IP Library › Granted Patent US 8,540,987

Granted Patent B2

US 8,540,987 · App. 12/864,018 · Granted Sep 24, 2013

Composition for neutralizing botulinus toxin type-A, and human anti-botulinus toxin type-A antibody

Inventors: Masachika Azuma (Nagoya, JP); Motohide Takahashi (Musashimurayama, JP); Shunji Kozaki (Sakai, JP); Masafumi Mukamoto (Sakai, JP); Tomoko Kohda (Sakai, JP); Gene Kurosawa (Nagoya, JP); Yoshikazu Kurosawa (Nagoya, JP)

Assignees: Institute for Antibodies Co., Ltd.; Japan as Represented by Director-General of National Institute of Infectious Diseases; Osaka Prefecture University Public Corporation

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Quick Facts

Patent No.: US 8,540,987
App. No.: 12/864,018
Granted: Sep 24, 2013
Kind: B2

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Abstract

Provided herein is a means which is effective for botulism diseases and the prevention of the botulism diseases. Specifically provided is a plurality of human anti-botulinum toxin type-A antibodies having different epitopes from one another. Also specifically provided is a composition for neutralizing botulinum toxin type-A, which comprises a combination of two or more of the antibodies and which has a high neutralizing activity.

Claims (85)

1. A composition for neutralizing botulinum toxin type-A comprising:

a first human anti-botulinum toxin type-A antibody that recognizes an epitope which is recognized by an antibody having a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8;

a second human anti-botulinum toxin type-A antibody that recognizes an epitope which is recognized by an antibody having a VH comprising the amino acid sequence of SEQ ID NO: 36 and a VL comprising the amino acid sequence of SEQ ID NO: 40; and

a third human anti-botulinum toxin type-A antibody that recognizes an epitope which is recognized by an antibody having a VH comprising the amino acid sequence of SEQ ID NO: 44 and a VL comprising the amino acid sequence of SEQ ID NO: 48, or that recognizes an epitope which is recognized by an antibody having a VH comprising the amino acid sequence of SEQ ID NO: 52 and a VL comprising the amino acid sequence of SEQ ID NO: 56.

2. The composition for neutralizing botulinum toxin type-A according to claim 1 , wherein:

the first human anti-botulinum toxin type-A antibody is any one of antibodies selected from the group consisting of the following (1) to (3);

the second human anti-botulinum toxin type-A antibody is an antibody of the following (4) or (5); and

the third human anti-botulinum toxin type-A antibody is any one of antibodies selected from the group consisting of the following (6) to (8):

(1) an antibody having a heavy chain complementarity-determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 7;

(2) an antibody having a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15;

(3) an antibody having a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 23;

(4) an antibody having a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 26, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 27, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 29, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 30, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 31;

(5) an antibody having a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 34, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 35, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 37, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 39;

(6) an antibody having a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 41, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 42, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 43, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 45, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 47;

(7) an antibody having a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 49, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 50, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 51, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 53, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 54, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 55; and

(8) an antibody having a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 57, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 58, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 59; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 61, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 62, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 63.

3. The composition for neutralizing botulinum toxin type-A according to claim 2 , wherein:

the first human anti-botulinum toxin type-A antibody is any one of antibodies selected from the group consisting of the above-mentioned (1) to (3);

the second human anti-botulinum toxin type-A antibody is the above-mentioned antibody (4) or (5);

the third human anti-botulinum toxin type-A antibody is the above-mentioned antibody (6); and

the above-mentioned antibody (7) or (8) is further comprised as a fourth human anti-botulinum toxin type-A antibody.

4. The composition for neutralizing botulinum toxin type-A according to claim 2 , wherein:

the first human anti-botulinum toxin type-A antibody is the above-mentioned antibody (1);

the second human anti-botulinum toxin type-A antibody is the above-mentioned antibody (5); and

the third human anti-botulinum toxin type-A antibody is the above-mentioned antibody (6).

5. The composition for neutralizing botulinum toxin type-A according to claim 4 , wherein the above-mentioned antibody (7) is further comprised as a fourth human anti-botulinum toxin type-A antibody.

6. The composition for neutralizing botulinum toxin type-A according to claim 2 , wherein:

the first human anti-botulinum toxin type-A antibody is the above-mentioned antibody (1);

the second human anti-botulinum toxin type-A antibody is the above-mentioned antibody (5); and

the third human anti-botulinum toxin type-A antibody is the above-mentioned antibody (7).

7. The composition for neutralizing botulinum toxin type-A according to claim 6 , wherein the above-mentioned antibody (4) is further comprised as a fourth human anti-botulinum toxin type-A antibody.

8. The composition for neutralizing botulinum toxin type-A according to claim 2 , wherein:

the above-mentioned antibody (1) has a VH comprising the amino acid sequence of SEQ ID NO: 4 and a VL comprising the amino acid sequence of SEQ ID NO: 8;

the above-mentioned antibody (2) has a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 16;

the above-mentioned antibody (3) has a VH comprising the amino acid sequence of SEQ ID NO: 20 and a VL comprising the amino acid sequence of SEQ ID NO: 24;

the above-mentioned antibody (4) has a VH comprising the amino acid sequence of SEQ ID NO: 28 and a VL comprising the amino acid sequence of SEQ ID NO: 32;

the above-mentioned antibody (5) has a VH comprising the amino acid sequence of SEQ ID NO: 36 and a VL comprising the amino acid sequence of SEQ ID NO: 40;

the above-mentioned antibody (6) has a VH comprising the amino acid sequence of SEQ ID NO: 44 and a VL comprising the amino acid sequence of SEQ ID NO: 48;

the above-mentioned antibody (7) has a VH comprising the amino acid sequence of SEQ ID NO: 52 and a VL comprising the amino acid sequence of SEQ ID NO: 56; and

the above-mentioned antibody (8) has a VH comprising the amino acid sequence of SEQ ID NO: 60 and a VL comprising the amino acid sequence of SEQ ID NO: 64.

9. The composition for neutralizing botulinum toxin type-A according to claim 3 , wherein: