Anti-IL1RAP antibodies
The present invention provides binding proteins, such as antibodies and antigen-binding fragments, which specifically bind to human interleukin-1 receptor accessory protein (hu-IL1RAP) and fully block the IL-1, IL-33, and IL-36 intracellular signaling pathways. Compositions comprising such binding proteins and methods of making and using such binding proteins are also provided.
1. An anti-ID RAP antibody comprising: (i) a first light chain hypervariable region (HVR-L1), a second light chain hypervariable region (HVR-L2), and a third light chain hypervariable region (HVR-L3), and (ii) a first heavy chain hypervariable region (HVR-H1), a second heavy chain hypervariable region (HVR-H2), and a third heavy chain hypervariable region (HVR-H3); wherein:
(a) HVR-L1 comprises an amino acid sequence of SEQ ID NO: 11;
(b) HVR-L2 comprises an amino acid sequence selected from SEQ ID NO: 37, and 54;
(c) HVR-L3 comprises an amino acid sequence selected from SEQ ID NO: 63, 69, and 70;
(d) HVR-H1 comprises an amino acid sequence of SEQ ID NO: 78;
(e) HVR-H2 comprises an amino acid sequence selected from SEQ ID NO: 191, and 195;
(f) HVR-H3 comprises an amino acid sequence selected from SEQ ID NO: 203 and 215.
2. The antibody of claim 1 , wherein the antibody comprises:
a first light chain framework region (FR-L1) comprising an amino acid sequence of SEQ ID NO: 244;
a second light chain framework region (FR-L2) comprising an amino acid sequence of SEQ ID NO: 246;
a third light chain framework region (FR-L3) comprising an amino acid sequence of SEQ ID NO: 247; and
a fourth light chain framework region (FR-L4) comprising an amino acid sequence of SEQ ID NO: 248; or
a first heavy chain framework region (FR-H1) comprising an amino acid sequence of SEQ ID NO: 253;
a second heavy chain framework region (FR-H2) comprising an amino acid sequence of SEQ ID NO: 254;
a third heavy chain framework region (FR-H3) comprising an amino acid sequence of SEQ ID NO: 255; and
a fourth heavy chain framework region (FR-H4) comprising an amino acid of SEQ ID NO: 256.
3. The antibody of claim 1 , wherein the antibody comprises a light chain variable domain (V L ) amino acid sequence having at least 90% identity to SEQ ID NO: 259; and/or a heavy chain variable domain (V H ) amino acid sequence having at least 90% identity to SEQ ID NO: 290.
4. The antibody of claim 3 , wherein the antibody comprises:
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 259, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 290;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 268, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 307;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 268, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 298;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 307;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 298;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 297;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 270, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 307; or
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 270, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 298.
5. The antibody of claim 1 , wherein the antibody comprises a light chain (LC) amino acid sequence having at least 90% identity to SEQ ID NO: 328; and/or a heavy chain (HC) amino acid sequence having at least 90% identity to SEQ ID NO: 332.
6. The antibody of claim 5 , wherein the antibody comprises:
the light chain (LC) amino acid sequence of SEQ ID NO: 328, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 332;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 334;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 334;
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335;
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333; or
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 334.
7. The antibody of claim 1 , wherein the antibody decreases an IL-1 stimulated signal, an IL-33 stimulated signal, and/or an IL-36 stimulated signal by at least 90%.
8. The antibody of claim 1 , wherein the antibody decreases an intracellular signal initiated by one or more of IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ agonist binding to its cognate receptor by at least 90%.
9. The antibody of claim 1 , wherein the antibody specifically binds to one or more amino acid residues within domain 3 of human ID RAP, wherein domain 3 comprises positions 238-367 of the amino acid sequence of SEQ ID NO: 1 or 3.
10. The antibody of claim 1 , wherein the antibody does not bind to amino acid residues within domain 1 or domain 2 of human ID RAP; optionally, wherein domain 1 and domain 2 comprise positions 21-237 of the amino acid sequence of SEQ ID NO: 1 or 3.
11. The antibody of claim 1 , wherein the antibody cross-reacts with a cynomolgus monkey ID RAP polypeptide of SEQ ID NO: 8.
12. The antibody of claim 1 , wherein the antibody is a full-length antibody of class IgG; optionally, wherein the class IgG antibody has an isotype selected from IgG1, IgG2, IgG3, and IgG4.
13. The antibody of claim 12 , wherein the antibody is an Fc region variant; optionally wherein the Fc region variant alters effector function or alters half-life.
14. The antibody of claim 13 , wherein the Fc region variant comprises a set of YTE mutations.
15. The antibody of claim 13 , wherein the Fc region variant decreases effector function.
16. A pharmaceutical composition comprising an antibody of claim 1 and a pharmaceutically acceptable carrier.
17. An anti-ID RAP antibody comprising:
a first light chain hypervariable region (HVR-L1) of SEQ ID NO: 11, a second light chain hypervariable region (HVR-L2) of SEQ ID NO: 54, a third light chain hypervariable region (HVR-L3) of SEQ ID NO: 63; and a first heavy chain hypervariable region (HVR-H1) of SEQ ID NO: 78, a second heavy chain hypervariable region (HVR-H2) of SEQ ID NO: 191, and a third heavy chain hypervariable region (HVR-H3) of SEQ ID NO: 215;
a first light chain hypervariable region (HVR-L1) of SEQ ID NO: 11, a second light chain hypervariable region (HVR-L2) of SEQ ID NO: 54, a third light chain hypervariable region (HVR-L3) of SEQ ID NO: 63; and a first heavy chain hypervariable region (HVR-H1) of SEQ ID NO: 78, a second heavy chain hypervariable region (HVR-H2) of SEQ ID NO: 195, and a third heavy chain hypervariable region (HVR-H3) of SEQ ID NO: 203;
a first light chain hypervariable region (HVR-L1) of SEQ ID NO: 11, a second light chain hypervariable region (HVR-L2) of SEQ ID NO: 54, a third light chain hypervariable region (HVR-L3) of SEQ ID NO: 69; and a first heavy chain hypervariable region (HVR-H1) of SEQ ID NO: 78, a second heavy chain hypervariable region (HVR-H2) of SEQ ID NO: 191, and a third heavy chain hypervariable region (HVR-H3) of SEQ ID NO: 215;
a first light chain hypervariable region (HVR-L1) of SEQ ID NO: 11, a second light chain hypervariable region (HVR-L2) of SEQ ID NO: 54, a third light chain hypervariable region (HVR-L3) of SEQ ID NO: 69; and a first heavy chain hypervariable region (HVR-H1) of SEQ ID NO: 78, a second heavy chain hypervariable region (HVR-H2) of SEQ ID NO: 195, and a third heavy chain hypervariable region (HVR-H3) of SEQ ID NO: 203;
a first light chain hypervariable region (HVR-L1) of SEQ ID NO: 11, a second light chain hypervariable region (HVR-L2) of SEQ ID NO: 54, a third light chain hypervariable region (HVR-L3) of SEQ ID NO: 70; and a first heavy chain hypervariable region (HVR-H1) of SEQ ID NO: 78, a second heavy chain hypervariable region (HVR-H2) of SEQ ID NO: 191, and a third heavy chain hypervariable region (HVR-H3) of SEQ ID NO: 215; or
a first light chain hypervariable region (HVR-L1) of SEQ ID NO: 11, a second light chain hypervariable region (HVR-L2) of SEQ ID NO: 54, a third light chain hypervariable region (HVR-L3) of SEQ ID NO: 70; and a first heavy chain hypervariable region (HVR-H1) of SEQ ID NO: 78, a second heavy chain hypervariable region (HVR-H2) of SEQ ID NO: 195, and a third heavy chain hypervariable region (HVR-H3) of SEQ ID NO: 203.
18. An anti-ID RAP antibody comprising:
a first light chain complementary determining region (CDR-L1) of SEQ ID NO: 11, a second light chain complementary determining region (CDR-L2) of SEQ ID NO: 54, a third light chain complementary determining region (CDR-L3) of SEQ ID NO: 63; and a first heavy chain complementary determining region (CDR-H1) of SEQ ID NO: 122, a second heavy chain complementary determining region (CDR-H2) of SEQ ID NO: 191, and a third heavy chain complementary determining region (CDR-H3) of SEQ ID NO: 229;
a first light chain complementary determining region (CDR-L1) of SEQ ID NO: 11, a second light chain complementary determining region (CDR-L2) of SEQ ID NO: 54, a third light chain complementary determining region (CDR-L3) of SEQ ID NO: 63; and a first heavy chain complementary determining region (CDR-H1) of SEQ ID NO: 122, a second heavy chain complementary determining region (CDR-H2) of SEQ ID NO: 195, and a third heavy chain complementary determining region (CDR-H3) of SEQ ID NO: 227;
a first light chain complementary determining region (CDR-L1) of SEQ ID NO: 11, a second light chain complementary determining region (CDR-L2) of SEQ ID NO: 54, a third light chain complementary determining region (CDR-L3) of SEQ ID NO: 69; and a first heavy chain complementary determining region (CDR-H1) of SEQ ID NO: 122, a second heavy chain complementary determining region (CDR-H2) of SEQ ID NO: 191, and a third heavy chain complementary determining region (CDR-H3) of SEQ ID NO: 229;
a first light chain complementary determining region (CDR-L1) of SEQ ID NO: 11, a second light chain complementary determining region (CDR-L2) of SEQ ID NO: 54, a third light chain complementary determining region (CDR-L3) of SEQ ID NO: 69; and a first heavy chain complementary determining region (CDR-H1) of SEQ ID NO: 122, a second heavy chain complementary determining region (CDR-H2) of SEQ ID NO: 195, and a third heavy chain complementary determining region (CDR-H3) of SEQ ID NO: 227;
a first light chain complementary determining region (CDR-L1) of SEQ ID NO: 11, a second light chain complementary determining region (CDR-L2) of SEQ ID NO: 54, a third light chain complementary determining region (CDR-L3) of SEQ ID NO: 70; and a first heavy chain complementary determining region (CDR-H1) of SEQ ID NO: 122, a second heavy chain complementary determining region (CDR-H2) of SEQ ID NO: 191, and a third heavy chain complementary determining region (CDR-H3) of SEQ ID NO: 229; or
a first light chain complementary determining region (CDR-L1) of SEQ ID NO: 11, a second light chain complementary determining region (CDR-L2) of SEQ ID NO: 54, a third light chain complementary determining region (CDR-L3) of SEQ ID NO: 70; and a first heavy chain complementary determining region (CDR-H1) of SEQ ID NO: 122, a second heavy chain complementary determining region (CDR-H2) of SEQ ID NO: 195, and a third heavy chain complementary determining region (CDR-H3) of SEQ ID NO: 227.
19. An anti-ID RAP antibody comprising:
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 268, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 307;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 268, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 298;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 307;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 269, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 298;
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 270, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 307; or
the light chain variable domain (V L ) amino acid sequence of SEQ ID NO: 270, and the heavy chain variable domain (V H ) amino acid sequence of SEQ ID NO: 298.
20. An anti-ID RAP antibody comprising:
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335 or 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 329, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333 or 334;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335 or 336;
the light chain (LC) amino acid sequence of SEQ ID NO: 330, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333 or 334;
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 335 or 336; or
the light chain (LC) amino acid sequence of SEQ ID NO: 331, and the heavy chain (HC) amino acid sequence of SEQ ID NO: 333 or 334.