How neutralizing antibody (NAb) work (mechanisms of action, MOA)

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Definition--What is neutralizing antibody (NAb)?

Regarding neutralizing antibody activity, Neutralization can be achieved through four main mechanisms2:

(1)NAbs binding to viral surface proteins and blocking their interaction with the host cell receptor and infection;

(2)NAbs binding to viral protein epitopes that interact with host cell coreceptors that are key for viral infection;

(3)NAbs binding to viral epitopes that are not essential for host cell receptor binding but are necessary for conformational changes needed for membrane fusion. A variant of this mechanism would be the capability of NAbs to bind to proteins essential for host cell receptor binding, but NAbs are bound to distal epitopes of fusogenic proteins (internalized), preventing complete fusion. The above mechanisms can be classified as inhibition of the entry of the virus into host cells; other mechanisms may provide post-binding inhibition. Some viruses require internalization and a pH decrease to trigger conformational changes and to perform viral membrane fusion.

(4)The fourth mechanism of neutralization can occur once the virus are inside endosomes; the junction of the antibodies to viral surface proteins inhibits the necessary changes for the fusion of the viral membrane, causing neutralization. This last mechanism could target enveloped and naked virus particles, and it is a post-internalization neutralization.

Take “Interaction of SARS-CoV-2 with its receptors and neutralization mechanisms” as an example (Figure 2). S1 contains the receptor-binding domain (RBD) and directly binds to ACE2 to gain entry into host cells. There are four neutralizing mechanisms2: (1) NAbs bound to the receptor-binding protein (S) and block its interaction with ACE2; (2) the virion establishes contact between its binding protein and the receptor on the cell surface, and NAbs block subsequent steps, such as binding to a coreceptor; (3) the virion is about to fuse with the cell membrane, but NAbs are bound to proteins that are not essential for cell receptor binding but exert conformational changes that do not allow virus internalization with the cell membrane; (4) NAbs prevent the virion from merging its envelope with the vesicular membrane (endosome) and begin viral replication, and the binding of the antibody to the virus inhibits the conformational changes necessary for membrane fusion.

Figure 2. Interaction of SARS-CoV-2 with its receptors and neutralization mechanisms2. (A) S1 contains the receptor-binding domain (RBD) and directly binds to ACE2 to gain entry into host cells. (B) Neutralizing mechanisms. Abbreviations: ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane serine protease 2.

Reference

1.Morales-Nunez, J.J., et al., Overview of Neutralizing Antibodies and Their Potential in COVID-19. Vaccines (Basel), 2021. 9(12).

FDA approved neutralizing antibodies (NAb) and our products

1. SARS-CoV-2 neutralizing antibodies (NAb)

SARS-CoV-2, the novel coronavirus responsible for the ongoing COVID-19 pandemic, has been spreading rampantly. The global scientific community has responded rapidly to understand immune correlates of protection to develop vaccines and immunotherapeutic against the virus. The RBD of spike plays a critical role in the very first step of the virus life cycle. The neutralizing antibodies (nAbs) that target the receptor binding domain (RBD) of viral spike (S) glycoprotein3.

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NA
SARS-CoV-2 Spike
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SARS-CoV-2Spike RBD
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SARS-CoV-2 Spike RBD
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Etesevimab
NA
SARS-CoV-2 Spike RBD
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Imdevimab
NA
SARS-CoV-2 Spike RBD
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NA
SARS-CoV-2 Spike RBD
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NA
SARS-CoV-2 Spike RBD
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NA
SARS-CoV-2 Spike
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NA
SARS-CoV-2 Spike RBD
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Beludavimab
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SARS-CoV-2 Spike RBD
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NA
SARS-CoV-2 Spike RBD
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Pre-Made Rimteravimab biosimilar, Whole Mab: Anti-SARS-CoV-2 Spike RBD therapeutic antibody
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NA
SARS-CoV-2 Spike RBD
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2. Human Immunodeficiency Virus (HIV) neutralizing antibodies (NAb)

The glycoprotein (gp) 120 subunit is an important part of the envelope spikes that decorate the surface of HIV-1 and a major target for neutralizing antibodies.

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Suvizumab
HIV-1 gp120
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HIV-1 gp120 CD4bs
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3. Hepatitis B virus (HBV) neutralizing antibodies (NAb)

Hepatitis B virus (HBV) surface antigen (HBsAg) is considered to be the most important target for the diagnosis and immune prophylaxis of HBV infection. HBsAg-specific monoclonal antibodies (MAbs) are extensively used for studying the complex structure of the HBsAg, mapping the neutralizing epitopes and development of HBV diagnostic tests.

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HBV (hepatitis B virus) [Hepatitis B virus]
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4. Rabies virus neutralizing antibodies (NAb)

Rabies virus is the causative agent of the rabies. The Rabies Virus Spike Glycoproteins are the important protein responsible for the virus entry and the major target of neutralizing antibodies. GeneMedi offers the Rabies Virus Spike Glycoprotein G, Rabies Virus Surface Glycoprotein 4 (gp4) Epitope 1, Rabies Virus Strain ERA GP Ectodomain Epitope G-II, Rabies Virus Spike Glycoprotein G, Rabies Virus Strain ERA GP Ectodomain Epitope G-III, RV Antigenic Site III, RV Antigenic Site III-specific monoclonal antibodies (MAbs) for therapeutic application and development of Rabies virus diagnostic tests.

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5. Respiratory syncytial virus (RSV) neutralizing antibodies (NAb)

Respiratory syncytial virus (RSV) enters into the host cells through the type I fusion (F) glycoprotein. Neutralizing monoclonal antibodies, such as Suptavumab, Palivizumab, Nirsevimab, Motavizumab, Gontivimab, and felvizumab target the major antigenic sites on the RSV F glycoprotein and neutralize the entry process.

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6. Zaire Ebola virus neutralizing antibodies (NAb)

Zaire Ebola virus belongs to the family Filoviridae, which are highly lethal and it outbreaks since emerging in 1967, including a sustained epidemic in West Africa from 2013 to 2015. Zaire Ebolavirus (EBOV) glycoprotein (GP) is now the key target of antibodies. GP is composed of ectodomain GP1 and a trans-membrane fusion domain GP2. GP1 and GP2 helps the virus to enter host cell through attachment, uptake, and fusion. GeneMedi offers the monoclonal antibodies (MAbs) against Zaire Ebolavirus GP, and Zaire Ebolavirus GP1 for therapeutic application and development of diagnostic tests.

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7. Influenza virus neutralizing antibodies (NAb)

Influenza is a transmissible acute respiratory disease caused by the influenza virus. The glycoprotein, hemagglutinin (HA) of influenza virus plays an important role during the viral infection. It helps the virus to bind the cell surface receptors, and transfer the genetic materials into the host cytoplasm through fusion. The neutralizing antibodies against the haemagglutinin (HA) offer the protection against influenza virus infection. GeneMedi offers the monoclonal antibodies (MAbs) against Influenza A HA, Influenza B Virus and Influenza A HA2 for therapeutic application and development of diagnostic tests.

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8. Human cytomegalovirus (HCMV) neutralizing antibodies (NAb)

Human cytomegalovirus (HCMV) causes life-threatening illness in immunosuppressed patients. HCMV envelope proteins viz. glycoprotein B (gB), gH, gL, gO and UL128/UL130/UL131A are essential for the fusion of virus with the host plasma membranes to enter into the host cell. The gB protein is the direct mediator of cell fusion and it requires gH/gL/gO protein complex for activation. HCMV gB or gH/gL proteins provoke HCMV neutralizing antibodies to prevent the entry of virus into both fibroblasts and epithelial cells. GeneMedi offers the monoclonal antibodies (MAbs) against envelope glycoprotein H (gH) and envelope glycoprotein B (gB) for therapeutic application and development of human cytomegalovirus diagnostic tests.

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Pre-Made Sevirumab Biosimilar, Whole Mab: Anti-Hcmv (Human Cytomegalovirus) Envelope Glycoprotein H (Gh) [Human Betaherpesvirus 5] therapeutic antibody
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9. Human endogenous retroviral envelope protein HERV-W-Env neutralizing antibodies (NAb)

Temelimab (formerly called GNbAC1) is an immunoglobulin (Ig) G4 monoclonal antibody that targets the human endogenous retroviral envelope protein HERV-W-Env, shown to be associated with the pathogenesis of certain autoimmune disorders such as multiple sclerosis (MS) and type 1 diabetes mellitus (T1D). By neutralizing HERV-W-Env, temelimab could act as a disease-modifying therapy for these disorders. Hence, GeneMedi offers the monoclonal antibodies against MRSV envelope protein for therapeutic application and development of diagnostic tests.

10. Pseudomonas aeruginosa infections neutralizing antibodies (NAb)

Pseudomonas aeruginosa is a main source of health-care related infections, including pneumonia and infections associated with urinary tract, wounds, burns, and the bloodstream.  P. aeruginosa invades the eukaryotic host cells through the type III secretion system (T3SS). This T3SS helps the bacteria to translocate effector proteins directly into host cells. Mammalian immune systems produce neutralizing antibodies (Ab) against T3SS proteins during infection to inhibit the Pseudomonas aeruginosa infections. Hence, GeneMedi offers the different kind of antibodies such as pegylated, Fab, and Bispecific mAb against the PcrV type III secretion system of Pseudomonas aeruginosa.

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Pre-Made Rivabazumab biosimilar, Fab: Anti-PcrV type III secretion system therapeutic antibody
Rivabazumab
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11. Measles virus (MeV) neutralizing antibodies (NAb)

Measles virus (MeV) causes an extremely transmissible respiratory disease and it has also been used as an oncolytic platform. MeV enter into the cells through the cellular receptors such as SLAM (signaling lymphocyte-activating molecule) and PVRL4 (poliovirus receptor-like 4) (nectin-4). Hence, the antibodies against PVRL4 could block measles virus infections. GeneMedi offers monoclonal antibodies against the PVRL4 to prevent the MeV infection.

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12. Anthrax protective antigen (PA) neutralizing antibodies (NAb)

Bacillus anthracis is the causative agent of anthrax. The protective antigen is an important element of the anthrax toxin. It helps bacteria to transfer the enzymatic components into the host cell, through the formation spanning pore on the membrane. antibiotics are effective at the early stages of anthrax, but antibiotics are no longer effective with the accumulation of anthrax toxin. Therefore, the anti-toxin antibody is the most promising approach to treat the anthrax. GeneMedi offers the monoclonal antibodies (MAbs) against anthrax protective antigen.

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Pre-Made Raxibacumab Biosimilar, Whole Mab: Anti-Anthrax Protective Antigen (Pa) [Bacillus Anthracis] therapeutic antibody
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13. Shiga toxins (Stxs) neutralizing antibodies (NAb)

Shiga toxins (Stxs) are cytotoxic proteins secreted by Shigella dysenteriae 1 and some serogroups of Escherichia coli (called Stx1 in E. coli). Shiga toxin producing E. coli (STEC) are foodborne pathogens that may colonize and damage the human colon to access to the bloodstream and damage the organs such as kidney and brain. Presently, there are no specific protective treatment against Stx intoxication, and it based on the rehydration therapy, and dialysis. The neutralization of Stx using neutralizing antibody is one of the promising approaches. Therefore, GeneMedi offers monoclonal antibody against Shiga Toxin Type 1 and Type 2.

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Pre-Made Urtoxazumab Biosimilar, Whole Mab: Anti-E.Coli Shiga-Like Toxin 2 B Subunit therapeutic antibody
urtoxazumab
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14. Toxin A neutralizing antibodies (NAb)

Clostridium difficile continues to be one of the most prevalent hospital-acquired bacterial infections in the developed world. Alternative approaches under investigation to combat the anaerobic Gram-positive bacteria include fecal transplantation therapy, vaccines, and antibody-based immunotherapies. Inhibitory antibodies that recognize the primary C. difficilevirulence factors, toxin A and toxin B, are the most popular passive immunotherapies under investigation.

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15. Others neutralizing antibodies (NAb)

Monoclonal antibodies (mAbs) against bacterial infections are more effective way to treat the antibiotic resistant strains. The antibacterial mAbs have several advantages such as reducing the antibiotic toxicity, treatment time and disease complications. there are numerous mAb products are under development for a range of infectious diseases. Currently, GeneMedi offers mAbs against gram negative bacteria, Staphylococcus epidermidis, Staphylococcus aureus and so on.

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View the Knowledge base of neutralizing antibody (NAb):

    – The Landscape of Neutralizing antibodies (NAb): Production, Mechanisms of Action (MOA), FDA approved-antibodies, and Functional assay
    – Introduction of neutralizing antibody (NAb)
    – How to produce neutralizing antibody (NAb) (production)
    – How neutralizing antibody (NAb) work (mechanisms of action, MOA)
    – FDA approved neutralizing antibodies (NAb) and our products
    – SARS-CoV-2 neutralizing antibodies (NAb)
    – Human Immunodeficiency Virus (HIV) neutralizing antibodies (NAb)
    – Hepatitis B virus (HBV) neutralizing antibodies (NAb)
    – Rabies virus neutralizing antibodies (NAb)
    – Respiratory syncytial virus (RSV) neutralizing antibodies (NAb)
    – Zaire Ebola virus neutralizing antibodies (NAb)
    – Influenza virus neutralizing antibodies (NAb)
    – Human cytomegalovirus (HCMV) neutralizing antibodies (NAb)
    – Human endogenous retroviral envelope protein HERV-W-Env neutralizing antibodies (NAb)
    – Pseudomonas aeruginosa infections neutralizing antibodies (NAb)
    – Measles virus (MeV) neutralizing antibodies (NAb)
    – Anthrax protective antigen (PA) neutralizing antibodies (NAb)
    – Shiga toxins (Stxs) neutralizing antibodies (NAb)
    – Toxin A neutralizing antibodies (NAb)
    – FDA approved neutralizing antibodies (NAb)
    – Functional assay for neutralizing antibodies (NAb) discovery–Pseudotype virus (psedovirus, PSV) based and Neutralization Assays