic hypermutation in order to produce high affinity, antigen-specific antibody upon exposure to antigen. BCR repertoire analysis in a subset of patients revealed the emergence of novel B cell clones that were not present in the peripheral blood prior to treatment ( Figure 4C ).

These new B cell clones were limited to 2-40 clones per patient and appeared with frequencies as high as 1:100 B cells, consistent with a robust clonal expansion following an antigen-specific response ( Figure 4C ). The cognate antigens recognized by these new B cell clones are currently . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Five patients have been treated in the 0.3 mg/kg and five in the 1.0 mg/kg cohorts ( Table 1 ).

The median age was 64 years (range 28-76) and all had comorbidities including diabetes (4), hypertension (2), obesity (7,) and/or cancer (2) . The median duration from presentation of symptoms (POS) to CPI-006 administration was 8 days (range 1-21 days). No infusion related reactions or other treatment related adverse events have been observed. All patients recovered with improvement of inflammatory markers and symptoms and were discharged at a median of 4 days after hospitalization (Table 1) .

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The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.10.20191486 doi: medRxiv preprint IgG and IgM antibody titers against the SARS-CoV-2 TS and/or RBD rapidly increased in 8/8 evaluable patients within 7 days of a single infusion of low doses of CPI-006 ( Figure 5A , 5B).

One patient did not have a pre-treatment sample available, but had a sample collected 24 hours after CPI-006 administration and this sample exhibited a high antibody titer. Similar results were observed in anti-SARS-Cov-2 IgA titers (data not shown). No correlation between time after POS and pre-treatment serum antibody levels has been observed as 9/9 evaluable patients had low pre-treatment titers despite relatively long durations of symptoms. For example, one patient had low titers at 21 days after onset of symptoms, but produced IgG and IgM titers rapidly rising to >100,000 and extending 28 days after administration of CPI-006, equivalent to 49 days POS. A corresponding increase in neutralizing antibody levels, measured by the ability to block recombinant RBD binding to human ACE2, was also observed ( Figure   5C ). Results in this assay have been shown by others to correlate with results in the live viral plaque reduction neutralization assay test (PRNTs). [26] Continually increasing IgG and IgM levels to viral TS or RBD antigens and neutralization antibodies were observed out to 28 days post treatment. It appears that prolonged high titer humoral response is possible as one patient has escalating levels out to 56 days. Antibody levels reached higher titers compared to convalescent sera from recovered patients with more favorable clinical characteristics (convalescent sera collected at 4-6 weeks POS, no comorbidities, and median age of 40) ( Figure   6A -6C). Immunophenotyping of PBMCs at baseline and 14-or 28-days after treatment provided preliminary evidence that CPI-006 increased the frequency of memory B cells in two of two evaluated patients treated with 0.3 mg/kg ( Figure 7A ). An increased frequency of memory/effector CD4 POS and CD8 POS T cells was also observed ( Figure . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09. 10.20191486 doi: medRxiv preprint Studies in cancer patients demonstrated diversification of the BCR repertoire by stimulating the emergence and expansion of novel B cell clones. These findings indicate that CPI-006 can activate CD73 POS B cells to elicit antigen specific humoral and memory responses that display functional hallmarks associated with protective immunity. These effects are independent of CD73 enzymatic activity as addition of adenosine analogs or blockade of CD73 enzymatic activity alone has no effect on B cell activation in vitro. To our knowledge, CPI-006 is the only anti-CD73 antibody or small molecule inhibitor in development with the ability to directly activate B or T cells.

CD73 was originally characterized as a costimulatory molecule for T cells, but our results demonstrate that CPI-006 predominantly activates B cells. [11] Human CD73 is expressed on IgD POS IgM DIM/NEG naïve B cells, and CD27 POS memory B cells expressing IgG or IgA. [14] CPI-006 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. [27] This increased lymphoid residence time provides time to complete B cell activation and interact with CD4 POS T follicular helper cells to shape downstream immune responses. While B cell activation with CPI-006 is independent of adenosine blockade in vitro, the CD73 enzymatic blockade may be complementary in vivo as adenosine has been shown to restrict lymphocyte migration into lymph nodes in preclinical animal models. [28] Additional studies will clarify if this temporary sequestration in lymph tissues is the dominant mechanism by which CPI-006 diversifies the BCR repertoire and promotes the development memory B and T cells.

This study demonstrates that antibody titers to TS and RBD with neutralizing activity toward RBD increase within 7 days in patients treated with a single, low dose of CPI-006. The single, low doses evaluated in our study thus far are noteworthy as the maximal concentrations of CPI-006 in plasma are modeled to exceed the 1 µg/ml threshold needed for maximal B cell activation yet low enough to be rapidly cleared. Although CPI-006 was delivered intravenously in this study, the effects seen with low doses indicate that alternative routes of delivery such as subcutaneous or intramuscular administration are feasible.

Most patients with COVID-19 become seropositive for IgG/IgM/IgA within 2-3 weeks following onset of symptoms. [29] However, all of the patients on this trial had low levels of anti-SARS-CoV2 antibodies at the time of hospitalization despite a wide range of duration of prior symptoms from 1-21 days. The lack of response in these patients may be related to host factors . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.10.20191486 doi: medRxiv preprint reducing the ability to mount a humoral response or other unknown immunosuppressive effects of viral infection. CPI-006 may overcome this apparent immunodeficiency as we observed robust anti-SARS-CoV-2 antibody responses induced by CPI-006 in patients with long POS and low pre-treatment titers. The kinetics following seroconversion are still being clarified, but others have reported that antibody titers in COVID-19 patients plateau approximately 6 days after seroconversion before steadily declining in the following weeks (IgM/IgA) to months (IgG). [29] Our preliminary results show that anti-SARS-CoV2 titers continue to rise without plateauing in the weeks following treatment, possibly hinting at a more robust and durable humoral response that would theoretically improve clinical outcomes in COVID-19 patients.

These effects may also serve to reduce viral transmission and expand the pool of qualified convalescent plasma donors.

Temporary protection against SARS-CoV-2 can be imparted by circulating neutralizing antibodies, but the key to long term immunity lies in the production of antigen-specific memory . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.10.20191486 doi: medRxiv preprint cautiously optimistic that longitudinal assessments of neutralizing antibody titers and B and T cell functional assays will clarify the contribution of CPI-006 to humoral and cellular immune responses. We encourage the reader to consider the results presented here as a work in progress that we intend to update regularly as additional safety, efficacy, and biomarker data become available.

Antibodies CPI-006 was engineered by isolating VH and VL regions from the parental hybridoma generated by immunizing mice with human CD73 and screening for inhibition of CD73 activity.

Humanization was performed by inserting CDRs isolated from the hybridoma into a human framework and the antibody was expressed as a human kappa/IgG1 antibody with the N297Q mutation introduced into the CH2 region to eliminate FcgR binding. MEDI9447 was cloned using the VH and VL chain sequences published in WO 2016/075099 AI application patent and was expressed as a human lambda/IgG1-TM antibody. Both antibodies were expressed in Expi- is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.10.20191486 doi: medRxiv preprint 

Control . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.10.20191486 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 15, 2020. . https://doi.org/10.1101/2020.09.10.20191486 doi: medRxiv preprint

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Days After Symptoms Onset

Deborah Strahs, Bradley Wolfe, Katherine Woodward, Jingrong Xu, and other current and former Corvus employees for administrative, clinical, and scientific support. We thank the patients, their families, and the physicians, nurses, and staff at Temple University Hospital and Mount Sinai Hospital for their participation in these clinical studies.