Claims
[Claim 1] An anti-human Tie2 antibody or an antigen-binding fragment thereof,
comprising four heavy chain variable regions and four light chain variable regions, wherein
the heavy chain variable region comprises CDR1 consisting of the amino acid sequence of the amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of the amino acid numbers 50 to 66 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of the amino acid numbers 99 to 111 of SEQ ID NO: 2;
the light chain variable region comprises CDR1 consisting of the amino acid sequence of the amino acid numbers 24 to 39 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of the amino acid numbers 55 to 61 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of the amino acid numbers 94 to 102 of SEQ ID NO: 4; and
the one heavy chain variable region and the one light chain variable region constitute one antigen-binding site, and the antibody or the antigen-binding fragment comprises four antigen-binding sites.
[Claim 2] The anti-human Tie2 antibody or the antigen-binding fragment thereof
according to claim 1, selected from (1) or (2) below:
(1) an anti-human Tie2 antibody or an antigen-binding fragment thereof,
comprising four heavy chain variable regions and four light chain variable regions, in
which
the heavy chain variable region consists of the amino acid sequence of the amino acid numbers 1 to 122 of SEQ ID NO: 2,
the light chain variable region consists of the amino acid sequence of the amino acid numbers 1 to 113 of SEQ ID NO: 4, and
the one heavy chain variable region and the one light chain variable region constitute one antigen-binding site, and the antibody or the antigen-binding fragment comprises four antigen-binding sites; and
(2) an anti-human Tie2 antibody or an antigen-binding fragment thereof which is
m antibody or an antigen-binding fragment thereof derived from posttranslational
■nodification of the anti-human Tie2 antibody or the antigen-binding fragment thereof of
;o.
Claim 3] The anti-human Tie2 antibody according to claim 1, wherein
the antibody comprises two heavy chains and four light chains;

each heavy chain comprises two structures consisting of a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of the amino acid numbers 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of the amino acid numbers 50 to 66 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of the amino acid numbers 99 to 111 of SEQ ID NO: 2 and a CH1 region, a CH2 region, and a CH3 region, and the carboxy terminus (C terminus) of one of the structures is linked to the amino terminus (N terminus) of the other structure through a linker; and
each light chain comprises a light chain variable region comprising CDR1 consisting of the amino acid sequence of the amino acid numbers 24 to 39 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of the amino acid numbers 55 to 61 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of the amino acid numbers 94 to 102 of SEQ ID NO: 4, and a light chain constant region.
[Claim 4] The anti-human Tie2 antibody according to claim 3, selected from (1) or
(2) below:
(1) an anti-human Tie2 antibody comprising two heavy chains and four light
chains, in which
each heavy chain comprises two structures consisting of a heavy chain variable region consisting of the amino acid sequence of the amino acid numbers 1 to 122 of SEQ ID NO: 2 and a CHI region, a CH2 region, and a CH3 region, and the C terminus of one o: the structures is linked to the N terminus of the other structure through a linker; and
each light chain comprises a light chain variable region consisting of the amino acid sequence of the amino acid numbers 1 to 113 of SEQ ID NO: 4, and a light chain constant region; and
(2) an anti-human Tie2 antibody, which is an antibody derived from
posttranslational modification of the anti-human Tie2 antibody of (1).
[Claim 5] The anti-human Tie2 antibody according to claim 4, wherein
the anti-human Tie2 antibody comprises two heavy chains and four light chains; each heavy chain comprises two structures consisting of a heavy chain variable region consisting of the amino acid sequence of the amino acid numbers 1 to 122 of SEQ ID NO: 2 and a CHI region, a CH2 region, and a CH3 region, and the C terminus of one o] the structures is linked to the N terminus of the other structure through a linker; and
each light chain comprises a light chain variable region consisting of the amino acid sequence of the amino acid numbers 1 to 113 of SEQ ID NO: 4, and a light chain constant region.
[Claim 6] An anti-human Tie2 antibody which is an antibody derived from

posttranslational modification of the anti-human Tie2 antibody according to claim 5.
[Claim 7] The anti-human Tie2 antibody according to claim 6, wherein the
posttranslational modification is pyroglutamylation at the N terminus of the heavy chain variable region and/or deletion of lysine at the C terminus of the heavy chain.
[Claim 8] The anti-human Tie2 antibody according to claim 4, comprising two
heavy chains consisting of the amino acid sequence shown by SEQ ID NO: 2 and four light chains consisting of the amino acid sequence shown by SEQ ID NO: 4.
[Claim 9] The anti-human Tie2 antibody according to claim 4, comprising two
heavy chains consisting of the amino acid sequence shown by SEQ ID NO: 6 and four light chains consisting of the amino acid sequence shown by SEQ ID NO: 4.
[Claim 10] The anti-human Tie2 antibody according to claim 4, comprising two
heavy chains consisting of the amino acid sequence shown by SEQ ID NO: 10 and four light chains consisting of the amino acid sequence shown by SEQ ID NO: 4.
[Claim 11 ] An anti-human Tie2 antibody which is an antibody derived from
posttranslational modification of the anti-human Tie2 antibody according to any one of claims 8 to 10.
[Claim 12] The anti-human Tie2 antibody according to claim 11, wherein the
posttranslational modification is pyroglutamylation at the N terminus of the heavy chain variable region and/or deletion of lysine at the C terminus of the heavy chain.
[Claim 13] The anti-human Tie2 antibody according to claim 11, comprising two
heavy chains consisting of the amino acid sequence of the amino acid numbers 1 to 678 of SEQ ID NO: 2 and four light chains consisting of the amino acid sequence shown by SEQ ID NO: 4.
[Claim 14] A tetravalent anti-human Tie2 antibody or an antigen-binding fragment
thereof, binding to the same human Tie2 epitope as the anti-human Tie2 antibody according to claim 8 or 13.
[Claim 15] The tetravalent anti-human Tie2 antibody or the antigen-binding fragment
thereof according to Claim 14, wherein the human Tie2 epitope is the human Tie2 epitope containing the amino acid of the amino acid numbers 192, 195 and 197 of Accession No.

NP000450.2.
[Claim 16] A polynucleotide comprising a base sequence encoding the heavy chain
variable region of the anti-human Tie2 antibody or the antigen-binding fragment thereof according to claim 2.
[Claim 17] A polynucleotide comprising a base sequence encoding the light chain
variable region of the anti-human Tie2 antibody or the antigen-binding fragment thereof according to claim 2.
[Claim 18] A polynucleotide comprising a base sequence encoding the heavy chain of
the anti-human Tie2 antibody according to any one of claims 8 to 10.
[Claim 19] A polynucleotide comprising a base sequence encoding the light chain of
the anti-human Tie2 antibody according to any one of claims 8 to 10.
[Claim 20] An expression vector comprising the polynucleotide according to claim 16
and/or 17.
[Claim 21] An expression vector comprising the polynucleotide according to claim 18
and/or 19.
[Claim 22] A host cell transformed with the expression vector according to claim 20,
which is selected from the group consisting of (a) to (d) below:
(a) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain variable region of the anti-human
Tie2 antibody or the antigen-binding fragment thereof according to claim 2, and a
polynucleotide comprising a base sequence encoding the light chain variable region of the
antibody or an antigen-binding fragment thereof;
(b) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain variable region of the anti-human
Tie2 antibody or the antigen-biding fragment thereof according to claim 2 and an
expression vector comprising a polynucleotide comprising a base sequence encoding the
light chain variable region of the antibody or an antigen-binding fragment thereof;
(c) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain variable region of the anti-human
Tie2 antibody or the antigen-binding fragment thereof according to claim 2; and
(d) a host cell transformed with an expression vector comprising a polynucleotide

comprising a base sequence encoding the light chain variable region of the anti-human Tie2 antibody or the antigen-binding fragment thereof according to claim 2.
[Claim 23] A host cell transformed with the expression vector according to claim 21,
selected from the group consisting of (a) to (d) below:
(a) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain of the anti-human Tie2 antibody
according to any one of claims 8 to 10 and a polynucleotide comprising a base sequence
encoding the light chain of the antibody;
(b) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain of the anti-human Tie2 antibody
according to any one of claims 8 to 10 and an expression vector comprising a
polynucleotide comprising a base sequence encoding the light chain of the antibody;
(c) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain of the anti-human Tie2 antibody
according to any one of claims 8 to 10; and
(d) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the light chain of the anti-human Tie2 antibody
according to any one of claims 8 to 10.
[Claim 24] A method for producing an anti-human Tie2 antibody or an antigen-
binding fragment thereof, comprising culturing host cell(s) selected from the group consisting of (a) to (c) below to express a tetravalent anti-human Tie2 antibody or an antigen-binding fragment thereof:
(a) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain variable region of the anti-human
Tie2 antibody or the antigen-binding fragment thereof according to claim 2 and a
polynucleotide comprising a base sequence encoding the light chain variable region of the
antibody or the antigen-binding fragment thereof;
(b) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain variable region of the anti-human
Tie2 antibody or the antigen-binding fragment thereof according to claim 2 and an
expression vector comprising a polynucleotide comprising a base sequence encoding the
light chain variable region of the antibody or the antigen-binding fragment thereof; and
(c) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain variable region of the anti-human
Tie2 antibody or the antigen-binding fragment thereof according to claim 2 and a host cell
transformed with an expression vector comprising a polynucleotide comprising a base

sequence encoding the light chain variable region of the antibody or the antigen-binding fragment thereof.
[Claim 25] A method for producing an anti-human Tie2 antibody, comprising
culturing host cell(s) selected from the group consisting of (a) to (c) below to express an anti-human Tie2 antibody:
(a) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain of the anti-human Tie2 antibody
according to any one of claims 8 to 10 and a polynucleotide comprising a base sequence
encoding the light chain of the antibody;
(b) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain of the anti-human Tie2 antibody
according to any one of claims 8 to 10 and an expression vector comprising a
polynucleotide comprising a base sequence encoding the light chain of the antibody; and
(c) a host cell transformed with an expression vector comprising a polynucleotide
comprising a base sequence encoding the heavy chain of the anti-human Tie2 antibody
according to any one of claims 8 to 10 and a host cell transformed with an expression
vector comprising a polynucleotide comprising a base sequence encoding the light chain of
the anti-human Tie2 antibody.
[Claim 26] An anti-human Tie2 antibody or an antigen-binding fragment thereof,
produced by the method according to claim 24.
[Claim 27] An anti-human Tie2 antibody produced by the method according to claim
25.
[Claim 28] A pharmaceutical composition comprising the anti-human Tie2 antibody
or the antigen-binding fragment thereof according to any one of claims 1 to 13, 26, and 27, and a pharmaceutical^ acceptable excipient.
[Claim 29] A pharmaceutical composition comprising the anti-human Tie2 antibody
according to claim 5, the anti-human Tie2 antibody according to claim 6, and a pharmaceutically acceptable excipient.
[Claim 30] A pharmaceutical composition comprising the anti-human Tie2 antibody
according to claim 8, the anti-human Tie2 antibody according to claim 13, and a phannaceutically acceptable excipient.

[Claim 31] The pharmaceutical composition according to any one of claims 28 to 30,
which is a pharmaceutical composition for preventing or treating diabetic macular edema, diabetic retinopathy, or critical limb ischemia.
[Claim 32] A method for preventing or treating diabetic macular edema, diabetic
retinopathy, or critical limb ischemia, comprising administering a therapeutically effective amount of the anti-human Tie2 antibody or the antigen-binding fragment thereof according to any one of claims 1 to 13, 26, and 27.
[Claim 33] The anti-human Tie2 antibody or the antigen-binding fragment thereof
according to any one of claims 1 to 13,26, and 27, for preventing or treating diabetic macular edema, diabetic retinopathy, or critical limb ischemia.
[Claim 34] Use of the anti-human Tie2 antibody or the antigen-binding fragment
thereof according to any one of claims 1 to 13,26, and 27 for manufacture of a pharmaceutical composition for preventing or treating diabetic macular edema, diabetic retinopathy, or critical limb ischemia.