Neutralizing molecules to influenza viruses

Inactive Publication Date: 2012-05-24
I2 PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036]In another aspect, the present invention provides engineered antibodies or binding molecules with reduced oxidative potential. In one embodiment, the engineered antibody or binding molecule with reduced oxidative potential is an antibody binding to a hemagglutinin of an influenza A virus having the ability to infect humans neutralizing at least one isolate of an influenza A virus having one or more methi

Problems solved by technology

It causes mild to severe illness, and at times can lead to death.
Although influenza vaccines are available, because a vaccine against one influenza virus type or subtyp

Method used

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  • Neutralizing molecules to influenza viruses
  • Neutralizing molecules to influenza viruses
  • Neutralizing molecules to influenza viruses

Examples

Experimental program
Comparison scheme
Effect test

example 1

Antibody Libraries from Influenza Donors

[0217]Donors selected for inclusion into the Comprehensive Influenza Library were confirmed to have had a previous influenza infection, been approximately 5 years old at the time of a the 1957 H2N2 or 1968 H3N2 influenza pandemics, and to be in current good health. Serology on a panel of H1N1 A / NewCaledonia / 20 / 99, H3N2 A / Panama / 2007 / 99 and H5N1 A / Vietnam / 1203 / 2004 virus or hemagglutinin proteins was performed to confirm the presence of antibodies to the hemagglutinin proteins.

[0218]First 5-20 ml of bone marrow was collected from each donor meeting the selection criteria and mixed with RNA later (Applied Biosystems) per the manufacturer's instructions to preserve the integrity of cellular RNA. RNA was isolated using a TRI-BD reagent protocol (Sigma-Aldrich).

[0219]Heavy chain and light chain repertoires were recovered from each donor derived RNA by RT-PCR using random primed cDNA template for heavy chains, oligo dT primed cDNA template for light...

example 2

Preparation of Neutralizing Antibodies

[0223]Antibodies derived from human bone marrow phage display antibody libraries (see Example 1) were converted and tested as mammalian expressed immunoglobulins, as previously described (see also, Kashyap A K et al., Proc Natl Acad Sci USA. 2008 Apr. 22; 105(16):5986-91). The heavy chains fell into two sequence classes:

(SEQ ID NO: 1)QVQLQESGGGLVQPGESLRLSCVGSGSSFGESTLSYYAVSWVRQAPGKGLEWLSIINAGGGDIDYADSVEGRFTISRDNSKETLYLQMTNLRVEDTGVYYCAKHMSMQQVVSAGWERADLVGDAFDVWGQGTMVTVSS(SEQ ID NO: 2)QVQLQQSGPRLVKPSQTLSLTCAISGDSVSGDSGTWNWIRQSPSRGLEWLGRTYYRSKWYNDYAESVKSRIVIKADTSKNEFSLQLNSVTPEDTAIYYCARAGVKIFGLIVGALDNWGRGTLVTVSS

[0224]The underlined hypervariable CDR regions are shown for the heavy chains as follows.

(SEQ ID NO: 7)GESTLSYYAVS(SEQ ID NO: 8)WLSIINAGGGDID(SEQ ID NO: 9)AKHMSMQQVVSAGWERADLVGDAFD(SEQ ID NO: 10)SGDSGTWN(SEQ ID NO: 11)WLGRTYYRSKWYND(SEQ ID NO: 12)ARAGVKIFGLIVGALD

[0225]The heavy chain described by SEQ ID NO:1 was found to pair with one lambda ...

example 3

Generating Universal Influenza Vaccines

[0233]The goal of vaccine design against heterogeneous pathogens is to identify and design effective and broadly protective antigens. In the case of influenza, considerable historical efforts have gone into the empirical testing of conserved linear sequences and regions with little success. A plausible reason for these failures is a lack of knowledge that focused responses against antigenic test articles are actual bona fide productive sites for neutralization of an antigen on the pathogen in the setting of an actual infection. For influenza one would be expect to find these bona fide solutions within the repertoires of survivors of an influenza infection. In our case we have demonstrated that certain antibodies amongst a large collection of antibodies are capable of neutralizing multiple subtypes of Influenza. Some of these antibodies neutralize influenza through classical inhibition of hemagglutination. Collectively, we expect that the design...

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Abstract

The present invention concerns methods and means for identifying, producing, and engineering neutralizing antibodies against influenza A viruses, and to the neutralizing antibodies produced. In particular, the invention concerns neutralizing antibodies against various influenza A virus subtypes, and methods and means for making such antibodies.

Description

FIELD OF THE INVENTION[0001]The present invention concerns methods and means for identifying, producing, and engineering neutralizing molecules against influenza A viruses, and to the neutralizing molecules produced. The invention further concerns various uses of the molecules produced, including the design and production of vaccines utilizing the binding sites of the neutralizing molecules of the present invention on the target influenza A virus.BACKGROUND OF THE INVENTION[0002]The flu is a contagious respiratory illness caused by influenza viruses. It causes mild to severe illness, and at times can lead to death. Annually, in the United States, influenza is contracted by 5-20% of the population, hospitalizing about 200,000, and causing the deaths of about 36,000.[0003]Influenza viruses spread in respiratory droplets caused by coughing and sneezing, which are usually transmitted from person to person. Immunity to influenza surface antigens, particularly hemagglutinin, reduces the l...

Claims

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Application Information

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IPC IPC(8): A61K39/42C07K19/00A61P37/04A61K39/145A61P31/16C07K16/00C07K16/10
CPCC07K2317/21A61K2039/505C07K2317/76C07K2317/56C07K16/1018C07K2317/565A61P31/16A61P37/04A61K9/0043A61K9/0053A61K39/145A61K2039/5252A61K2039/5254A61K2039/54A61K2039/543A61K2039/55C07K2317/33C07K2317/567C07K2317/92C12N7/00C12N2760/16134
Inventor HOROWITZ, LAWRENCEBHATT, RAMESHKASHYAP, ARUN
Owner I2 PHARMA INC
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