Anti-AXL antibody

Patent metadata

Field	Value
Publication number	US-9340615-B2
Application number	US-201013320317-A
Country	US
Kind code	B2
Filing date	May 14, 2010
Priority date	May 15, 2009
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

An objective of the present invention is to decrease the immunogenicity of mouse-derived anti-AXL antibodies in humans by humanizing them. The present invention provides antibodies that can bind to a specific region in Anexelekto (AXL) and humanized antibodies that are produced based on such antibodies. The anti-AXL antibodies of the present invention have high antitumor activity, and are useful as agents for decreasing the AXL expression level, antitumor agents, and diagnostic agents for cancer.

First claim

The invention claimed is:

1. An antibody that recognizes fibronectin type III domain 1 (FND1) of anexelekto (AXL), which is an antibody of any one of (1) to (3) below:
(1) an antibody comprising a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 33 to 37, a CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 38 to 48, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49; and a light chain variable region comprising a CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 84 to 89, a CDR2 comprising the amino acid sequence of SEQ ID NO: 90, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 91; wherein the amino acid sequence of the heavy chain variable region comprises at least one of the following amino acid residues:
(a) the amino acid residue at position 31 by Kabat numbering in the heavy chain variable region is aspartic acid, glutamic acid, lysine, or arginine;
(b) the amino acid residue at position 40 by Kabat numbering in the heavy chain variable region is proline;
(c) the amino acid residue at position 41 by Kabat numbering in the heavy chain variable region is arginine;
(d) the amino acid residue at position 43 by Kabat numbering in the heavy chain variable region is glutamine or glutamic acid;
(e) the amino acid residue at position 44 by Kabat numbering in the heavy chain variable region is arginine;
(f) the amino acid residue at position 48 by Kabat numbering in the heavy chain variable region is isoleucine;
(g) the amino acid residue at position 61 by Kabat numbering in the heavy chain variable region is glutamic acid, lysine, or arginine;
(h) the amino acid residue at position 62 by Kabat numbering in the heavy chain variable region is glutamic acid;
(i) the amino acid residue at position 64 by Kabat numbering in the heavy chain variable region is glutamine;
(j) the amino acid residue at position 65 by Kabat numbering in the heavy chain variable region is aspartic acid; and
(k) the amino acid residue at position 105 by Kabat numbering in the heavy chain variable region is glutamic acid or arginine;

(2) an antibody comprising a heavy chain variable region of SEQ ID NO: 2 (H0); and
(3) an antibody comprising a light chain variable region of SEQ ID NO: 65 (L0).

2. A humanized antibody that recognizes FND1 domain of AXL, which is an antibody of any one of (1) to (5) below:
(1) an antibody comprising a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 33 to 37, a CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 38 to 48, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49, as well as an FR1 comprising the amino acid sequence of SEQ ID NO: 51, an FR2 comprising the amino acid sequence of SEQ ID NO: 53, an FR3 comprising the amino acid sequence of SEQ ID NO: 109 or 58, and an FR4 comprising the amino acid sequence of SEQ ID NO: 61;
(2) an antibody comprising the heavy chain variable region of SEQ ID NO: 2 (H0);
(3) an antibody comprising a light chain variable region comprising a CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 84 to 89, a CDR2 comprising the amino acid sequence SEQ ID NO: 90, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 91, as well as an FR1 comprising the amino acid sequence of SEQ ID NO: 93, an FR2 comprising the amino acid sequence of SEQ ID NO: 96, an FR3 comprising the amino acid sequence of SEQ ID NO: 101, and an FR4 comprising the amino acid sequence of SEQ ID NO: 103;
(4) an antibody comprising the light chain variable region of SEQ ID NO: 65; and
(5) an antibody comprising the heavy chain variable region of (1) and the light chain variable region of (3).

3. The antibody of claim 1 , wherein the antibody comprises the heavy chain variable region of (1) with a glycine at position 94 by Kabat numbering.

4. The antibody of claim 1 , wherein the antibody comprises the light chain variable region of (1), and the amino acid sequence of the light chain variable region of (1) comprises at least one of the following amino acid residues:
(1) the amino acid residue at position 17 by Kabat numbering in the light chain variable region is arginine;
(2) the amino acid residue at position 24 by Kabat numbering in the light chain variable region is glutamine;
(3) the amino acid residue at position 27 by Kabat numbering in the light chain variable region is glutamic acid or arginine;
(4) the amino acid residue at position 29 by Kabat numbering in the light chain variable region is alanine;
(5) the amino acid residue at position 42 by Kabat numbering in the light chain variable region is glutamic acid or glutamine;
(6) the amino acid residue at position 45 by Kabat numbering in the light chain variable region is lysine;
(7) the amino acid residue at position 100 by Kabat numbering in the light chain variable region is arginine;
(8) the amino acid residue at position 104 by Kabat numbering in the light chain variable region is valine; and
(9) the amino acid residue at position 107 by Kabat numbering in the light chain variable region is glutamic acid.

5. The antibody of claim 1 , comprising at least any one of the following heavy chain variable regions:
(1) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(2) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 34, a CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(3) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 35, a CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(4) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 39, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(5) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 40, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(6) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(7) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 42, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(8) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 43, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(9) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 44, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(10) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 45, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(11) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 49;
(12) a heavy chain v

Assignees

• Maeda Atsuhiko
• Miyamoto Hajime
• Kuramochi Taichi
• Matsuo Atsushi
• Igawa Tomoyuki
• Shiraiwa Hirotake
• Tsunoda Hiroyuki
• Tachibana Tatsuhiko
• Chugai Pharmaceutical Co Ltd

Inventors

• Maeda Atsuhiko
• Miyamoto Hajime
• Kuramochi Taichi
• Matsuo Atsushi
• Igawa Tomoyuki
• Shiraiwa Hirotake
• Tsunoda Hiroyuki
• Tachibana Tatsuhiko

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/303

  Liver or Pancreas · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title