Bispecific caninized antibodies and bispecific binding partners for treating atopic dermatitis
The present invention provides compositions for treating canine atopic dermatitis that comprise a fusion protein that binds canine IL-22, a caninized anti-pruritic antibody, and a caninized anti-inflammatory antibody. The present invention further provides compositions that comprise a bispecific binding partners that comprises that fusion protein and a caninized anti-pruritic antibody or a caninized anti-inflammatory antibody, or alternatively, a bispecific antibody comprising a caninized anti-pruritic antibody and a caninized anti-inflammatory antibody, which in addition comprises a fusion protein that binds canine IL-22.
1 . A composition for treating atopic dermatitis in canines, wherein the composition comprises a bispecific binding partner comprising a heterodimer of (i) a fusion protein that binds canine IL-22 and (ii) a monomer of a caninized anti-pruritic antibody comprising a light chain and a heavy chain;
wherein the fusion protein that binds canine IL-22 is selected from the group consisting of a canine IL-22RA1-Fc fusion protein and a canine IL-22RA2-Fc fusion protein,
wherein the caninized anti-pruritic antibody is a caninized interleukin-31 (IL-31) antibody or a caninized interleukin-31 receptor alpha (IL-3IRA) antibody;
wherein (a) the light chain of the caninized IL-31 antibody comprises a light chain variable region (VL) having an amino acid sequence of a VL of a light chain having the amino acid sequence of SEQ ID NO:11; and (b) the heavy chain of the caninized IL-31 antibody comprises a heavy chain variable region (VH) having an amino acid sequence of a VH of a heavy chain having the amino acid sequence of SEQ ID NO:15; or
wherein (a) the light chain of the caninized IL-31 antibody comprises a VL having an amino acid sequence of a VL of a light chain having the amino acid sequence of SEQ ID NO:12; and (b) the heavy chain of the caninized IL-31 antibody comprises a VH having an amino acid sequence of a VH of a heavy chain having the amino acid sequence of SEQ ID NO:18; or
wherein (a) the light chain of the caninized IL-3IRA antibody comprises a VL having an amino acid sequence of a VL of a light chain having the amino acid sequence of SEQ ID NO:52; and (b) the heavy chain of the caninized IL-3IRA antibody comprises a VH having an amino acid sequence of a VH of a heavy chain having the amino acid sequence of SEQ ID NO:53.
2 . The composition of claim 1 , wherein the fusion protein that binds canine IL-22 is the canine IL-22RA1-Fc fusion protein that comprises the amino acid sequence of SEQ ID NO:16.
3 . The composition of claim 1 , wherein the fusion protein that binds canine IL-22 is the IL-22RA2-canine Fc fusion protein that comprises the amino acid sequence of SEQ ID NO:17.
4 . The composition of claim 1 , wherein the caninized anti-pruritic antibody is the caninized IL-31 antibody; and wherein the light chain comprises the amino acid sequence of SEQ ID NO:12 and the heavy chain comprises the amino acid sequence of SEQ ID NO:18; or wherein the light chain comprises the amino acid sequence of SEQ ID NO:11 and the heavy chain comprises the amino acid sequence of SEQ ID NO:15.
5 . The composition of claim 1 , wherein the light chain of the caninized IL-31 antibody has been modified to comprise a heavy chain constant region 1 (CH1) from the heavy chain of the caninized IL-31 antibody in place of a constant light domain (CL); and wherein the heavy chain of the caninized IL-31 antibody has been modified to comprise the constant light domain (CL) from the light chain of the caninized IL-31 antibody in place of the CH1.
6 . The composition of claim 1 , wherein the composition further comprises a caninized anti-inflammatory antibody that is a caninized IL-4R alpha antibody, wherein the caninized IL-4R alpha antibody comprises a heavy chain variable region (VH) comprising a VH complementary determining region 1 (VH CDR1), a VH CDR2, a VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2 and a VL CDR3; and wherein
the VH CDR1 comprises the amino acid sequence of SEQ ID NO:40;
the VH CDR2 comprises the amino acid sequence of SEQ ID NO:42;
the VH CDR3 comprises the amino acid sequence of SEQ ID NO:44;
the VL CDR1 comprises the amino acid sequence of SEQ ID NO:46;
the VL CDR2 comprises the amino acid sequence of SEQ ID NO:48; and
the VL CDR3 comprises the amino acid sequence of SEQ ID NO:50.
7 . The composition of claim 6 , wherein the caninized IL-4R alpha antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:4 and a heavy chain comprising the amino acid sequence of SEQ ID NO:5.
8 . The composition of claim 1 , further comprising one or more additional components selected from the group consisting of a Janus kinase (JAK) inhibitor, a spleen tyrosine kinase (SYK) inhibitor, or an antagonist to a chemoattractant receptor-homologous molecule expressed on TH2 cells.
9 . The composition of claim 8 , wherein the JAK inhibitor is
(a) a compound of the formula of:
where R 1 is C 1-4 alkyl optionally substituted with hydroxy, or a pharmaceutically acceptable salt thereof; or
(b) a compound having the structure of:
or a pharmaceutically acceptable salt thereof.
10 . A method of treating atopic dermatitis comprising administering the composition of claim 1 , to a canine that has atopic dermatitis.
11 . The composition of claim 1 , wherein the caninized anti-pruritic antibody is the caninized IL-3IRA antibody, and wherein the light chain comprises the amino acid sequence of SEQ ID NO:52 and the heavy chain comprises the amino acid sequence of SEQ ID NO:53.
12 . The composition of claim 1 , wherein the fusion protein that binds canine IL-22 and the monomer of the caninized anti-pruritic antibody comprise a first and a second modified canine Fc regions, respectively; and wherein the first and the second modified canine Fc regions form a heterodimer with each other.
13 . The composition of claim 12 , wherein relative to the sequence of canine IgG-B Fc region (SEQ ID NO:14), the first modified canine Fc region comprises substitutions T132W and S120C, and the second modified canine Fc regions comprises substitutions T132S, L134A, Y175V, and Y115C; or the first modified canine Fc region comprises substitutions T132S, L134A, Y175V, and Y115C, and the second modified canine Fc regions comprises substitutions T132W and S120C.
14 . A composition for treating atopic dermatitis in canines comprising a bispecific antibody that comprises a monomer of a caninized anti-pruritic antibody comprising a heavy chain and a light chain and a monomer of a caninized anti-inflammatory antibody comprising a heavy chain and a light chain;
wherein the caninized anti-pruritic antibody is a caninized interleukin-31 receptor alpha (IL-3IRA) antibody and the caninized anti-inflammatory antibody is a caninized interleukin-4 receptor alpha (IL-4R alpha) antibody;
wherein (a) the light chain of the caninized IL-4R alpha antibody comprises a light chain variable region (VL) comprising a VL Complementarity-Determining Region 1 (CDR1), a VL CDR2, and a VL CDR3 and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3: wherein the VL CDR1 comprises the sequence of SEQ ID NO: 34, the VL CDR2 comprises the sequence of SEQ ID NO:36, the VL CDR3 comprises the sequence of SEQ ID NO:38, the VH CDR1 comprises the sequence of SEQ ID NO:28, the VH CDR2 comprises the sequence of SEQ ID NO:30, and the VH CDR3 comprises the sequence of SEQ ID NO:32; and
wherein (a) the light chain of the caninized IL-3IRA antibody comprises a VL having an amino acid sequence of a VL of a light chain having the amino acid sequence of SEQ ID NO:52 and (b) the heavy chain of the caninized IL-31RA antibody comprises a VH having an amino acid sequence of a VH of a heavy chain having the amino acid sequence of SEQ ID NO:53.
15 . The composition of claim 14 , wherein the light chain of the caninized IL-4R alpha antibody has been modified to comprise a heavy chain constant region 1 (CH1) from the heavy chain of the caninized IL-4R alpha antibody in place of a constant light domain (CL); and wherein the heavy chain of the caninized IL-4R alpha antibody has been modified to comprise the constant light domain (CL) from the light chain of the caninized IL-4R alpha antibody in place of the CH1.
16 . The composition of claim 14 , wherein the light chain of the caninized IL-3IRA antibody comprises the amino acid sequence of SEQ ID NO:52, and the heavy chain of the caninized IL-3IRA antibody comprises the amino acid sequence of SEQ ID NO:53.
17 . The composition of claim 14 , further comprising a canine IL-22RA1-Fc fusion protein that comprises the amino acid sequence of SEQ ID NO:2.
18 . The composition of claim 14 , further comprising a canine IL-22RA2-Fc fusion protein that comprises the amino acid sequence of SEQ ID NO:3.
19 . The composition of claim 14 , wherein the heavy chain of the caninized IL-4R alpha antibody and the heavy chain of the caninized IL-3IRA antibody further comprise a first and a second modified canine Fc regions, respectively; and wherein the first and the second modified canine Fc regions form a heterodimer with each other.