Monoclonal antibodies

The development of highly successful monoclonal antibody-based therapies for cancer and immune disorders has created a wealth of expertise and manufacturing capabilities. As long as all other therapies fail or have only modest effects, monoclonal antibodies are the hope for the near future. There is no doubt that antibodies with high and broad neutralizing capacity, many of them directed to the receptor binding domain (RBD) of SARS-CoV-2, are promising candidates for prophylactic and therapeutic treatment. On the other hand, these antibodies will have to go through all phases of clinical trial testing programs, which will take time. Safety and tolerability, in particular, is an important issue. The production of larger quantities is also likely to cause problems. Finally, there is the issue that mAbs are complex and expensive to produce, leaving people from poor countries locked out (Ledford 2020).

No antibody has been thoroughly tested in humans to date. However, some are very promising. The ‘COVID-19 antibodysphere’ (Amgen, AstraZeneca, Vir, Regeneron, Lilly, Adagio) is building partnerships. Several mAbs entered clinical trials in the summer of 2020. Trials will include treatment of patients with SARS-CoV-2 infection, with varying degrees of illness, to block disease progression. Given the long half-life of most mAbs (approximately 3 weeks for IgG1), a single infusion should be sufficient.

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AcalabrutinibAnticomplement therapiesAzithromycinCamostatChloroquineColchicineConvalescent plasmaCorticosteroidsCytokine blockersFamotidineFavipiravirG-CSFHuman recombinant soluble ACE2HydroxychloroquineIbrutinibIloprostInterferonsJAK inhibitorsLeflunomideLopinavirMonoclonal antibodiesN-acetylcysteineOseltamivir(other) Protease inhibitors(other) RdRp inhibitorsREGN-COV2Umifenovir

Outlook | References



Other mAbs, some key papers:

  • The first report of a human monoclonal antibody that neutralizes SARS-CoV-2 (Wang 2020). 47D11 binds a conserved epitope on the spike RBD explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor-binding inhibition. This antibody could be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2.
  • From 60 convalescent patients, 14 potent neutralizing antibodies were identified by high-throughput single B cell RNA-sequencing (Cao 2020). The most potent one, BD-368-2, exhibited an IC50 of 15 ng/mL against SARS-CoV-2, displaying strong therapeutic efficacy in mice. The epitope overlaps with the ACE2 binding site.
  • Several mAbs from ten convalescent COVID-19 patients. The most interesting mAb, named 4A8, exhibited high neutralization potency but did not bind the RBD (like most other mAbs). Cryo-EM revealed that the epitope of 4A8 seems to be the N terminal domain (NTD) of the S protein (Chi 2020).
  • Isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells of eight SARS-CoV-2 infected individuals. Some antibodies showed potent anti-SARS-CoV-2 neutralization activity that correlates with their competitive capacity with ACE2 for RBD binding (Ju 2020).
  • CR3022 tightly binds the RBD and neutralizes SARS-CoV-2 (Huo 2020). The highly conserved, structure-stabilising epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. The mechanism of neutralisation is new and was not seen for coronaviruses.
  • H014 neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar level by engaging the S receptor binding domain. In the hACE2 mouse model, H014 prevented pulmonary pathology. H014 seems to prevent attachment of SARS-CoV-2 to its host cell receptors (Lv 2020).
  • Four human neutralizing monoclonal antibodies were isolated from a convalescent patient. B38 and H4 blocked the binding between the virus S protein RBD and the cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD. In a mouse model, both antibodies reduced viral titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity (Wu 2020).
  • Of a total of 178 S1 and RBD binding human monoclonal antibodies from the memory B cells of 11 recently recovered patients, the best one, 414-1, showed neutralizing IC50 at 1.75 nM (Wan J 2020). Epitope mapping revealed that the antibodies bound to 3 different RBD epitopes, and epitope B antibody 553-15 could substantially enhance neutralizing abilities of most other neutralizing antibodies.
  • Isolation and characterization of two ultra-potent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that were identified among almost 800 screened Abs isolated from 12 COVID-19 patients (Tortorici 2020). Both nAbs protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block ACE2 attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Cocktails including S2M11, S2E12 or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions.
  • Using a high-throughput rapid system for antibody discovery, more than 1000 mAbs were isolated from 3 convalescent donors by memory B cell selection using SARS-CoV-2 S or RBD recombinant proteins. Of note, only a small fraction was neutralizing, highlighting the value of deep mining of responses to access the most potent Abs. RBD-nAbs that directly compete with ACE2 are clearly the most preferred for prophylactic and therapeutic applications, and as reagents to define nAb epitopes for vaccine. With these nABs, Syrian hamsters were protected from weight loss. However, animals that received higher doses also showed body weight loss, possibly indicating antibody-mediated enhanced disease (Rogers 2020).
  • Antibodies from convalescent patients had low levels of somatic hypermutation. Electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites. In total, 19 neutralizing antibodies were identified that target a diverse range of antigenic sites on the S protein, of which two showed picomolar (very strong!) neutralizing activities (Brouwer 2020).
  • Isolation of 61 SARS-CoV-2-neutralizing mAbs from 5 hospitalized patients, among which are 19 mAbs that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus inhibitory concentrations of 0.7 to 9 ng/mL (Liu 2020).
  • Antibody domains and fragments such as VH (heavy chain variable domain, 15 kDa) are attractive antibody formats for candidate therapeutics. They may have better tissue penetration compared to full-sized antibodies. One of those VHs, ab8, in an Fc (human IgG1, crystallizable fragment) fusion format, showed potent neutralization activity and specificity against SARS-CoV-2 both in vitro and in mice and hamsters, possibly enhanced by its relatively small size (Li 2020).

COVID Reference chapters:

Epidemiology | Transmission | Prevention | Virology | Immunology | Diagnosis | Clinical Manifestations | Treatment | Severe COVID-19 | Comorbidities / Special Populations | Pediatrics| Timeline | Preface

By Christian Hoffmann