key: cord-0871612-0bx27v98
authors: Piepenbrink, Michael S.; Park, Jun-Gyu; Oladunni, Fatai S.; Deshpande, Ashlesha; Basu, Madhubanti; Sarkar, Sanghita; Loos, Andreas; Woo, Jennifer; Lovalenti, Phillip; Sloan, Derek; Ye, Chengjin; Chiem, Kevin; Erdmann, Nathaniel B.; Goepfert, Paul A.; Truong, Vu L.; Walter, Mark R.; Martinez-Sobrido, Luis; Kobie, James J.
title: Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters
date: 2020-10-14
journal: bioRxiv
DOI: 10.1101/2020.10.14.339150
sha: 369d2f401779d1bfc8e73f3702ee3e63ed344660
doc_id: 871612
cord_uid: 0bx27v98

SARS-CoV-2 infection results in viral burden in the upper and lower respiratory tract, enabling transmission and often leading to substantial lung pathology. Delivering the antiviral treatment directly to the lungs has the potential to improve lung bioavailability and dosing efficiency. As the SARS-CoV-2 Receptor Binding Domain (RBD) of the Spike (S) is increasingly deemed to be a clinically validated target, RBD-specific B cells were isolated from patients following SARS-CoV-2 infection to derive a panel of fully human monoclonal antibodies (hmAbs) that potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, has high affinity for SARS-CoV-2 RBD which enables its direct inhibition of RBD binding to ACE2. The 1212C2 hmAb exhibits in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhale treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration. Taken together, these results warrant an accelerated clinical development of 1212C2 hmAb formulated and delivered via inhalation for the prevention and treatment of SARS-CoV-2 infection.

The SARS-CoV-2 global pandemic has infected over thirty million people and has resulted in over one million deaths so far. It is expected that new infections will continue for many more months, and the virus will persist endemically for years. Although severe infections and deaths have been reported in all ages and demographics, those over 65 years old and those with pre-existing conditions are at highest risk for death (1-5). Thus far, no drug or vaccine has been approved by the FDA for the treatment or prevention of SARS-CoV-2 infection. Moreover in the US, the number of COVID-19 patients that are hospitalized represent a small fraction (~10%) of the active cases, which implies that the vast majority of COVID-19 symptomatic patients are not hospitalized and need treatment (6). Therefore, facilitating greater treatment coverage will be of importance to control transmissibility and healthcare burden.

Neutralizing antibodies (NAbs) induced either by natural infection or vaccination are likely to be critical for protection from SARS-CoV-2 infection and have been correlated with protection from SARS-CoV-2 in animal studies (7) (8) (9) , and passive transfer of neutralizing mAbs has demonstrated prophylactic and therapeutic activity against SARS-CoV-2 infection (10) (11) (12) . Emerging results in humans treated with convalescent plasma with high titer NAbs suggest therapeutic activity (13, 14) . The primary target for SARS-CoV-2 neutralizing antibodies is the Receptor Binding Domain (RBD), whereby antibodies are expected to inhibit the binding of the SARS-CoV-2 Spike (S) protein to the host Angiotensin Converting Enzyme 2 (ACE2), preventing viral attachment.

Already, several human monoclonal antibodies (hmAbs) have been isolated from patients following SARS-CoV-2 infection that are specific for RBD, neutralize SARS-CoV-2, and have anti-viral activity in animal models (10, 15) . RBD is used predominantly as the target in clinical stage vaccines and antibody candidates, with preliminary positive clinical responses reported (6, 16).

To obtain more precise resolution of the RBD-specific NAb response, a panel of RBD specific hmAbs were isolated and their molecular features, reactivity profiles and in vitro and in vivo anti-viral activities were defined. Several high affinity hmAbs with modest somatic hypermutation and potent SARS-CoV-2 neutralizing activity were isolated from IgG, IgA, and IgM memory B cells. In this report, we show that 1212C2 hmAb demonstrated substantial prophylactic and therapeutic activity in hamsters when delivered parenterally. Moreover, when delivered as inhaled liquid aerosols using a commercially available nebulizer, 1212C2 mediated eradication of lung viral load at a substantially higher dosing efficiency than the parenteral route of administration. The combination of a potent SARS-CoV-2 mAb and inhaled, local lung delivery using widely available nebulizers could provide for a promising treatment option.

To identify and isolate RBD-specific B cells, recombinant RBD protein was expressed, biotinylated, and used to form streptavidin-conjugated RBD tetramers to various fluorochromes. Peripheral blood CD27+ memory B cells binding RBD were single cell sorted from convalescent SARS-CoV-2 patients and the immunoglobulin heavy and light chain variable regions of the B cells cloned to generate IgG1 recombinant hmAbs (Fig 1A) . Twenty hmAbs were isolated that exhibited substantial binding to SARS-CoV-2 RBD. These hmAbs all bound to recombinant SARS-CoV-2 RBD and S1 D614G proteins and exhibited varying reactivity SARS-CoV-2 S1S2 protein (Fig 1B) . As expected, minimal to no reactivity was observed to SARS-CoV-2 Nucleocapsid (N) protein or HepG2 cell lysate for most hmAbs, indicating high specificity for SARS-CoV-2 RBD and minimal off-target binding.

REGN10987, REGN10933, and CB6/JS016 hmAbs were synthesized and included as positive controls (15, 17) . To ascertain the avidity of the hmAbs for SARS-CoV-2 RBD, their binding stability was determined in the presence of the chaotropic agent 8M urea.

The hmAbs 1206D1, 1212C2, 1212F5, and 1215D1 retained at least 50% of their binding activity to SARS-CoV-2 RBD and S protein (Fig 1C) . Binding affinity to RBD was further tested for a subset of the hmAbs by surface plasmon resonance (SPR), demonstrating a variety of high affinity hmAbs exhibiting equilibrium dissociation constants (KD) ranging from 77 pM to ~9 nM (Fig 1D) . Several of the hmAbs (1212C2, 1215D1, 1215D5) exhibited ~10-fold higher affinity to RBD than control hmAbs (REGN10987, REGN10933 (17) , and CB6/JS016 (15)), predominantly due to their slower off rates (kd). These results indicate that this panel of hmAbs recognize SARS-CoV-2 RBD specifically and with high affinity.

Recognition and neutralization of SARS-CoV-2. The process of entry into a susceptible host cell is an important determinant of infectivity and pathogenesis of viruses, including coronaviruses (18, 19) . SARS-CoV-2 relies on the ability of its S glycoprotein to bind to the ACE2 receptor through its RBD driving a conformational change that culminates in the fusion of the viral envelope with the host cell membrane, and cell entry (20) . The hmAbs were tested for neutralization of live SARS-CoV-2 using a virus plaque reduction microneutralization (PRMNT) assay we previously described (21) , with the hmAb and virus pre-incubated prior to culture with susceptible Vero E6 cells (pre-treatment) or allowing virus adsorption to Vero E6 cells to occur for 1 hour prior to addition of the hmAb (post-treatment). This gives an opportunity for the virus to initiate viral entry by binding to the cell surface receptor, potentially distinguishing the hmAb's ability to preferentially block later steps of virus entry into the cell or by inhibiting the cell-to-cell spread of virus progeny. The panel of hmAbs neutralized SARS-CoV-2 in both pre-and post-treatment conditions at NT 50 of 1 μg/ml or less, with 1212F5, 1212C2, and 1213H7 exhibiting the highest potency, with NT 50 of 100 ng/ml or less (Fig 2A) . The hmAb 1215D1 was more effective in neutralizing in post-treatment (NT 50 = 59 ng/ml) compared to pre-treatment (NT 50 = 226 ng/ml)). The 1212C2 hmAb was particularly potent (pre NT 50 = 45 ng/ml, post NT 50 = 32 ng/ml) (Fig 2B) . Testing of 1212C2 in a SARS-CoV-2 VSV vectored pseudovirus assay confirmed its potent neutralizing activity (NT 50 = 1.9 ng/ml) that was similar to REGN10987 and CB6/JS016 (Supplemental Table 1 ).

The panel of hmAbs clearly recognized SARS-CoV-2-infected Vero E6 cells as evident by immunofluorescence (Fig 2C and Supplemental Figure 1) . No background staining of mock-infected cells was evident with any of the hmAbs, consistent with their high affinity specificity for SARS-CoV-2 S. The hmAbs also exhibited binding to SARS-CoV-2 viral lysate (Supplemental Figure 2) . The ability of the hmAbs to directly inhibit the binding of RBD to ACE2 was determined using HEK293 cells overexpressing ACE2. All of the tested RBD-specific hmAbs inhibited the binding of recombinant SARS-CoV-2 RBD protein to the ACE2 expressing cells (Fig 2D) . Inhibition was nearly complete with the exceptions of 1206D1, 1207B4, and 1215D1. These results demonstrate the potent in vitro neutralizing and binding activity of these SARS-CoV-2 RBD specific hmAbs.

Molecular features and clonal dynamics. The most potent hmAbs, 1212C2 and 1212F5 were both isolated from IgM+ B cells, belong to the same clonal lineage that utilizes the VH1-2 heavy chain gene, and exhibited modest somatic hypermutation, with 1212C2 further mutated from germline compared to 1212F5 (8.2% vs 6.1% amino acid VH) ( Table 1) . Most of the hmAbs were isolated from IgG1 expressing B cells, while 1215D1 and 1212C8 were isolated from IgA expressing B cells. All hmAbs exhibited somatic hypermutation (2.0%-9.1% VH) suggesting they arose from multiple rounds of germinal center reactions. VH3-66 and Vk1-9 gene usage was dominant among the hmAbs. Targeted VH-deep sequencing of the 1212C2/1212F5 clonal lineage from contemporary peripheral blood B cells identified numerous members (Fig 3) . SPR epitope mapping was performed and used to cluster the hmAbs into five major epitopes (A-E, Fig 4) . With one exception, all isolated hmAbs are part of the A epitope, that includes 1212C2. Thus, 1212C2 efficiently blocked all hmAbs from binding to RBD, except 1215B11 (E epitope), whose epitope overlaps with CR0322. Within the footprint of the A epitope there are several sub-epitopes. In particular, we highlight hmAbs 1207B4/1215D1 (B-epitope) and 1213H7 (C-epitope) that exhibit essentially no overlap with one another, based on their ability to simultaneously bind RBD at greater than 90% of their expected binding levels.

Consistent with their distinct classification, B-epitope hmAbs exhibit a reduced ability to block RBD attachment to ACE2 expressing cells (Fig 2D) .

Prophylactic and therapeutic activity in hamsters. The in vivo activity of 1212C2 and 1206D1 was evaluated in the golden Syrian hamster model of SARS-CoV-2 infection (22) . 1212C2 was chosen based on its potent in vitro neutralizing activity and high affinity, while 1206D1 was chosen based on its in vitro neutralizing activity and distinct affinity and reactivity profile from 1212C2.

To test for prophylactic activity, 10 mg/kg of hmAb was administered by intraperitoneal (IP) injection 6 hours prior to intranasal (IN) challenge with SARS-CoV-2. At 2 days post infection (dpi), all PBS control and isotype control hamsters had detectable live virus as measured by plaque assay in their nasal turbinate and lungs. In contrast at 2 dpi, hamsters that received 1212C2 already started to exhibit meaningful viral load reduction in their nasal turbinate and lungs (Fig 5A) . At 4 dpi virus was detected in the nasal turbinates and lungs of all hamsters in the PBS and isotype control groups, although an overall decrease compared to 2 dpi, consistent with the viral dynamics of SARS-CoV-2 infection in hamsters (22) . In comparison to the control groups at 4 dpi, prophylactically treated 1212C2 hamsters exhibited eradication of viral loads in the nasal turbinates and lungs in 3 of 4 animals. Consistent with the viral load reduction, 1212C2 treated animals exhibited significantly less lung pathology compared to the PBS treated group at 2 dpi and 4dpi, with this reduction also reaching significance compared to the isotype control group at 4 dpi (Fig 5C) . There was ~80% reduction in lung pathology at 4 dpi when 1212C2 was given prophylactically. 1206D1 hmAb exhibited modest activity, noted by 50% of hamsters having no detectable virus in the nasal turbinate, and all 1206D1 hamsters having detectable virus in the lungs, although trending to lower titers compared to PBS and isotype control groups. These in vivo results are consistent with the lower in vitro viral neutralization activity of 1206D1 in comparison to 1212C2 (Fig 2A) .

Overall, 1212C2 demonstrated substantial prophylactic activity as evident by sterilizing protection in 63% of hamsters. of the 1212C2 treated hamsters (Fig 5B) . Overall, 1212C2 demonstrated substantial therapeutic activity, reducing virus to undetectable levels in 75% of the treated hamsters.

congestion, and atelectasis (22) . Therapeutically, significantly less lung pathology was also observed in the 1212C2 treated hamster group compared to the PBS treated group, and ~58% reduction in lung pathology in 1212C2 group compared to the control hamsters ( Fig 5D) . Importantly, these differences observed in lung lesions are consistent with the viral burden seen in the upper and lower respiratory tract ( Table 2 ). Intraperitoneal administration of approximately 25 mg/kg of hmAb resulted in high serum concentration but little to no detectable hmAb in the BAL at 30 mins post treatment (Supplemental Table 2 ). However, 42 hours later, the hmAb was detectable in the BAL, suggesting that IP injected hmAb gradually penetrates the lungs from the serum compartment.

Inhalation (IH) administration of the hmAb using liquid aerosols delivered whole body to the animals from a commercially available nebulizer (Aerogen Aeroneb Solo nebulizer)

showed that approximately 1.7% of the inhaled dose was deposited in the BAL. The low percentage of the inhaled dose that is deposited in the lungs of hamsters is in line with prior lung uptake studies for the approximately 4 µm diameter droplets produced by the nebulizer used here (volume mean diameter measured by laser diffraction 4.1 µm), and is a result of a higher degree of inertial impaction of liquid aerosols in the upper airways of small animals (24) . Nevertheless, such lung deposited (BAL) dose is still substantially higher at both time points than the BAL concentration achieved with the IP route. A higher lung deposited dose afforded by the inhaled route demonstrates higher delivery efficiency to the lungs than the IP route. At 42 hours post-inhaled dose, the mAb is significantly cleared from the BAL, which appears to be faster clearance rate than an expected lung half-life of ~8 days reported in other studies (45) . At 4 dpi virus was detected in the nasal turbinate and lungs of all infected control hamsters (saline and isotype hmAb), with a trend toward modest non-specific reduction in viral titer in nasal turbinate only with isotype control hmAb (Fig 6B) . Viral titers were only sporadically detected in the nasal turbinates of the 1212C2 treated groups, with the exception of detectable virus in all of the 0.6 mg/kg inhaled 1212C2-HLE-LALA group.

At 4 dpi there was no detectable viral titer in the lungs of any 1212C2 treated hamsters, including the 0.6 mg/kg IH 1212C2-HLE-LALA group, representing at least a 2-log reduction compared to control groups. Lung pathology was evident at 4 dpi, particularly in the control groups, however overall, relative to non-infected hamsters, no lung pathology was evident in 9/24 (37.5%) of the 1212C2 treated hamsters, compared with lung pathology evident in 11/12 (91.7%) of the control treated infected hamsters (Fig   6C) . At 4 dpi lung lesions were significantly decreased in hamsters that were treated with 3.2 mg/kg and 0.6 mg/kg of inhaled 1212C2 hmAb compared to PBS treated hamsters.

With regard to effector function removal brought about by the addition of the LALA mutation, animals treated 1212C2-HLE-LALA appeared to achieve comparable viral reduction as the un-modified 1212C2 mAb. Overall these results confirm the therapeutic activity of 1212C2 hmAb against SARS-CoV-2 infection and suggest increased efficacy of inhaled 1212C2 hmAb, with elimination of viral lung burden with a single inhaled dose of just 0.6 mg/kg. As shown in Suppl. Table 2 Subsequently, 1215D1 should be evaluated for its in vivo efficacy, and discern if the post-treatment neutralization assay is a more sensitive indicator of in vivo efficacy.

Epitope mapping suggests that 1212C2 has a large footprint on the RBD, blocking the binding of several other neutralizing hmAbs encoded by diverse heavy and light chain variable region genes. Efforts are ongoing to solve the 1212C2 -RBD structure to adequately define the epitope.

The high affinity binding of 1212C2 to SARS-CoV-2 RBD, mediating its ability to block RBD attachment to ACE2, and subsequent potent neutralization of SARS-CoV-2 even when added after virus has been added to culture, demonstrate its direct and substantial anti-viral activity. These properties likely contribute to its prophylactic and therapeutic ability to protect hamsters from SARS-CoV-2 challenge, reducing viral burden and the development of lung pathology. 1212C2 was similarly effective in treating SARS-CoV-2 infection in hamsters, reducing viral burden and lung pathology when administered by parenteral route at clinically relevant doses.

As the portal of entry for SARS-CoV-2 virus is the respiratory tract, with the lungs serving as the key target organ for pathogenesis, delivering directly the mAbs to the lungs using inhalation is a logical approach. While aerosols delivery of drugs to the lungs is significantly more inefficient in small animals as compared to humans (~1% of the inhaled dose is deposited in the lungs for rodents as compared to ~50% in humans), our data showed that inhaled delivery of mAbs to the lung BAL in hamsters is still substantially more efficient than that achieved using the IP route (Supplemental Table   2 ), When comparing the inhaled route to the IP route in the hamster challenge study, therapeutic efficacy was achieved at a significantly higher efficiency was observed for the inhaled route. Inhaled administration of 1212C2 hmAb resulted in sterilizing therapeutic protection at all tested doses, with the lowest inhaled dose of 0.6 mg/kg which corresponds to 0.01 mg/kg of lung deposited dose (or a human equivalent inhaled dose of 0.03 mg/kg). In contrast, mAbs against SARS-CoV-2 that have been reported to date required at least 5 mg/kg or above to achieve therapeutic efficacy when administered parenterally (15, (34) (35) (36) . Therefore, inhaled 1212C2 has the potential to profoundly facilitate dose-sparing and treatment coverage compared to conventional parenteral administration. There are several commercial inhaled protein therapeutic products and many more inhaled protein therapeutics that are in various stages of clinical evaluations, most with attractive safety profile. Several mAbs have also been clinically evaluated as inhaled aerosols with demonstrated preliminary safety and tolerability (6, 16, 37, 38) , suggesting the practicality of formulating 1212C2 for selfadministered inhalation. Over 90% of all symptomatic COVID-19 patients are not

hospitalized, but they all still need treatment to minimize the potential for transmission and limit complications from viral infection. This is a large unmet COVID-19 population and having a convenient self-administered dose that can be done on an outpatient basis or at home using commercially available nebulizer devices could materially impact treatment coverage, reducing transmissibility, and ultimately the viral burden of the population. Epitope mapping was performed by capturing RBD-FC to CM-5 sensor chips using an anti-murine FC capture kit (Cytiva). The running buffer was the same as used for RBD / hmAb affinity measurements. hmAbs were sequentially injected, up to 6 NmAbs in one series, over the RBD-FC surface. The first hmAb was injected at 100 nM concentration, and subsequent hmAbs were injected at 50nM concentrations. Each hmAb was injected for 90 seconds over the RBD-FC, followed by a 60 second dissociation phase.

The flowrate for the epitope mapping studies was 30 µL/min. After the final injection, After 1 h incubation at 37C and 5% CO 2 , another 100 μ l of media containing 2% FBS, was added, and cells were incubated for 24 more hrs. After this time, luciferase activity was measured using Passive Lysis Buffer (Promega E1941) and Luciferase substrate (Promega E151A) following the manufacturer's instructions. Neutralization was calculated as the percent reduction of luciferase readings as compared to no-antibodycontrols.

We have previously demonstrated that golden Syrian hamsters Resulting pathology were represented as the percent of the total lung surface area. Left side of the lungs were used for histopathology and the right side was used for viral titers.

The hmAb 1212C2 was also assessed in an in vivo therapeutic experiment. At the start of the experiment, 12, 6-week old, female hamsters were administered 2x10 5 were performed using an in-house custom analysis pipeline as previously described (39, 43) . All sequences were aligned using IMGT.org/HighVquest (44 Distribution of pathologic lesion, including consolidation, congestion, and pneumonic lesions were measured using ImageJ and represented as the percent of the total lung surface area in prophylactically treated (C) and therapeutically treated (D) animals.

Each symbol represents an individual animal. were measured using ImageJ and represented as the percent of the total lung surface area. * p<0.05, ** p<0.005, *** p<0.0005 compared to PBI IP treated group.

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We are grateful for the clinical research staff that enabled this project and for the technical assistance provided by Christopher Bates, Reuben Burch, Eric Carlin, and