NZ771227B2 - Anti-il36r antibodies - Google Patents

Abstract

The present invention provides antibodies and antigen-binding fragments (e.g., human antibodies) that bind specifically to human IL-36 receptor. Methods for treating or preventing diseases mediated by IL36R (e.g., skin or colon inflammatory conditions such as palmo-plantar pustular psoriasis, palmoplantar pustulosis, generalized pustular psoriasis, ulcerative colitis or IBD) using the antibodies and fragments are also provided along with methods of making the antibodies and fragments.

Claims (16)

WE CLAIM:

1. An isolated antibody or antigen-binding fragment thereof which ically binds to Interleukin-36 Receptor ) comprising: (a) a heavy chain globulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid ce set forth in SEQ ID NO: 2, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that ses the amino acid sequence set forth in SEQ ID NO: 10; (b) a heavy chain immunoglobulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain immunoglobulin variable region comprising the , CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 26; (c) a heavy chain immunoglobulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 34, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain globulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 42; (d) a heavy chain immunoglobulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 50, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 58; (e) a heavy chain immunoglobulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 66, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain globulin variable region that comprises the amino acid ce set forth in SEQ ID NO: 74; (f) a heavy chain immunoglobulin variable region comprising the , CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 82, and a light chain immunoglobulin variable region sing the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 90; (g) a heavy chain immunoglobulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that comprises the amino acid ce set forth in SEQ ID NO: 106; (h) a heavy chain immunoglobulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 114, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin le region that comprises the amino acid ce set forth in SEQ ID NO: 122; (i) a heavy chain globulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122; (j) a heavy chain immunoglobulin le region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that ses the amino acid sequence set forth in SEQ ID NO: 146; (k) a heavy chain immunoglobulin variable region comprising the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 154, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 162; or (l) a heavy chain immunoglobulin variable region sing the CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin le region that comprises the amino acid sequence set forth in SEQ ID NO: 170, and a light chain immunoglobulin variable region comprising the CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122.

2. An antibody or antigen-binding fragment f of claim 1 which is ed by a method sing: (a) introducing one or more polynucleotides encoding the heavy and light chain globulin le regions of said antibody or antigen-binding fragment thereof into an isolated host cell; (b) culturing the host cell in a medium under conditions ble to expression of the polynucleotide; and (c) optionally, ing the antibody or antigen-binding fragment thereof from the host cell and/or medium in which the host cell is grown.

3. The isolated antibody or antigen-binding fragment thereof of claim 2 wherein the host cell is a Chinese hamster ovary cell.

4. A composition or kit comprising an antibody or antigen-binding fragment thereof of claim

5. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a ceutically acceptable carrier.

6. The pharmaceutical composition of claim 5 in association with a further therapeutic agent.

7. The pharmaceutical composition of claim 5 in association with a further therapeutic agent, wherein the further therapeutic agent is a member selected from the group consisting of an anti-tumor necrosis factor (TNF) alpha antibody or antigen-binding fragment thereof, one or more human TNF receptors or fragments thereof linked to an immunoglobulin, an Interleukin-17 inhibitor, an Interleukin-23 p19 inhibitor, an Interleukin-12 p40 inhibitor, guselkumab, numab, brodalumab, ixekizumab, secukinumab, infliximab, adalimumab, etanercept, dupilumab, sarilumab, tocilizumab, golimumab, abatacept, tofacitinib, abatacept, a eroidal anti-inflammatory drug (NSAID), ibuprofen, naproxen, acetaminophen, aspirin, celecoxib, cyclophosphamide, methotrexate, a osteroid, cortisone and prednisone.

8. A complex comprising an antibody or antigen-binding fragment thereof of claim 1 bound to a IL36R polypeptide.

9. A vessel or injection device comprising the dy or antigen-binding fragment thereof of claim 1 or a ceutical composition comprising said antibody or fragment and a pharmaceutically able carrier.

10. An isolated antibody or antigen-binding fragment f which specifically binds to Interleukin-36 Receptor (IL36R) comprising: a heavy chain immunoglobulin variable region comprising a CDR-H1 sing the amino acid sequence set forth in SEQ ID NO: 4, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 8, a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 16; a heavy chain globulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 24, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 28, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 32; a heavy chain immunoglobulin variable region comprising a CDR-H1 sing the amino acid sequence set forth in SEQ ID NO: 36, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 40, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a CDR-L2 sing the amino acid sequence set forth in SEQ ID NO: 46, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 48; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 52, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 56, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 60, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 62, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 64; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 68, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 70, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 72, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 76, a CDR-L2 sing the amino acid sequence set forth in SEQ ID NO: 78, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 80; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a CDR-H2 comprising the amino acid ce set forth in SEQ ID NO: 86, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a light chain immunoglobulin variable region comprising a CDR-L1 sing the amino acid sequence set forth in SEQ ID NO: 92, a CDR-L2 comprising the amino acid ce set forth in SEQ ID NO: 94, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 96; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 100, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid ce set forth in SEQ ID NO: 108, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 110, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 118, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 120, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR-L2 sing the amino acid sequence set forth in SEQ ID NO: 126, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 128; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 132, a CDR-H2 comprising the amino acid ce set forth in SEQ ID NO: 134, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 136, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR-L2 sing the amino acid sequence set forth in SEQ ID NO: 126, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 128; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 140, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 142, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 148, a CDR-L2 sing the amino acid ce set forth in SEQ ID NO: 150, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 152; a heavy chain immunoglobulin or variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 156, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 158, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 160, and a light chain immunoglobulin variable region sing a CDR-L1 comprising the amino acid ce set forth in SEQ ID NO: 164, a CDR-L2 sing the amino acid sequence set forth in SEQ ID NO: 166, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 168; or a heavy chain immunoglobulin variable region comprising a CDR-H1 sing the amino acid ce set forth in SEQ ID NO: 172, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 174, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 176, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 128.

11. The antibody or antigen-binding fragment of claim 10 comprising: a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 8, and at least 90% identical to SEQ ID NO: 2, and a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 16, and at least 90% identical to SEQ ID NO: 10; a heavy chain globulin variable region comprising a CDR-H1 sing the amino acid sequence set forth in SEQ ID NO: 20, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 24, and at least 90% identical to SEQ ID NO: 18 a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 28, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 30, a CDR-L3 comprising the amino acid ce set forth in SEQ ID NO: 32, and at least 90% identical to SEQ ID NO: 26; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 36, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 40, and at least 90% identical to SEQ ID NO: 34, a light chain immunoglobulin variable region comprising a CDR-L1 sing the amino acid sequence set forth in SEQ ID NO: 44, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and at least 90% identical to SEQ ID NO: 42; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid ce set forth in SEQ ID NO: 52, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 54, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 56, and at least 90% identical to SEQ ID NO: 50, a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 60, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR-L3 sing the amino acid sequence set forth in SEQ ID NO: 64, and at least 90% identical to SEQ ID NO: 58; a heavy chain globulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 68, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 70, a CDR-H3 comprising the amino acid ce set forth in SEQ ID NO: 72, and at least 90% identical to SEQ ID NO: 66; a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 76, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 78, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 80, and at least 90% identical to SEQ ID NO: 74; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 86, a CDR-H3 sing the amino acid sequence set forth in SEQ ID NO: 88, and at least 90% identical to SEQ ID NO: 82, a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 92, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 94, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 96, and at least 90% identical to SEQ ID NO: 90; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 100, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 102, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 104, and at least 90% identical to SEQ ID NO: 98, a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 108, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 110, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 112, and at least 90% identical to SEQ ID NO: 106; a heavy chain globulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 116, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 118, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 120, and at least 90% identical to SEQ ID NO: 114, a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid ce set forth in SEQ ID NO: 124, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 126, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and at least 90% identical to SEQ ID NO: 122; a heavy chain globulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 132, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 134, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 136, and at least 90% identical to SEQ ID NO: 130, a light chain immunoglobulin variable region sing a CDR-L1 sing the amino acid sequence set forth in SEQ ID NO: 124, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 126, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and at least 90% identical to SEQ ID NO: 122; a heavy chain immunoglobulin variable region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 140, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 142, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 144, and at least 90% identical to SEQ ID NO: 138, a light chain immunoglobulin variable region sing a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 148, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 150, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 152, and at least 90% identical to SEQ ID NO: 146; a heavy chain immunoglobulin le region comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 156, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 158, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 160, and at least 90% identical to SEQ ID NO: 154, a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 164, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 166, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 168, and at least 90% identical to SEQ ID NO: 162; a heavy chain immunoglobulin variable region comprising a CDR-H1 sing the amino acid sequence set forth in SEQ ID NO: 172, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 174, a CDR-H3 comprising the amino acid ce set forth in SEQ ID NO: 176, and at least 90% identical to SEQ ID NO: 170, a light chain immunoglobulin variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a CDR-L2 comprising the amino acid ce set forth in SEQ ID NO: 126, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and at least 90% identical to SEQ ID NO: 122.

12. An isolated antibody or antigen-binding fragment thereof which specifically binds to eukin-36 Receptor (IL36R) comprising: (a) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 2, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; (b) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain immunoglobulin variable region that comprises the amino acid ce set forth in SEQ ID NO: 26; (c) a heavy chain immunoglobulin variable region that ses the amino acid sequence set forth in SEQ ID NO: 34, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 42; (d) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 50, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 58; (e) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 66, and a light chain globulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 74; (f) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 82, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 90; (g) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106; (h) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 114, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122; (i) a heavy chain globulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122; (j) a heavy chain globulin le region that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a light chain globulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 146; (k) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 154, and a light chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 162; or (l) a heavy chain immunoglobulin variable region that comprises the amino acid sequence set forth in SEQ ID NO: 170, and a light chain immunoglobulin variable region that ses the amino acid sequence set forth in SEQ ID NO: 122.

13. The dy or antigen-binding fragment thereof of claim 12 wherein the heavy chain immunoglobulin variable region is linked to an IgG heavy chain constant region and the light chain immunoglobulin variable region is linked to a kappa light chain constant region.

14. The antibody or antigen-binding fragment thereof of claim 12 comprising: (a) a heavy chain immunoglobulin that comprises the amino acid ce set forth in SEQ ID NO: 180, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 182; (b) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 184, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 186; (c) a heavy chain immunoglobulin that comprises the amino acid ce set forth in SEQ ID NO: 188, and a light chain immunoglobulin that comprises the amino acid ce set forth in SEQ ID NO: 190; (d) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 192, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 194; (e) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 196, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 198; (f) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 200, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 202; (g) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 204, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 206; (h) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 208, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 210; (i) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 212, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 214; (j) a heavy chain immunoglobulin that comprises the amino acid ce set forth in SEQ ID NO: 216, and a light chain immunoglobulin that comprises the amino acid ce set forth in SEQ ID NO: 218; (k) a heavy chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 220, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 222; or (l) a heavy chain immunoglobulin that comprises the amino acid ce set forth in SEQ ID NO: 224, and a light chain immunoglobulin that comprises the amino acid sequence set forth in SEQ ID NO: 226.

15. The antibody or antigen-binding fragment thereof of claim 12 which is an antibody.

16. The antibody or antigen-binding fragment thereof of claim 12 which is multispecific. gmime 8 an4a 20$ me 92 ngmH .0233 .m w > OFF $55583 $5568; m . Oz__>_< om “o<2 mzzszme N.\+ m>3mqwmwm m>3mqwmwm Sm a: ow < m co? EmE: 55E omEsm 225m a ow wmwzéo z H on .2350. < om USEDm?gmzzg?mzmmzomm358$QO oww?ao quq/mmdaowmmoo?zq Scheme. om 92 Mmm>mo wmm>mo Name? 02:): F \\§ ! om Iv: Smgmgmmwmo?wwumm?gm mgqmzzoqwqmzmdazamm 2 ON H Emwvng/m S gmwmmqmqe?mmoe??m mgomqegmwmmqm?gmogim NE: 81% 2:73 3* TS 8*:me mmoowimwm _ 33.9me mammoz?mwm S; m>mmwo$§wm -3me mmoowimwm SLTmeH M>NmQOF¢Hm¢m H_Ho*HH|m>me M>Nmmoww?mwm SUBSTITUTE SHEET (RULE 26) mm>e>qewowz mm>e>qewooz om 4mm wwwmwmwm mmmmgulmmw om mom Emm Name? mo N ommamzzoqwqmzmmzommHemmwm>wm¢.No*wb_?o*om ?mmmwmmqmqe?mo?am mHm>MwaomBamBmeoooww>MwawmBamBmeoooww> 81%me >w?mwm HQ_Ho*m-m>me m>wao>¢Hmwm _ SLTmBGH M>waoww?mwm Ho*whme_Ho*HH|m>me M>mmwoww?mwm SUBSTWUTESHEET(RULE26) 332 N- $22 N- 35 Q. It; It; 35 w- zo_N_m_Iz_ zo_N§sz028 :N- 3353 0m a- 5353 u_m a-u-V:éé-s-ma .GE zo_N_m__-_z_ 2- amazemm omgzwmm 295N2528§28m .OE ggzam $2- was w o2 was; 3.3 $22 @022 N- 35 35 _-_N_>> w- mm IN; zo_N_m__-_z_ 8 22 mm. e3 .0E _Iz_ zo_N§szozoo§z$m 2- 3353 :- .OE mwgzemm 33281 02-023mm N72- was ”33 Nota? 3.0.0 82: N- 822 N- 35 w- 35 IE, w- 22215328 o- ; IE, w 3353 zo_N§szuzooo§z$m e- zo_N_m_Iz_ UNFV zo_N_m__-_z_ 2- 2- 3353 a- .OE :- .OE mmgzomm ggzé 2- a- :- agzwmm m- e- :- was max? SUBSTITUTE SHEET (RULE 26) on 82?: 8%.: NV 285%: 383%: 1? LmT 8 ”N 3232: v a $383 835% .GE s mean: mean: I? Iml «IN NOH.mN 1...ON0O SUBSTITUTE SHEET (RULE 26) SEQUENCE G <110> Regeneron Pharmaceuticals, Inc. <120> Anti-IL36R dies <130> 36432PCT (10484) <150>