# US 2010/0166773 A1 · Therapeutic monoclonal antibodies that neutralize botulinum neurotoxins

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- Number: US 2010/0166773 A1
- Document ID: US20100166773A1
- Status: Published application
- Kind: A1
- Application number: 12/528,601
- Filed: 2008-03-21
- Published: 2010-07-01
- Earliest claimed: 2007-06-05
- Assignees: The Regents of the University of California
- Inventors: James D. Marks; Isin N. Geren; Maria Consuelo Garcia; Jianlong Lou; Ali Razai
- Web page: https://patentgrep.com/patent/US20100166773A1

## CPC

- C07K 16/40: against enzymes
- A61P 31/04: Antibacterial agents
- C07K 16/1282: Clostridium (G)
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- 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
- 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

## Abstract

This invention provides antibodies that specifically bind to and typically neutralize botulinum neurotoxins (e.g., BoNT/A, BoNT/B, BoNT/E, etc.) and the epitopes bound by those antibodies. The antibodies and derivatives thereof and/or other antibodies that specifically bind to the neutralizing epitopes provided herein can be used to neutralize botulinum neurotoxin and are therefore also useful in the treatment of botulism.

## Claims

### Claim at position 1

1-31. (canceled)

### Claim 32

An isolated antibody that specifically binds an epitope of a Botulinum neurotoxin (BoNT) that is specifically bound by an antibody expressed by clone 2B18.1, 1B18, B6, B6.1, 3E2, 3E6, 3E6.1, 4E16.1, 4E16, 4E17, 4E17.1, B12, B12.1, B12.2, 6A12, B1.1, B8, B8.1, 4B17, 1B22, 2A10, 3E1, 3E3, 3E4, 3E4.1, 3E5, 3E6, 3E6.1, 4E11, or 4E12.

### Claim 33 (depends on 32)

The isolated antibody of claim 32, wherein said antibody comprises:
a) a VH CDR1 comprising an amino acid sequence of SEQ ID NO:369;
b) a VH CDR2 comprising an amino acid sequence of SEQ ID NO:371; and
c) a VH CDR3 comprising an amino acid sequence of SEQ ID NO:373.

### Claim 34 (depends on 33)

The isolated antibody of claim 33, wherein said antibody comprises:
a) a VL CDR1 comprising an amino acid sequence of SEQ ID NO:495;
b) a VL CDR2 comprising an amino acid sequence of SEQ ID NO:497; and
c) a VL CDR3 comprising an amino acid sequence of SEQ ID NO:499

### Claim 35 (depends on 34)

The isolated antibody of claim 34, wherein said antibody comprises:
a) a heavy chain comprising an amino acid sequence of SEQ ID NO:18;
b) a light chain comprising an amino acid sequence of SEQ ID NO:35.

### Claim 36 (depends on 32)

The isolated antibody of claim 32, wherein said antibody comprises:
a) a VH CDR1 comprising an amino acid sequence of SEQ ID NO:348;
b) a VH CDR2 comprising an amino acid sequence of SEQ ID NO:350; and
c) a VH CDR3 comprising an amino acid sequence of SEQ ID NO:352.

### Claim 37 (depends on 36)

The isolated antibody of claim 36, wherein said antibody comprises:
a) a VL CDR1 comprising an amino acid sequence of SEQ ID NO:474;
b) a VL CDR2 comprising an amino acid sequence of SEQ ID NO:476; and
c) a VL CDR3 comprising an amino acid sequence of SEQ ID NO:478.

### Claim 38 (depends on 37)

The isolated antibody of claim 37, wherein said antibody comprises:
a) a heavy chain comprising an amino acid sequence of SEQ ID NO:15;
b) a light chain comprising an amino acid sequence of SEQ ID NO:32.

### Claim 39 (depends on 32)

The isolated antibody of claim 32, wherein said antibody comprises:
a) a VH CDR1 comprising an amino acid sequence of SEQ ID NO:299;
b) a VH CDR2 comprising an amino acid sequence of SEQ ID NO:301; and
c) a VH CDR3 comprising an amino acid sequence of SEQ ID NO:303.

### Claim 40 (depends on 39)

The isolated antibody of claim 39, wherein said antibody comprises:
a) a VL CDR1 comprising an amino acid sequence of SEQ ID NO:425;
b) a VL CDR2 comprising an amino acid sequence of SEQ ID NO:427; and
c) a VL CDR3 comprising an amino acid sequence of SEQ ID NO:429.

### Claim 41 (depends on 40)

The isolated antibody of claim 40, wherein said antibody comprises:
a) a heavy chain comprising an amino acid sequence of SEQ ID NO:8;
b) a light chain comprising an amino acid sequence of SEQ ID NO:25.

### Claim 42 (depends on 32)

The isolated antibody of claim 32, wherein said antibody comprises:
a) a VH CDR1 comprising an amino acid sequence of SEQ ID NO:83;
b) a VH CDR2 comprising an amino acid sequence of SEQ ID NO:85; and
c) a VH CDR3 comprising an amino acid sequence of SEQ ID NO:87.

### Claim 43 (depends on 42)

The isolated antibody of claim 42, wherein said antibody comprises:
a) a VL CDR1 comprising an amino acid sequence of SEQ ID NO:187;
b) a VL CDR2 comprising an amino acid sequence of SEQ ID NO:189; and
c) a VL CDR3 comprising an amino acid sequence of SEQ ID NO:191.

### Claim 44 (depends on 43)

The isolated antibody of claim 43, wherein said antibody comprises:
a) a heavy chain comprising an amino acid sequence of SEQ ID NO:40;
b) a light chain comprising an amino acid sequence of SEQ ID NO:55.

### Claim 45 (depends on 32)

The isolated antibody of claim 32, wherein said antibody comprises:
a) a VH CDR1 comprising an amino acid sequence of SEQ ID NO:118;
b) a VH CDR2 comprising an amino acid sequence of SEQ ID NO:120; and
c) a VH CDR3 comprising an amino acid sequence of SEQ ID NO:122.

### Claim 46 (depends on 45)

The isolated antibody of claim 45, wherein said antibody comprises:
a) a VL CDR1 comprising an amino acid sequence of SEQ ID NO:229;
b) a VL CDR2 comprising an amino acid sequence of SEQ ID NO:231; and
c) a VL CDR3 comprising an amino acid sequence of SEQ ID NO:233.

### Claim 47 (depends on 46)

The isolated antibody of claim 46, wherein said antibody comprises:
a) a heavy chain comprising an amino acid sequence of SEQ ID NO:46;
b) a light chain comprising an amino acid sequence of SEQ ID NO:61.

### Claim 48 (depends on 32)

The isolated antibody of claim 32, wherein said antibody comprises:
a) a VH CDR1 comprising an amino acid sequence of SEQ ID NO:145;
b) a VH CDR2 comprising an amino acid sequence of SEQ ID NO:147; and
c) a VH CDR3 comprising an amino acid sequence of SEQ ID NO:149.

### Claim 49 (depends on 48)

The isolated antibody of claim 48, wherein said antibody comprises:
a) a VL CDR1 comprising an amino acid sequence of SEQ ID NO:257;
b) a VL CDR2 comprising an amino acid sequence of SEQ ID NO:259; and
c) a VL CDR3 comprising an amino acid sequence of SEQ ID NO:261.

### Claim 50 (depends on 49)

The isolated antibody of claim 49, wherein said antibody comprises:
a) a heavy chain comprising an amino acid sequence of SEQ ID NO:50;
b) a light chain comprising an amino acid sequence of SEQ ID NO:65.

### Claim 51 (depends on 32)

The isolated antibody of claim 32, wherein said antibody comprises:
a) a VH CDR1 comprising an amino acid sequence of SEQ ID NO:159;
b) a VH CDR2 comprising an amino acid sequence of SEQ ID NO:161; and
c) a VH CDR3 comprising an amino acid sequence of SEQ ID NO:163.

### Claim 52 (depends on 51)

The isolated antibody of claim 51, wherein said antibody comprises:
a) a VL CDR1 comprising an amino acid sequence of SEQ ID NO:271;
b) a VL CDR2 comprising an amino acid sequence of SEQ ID NO:273; and
c) a VL CDR3 comprising an amino acid sequence of SEQ ID NO:275.

### Claim 53 (depends on 52)

The isolated antibody of claim 52, wherein said antibody comprises:
a) a heavy chain comprising an amino acid sequence of SEQ ID NO52;
b) a light chain comprising an amino acid sequence of SEQ ID NO:67.

### Claim 54 (depends on 32)

The antibody of claim 32, wherein said antibody is a single chain Fv (scFv), IgG, Fab, (Fab′)2, or (scFv′)2.

### Claim 55 (depends on 32)

A composition comprising two different antibodies for a BoNT serotype, wherein a first antibody of said two different antibodies is an antibody in accordance to claim 32.

### Claim 56 (depends on 55)

The composition of claim 55, wherein a second antibody of said two different antibodies is an antibody expressed by a clone selected from the group consisting of B12.1, 2B18.1, B6.1, 3E2, 3E6.1, 4E16.1, or 4E17.1

### Claim 57 (depends on 32)

A method of neutralizing botulinum neurotoxin in a mammal, said method comprising administering to said mammal two different antibodies for a BoNT serotype, wherein a first antibody of said two different antibodies is an antibody in accordance to claim 32.

### Claim 58 (depends on 55)

A kit for neutralizing a Botulinum neurotoxin, said kit comprising:
a composition according to claim 55; and
instructional materials teaching the use of said composition to bind to a Botulinum neurotoxin.