key: cord-0702285-2z1t91cz authors: Yang, Lifei; Liu, Weihan; Yu, Xin; Wu, Meng; Reichert, Janice M; Ho, Mitchell title: COVID-19 Antibody Therapeutics Tracker: A Global Online Database of Antibody Therapeutics for the Prevention and Treatment of COVID-19 date: 2020-08-19 journal: Antib Ther DOI: 10.1093/abt/tbaa020 sha: 6a5aa98060cd22a908ea96f5b4a62d5faccf7263 doc_id: 702285 cord_uid: 2z1t91cz Facing the COVID-19 global healthcare crisis, scientists worldwide are collaborating to develop prophylactic and therapeutic interventions against the disease. Antibody therapeutics hold enormous promise for treatment of COVID-19. In March 2020, the Chinese Antibody Society, in collaboration with The Antibody Society, initiated the “COVID-19 Antibody Therapeutics Tracker” (“Tracker”) (https://chineseantibody.org/covid-19-track/) program to track the antibody-based COVID-19 interventions in preclinical and clinical development globally. The data are collected from the public domain and verified by volunteers on an ongoing basis. Here, we present exploratory data analyses and visualization to demonstrate the latest trends of COVID-19 antibody development, based on data for over 150 research and development programs and molecules included in the “Tracker” as of August 8(th), 2020. We categorized the data mainly by their targets, formats, development status, developers and country of origin. Although details are limited in some cases, all of the anti-SARS-CoV-2 antibody candidates appear to target the viral spike protein (S protein), and most are full length monoclonal antibodies. Most of the current COVID-19 antibody therapeutic candidates in clinical trials are repurposed drugs aimed at targets other than virus-specific proteins, while most of these virus-specific therapeutic antibodies are in discovery or preclinical studies. As of August 8, 2020, eight antibody candidates targeting the SARS-CoV-2 S protein have entered clinical studies, including LY-CoV555, REGN-COV2, JS016, TY027, CT-P59, BRII-196, BRII-198 and SCTA01. Ongoing clinical trials of SARS-CoV-2 neutralizing antibodies will help define the utility of these antibodies as a new class of therapeutics for treating COVID-19 and future coronavirus infections. The data included in the "Tracker" are collected from resources in the public domain by volunteers from The Antibody Society and the Chinese Antibody Society on an ongoing basis. As shown in Table 1 , as a first approach, the data are collected from a variety of sources, including published literature, preprints, company websites, biotech newsfeeds, social media, government databases, and summarized. To reduce the amount of the manual work, when possible, an automatic process is being developed and integrated to retrieve data from online databases such as ClinicalTrials.gov by command-line tools (4) . For example, to construct queries based on the Application Programming Interface (API) tool of ClinicalTrials.gov, query uniform resource locator (url) for all study records (i.e "full studies url") was used as the base query and supplied with additional parameters, including a search expression string containing search fields, values, and logical operators for search and filtering. Two versions of such queries were built and embedded in a Python script that iteratively sends requests for every 100 hits until all hits are exhausted. Returned hits from both queries, in JavaScript Object Notation (JSON) format, were further processed by the Python script for manual inspection to ensure relevancy. Relevant entries were then logged into an SQLite database indexed by NCTID (unique study ID). When updating the database, the NCTID of a returned hit will be compared with that of existing entries in the database. If it does not exist in the database, it will be flagged for manual review and if relevant, it will be entered into the database. Otherwise, its clinical phase will be updated automatically. An example of our script with detailed explanation for usage can be found in the Github repository (https://github.com/xinyu-dev/cas-covid-mab-tracker). Therapeutics programs based on non-antibody proteins with the similar mechanisms of actions as antibodies, such as recombinant ACE2 protein and Fc-fusion proteins, are also included. Unrelated information such as diagnostic antibodies, polyclonal plasma from I P T convalescent patients, and clinical trials without specific indications to COVID-19 patients in experimental design, were excluded. For quality evaluation, all the final data included in the "Tracker" were cross-verified manually by at least two independent volunteers. For presentation in the "Tracker", we categorized the following data: target, molecular format, development status, developer, country of origin and the supporting reference. To build the "Tracker", the data table containing filtered results was uploaded to the website of the Chinese Antibody Society, which was build using WordPress. We used WPDatatable Plugin to integrate the data table from backend to front end of the webpage. On our "Tracker" website, the whole dataset was displayed as an interactive table, and grouped by the categories we defined above. We also performed analysis and visualization based on the key features of the collected antibody therapeutic data that are most relevant to the scientific community and general public. These include the numbers of therapeutic targets, formats, and program development status of the antibody therapeutics. In addition, we plotted the distribution of program development status by country to track the progress of COVID-19 antibody therapeutics programs globally. To further elaborate the function of the "Tracker", we performed data visualization and analysis based on the key features of the collected antibody therapeutic data, including antibody targets, formats, and development status. Neutralizing antibodies are critical components in host immune responses to viral pathogens (3) . As an enveloped singlestrand RNA virus, SARS-CoV-2 enters into a human cell through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2) (5, 6) . The structures of SARS-CoV-2 S protein trimer (7) and human ACE2 (8) shows that the receptor binding domain (RBD) on the SARS-CoV-2 S protein S1 subunit directly contacts with human ACE2 (8) . Therefore, the S protein, in particularly the RBD or the S1 subunit, is the primary target for most neutralizing antibodies. As shown in Figure 1A , the "Tracker" is currently tracking 153 programs and molecules for COVID-19 interventions from discovery to clinical development. Among these, 89 target the SARS-COV-2 S protein as antiviral interventions by blocking virus entry. Most of the anti-SARS-COV-2 antibodies were isolated from single memory B cells derived from convalescent patients or immunized transgenic animals. Regeneron Pharmaceuticals Inc (Regeneron) used both approaches to isolate antibodies that bind distinct and non-overlapping epitopes on the monomeric RBD of the spike protein with high affinity (K D = 0.56 to 45.2 nM) (9). These antibodies have potent neutralization activities against pseudoviral particles or live virus with IC 50 values of 1-10 pM (10) Using an in vitro assay, they found escape mutants were not generated following treatment with a cocktail composed of non-competing antibodies. Regeneron is developing two of their antibodies as the cocktail treatment REGN-COV2 (REGN10933+REGN10987) ( Table 2 ). In another study, groups from Chinese Academy of Sciences in Beijing and Junshi Biosciences in Shanghai reported two human antibodies (CA1 and CB6) have been isolated from a convalescent COVID-19 patient using single B cell sorting and cloning techniques (11) . The human antibodies showed potent neutralization activity in vitro against SARS-CoV-2 with IC 50 of 0.036 ± 0.007 μg/mL (0.24 ± 0.047 nM) for CB6 and 0.38 μg/mL (2.53 nM) for CA1. Structural analysis revealed that CB6 is an ACE2 blocker that (Table 2) . ). Considering the proven role of cytokine dysregulation in causing this hyperinflammation, especially in the lungs, existing drugs targeting these mediators are being repurposed for the treatment of COVID-19 (12) . As shown in Figure 1A , 61 of the molecules included in the "Tracker" were developed to target the host immune system for other indications, but were repurposed to treat COVID-19 by potentially alleviating COVID-19-related symptoms, such as cytokine storm and inflammation, instead of directly killing the viruses. For example, the IL-6 inhibitors levilimab, tocilizumab, sarilumab, olokizumab and siltuximab are being tested against COVID-19 (12-14). As shown in Figure (https://kodiak.com/press-releases/kodiak-sciences-announces-first-quarter-2020-financial-results-and-recent-business-highlights/), CD16/SARS-CoV-2 (https://www.gtbiopharma.com/news-media/press-releases/detail/182/gt-biopharma-and-cytovance-biologicsannounce-collaboration%7C%7CGT%20Biopharma). Fusion protein and other formats, such as DARPin, mRNA-encoding mAb, radiotherapeutics, are also being tested for the treatment of COVID-19. Among the programs and molecules we are tracking, over 60% are in discovery and preclinical stages (Figure 2A) Table 2 ). The trial is a randomized, double-blind and placebo-controlled study to evaluate the tolerability, safety, pharmacokinetic and immunogenicity of JS016 in healthy subjects. TY027 was developed by Tychan in partnership with the whole-of-Singapore government engagement (Table 2 ). TY027 is being explored for the treatment of patients with COVID-19 to slow the progression of the disease and accelerate recovery, as well as for its potential to provide temporary protection against infection of Based on the number of research and development programs, the United States and China are the top two countries in developing COVID-19 antibody therapeutics, followed by Canada, Germany, South Korea, UK, and France ( Figure 2B ). The COVID-19 pandemic is causing unprecedented worldwide impacts on healthcare, research and economies. To bring the pandemic under control, development of effective treatments is urgently needed. To help address the emergent information needs, our "Tracker" provides a useful reference for researchers and the public to track current progress of drugs developed for COVID-19. (22), SARS-CoV-2 (23-26) have caused major outbreaks and substantial disruption due to the lack of human immunity and facile transmission of the virus. It has been proposed that a so-called "universal" target or strategy for inhibiting both SARS-CoV and SARS-CoV-2 or even all coronaviruses should be identified to allow treatment of not only the current COVID-19 pandemic, but also future SARS-related coronavirus infections (3) . In proof-of-concept studies, neutralizing antibodies, such as 47D11 (27), S309(28), VHH-72 (29) , and ADI55689/ADI56046 (30), against highly conserved region of RBD or the S1 subunit of the SARS-CoV-2 spike protein have also been shown to possess neutralizing activities against SARS-CoV. With an exception of VHH-72, these mAbs are fully human IgG molecules, which is a format suitable for therapeutic development, but more potent cross-neutralizing antibodies might be needed for clinical studies. Although it is challenging to develop "universal" antibodies targeting coronaviruses, efforts are currently being made to isolate broad and potent neutralizing antibodies against multiple coronaviruses, including SARS-CoV-2 (https://www.fiercebiotech.com/biotech/adagio-debuts-50m-to-fight-covid-19-and-nextpandemic). Current challenges in developing neutralizing antibodies against SARS-CoV-2 include mutations in the spike protein (31) . Mutations in the virus can lead to escape variants (32) . Combination of multiple mechanisms and binding domains has been reported in MERS-CoV (33) and SARS-CoV (32) antibody development. A combination (cocktail) of two antibodies that recognize different non-competing epitopes of the RBD or the spike protein of SARS-CoV-2 has been developed for clinical trials to treat COVID-19 (10) . Since each of the non-competing neutralizing antibodies targeting the RBD of the spike protein has potent activity against the SARS-CoV-2 virus, combination of these antibodies does not show superior neutralizing activities in culture. Nevertheless, the major advantage for the cocktail strategy is the ability to prevent epitope escape. More cocktail therapies that involve multiple targets or Antibodies that target the spike protein other than the S1 subunit have rarely been reported so far. The S2 subunit, in particular heptad repeat (HR) loops including HR1 and HR2 domains, required for membrane fusion has been suggested as another potentially (3) . The 1A9 antibody is a monoclonal antibody that binds the HR2 domain on the S2 subunit of SARS-CoV (35) . Since the S2 subunit is highly conserved, it would be interesting to explore whether such antibodies have broad neutralizing activities against both SARS-CoV and SARS-CoV-2. A broad inhibitor targeting the HR region might be useful for treatment of infection by current and future SARS-related coronavirus. Such a concept has been demonstrated in studies of peptide-based pan-coronavirus fusion inhibitors (36, 37) . A cocktail therapy that combines both ACE2 (S1) blockers and S2 inhibitors in two distinct functional domains of the spike protein would be worthwhile developing and testing. Host cell targets such as heparan sulfate proteoglycans (HSPGs) may provide the initial sites for virus attachment and entry (38) . Blocking the HSPGs on human cells by therapeutic antibodies has been proposed for treating COVID-19 and other virus infections (3, 39) . The D614G mutation on the SARS-CoV-2 spike protein has been recently identified for its role in increasing infectivity (15) . Structural models predict that D614G would disrupt contacts between the S1 and S2 domains of the spike protein and cause significant shifts in conformation. It should be useful to closely monitor and analyze the mutations of SARS-CoV-2 as it spreads worldwide so neutralizing antibodies effective for multiple strains of the virus can be developed (40) (41) (42) . Step 1 Data Acquisition Source: public domains Method: 1) Entries from search engines, company websites, biotech news feed, social media, and government databases were collected. 2) When an Application Programming Interface (API) tool is available, such as in the case of ClinicalTrials.gov, Python scripts developed in-house were used for automatic querying and retrieval. Filtering: Entries describing preclinical or clinical development of diagnostic antibodies, polyclonal antibodies, convalescent plasma therapies, immune globulin intravenous (IGIV) therapies, small molecules, and recombinant proteins other than immunoglobin (Ig), Ig fragments, and Ig fusion proteins were removed from our collection. Studies and clinical trials without explicitly stating COVID-19 or SARS-CoV-2 as their indication or target were also eliminated. Filtering was performed manually unless an API tool was available, in which case, it was performed by the Python scripts mentioned above. Validation: Validation of each entries we retained in our collection is performed manually, by inspecting and cross-validating using multiple sources if possible. Data analysis was performed, and statistics on key aspects, such as drug targets, format and clinical status were generated using R and Python Interactive non-antibody recombinant protein (rhACE2), and DARPin, mRNA-encoding mAb and radiotherapeutic formats. The number of programs for each target and format are shown, followed by the proportion to the total number of all programs in paraphrase. Figure 1 is based on "Tracker" data as of August 8 th , 2020. clinical trials is color-coded from dark blue (the earliest phase) to dark red (the latest phase). For therapeutic candidates being developed across multiple countries, each participating country has been counted separately in this chart. Figure 2 is based on "Tracker" data as of August 8 th , 2020. 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Cell Broad neutralization of SARS-related viruses by human monoclonal antibodies Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2 Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability Monoclonal antibodies targeting the HR2 domain and the region immediately upstream of the HR2 of the S protein neutralize in vitro infection of severe acute respiratory syndrome coronavirus Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses Phylogenetic network analysis of SARS-CoV-2 genomes Patient-derived mutations impact pathogenicity of SARS-CoV-2 Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2 We thank Xiao Xiao, Cong Yao, and Bo Liu for critical reading of the manuscript. We acknowledge Ningxuan Zhou, Zhezhen Wang, The authors declare no competing financial interests.