Humanized anti-IL-1R3 antibodies
The present disclosure relates to humanized antibodies that specifically bind to IL-1R3 or a fragment or derivative thereof or a polypeptide that contains at least a portion of said antibody that is sufficient to confer IL-1R3 binding specificity. Said antibodies inhibit IL-1R3 induced NFkB activity. They also inhibit IL-1alpha, IL-1beta, IL-33, and/or IL-36 stimulated NFkB activity. The disclosure further relates to use of said humanized antibody in the treatment of an IL-1R3 mediated disease such as cancer. The disclosure finally encompasses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody according to the invention. The pharmaceutical composition can be used in treating a IL-1R3 mediated disease such as cancer.
1. An antibody that specifically binds to IL-1R3, or an antibody fragment or an antibody derivative thereof, comprising:
a) a heavy chain variable region (VH) comprising the complementarity determining regions comprising CDR-H1, CDR-H2, and CDR-H3,
wherein the CDR-H1 region comprises an amino acid sequence set forth in SEQ ID NO: 79,
wherein the CDR-H2 region comprises an amino acid sequence set forth in SEQ ID NO: 96,
and wherein the CDR-H3 region comprises an amino acid sequence set forth in SEQ ID NO: 113; and
b) a light chain variable region (VL) comprising the complementarity determining regions comprising CDR-L1, CDR-L2, and CDR-L3,
wherein the CDR-L1 region comprises an amino acid sequence set forth in SEQ ID NO: 130,
wherein the CDR-L2 region comprises an amino acid sequence set forth in SEQ ID NO: 147, and
wherein the CDR-L3 region comprises an amino acid sequence set forth in SEQ ID NO: 175.
2. The antibody or antibody fragment or antibody derivative thereof of claim 1 , wherein the VH region comprises an amino acid sequence set forth in SEQ ID NO: 28, and the VL region comprises an amino acid sequence set forth in SEQ ID NO: 174.
3. The antibody, according to claim 1 , comprising a human IgG1 Fc region comprising at least amino acid substitutions at L234A and L235A of the human IgG1 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system.
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody according to claim 1 .
5. The antibody, or antibody fragment or antibody derivative thereof according to claim 1 , comprising a human IgG4 Fc region comprising at least amino acid substitutions at S228P and L235E of the human IgG4 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system.
6. An antibody that specifically binds to IL-1R3, the comprising:
a) a VH region comprising an amino acid sequence set forth in SEQ ID NO: 28;
b) a VL region comprising an amino acid sequence set forth in SEQ ID NO: 174; and
c) a human IgG1 Fc region comprising at least amino acid substitutions at L234A and L235A of the human IgG1 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody according to claim 6 .
8. An antibody that specifically binds to IL-1R3, the comprising:
a) a VH region comprising an amino acid sequence set forth in SEQ ID NO: 28;
b) a VL region comprising an amino acid sequence set forth in SEQ ID NO: 174; and
c) a human IgG4 Fc region comprising at least amino acid substitutions at S228P and L235E of the human IgG4 Fc region, wherein the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system.
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody according to claim 8 .