Caninized rat antibodies to canine interleukin-31 receptor alpha
The present invention provides caninized rat antibodies to canine IL-31 receptor alpha that have a high binding affinity for canine IL-31 receptor alpha, and that can block the binding of canine IL-31 to canine IL-31 receptor alpha. The present invention further provides the use of the antibodies for the treatment of atopic dermatitis in dogs.
1 . An isolated mammalian antibody or antigen binding fragment thereof that binds canine interleukin-31 receptor alpha (canine IL-31RA) comprising a set of six complementary determining regions (CDRs), three of said six CDRs are heavy chain CDRs (HCDRs): CDR heavy 1 (HCDR1), CDR heavy 2 (HCDR2), and CDR heavy 3 (HCDR3), and three of said six CDRs are light chain CDRs (LCDRs): CDR light 1 (LCDR1), CDR light 2 (LCDR2), and CDR light 3 (LCDR3); and
wherein the set of six CDRs are selected from the group of sets consisting of (a)-(f);
wherein for set (a):
HCDR1 comprises the amino acid sequence of SEQ ID NO: 31;
HCDR2 comprises the amino acid sequence of SEQ ID NO: 32;
HCDR3 comprises the amino acid sequence of SEQ ID NO: 33;
LCDR1 comprises the amino acid sequence of SEQ ID NO: 34;
LCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and
LCDR3 comprises the amino acid sequence of SEQ ID NO: 36;
wherein for set (b):
HCDR1 comprises the amino acid sequence of SEQ ID NO: 31;
HCDR2 comprises the amino acid sequence of SEQ ID NO: 32;
HCDR3 comprises the amino acid sequence of SEQ ID NO: 33;
LCDR1 comprises the amino acid sequence of SEQ ID NO: 34;
LCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and
LCDR3 comprises the amino acid sequence of SEQ ID NO: 36;
wherein for set (c):
HCDR1 comprises the amino acid sequence of SEQ ID NO: 31;
HCDR2 comprises the amino acid sequence of SEQ ID NO: 32;
HCDR3 comprises the amino acid sequence of SEQ ID NO: 33;
LCDR1 comprises the amino acid sequence of SEQ ID NO: 38;
LCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and
LCDR3 comprises the amino acid sequence of SEQ ID NO: 36;
wherein for set (d):
HCDR1 comprises the amino acid sequence of SEQ ID NO: 31;
HCDR2 comprises the amino acid sequence of SEQ ID NO: 32;
HCDR3 comprises the amino acid sequence of SEQ ID NO: 43;
LCDR1 comprises the amino acid sequence of SEQ ID NO: 44;
LCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and
LCDR3 comprises the amino acid sequence of SEQ ID NO: 45;
wherein for set (e):
HCDR1 comprises the amino acid sequence of SEQ ID NO: 31;
HCDR2 comprises the amino acid sequence of SEQ ID NO: 32;
HCDR3 comprises the amino acid sequence of SEQ ID NO: 39;
LCDR1 comprises the amino acid sequence of SEQ ID NO: 40;
LCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and
LCDR3 comprises the amino acid sequence of SEQ ID NO: 36; and
wherein for set (f):
HCDR1 comprises the amino acid sequence of SEQ ID NO: 31;
HCDR2 comprises the amino acid sequence of SEQ ID NO: 41;
HCDR3 comprises the amino acid sequence of SEQ ID NO: 39;
LCDR1 comprises the amino acid sequence of SEQ ID NO: 42;
LCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and
LCDR3 comprises the amino acid sequence of SEQ ID NO: 36.
2 . The isolated mammalian antibody or antigen binding fragment thereof of claim 1 , wherein when bound to canine IL-31RA the antibody binds to an epitope comprised by the amino acid sequence selected from the group consisting of SEQ ID NO: 104, SEQ ID NO: 105, and both SEQ ID NO: 104 and SEQ ID NO: 105.
3 . The isolated mammalian antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof binds canine IL-31RA and blocks the binding of canine IL-31RA to canine interleukin-31.
4 . The isolated mammalian antibody or antigen binding fragment thereof of claim 3 , that is a caninized antibody or a caninized antigen binding fragment thereof.
5 . The caninized antibody or antigen binding fragment thereof of claim 4 , comprising a hinge region that comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, and SEQ ID NO: 82.
6 . The caninized antibody or antigen binding fragment thereof of claim 4 , comprising a heavy chain comprising a modified canine IgG-B (IgG-Bm) comprising the amino acid sequence of SEQ ID NO: 78.
7 . The caninized antibody or antigen binding fragment thereof of claim 4 , wherein the caninized IL-31RA antibody comprises a light chain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 83, SEQ ID NO: 86, and SEQ ID NO: 87; and a heavy chain comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 84 and SEQ ID NO: 85.
8 . The caninized antibody or antigen binding fragment thereof of claim 7 , wherein the caninized IL-31RA antibody comprises:
a light chain comprising the amino acid sequence of SEQ ID NO: 83 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 84; or
a light chain comprising the amino acid sequence of SEQ ID NO: 83 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 85; or
a light chain comprising the amino acid sequence of SEQ ID NO: 86 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 84; or
a light chain comprising the amino acid sequence of SEQ ID NO: 86 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 85; or
a light chain comprising the amino acid sequence of SEQ ID NO: 87 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 84; or
a light chain comprising the amino acid sequence of SEQ ID NO: 87 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 85.
9 . An isolated nucleic acid that encodes a chain of the caninized antibody of claim 4 , selected from the group consisting of a heavy chain of the caninized antibody or antigen binding fragment thereof, a light chain of the caninized antibody or antigen binding fragment thereof, or both the heavy chain of the caninized antibody or antigen binding fragment thereof and the light chain of the caninized antibody or antigen binding fragment thereof.
10 . An expression vector comprising the isolated nucleic acid of claim 9 .
11 . A host cell comprising the expression vector of claim 10 .
12 . A pharmaceutical composition comprising the caninized antibody or antigen binding fragment thereof of claim 4 , and a pharmaceutically acceptable carrier or diluent.
13 . A method of aiding in the blocking the pruritus associated with atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 12 .