Learning from past failures: Challenges with monoclonal antibody therapies for COVID-19

Lai, Samuel K.; McSweeney, Morgan D.; Pickles, Raymond J.

doi:10.1016/j.jconrel.2020.11.057

Cited by 23 publications

(21 citation statements)

References 89 publications

(62 reference statements)

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“…Remarkably, the ability of 76clAbs to recognize an essential and conserved spike antigenic epitope translates into the neutralization of the delta variant and the so far identified VBMs, some of which known to drive escape of approved and investigational mAbs (22). The single chain antibodies here proposed for nasal or lung topical delivery might overcome limitations of parenteral mAbs aimed for a systemic passive immunization (23). Developed as a complementary approach to the existing vaccination and passive systemic immunization, that do not induce a robust mucosal defense (24), this class of antibodies may contribute to halt the SARS-CoV-2 infection at its early stages.…”

Section: Regarding the Biochemical Properties Of 76clabs Size Exclusion Chromatography (Sec-hplc)mentioning

confidence: 99%

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy

Minenkova

Santapaola

et al. 2021

Preprint

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As of June 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global emergency and effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. SARS-CoV-2-neutralizing monoclonal antibodies (mAbs) represent a promising approach to COVID-19 therapy. However, the recently described accumulating mutations in the SARS-CoV-2 spike protein are challenging the efficacy of approved and investigational mAbs, whose widespread use is also hampered by their significant costs and possible side effects, including Antibody-Dependent Enhancement (ADE). Here we describe a cluster of SARS-CoV-2 neutralizing human single chain variable fragment antibodies, identified by phage display, sharing a common VH CDR3 sequence. Phage libraries were built by amplifying variable domains of immunoglobulin genes from cDNA derived from lymphocytes of COVID-19 convalescent subjects living in Bergamo, Italy. The scFv76-cluster antibodies (scFv76-cl Abs) exhibit high affinity for the spike receptor binding domain (RBD) of Wuhan strain and emerging variants, leading to inhibition of RBD/human ACE2 interaction. The antigenic epitope recognized by scFv76 was mapped in the receptor binding motif (RBM) of RBD at residues L455, F456, Y473, N487 and Y489. None of these residues has been to date listed among the RBD mutations of SARS-CoV-2 variants of concern (VOCs), suggesting an important role of such epitope in viral infectivity. Treatment with scFv76-cl Abs is effective against SARS-CoV-2, as determined by in vitro experiments of viral infection, replication, cytopathogenicity and spike-mediated syncytia formation. Moreover, their intranasal administration is shown to counteract infection in two independent animal models. Overall, the biochemical and biological characteristics of scFv76-cl Abs are compatible with their clinical use for COVID-19 therapy by intranasal or aerosol administration. To our knowledge, this is the first example of promising human anti-SARS-CoV-2 scFv antibodies as drug candidates for COVID-19 therapy.

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Section: Regarding the Biochemical Properties Of 76clabs Size Exclusion Chromatography (Sec-hplc)mentioning

confidence: 99%

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy

Minenkova

Santapaola

et al. 2021

Preprint

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“…However, it has been reported that the treatment with CCP has little effect on the outcome of the disease in hospitalized patients [37][38][39][40]. Likewise, mAb has limited efficacy once patients are hospitalized, but there is clinical benefit when mAb are administered early in the course of disease [41][42][43][44]. Preliminary results suggest that hIG may act in a similar way, that is, by preventing patient hospitalization [45].…”

Section: Discussionmentioning

confidence: 99%

Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Hyperimmune Immunoglobulin Demonstrates Potent Neutralization and Antibody-Dependent Cellular Cytotoxicity and Phagocytosis Through N and S Proteins

Díez

Romero

Cruz

et al. 2021

The Journal of Infectious Diseases

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Background Although COVID-19 vaccinations have provided a significant reduction in infections, effective COVID-19 treatments remain an urgent need. Methods Functional characterization of anti-SARS-CoV-2 hyperimmune immunoglobulin (hIG) from human convalescent plasma was performed by different virus neutralization methodologies (plaque reduction, virus induced cytotoxicity, TCID50 reduction and immunofluorimetry) at different laboratories using geographically different SARS-CoV-2 isolates (USA (1), Italy (1), Spain (2): 2 containing the D614G mutation). Neutralization capacity against the original Wuhan SARS-CoV-2 strain and variants (D614G mutant, B.1.1.7, P.1 and B.1.351) was evaluated using a pseudovirus expressing the corresponding spike (S) protein. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) was also evaluated. Results All SARS-CoV-2 isolates were potently neutralized by hIG as shown by all four methodologies. Wild-type SARS-CoV-2 and variants were effectively neutralized using the pseudovirus. hIG induced ADCC and ADCP against SARS-CoV-2 N and S proteins but not E protein. Very low concentrations (25-100 µg IgG/mL) were required. A potent effect was triggered by antibodies in hIG solutions against the SARS-CoV-2 S and N proteins. Conclusions Beyond neutralization, IgG Fc-dependent pathways may play a role in combatting SARS-CoV-2 infections using COVID-19 hIG. This could be especially relevant for the treatment of more neutralization-resistant SARS-CoV-2 variants.

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“…Next-generation mAb candidates are in preclinical and clinical trials some demonstrating promise as a superior drug, e.g., nirsevimab [79,80]. mAbs including motavizumab and suptavumab (REGN2222) have recently failed to reach clinical trial endpoints [81]. Small-and large-molecule drugs in RSV therapeutic development have recently been reviewed [82].…”

Section: Rsv Epidemiologymentioning

confidence: 99%

Immunopathology of RSV: An Updated Review

Bergeron

Tripp

2021

Viruses

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RSV is a leading cause of respiratory tract disease in infants and the elderly. RSV has limited therapeutic interventions and no FDA-approved vaccine. Gaps in our understanding of virus–host interactions and immunity contribute to the lack of biological countermeasures. This review updates the current understanding of RSV immunity and immunopathology with a focus on interferon responses, animal modeling, and correlates of protection.

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Learning from past failures: Challenges with monoclonal antibody therapies for COVID-19

Cited by 23 publications

References 89 publications

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy

Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Hyperimmune Immunoglobulin Demonstrates Potent Neutralization and Antibody-Dependent Cellular Cytotoxicity and Phagocytosis Through N and S Proteins

Immunopathology of RSV: An Updated Review

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