# US 8,192,927 B2 · Human bind molecules capable of neutralizing influenza virus h5n1 and uses thereof

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- Number: US 8,192,927 B2
- Document ID: US8192927B2
- Status: Granted
- Kind: B2
- Application number: 12/310,812
- Filed: 2007-09-06
- Published: 2009-12-17
- Granted: 2012-06-05
- Earliest claimed: 2006-09-07
- Assignees: Crucell Holland B.V.
- Inventors: Edward Norbert Van Den Brink; Cornelis Adriaan De Kruif; Mark Throsby
- Web page: https://patentgrep.com/patent/US8192927B2

## CPC

- C07K 16/108: Orthomyxoviridae (F), e.g. influenza virus
- A61P 31/16: for influenza or rhinoviruses
- G01N 33/56983: {Viruses}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C12N 2760/00011: Details
- C12N 2760/00061: Methods of inactivation or attenuation
- C12N 2760/16011: Orthomyxoviridae
- C12N 2760/16061: Methods of inactivation or attenuation
- C12N 2760/16111: Influenzavirus A, i.e. influenza A virus
- G01N 2333/11: Orthomyxoviridae, e.g. influenza virus
- G01N 2469/10: Detection of antigens from microorganism in sample from host
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention relates to binding molecules such as human monoclonal antibodies that bind to influenza virus H5N1 and have neutralizing activity against influenza virus H5N1. The disclosure provides nucleic acid molecules encoding the antibodies, their sequences and compositions comprising the antibodies and methods of identifying or producing the antibodies. The antibodies can be used in the diagnosis, prophylaxis and/or treatment of an influenza virus H5N1 infection. In a preferred embodiment, the antibodies provide cross-subtype protection in vivo, such that infections with H5, H2, H6, H9 and H1-based influenza subtypes can be prevented and/or treated.

## Claims

### Claim 1

An isolated binding molecule able to recognize and bind an epitope in an HA2 subunit of an influenza hemagglutinin protein (HA), wherein said binding molecule is human and has neutralizing activity against an influenza virus of H5 subtype, and wherein said binding molecule comprises a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, and a CDR3 region of SEQ ID NO:3, and framework regions of amino acids encoded by germline gene VH1-69.

### Claim 2 (depends on 1)

The binding molecule according to claim 1, wherein said binding molecule also has neutralizing activity against an influenza virus comprising HA of the H1 subtype.

### Claim 3

An isolated binding molecule able to bind an HA2 subunit of an influenza HA selected from the group consisting of:
a) binding molecule comprising a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, a and CDR3 region of SEQ ID NO:3; and a light chain comprising a CDR1 region of SEQ ID NO:4, a CDR2 region of SEQ ID NO:5, and a CDR3 region of SEQ ID NO:6,
b) a binding molecule comprising a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, a CDR3 region of SEQ ID NO:3; and a light chain comprising a CDR1 region of SEQ ID NO:7, a CDR2 region of SEQ ID NO:8, and a CDR3 region of SEQ ID NO:9,
c) a binding molecule comprising a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, a CDR3 region of SEQ ID NO:3; and a light chain comprising a CDR1 region of SEQ ID NO:10, a CDR2 region of SEQ ID NO:11, and a CDR3 region of SEQ ID NO:12,
d) a binding molecule comprising a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, a CDR3 region of SEQ ID NO:3; and a light chain comprising a CDR1 region of SEQ ID NO:13, a CDR2 region of SEQ ID NO:14, and a CDR3 region of SEQ ID NO:15,
e) a binding molecule comprising a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, a CDR3 region of SEQ ID NO:3; and a light chain comprising a CDR1 region of SEQ ID NO:33, a CDR2 region of SEQ ID NO:34, and a CDR3 region of SEQ ID NO:35, and
f) a binding molecule comprising a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, a CDR3 region of SEQ ID NO:3; and a light chain comprising a CDR1 region of SEQ ID NO:36, a CDR2 region of SEQ ID NO:37, and a CDR3 region of SEQ ID NO:38.

### Claim 4 (depends on 3)

The binding molecule according to claim 3, wherein the binding molecule comprises a heavy chain comprising a CDR1 region of SEQ ID NO:1, a CDR2 region of SEQ ID NO:2, a CDR3 region of SEQ ID NO:3; and a light chain comprising a CDR1 region of SEQ ID NO:13, a CDR2 region of SEQ ID NO:14, and a CDR3 region of SEQ ID NO:15.

### Claim 5 (depends on 1)

The binding molecule according to claim 1, wherein said binding molecule is a human monoclonal antibody.

### Claim 6 (depends on 1)

A method of producing the isolated binding molecule of claim 1 comprising:
expressing an isolated nucleic acid molecule encoding said binding molecule in a suitable host cell so as to produce the binding molecule.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising:
the binding molecule according to claim 1, and
a pharmaceutically acceptable excipient.

### Claim 8 (depends on 2)

The binding molecule of claim 2, wherein the binding molecule also has neutralizing activity against an influenza virus of subtype H2, H6, and/or H9.

### Claim 9 (depends on 5)

A method of diagnosing an influenza infection of the type wherein a monoclonal antibody binds an influenza virus in a sample from the subject, wherein the improvement comprises:
utilizing the monoclonal antibody of claim 5 in the method.

### Claim 10 (depends on 5)

A method of treating an influenza infection of the type wherein a monoclonal antibody that binds an influenza virus is administered to a subject, wherein the improvement comprises:
utilizing the monoclonal antibody of claim 5 in the method.

### Claim 11

An isolated binding molecule able to recognize and bind an epitope in an HA2 subunit of an influenza hemagglutinin protein, wherein the binding molecule comprises a heavy chain comprising a CDR1 region of SEQ ID NO: 1, a CDR2 region of SEQ ID NO: 2, and a CDR3 region of SEQ ID NO: 3, and a light chain comprising a CDR1 region of SEQ ID NO: 13, a CDR2 region of SEQ ID NO: 14, and a CDR3 region of SEQ ID NO: 15; wherein the heavy chain and the light chain have a framework encoded by germline gene VH1-69; and wherein the binding molecule has neutralizing activity against an influenza virus of H5 subtype.