JPWO2019183499A5 - - Google Patents

Description

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Preferred methods and materials will be described below, but methods and materials similar to or equivalent to those described herein can also be used in the practice or testing of the methods and compositions disclosed herein. All publications, patent applications, patents, and other references referred to herein are incorporated by reference in their entirety.
In the embodiment of the present invention, for example, the following items are provided.
(Item 1)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27 and has the following characteristics:
(I) Equilibrium dissociation constant (K) of 15 nM or less for human IL-27 _D ) To combine;
(Ii) Block the binding of IL-27 to the IL-27 receptor;
(Iii) Inhibits or reduces STAT1 and / or STAT3 phosphorylation in cells;
(Iv) Inhibits or reduces IL-27-mediated inhibition of CD161 expression in cells;
(V) Inhibits or reduces IL-27-mediated PD-L1 and / or TIM-3 expression in cells; and
(Vi) Induces or enhances PD-1-mediated secretion of one or more cytokines from cells
The antibody or antigen-binding portion thereof exhibiting at least one or more of the above.
(Item 2)
The equilibrium dissociation constant (K) in which the antibody or its antigen-binding moiety is 15 nM or less on human IL-27. _D ), The isolated monoclonal antibody according to item 1 or an antigen-binding portion thereof.
(Item 3)
The isolated monoclonal antibody or antigen-binding portion thereof according to item 1 or 2, wherein the antibody or its antigen-binding portion binds to mouse IL-27.
(Item 4)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) Heavy chain CDR1 consisting of N-GFTFXXXX-C (SEQ ID NO: 408), heavy chain CDR2 consisting of N-ISSSXXYI-C (SEQ ID NO: 409), and heavy chain CDR3 sequence set forth in SEQ ID NO: 163; and each. The light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 169, 170 and 171; or
(Ii) Heavy chain CDR1 consisting of N-FTFXXXXMN-C (SEQ ID NO: 410), heavy chain CDR2 consisting of N-XISSSXXYIXYADSVKG-C (SEQ ID NO: 411), and heavy chain CDR3 sequence of SEQ ID NO: 166; and each. The antibody or antigen-binding portion thereof comprising a heavy chain CDR and a light chain CDR selected from the group consisting of the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 172, 173 and 174.
(Item 5)
The heavy chain CDR1 is composed of N-GFTF [S / A / R] [S / R] [T / Y] [G / S] -C (SEQ ID NO: 412), and the heavy chain CDR2 is N-ISSS. It consists of [S / G] [S / A] YI-C (SEQ ID NO: 413); or the heavy chain CDR1 is N-FTF [S / A / R] [S / R] [T / Y] [G. / S] MN-C (SEQ ID NO: 414), and the heavy chain CDR2 is N- [G / S] ISSS [S / G] [S / A] YI [L / Y] YADSVKG-C (SEQ ID NO: 414). 415) The isolated monoclonal antibody according to item 4.
(Item 6)
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 161 and 162 and 163, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 169, 170 and 171 respectively. Have been described;
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 164, 165 and 166, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 172, 173 and 174, respectively. Have been described;
(Iii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 73, 74 and 75, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are in SEQ ID NOs: 81, 82 and 83, respectively. Have been described;
(Iv) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 76, 77 and 78, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 84, 85 and 86, respectively. Have been described;
(V) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 95, 96 and 97, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are found in SEQ ID NOs: 103, 104 and 105, respectively. Have been described;
(Vi) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 98, 99 and 100, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 106, 107 and 108, respectively. Have been described;
(Vii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 117, 118 and 119, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 125, 126 and 127, respectively. Have been described;
(Viii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 120, 121 and 122, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are in SEQ ID NOs: 128, 129 and 130, respectively. Have been described;
(Ix) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 139, 140 and 141, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 147, 148 and 149, respectively. Have been described;
(X) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 142, 143 and 144, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are located in SEQ ID NOs: 150, 151 and 152, respectively. Have been described;
(Xi) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 51, 52 and 53, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 59, 60 and 61, respectively. Described; or
(Xii) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 54, 55 and 56, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 62, 63 and 64, respectively. The isolated monoclonal antibody of item 4 described.
(Item 7)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) Heavy chain CDR1 consisting of N-GGSFSXYX-C (SEQ ID NO: 416), heavy chain CDR2 consisting of N-IDXSGXT-C (SEQ ID NO: 417), and N-ARXXXY [X], respectively. _{n = 0-1} DSS [X] _{n = 4-6} Heavy chain CDR3 sequence consisting of DX-C (SEQ ID NO: 418); and light chain CDR1 consisting of N-QXXSXY-C (SEQ ID NO: 419), light chain CDR2 consisting of N-DXS-C (SEQ ID NO: 420), and N. -Light chain CDR3 sequence consisting of QQXXDXPIT-C (SEQ ID NO: 421); or
(Ii) Heavy chain CDR1 consisting of N-GSFSXYXWS-C (SEQ ID NO: 422), heavy chain CDR2 consisting of N-SIDXSGXTXYNPSLKS-C (SEQ ID NO: 423), and N-ARXXXY [X], respectively. _{n = 0-1} DSS [X] _{n = 4-6} Heavy chain CDR3 sequence consisting of DX-C (SEQ ID NO: 418); and light chain CDR1 consisting of N-XASQXXSXYLX-C (SEQ ID NO: 424), light chain CDR2 consisting of N-DXSNXXT-C (SEQ ID NO: 425), and N. -The antibody or antigen-binding portion thereof comprising a heavy chain CDR and a light chain CDR selected from the group consisting of the light chain CDR3 sequence consisting of QQXXDXPIT-C (SEQ ID NO: 421).
(Item 8)
(I) The heavy chain CDR1 is composed of N-GGSFS [R / D] Y [E / Y] -C (SEQ ID NO: 426), and the heavy chain CDR2 is N-ID [W / Y] SG. [I / S] TC (SEQ ID NO: 427), N-AR [D / L] [P / G] [M / V] YY [-/ Y] DSS [VSTGSV / DLGF] D [V / Heavy chain CDR3 sequence consisting of I] -C (SEQ ID NO: 428); and light chain CDR1 consisting of NQ [S / D] [V / I] S [S / N] YC (SEQ ID NO: 429), Light chain CDR2 consisting of N-D [S / A] SC (SEQ ID NO: 430) and N-QQ [D / Y] [S / D] D [H / L] PIT-C (SEQ ID NO: 431). Light chain CDR3 sequence consisting of; or
(Ii) Each of the heavy chain CDR1 is composed of N-GSFS [R / D] Y [E / Y] WS-C (SEQ ID NO: 432), and the heavy chain CDR2 is N-SID [W / Y]. It consists of SG [I / S] T [N / E] YNPSLKS-C (SEQ ID NO: 433), N-AR [D / L] [P / G] [M / V] YY [-/ Y] DSS [VSTGSV]. / DLGF] D [V / I] -C (SEQ ID NO: 428) heavy chain CDR3 sequence; and N- [Q / R] ASQ [S / D] [V / I] S [S / N] YL [ Light chain CDR1 consisting of N / A] -C (SEQ ID NO: 434), light chain CDR2 consisting of N-D [S / A] SN [R / L] [A / E] TC (SEQ ID NO: 435), And the isolated monoclonal antibody of item 7 of the light chain CDR3 sequence consisting of NQQ [D / Y] [S / D] D [H / L] PIT-C (SEQ ID NO: 431).
(Item 9)
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 229, 230 and 231 respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 237, 238 and 239, respectively. Described; or
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 232, 233 and 234, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 240, 241 and 242, respectively. The isolated monoclonal antibody of item 7 described.
(Item 10)
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 251 and 252 and 253, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 259, 260 and 261 respectively. Described; or
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 254, 255 and 256, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 262, 263 and 264, respectively. The isolated monoclonal antibody of item 7 described.
(Item 11)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, the heavy chain CDR1, CDR2, and CDR3 sequences are described in SEQ ID NOs: 23, 24, and 25, respectively. The antibody or antigen-binding moiety thereof comprises a heavy chain CDR and a light chain CDR selected from the group consisting of the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 26, 27 and 28, respectively. ..
(Item 12)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 339, 340 and 341, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 347, 348 and 349, respectively. Has been; or
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 342, 343 and 344, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 350, 351 and 352, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR selected from the group consisting of.
(Item 13)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 185, 186 and 187, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 193, 194 and 195, respectively. Has been; or
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 188 and 189 and 190, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 196, 197 and 198, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR selected from the group consisting of.
(Item 14)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 207, 208 and 209, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 215, 216 and 217, respectively. Has been; or
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 210, 211 and 212, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 218, 219 and 220, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR selected from the group consisting of.
(Item 15)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 273, 274 and 275, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 281, 282 and 283, respectively. Has been; or
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 276, 277 and 278, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 284, 285 and 286, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR selected from the group consisting of.
(Item 16)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) Heavy chain CDR1 consisting of N-GFTFSYG-C (SEQ ID NO: 361), heavy chain CDR2 consisting of N-IXXDGSXK-C (SEQ ID NO: 436), and N-ARXAP [X], respectively. _{n = 3-8} Heavy chain CDR3 sequence consisting of DV-C (SEQ ID NO: 437); and light chain CDR1 consisting of N-QSXSSY-C (SEQ ID NO: 438), light chain CDR2 consisting of N-XXS-C (SEQ ID NO: 439), and N. -QQXXXXP [X] _{n = 0-1} Light chain CDR3 sequence consisting of TC (SEQ ID NO: 440); or
(Ii) Heavy chain CDR1 consisting of N-FTFSSYGMX-C (SEQ ID NO: 441), heavy chain CDR2 consisting of N-XIXXDGSXKYXDSVKG-C (SEQ ID NO: 442), and N-ARXAP [X], respectively. _{n = 3-8} Heavy chain CDR3 sequence consisting of DV-C (SEQ ID NO: 437); and light chain CDR1, N- [X] consisting of N-RASQSXSSYLX-C (SEQ ID NO: 443). _{n = 1-2} SS [X] _{n = 3-4} Light chain CDR2 consisting of —C (SEQ ID NO: 444) and N—QQXXXXP [X] _{n = 0-1} The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR selected from the group consisting of the light chain CDR3 sequence consisting of TC (SEQ ID NO: 440).
(Item 17)
(I) The heavy chain CDR1 is composed of N-GFTFSYG-C (SEQ ID NO: 361), and the heavy chain CDR2 is N-I [K / W] [Q / Y] DGS [E / N] K-. The heavy chain CDR3 sequence consists of C (SEQ ID NO: 445), the heavy chain CDR3 sequence consists of N-AR [D / G] AP [WDYDYYM / EYV] DV-C (SEQ ID NO: 446); and the light chain CDR1 consists of N-QS [ I / V] SSY-C (SEQ ID NO: 447), light chain CDR2 consisting of N- [A / D] [A / S] SC (SEQ ID NO: 448), light chain CDR3 sequence N. -Consists of QQ [S / Y] [Y / S] [V / L] [P / Y] P [W /-] TC (SEQ ID NO: 449); or (ii) each of the heavy chain CDR1s. , N-FTFSSYGM [S / H] -C (SEQ ID NO: 450), and the heavy chain CDR2 is N- [N / V] I [K / W] [Q / Y] DGS [E / N] KYY [ V / A] DSVKG-C (SEQ ID NO: 451), heavy chain CDR3 sequence consisting of N-AR [D / G] AP [WDYDYM / EYV] DV-C (SEQ ID NO: 446); and light chain CDR1 Is composed of N-RASQS [I / V] SSYL [N / A] -C (SEQ ID NO: 452), and the light chain CDR2 is N- [AA / D] SS [LQS / NRAT] -C (SEQ ID NO: 453). ), And the light chain CDR3 sequence consists of N—QQ [S / Y] [Y / S] [V / L] [P / Y] P [W / −] TC (SEQ ID NO: 449). Item 16. The isolated monoclonal antibody according to item 16.
(Item 18)
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 361, 362 and 363, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 369, 370 and 371, respectively;
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 364, 365 and 366, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 372, 373 and 374, respectively. 16. The isolated monoclonal antibody according to 16.
(Item 19)
(I) The heavy chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 383, 384 and 385, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 391, 392 and 393, respectively;
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 386, 387 and 388, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 394, 395 and 396, respectively. 16. The isolated monoclonal antibody according to 16.
(Item 20)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) Heavy chain CDR1 consisting of N-GFTFXXXX-C (SEQ ID NO: 408), heavy chain CDR2 consisting of N-IXXXXXXX-C (SEQ ID NO: 456), and N-AR [X] n =, respectively. _6-15 Heavy chain CDR3 sequence consisting of DX-C (SEQ ID NO: 458); as well as N-QS [X] _{n = 1-3} SS [X] _{n = 0-4} Light chain CDR1 consisting of Y-C (SEQ ID NO: 460), light chain CDR2 consisting of N-XXS-C (SEQ ID NO: 462), and N-QQXXXXP [X]. _{n = 0-1} Light chain CDR3 sequence consisting of TC (SEQ ID NO: 464); or
(Ii) Heavy chain CDR1 consisting of N-FTFXXXXMX-C (SEQ ID NO: 466), heavy chain CDR2 consisting of N-XIXXXXXXXXXYXDSVKG-C (SEQ ID NO: 468), and N-AR [X], respectively. _{n = 6-15} Heavy chain CDR3 sequence consisting of DX-C (SEQ ID NO: 470); and light chain CDR1, N- [X] consisting of N-RASQSXSSYLX-C (SEQ ID NO: 472). _{n = 1-2} S [X] _{n = 4-5} Light chain CDR2 consisting of —C (SEQ ID NO: 474) and N—QQXXXXP [X] _{n = 0-1} The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR selected from the group consisting of the light chain CDR3 sequence consisting of TC (SEQ ID NO: 476).
(Item 21)
(I) Each of the heavy chain CDR1 is composed of N-GFTF [S / A / R] [S / R] [T / Y] [G / S] -C (SEQ ID NO: 454), and the heavy chain CDR2 is , NI [S / K / W] [S / Q / Y] [S / D] [S / G] [S / A] [Y / E / N] [I / K] -C (SEQ ID NO: 455), the heavy chain CDR3 sequence consists of N-AR [DGGRTSYTAHATHNWF / DAPWDYDYM / GAPEYV] D [P / V] -C (SEQ ID NO: 457); and the light chain CDR1 consists of N-QS [VLF / I. / V] SS [NNKN /-] Y-C (SEQ ID NO: 459), light chain CDR2 consisting of N- [W / A / D] [A / S] SC (SEQ ID NO: 461). The light chain CDR3 sequence is N-QQ [H / S / Y] [A / Y / S] [S / V / L] [A / P / Y] P [P / W /-] TC (sequence). Consists of number 463); or
(Ii) The heavy chain CDR1 is N-FTF [S / A / R] [S / R] [T / Y] [G / S] M [N / S / H] -C (SEQ ID NO: 465, respectively). ), And the heavy chain CDR2 is N- [G / S / N / V] I [S / K / W] [S / Q / Y] [S / D] [S / G] [S / A]. It consists of [Y / E / N] [I / K] [L / Y] Y [V / A] DSVKG-C (SEQ ID NO: 467), and the heavy chain CDR3 sequence is N-AR [D / G] [GGRTSYTTATAHNWF. / APWDYDYM / APEYV] D [P / V] -C (SEQ ID NO: 469); and light chain CDR1 consists of N-RASQS [I / V] SSYL [N / A] -C (SEQ ID NO: 471). , Light chain CDR2 consists of N- [WA / AA / D] S [TRES / SLQS / SNRAT] -C (SEQ ID NO: 473), and the light chain CDR3 sequence is N-QQ [H / S / Y] [ Item 20. The isolated monoclonal antibody according to item 20, which comprises A / Y / S] [S / V / L] [A / P / Y] P [P / W / −] TC (SEQ ID NO: 475). ..
(Item 22)
Item 3. The isolated monoclonal antibody or antigen-binding moiety thereof according to any one of Items 1 to 21, wherein the antibody or an antigen-binding moiety thereof antagonizes IL-27.
(Item 23)
The isolated monoclonal antibody or antigen-binding portion thereof according to any one of items 1 to 22, wherein the antibody or an antigen-binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in cells.
(Item 24)
23. The isolated monoclonal antibody or antigen-binding portion thereof according to item 23, wherein the cell is an immune cell.
(Item 25)
23. The isolated monoclonal antibody or antigen-binding portion thereof according to item 23, wherein the cell is a cancer cell.
(Item 26)
The isolated monoclonal antibody or antigen-binding moiety thereof according to any one of Items 1 to 25, wherein the antibody or antigen-binding moiety thereof inhibits or reduces inhibition of CD161 expression in cells.
(Item 27)
The isolated monoclonal antibody or antigen-binding portion thereof according to item 26, wherein the cell is an immune cell.
(Item 28)
Item 2. The isolated monoclonal antibody or antigen-binding moiety thereof according to any one of Items 1 to 27, wherein the antibody or its antigen-binding moiety inhibits or reduces PD-L1 and / or TIM-3 expression in cells. ..
(Item 29)
Item 28. The isolated monoclonal antibody or antigen-binding portion thereof according to item 28, wherein the cell is an immune cell.
(Item 30)
29. The isolated monoclonal antibody or antigen-binding portion thereof according to item 29, wherein the cell is a cancer cell.
(Item 31)
29. The isolated monoclonal antibody or antigen-binding portion thereof according to item 29, wherein the cell is a cancer cell and the antibody or antigen-binding portion thereof inhibits or reduces PD-L1 expression in cancer cells.
(Item 32)
Item 3. The isolated monoclonal antibody according to any one of items 1-31, wherein the antibody or an antigen-binding moiety thereof induces or enhances the PD-1-mediated secretion of one or more cytokines from a cell. Or its antigen binding portion.
(Item 33)
32. The isolated monoclonal antibody or antigen-binding portion thereof according to item 32, wherein the one or more cytokines are IFNg, TNFα or IL-6.
(Item 34)
33. The isolated monoclonal antibody or antigen-binding portion thereof according to item 33, wherein the one or more cytokines are IFNg, IL-17, TNFα or IL-6.
(Item 35)
33. The isolated monoclonal antibody or antigen-binding portion thereof according to item 33, wherein the one or more cytokines are TNFα.
(Item 36)
Item 3. The isolated monoclonal antibody or antigen-binding portion thereof according to any one of Items 32 to 35, wherein the cell is an immune cell.
(Item 37)
Item 3. The isolated monoclonal antibody according to any one of Items 1 to 36, wherein the antibody is selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibodies. Its antigen binding part.
(Item 38)
37. The isolated monoclonal antibody or antigen-binding portion thereof according to item 37, wherein the antibody is an IgG1 antibody or an IgG4 antibody.
(Item 39)
38. The isolated monoclonal antibody or antigen binding moiety thereof according to item 38, wherein the antibody comprises a wild-type IgG1 heavy chain constant region.
(Item 40)
38. The isolated monoclonal antibody or antigen binding moiety thereof according to item 38, wherein the antibody comprises a wild-type IgG4 heavy chain constant region.
(Item 41)
The isolated monoclonal antibody or antigen-binding portion thereof according to any one of items 1 to 40, wherein the antibody comprises an Fc domain containing at least one mutation.
(Item 42)
The isolated monoclonal antibody or antigen-binding portion thereof according to item 41, wherein the antibody comprises a mutant IgG1 heavy chain constant region.
(Item 43)
The isolated monoclonal antibody or antigen-binding portion thereof according to item 41, wherein the antibody comprises a mutant IgG4 heavy chain constant region.
(Item 44)
23. The isolated monoclonal antibody or antigen-binding portion thereof according to item 43, wherein the mutant IgG4 heavy chain constant region comprises any one, or a combination of, substituted S228P, L235E, L235A according to EU numbering.
(Item 45)
An isolated monoclonal antibody or antigen-binding moiety thereof that binds to substantially the same epitope as the antibody or antigen-binding moiety thereof according to any one of items 1-44.
(Item 46)
An isolated monoclonal antibody or antigen-binding portion thereof that binds to at least one of the amino acid residues to which the antibody according to any one of items 1 to 44 or the antigen-binding portion thereof binds.
(Item 47)
A mutation in the epitope to which the antibody or an antigen-binding portion thereof binds can bind to both the antibody or the antigen-binding portion thereof and the antibody according to any one of items 1-44 or the antigen-binding portion thereof. An isolated monoclonal antibody or antigen-binding moiety thereof that inhibits, reduces, or blocks.
(Item 48)
An isolated monoclonal antibody or antigen-binding portion thereof that binds to an epitope on IL-27 and the epitope is the same as or similar to the epitope to which the antibody molecule shown in Table 12 binds.
(Item 49)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 51, 52 and 53, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 59, 60 and 61, respectively;
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 73, 74 and 75, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 81, 82 and 83, respectively;
(Iii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 95, 96 and 97, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 103, 104 and 105, respectively;
(Iv) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 117, 118 and 119, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 125, 126 and 127, respectively;
(V) Heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 139, 140 and 141, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 147, 148 and 149, respectively;
(Vi) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 161, 162 and 163, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 169, 170 and 171 respectively;
(Vii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 185, 186 and 187, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 193, 194 and 195, respectively;
(Viii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 207, 208 and 209, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 215, 216 and 217, respectively;
(Ix) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 229, 230 and 231, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 237, 238 and 239, respectively;
(X) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 251, 252 and 253, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 259, 260 and 261, respectively;
(Xi) Heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 273, 274 and 275, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 281, 282 and 283, respectively;
(Xii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 295, 296 and 297, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 303, 304 and 305, respectively;
(Xiii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 317, 318 and 319, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 325, 326 and 327, respectively;
(Xiv) Heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 339, 340 and 341, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 347, 348 and 349, respectively;
(Xv) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 361, 362 and 363, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 369, 370 and 371, respectively; and
(Xvi) Select from the group consisting of the heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 383, 384 and 385, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 391, 392 and 393, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR.
(Item 50)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 54, 55 and 56, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 62, 63 and 64, respectively;
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 76, 77 and 78, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 84, 85 and 86, respectively;
(Iii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 98, 99 and 100, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 106, 107 and 108, respectively;
(Iv) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 120, 121 and 122, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 128, 129 and 130, respectively;
(V) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 142, 143 and 144, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 150, 151 and 152, respectively;
(Vi) Heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 164, 165 and 166, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 172, 173 and 174, respectively;
(Vii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 188, 189 and 190, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 196, 197 and 198, respectively;
(Viii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 210, 211 and 212, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 218, 219 and 220, respectively;
(Ix) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 232, 233 and 234, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 240, 241 and 242, respectively;
(X) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 254, 255 and 256, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 262, 263 and 264, respectively;
(Xi) Heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 276, 277 and 278, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 284, 285 and 286, respectively;
(Xii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 298, 299 and 300, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 306, 307 and 308, respectively;
(Xiii) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 320, 321 and 322, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 328, 329 and 330, respectively;
(Xiv) Heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 342, 343 and 344, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 350, 351 and 352, respectively;
(Xv) The heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 364, 365 and 366, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 372, 373 and 374, respectively; and
(Xvi) Select from the group consisting of the heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 386, 387 and 388, respectively, and the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 394, 395 and 396, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR.
(Item 51)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, comprising heavy chain CDRs and light chain CDRs, wherein the heavy chain CDR1, CDR2 and CDR3 sequences are: The antibody or antigen-binding portion thereof, respectively, set forth in SEQ ID NOs: 164, 165 and 166, wherein the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 172, 173 and 174, respectively.
(Item 52)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, which comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is SEQ ID NO: The light chain variable region comprises an amino acid sequence selected from the group consisting of 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 376 and 389. The antibody or antigen thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65, 87, 109, 131, 153, 175, 199, 221, 243, 265, 287, 309, 331, 353, 375 and 397. Joining part.
(Item 53)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) SEQ ID NOs: 57 and 65, respectively;
(Ii) SEQ ID NOs: 79 and 87, respectively;
(Iii) SEQ ID NOs: 101 and 109, respectively;
(Iv) SEQ ID NOs: 123 and 131, respectively;
(V) SEQ ID NOs: 145 and 153, respectively;
(Vi) SEQ ID NOs: 167 and 175, respectively;
(Vii) SEQ ID NOs: 191 and 199, respectively;
(Viii) SEQ ID NOs: 213 and 221; respectively;
(Ix) SEQ ID NOs: 235 and 243, respectively;
(X) SEQ ID NOs: 257 and 265, respectively;
(Xi) SEQ ID NOs: 279 and 287, respectively;
(Xii) SEQ ID NOs: 301 and 309, respectively;
(Xiii) SEQ ID NOs: 323 and 331, respectively;
(Xiv) SEQ ID NOs: 345 and 353, respectively;
(Xv) SEQ ID NOs: 367 and 375; and, respectively.
(Xvi) The antibody or antigen-binding portion thereof comprising a heavy chain variable region and a light chain variable region containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 389 and 397, respectively.
(Item 54)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, which comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is SEQ ID NO: An amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 376 and 389. The light chain variable region comprises the group consisting of SEQ ID NOs: 65, 87, 109, 131, 153, 175, 199, 221 and 243, 265, 287, 309, 331, 353, 375 and 397. The antibody or antigen-binding portion thereof, wherein the amino acid sequence comprises an amino acid sequence that is at least 90% identical.
(Item 55)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) SEQ ID NOs: 57 and 65, respectively;
(Ii) SEQ ID NOs: 79 and 87, respectively;
(Iii) SEQ ID NOs: 101 and 109, respectively;
(Iv) SEQ ID NOs: 123 and 131, respectively;
(V) SEQ ID NOs: 145 and 153, respectively;
(Vi) SEQ ID NOs: 167 and 175, respectively;
(Vii) SEQ ID NOs: 191 and 199, respectively;
(Viii) SEQ ID NOs: 213 and 221; respectively;
(Ix) SEQ ID NOs: 235 and 243, respectively;
(X) SEQ ID NOs: 257 and 265, respectively;
(Xi) SEQ ID NOs: 279 and 287, respectively;
(Xii) SEQ ID NOs: 301 and 309, respectively;
(Xiii) SEQ ID NOs: 323 and 331, respectively;
(Xiv) SEQ ID NOs: 345 and 353, respectively;
(Xv) SEQ ID NOs: 367 and 375; and, respectively.
(Xvi) The antibody or antigen-binding portion thereof comprises a heavy chain variable region and a light chain variable region containing an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 389 and 397, respectively. ..
(Item 56)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, a heavy chain variable region and a light chain containing the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively. The antibody or antigen-binding portion thereof, which comprises a variable region.
(Item 57)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27 and is at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region containing a sequence.
(Item 58)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, comprising heavy and light chains, wherein the heavy chains are SEQ ID NOs: 67, 89, 111, It comprises an amino acid sequence selected from the group consisting of 133, 155, 177, 201, 243, 245, 267, 289, 311, 333, 355, 377 and 399, wherein the light chain comprises SEQ ID NOs: 69, 91, 113. The antibody or antigen-binding portion thereof comprising an amino acid sequence selected from the group consisting of 135, 157, 179, 203, 225, 247, 269, 291, 313, 335, 357, 379 and 401.
(Item 59)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, comprising heavy and light chains, wherein the heavy chains are SEQ ID NOs: 67, 89, 111, The light chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of 133, 155, 177, 201, 243, 245, 267, 289, 311, 333, 355, 377 and 399. Is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 91, 113, 135, 157, 179, 203, 225, 247, 269, 291, 313, 335, 357, 379 and 401. The antibody or antigen-binding portion thereof, which comprises an amino acid sequence that is.
(Item 60)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27 and comprises a heavy chain and a light chain, wherein the heavy chain is SEQ ID NO: 71, 93, 115. It comprises an amino acid sequence selected from the group consisting of 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381 and 403, wherein the light chain comprises SEQ ID NOs: 69, 91, 113. The antibody or antigen-binding portion thereof comprising an amino acid sequence selected from the group consisting of 135, 157, 179, 203, 225, 247, 269, 291, 313, 335, 357, 379 and 401.
(Item 61)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27 and comprises a heavy chain and a light chain, wherein the heavy chain is SEQ ID NO: 71, 93, 115. The light chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381 and 403. Is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 69, 91, 113, 135, 157, 179, 203, 225, 247, 269, 291, 313, 335, 357, 379 and 401. The antibody or antigen-binding portion thereof, which comprises an amino acid sequence that is.
(Item 62)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) SEQ ID NOs: 67 and 69, respectively;
(Ii) SEQ ID NOs: 89 and 91, respectively;
(Iii) SEQ ID NOs: 111 and 113, respectively;
(Iv) SEQ ID NOs: 133 and 135, respectively;
(V) SEQ ID NOs: 155 and 157, respectively;
(Vi) SEQ ID NOs: 177 and 179, respectively;
(Vii) SEQ ID NOs: 201 and 203, respectively;
(Viii) SEQ ID NOs: 243 and 225, respectively;
(Ix) SEQ ID NOs: 245 and 247, respectively;
(X) SEQ ID NOs: 267 and 269, respectively;
(Xi) SEQ ID NOs: 289 and 291; respectively;
(Xii) SEQ ID NOs: 311 and 313, respectively;
(Xiii) SEQ ID NOs: 333 and 335, respectively;
(Xiv) SEQ ID NOs: 355 and 357, respectively;
(Xv) SEQ ID NOs: 377 and 379, respectively; and
(Xvi) The antibody or antigen-binding portion thereof comprising a heavy chain and a light chain containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 399 and 401, respectively.
(Item 63)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) SEQ ID NOs: 67 and 69, respectively;
(Ii) SEQ ID NOs: 89 and 91, respectively;
(Iii) SEQ ID NOs: 111 and 113, respectively;
(Iv) SEQ ID NOs: 133 and 135, respectively;
(V) SEQ ID NOs: 155 and 157, respectively;
(Vi) SEQ ID NOs: 177 and 179, respectively;
(Vii) SEQ ID NOs: 201 and 203, respectively;
(Viii) SEQ ID NOs: 243 and 225, respectively;
(Ix) SEQ ID NOs: 245 and 247, respectively;
(X) SEQ ID NOs: 267 and 269, respectively;
(Xi) SEQ ID NOs: 289 and 291; respectively;
(Xii) SEQ ID NOs: 311 and 313, respectively;
(Xiii) SEQ ID NOs: 333 and 335, respectively;
(Xiv) SEQ ID NOs: 355 and 357, respectively;
(Xv) SEQ ID NOs: 377 and 379, respectively; and
(Xvi) The antibody or antigen-binding portion thereof comprising a heavy chain and a light chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 399 and 401, respectively.
(Item 64)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) SEQ ID NOs: 71 and 69, respectively;
(Ii) SEQ ID NOs: 93 and 91, respectively;
(Iii) SEQ ID NOs: 115 and 113, respectively;
(Iv) SEQ ID NOs: 137 and 135, respectively;
(V) SEQ ID NOs: 159 and 157, respectively;
(Vi) SEQ ID NOs: 181 and 179, respectively;
(Vii) SEQ ID NOs: 205 and 203, respectively;
(Viii) SEQ ID NOs: 227 and 225, respectively;
(Ix) SEQ ID NOs: 249 and 247, respectively;
(X) SEQ ID NOs: 271 and 269, respectively;
(Xi) SEQ ID NOs: 293 and 291; respectively;
(Xii) SEQ ID NOs: 315 and 313, respectively;
(Xiii) SEQ ID NOs: 337 and 335, respectively;
(Xiv) SEQ ID NOs: 359 and 357, respectively;
(Xv) SEQ ID NOs: 381 and 379, respectively; and
(Xvi) The antibody or antigen-binding portion thereof comprising a heavy chain and a light chain containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 403 and 401, respectively.
(Item 65)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, and the following:
(I) SEQ ID NOs: 71 and 69, respectively;
(Ii) SEQ ID NOs: 93 and 91, respectively;
(Iii) SEQ ID NOs: 115 and 113, respectively;
(Iv) SEQ ID NOs: 137 and 135, respectively;
(V) SEQ ID NOs: 159 and 157, respectively;
(Vi) SEQ ID NOs: 181 and 179, respectively;
(Vii) SEQ ID NOs: 205 and 203, respectively;
(Viii) SEQ ID NOs: 227 and 225, respectively;
(Ix) SEQ ID NOs: 249 and 247, respectively;
(X) SEQ ID NOs: 271 and 269, respectively;
(Xi) SEQ ID NOs: 293 and 291; respectively;
(Xii) SEQ ID NOs: 315 and 313, respectively;
(Xiii) SEQ ID NOs: 337 and 335, respectively;
(Xiv) SEQ ID NOs: 359 and 357, respectively;
(Xv) SEQ ID NOs: 381 and 379, respectively; and
(Xvi) The antibody or antigen-binding portion thereof comprising a heavy chain and a light chain containing an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 403 and 401, respectively.
(Item 66)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, comprising heavy and light chains comprising the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively. , The antibody or its antigen-binding portion.
(Item 67)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27 and is at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain and a light chain containing a sequence.
(Item 68)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, comprising heavy and light chains comprising the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively. , The antibody or its antigen-binding portion.
(Item 69)
An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27 and is at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively. The antibody or antigen-binding portion thereof, comprising a heavy chain and a light chain containing a sequence.
(Item 70)
A pharmaceutical composition comprising the isolated monoclonal antibody or antigen-binding moiety thereof according to any one of the preceding items, and a pharmaceutically acceptable carrier.
(Item 71)
A nucleic acid comprising the light chain, heavy chain, or nucleotide sequence encoding both the light chain and the heavy chain of the isolated monoclonal antibody or antigen-binding portion thereof according to any one of items 1 to 69.
(Item 72)
An expression vector comprising the nucleic acid of item 71.
(Item 73)
Cells transformed with the expression vector according to item 72.
(Item 74)
A method for producing a monoclonal antibody or an antigen-binding portion thereof that specifically binds to human IL-27, under conditions that allow the cells according to item 73 to express the monoclonal antibody or the antigen-binding portion thereof. Said method comprising maintaining.
(Item 75)
74. The method of item 74, further comprising obtaining said monoclonal antibody or antigen binding portion thereof.
(Item 76)
A method of inhibiting or reducing STAT1 and / or STAT3 phosphorylation in a cell, wherein the cell is contacted with an isolated monoclonal antibody or antigen binding fragment according to any one of items 1-69. The method comprising, wherein the antibody or antigen binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in cells.
(Item 77)
A method of inhibiting or reducing the inhibition of CD161 expression in a cell, comprising contacting the cell with an isolated monoclonal antibody or antigen binding fragment according to any one of items 1-69. The method described above, wherein the antibody or antigen-binding portion thereof inhibits or reduces inhibition of CD161 expression in cells.
(Item 78)
A method of inhibiting or reducing PD-L1 and / or TIM-3 expression in a cell, wherein the cell is contacted with the isolated monoclonal antibody or antigen binding fragment according to any one of items 1 to 69. The method, wherein the antibody or antigen-binding portion thereof inhibits or inhibits PD-L1 and / or TIM-3 expression in cells.
(Item 79)
A method of inducing or enhancing the secretion of one or more cytokines from a cell, wherein the cell is contacted with the isolated monoclonal antibody or antigen binding fragment according to any one of items 1-69. That method, wherein the antibody or antigen-binding portion thereof induces or enhances PD-1-mediated secretion of one or more cytokines from a cell.
(Item 80)
A method of stimulating an immune response of a subject, wherein an effective amount of the isolated monoclonal antibody or antigen-binding fragment according to any one of items 1 to 69 or the pharmaceutical composition according to item 70. The above-mentioned method comprising administering.
(Item 81)
A method for treating a cancer of a subject, wherein an effective amount of the isolated monoclonal antibody or antigen-binding fragment according to any one of items 1 to 69 or the pharmaceutical composition according to the item 70 is given to the subject. The above-mentioned method comprising administering.
(Item 82)
A method of stimulating an immune response or treating a subject, wherein the subject is an isolated monoclonal antibody or antigen binding fragment or item 70 according to any one of items 1 to 69 of an effective amount. The antibody or antigen-binding portion thereof or the pharmaceutical composition inhibits or reduces STAT1 and / or STAT3 phosphorylation in cells, thereby stimulating the immune response. Or the method of treating the cancer.
(Item 83)
A method of stimulating an immune response or treating a subject, wherein the subject is an isolated monoclonal antibody or antigen binding fragment or item 70 according to any one of items 1 to 69 of an effective amount. The antibody or antigen-binding portion thereof or the pharmaceutical composition comprises administering the pharmaceutical composition according to the above, thereby inhibiting or reducing the inhibition of CD161 expression in cells, thereby stimulating or said the immune response. The above-mentioned method for treating an antibody.
(Item 84)
A method of stimulating an immune response or treating a subject, wherein the subject is an isolated monoclonal antibody or antigen binding fragment or item 70 according to any one of items 1 to 69 of an effective amount. The antibody or antigen-binding portion thereof or the pharmaceutical composition inhibits or reduces PD-L1 and / or TIM-3 expression on cells, thereby comprising the administration of the pharmaceutical composition according to the above. The method of stimulating a response or treating the cancer.
(Item 85)
A method of stimulating an immune response or treating a subject, wherein the subject is an isolated monoclonal antibody or antigen binding fragment or item 70 according to any one of items 1 to 69 of an effective amount. The antibody or antigen-binding portion thereof or the pharmaceutical composition induces or enhances PD-1-mediated secretion of one or more cytokines from a cell, comprising administering the pharmaceutical composition according to the above. The method of stimulating the immune response or treating the cancer.
(Item 86)
The cancers are lung cancer (eg, non-small cell lung cancer), sarcoma, testis cancer, ovarian cancer, pancreatic cancer, breast cancer (eg, triple negative breast cancer), melanoma, head and neck cancer (eg, squamous epithelial head and neck cancer). ), Colon-rectal cancer, bladder cancer, endometrial cancer, prostate cancer, thyroid cancer, hepatocellular carcinoma, gastric cancer, brain cancer, lymphoma (eg DL-BCL), leukemia (eg AML) or renal cancer (eg AML) Item 8. The method according to any one of items 81 to 85, which is selected from renal cell carcinoma (eg, clear cell carcinoma of the kidney).
(Item 87)
Exposed to an anti-PD-1 antibody that enhances the activity of one or more of the anti-PD-1 antibodies (eg, enhances PD-1-mediated cytokine secretion, enhances anti-PD-1-mediated TNFα secretion, 1 The method described above comprising exposure to an antibody or an antigen-binding portion thereof, thereby enhancing the activity of one or more of the anti-PD-1 antibodies.
(Item 88)
A pharmaceutical composition comprising an anti-PD-1 antibody, the antibody according to any one of items 1 to 69 or an antigen-binding moiety thereof, and a pharmaceutically acceptable carrier.
(Item 89)
A kit comprising an anti-PD-1 antibody and an antibody according to any one of items 1 to 69 or an antigen-binding portion thereof, and instructions for use thereof for simultaneous or sequential administration.
(Item 90)
The isolated monoclonal antibody or antigen-binding portion thereof is administered in combination with one or more additional therapeutic agents or procedures, wherein the second therapeutic agent or procedure is a chemotherapeutic, targeted anti-cancer therapy. A group consisting of tumor lytic agents, cytotoxic agents, immune system therapies, cytokines, surgical procedures, radiological procedures, costimulatory molecule activators, inhibitory molecule inhibitors, vaccines, or cellular immunotherapies, or a combination thereof. The method according to any one of items 80 to 86, which is selected from.
(Item 91)
The one or more additional therapeutic agents include PD-1 antagonists, PD-L1 inhibitors, TIM-3 inhibitors, LAG-3 inhibitors, TIGIT inhibitors, CD112R inhibitors, TAM inhibitors, STING agonists, 4-1. The method of item 90, which is a 4-1BB agonist, or a combination thereof.
(Item 92)
91. The method of item 91, wherein the one or more additional therapeutic agents are PD-1 antagonists.
(Item 93)
92. The method of item 92, wherein the PD-1 antagonist is selected from the group consisting of PDR001, nivolumab, pembrolizumab, pidirizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, and AMP-224.
(Item 94)
The method according to item 91, wherein the PD-L1 inhibitor is selected from the group consisting of FAZ053, atezolizumab, avelumab, durvalumab, and BMS-936559.
(Item 95)
The one or more additional therapeutic agents are sunitinib (Sentent®), cabozantinib (Cabometyx®), axitinib (Inlyta®), lembatinib (Lenvima®), everolimus ( Afinitor®), bevasizumab (Avastin®), epacadostat, NKTR-214 (CD-122 bias agonist), tibozanib (Fotivda®), abexinostat, ipilimumab (Yervoy®). , Tremelimumab, Pazopanib (Votrient®), Sorafenib (Nexavar®), Everolimus (Torisel®), Ramsilmab (Cyramza®), Nivolumab, Sunitinib, Bororanib (X-82) Legorafenib (Stivalgo®), Donafenib (multikinase inhibitor), Kamrelizumab (SHR-1210), Pexastimodin debasilepbec (JX-594), Ramsilmab (Cyramza®), Apatinib (YN968D1) ), Encapsulated doxorubicin (Thermodox®), Tibantinib (ARQ197), ADI-PEG20, Vinimetinib, Apatinib mesylate, Nintedanib, Lilylumab, Nivolumab (Opdivo® registered trademark), Pembrolizumab® , Atezolizumab (Tecentriq®), Avelumab (Bavencio®), Durvalumab (Imfimzi®), Semiprimab-rwlc (Libtayo®), Chisrelismab, and Spartarizumab. The method according to item 91.
(Item 96)
91. The method of item 91, wherein the one or more additional therapeutic agents is a TIM-3 inhibitor and, optionally, the TIM-3 inhibitor is MGB453 or TSR-022.
(Item 97)
The one or more additional therapeutic agents are LAG-3 inhibitors, and optionally the LAG-3 inhibitor is selected from the group consisting of LAG525, BMS-986016, and TSR-033. The method according to item 91.
(Item 98)
91. The method of item 91, wherein the one or more additional therapeutic agents are TIGIT inhibitors.
(Item 99)
91. The method of item 91, wherein the one or more additional therapeutic agents are CD112R inhibitors.
(Item 100)
91. The method of item 91, wherein the one or more additional therapeutic agents are TAM (Axl, Mer, Tyro) inhibitors.
(Item 101)
91. The method of item 91, wherein the one or more additional therapeutic agents are 4-1BB agonists.
(Item 102)
91. The method of item 91, wherein the one or more additional therapeutic agents are tyrosine kinase inhibitors (TKIs).
(Item 103)
A method for detecting IL-27 or EBI3 in a sample from a subject, wherein (a) the sample from the subject is detected in the presence of a detection antibody and IL-27 or EBI3 in the sample. Contacting under conditions that allow the antibody to form a detection antibody-EBI3 complex, wherein the detection antibody is the antibody according to any one of items 1-69 or an antigen-binding fragment thereof. And (b), if present, said method comprising detecting the presence of said complex produced in step (a).
(Item 104)
A method for detecting IL-27-related cancer in a subject, wherein (a) a sample from a subject suspected of having IL-27-related cancer is contained in the sample with a detection antibody and IL-27 or EBI3. The step of contacting, if present, under conditions that allow the detection antibody to form a detection antibody-EBI3 complex, wherein the detection antibody is the antibody or antibody according to any one of items 1-69. The method comprising detecting the presence of said complex produced in step (a), which is the antigen-binding portion and (b) is present.
(Item 105)
The method of item 103 or 104, wherein the detection antibody is bound to a detectable label.
(Item 106)
The method further comprises contacting the sample with a capture antibody to produce a complex comprising IL-27 or EBI3 and the capture antibody when IL-27 or EBI3 is present in the sample. The method according to any one of items 103 to 105, wherein the capture antibody is the antibody according to any one of items 1 to 69 or an antigen-binding portion thereof.
(Item 107)
106. The method of item 106, wherein the capture antibody is immobilized on a solid support.
(Item 108)
The method according to any one of items 103 to 107, wherein the sample is brought into contact with the capture antibody before the detection antibody.
(Item 109)
The method according to any one of items 103 to 108, wherein the sample is a body fluid sample.
(Item 110)
The method of item 109, wherein the fluid sample is blood, serum, plasma, cytolysis or tissue lysate.
(Item 111)
Any of items 104 to 110, wherein the cancer is selected from renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), lung cancer, gastroesophageal cancer, ovarian cancer, endometrial cancer, melanoma, leukemia and lymphoma. Or the method described in item 1.
(Item 112)
The method of item 111, wherein the cancer is renal cell carcinoma (RCC).
(Item 113)
The method of item 111, wherein the cancer is hepatocellular carcinoma (HCC).
(Item 114)
111. The method of item 111, wherein the cancer is selected from leukemia and lymphoma.
(Item 115)
The method of item 111, wherein the cancer is ovarian cancer.
(Item 116)
Item 1. The use of the isolated monoclonal antibody or antigen-binding portion thereof according to Item 70, or the pharmaceutical composition according to Item 70.
(Item 117)
The isolated monoclonal antibody or antigen-binding portion thereof according to any one of items 1 to 69, or the pharmaceutical composition according to item 70, and its use in stimulating an immune response of a subject or treating a cancer of a subject. A kit that includes instructions in combination with one or more additional therapeutic agents or procedures, optionally accompanied by instructions.
(Item 118)
An instruction manual for detecting IL-27 in a sample from the isolated monoclonal antibody or antigen-binding portion thereof according to any one of items 1 to 69 and a control is described in the subject IL-27 association. A kit that includes optional instructions for detecting antibodies.

Claims (17)

An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, and the following:
(I) Heavy chain CDR1 consisting of N-GFTFXXXX-C (SEQ ID NO: 408), heavy chain CDR2 consisting of N-ISSSXXYI-C (SEQ ID NO: 409), and heavy chain CDR3 sequence set forth in SEQ ID NO: 163; and each. From the light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 169, 170 and 171; or from the heavy chain CDR1, N-XISSSXXYIXYADSVKG-C (SEQ ID NO: 411) consisting of (ii) N-FTFXXXXMN-C (SEQ ID NO: 410). Heavy chain CDR2 and heavy chain CDR3 sequence set forth in SEQ ID NO: 166; and heavy chain CDR and light chain selected from the group consisting of light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 172, 173 and 174, respectively. The antibody or antigen-binding portion thereof, comprising a chain CDR. The heavy chain CDR1 is composed of N-GFTF [S / A / R] [S / R] [T / Y] [G / S] -C (SEQ ID NO: 412), and the heavy chain CDR2 is N-ISSS. It consists of [S / G] [S / A] YI-C (SEQ ID NO: 413); or the heavy chain CDR1 is N-FTF [S / A / R] [S / R] [T / Y] [G. / S] MN-C (SEQ ID NO: 414), and the heavy chain CDR2 is N- [G / S] ISSS [S / G] [S / A] YI [L / Y] YADSVKG-C (SEQ ID NO: 414). The isolated monoclonal antibody according to claim 1 , comprising 415). (I) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 161 and 162 and 163, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 169, 170 and 171 respectively. Have been described;
(Ii) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 164, 165 and 166, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 172, 173 and 174, respectively. Have been described;
(Iii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 73, 74 and 75, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are in SEQ ID NOs: 81, 82 and 83, respectively. Have been described;
(Iv) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 76, 77 and 78, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 84, 85 and 86, respectively. Have been described;
(V) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 95, 96 and 97, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are found in SEQ ID NOs: 103, 104 and 105, respectively. Have been described;
(Vi) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 98, 99 and 100, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 106, 107 and 108, respectively. Have been described;
(Vii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 117, 118 and 119, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 125, 126 and 127, respectively. Have been described;
(Viii) The heavy chain CDR1, CDR2 and CDR3 sequences are described in SEQ ID NOs: 120, 121 and 122, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are in SEQ ID NOs: 128, 129 and 130, respectively. Have been described;
(Ix) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 139, 140 and 141, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 147, 148 and 149, respectively. Have been described;
(X) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 142, 143 and 144, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are located in SEQ ID NOs: 150, 151 and 152, respectively. Have been described;
(Xi) The heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 51, 52 and 53, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 59, 60 and 61, respectively. Described; or (xii) the heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 54, 55 and 56, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are respectively SEQ ID NO: 62, 63 and 64, the isolated monoclonal antibody of claim 1 or 2 . (I) The antibody or antigen-binding portion thereof antagonizes IL-27 and / or
(Ii) The antibody or antigen-binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in cells, and the cells are, if necessary, immune cells or cancer cells, and / or.
(Iii) The antibody or antigen-binding portion thereof inhibits or reduces inhibition of CD161 expression in cells and / or
(Iv) The antibody or antigen-binding portion thereof inhibits or reduces PD-L1 and / or TIM-3 expression in cells, and / or
(V) The antibody or antigen-binding portion thereof induces or enhances the PD-1-mediated secretion of one or more cytokines from a cell, and if necessary, the one or more cytokines are IFNg. , IL-17, TNFα and / or IL-6,
The isolated monoclonal antibody according to any one of claims 1 to 3 or an antigen-binding portion thereof. The antibody comprises (i) wild-type IgG1 heavy chain constant region , (ii) wild-type IgG4 heavy chain constant region, (iii) mutant IgG1 heavy chain constant region, or (iv) mutant IgG4 heavy chain constant region. The isolated monoclonal antibody according to any one of claims 1 to 4, or an antigen-binding portion thereof. The isolated monoclonal antibody or antigen-binding portion thereof according to claim 5 , wherein the mutant IgG4 heavy chain constant region comprises any one or a combination of substitutions S228P, L235E, L235A according to EU numbering. .. The isolated monoclonal antibody according to any one of claims 1 to 6 or an antigen-binding portion thereof, wherein the following:
(I) SEQ ID NOs: 167 and 175, respectively;
( Ii ) SEQ ID NOs: 57 and 65, respectively;
( Iii ) SEQ ID NOs: 79 and 87, respectively;
( Iv ) SEQ ID NOs: 101 and 109, respectively;
( V ) SEQ ID NOs: 123 and 131, respectively;
( Vi ) SEQ ID NOs: 145 and 153, respectively;
(Vii) SEQ ID NOs: 191 and 199, respectively;
(Viii) SEQ ID NOs: 213 and 221; respectively;
(Ix) SEQ ID NOs: 235 and 243, respectively;
(X) SEQ ID NOs: 257 and 265, respectively;
(Xi) SEQ ID NOs: 279 and 287, respectively;
(Xii) SEQ ID NOs: 301 and 309, respectively;
(Xiii) SEQ ID NOs: 323 and 331, respectively;
(Xiv) SEQ ID NOs: 345 and 353, respectively;
(Xv) Heavy chain variable region and light chain containing an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 367 and 375; and (xvi), respectively. The antibody or antigen-binding portion thereof, which comprises a variable region. The isolated monoclonal antibody according to any one of claims 1 to 7 or an antigen-binding portion thereof, which comprises a heavy chain variable region and a light chain variable containing the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively. The antibody or antigen-binding portion thereof, which comprises a region. The isolated monoclonal antibody according to any one of claims 1 to 8 or the antigen-binding portion thereof, (i) the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively, or (ii), respectively. The antibody or antigen-binding portion thereof comprises a heavy chain and a light chain containing an amino acid sequence that is at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 181 and 179 . The isolated monoclonal antibody or antigen-binding moiety thereof according to any one of claims 1 to 9 , wherein (i) the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively, or (ii) , respectively. The antibody or antigen-binding portion thereof, comprising heavy and light chains comprising the amino acid sequences set forth in SEQ ID NOs: 181 and 179. A pharmaceutical composition comprising the isolated monoclonal antibody according to any one of claims 1 to 10 or an antigen-binding portion thereof, and a pharmaceutically acceptable carrier. A nucleic acid comprising a light chain, a heavy chain, or a nucleotide sequence encoding both a light chain and a heavy chain of the isolated monoclonal antibody according to any one of claims 1 to 10 or an antigen-binding portion thereof. An expression vector comprising the nucleic acid according to claim 12 . A cell transformed with the expression vector according to claim 13 . A method for producing a monoclonal antibody or an antigen-binding portion thereof that specifically binds to human IL-27, wherein the cell according to claim 14 can express the monoclonal antibody or the antigen-binding portion thereof. Said method comprising maintaining in. (I) Inhibits or reduces STAT1 and / or STAT3 phosphorylation in cells, (ii) Inhibits or reduces inhibition of CD161 expression in cells, (iii) Inhibits PD-L1 and / or TIM-3 expression in cells Or decreased, according to any one of claims 1-10 , for (v) inducing or enhancing the secretion of one or more cytokines from the cell, or (v) stimulating the immune response of the subject. A composition comprising an isolated monoclonal antibody or antigen-binding fragment of. 11. A composition comprising an isolated monoclonal antibody or antigen-binding fragment according to any one of claims 1 to 10 for stimulating an immune response or treating cancer of a subject. Pharmaceutical composition .