Invented by Lisa A. Purcell, Jonathan Viau, William Olson, Regeneron Pharmaceuticals Inc
Human antibodies to influenza hemagglutinin are a promising alternative to traditional flu vaccines. These antibodies are produced by the human immune system in response to exposure to the flu virus. They target the hemagglutinin protein on the surface of the virus, which is responsible for binding to host cells and causing infection.
The market for human antibodies to influenza hemagglutinin is driven by several factors. Firstly, the high prevalence of influenza and the need for effective treatments and prevention strategies have led to increased demand for these antibodies. Secondly, the limitations of traditional flu vaccines, such as their low efficacy against certain strains and the need for annual updates, have created a need for alternative approaches.
Several companies are currently developing human antibodies to influenza hemagglutinin. These include Sanofi, Regeneron, and Eli Lilly, among others. These companies are using various approaches to develop their products, including monoclonal antibodies, polyclonal antibodies, and antibody cocktails.
Monoclonal antibodies are produced by cloning a single type of antibody-producing cell, resulting in a highly specific and consistent product. Polyclonal antibodies, on the other hand, are produced by injecting animals with the flu virus and harvesting their antibodies. Antibody cocktails are a combination of multiple monoclonal antibodies that target different parts of the hemagglutinin protein.
The market for human antibodies to influenza hemagglutinin is expected to grow significantly in the coming years. According to a report by Grand View Research, the global market for influenza therapeutics is expected to reach $7.9 billion by 2025, driven by the increasing prevalence of the flu and the need for effective treatments.
In conclusion, the market for human antibodies to influenza hemagglutinin is a promising area of research and development. These antibodies have the potential to provide a more effective and long-lasting alternative to traditional flu vaccines. With several companies investing in this area, the market is expected to grow rapidly in the coming years, providing new treatment options for patients and healthcare providers alike.
The Regeneron Pharmaceuticals Inc invention works as follows
The present invention provides monoclonal antibody fragments or antigen-binding pieces thereof that bind to influenza hemagglutinin protein. Pharmaceutical compositions containing the antibodies are also provided and the methods of using them. The invention provides a method of treating or preventing influenza by using antibodies that inhibit or neutralize influenza virus activity. The invention may allow for the use of one or more antibodies that bind the influenza HA to prevent viral attachment and/or entry into host cell. The invention’s antibodies can be used therapeutically or prophylactically. They may also be combined with other antiviral agents or vaccines.
Background for Human antibodies to influenza hemagglutinin
Influenza, which is highly contagious, has a long history marked by epidemics, pandemics and resurgences. Despite annual vaccinations, influenza infections cause substantial morbidity or mortality.
Influenza viruses are classified as A, B, and C. Additionally, subtypes of influenza A viruses can also be classified based on allelic variations in antigenic areas of two genes that encode surface glycoproteins (hemagglutinin and neuraminidase) which are essential for viral attachment and entry to the host cell.
Hemagglutinin, a trimeric glycoprotein, contains two structural domains. The globular head domain consists of the receptor binding site (which is subject to frequent antigenic shift) and the stem area (more conserved among different strains of influenza virus). The precursor to the HA protein (HA0) is synthesized. Two subunits (HA1 & HA2) are produced by proteolytic processing. These two units associate to form the stem/globular-head structure. Attachment of virus to cells is achieved by the HA1 peptide. The stem-like structure of the HA2 peptide mediates the fusion between viral and cell membranes in endosomes. This allows for the release of the ribonucleoprotein compound into the cytoplasm.
Currently, there is a total of eighteen subtypes that are defined by the hemagglutinin protein (H1-H18). There are two types of HAs: H1, H2, H5, and H6. Group 2 includes H3, HC4, HS7, HL10, and H15 subtypes. The H1 and H2 subtypes are in Group 1. While H5 and H6 make up the H5 and H6 subtypes, H9 and H11 and H16 and H17 subtypes. H4 and H7 make up group 2.
Antigenic drift is a process that results in new strains of the same type of virus. This refers to mutations in the NA or HA molecules which create new epitopes. This means that every year a new vaccine must also be made against emerging viruses. It is a costly and inefficient process. Although technological advancements have made it possible to produce better influenza antigen(s) to be used in vaccine compositions, there is still a need for additional protection to deal with emerging strains or subtypes of influenza.
A vaccine composition that contains the antigen of concern (e.g. Although the idea of a vaccine composition containing the antigen of interest (e.g., HA or NA) is generally considered to be a good strategy to generate broad neutralizing antibodies in patients is not always a good one. A vaccine composition containing the antigen of concern may not be effective in all patients. This is the case for the elderly, immunocompromised patients, and the very young. It may be beneficial to provide a vaccine composition that contains broadly neutralizing antibodies. These broadening antibodies may target epitopes commonly found in a variety strains of Group 1 or Group 2 subtypes.
To date, there have been few successes in finding antibodies that broadly neutralize and inhibit influenza viruses. Okuno et al. Immunization of mice with influenza A/Okuda/57 was performed (H2N2). The antibody C179 was isolated and bound to a conserved conformational epitope within HA2. This antibody neutralized the subtypes H1, H1 and H5 influenza A viruses in vitro as well as in vivo (Okuno, et al. (1993) J. Virol. 67(5):2552-2558). Throsby et al. Throsby et. al. identified 13 monoclonal antibodies made from human B cells which had broad activity against subtypes of Group 1 (Throsby and co. (2008), PLOS One 3(2):e3942 Sui et al. Sui et al. identified F10, a monoclonal antibody that binds H5 and other Group 1 virus (Sui, (2009), Nat. Struct. Mol. Biol. 16(3):265-273).
However, despite decades of research in this field, only a handful of antibodies are currently in clinical studies to assess their effectiveness in neutralizing influenza viruses of different subtypes. (See, for instance, antibodies under development Crucell Holland (US2012/0276115), US2014/0065156 and U.S. Pat. No. 8,470,327, US2014/0120113, EP2731967, U.S. Pat. No. No. Nos. 8,444,986, 8,574,581, 8,637,644, 8,637,645, 8,383,121, 8,540,996, 8,574,830, 8,540,995); HUMABS Biosciences/Institute for Research in Biomedicine (U.S. Pat. No. No. There is still an artful need to find new antibodies that can neutralize multiple influenza A virus subtypes, so they can be used to treat or prevent the infection.
The present invention contains antibodies and antigen binding fragments that bind influenza Hemagglutinin (HA). The present invention provides antibodies that can be used to inhibit or neutralize influenza HA activity. The antibodies can be used to prevent the virus from entering host cells and/or block attachment of the virus to host cells. The antibodies may also inhibit cell-to-cell transmission. The antibodies may be useful in treating, preventing or alleviating at least one sign of an influenza virus infection in some cases. The antibodies can be used prophylactically, therapeutically, or even as a treatment for a person who is at high risk of contracting influenza virus infection. Some embodiments allow compositions that contain at least one antibody to be administered to patients who are not able to receive a vaccine or who have a medical condition that may make it difficult to administer vaccines. Compositions that contain at least one antibody may be given to hospitalized patients, nursing home residents, or other high-risk patients in the event of an influenza epidemic. Compositions containing at most one antibody may be given to patients as a first-line treatment in certain instances. This is for the case when a predicted yearly vaccine fails or if there is a pandemic of an antigenic strain.
The invention’s antibodies can be full-length (for instance, an IgG1 antibody or an IgG4 antibody), or they may contain only an antigen binding portion (for instance, a F(ab)Fab). )2 or the scFv segment), and can be modified to alter functionality (Reddy et.al., 2000; J. Immunol. 164:1925-1933). The antibodies can be bispecific in certain embodiments.
In a first embodiment, the invention provides isolated monoclonal monoclonal antibodies and antigen-binding fragments of the same that bind to the influenza HA.
The present invention is an isolated recombinant antigen or antigen-binding segment of an antibody that binds specifically to influenza A hemagglutinin, (HA) in one embodiment. The antibody has at least two or more the following characteristics:
(a), is a monoclonal human antibody;
(b) Binds to influenza HA with an intra-bio-layer interferometer-based biosensor (OctetHTX assay);
(d), demonstrates the neutralization of group one influenza A viruses H1N1, H5N1, and H9N1, with an IC50 less than 130 nM.
(e), demonstrates complement mediated lysis infected cells by influenza virus with an EC50 less than 66 nM.
(f), demonstrates protection as demonstrated by higher survival rates in an animal model for influenza virus infection, administered before or after the virus challenge; or
(g), where the antigen-binding fragment or antibody comprises three heavy chains complementarity determining (CDRs) (HCDR1,HCDR2 or HCDR3) within any of the heavy chain variable regions (HCVRs) sequences in Table 1 and Table 12. Three light chain CDRs, LCDR1, LCDR2 or LCDR3, are contained within any of the light chain variable regions (LCVRs) sequences in Table 1 and Table 12.
In one embodiment, the invention’s antibody shows a dissociative life in monkeys about 1.5 times greater than the Control I antibody mAb. In mice, it has a dissociative life in mice about 2x greater than the Control I antibody mAb.
In some embodiments, an antibody according to the invention shows an increase in protection compared to oseltamivir when administered 48 hours or 72 hours after infection to a mammal with influenza virus.
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