Anti-il-27 antibodies and uses thereof

Abstract

To provide anti-IL-27 antibodies and uses thereof.SOLUTION: The present disclosure relates to anti-IL-27 antibodies and antigen-binding portions thereof. The disclosure also relates to methods for treating or ameliorating one or more symptoms of a disease, such as cancer, by administering the antibodies or antigen-binding portions thereof. The present disclosure also relates to methods for detecting IL-27, e.g., in a subject or sample. Disclosed herein are antibodies or antigen-binding portions thereof that specifically bind to and antagonize human IL-27 (interleukin 27) with high affinity and specificity. Nucleic acid molecules encoding the antibody molecules, expression vectors, host cells, and methods of making the antibody molecules are also provided. Pharmaceutical compositions comprising the antibody molecules are also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 646,496, filed March 22, 2018, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates generally to compositions and methods for modulating IL-27 signaling. More specifically, the present disclosure relates to immunogenic compositions (e.g., antibodies, antibody fragments, etc.) that bind to IL-27 and modulate IL-27 signaling. [Background technology]

[0003] In recent years, a growing body of evidence has demonstrated that the immune system functions as an important barrier against tumor formation and progression. The principle that naturally occurring T cells with anti-tumor potential or activity exist in cancer patients has rationalized the development of immunotherapy approaches in oncology. Immune cells such as T cells, macrophages, and natural killer cells exhibit anti-tumor activity and can effectively control the development and growth of malignant tumors. Tumor-specific or tumor-associated antigens can direct immune cells to recognize and eliminate malignancies (Chen & Mellman, (2013) Immunity 39(1):1-10). Despite the existence of tumor-specific immune responses, malignant tumors often escape or evade immune attack through various immunoregulatory mechanisms, resulting in failure to control tumor development and progression (Motz & Coukos, (2013) Immunity 39(1):61-730). Indeed, an emerging hallmark of cancer is the exploitation of these immunoregulatory mechanisms and the abrogation of antitumor immune responses, resulting in tumor evasion and escape from immunological killing (Hanahan and Weinberg (2011) Cell 144(5):646-674).

[0004] IL-27 is a heterodimeric cytokine composed of two subunits (EBI3 and IL-27p28). IL-27 is structurally related to both the IL-12 and IL-6 cytokine families. IL-27 binds to and mediates signaling through a heterodimeric receptor composed of IL-27Rα (WSX1) and gp130 chains, which mediates signaling primarily through STAT1 and STAT3. Initial reports characterized IL-27 as an immunopotentiating cytokine that supports CD4+ T cell proliferation, T helper (Th)1 cell differentiation, and IFN-γ production, often acting in concert with IL-12. Subsequent studies have demonstrated that IL-27 exhibits complex immunoregulatory functions, resulting in pro- or anti-inflammatory effects depending on the biological context and experimental model used. IL-27 can drive the expression of different immunoregulatory molecules in human cancer cells, which may support local perturbation of immune responses in vivo (Fabbi et al., (2017) Mediators Inflamm 3958069. Published online February 1, 2017. doi:10.1155 / 2017 / 3958069, and references contained therein). Despite significant advances in cancer treatment and management, there remains a need for new and effective therapies for treating and managing cancer. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Chen & Mellman, (2013) Immunity 39(1):1-10 [Non-patent document 2] Motz & Coukos, (2013) Immunity 39(1):61-730 [Non-patent document 3] Hanahan and Weinberg (2011) Cell 144(5):646-674 [Non-patent document 4] Fabbi et al.,(2017)Mediators Inflamm 3958069 Summary of the Invention [Means for solving the problem]

[0006] Disclosed herein are antibodies, or antigen-binding portions thereof, that specifically bind to and antagonize human IL-27 (interleukin-27) with high affinity and specificity. Nucleic acid molecules encoding the antibody molecules, expression vectors, host cells, and methods for making the antibody molecules are also provided. Pharmaceutical compositions comprising the antibody molecules are also provided. The anti-IL-27 antibodies, or antigen-binding portions thereof, disclosed herein can be used (alone or in combination with other therapeutic agents or procedures) to treat, prevent, and / or diagnose disorders, including immune disorders and cancer. Thus, disclosed herein are compositions and methods for treating and / or diagnosing various disorders, including cancer and immune disorders, using anti-IL-27 antibody molecules.

[0007] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, has the following properties: (i) an equilibrium dissociation constant (K D (ii) block the binding of IL-27 to the IL-27 receptor; (iii) inhibit or reduce STAT1 and / or STAT3 phosphorylation in the cell; (iv) inhibit or reduce inhibition of CD161 expression in the cell; (v) inhibit or reduce PD-L1 and / or TIM-3 expression in the cell; (vi) induce or enhance PD-1-mediated secretion of one or more cytokines from the cell; and (vii) exhibit at least one or more combinations of (i)-(vi).

[0008] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, binds to human IL-27 with an equilibrium dissociation constant (K D ) to join them.

[0009] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, binds to recombinant human IL-27 or murine IL-27.

[0010] In one aspect, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising: (i) a heavy chain CDR1 is N-GFTFXXXX-C (SEQ ID NO: 408), a heavy chain CDR2 is N-ISSSXXYI-C (SEQ ID NO: 409), and a heavy chain CDR3 sequence is SEQ ID NO: 163; and (ii) a light chain CDR1, CDR2, and CDR3 sequence is or (ii) the heavy chain CDR1 is N-FTFXXXXMN-C (SEQ ID NO: 410), the heavy chain CDR2 is N-XISSSXXYIXYADSVKG-C (SEQ ID NO: 411), and the heavy chain CDR3 sequence is SEQ ID NO: 166; and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 172, 173, and 174, respectively.

[0011] In one embodiment, the heavy chain CDR1 is N-GFTF[S / A / R][S / R][T / Y][G / S]-C (sequence number 412) and the heavy chain CDR2 is N-ISSS[S / G][S / A]YI-C (sequence number 413); or the heavy chain CDR1 is N-FTF[S / A / R][S / R][T / Y][G / S]MN-C (sequence number 414) and the heavy chain CDR2 is N-[G / S]ISSS[S / G][S / A]YI[L / Y]YADSVKG-C (sequence number 415).

[0012] In another embodiment, the respective heavy and light chain CDRs are: (i) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 161, 162, and 163, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 169, 170, and 171, respectively; (ii) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 164, 165, and 166, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 172, 173, and 174, respectively; (iii) the heavy chain CDR1, CDR2, and CDR3 sequences are (iv) the heavy chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 76, 77 and 78, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 84, 85 and 86, respectively; (v) the heavy chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 95, 96 and 97, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are SEQ ID NOs: 103, 104 and 105, respectively. (vi) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 98, 99, and 100, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 106, 107, and 108, respectively; (vii) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 117, 118, and 119, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 125, 126, and 127, respectively; (viii) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 120, 121, and 122, respectively. 22, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 128, 129, and 130, respectively; (ix) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 139, 140, and 141, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 147, 148, and 149, respectively; (x) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 142, 143, and 144, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 150, 151, and 152, respectively;(xi) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 51, 52, and 53, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 59, 60, and 61, respectively; or (xii) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 54, 55, and 56, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 62, 63, and 64, respectively;

[0013] Another aspect of the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises: (i) a heavy chain CDR1 is N-GGSFSXYX-C (SEQ ID NO: 416), a heavy chain CDR2 is N-IDXSGXT-C (SEQ ID NO: 417), and a heavy chain CDR3 is N-ARXXXYY[X] n=0-1 DSS[X] n=4-6 and (ii) the heavy chain CDR1 is N-GSFSXYXWS-C (SEQ ID NO: 422), the heavy chain CDR2 is N-SIDXSGXTXYNPSLKS-C (SEQ ID NO: 423), and the heavy chain CDR3 sequence is N-ARXXXYY[X] n=0-1 DSS[X] n=4-6 DX-C (SEQ ID NO: 418); and light chain CDR1 is N-XASQXXSXYLX-C (SEQ ID NO: 424), light chain CDR2 is N-DXSNXXT-C (SEQ ID NO: 425), and light chain CDR3 is N-QQXXDXPIT-C (SEQ ID NO: 421).

[0014] In certain embodiments, (i) the heavy chain CDR1 is N-GGSFS[R / D]Y[E / Y]-C (SEQ ID NO: 426), the heavy chain CDR2 is N-ID[W / Y]SG[I / S]TC (SEQ ID NO: 427), and the heavy chain CDR3 is N-AR[D / L][P / G][M / V]YY[- / Y]DSS[VSTGSV / DLGF]D[V / I]-C (SEQ ID NO: 428), respectively; and the light chain CDR1 is NQ[S / D][V / I]S[S / N]YC (SEQ ID NO: 429), the light chain CDR2 is ND[S / A]SC (SEQ ID NO: 430), and the light chain CDR3 is N-QQ[D / Y][S / D]D[H / L]PIT-C (SEQ ID NO: 431), respectively; or (ii) the heavy chain CDR heavy chain CDR1 is N-GSFS[R / D]Y[E / Y]WS-C (SEQ ID NO: 432), heavy chain CDR2 is N-SID[W / Y]SG[I / S]T[N / E]YNPSLKS-C (SEQ ID NO: 433), and heavy chain CDR3 is N-AR[D / L][P / G][M / V]YY[- / Y]DSS[VSTGSV / DLGF]D[V / I]-C (SEQ ID NO: 428); and light chain CDR1 is N-[Q / R]ASQ[S / D][V / I]S[S / N]YL[N / A]-C (SEQ ID NO: 434), light chain CDR2 is ND[S / A]SN[R / L][A / E]TC (SEQ ID NO: 435), and light chain CDR3 is N-QQ[D / Y][S / D]D[H / L]PIT-C (SEQ ID NO: 431).

[0015] In some embodiments, (i) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 229, 230, and 231, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 237, 238, and 239, respectively; or (ii) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 232, 233, and 234, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 240, 241, and 242, respectively.

[0016] In certain embodiments, (i) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 251, 252, and 253, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 259, 260, and 261; or (ii) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 254, 255, and 256, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 262, 263, and 264, respectively.

[0017] Another aspect of the present disclosure provides an isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, wherein the antibody or antigen-binding portion thereof comprises heavy chain and light chain CDRs, wherein the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 23, 24, and 25, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 26, 27, and 28, respectively.

[0018] An additional aspect of the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises heavy and light chain CDRs in which: (i) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 339, 340, and 341, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 347, 348, and 349, respectively; or (ii) the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 342, 343, and 344, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 350, 351, and 352, respectively.

[0019] Another aspect of the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises: (i) heavy chain CDRs and light chain CDRs, wherein the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 185, 186, and 187, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 193, 194, and 195, respectively; or (ii) heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 188, 189, and 190, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 196, 197, and 198, respectively.

[0020] One aspect of the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises: (i) heavy chain CDRs and light chain CDRs, wherein the heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 207, 208, and 209, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 215, 216, and 217, respectively; or (ii) heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 210, 211, and 212, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 218, 219, and 220, respectively.

[0021] An additional aspect of the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises: (i) heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 273, 274, and 275, respectively, and light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 281, 282, and 283, respectively; or (ii) heavy chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 276, 277, and 278, respectively, and light chain CDR1, CDR2, and CDR3 sequences are SEQ ID NOs: 284, 285, and 286, respectively.

[0022] One aspect of the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising: (i) a heavy chain CDR1 is N-GFTFSSYG-C (SEQ ID NO: 361), a heavy chain CDR2 is N-IXXDGSXK-C (SEQ ID NO: 436), and a heavy chain CDR3 is N-ARXAP[X] n=3-8 DV-C (SEQ ID NO: 437); and light chain CDR1 is N-QSXSSY-C (SEQ ID NO: 438), light chain CDR2 is N-XXS-C (SEQ ID NO: 439), and light chain CDR3 is N-QQXXXXP[X] n=0-1 or (ii) the heavy chain CDR1 is N-FTFSSYGMX-C (SEQ ID NO: 441), the heavy chain CDR2 is N-XIXXDGSXKYYXDSVKG-C (SEQ ID NO: 442), and the heavy chain CDR3 is N-ARXAP[X] n=3-8 and the light chain CDR1 is N-RASQSXSSYLX-C (SEQ ID NO: 443) and the light chain CDR2 is N-[X] n=1-2 SS[X] n=3-4 -C (SEQ ID NO: 444), and the light chain CDR3 is N-QQXXXXP[X] n=0-1 TC (SEQ ID NO: 440).

[0023] In certain embodiments, (i) the heavy chain CDR1 is N-GFTFSSYG-C (SEQ ID NO: 361), the heavy chain CDR2 is NI[K / W][Q / Y]DGS[E / N]KC (SEQ ID NO: 445), and the heavy chain CDR3 is N-AR[D / G]AP[WDIYDYYM / EYV]DV-C (SEQ ID NO: 446), respectively; and the light chain CDR1 is N-QS[I / V]SSY-C (SEQ ID NO: 447), the light chain CDR2 is N-[A / D][A / S]SC (SEQ ID NO: 448), and the light chain CDR3 is N-QQ[S / Y][Y / S][V / L][P / Y]P[W / -]TC (SEQ ID NO: 449), respectively; or (ii) the heavy chain CDR1 is N-GFTFSSYG-C (SEQ ID NO: 361), the heavy chain CDR2 is N-[K / W][Q / Y]DGS[E / N]KC (SEQ ID NO: 445), and the heavy chain CDR3 is N-AR[D / G]AP[WDIYDYYM / EYV]DV-C (SEQ ID NO: 446), respectively; R1 is N-FTFSSYGM[S / H]-C (sequence number 450), heavy chain CDR2 is N-[N / V]I[K / W][Q / Y]DGS[E / N]KYY[V / A]DSVKG-C (sequence number 451), heavy chain CDR3 is N-AR[D / G]AP[WDIYDYYM / EYV]DV-C (sequence number 446); and light chain CDR1 is N-RASQS[I / V]SSYL[N / A]-C (sequence number 452), light chain CDR2 is N-[AA / D]SS[LQS / NRAT]-C (sequence number 453), and light chain CDR3 is N-QQ[S / Y][Y / S][V / L][P / Y]P[W / -]TC (sequence number 449).

[0024] In some embodiments, (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; or (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.

[0025] In one embodiment, (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; or (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.

[0026] Another aspect of the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising: (i) a heavy chain CDR1 is N-GFTFXXXX-C (SEQ ID NO: 408), a heavy chain CDR2 is N-IXXXXXXX-C (SEQ ID NO: 456), and a heavy chain CDR3 is N-AR[X] n=6-15 DX-C (SEQ ID NO: 458); and light chain CDR1 is N-QS[X] n=1-3 SS[X] n=0-4 YC (SEQ ID NO: 460), light chain CDR2 is N-XXS-C (SEQ ID NO: 462), and light chain CDR3 is N-QQXXXXP[X] n=0-1 or (ii) the heavy chain CDR1 is N-FTFXXXXMX-C (SEQ ID NO: 466), the heavy chain CDR2 is N-XIXXXXXXXXYXDSVKG-C (SEQ ID NO: 468), and the heavy chain CDR3 is N-AR[X] n=6-15 and light chain CDR1 is N-RASQSXSSYLX-C (SEQ ID NO: 472) and light chain CDR2 is N-[X]DX-C (SEQ ID NO: 470). n=1-2 S[X] n=4-5 -C (SEQ ID NO: 474), and light chain CDR3 is N-QQXXXXP[X] n=0-1 TC (SEQ ID NO: 476).

[0027] In certain embodiments, (i) the heavy chain CDR1 is N-GFTF[S / A / R][S / R][T / Y][G / S]-C (SEQ ID NO: 454), 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), and the heavy chain CDR3 is N-AR[DGGRTSYTATAHNWF / DAPWDIYDYYM / GAPEYV]D[ and light chain CDR1 is N-QS[VLF / I / V]SS[NNKN / -]YC (SEQ ID NO: 459), light chain CDR2 is N-[W / A / D][A / S]SC (SEQ ID NO: 461), and light chain CDR3 is N-QQ[H / S / Y][A / Y / S][S / V / L][A / P / Y]P[P / W / -]TC (SEQ ID NO: 463); or (ii) each of the heavy chain CDR1 is and heavy chain CDR3 is N-AR[D / G][GGRTSYTATAHNWF / APWDIYDYYM / A]. and light chain CDR1 is N-RASQS[I / V]SSYL[N / A]-C (SEQ ID NO: 471), light chain CDR2 is N-[WA / AA / D]S[TRES / SLQS / SNRAT]-C (SEQ ID NO: 473), and light chain CDR3 is N-QQ[H / S / Y][A / Y / S][S / V / L][A / P / Y]P[P / W / -]TC (SEQ ID NO: 475).

[0028] In some embodiments, the isolated monoclonal antibody or antigen-binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell. In some embodiments, the cell is an immune cell. In some embodiments, the cell is a cancer cell.

[0029] In some embodiments, the isolated monoclonal antibody or antigen-binding portion thereof inhibits or reduces inhibition of CD161 expression in the cell (e.g., restores or alleviates inhibition of CD161 expression in the cell). In some embodiments, the cell is an immune cell.

[0030] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, inhibits or reduces IL-27-mediated PD-L1 and / or TIM-3 expression in a cell. In some embodiments, PD-L1 expression is inhibited or reduced. In some embodiments, TIM-3 expression is inhibited or reduced. In some embodiments, both PD-L1 expression and TIM-3 expression are reduced. In some embodiments, the cell is an immune cell.

[0031] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, induces or enhances PD-1-mediated secretion of one or more cytokines from a cell. In some embodiments, the one or more cytokines are TNFα. In some embodiments, the one or more cytokines are IL-6. In some embodiments, the one or more cytokines are TNFα and IL-6. In some embodiments, the cell is an immune cell.

[0032] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, is selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibodies. In some embodiments, the antibody is an IgG1 antibody or an IgG4 antibody. In some embodiments, the antibody comprises a wild-type IgG1 heavy chain constant region. In some embodiments, the antibody comprises a wild-type IgG4 heavy chain constant region. In some embodiments, the antibody comprises an Fc domain comprising at least one mutation. In some embodiments, the antibody comprises a mutated IgG1 heavy chain constant region. In some embodiments, the antibody comprises a mutated IgG4 heavy chain constant region. In some embodiments, the mutated IgG4 heavy chain constant region comprises any one of the substitutions S228P, L235E, L235A, or a combination thereof, according to EU numbering.

[0033] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that binds to substantially the same epitope on IL-27 as an antibody, or antigen-binding portion thereof, of any one of the preceding embodiments.

[0034] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that binds to at least one of the amino acid residues comprising IL-27 to which the antibody, or antigen-binding portion thereof, of any one of the preceding embodiments binds.

[0035] In some embodiments, the present disclosure provides an isolated monoclonal antibody or antigen-binding portion thereof, wherein a mutation in the epitope on IL-27 to which the antibody or antigen-binding portion thereof binds inhibits, reduces, or blocks binding to both the antibody or antigen-binding portion thereof and the antibody or antigen-binding portion thereof according to any one of the preceding embodiments.

[0036] In some embodiments, the present disclosure provides isolated monoclonal antibodies or antigen-binding portions thereof that bind to an epitope on IL-27, which epitope is the same as or similar to an epitope bound by an antibody molecule listed in Table 12.

[0037] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (i) heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 51, 52 and 53, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 59, 60 and 61, respectively; (ii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 73, 74, and 75, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 81, 82, and 83, respectively; (iii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 95, 96, and 97, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 103, 104, and 105, respectively; (iv) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 117, 118, and 119, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 161, 162, and 163, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 169, 170, and 171, respectively; (vii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 185, 186, and 187, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 193, 194, and 195, respectively; (viii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 207, 208, and 209, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 215, 216, and 217, respectively; (ix) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 229, 230, and 231, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 237, 238, and 239, respectively; (x) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 251, 252, and 253, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 295, 296, and 297, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 303, 304, and 305, respectively; (xiii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 317, 318, and 319, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 361, 362, and 363, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 369, 370, and 371, respectively; and (xvi) comprises heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 383, 384, and 385, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 391, 392, and 393, respectively.

[0038] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises heavy chain CDRs and light chain CDRs, wherein the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 161, 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.

[0039] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (i) heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 54, 55 and 56, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 62, 63 and 64, respectively; (ii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 76, 77, and 78, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 84, 85, and 86, respectively; (iii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 98, 99, and 100, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 106, 107, and 108, respectively; (iv) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 120, 121, and 122, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 128, 129, and 130, respectively; (v) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 142, 143, and 144, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 188, 189, and 190, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 196, 197, and 198, respectively; (viii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 210, 211, and 212, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 218, 219, and 220, respectively; (ix) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 232, 233, and 234, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 240, 241, and 242, respectively; (x) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 254, 255, and 256, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 298, 299, and 300, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 306, 307, and 308, respectively; (xiii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 320, 321, and 322, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 364, 365, and 366, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 372, 373, and 374, respectively; and (xvi) comprises heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 386, 387, and 388, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 394, 395, and 396, respectively.

[0040] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises heavy chain and light chain CDRs, wherein 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.

[0041] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain CDR and a light chain CDR, wherein the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 are SYSMS (SEQ ID NO: 23), YISYDGGSAYYPDTVKG (SEQ ID NO: 24), and HGDYDDDDAMDY (SEQ ID NO: 25), respectively, and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 are RASENIYSYLA (SEQ ID NO: 26), NAETLTE (SEQ ID NO: 27), and QHHYGTPLT (SEQ ID NO: 28), respectively.

[0042] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 367, and 389, and the light chain variable region comprises 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.

[0043] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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, respectively; and (xvi) comprising a heavy chain variable region and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 389 and 397, respectively.

[0044] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 367, and 389, and the light chain variable region comprises an amino acid sequence at least 90% identical to 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.

[0045] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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, respectively; and (xvi) comprises a heavy chain variable region and a light chain variable region comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 389 and 397, respectively.

[0046] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively.

[0047] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively.

[0048] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 67, 89, 111, 133, 155, 177, 201, 223, 245, 267, 289, 311, 333, 355, 377, and 399, and the light chain comprises an 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.

[0049] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 67, 89, 111, 133, 155, 177, 201, 223, 245, 267, 289, 311, 333, 355, 377, and 399, and the light chain comprises an amino acid sequence at least 90% identical to an 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.

[0050] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 93, 115, 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381, and 403, and the light chain comprises an 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.

[0051] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 93, 115, 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381, and 403, and the light chain comprises an amino acid sequence at least 90% identical to an 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.

[0052] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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: 223 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) comprising a heavy chain and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 399 and 401, respectively.

[0053] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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: 223 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) comprises a heavy chain and a light chain comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 399 and 401, respectively.

[0054] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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) comprising a heavy chain and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 403 and 401, respectively.

[0055] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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) heavy and light chains comprising amino acid sequences at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 403 and 401, respectively.

[0056] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively.

[0057] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively.

[0058] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively.

[0059] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively.

[0060] In some embodiments, the present disclosure provides a method for inhibiting or reducing STAT1 and / or STAT3 phosphorylation in a cell, the method comprising contacting the cell with an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, wherein the antibody or antigen-binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in the cell.

[0061] In some embodiments, the present disclosure provides a method of inhibiting or reducing IL-27-mediated inhibition of CD161 expression in a cell, the method comprising contacting the cell with an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, wherein the antibody or antigen-binding portion thereof inhibits or reduces the inhibition of CD161 expression in the cell.

[0062] In some embodiments, the present disclosure provides methods for inhibiting or reducing IL-27-mediated expression of PD-L1 and / or TIM-3 expression in a cell, the method comprising contacting the cell with an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, wherein the antibody or antigen-binding portion thereof inhibits PD-L1 and / or TIM-3 expression in the cell.

[0063] In some embodiments, the present disclosure provides methods of inducing or enhancing secretion of one or more cytokines from a cell, the method comprising contacting the cell with an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, wherein the antibody or antigen-binding portion thereof induces or enhances PD-1-mediated secretion of one or more cytokines from the cell.

[0064] In some embodiments, the present disclosure provides a method of stimulating an immune response in a subject, the method comprising administering to the subject an effective amount of an isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes IL-27, provided by the present disclosure, or a pharmaceutical composition comprising the antibody or antigen-binding portion thereof and a pharmaceutically acceptable carrier.

[0065] In some embodiments, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of an isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes IL-27, or a pharmaceutical composition comprising the antibody or antigen-binding portion thereof, provided by the present disclosure, and a pharmaceutically acceptable carrier.

[0066] In some embodiments, the present disclosure provides methods of stimulating an immune response or treating cancer in a subject, the methods comprising administering to the subject an effective amount of an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, or a pharmaceutical composition comprising the antibody or antigen-binding portion thereof and a pharmaceutically acceptable carrier, wherein the antibody or antigen-binding portion thereof, or pharmaceutical composition inhibits or reduces STAT1 and / or STAT3 phosphorylation in cells, thereby stimulating the immune response or treating the cancer.

[0067] In some embodiments, the present disclosure provides methods of stimulating an immune response or treating cancer in a subject, the methods comprising administering to the subject an effective amount of an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, or a pharmaceutical composition comprising the antibody or antigen-binding portion thereof and a pharmaceutically acceptable carrier, wherein the antibody or antigen-binding portion thereof, or pharmaceutical composition inhibits or reduces IL-27-mediated inhibition of CD161 expression in cells, thereby stimulating the immune response or treating the cancer.

[0068] In some embodiments, the present disclosure provides methods of stimulating an immune response or treating cancer in a subject, the methods comprising administering to the subject an effective amount of an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, or a pharmaceutical composition comprising the antibody or antigen-binding portion thereof and a pharmaceutically acceptable carrier, wherein the antibody or antigen-binding portion thereof, or pharmaceutical composition inhibits or reduces IL-27-mediated expression of PD-L1 and / or TIM-3 in cells, thereby stimulating the immune response or treating the cancer.

[0069] In some embodiments, the present disclosure provides methods of stimulating an immune response or treating cancer in a subject, the methods comprising administering to the subject an effective amount of an isolated monoclonal antibody or antigen-binding fragment provided by the present disclosure, or a pharmaceutical composition comprising the antibody or antigen-binding portion thereof and a pharmaceutically acceptable carrier, wherein the antibody or antigen-binding portion thereof, or pharmaceutical composition induces or enhances PD-1-mediated secretion of one or more cytokines from cells, thereby stimulating the immune response or treating the cancer.

[0070] In some embodiments, the cancer is selected from lung cancer (e.g., non-small cell lung cancer), sarcoma, testicular cancer, ovarian cancer, pancreatic cancer, breast cancer (e.g., triple-negative breast cancer), melanoma (including, e.g., uveal melanoma, etc.), head and neck cancer (e.g., squamous cell head and neck cancer), colorectal cancer, bladder cancer, endometrial cancer, prostate cancer, thyroid cancer, hepatocellular carcinoma, gastric cancer, brain cancer, lymphoma (e.g., DL-BCL), leukemia (e.g., AML), or kidney cancer (e.g., renal cell carcinoma, e.g., clear cell renal carcinoma).

[0071] In some embodiments, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds and antagonizes IL-27, provided by the present disclosure, in combination with one or more additional therapeutic agents or procedures, wherein the second therapeutic agent or procedure is selected from the group consisting of chemotherapy, a targeted anti-cancer therapy (including, for example, a tyrosine kinase inhibitor (TKI)), an oncolytic agent, a cytotoxic agent, an immune system therapy, a cytokine, a surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy, or a combination thereof.

[0072] In some embodiments, the one or more additional therapeutic agents is a PD-1 antagonist, a PD-L1 inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, a CD112R inhibitor, a TAM inhibitor, a STING agonist, a 4-1BB agonist, or a combination thereof.

[0073] In some embodiments, the one or more additional therapeutic agents is a PD-1 antagonist, hi some embodiments, the PD-1 antagonist is selected from the group consisting of PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, and AMP-224.

[0074] In certain embodiments, the one or more additional therapeutic agents is a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is selected from the group consisting of FAZ053, atezolizumab, avelumab, durvalumab, and BMS-936559. In some embodiments, the present disclosure provides a method of enhancing one or more activities of an anti-PD-1 antibody (e.g., enhancing PD-1-mediated cytokine secretion, enhancing anti-PD-1-mediated TNFα secretion, enhancing anti-PD-1-mediated IL-6 secretion from cells exposed to the anti-PD-1 antibody), the method comprising exposing a cell to an antibody, or antigen-binding portion thereof, provided by the present disclosure, simultaneously or sequentially with the anti-PD-1 antibody, thereby enhancing one or more activities of the anti-PD-1 antibody.

[0075] In certain embodiments, the present disclosure provides pharmaceutical compositions comprising an anti-PD-1 antibody and / or an anti-PD-L1 antibody, as well as an antibody or antigen-binding portion thereof disclosed herein (e.g., an anti-IL-27 antibody), and a pharmaceutically acceptable carrier.

[0076] In related embodiments, the disclosure provides kits comprising an anti-PD-1 antibody and / or an anti-PD-L1 antibody and an antibody or antigen-binding portion thereof disclosed herein (e.g., an anti-IL-27 antibody), for simultaneous or sequential administration, and instructions for use thereof.

[0077] In some embodiments, the one or more additional therapeutic agents is a TIM-3 inhibitor, optionally, the TIM-3 inhibitor is MGB453 or TSR-022.

[0078] In some embodiments, the one or more additional therapeutic agents is a LAG-3 inhibitor, optionally wherein the LAG-3 inhibitor is selected from the group consisting of LAG525, BMS-986016, and TSR-033.

[0079] In some embodiments, the one or more additional therapeutic agents are TIGIT inhibitors. In some embodiments, the one or more additional therapeutic agents are CD112R inhibitors. In some embodiments, the one or more additional therapeutic agents are TAM (Axl, Mer, Tyro) inhibitors. In some embodiments, the one or more additional therapeutic agents are STING agonists. In some embodiments, the one or more additional therapeutic agents are 4-1BB agonists.

[0080] In some embodiments, the present disclosure provides a method for detecting IL-27 in a sample from a subject, the method comprising: (a) contacting the sample from the subject with a detection antibody under conditions that allow the detection antibody to form a detection antibody-IL-27 complex, if IL-27 is present in the sample, wherein the detection antibody is an antibody or antigen-binding fragment thereof provided by the present disclosure; and (b) detecting the presence of the complex produced in step (a), if present.

[0081] In some embodiments, the present disclosure provides a method for detecting IL-27-associated cancer in a subject, the method comprising: (a) contacting a sample from a subject suspected of having an IL-27-associated cancer with a detection antibody under conditions that allow the detection antibody to form a detection antibody-IL-27 complex if IL-27 is present in the sample, wherein the detection antibody is an antibody or antigen-binding portion thereof provided by the present disclosure; and (b) detecting the presence of the complex produced in step (a), if present. In some embodiments, the detection antibody is conjugated to a detectable label. In some embodiments, the method further comprises contacting the sample with a capture antibody to produce a complex comprising IL-27 and the capture antibody if IL-27 is present in the sample, wherein the capture antibody is an antibody or antigen-binding portion thereof provided by the present disclosure.

[0082] In some embodiments, the detection antibody or capture antibody comprises heavy chain CDRs and light chain CDRs, and the amino acid sequences of heavy chain CDR1, CDR2, and CDR3 are SYSMS (SEQ ID NO: 23), YISYDGGSAYYPDTVKG (SEQ ID NO: 24), and HGDYDDDDAMDY (SEQ ID NO: 25), respectively, and the amino acid sequences of light chain CDR1, CDR2, and CDR3 are RASENIYSYLA (SEQ ID NO: 26), NAETLTE (SEQ ID NO: 27), and QHHYGTPLT (SEQ ID NO: 28), respectively.

[0083] In some embodiments, the detection antibody or capture antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NO:1 and SEQ ID NO:3, respectively.

[0084] In some embodiments, the capture antibody is immobilized on a solid support. In some embodiments, the sample is contacted with the capture antibody before the detection antibody. In some embodiments, the sample is a bodily fluid sample. In some embodiments, the fluid sample is blood, serum, plasma, a cell lysate, or a tissue lysate.

[0085] In some embodiments, the cancer is selected from renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), lung cancer, gastroesophageal cancer, ovarian cancer, endometrial cancer, melanoma, leukemia, and lymphoma. In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is selected from leukemia and lymphoma. In some embodiments, the cancer is acute myeloid leukemia (AML).

[0086] definition Terms used in the claims and specification are defined as follows, unless otherwise specified.

[0087] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0088] As used herein, "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to those of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular value, taking into account the context in which it is used.

[0089] As used herein, the term "agonist" refers to any molecule that partially or fully promotes, induces, increases, and / or activates the biological activity of a native polypeptide disclosed herein. Suitable agonist molecules specifically include agonist antibodies or antibody fragments, fragments or amino acid sequence variants of native polypeptides, peptides, or proteins. In some embodiments, activation in the presence of an agonist is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% higher than the signal measured using a negative control under comparable conditions. Also disclosed herein are methods for identifying agonists suitable for use in the disclosed methods. For example, these methods include, but are not limited to, binding assays such as enzyme-linked immunosorbent assays (ELISAs), Forte Bio© systems, and radioimmunoassays (RIAs). These assays determine the ability of an agonist to bind to a polypeptide of interest (e.g., a receptor or ligand) and thus indicate the ability of the agonist to promote, increase, or activate the activity of the polypeptide. The efficacy of an agonist, such as the ability of an agonist to activate or promote the function of a polypeptide, can also be determined using a functional assay. For example, a functional assay can include contacting a polypeptide with a candidate agonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide. The potency of an agonist is typically determined by its EC 50 The EC value is defined as the concentration required to activate 50% of the agonist response. 50 The lower the value, the more potent the agonist and the lower the concentration required to activate a maximal biological response.

[0090] As used herein, the term "alanine scanning" refers to a technique used to determine the contribution of a particular wild-type residue to the stability or function(s) (e.g., binding affinity) of a given protein or polypeptide. This technique involves substituting alanine residues for wild-type residues in the polypeptide, followed by evaluation of the stability or function(s) (e.g., binding affinity) of the alanine-substituted derivative or mutant polypeptide and comparison with the wild-type polypeptide. Techniques for substituting alanine for wild-type residues in polypeptides are known in the art.

[0091] The term "ameliorate" refers to any therapeutically beneficial outcome in the treatment of a disease state, e.g., cancer, including prevention, reduction in severity or progression, remission, or cure.

[0092] As used herein, the term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as amino acids that have been later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, i.e., compounds with an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics refer to chemical compounds that have a structure different from the general chemical structure of an amino acid but that function in a manner similar to a naturally occurring amino acid.

[0093] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter abbreviations.

[0094] As used herein, an "amino acid substitution" refers to the replacement of at least one existing amino acid residue in a predetermined amino acid sequence (the amino acid sequence of the starting polypeptide) with a second, different, "replacement" amino acid residue. An "amino acid insertion" refers to the incorporation of at least one additional amino acid into a predetermined amino acid sequence. Insertions typically consist of the insertion of one or two amino acid residues, although larger "peptide insertions," e.g., of about 3 to about 5, or even up to about 10, 15, or 20 amino acid residues, can also be made. The inserted residue(s) can be naturally occurring or non-naturally occurring, as disclosed above. An "amino acid deletion" refers to the removal of at least one amino acid residue from a predetermined amino acid sequence.

[0095] As used herein, the terms "amount" or "level" are used in the broadest sense and refer to the quantity, concentration, or abundance of a substance (e.g., a metabolite, small molecule, protein, mRNA, marker). When referring to a metabolite or small molecule (e.g., a drug), the terms "amount," "level," and "concentration" are generally used interchangeably and generally refer to a detectable amount in a biological sample. An "elevated level" or "increased level" refers to an increase in the quantity, concentration, or abundance of a substance in a sample compared to a control sample, e.g., one derived from one or more individuals not afflicted with a disease or disorder (e.g., cancer), or an internal control. In some embodiments, an elevated level of a substance (e.g., a drug) in a sample refers to an increase in the amount of the substance of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% relative to the amount of the substance in a control sample, as determined by techniques known in the art (e.g., HPLC). A "decreased level" refers to a reduction in the quantity, concentration, or abundance of a substance (e.g., a drug) in an individual compared to a control, e.g., one or more individuals not afflicted with a disease or disorder (e.g., cancer), or an internal control. In some embodiments, a reduced level refers to little or no detectable quantity, concentration, or abundance. In some embodiments, a reduced level of a substance (e.g., a drug) in a sample refers to a reduction in the amount of the substance of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% relative to the amount of the substance in a control sample, as determined by techniques known in the art (e.g., HPLC).

[0096] When referring to a protein, mRNA, or marker such as those described herein, the terms "level of expression" or "expression level" are generally used interchangeably and generally refer to the detectable amount of a protein, mRNA, or marker in a biological sample. In some aspects, the detectable amount or detectable level of a protein, mRNA, or marker is related to the likelihood of a response to an agent such as those described herein. "Expression" generally refers to the process by which the information contained within a gene is converted into a structure (e.g., a protein marker such as PD-L1) that is present and operational within a cell. Thus, as used herein, "expression" can refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide). Fragments of a transcribed polynucleotide, a translated polypeptide, or a polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide) should also be considered expressed, regardless of whether they are derived from a transcript generated by alternative splicing or a degraded transcript, or from post-translational processing of a polypeptide, for example, by proteolysis. "Expressed genes" include genes that are transcribed into polynucleotides as mRNA and then translated into polypeptides, and also include genes that are transcribed into RNA but not translated into polypeptides (e.g., transfer RNA and ribosomal RNA). "Elevated expression," "elevated expression level," or "elevated level" refers to an increase in expression or an increase in the level of a substance in a sample compared to a control sample, e.g., one or more individuals not afflicted with a disease or disorder (e.g., cancer), or an internal control.In some embodiments, elevated expression of a substance (e.g., a protein marker such as PD-L1) in a sample refers to an increase in the amount of the substance of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% relative to the amount of the substance in a control sample, as determined by techniques known in the art (e.g., FACS). "Decreased expression," "decreased expression level," or "decreased level" refers to a reduced expression or reduced level of a substance (e.g., a protein marker) in an individual compared to a control, e.g., one or more individuals not afflicted with a disease or disorder (e.g., cancer), or an internal control. In some embodiments, decreased expression refers to little or no expression. In some embodiments, reduced expression of a substance (e.g., a protein marker) in a sample refers to a reduction in the amount of the substance of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% relative to the amount of the substance in a control sample, as determined by techniques known in the art (e.g., FACS).

[0097] As used herein, the term "angiogenesis" or "neovascularization" refers to the process by which new blood vessels develop from pre-existing blood vessels (Varner et al., (1999) Angiogen. 3:53-60; Mousa et al., (2000) Angiogen. Stim. Inhib. 35:42-44; Kim et al., (2000) Amer. J. Path. 156:1345-1362; Kim et al., (2000) J. Biol. Chem. 275:33920-33928; Kumar et al. (2000) Angiogenesis: From Molecular to Integrative Pharm. 169-180). Endothelial cells derived from pre-existing blood vessels or circulating endothelial stem cells (Takahashi et al., (1995) Nat. Med. 5:434-438; Isner et al., (1999) J. Clin. Invest. 103:1231-1236) are activated to migrate, proliferate, and differentiate into lumen-bearing structures to form new blood vessels in response to growth factor or hormonal cues or hypoxic or ischemic conditions. During ischemia, such as occurs in cancer, the need for increased oxygen load and nutrient delivery apparently induces the secretion of angiogenic factors by the affected tissue; these factors stimulate new blood vessel formation. Several additional terms are related to angiogenesis.

[0098] As used herein, the term "antagonist" refers to any molecule that partially or completely blocks, inhibits, or neutralizes the biological activity of a native polypeptide disclosed herein. Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments, fragments, or amino acid sequence variants of native polypeptides, peptides, or proteins. In some embodiments, inhibition in the presence of an antagonist is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% lower than the signal measured using a negative control under comparable conditions. Also disclosed herein are methods for identifying antagonists suitable for use in the disclosed methods. For example, these methods include, but are not limited to, enzyme-linked immunosorbent assays (ELISAs), Forte Bio© systems, radioimmunoassays (RIAs), Meso Scale Discovery assays (e.g., Meso Scale Discovery electrochemiluminescence (MSD-ECL)), and bead-based Luminex® assays. These assays determine the ability of an antagonist to bind to a polypeptide of interest (e.g., a receptor or ligand), and thus indicate the ability of the antagonist to inhibit, neutralize, or block the activity of the polypeptide. The efficacy of an antagonist, such as the ability of an antagonist to inhibit the function of a polypeptide or agonist, can also be determined using functional assays. For example, a functional assay can include contacting a polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide. The potency of an antagonist can be determined by its IC 50It can be usually defined by its IC value (the concentration required to inhibit 50% of the agonist response). 50 The lower the value, the more potent the antagonist and the lower the concentration required to inhibit the maximal biological response.

[0099] As used herein, the phrase "antibody or antigen-binding portion thereof that antagonizes human IL-27" refers to an antibody that antagonizes at least one art-recognized activity of human IL-27 (e.g., IL-27 biological activity and / or downstream pathway(s) mediated by IL-27 signaling or other IL-27-mediated function), e.g., associated with at least a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more reduction in human IL-27 activity. Further examples of IL-27 biological activity and / or downstream pathway(s) mediated by IL-27 signaling or other IL-27-mediated function are described in more detail herein below and elsewhere.

[0100] As used herein, the term "anti-IL-27 antagonist antibody" (interchangeably referred to as "anti-IL-27 antibody") refers to an antibody that specifically binds to IL-27 and inhibits IL-27 biological activity and / or downstream pathway(s) mediated by IL-27 signaling or other IL-27-mediated function. Anti-IL-27 antagonist antibodies include antibodies that block, antagonize, suppress, inhibit, or reduce IL-27 biological activity (e.g., ligand binding, enzymatic activity), including receptor binding and / or downstream pathways mediated by IL-27 signaling or function, such as eliciting a cellular response to IL-27 or its metabolites. In some embodiments, anti-IL-27 antagonist antibodies provided by the present disclosure bind to human IL-27 and prevent, block, or inhibit binding of human IL-27 to its cognate or normal receptor (e.g., IL-27 receptor) or one or more receptor subunits (e.g., gp130 and / or IL-27Rα (also known as WSX1 / TCCR)). In some embodiments, anti-IL-27 antagonist antibodies prevent, block, or inhibit binding of human IL-27 to gp130. In some embodiments, anti-IL-27 antagonist antibodies prevent, block, or inhibit binding of human IL-27 to IL-27Rα. In some embodiments, anti-IL-27 antagonist antibodies prevent, block, or inhibit dimerization of IL-27 monomers. In some embodiments, anti-IL-27 antibodies specifically bind to EBI3 monomers. In some embodiments, the anti-IL-27 antibody specifically binds to the IL-27p28 monomer. In some embodiments, the anti-IL-27 antibody specifically binds to both IL-27 monomers. In some embodiments, the anti-IL-27 antibody specifically binds to non-adjacent epitopes that include both EBI3 and p28. In some embodiments, the anti-IL-27 antibody inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell. In some embodiments, the anti-IL-27 antibody inhibits or reduces inhibition of CD161 expression in a cell (e.g., restores or alleviates IL-27-mediated inhibition of CD161 expression in a cell). In some embodiments, the anti-IL-27 antibody inhibits or reduces PD-L1 and / or TIM-3 expression in a cell.In some embodiments, the anti-IL-27 antibody induces or enhances PD-1-mediated secretion of one or more cytokines from cells. In some embodiments, the anti-IL-27 antagonist antibody binds to human IL-27 and stimulates or enhances an anti-tumor response. In some embodiments, the anti-IL-27 antagonist antibody binds to human IL-27 with an affinity of 15 nM or less. In some embodiments, the anti-IL-27 antagonist antibody binds to human IL-27 and comprises a wild-type or mutant IgG1 heavy chain constant region or a wild-type or mutant IgG4 heavy chain constant region. Examples of anti-IL-27 antagonist antibodies are provided herein.

[0101] As used herein, the term "antibody" refers to a whole antibody comprising two light chain polypeptides and two heavy chain polypeptides. Whole antibodies include different antibody isotypes, including IgM, IgG, IgA, IgD, and IgE antibodies. The term "antibody" includes polyclonal antibodies, monoclonal antibodies, chimeric or chimeric antibodies, humanized antibodies, primatized antibodies, deimmunized antibodies, and fully human antibodies. Antibodies can be generated in or derived from various species, e.g., mammals, such as humans, non-human primates (e.g., orangutans, baboons, or chimpanzees), horses, cows, pigs, sheep, goats, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats, and mice. Antibodies can be purified or recombinant. As used herein, the terms "antibody fragment," "antigen-binding fragment," or similar terms refer to fragments of antibodies that retain the ability to bind to and inhibit the activity of a target antigen (e.g., IL-27). Such fragments include, for example, single-chain antibodies, single-chain Fv fragments (scFv), Fd fragments, Fab fragments, Fab' fragments, or F(ab')2 fragments. An scFv fragment is a single polypeptide chain that contains both the heavy and light chain variable regions of the antibody from which the scFv is derived. Additionally, intrabodies, minibodies, triabodies, and diabodies are included within the definition of antibody and are suitable for use in the methods described herein. See, e.g., Todorovska et al., (2001) J. Immunol. Methods 248(1):47-66; Hudson and Kortt, (1999) J. Immunol. Methods 231(1):177-189; Poljak, (1994) Structure 2(12):1121-1123; Rondon and Marasco, (1997) Annu. Rev. Microbiol. 51:257-283, the disclosures of each of which are incorporated herein by reference in their entireties.

[0102] As used herein, the term "antibody fragment" also includes single domain antibodies, such as, for example, camelized single domain antibodies. See, e.g., Muyldermans et al., (2001) Trends Biochem. Sci. 26:230-235; Nuttall et al., (2000) Curr. Pharm. Biotech. 1:253-263; Reichmann et al., (1999) J. Immunol. Meth. 231:25-38; PCT Application Publication Nos. WO 94 / 04678 and WO 94 / 25591; and U.S. Patent No. 6,005,079, all of which are incorporated herein by reference. In some embodiments, the present disclosure provides single domain antibodies comprising two VH domains that have been modified to form a single domain antibody.

[0103] In some embodiments, the antigen-binding fragment comprises a variable region of a heavy chain polypeptide and a variable region of a light chain polypeptide. In some embodiments, the antigen-binding fragment described herein comprises the CDRs of the light and heavy chain polypeptides of the antibody.

[0104] The term "antigen-presenting cell" or "APC" refers to a cell that presents foreign antigens complexed with MHC on its surface. T cells recognize this complex using the T cell receptor (TCR). Examples of APCs include, but are not limited to, B cells, dendritic cells (DCs), peripheral blood mononuclear cells (PBMCs), monocytes (such as THP-1), B lymphoblastoid cells (such as C1R.A2 and 1518 B-LCL), and monocyte-derived dendritic cells (DCs). Some APCs internalize antigens either by phagocytosis or receptor-mediated endocytosis.

[0105] The term "antigen presentation" refers to the process by which APCs capture antigens and enable their recognition by T cells, for example, as components of MHC-I and / or MHC-II complexes.

[0106] As used herein, the term "apoptosis" refers to the process of programmed cell death that occurs in multicellular organisms (e.g., humans). The highly regulated biochemical and molecular events that lead to apoptosis result in observable and characteristic morphological changes in cells, including membrane blebbing, cell volume shrinkage, chromosomal DNA condensation and fragmentation, and mRNA decay. A common method for identifying cells, including T cells, undergoing apoptosis is to expose them to a fluorophore-conjugated protein (annexin V). Annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine on the outer leaflet of the plasma membrane, an early indicator that the cell is undergoing apoptosis.

[0107] As used herein, the term "B cell" (or "B lymphocyte") refers to a type of white blood cell of the lymphocyte subtype. B cells function in the humoral immune component of the adaptive immune system by secreting antibodies. B cells also present antigens and secrete cytokines. B cells differ from the other two classes of lymphocytes, T cells and natural killer cells, in that they express a B cell receptor (BCR) on their cell membrane. The BCR enables B cells to bind to specific antigens, against which they will mount an antibody response.

[0108] As used herein, the term "binds to immobilized IL-27" refers to the ability of an antibody of the disclosure to bind to IL-27, e.g., that is expressed on the surface of a cell or that is attached to a solid support.

[0109] As used herein, the term "bispecific" or "bifunctional antibody" refers to an artificial hybrid antibody having two different heavy / light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods, including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann, (1990) Clin. Exp. Immunol. 79:315-321; Kostelny et al., (1992) J. Immunol. 148:1547-1553.

[0110] Traditionally, recombinant production of bispecific antibodies is based on the coexpression of two immunoglobulin heavy / light chain pairs, where the two heavy / light chain pairs have different specificities (Milstein and Cuello, (1983) Nature 305:537-539). Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The heavy chain variable region fusion is preferably with an immunoglobulin heavy chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. For further details of exemplary currently known methods for generating bispecific antibodies, see, e.g., Suresh et al., (1986) Methods Enzymol. 121:210; PCT Publication No. WO 96 / 27011; Brennan et al., (1985) Science 229:81; Shalaby et al., J. Exp. Med. (1992) 175:217-225; Kostelny et al., (1992) J. Immunol. 148(5):1547-1553; Hollinger et al., (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Gruber et al., (1994) J. Immunol. 152:5368; and Tutt et al. See, e.g., W. et al., (1991) J. Immunol. 147:60. Bispecific antibodies also include cross-linked or heteroconjugate antibodies. Heteroconjugate antibodies may be made using any convenient cross-linking method. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat. No. 4,676,980, along with several cross-linking techniques.

[0111] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. See, e.g., Kostelny et al. (1992) J Immunol 148(5):1547-1553. The leucine zipper peptides from Fos and Jun proteins can be linked to the Fab' portions of two different antibodies by gene fusion. Antibody homodimers can be reduced at the hinge region to form monomers and then re-oxidized to form antibody heterodimers. This method can also be used to produce antibody homodimers. The "diabody" technology described by Hollinger et al. (1993) Proc Natl Acad Sci USA 90:6444-6448 provides an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker that is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for generating bispecific antibody fragments by the use of single-chain Fv (scFv) dimers has also been reported. See, e.g., Gruber et al. (1994) J Immunol 152:5368. Alternatively, the antibodies can be "linear antibodies," as described, e.g., in Zapata et al. (1995) Protein Eng. 8(10):1057-1062. Briefly, these antibodies comprise a pair of tandem Fd segments (VH-CH1-VH-CH1) that form a pair of antigen-binding regions. Linear antibodies can be bispecific or monospecific.

[0112] Antibodies with more than one valency (e.g., trispecific antibodies) are contemplated, see, e.g., Tutt et al. (1991) J Immunol 147:60.

[0113] The present disclosure also encompasses variant forms of multispecific antibodies, such as the dual variable domain immunoglobulin (DVD-Ig) molecules described in Wu et al. (2007) Nat Biotechnol 25(11):1290-1297. DVD-Ig molecules are designed in which two different light chain variable domains (VL) from two different parent antibodies are linked in tandem by recombinant DNA technology, either directly or via a short linker, followed by a light chain constant domain. Similarly, the heavy chain comprises two different heavy chain variable domains (VH) linked in tandem, followed by a constant domain CH1 and an Fc region. Methods for generating DVD-Ig molecules from two parent antibodies are further described, for example, in PCT Publication Nos. WO08 / 024188 and WO07 / 024715. In some embodiments, bispecific antibodies are tandem Fab immunoglobulins in which a light chain variable region with a second specificity is fused to the heavy chain variable region of a whole antibody. Such antibodies are described, for example, in International Patent Application Publication No. WO2015 / 103072.

[0114] As used herein, "cancer antigen" or "tumor antigen" refers to (i) tumor-specific antigens, (ii) tumor-associated antigens, (iii) cells expressing tumor-specific antigens, (iv) cells expressing tumor-associated antigens, (v) embryonic antigens on tumors, (vi) autologous tumor cells, (vii) tumor-specific membrane antigens, (viii) tumor-associated membrane antigens, (ix) growth factor receptors, (x) growth factor ligands, and (xi) any other type of antigen or antigen-presenting cell or substance associated with cancer.

[0115] As used herein, the term "cancer-specific immune response" refers to an immune response elicited by the presence of a tumor, cancer cells, or cancer antigen. In certain embodiments, the response includes proliferation of cancer antigen-specific lymphocytes. In certain embodiments, the response includes expression and upregulation of antibodies and T cell receptors, and the formation and release of lymphokines, chemokines, and cytokines. Both the innate and adaptive immune systems interact to mount an antigen response against a tumor, cancer cells, or cancer antigen. In certain embodiments, the cancer-specific immune response is a T cell response.

[0116] The term "carcinoma" is art-recognized and refers to malignant tumors of epithelial or endocrine tissue, including respiratory system cancer, digestive system cancer, genitourinary system cancer, testicular cancer, breast cancer, prostate cancer, endocrine system cancer, and melanoma. The anti-IL-27 antibodies described herein can be used to treat patients who have, are suspected of having, or may be at high risk of developing any type of cancer, including renal cancer or melanoma, or any viral disease. Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon, and ovary. The term also includes carcinosarcoma, which includes malignant tumors composed of carcinomatous and sarcomatous tissue. "Adenocarcinoma" refers to carcinomas derived from glandular tissue or in which tumor cells form recognizable glandular structures.

[0117] As used herein, the term "CD112R" refers to a member of the poliovirus receptor-like protein family and is a co-inhibitory receptor for human T cells. CD112R is preferentially expressed on T cells and inhibits signals mediated by the T cell receptor. CD112, which is widely expressed on antigen-presenting cells and tumor cells, is a ligand for CD112R. CD112R competes with CD226 for binding to CD112. Interfering with CD112R-CD112 interaction enhances human T cell responses. CD112R as a novel checkpoint for human T cells through its interaction with CD112. As used herein, the term "CD112R inhibitor" refers to an agent that interferes with, blocks, or inhibits the biological function or activity of CD112R.

[0118] As used herein, the term "CD137" (or "4-1BB") refers to a member of the tumor necrosis factor (TNF) receptor superfamily. 4-1BB is a costimulatory immune checkpoint molecule primarily for activated T cells. Cross-linking of CD137 enhances T cell proliferation, IL-2 secretion, survival, and cytolytic activity. As used herein, the term "4-1BB agonist" refers to an agent that stimulates, induces, or increases one or more functions of 4-1BB. An exemplary 4-1BB agonist is utomilumab (PF-05082566), a fully human IgG2 monoclonal antibody that targets 4-1BB and stimulates T cells.

[0119] As used herein, the term "CD161" (also known as killer cell lectin-like receptor subfamily B, member 1 (KLRB1); NK1.1, or NKR-P1A) refers to a member of the C-type lectin superfamily. CD161 is a marker for T cells, and CD161 expression is associated with T cell infiltration into the tumor microenvironment of many different cancer types. CD161 is further described in Fergusson et al., (2014) Cell Reports 9(3):1075-1088, which is incorporated herein by reference in its entirety.

[0120] As used herein, the term "IL-27" or "interleukin-27" refers to the IL-27 cytokine. IL-27 is related to the IL-6 / IL-12 cytokine family and is a heterodimeric cytokine containing a first subunit known as Epstein-Barr virus-induced gene 3 (EBI3; also known as IL-27 subunit β and IL-27B) and a second subunit known as IL-27p28 (also known as IL30, IL-27 subunit α, and IL-27A). IL-27 is primarily synthesized by activated antigen-presenting cells, including monocytes, endothelial cells, and dendritic cells (Jankowski et al. (2010) Arch. Immunol. Ther. Exp. 58:417-425; Diakowski et al. (2013) Adv. Clin. Exp. Med. (2013) 22(5):683-691). Although IL-27 may have pro-inflammatory effects, numerous studies have demonstrated its important role as an immunosuppressant (Shimizu et al. (2006) J. Immunol. 176:7317-7324; Hisada et al. (2004) Cancer Res. 64:1152-1156; Diakowski (2013) supra). Initially described as a factor promoting the initiation of Th1 responses, IL-27 was later found to play a key T cell suppressive role by limiting Th1 responses, inhibiting Th2 and Th17 cell differentiation, and controlling the development of Tr1 and other T regulatory cell populations (Dietrich et al. (2014) J. Immunol. 192:5382-5389). In addition to its role as an immunoregulatory factor, IL-27 regulates angiogenesis, hematopoiesis, and osteoclastogenesis (ibid.).

[0121] IL-27 signals through the heterodimeric type I cytokine receptor (IL-27 receptor or IL-27R), which contains a first subunit known as WSX1 (also known as IL-27 receptor subunit α, IL-27RA, T-cell type 1 cytokine receptor (TCCR), and cytokine receptor-like 1 (CRL1)) and a second subunit known as gp130 (also known as interleukin-6 signal transducer and activator (IL6ST), interleukin-6 receptor subunit β (IL-6RB), and oncostatin M receptor). gp130 is also a receptor subunit for IL-6 family cytokines (Liu et al. (2008) Scan. J. Immunol. 68:22-299; Diakowski (2013) supra). IL-27 signaling through IL-27R activates multiple signaling cascades, including the JAK-STAT and p38 MAPK pathways.

[0122] EBI3 is also thought to have biological functions independent of p28 or IL-27 heterodimers. For example, EBI3 also interacts with p35 to form the heterodimeric cytokine IL-35 (Yoshida et al. (2015) Annu. Rev Immunol. 33:417-43), and has been shown to be selectively overexpressed in certain cell types without a corresponding increase in p28 or IL-27 (Larousserie et al. (2005) Am. J. Pathol. 166(4):1217-28).

[0123] The amino acid sequence of an exemplary human EBI3 protein is provided in SEQ ID NO: 698 (NCBI Reference Sequence: NP_005746.2; N-MTPQLLLALVLWASCPPCSGRKGPPAALTLPRVQCRASRYPIAVDCSWTLPPAPNSTSPVSFIATYRLGMAARGHSWPCLQQTPTSTSCTITDVQLFSMAPYVLNVTAVHPWGSSSSFVPFITEHIIKPDPPEGVRLSPLAERQLQVQWEPPGSWPFPEIFSLKYWIRYKRQGAARFHRVGPIEATSFILRAVRPRARYYVQVAAQDLTDYGELSDWSLPATATMSLGK-C). The amino acid sequence of an exemplary human p28 protein is provided in SEQ ID NO: 699 (NCBI Reference Sequence: NP_663634.2; N-MGQTAGDLGWRLSLLLLPLLLVQAGVWGFPRPPGRPQLSLQELRREFTVSLHLARKLLSEVRGQAHRFAESHLPGVNLYLLPLGEQLPDVSLTFQAWRRLSDPERLCFISTTLQPFHALLGGLGTQGRWTNMERMQLWAMRLDLRDLQRHLRFQVLAAGFNLPEEEEEEEEEEEEERKGLLPGALGSALQGPAQVSWPQLLSTYRLLHSLELVLSRAVRELLLLSKAGHSVWPLGFPTLSPQP-C).The amino acid sequence of an exemplary human WSX1 protein is provided in SEQ ID NO: 700 (NCBI Reference Sequence: NP_004834.1; N--C).The amino acid sequence of an exemplary human gp130 protein is provided in SEQ ID NO: 701 (NCBI Reference Sequence: NP_002175.2; N--C).

[0124] As used herein, the term "compete," when used in the context of antigen binding proteins (e.g., immunoglobulins, antibodies, or antigen-binding fragments thereof) that compete for binding to the same epitope, refers to an interaction between the antigen binding proteins as determined by an assay (e.g., competitive binding assay, cross-blocking assay) in which a test antigen binding protein (e.g., test antibody) inhibits (e.g., reduces or blocks) the specific binding of a reference antigen binding protein (e.g., reference antibody) to a common antigen (e.g., IL-27 or a fragment thereof).

[0125] A polypeptide or amino acid sequence "derived from" a specified polypeptide or protein refers to the origin of the polypeptide. Preferably, a polypeptide or amino acid sequence derived from a particular sequence has an amino acid sequence that is essentially identical to that sequence, or a portion thereof, where that portion consists of at least 10-20 amino acids, preferably at least 20-30 amino acids, more preferably at least 30-50 amino acids, or is otherwise identifiable to one of skill in the art as having its origin in the sequence. A polypeptide derived from another peptide may have one or more mutations relative to the starting polypeptide, e.g., one or more amino acid residues substituted with another amino acid residue, or an insertion or deletion of one or more amino acid residues.

[0126] Polypeptides can include amino acid sequences that do not occur in nature. Such variants necessarily have less than 100% sequence identity or similarity with the starting molecule. In certain embodiments, variants will have an amino acid sequence identity or similarity of about 75% to less than 100%, more preferably about 80% to less than 100%, more preferably about 85% to less than 100%, more preferably about 90% to less than 100% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%), and most preferably about 95% to less than 100%, with the amino acid sequence of the starting polypeptide, e.g., over the length of the mutant molecule.

[0127] In certain embodiments, there is one amino acid difference between the starting polypeptide sequence and the sequence derived therefrom. Identity or similarity with respect to this sequence is defined herein as the percentage of amino acid residues in a candidate sequence that are identical (i.e., the same residues) to the starting amino acid residues after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. In certain embodiments, a polypeptide consists of, consists essentially of, or comprises an amino acid sequence selected from the sequences set forth in Table 12. In certain embodiments, a polypeptide comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the sequences set forth in Table 12. In certain embodiments, a polypeptide comprises a contiguous amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to a contiguous amino acid sequence selected from the sequences set forth in Table 12. In certain embodiments, a polypeptide comprises an amino acid sequence having at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, or 500 (or any integer within these numbers) contiguous amino acids of an amino acid sequence selected from the sequences set forth in Table 12.

[0128] In certain embodiments, the antibodies of the present disclosure are encoded by a nucleotide sequence. The nucleotide sequences of the present invention can be useful in many applications, such as cloning, gene therapy, protein expression and purification, mutagenesis, DNA vaccination of a host in need thereof, antibody generation for, e.g., passive immunization, PCR, primer and probe generation, etc. In certain embodiments, the nucleotide sequences of the present invention comprise, consist of, or consist essentially of a nucleotide sequence selected from the sequences set forth in Table 12. In certain embodiments, the nucleotide sequence comprises a nucleotide sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleotide sequence selected from the sequences set forth in Table 12. In certain embodiments, the nucleotide sequence comprises a contiguous nucleotide sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to a contiguous nucleotide sequence selected from the sequences set forth in Table 12. In certain embodiments, the nucleotide sequence comprises a nucleotide sequence having at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, or 500 (or any integer between these numbers) contiguous nucleotides of a nucleotide sequence selected from the sequences set forth in Table 12.

[0129] Those skilled in the art will also understand that antibodies suitable for use in the methods disclosed herein can be altered so that they differ in sequence from the naturally occurring or native sequence from which they are derived, while retaining the desired activity of the native sequence. For example, nucleotide or amino acid substitutions can be made that result in conservative substitutions or changes at "non-essential" amino acid residues. Mutations can be introduced by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis.

[0130] Antibodies suitable for use in the methods disclosed herein may contain conservative amino acid substitutions at one or more amino acid residues, for example, at essential or non-essential amino acid residues. A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art and include basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, non-essential amino acid residues in a binding polypeptide are preferably replaced with another amino acid residue from the same side chain family. In certain embodiments, a series of amino acids can be replaced with structurally similar contiguous strings that differ in the order and / or composition of side chain family members. Alternatively, in certain embodiments, mutations can be introduced randomly throughout all or part of a coding sequence, such as by saturation mutagenesis, and the resulting mutants can be incorporated into binding polypeptides of the invention and screened for their ability to bind to a desired target.

[0131] As used herein, the term antigen "cross-presentation" refers to the presentation of exogenous protein antigens to T cells via MHC class I and class II molecules on APCs.

[0132] As used herein, the term "cross-reactive" refers to the ability of an antibody of the present disclosure to bind to IL-27 from a different species. For example, an antibody of the present disclosure that binds to human IL-27 may also bind to IL-27 from another species. As used herein, cross-reactivity is measured by specific reactivity with purified antigen in a binding assay (e.g., SPR, ELISA) or by binding to cells that physiologically express IL-27, or by otherwise detecting a functional interaction. Methods for determining cross-reactivity include standard binding assays as described herein, for example, by Biacore™ surface plasmon resonance (SPR) analysis using a Biacore™ 2000SPR instrument (Biacore AB, Uppsala, Sweden), or flow cytometry techniques.

[0133] As used herein, the term "cytotoxic T lymphocyte (CTL) response" refers to an immune response induced by cytotoxic T cells. CTL responses are primarily CD8 + Mediated by T cells.

[0134] As used herein, the term "dendritic cell" or "DC" refers to a type of antigen-presenting cell, a white blood cell derived from bone marrow (BM) that is the most potent type of antigen-presenting cell. DCs capture and process antigens, converting proteins into peptides that are displayed on major histocompatibility complex (MHC) molecules for recognition by T cells. DCs are heterogeneous, including myeloid and plasmacytoid DCs. While all DCs are capable of uptake, processing, and presentation of antigens to naive T cells, DC subtypes possess distinct markers and differ in location, migration route, detailed immune function, and dependence on infectious or inflammatory stimuli for their generation. During the development of adaptive immune responses, DC phenotype and function play a role in the initiation of tolerance, memory, and polarized T helper 1 (Th1), Th2, and Th17 differentiation.

[0135] As used herein, the term "dendritic cell activation" refers to the transition from immature dendritic cells to mature dendritic cells. Activated dendritic cells include mature dendritic cells and dendritic cells undergoing the transitional process, and the expression of CD80 and CD86, which induce costimulatory signals, increases with activation stimuli. Mature human dendritic cells are cells that are positive for the expression of CD40, CD80, CD86, and HLA class II (e.g., HLA-DR). Immature dendritic cells can be distinguished from mature dendritic cells based on markers selected from the group consisting of CD80 and CD86. Immature dendritic cells are weakly positive, or preferably negative, for these markers, while mature dendritic cells are positive. The identification of mature dendritic cells is routinely performed by those skilled in the art, and methods for measuring the above-mentioned markers and their expression are well known to those skilled in the art.

[0136] As used herein, "EC 50 The term "maximum response" refers to the concentration of an antibody or antigen-binding portion thereof that induces a response in either an in vitro or in vivo assay that is 50% of the maximum response, i.e., halfway between the maximum response and the baseline.

[0137] As used herein, the term "effective dose" or "effective administration amount" is defined as an amount sufficient to achieve or at least partially achieve a desired effect. The term "therapeutically effective dose" is defined as an amount sufficient to cure or at least partially halt the disease and its complications in a patient already suffering from the disease. Amounts effective for this use will depend on the severity of the disorder being treated and the overall state of the patient's own immune system.

[0138] As used herein, the term "epitope" or "antigenic determinant" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds. The term "epitope mapping" refers to the process or method of identifying the binding site, or epitope, of an antibody or its antigen-binding fragment on its target protein antigen. Epitope mapping methods and techniques are provided herein. Epitopes can be formed both from contiguous amino acids and from non-contiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. Epitopes typically contain at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in a unique spatial conformation. Methods for determining which epitope a given antibody binds (i.e., epitope mapping) are well known in the art and include, for example, immunoblotting and immunoprecipitation assays, in which overlapping or consecutive peptides from IL-27 are tested for reactivity with a given anti-IL-27 antibody. Methods for determining the spatial structure of epitopes include techniques in the art and described herein, such as x-ray crystallography and two-dimensional nuclear magnetic resonance (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, GE Morris, Ed. (1996)).

[0139] The present disclosure also encompasses antibodies that bind to epitopes on IL-27 that include all or part of (e.g., the same or overlapping regions or regions between or spanning) the epitopes recognized by the specific antibodies described herein.

[0140] The present disclosure also encompasses antibodies that bind to the same epitope and / or that compete with the antibodies described herein for binding to human IL-27. Antibodies that recognize the same epitope or compete for binding can be identified using conventional techniques. Such techniques include, for example, immunoassays that show the ability of one antibody to block the binding of another antibody to a target antigen, i.e., competitive binding assays. Competitive binding is determined in an assay in which the immunoglobulin under test inhibits the specific binding of a reference antibody to a common antigen, such as IL-27. Many types of competitive binding assays are known, such as solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competition assays (see Stahl et al., Methods in Enzymology 9:242 (1983)), solid-phase direct biotin-avidin EIA (see Kirkland et al., J. Immunol. 137:3614 (1986)), solid-phase direct label assays, solid-phase direct label sandwich assays (see Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988)), solid-phase direct label RIA using I-125 labels (see Morel et al., Mol. Immunol. 25(1):7 (1988)), solid-phase direct biotin-avidin EIA (see Cheung et al., Virology 176:546 (1990)), and direct-labeled RIA (Moldenhauer et al., Scand. J. Immunol. 32:77 (1990)). Typically, such assays involve the use of purified antigen bound to a solid surface or cells bearing either an unlabeled test immunoglobulin and a labeled reference immunoglobulin. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin. The test immunoglobulin is usually present in excess. Typically, when a competing antibody is present in excess, it will inhibit specific binding of the reference antibody to the common antigen by at least 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, or more.

[0141] Other techniques include epitope mapping, such as X-ray analysis of crystals of antigen:antibody complexes, which provide atomic resolution of epitopes, and mass spectrometry combined with hydrogen / deuterium (H / D) exchange to examine the conformation and dynamics of antigen:antibody interactions. Other methods monitor antibody binding to antigen fragments or mutated variants of the antigen, where loss of binding due to modification of amino acid residues within the antigen sequence is often considered an indication of epitope components. Additionally, computational combinatorial methods can also be used for epitope mapping. These methods rely on the ability of a given antibody to affinity isolate specific short peptides from a combinatorial phage-displayed peptide library. The peptides are then used as clues to define the epitope corresponding to the antibody used to screen the peptide library. Regarding epitope mapping, computational algorithms have also been developed that have been shown to map conformationally discontinuous epitopes.

[0142] As used herein, the term "Fc-mediated effector function" or "Fc effector function" refers to a biological activity of an antibody other than the primary function and target of the antibody. For example, the effector function of a therapeutic agnostic antibody is a biological activity other than activation of a target protein or pathway. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity, Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), lack of activation of platelets expressing Fc receptors, and B cell activation. Many effector functions are initiated by Fc binding to an Fcγ receptor. In some embodiments, a tumor antigen-targeting antibody has an effector function, e.g., ADCC activity. In some embodiments, the tumor antigen-targeting antibody described herein comprises a mutated constant region that has increased effector function (e.g., increased ability to mediate ADCC) compared to the unmodified form of the constant region.

[0143] As used herein, the term "Fc receptor" refers to a polypeptide found on the surface of immune effector cells that is bound by the Fc region of an antibody. In some embodiments, the Fc receptor is an Fcγ receptor. There are three subclasses of Fcγ receptors: FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16). All four IgG isotypes (IgG1, IgG2, IgG3, and IgG4) bind to and activate the Fc receptors FcγRI, FcγRIIA, and FcγRIIIA. FcγRIIB is an inhibitory receptor; therefore, antibodies that bind to this receptor do not activate complement and cellular responses. FcγRI is a high-affinity receptor that binds to IgG in a monomeric form, while FcγRIIA and FcγRIIA are low-affinity receptors that bind IgG only in a multimeric form and have slightly lower affinity. Binding of antibodies to Fc receptors and / or C1q is governed by specific residues or domains within the Fc region. Binding also depends on residues located within the hinge region and CH2 portion of the antibody. In some embodiments, the agonistic and / or therapeutic activity of the antibodies described herein depends on binding of the Fc region to an Fc receptor (e.g., FcγR). In some embodiments, the agonistic and / or therapeutic activity of the antibodies described herein is enhanced by binding of the Fc region to an Fc receptor (e.g., FcγR).

[0144] A list of certain Fc receptor sequences employed in this disclosure is set forth below as Table 13.

[0145] As used herein, the term "glycosylation pattern" is defined as the pattern of carbohydrate units covalently attached to a protein, more specifically, an immunoglobulin protein. The glycosylation pattern of a heterologous antibody can be characterized as substantially similar to the glycosylation pattern naturally occurring for antibodies produced by a species of non-human transgenic animal if one skilled in the art would recognize the glycosylation pattern of the heterologous antibody as more similar to said pattern of glycosylation in the species of non-human transgenic animal than to the species from which the transgenic CH gene is derived.

[0146] As used herein, the term "human antibody" includes antibodies having variable and constant regions, if present, derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) (see, e.g., Lonberg et al., (1994) Nature 368(6474):856-859; Lonberg, (1994) Handbook of Experimental Pharmacology 113:49-101; Lonberg & Huszar, (1995) Intern. Rev. Immunol. 13:65-93, and Harding & Lonberg, (1995) Ann. NY Acad. Sci. 764:536-546). However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences (i.e., humanized antibodies).

[0147] As used herein, the term "heterologous antibody" is defined in relation to the transgenic non-human organism producing such an antibody. The term refers to an antibody that has an amino acid sequence or encoding nucleic acid sequence that corresponds to that found in an organism other than the transgenic non-human animal, and that generally originates from a species other than the species of the transgenic non-human animal.

[0148] The terms "induction of an immune response" and "enhancement of an immune response" are used interchangeably and refer to the stimulation of an immune response (i.e., passive or adaptive) to a particular antigen. The term "induce" when used in reference to inducing CDC or ADCC refers to the stimulation of a specific direct cell-killing mechanism.

[0149] As used herein, the term "immunogenic cell death" (also known as "immunogenic apoptosis") refers to a mode of cell death associated with the activation of one or more signaling pathways that induce the pre-death expression and release of damage-associated molecular pattern (DAMP) molecules (e.g., adenosine triphosphate, ATP) from tumor cells, resulting in increased immunogenicity of the tumor cells and their death in an immunogenic manner (e.g., by phagocytosis). As used herein, the term "immunogenic cell death inducer" refers to a chemical, biological, or pharmacological agent that induces an immunogenic cell death process, pathway, or mode.

[0150] As used herein, the terms "inhibit," "reduce," or "block" (e.g., referring to the inhibition or reduction of human IL-27-mediated phosphorylation of STAT1 and / or STAT3 in a cell) are used interchangeably and include both partial and complete inhibition / blocking. Inhibition / blocking of IL-27 reduces or alters the normal level or type of activity that occurs in the absence of inhibition or blockage. Inhibition and blocking are also intended to include any measurable reduction in the binding affinity of IL-27 when contacted with an anti-IL-27 antibody compared to IL-27 not contacted with the anti-IL-27 antibody, for example, inhibiting IL-27 binding by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.

[0151] As used herein, the terms "inhibiting angiogenesis," "reducing angiogenesis," and "reducing angiogenesis" refer to reducing the level of angiogenesis in a tissue to an amount that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or less of the amount in a corresponding control tissue, and most preferably the same as the level observed in the control tissue.

[0152] As used herein, the term "inhibit proliferation" (e.g., referring to a cell) is intended to include any measurable reduction in proliferation of the cell, e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100% inhibition of proliferation of the cell.

[0153] As used herein, a subject "in need of prevention," "in need of treatment," or "in need of" refers to one who, according to the judgment of an appropriate health care professional (e.g., in the case of a human, a physician, nurse, or nurse practitioner; in the case of a non-human mammal, a veterinarian), would reasonably benefit from a given treatment (e.g., treatment with a composition comprising an anti-IL-27 antibody).

[0154] The term "in vivo" refers to a process that occurs within a living organism.

[0155] As used herein, the term "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to human IL-27 is substantially free of antibodies that specifically bind to antigens other than IL-27). However, an isolated antibody that specifically binds to an epitope may have cross-reactivity to other IL-27 proteins from different species. However, the antibody continues to exhibit specific binding to human IL-27 in specific binding assays such as those described herein. In addition, an isolated antibody is typically substantially free of other cellular material and / or chemicals. In some embodiments, a combination of "isolated" antibodies with different IL-27 specificities is combined in a well-defined composition.

[0156] As used herein, the term "isolated nucleic acid molecule" refers to an antibody or antibody portion that binds IL-27 (e.g., V H , V L , CDR3) of the heavy chain (V) of the anti-IL-27 antibody monoclonal antibody described herein, and is intended to refer to a nucleic acid molecule in which the nucleotide sequence encoding the antibody or antibody portion does not include other nucleotide sequences encoding antibodies or antibody portions that bind to antigens other than IL-27, and other sequences may naturally flank the nucleic acid in human genomic DNA. For example, a sequence selected from the sequences set forth in Table 12 may be selected from the heavy chain (V) of the anti-IL-27 antibody monoclonal antibody described herein. H ) variable region and light chain (V L ) corresponds to a nucleotide sequence containing the variable region.

[0157] As used herein, "isotype" refers to the antibody class (e.g., IgM or IgG1) encoded by the heavy chain constant region genes. In some embodiments, human monoclonal antibodies of the present disclosure are of the IgG1 isotype. In some embodiments, human monoclonal antibodies of the present disclosure are of the IgG2 isotype. In some embodiments, human monoclonal antibodies of the present disclosure are of the IgG3 isotype. In some embodiments, human monoclonal antibodies of the present disclosure are of the IgG4 isotype. As will be apparent to one of skill in the art, identifying antibody isotypes (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE) is routine in the art and generally involves a combination of sequence alignments using known antibodies, published Fc variant sequences, and conserved sequences.

[0158] As used herein, the term "isotype switching" refers to the phenomenon in which the class or isotype of an antibody changes from one Ig class to one of the other Ig classes.

[0159] As used herein, "KD" or "K D The term K refers to the equilibrium dissociation constant of the binding reaction between an antibody and an antigen. D The value of K is the ratio of the antibody's dissociation rate constant (kd) to the antibody's association rate constant (ka). D The value of K is inversely proportional to the binding affinity of the antibody for the antigen. D The smaller the value, the higher the affinity of the antibody for its antigen. Affinity is the strength of binding of a single molecule to its ligand and is typically expressed as the equilibrium dissociation constant (K D ) and this equilibrium dissociation constant is used to assess and rank the strength of bimolecular interactions.

[0160] As used herein, "kd" or "k d (or "koff" or "k off」The term kd is intended to refer to the dissociation rate constant for the dissociation of an antibody from the antibody / antigen complex. The kd value is a numerical representation of the rate at which the complex decays or dissociates per second, and is expressed as kd / s. -1 It is expressed in units of .

[0161] As used herein, "ka" or "k a (or "kon" or "k on The term ka is intended to refer to the association rate constant for the association of an antigen and an antibody. The value of ka is a numerical representation of the number of antibody / antigen complexes formed per second in a 1 molar (1M) solution of antibody and antigen, and M -1 seconds -1 It is expressed in units of .

[0162] As used herein, the term "leukocyte" refers to a type of white blood cell that is involved in defending the body against infectious organisms and foreign substances. Leukocytes are produced in the bone marrow. There are five major types of white blood cells, divided into two main groups: polymorphonuclear leukocytes (neutrophils, eosinophils, basophils) and mononuclear leukocytes (monocytes and lymphocytes).

[0163] As used herein, the term "lymphocyte" refers to a type of white blood cell or leukocyte that is involved in the body's immune defenses. There are two main types of lymphocytes: B cells and T cells.

[0164] As used herein, the terms "linked," "fused," or "fusion" are used interchangeably. These terms refer to the joining of two or more elements or components or domains together by any means, including chemical conjugation or recombinant means. Methods of chemical conjugation (e.g., using heterobifunctional crosslinkers) are known in the art.

[0165] As used herein, " local administration " or " local delivery " refers to delivery that does not rely on the transport of a composition or agent to its intended target tissue or site through the vascular system.For example, the composition can be delivered by injection or implantation of the composition or agent, or by injection or implantation of a device containing the composition or agent.Following local administration near the target tissue or site, the composition or agent, or one or more components thereof, can diffuse to the intended target tissue or site.

[0166] As used herein, "MHC molecule" refers to two types of molecules, MHC class I and MHC class II. MHC class I molecules present antigens to specific CD8+ T cells, and MHC class II molecules present antigens to specific CD4+ T cells. Antigens delivered exogenously to APCs are processed primarily to associate with MHC class II. In contrast, antigens delivered endogenously to APCs are processed primarily to associate with MHC class I.

[0167] As used herein, the term "monoclonal antibody" refers to an antibody that displays a single binding specificity and affinity for a particular epitope. Accordingly, the term "human monoclonal antibody" refers to an antibody that displays a single binding specificity and has variable and optional constant regions derived from human germline immunoglobulin sequences. In some embodiments, human monoclonal antibodies are produced by hybridomas comprising B cells obtained from a transgenic non-human animal, e.g., a transgenic mouse, whose genome comprises human heavy chain and light chain transgenes fused to an immortalized cell.

[0168] As used herein, the term "monocyte" refers to a type of white blood cell that can differentiate into macrophages and dendritic cells to mediate an immune response.

[0169] As used herein, the term "natural killer (NK) cells" refers to a type of cytotoxic lymphocyte. These are large, usually granular, non-T, non-B lymphocytes that kill certain tumor cells and are important in innate immunity against viruses and other intracellular pathogens, as well as in antibody-dependent cell-mediated cytotoxicity (ADCC).

[0170] As used herein, the term "naturally occurring," when applied to an object, refers to the fact that the object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses), that can be isolated from a natural source, and that has not been artificially modified in a laboratory is naturally occurring.

[0171] As used herein, "non-switching isotype" refers to the heavy chain isotype class produced in the absence of isotype switching, and the CH gene encoding the non-switching isotype is typically the first CH gene immediately downstream of the VDJ gene where functional rearrangement occurs. Isotype switching is classified as classical or non-classical isotype switching. Classical isotype switching occurs through recombination events involving at least one switch sequence region in the transgene. Non-classical isotype switching can occur, for example, through homologous recombination between human σμ and human Σμ (δ-associated deletion). Alternative non-classical switching mechanisms, such as inter-transgene and / or inter-chromosomal recombination, can also occur and lead to isotype switching.

[0172] As used herein, the term "nucleic acid" refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. Unless otherwise specified, the term encompasses nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise specified, a particular nucleic acid sequence also implicitly encompasses conservatively modified mutants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081, 1991; Ohtsuka et al., Biol. Chem. 260:2605-2608, 1985; and Cassol et al., 1992; Rossolini et al., Mol. Cell. Probes 8:91-98, 1994). For arginine and leucine, modifications at the second base can also be conservative. The term nucleic acid is used interchangeably with gene, cDNA, and mRNA encoded by a gene.

[0173] As used herein, a polynucleotide can be composed of any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, a polynucleotide can be composed of single-stranded DNA, double-stranded DNA, DNA that is a mixture of single-stranded and double-stranded regions, single-stranded RNA, double-stranded RNA, and RNA that is a mixture of single-stranded and double-stranded regions, or hybrid molecules containing DNA and RNA that can be single-stranded or, more typically, double-stranded or a mixture of single-stranded and double-stranded regions. In addition, a polynucleotide can be composed of RNA or DNA, or triple-stranded regions containing both RNA and DNA. A polynucleotide can also contain one or more modified bases or DNA or RNA backbones modified for stability or other reasons. "Modified" bases include, for example, tritylated bases and minor bases such as inosine. Various modifications can be made to DNA and RNA, and thus "polynucleotide" encompasses chemically, enzymatically, or metabolically modified forms.

[0174] A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence. With respect to transcription control sequences, operably linked means that the DNA sequences being linked are contiguous, and, where necessary to join two protein-coding regions, contiguous and in reading frame. With respect to switch sequences, operably linked indicates that the sequences are capable of effecting switch recombination.

[0175] As used herein, "parenteral administration," "administering parenterally," and other grammatically equivalent phrases refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intranasal, intraocular, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0176] As used herein, the term "patient" includes human and other mammalian subjects receiving either prophylactic or therapeutic treatment.

[0177] As used herein, the term "PD-1 antagonist" refers to any chemical compound or biological molecule that inhibits the PD-1 signaling pathway or otherwise inhibits PD-1 function in a cell (e.g., an immune cell). In some embodiments, the PD-1 antagonist blocks the binding of PD-L1 to PD-1 and / or PD-L2 to PD-1. In some embodiments, the PD-1 antagonist specifically binds to PD-1. In some embodiments, the PD-1 antagonist specifically binds to PD-L1.

[0178] The term "percent identity," in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences or subsequences that have a specified percentage (%) of nucleotide or amino acid residues that are identical when compared and aligned for maximum correspondence, as determined using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN, or other algorithms available to those skilled in the art) or by visual inspection. Depending on the application, the "percent identity" can exist over a region of the compared sequences, e.g., a functional domain, or over the entire length of the two sequences being compared. For sequence comparison, typically, one sequence serves as a reference sequence to which a test sequence is compared. When using a sequence comparison algorithm, the test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity of the test sequence(s) relative to the reference sequence based on the designated program parameters.

[0179] Optimal alignment of sequences for comparison can be performed, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0180] One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the website of the National Center for Biotechnology Information.

[0181] Generally, as used herein, "pharmaceutically acceptable" refers to compounds, substances, compositions and / or dosage forms that are within the scope of sound medical judgment and suitable for use in contact with the tissues, organs, and / or body fluids of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0182] As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The compositions can include pharmaceutically acceptable salts, e.g., acid addition salts or base addition salts (see, e.g., Berge et al. (1977) J Pharm Sci 66:1-19).

[0183] As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably to refer to a polymer of amino acid residues. These terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of a corresponding naturally occurring amino acid, as well as to naturally occurring and non-naturally occurring amino acid polymers.

[0184] As used herein, the term "preventing" when used with respect to a condition refers to the administration of a composition that reduces the frequency of or delays the onset of symptoms of a medical condition in a subject compared to a subject who does not receive the composition.

[0185] As used herein, the terms "purified" or "isolated" as applied to any of the proteins (antibodies or fragments) described herein refer to a polypeptide that has been separated or purified from components that naturally accompany it (e.g., proteins or other naturally occurring biomolecules or organic molecules), e.g., other proteins, lipids, and nucleic acids of prokaryotes that express the protein. Typically, a polypeptide is purified when it constitutes at least 60% (e.g., at least 65, 70, 75, 80, 85, 90, 92, 95, 97, or 99%) by weight of the total protein in a sample.

[0186] As used herein, the term "programmed cell death protein 1" or "PD-1" refers to the programmed cell death protein 1 polypeptide, an immunoinhibitory receptor belonging to the CD28 family, which in humans is encoded by the PDCD1 gene. Alternative or synonymous names for PD-1 include PDCD1, PD1, CD279, and SLEB2. In vivo, PD-1 is primarily expressed on preactivated T cells, B cells, and myeloid cells and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, as well as analogs that share at least one epitope with hPD-1. The complete hPD-1 sequence can be found in GenBank accession number AAC51773.

[0187] As used herein, the term "programmed death-ligand-1" or "PD-L1" refers to one of the two cell surface glycoprotein ligands for PD-1 (the other being PD-L2), which downregulates T cell activation and cytokine secretion upon binding to PD-1. Alternative names and synonyms for PD-L1 include PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, as well as analogs that share at least one epitope with hPD-L1. The complete hPD-L1 sequence can be found in GenBank Accession No. Q9NZQ7.

[0188] PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745). The interaction between PD-1 and PD-L1 can function as an immune checkpoint, resulting in the reduction of T cell receptor-mediated proliferation (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66). Blocking the local interaction of PD-1 with PD-L1 or PD-L2 can reverse immune suppression, and the effect is additive when the interaction between PD-1 and PD-L2 is also blocked (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).

[0189] For some cancers, tumor survival and growth are maintained by tumor-mediated modulation of immune checkpoints. This modulation can lead to the disruption of anti-cancer immune system function. For example, recent studies have shown that expression of immune checkpoint receptor ligands, such as PD-L1 and PD-L2, by tumor cells can downregulate immune system activity in the tumor microenvironment, particularly by suppressing T cells, promoting cancer immune evasion. PD-L1 is highly expressed by a variety of human cancers (Dong et al., (2002) Nat Med 8:787-789). PD-L1 receptor, PD-1, is expressed on lymphocytes (e.g., activated T cells) and is normally involved in downregulating the immune system and promoting self-tolerance, particularly by suppressing T cells. However, when PD-1 receptors expressed on T cells bind to their cognate PD-L1 ligands on tumor cells, the resulting T cell suppression contributes to a compromised immune response against tumors (e.g., reducing tumor-infiltrating lymphocytes or establishing immune evasion by cancer cells).

[0190] Large sample sets of ovarian, renal, colorectal, pancreatic, liver, and melanoma cancers have shown that PD-L1 expression correlates with poor prognosis and reduces overall survival regardless of subsequent treatment (e.g., Dong et al., (2002) Nat Med 8(8):793-800; Yang et al., (2008) Invest Ophthalmol Vis Sci 49(6):2518-2525; Ghebeh et al., (2006) Neoplasia 8:190-198; Hamanishi et al., (2007) Proc Nat Acad Sci USA 104:3360-3365; Thompson et al., (2006) Clin Genitourin Cancer 5:206-211; Nomi et al., (2005) Clin Cancer Res 11:2947-2953;Inman et al.,(2007)Cancer 109:1499-1505;Shimauchi et al. (2007) Int J Cancer 121:2585-2590; Gao et al., (2009) Clin Cancer Res 15:971-979; Nakanishi et al., (2007) Cancer Immunol Immunother 56:1173-1182; Hino et al., (2010) Cancer 116(7):1757-1766). Similarly, PD-1 expression on tumor lymphocytes has been found to indicate dysfunctional T cells in breast cancer (Kitano et al., (2017) ESMO Open 2(2):e000150) and melanoma (Kleffel et al., (2015) Cell 162(6):1242-1256). For example, PD-1 antagonists, such as those that affect the function of the PD-1 / PD-L1 / PD-L2 signaling axis and / or that interfere with the interaction between PD-1 and PD-L1 and / or PD-L2, have been developed and represent a novel class of anti-tumor inhibitors that function through modulation of immune cell-tumor cell interactions.

[0191] As used herein, the term "rearranged" refers to a V segment positioned immediately adjacent to a DJ or J segment, respectively, to form a complete V H or V L This refers to the configuration of a heavy or light chain immunoglobulin locus in a conformation that essentially encodes a domain. Rearranged immunoglobulin loci can be identified by comparison to germline DNA, and rearranged loci will have at least one recombined heptamer / 9amer homologous element.

[0192] As used herein, a "recombinant host cell" (or simply "host cell") is intended to refer to a cell into which a recombinant expression vector has been introduced. It is understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur over successive generations due to mutation or environmental influences, such progeny may not actually be identical to the parent cell, but are still included within the scope of the term "host cell" as used herein.

[0193] As used herein, the term "recombinant human antibody" includes all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as, for example, (a) antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomal for human immunoglobulin genes or from hybridomas prepared therefrom, (b) antibodies isolated from host cells transformed to express the antibody, e.g., from transfectomas, (c) antibodies isolated from recombinant combinatorial human antibody libraries, and (d) antibodies prepared, expressed, produced, or isolated by any other means involving splicing of human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies contain variable and constant regions that utilize particular human germline immunoglobulin sequences encoded by germline genes, but include subsequent rearrangements and mutations that occur, for example, during antibody maturation. As known in the art (e.g., Lonberg (2005) Nature Biotech. 23(9):1117-1125), variable regions contain antigen-binding domains, which are encoded by different genes that rearrange to form antibodies specific to foreign antigens. In addition to rearrangement, variable regions can be further modified by multiple single amino acid changes (termed somatic mutations or hypermutations) to increase the affinity of the antibody for the foreign antigen. The constant regions will further change in response to antigen (i.e., isotype switching). Thus, rearranged and somatically mutated nucleic acid molecules encoding light and heavy chain immunoglobulin polypeptides in response to antigen may not share sequence identity with the original nucleic acid molecules, but instead will be substantially identical or similar (i.e., have at least 80% identity).

[0194] As used herein, the term "reference antibody" (used interchangeably with "reference mAb") or "reference antigen-binding protein" refers to an antibody or antigen-binding fragment thereof that binds to a particular epitope on IL-27 and is used to establish a relationship between itself and one or more distinct antibodies, the relationship being the binding of the reference antibody and the one or more distinct antibodies to the same epitope on IL-27. As used herein, the term also alludes to an anti-IL-27 antibody that is useful as a competitor in tests or assays such as those described herein (e.g., competitive binding assays), which assays are useful for discovering, identifying, or developing one or more distinct antibodies that bind to the same epitope.

[0195] As used herein, the terms "specific binding," "selective binding," "selectively binds," and "specifically binds" refer to an antibody that binds to an epitope on a predetermined antigen. Typically, an antibody binds to an epitope of approximately 10 as determined by surface plasmon resonance (SPR) technology on a BIACORE 2000 instrument using recombinant human IL-27 as the analyte and the antibody as the ligand. -6 Less than M, e.g., about 10 -7 , 10 -8 M, 10 -9 M or 10 -10 The equilibrium dissociation constant (K D ) and binds to a predetermined antigen with an affinity that is at least two-fold greater than the affinity of binding to a nonspecific antigen other than the predetermined antigen or a closely related antigen (e.g., BSA, casein). In certain embodiments, an antibody that specifically binds to IL-27 has an affinity of approximately 100 nM (10) as determined by surface plasmon resonance (SPR) technology on a BIACORE 2000 instrument using recombinant human IL-27 as the analyte and the antibody as the ligand. -7 M), optionally approximately 50 nM (5 × 10 -8 M), optionally less than approximately 15 nM (1.5 × 10 -8 M), optionally less than approximately 10 nM (10 -8 M), optionally less than approximately 5 nM (5 × 10-9 M), optionally around 1 nM (10 -9 M), optionally approximately 0.1 nM (10 -10 M), optionally approximately 0.01 nM (10 -11 M) or even lower equilibrium dissociation constant (K D ), and binding to a predetermined antigen occurs with an affinity that is at least two-fold greater than the affinity of the antibody for binding to a nonspecific antigen other than the predetermined antigen or a closely related antigen (e.g., BSA, casein). The phrases "antibody that recognizes an antigen" and "antibody specific for an antigen" are used interchangeably herein with the term "antibody that specifically binds to an antigen."

[0196] As used herein, the term "STAT1 phosphorylation" refers to the phosphorylation of the signal transducer and activator of transcription 1 (STAT1) polypeptide, a transcription factor encoded by the STAT1 gene in humans. STAT molecules are phosphorylated by receptor-associated kinases, resulting in activation and dimerization by forming homo- or heterodimers that translocate to the nucleus and function as transcription factors. STAT1 can be activated (i.e., phosphorylated) in response to signal transduction via several ligands, including IL-27. IL-27 signaling through IL-27R results in the phosphorylation of STAT1 (pSTAT1). STAT1 plays an important role in the expression of genes involved in cell survival, viability, and pathogen response. Methods for determining STAT1 phosphorylation as a result of IL-27 signaling include, but are not limited to, flow cytometry analysis of cells labeled with an antibody that specifically recognizes phosphorylated STAT1 (see, e.g., Tochizawa et al., (2006) J Immunol Methods 313(1-2):29-37).

[0197] As used herein, the term "STAT3 phosphorylation" refers to the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) polypeptide, a transcription factor encoded by the STAT3 gene in humans. STAT3 mediates the expression of various genes in response to cell stimuli and thus plays an important role in many cellular processes, such as cell proliferation and apoptosis. Methods for determining STAT3 phosphorylation as a result of IL-27 signaling include, but are not limited to, analyzing cells or cell extracts labeled with an antibody that specifically recognizes phosphorylated STAT3 (see, for example, Fursov et al., (2011) Assay Drug Dev Technol 9(4):420-429).

[0198] As used herein, the term "switch sequence" refers to the DNA sequences responsible for switch recombination. The "switch donor" sequence, typically a μ switch region, will be 5′ (i.e., upstream) of the construct region to be deleted during switch recombination. The "switch acceptor" region will be between the construct region to be deleted and the replacement constant region (e.g., γ, ε, etc.). Because there are no specific sites where recombination will always occur, the final gene sequence will typically be unpredictable from the construct.

[0199] As used herein, the term "subject" includes any human or non-human animal. For example, the methods and compositions of the present invention can be used to treat a subject having an immune disorder. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, reptiles, etc.

[0200] With respect to nucleic acids, the term "substantial homology" indicates that two nucleic acids, or designated sequences thereof, when optimally aligned and compared, are identical in at least about 80%, usually at least about 90% to 95%, and more preferably at least about 98% to 99.5% of the nucleotides, with appropriate nucleotide insertions or deletions. Alternatively, substantial homology exists when the segments are capable of hybridizing under selective hybridization conditions to the complementary sequence of the strand.

[0201] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., percent homology = number of identical positions / total number of positions x 100), and takes into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0202] The percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), which uses a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. The percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)), which has been incorporated into the ALIGN program (version 2.0), which uses a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Additionally, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48): 444-453 (1970)) algorithm, which is incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0203] The nucleic acid and protein sequences of the present disclosure can further be used as "query sequences" to search public databases, for example, to identify related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed using the NBLAST program, score = 100, word length = 12, to obtain nucleotide sequences homologous to the nucleic acid molecules of the present invention. BLAST protein searches can be performed using the XBLAST program, score = 50, word length = 3, to obtain amino acid sequences homologous to the protein molecules of the present invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http: / / www.ncbi.nlm.nih.gov.

[0204] Nucleic acids may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form. Nucleic acids are "isolated" or "substantially purified" when they have been purified away from other cellular components or other contaminants, such as other intracellular nucleic acids or proteins, by standard techniques, including alkali / SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis, and other techniques known in the art. See F. Ausubel, et al., ed., Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York (1987).

[0205] The nucleic acid compositions of the present disclosure, whether derived from cDNA, genomic, or mixtures thereof, often have naturally occurring sequences (except for modified restriction sites, etc.), which may be mutated according to standard techniques to provide gene sequences. For coding sequences, these mutations may affect the amino acid sequence, as appropriate. Specifically contemplated are DNA sequences that are substantially homologous to or derived from naturally occurring V, D, J, constant, switch, and other such sequences described herein (where "derived" indicates that one sequence is identical to or modified from another sequence).

[0206] As used herein, the term "STING" (or TMEM173) refers to stimulator of interferon genes, a protein that functions both as a direct cytosolic DNA sensor and an adaptor protein. In humans, STING is encoded by the TMEM173 gene. STING plays an important role in innate immunity. STING induces the production of type I interferons when cells are infected with intracellular pathogens, such as viruses, mycobacteria, and intracellular parasites. Type I interferons, mediated by STING, protect infected cells and neighboring cells from local infection by binding to the same cells and neighboring cells that secrete them. An exemplary amino acid sequence of STING is provided by the NCBI Genbank database under accession number NP_001288667.

[0207] The term "T cell" refers to a type of white blood cell that can be distinguished from other white blood cells by the presence of T cell receptors on the cell surface. There are several subsets of T cells, including T helper cells (also known as T H cells or CD4 + T cells) and subtypes, e.g., T H 1. T H 2. T H 3. T H 17, T H 9, and T FH cells, cytotoxic T cells (also known as T C cells, CD8 +T cells, cytotoxic T lymphocytes, T killer cells, killer T cells), memory T cells and subtypes, such as central memory T cells (T CM cells), effector memory T cells (T EM and T EMRA cells), and resident memory T cells (T RM cells), regulatory T cells (also known as T reg cells or suppressor T cells) and subtypes, e.g., CD4 + FOXP3 + T reg cells, CD4 + FOXP3 - T reg cells, Tr1 cells, Th3 cells, and T reg 17 cells, natural killer T cells (also known as NKT cells), mucosal-associated invariant T cells (MAIT), and gamma delta T cells (γδ T cells), such as Vγ9 / Vδ2 T cells. Any one or more of the T cells mentioned above or not mentioned may be the target cell type for the methods of use of the present invention.

[0208] As used herein, the term "T cell-mediated response" refers to a response that is mediated by effector T cells (e.g., CD8 + cells) and helper T cells (e.g., CD4 + "T-cell mediated responses" refers to any response mediated by T cells, including but not limited to T cells. T cell mediated responses include, for example, T cell cytotoxicity and proliferation.

[0209] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose," or similar terms used herein, is intended to mean an amount of an agent (e.g., an anti-IL-27 antibody or antigen-binding fragment thereof) that can elicit a desired biological or medical response (e.g., improvement in one or more symptoms of cancer).

[0210] As used herein, the term "TAM receptor" refers to TAM receptor protein tyrosine kinases (TYRO3, AXL, and MER). TAM receptors are involved in regulating immune system homeostasis. In the cancer environment, TAM receptors have a dual regulatory role, managing the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of various immune cells. Further description of TAM receptors can be found in Paolino and Penninger (2016) Cancers 8(97):doi:10.3390 / cancers8100097). As used herein, the term "TAM receptor inhibitor" or "TAM inhibitor" refers to an agent that inhibits, blocks, or reduces the function or activity of a TAM receptor.

[0211] As used herein, "TIGIT" or "T cell immunoreceptor having Ig and ITIM domains" refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term also encompasses naturally occurring variants of TIGIT, such as splice variants or allelic variants. The amino acid sequence of an exemplary human TIGIT can be found under UniProt accession number Q495A1.

[0212] As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or prophylactic measures as described herein. Methods of "treatment" employ administration of a human antibody of the present disclosure to a subject in need of such treatment, e.g., a subject in need of an enhanced immune response to a particular antigen or a subject who is likely to ultimately acquire such a disorder, to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of a disorder or a recurrent disorder, or to prolong the subject's survival beyond that expected in the absence of such treatment.

[0213] As used herein, the term "tumor microenvironment" (or "cancer microenvironment"; abbreviated TME) refers to the cellular environment or milieu in which a tumor or neoplasm resides, including surrounding blood vessels and non-cancerous cells, including, but not limited to, immune cells, fibroblasts, bone marrow-derived inflammatory cells, and lymphocytes. Signaling molecules and the extracellular matrix are also included in the TME. Tumors and the surrounding microenvironment are closely associated and constantly interact. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis, and inducing peripheral immune tolerance, while immune cells within the microenvironment can influence tumor cell growth and development.

[0214] As used herein, the term "unrearranged" or "germline configuration" refers to a configuration in which the V segment has not recombined immediately adjacent to a D or J segment.

[0215] As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, into which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors"). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include other forms of expression vectors, such as viral vectors (eg, replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0216] 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 are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the methods and compositions of this disclosure. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In an 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, wherein the antibody has the following characteristics: (i) Human IL-27 has an equilibrium dissociation constant (K) of 15 nM or less D ) to join; (ii) blocking the binding of IL-27 to the IL-27 receptor; (iii) inhibiting or reducing STAT1 and / or STAT3 phosphorylation in cells; (iv) inhibiting or reducing IL-27-mediated inhibition of CD161 expression in cells; (v) inhibiting or reducing IL-27-mediated PD-L1 and / or TIM-3 expression in cells; and (vi) inducing or enhancing PD-1-mediated secretion of one or more cytokines from cells The antibody or antigen-binding portion thereof exhibits at least one or more of the following: (Item 2) The antibody or antigen-binding portion thereof binds to human IL-27 with an equilibrium dissociation constant (K D 2. The isolated monoclonal antibody or antigen-binding portion thereof according to claim 1, wherein the antibody binds to the nucleotide sequence (SEQ ID NO: 1) at the nucleotide sequence (SEQ ID NO: 2). (Item 3) 3. The isolated monoclonal antibody or antigen-binding portion thereof of item 1 or 2, wherein the antibody or antigen-binding portion thereof binds to mouse IL-27. (Item 4) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) a heavy chain CDR1 consisting of N-GFTFXXXX-C (SEQ ID NO: 408), a heavy chain CDR2 consisting of N-ISSSXXYI-C (SEQ ID NO: 409), and a heavy chain CDR3 sequence set forth in SEQ ID NO: 163; and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 169, 170, and 171, respectively; or (ii) the antibody or antigen-binding portion thereof, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of a heavy chain CDR1 consisting of N-FTFXXXXMN-C (SEQ ID NO: 410), a heavy chain CDR2 consisting of N-XISSSXXYIXYADSVKG-C (SEQ ID NO: 411), and the heavy chain CDR3 sequence set forth in SEQ ID NO: 166; and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 172, 173, and 174, respectively. (Item 5) Item 6. The isolated monoclonal antibody of Item 4, wherein the heavy chain CDR1 consists of N-GFTF[S / A / R][S / R][T / Y][G / S]-C (SEQ ID NO: 412) and the heavy chain CDR2 consists of N-ISSS[S / G][S / A]YI-C (SEQ ID NO: 413); or the heavy chain CDR1 consists of N-FTF[S / A / R][S / R][T / Y][G / S]MN-C (SEQ ID NO: 414) and the heavy chain CDR2 consists of N-[G / S]ISSS[S / G][S / A]YI[L / Y]YADSVKG-C (SEQ ID NO: 415). (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 161, 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; (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; (iii) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 73, 74, and 75, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 81, 82, and 83, respectively; (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; (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 set forth in SEQ ID NOs: 103, 104, and 105, respectively; (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; (vii) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 117, 118, and 119, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 125, 126, and 127, respectively; (viii) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 120, 121, and 122, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 128, 129, and 130, respectively; (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; (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 set forth in SEQ ID NOs: 150, 151, and 152, respectively; (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; or (xii) The isolated monoclonal antibody according to item 4, wherein 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. (Item 7) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) a heavy chain CDR1 consisting of N-GGSFSXYX-C (SEQ ID NO: 416), a heavy chain CDR2 consisting of N-IDXSGXT-C (SEQ ID NO: 417), and a heavy chain CDR3 consisting of N-ARXXXYY[X] n=0-1 DSS[X] n=4-6 a heavy chain CDR3 sequence consisting of N-QXXSXY-C (SEQ ID NO: 418); and a light chain CDR1 consisting of N-DXS-C (SEQ ID NO: 420), a light chain CDR2 consisting of N-QQXXDXPIT-C (SEQ ID NO: 421); or (ii) a heavy chain CDR1 consisting of N-GSFSXYXWS-C (SEQ ID NO: 422), a heavy chain CDR2 consisting of N-SIDXSGXTXYNPSLKS-C (SEQ ID NO: 423), and a heavy chain CDR3 consisting of N-ARXXXYY[X] n=0-1 DSS[X] n=4-6 the antibody or antigen-binding portion thereof, comprising a heavy chain CDR and a light chain CDR selected from the group consisting of a heavy chain CDR3 sequence consisting of N-XASQXXSXYLX-C (SEQ ID NO: 418); and a light chain CDR1 consisting of N-DXSNXXT-C (SEQ ID NO: 425), a light chain CDR2 consisting of N-QQXXDXPIT-C (SEQ ID NO: 421). (Item 8) (i) a heavy chain CDR1 consisting of N-GGSFS[R / D]Y[E / Y]-C (SEQ ID NO: 426), a heavy chain CDR2 consisting of N-ID[W / Y]SG[I / S]TC (SEQ ID NO: 427), and a heavy chain CDR3 sequence consisting of N-AR[D / L][P / G][M / V]YY[- / Y]DSS[VSTGSV / DLGF]D[V / I]-C (SEQ ID NO: 428); and a light chain CDR1 consisting of NQ[S / D][V / I]S[S / N]YC (SEQ ID NO: 429), a light chain CDR2 consisting of ND[S / A]SC (SEQ ID NO: 430), and a light chain CDR3 sequence consisting of N-QQ[D / Y][S / D]D[H / L]PIT-C (SEQ ID NO: 431); or (ii) A heavy chain CDR1 comprising N-GSFS[R / D]Y[E / Y]WS-C (SEQ ID NO: 432), a heavy chain CDR2 comprising N-SID[W / Y]SG[I / S]T[N / E]YNPSLKS-C (SEQ ID NO: 433), and a heavy chain CDR comprising N-AR[D / L][P / G][M / V]YY[- / Y]DSS[VSTGSV / DLGF]D[V / I]-C (SEQ ID NO: 428), respectively. 8. The isolated monoclonal antibody of item 7, having a light chain CDR1 consisting of N-[Q / R]ASQ[S / D][V / I]S[S / N]YL[N / A]-C (sequence number 434), a light chain CDR2 consisting of ND[S / A]SN[R / L][A / E]TC (sequence number 435), and a light chain CDR3 sequence consisting of N-QQ[D / Y][S / D]D[H / L]PIT-C (sequence number 431). (Item 9) (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 229, 230, and 231, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 237, 238, and 239, respectively; or (ii) The isolated monoclonal antibody according to item 7, wherein the heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 232, 233 and 234, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 240, 241 and 242, respectively. (Item 10) (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 251, 252, and 253, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 259, 260, and 261, respectively; or (ii) The isolated monoclonal antibody according to item 7, wherein the heavy chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 254, 255 and 256, respectively, and the light chain CDR1, CDR2 and CDR3 sequences are set forth in SEQ ID NOs: 262, 263 and 264, respectively. (Item 11) An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 23, 24, and 25, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 26, 27, and 28, respectively. (Item 12) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 339, 340, and 341, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 347, 348, and 349, respectively; or (ii) The antibody or antigen-binding portion thereof, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of: 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. (Item 13) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 185, 186, and 187, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 193, 194, and 195, respectively; or (ii) The antibody or antigen-binding portion thereof, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 188, 189, and 190, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 196, 197, and 198, respectively. (Item 14) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 207, 208, and 209, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 215, 216, and 217, respectively; or (ii) The antibody or antigen-binding portion thereof, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of: heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 210, 211, and 212, respectively; and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 218, 219, and 220, respectively. (Item 15) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 273, 274, and 275, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 281, 282, and 283, respectively; or (ii) The antibody or antigen-binding portion thereof, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of 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. (Item 16) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) a heavy chain CDR1 consisting of N-GFTFSSYG-C (SEQ ID NO: 361), a heavy chain CDR2 consisting of N-IXXDGSXK-C (SEQ ID NO: 436), and a heavy chain CDR3 consisting of N-ARXAP[X] n=3-8 a heavy chain CDR3 sequence consisting of N-QSXSSY-C (SEQ ID NO: 437); and a light chain CDR1 consisting of N-XXS-C (SEQ ID NO: 439), a light chain CDR2 consisting of N-QQXXXXP[X]n=0-1 a light chain CDR3 sequence consisting of: TC (SEQ ID NO: 440); or (ii) a heavy chain CDR1 consisting of N-FTFSSYGMX-C (SEQ ID NO: 441), a heavy chain CDR2 consisting of N-XIXXDGSXKYYXDSVKG-C (SEQ ID NO: 442), and N-ARXAP[X] n=3-8 a heavy chain CDR3 sequence consisting of N-RASQSXSSYLX-C (SEQ ID NO: 437); and a light chain CDR1 consisting of N-[X] n=1-2 SS[X] n=3-4 -C (SEQ ID NO: 444), and a light chain CDR2 consisting of N-QQXXXXP[X] n=0-1 TC (SEQ ID NO: 440), and a light chain CDR3 sequence consisting of: (Item 17) (i) the heavy chain CDR1 consists of N-GFTFSSYG-C (SEQ ID NO: 361), the heavy chain CDR2 consists of NI[K / W][Q / Y]DGS[E / N]KC (SEQ ID NO: 445), and the heavy chain CDR3 sequence consists of N-AR[D / G]AP[WDIYDYYM / EYV]DV-C (SEQ ID NO: 446), respectively; and the light chain CDR1 consists of N-QS[I / V]SSY-C (SEQ ID NO: 447), the light chain CDR2 consists of N-[A / D][A / S]SC (SEQ ID NO: 448), 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), respectively; or (ii) the heavy chain CDR1 consists of N-FTFSSYGM[S 17. The isolated monoclonal antibody of item 16, wherein the heavy chain CDR1 consists of the sequence N-[N / V]I[K / W][Q / Y]DGS[E / N]KYY[V / A]DSVKG-C (SEQ ID NO: 451) and the heavy chain CDR3 sequence consists of the sequence N-AR[D / G]AP[WDIYDYYM / EYV]DV-C (SEQ ID NO: 446); and the light chain CDR1 consists of the sequence N-RASQS[I / V]SSYL[N / A]-C (SEQ ID NO: 452), the light chain CDR2 consists of the sequence 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 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; or (ii) The isolated monoclonal antibody of item 16, wherein 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. (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; or (ii) The isolated monoclonal antibody of item 16, wherein 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. (Item 20) 1. An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, comprising: (i) a heavy chain CDR1 consisting of N-GFTFXXXX-C (SEQ ID NO: 408), a heavy chain CDR2 consisting of N-IXXXXXXX-C (SEQ ID NO: 456), and a heavy chain CDR3 consisting of N-AR[X]n= 6-15 a heavy chain CDR3 sequence consisting of DX-C (SEQ ID NO: 458); and N-QS[X] n=1-3 SS[X] n=0-4 A light chain CDR1 consisting of YC (SEQ ID NO: 460), a light chain CDR2 consisting of N-XXS-C (SEQ ID NO: 462), and a light chain CDR3 consisting of N-QQXXXXP[X] n=0-1 a light chain CDR3 sequence consisting of: TC (SEQ ID NO: 464); or (ii) a heavy chain CDR1 consisting of N-FTFXXXXMX-C (SEQ ID NO: 466), a heavy chain CDR2 consisting of N-XIXXXXXXXXYXDSVKG-C (SEQ ID NO: 468), and a heavy chain CDR3 consisting of N-AR[X] n=6-15 a heavy chain CDR3 sequence consisting of N-RASQSXSSYLX-C (SEQ ID NO: 470); and a light chain CDR1 consisting of N-[X] n=1-2 S[X] n=4-5 -C (SEQ ID NO: 474), and a light chain CDR2 consisting of N-QQXXXXP[X] n=0-1 TC (SEQ ID NO: 476), and a light chain CDR3 sequence consisting of: (Item 21) (i) The heavy chain CDR1 consists of N-GFTF[S / A / R][S / R][T / Y][G / S]-C (SEQ ID NO: 454), the heavy chain CDR2 consists of NI[S / K / W][S / Q / Y][S / D][S / G][S / A][Y / E / N][I / K]-C (SEQ ID NO: 455), and the heavy chain CDR3 sequence consists of N-AR[DGGRTSYTATAHNWF / DAPWDIYDYYM / GAPEYV and the light chain CDR1 consists of N-QS[VLF / I / V]SS[NNKN / -]YC (SEQ ID NO: 459), the light chain CDR2 consists of N-[W / A / D][A / S]SC (SEQ ID NO: 461), and the light chain CDR3 sequence consists of N-QQ[H / S / Y][A / Y / S][S / V / L][A / P / Y]P[P / W / -]TC (SEQ ID NO: 463); or (ii) the heavy chain CDR1 consists of N-FTF[S / A / R][S / R][T / Y][G / S]M[N / S / H]-C (SEQ ID NO: 465), the heavy chain CDR2 consists of N-[G / S / N / V]I[S / K / W][S / Q / Y][S / D][S / G][S / A][Y / E / N][I / K][L / Y]Y[V / A]DSVKG-C (SEQ ID NO: 467), and the heavy chain CDR3 sequence consists of N-AR[D / G][GGRTSYTATAHNWF / APWDIYDYYM / APEY and the light chain CDR1 consists of N-[WA / AA / D]S[TRES / SLQS / SNRAT]-C (SEQ ID NO: 473), and the light chain CDR3 sequence consists of N-QQ[H / S / Y][A / Y / S][S / V / L][A / P / Y]P[P / W / -]TC (SEQ ID NO: 475). (Item 22) 22. The isolated monoclonal antibody or antigen-binding portion thereof of any one of items 1 to 21, wherein the antibody or antigen-binding portion thereof antagonizes IL-27. (Item 23) 23. The isolated monoclonal antibody or antigen-binding portion thereof of any one of items 1 to 22, wherein the antibody or antigen-binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell. (Item 24) 24. The isolated monoclonal antibody or antigen-binding portion thereof of claim 23, wherein the cell is an immune cell. (Item 25) 24. The isolated monoclonal antibody or antigen-binding portion thereof of claim 23, wherein the cell is a cancer cell. (Item 26) 26. The isolated monoclonal antibody or antigen-binding portion thereof of any one of items 1 to 25, wherein the antibody or antigen-binding portion thereof inhibits or reduces inhibition of CD161 expression in a cell. (Item 27) 27. The isolated monoclonal antibody or antigen-binding portion thereof of item 26, wherein the cell is an immune cell. (Item 28) 28. The isolated monoclonal antibody or antigen-binding portion thereof of any one of items 1 to 27, wherein the antibody or antigen-binding portion thereof inhibits or reduces PD-L1 and / or TIM-3 expression in a cell. (Item 29) 29. The isolated monoclonal antibody or antigen-binding portion thereof of item 28, wherein the cell is an immune cell. (Item 30) 30. The isolated monoclonal antibody or antigen-binding portion thereof of item 29, wherein the cell is a cancer cell. (Item 31) 30. The isolated monoclonal antibody or antigen-binding portion thereof of paragraph 29, wherein the cell is a cancer cell and the antibody or antigen-binding portion thereof inhibits or reduces PD-L1 expression in the cancer cell. (Item 32) 32. The isolated monoclonal antibody or antigen-binding portion thereof of any one of paragraphs 1 to 31, wherein the antibody or antigen-binding portion thereof induces or enhances the PD-1-mediated secretion of one or more cytokines from a cell. (Item 33) 33. The isolated monoclonal antibody or antigen-binding portion thereof of claim 32, wherein the one or more cytokines are IFNg, TNFα, or IL-6. (Item 34) 34. The isolated monoclonal antibody or antigen-binding portion thereof of claim 33, wherein the one or more cytokines are IFNg, IL-17, TNFα, or IL-6. (Item 35) 34. The isolated monoclonal antibody or antigen-binding portion thereof of claim 33, wherein the one or more cytokines is TNFα. (Item 36) 36. 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) 37. The isolated monoclonal antibody or antigen-binding portion thereof 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. (Item 38) 38. The isolated monoclonal antibody or antigen-binding portion thereof of item 37, wherein the antibody is an IgG1 antibody or an IgG4 antibody. (Item 39) 39. The isolated monoclonal antibody or antigen-binding portion thereof of item 38, wherein the antibody comprises a wild-type IgG1 heavy chain constant region. (Item 40) 39. The isolated monoclonal antibody or antigen-binding portion thereof of item 38, wherein the antibody comprises a wild-type IgG4 heavy chain constant region. (Item 41) 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 comprising at least one mutation. (Item 42) 42. The isolated monoclonal antibody or antigen-binding portion thereof of item 41, wherein the antibody comprises a mutated IgG1 heavy chain constant region. (Item 43) 42. The isolated monoclonal antibody or antigen-binding portion thereof of item 41, wherein the antibody comprises a mutated IgG4 heavy chain constant region. (Item 44) 44. The isolated monoclonal antibody or antigen-binding portion thereof of item 43, wherein the mutated IgG4 heavy chain constant region comprises any one of the substitutions S228P, L235E, L235A, or a combination thereof, according to EU numbering. (Item 45) 45. An isolated monoclonal antibody or antigen-binding portion thereof that binds to substantially the same epitope as the antibody or antigen-binding portion thereof according to any one of items 1 to 44. (Item 46) 45. An isolated monoclonal antibody or antigen-binding portion thereof that binds to at least one of the amino acid residues to which the antibody or antigen-binding portion thereof according to any one of items 1 to 44 binds. (Item 47) 45. An isolated monoclonal antibody or antigen-binding portion thereof, wherein a mutation in the epitope to which the antibody or antigen-binding portion thereof binds inhibits, reduces, or blocks binding to both the antibody or antigen-binding portion thereof and the antibody or antigen-binding portion thereof of any one of items 1 to 44. (Item 48) An isolated monoclonal antibody, or antigen-binding portion thereof, that binds to an epitope on IL-27, wherein the epitope is the same as or similar to an epitope bound by an antibody molecule listed in Table 12. (Item 49) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (i) heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 51, 52 and 53, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 59, 60 and 61, respectively; (ii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 73, 74, and 75, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 81, 82, and 83, respectively; (iii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 95, 96, and 97, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 103, 104, and 105, respectively; (iv) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 117, 118, and 119, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 161, 162, and 163, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 169, 170, and 171, respectively; (vii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 185, 186, and 187, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 193, 194, and 195, respectively; (viii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 207, 208, and 209, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 215, 216, and 217, respectively; (ix) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 229, 230, and 231, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 237, 238, and 239, respectively; (x) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 251, 252, and 253, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 295, 296, and 297, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 303, 304, and 305, respectively; (xiii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 317, 318, and 319, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 361, 362, and 363, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 369, 370, and 371, respectively; and (xvi) The antibody or antigen-binding portion thereof, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 383, 384, and 385, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 391, 392, and 393, respectively. (Item 50) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (i) heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 54, 55 and 56, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 62, 63 and 64, respectively; (ii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 76, 77, and 78, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 84, 85, and 86, respectively; (iii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 98, 99, and 100, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 106, 107, and 108, respectively; (iv) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 120, 121, and 122, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 128, 129, and 130, respectively; (v) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 142, 143, and 144, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 188, 189, and 190, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 196, 197, and 198, respectively; (viii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 210, 211, and 212, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 218, 219, and 220, respectively; (ix) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 232, 233, and 234, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 240, 241, and 242, respectively; (x) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 254, 255, and 256, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 298, 299, and 300, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 306, 307, and 308, respectively; (xiii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 320, 321, and 322, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 364, 365, and 366, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 372, 373, and 374, respectively; and (xvi) The antibody or antigen-binding portion thereof, comprising heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 386, 387, and 388, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 394, 395, and 396, respectively. (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 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. (Item 52) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 367, and 389, and the light chain variable region comprises 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. (Item 53) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (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, respectively; and (xvi) The antibody or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 389 and 397, respectively. (Item 54) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 367, and 389, and the light chain variable region comprises an amino acid sequence that is at least 90% identical to 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. (Item 55) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (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, respectively; and (xvi) The antibody or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region comprising an amino acid sequence at least 90% identical to an 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, the antibody or antigen-binding portion thereof comprising a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively. (Item 57) An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, the antibody or antigen-binding portion thereof comprising a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively. (Item 58) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 67, 89, 111, 133, 155, 177, 201, 243, 245, 267, 289, 311, 333, 355, 377, and 399, and the light chain comprises an 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. (Item 59) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 67, 89, 111, 133, 155, 177, 201, 243, 245, 267, 289, 311, 333, 355, 377, and 399, and the light chain comprises an amino acid sequence at least 90% identical to an 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. (Item 60) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 93, 115, 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381, and 403, and the light chain comprises an 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. (Item 61) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 93, 115, 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381, and 403, and the light chain comprises an amino acid sequence that is at least 90% identical to an 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. (Item 62) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (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 selected from the group consisting of SEQ ID NOs: 399 and 401, respectively. (Item 63) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (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 at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 399 and 401, respectively. (Item 64) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (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 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 403 and 401, respectively. (Item 65) 1. An isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, comprising: (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 comprising an amino acid sequence at least 90% identical to an 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, the antibody or antigen-binding portion thereof comprising a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively. (Item 67) An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, the antibody or antigen-binding portion thereof comprising a heavy chain and a light chain comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively. (Item 68) An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, the antibody or antigen-binding portion thereof comprising a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively. (Item 69) An isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, the antibody or antigen-binding portion thereof comprising a heavy chain and a light chain comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively. (Item 70) A pharmaceutical composition comprising the isolated monoclonal antibody or antigen-binding portion thereof of any one of the preceding items and a pharmaceutically acceptable carrier. (Item 71) 70. A nucleic acid comprising a nucleotide sequence encoding the light chain, the heavy chain, or both the light and heavy chains of the isolated monoclonal antibody or antigen-binding portion thereof according to any one of items 1 to 69. (Item 72) 72. An expression vector comprising the nucleic acid of item 71. (Item 73) A cell transformed with the expression vector according to Item 72. (Item 74) 74. A method for producing a monoclonal antibody or antigen-binding portion thereof that specifically binds human IL-27, comprising maintaining the cell of claim 73 under conditions that allow expression of the monoclonal antibody or antigen-binding portion thereof. (Item 75) 75. The method of claim 74, further comprising obtaining the monoclonal antibody or antigen-binding portion thereof. (Item 76) 70. A method of inhibiting or reducing STAT1 and / or STAT3 phosphorylation in a cell, comprising contacting the cell with the isolated monoclonal antibody or antigen-binding fragment of any one of items 1 to 69, wherein the antibody or antigen-binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in the cell. (Item 77) 70. A method of inhibiting or reducing the inhibition of CD161 expression in a cell, comprising contacting the cell with the isolated monoclonal antibody or antigen-binding fragment of any one of items 1 to 69, wherein the antibody or antigen-binding portion thereof inhibits or reduces the inhibition of CD161 expression in the cell. (Item 78) 70. A method of inhibiting or reducing PD-L1 and / or TIM-3 expression in a cell, comprising contacting the cell with the isolated monoclonal antibody or antigen-binding fragment of any one of paragraphs 1 to 69, wherein the antibody or antigen-binding portion thereof inhibits or reduces PD-L1 and / or TIM-3 expression in the cell. (Item 79) 70. A method for inducing or enhancing secretion of one or more cytokines from a cell, comprising contacting the cell with the isolated monoclonal antibody or antigen-binding fragment of any one of paragraphs 1 to 69, wherein the antibody or antigen-binding portion thereof induces or enhances PD-1-mediated secretion of one or more cytokines from the cell. (Item 80) 71. A method for stimulating an immune response in a subject, comprising administering to the subject an effective amount of the isolated monoclonal antibody or antigen-binding fragment of any one of items 1 to 69 or the pharmaceutical composition of item 70. (Item 81) 71. A method for treating cancer in a subject, comprising administering to the subject an effective amount of the isolated monoclonal antibody or antigen-binding fragment of any one of items 1 to 69 or the pharmaceutical composition of item 70. (Item 82) 71. A method of stimulating an immune response in a subject or treating cancer, comprising administering to the subject an effective amount of the isolated monoclonal antibody or antigen-binding fragment thereof of any one of items 1 to 69 or the pharmaceutical composition of item 70, wherein the antibody or antigen-binding portion thereof or the pharmaceutical composition inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell, thereby stimulating the immune response or treating the cancer. (Item 83) 71. A method of stimulating an immune response in a subject or treating cancer, comprising administering to the subject an effective amount of the isolated monoclonal antibody or antigen-binding fragment thereof of any one of items 1 to 69 or the pharmaceutical composition of item 70, wherein the antibody or antigen-binding portion thereof or the pharmaceutical composition inhibits or reduces inhibition of CD161 expression in cells, thereby stimulating the immune response or treating the cancer. (Item 84) 71. A method of stimulating an immune response in a subject or treating cancer, comprising administering to the subject an effective amount of the isolated monoclonal antibody or antigen-binding fragment of any one of items 1 to 69 or the pharmaceutical composition of item 70, wherein the antibody or antigen-binding portion thereof or the pharmaceutical composition inhibits or reduces PD-L1 and / or TIM-3 expression on cells, thereby stimulating the immune response or treating the cancer. (Item 85) 71. A method of stimulating an immune response in a subject or treating cancer, comprising administering to the subject an effective amount of the isolated monoclonal antibody or antigen-binding fragment of any one of items 1 to 69 or the pharmaceutical composition of item 70, wherein the antibody or antigen-binding portion thereof or the pharmaceutical composition induces or enhances PD-1-mediated secretion of one or more cytokines from cells, thereby stimulating the immune response or treating the cancer. (Item 86) 86. The method of any one of items 81 to 85, wherein the cancer is selected from lung cancer (e.g., non-small cell lung cancer), sarcoma, testicular cancer, ovarian cancer, pancreatic cancer, breast cancer (e.g., triple-negative breast cancer), melanoma, head and neck cancer (e.g., squamous cell head and neck cancer), colorectal cancer, bladder cancer, endometrial cancer, prostate cancer, thyroid cancer, hepatocellular carcinoma, gastric cancer, brain cancer, lymphoma (e.g., DL-BCL), leukemia (e.g., AML), or kidney cancer (e.g., renal cell carcinoma, e.g., renal clear cell carcinoma). (Item 87) 70. A method for enhancing one or more activities of an anti-PD-1 antibody (e.g., enhancing PD-1-mediated cytokine secretion, enhancing anti-PD-1-mediated TNFα secretion, enhancing anti-PD-1-mediated IL-6 secretion from cells exposed to the anti-PD-1 antibody), comprising exposing a cell to the antibody or antigen-binding portion thereof of any one of paragraphs 1 to 69, either simultaneously or sequentially with the anti-PD-1 antibody, thereby enhancing one or more activities of the anti-PD-1 antibody. (Item 88) 70. A pharmaceutical composition comprising an anti-PD-1 antibody, and the antibody or antigen-binding portion thereof according to any one of items 1 to 69, and a pharmaceutically acceptable carrier. (Item 89) 69. A kit comprising an anti-PD-1 antibody and the antibody or antigen-binding portion thereof according to any one of items 1 to 69, for simultaneous or sequential administration, and instructions for use thereof. (Item 90) 87. The method of any one of paragraphs 80-86, wherein 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 selected from the group consisting of chemotherapy, targeted anti-cancer therapy, oncolytic agent, cytotoxic agent, immune system therapy, cytokine, surgical procedure, radiation procedure, activator of costimulatory molecules, inhibitor of inhibitory molecules, vaccine, or cellular immunotherapy, or a combination thereof. (Item 91) 91. The method of item 90, wherein the one or more additional therapeutic agents is a PD-1 antagonist, a PD-L1 inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, a CD112R inhibitor, a TAM inhibitor, a STING agonist, a 4-1BB agonist, or a combination thereof. (Item 92) 92. The method of claim 91, wherein the one or more additional therapeutic agents is a PD-1 antagonist. (Item 93) 93. The method of item 92, wherein the PD-1 antagonist is selected from the group consisting of PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, and AMP-224. (Item 94) 92. The method of 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 may be sunitinib (Sutent®), cabozantinib (Cabometyx®), axitinib (Inlyta®), lenvatinib (Lenvima®), everolimus (Afinitor®), bevacizumab (Avastin®), epacadostat, NKTR-214 (a CD-122 biased agonist), tivo Zanib (Fotivda®), abexinostat, ipilimumab (Yervoy®), tremelimumab, pazopanib (Votrient®), sorafenib (Nexavar®), temsirolimus (Torisel®), ramucirumab (Cyramza®), niraparib, savolitinib, boranib (X-82), regorafenib (Stivargo (R), donafenib (multikinase inhibitor), camrelizumab (SHR-1210), pexastimodine devasilepvec (JX-594), ramucirumab (Cyramza®), apatinib (YN968D1), encapsulated doxorubicin (Thermodox®), tivantinib (ARQ197), ADI-PEG20, binimetinib, apatinib mesylate, nintedanib, Lilly 92. The method of claim 91, wherein the therapeutic agent is selected from the group consisting of pembrolizumab, nivolumab (Opdivo®), pembrolizumab (Keytruda®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfimzi®), cemiplimab-rwlc (Libtayo®), tislelizumab, and spartalizumab. (Item 96) Item 97. 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. 92. The method of claim 91, wherein the one or more additional therapeutic agents is a LAG-3 inhibitor, optionally wherein the LAG-3 inhibitor is selected from the group consisting of LAG525, BMS-986016, and TSR-033. (Item 98) Item 92. The method of item 91, wherein the one or more additional therapeutic agents is a TIGIT inhibitor. (Item 99) 92. The method of item 91, wherein the one or more additional therapeutic agents is a CD112R inhibitor. (Item 100) Item 92. The method of item 91, wherein the one or more additional therapeutic agents is a TAM (Axl, Mer, Tyro) inhibitor. (Item 101) 92. The method of item 91, wherein the one or more additional therapeutic agents is a 4-1BB agonist. (Item 102) 92. The method of item 91, wherein the one or more additional therapeutic agents is a tyrosine kinase inhibitor (TKI). (Item 103) 70. A method for detecting IL-27 or EBI3 in a sample from a subject, the method comprising: (a) contacting the sample from the subject with a detection antibody under conditions that allow the detection antibody to form a detection antibody-EBI3 complex if IL-27 or EBI3 is present in the sample, wherein the detection antibody is the antibody or antigen-binding fragment thereof of any one of items 1 to 69; and (b) detecting the presence of the complex produced in step (a), if present. (Item 104) 70. A method for detecting IL-27-associated cancer in a subject, the method comprising: (a) contacting a sample from a subject suspected of having an IL-27-associated cancer with a detection antibody under conditions that allow the detection antibody to form a detection antibody-EBI3 complex if IL-27 or EBI3 is present in the sample, wherein the detection antibody is the antibody or antigen-binding portion thereof of any one of items 1 to 69; and (b) detecting the presence of the complex produced in step (a), if present. (Item 105) 105. The method of claim 103 or 104, wherein the detection antibody is conjugated to a detectable label. (Item 106) 106. The method of any one of items 103 to 105, wherein the method further comprises contacting the sample with a capture antibody to produce a complex comprising IL-27 or EBI3 and the capture antibody if IL-27 or EBI3 is present in the sample, wherein the capture antibody is the antibody or antigen-binding portion thereof of any one of items 1 to 69. (Item 107) 107. The method of claim 106, wherein the capture antibody is immobilized on a solid support. (Item 108) 108. The method of any one of items 103 to 107, wherein the sample is contacted with the capture antibody before the detection antibody. (Item 109) 109. The method according to any one of items 103 to 108, wherein the sample is a body fluid sample. (Item 110) 110. The method of claim 109, wherein the fluid sample is blood, serum, plasma, a cell lysate, or a tissue lysate. (Item 111) 111. The method according to any one 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. (Item 112) Item 112. The method of item 111, wherein the cancer is renal cell carcinoma (RCC). (Item 113) Item 112. The method of item 111, wherein the cancer is hepatocellular carcinoma (HCC). (Item 114) 112. The method of claim 111, wherein the cancer is selected from leukemia and lymphoma. (Item 115) Item 112. The method of item 111, wherein the cancer is ovarian cancer. (Item 116) 71. Use of the isolated monoclonal antibody or antigen-binding portion thereof of any one of items 1 to 69, or the pharmaceutical composition of item 70, for stimulating an immune response in a subject or for treating cancer in a subject, optionally in combination with one or more additional therapeutic agents or procedures. (Item 117) 70. A kit comprising 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 instructions for use in stimulating an immune response in a subject or treating cancer in a subject, optionally together with instructions for use in combination with one or more additional therapeutic agents or procedures. (Item 118) 70. A kit comprising the isolated monoclonal antibody or antigen-binding portion thereof of any one of items 1 to 69 and instructions for detecting IL-27 in a sample from a control, optionally together with instructions for detecting an IL-27-associated cancer in a subject. [Brief explanation of the drawings]

[0217] [Figure 1] 1 is a table providing affinity data for anti-IL-27 antibodies as indicated. Affinity measurements were performed using ForteBio and Meso Scale Discovery methods. [Figure 2] 1 is a graph showing binding of anti-IL-27 antibodies, as indicated, to plate-bound recombinant IL-27 as measured by ELISA. [Figure 3A] 1 is a bar chart.

[0023] Figure 1 is a graph showing inhibition of IL-27-mediated phosphorylation of STAT1 in human whole blood by anti-IL-27 antibodies as indicated, as measured by flow cytometry. [Figure 3B] Graphs showing inhibition of IL-27-mediated phosphorylation of STAT1 in human PBMCs by anti-IL-27 antibodies as indicated, as measured by flow cytometry. [Figure 3C] Graphs showing inhibition of IL-27-mediated phosphorylation of STAT1 in U937 cells by anti-IL-27 antibodies as indicated, as measured by flow cytometry. [Figure 3D]1 is a bar chart.FIG. 1 is a graph showing inhibition of IL-27-mediated phosphorylation of STAT1 in HUT-78 cells by anti-IL-27 antibodies, as indicated, as measured by flow cytometry. [Figure 3E] Graphs showing that SRF388 inhibits IL-27-mediated pSTAT1 in human whole blood T cells. [Figure 4]

[0023] Figure 1 is a graph showing reversal of IL-27-mediated inhibition of CD161 expression in T cells by various concentrations of anti-IL-27 antibodies, as indicated. CD161 expression was determined using flow cytometry. [Figure 5A] 1 is a graph showing the extent to which anti-IL-27 antibodies enhance PD-1 mediated secretion of TNFα in human PBMCs as measured by ELISA. [Figure 5B] 1 is a graph showing the extent to which anti-IL-27 antibodies enhance PD-1 mediated secretion of IL-6 in human PBMCs as measured by ELISA. [Figure 5C] 1 is a dot plot showing that SRF388 in combination with PD-1 blockade results in increased cytokine production in PBMCs from healthy donors and RCC patients (abbreviations: CBA = Cytometric Bead Array, IFNγ = interferon gamma, MSD = Meso Scale Discovery, PBMC = peripheral blood mononuclear cells, PD-1 = programmed death receptor-1, RCC = renal cell carcinoma, TNFα = tumor necrosis factor alpha). [Figure 5D] Figure 2 shows that IL-27 inhibits cytokine production after PD-1 blockade and is restored in combination with SRF388 (Abbreviations: Ctrl = control, ns = not significant, PBMC = peripheral blood mononuclear cells, rhIL-27 = recombinant human IL-27). [Figure 5E-1]Cytokine induction (specifically, TNFα, IFNγ, IL-6, and IL-17A) observed in PBMC cultures upon contact of the various indicated cell types with SRF388 antibody, αPD-1 antibody, or a combination of SRF388 and αPD-1 antibodies is summarized for the various indicated cell types. [Figure 5E-2] Cytokine induction (specifically, TNFα, IFNγ, IL-6, and IL-17A) observed in PBMC cultures upon contact of the various indicated cell types with SRF388 antibody, αPD-1 antibody, or a combination of SRF388 and αPD-1 antibodies is summarized for the various indicated cell types. [Figure 5F] The figure shows the effect of varying concentrations of individual antibodies (SRF405, SRF410, SRF411, SRF414, SRF416, SRF536, SRF543, SRF529, SRF381, SRF388 and Ab7) on pSTAT1 signaling in U937 (lymphoma) cells. [Figure 5G] The effect of varying concentrations of these individual antibodies on pSTAT1 signaling in PBMCs (peripheral blood mononuclear cells) is shown. [Figure 5H] The effect of varying concentrations of these individual antibodies on CD161 signaling in PBMCs (peripheral blood mononuclear cells) is shown. [Figure 5I] The effect of varying concentrations of these individual antibodies (except SRF414) on PD-L1 signaling in CD4 T lymphocytes (CD4 cells) is shown. [Figure 5J] The effect of varying concentrations of these individual antibodies (except SRF529) on PD-L1 signaling in monocytes is shown. [Figure 5K] The effect of varying concentrations of these individual antibodies (except SRF529) on TIM-3 signaling in monocytes is shown. [Figure 6A] Figure 10 is a graph showing inhibition of IL-27-mediated expression of PD-L1 by treatment of human monocytes with anti-IL-27 antibodies, as determined by flow cytometry. [Figure 6B]Figure 10 shows dose-dependent inhibition of IL-27-mediated expression of PD-L1 by treatment of human monocytes with various concentrations of an anti-IL-27 antibody that specifically binds to EBI3 monomer, as determined by flow cytometry. [Figure 6C] 1 is a graph showing inhibition of IL-27-mediated expression of TIM3 by treatment of human monocytes with anti-IL-27 antibodies, as determined by flow cytometry. [Figure 6D] Figure 10 is a graph showing inhibition of IL-27-mediated expression of PD-L1 by treatment of resting human T cells with anti-IL-27 antibodies, as determined by flow cytometry. [Figure 7A] 1 is a dot plot showing the number of superficial pulmonary B16F10 metastatic nodules (lung nodules) from B16F10 tumor-bearing mice treated with anti-IL27 antibody (SRF388), isotype control antibody, αWSX-1 antibody, or combined αPD-1 and αCTLA-4 antibodies, as indicated, as determined by visual counting of lung nodules isolated from the mice. [Figure 7B] 1 provides a graph showing the growth kinetics of bioluminescent B16-Luc tumors in mice treated with anti-IL-27 antibody (SRF388) or isotype control antibody, as determined by bioluminescence image analysis. [Figure 7C] Shown is a series of images of fixed sectioned lung tissue stained with hematoxylin and eosin isolated from B16F10 tumor-bearing mice treated with anti-IL27 antibody (SRF388), isotype control antibody, αWSX-1 antibody, or combined αPD-1 and αCTLA-4 antibodies as indicated. [Figure 7D]Figure 1 is a dot plot showing total tumor area as a percentage (%) of total tissue area of ​​fixed-sectioned lung B16F10 tumor tissue stained with hematoxylin and eosin, isolated from B16F10 tumor-bearing mice treated with anti-IL27 antibody (SRF388), isotype control antibody, αWSX-1 antibody, or combined αPD-1 and αCTLA-4 antibodies, as indicated, as determined by image analysis software. Similar reductions in the number of surface lung metastases and total tumor area were observed with IL-27RA (WSX-1)-mediated antibody blockade and anti-PD-1 + anti-CTLA-4 combination therapy. [Figure 8A] 1 provides a scatter plot showing microarray data of genes with expression changes of greater than 1.0 log2 fold change (black dots) in splenocytes isolated from mice overexpressing IL-27 after treatment with IL-27 minicircles. [Figure 8B] 8A provides a graph showing the expression levels of selected immunomodulatory genes, as indicated, in splenocytes similar to FIG. 8A. [Figure 8C] These results show that ectopic expression of human IL-27 induces inhibitory receptor expression on mouse T cells in vivo, and SRF388 reduces inhibitory receptor expression on T cells in vivo after IL-27 minicircle treatment. Six-week-old female Balb / c mice were injected with empty vector (control) or hIL-27 minicircles. (Top left and top right panels) PBMCs and (bottom left and bottom right panels) total splenocytes were collected 5 days after transfection, and cells were stained and analyzed by flow cytometry. Expression of the indicated markers was analyzed in CD4+ T cells (top left and bottom left panels) and CD8+ T cells (top right and bottom right panels). Analysis was performed using FlowJo software. [Figure 8D] Figure 1 shows that SRF388 inhibits the detection of minicircle-derived human IL-27 in mouse plasma. [Figure 9-1] A list of selected monoclonal antibody properties is presented. [Figure 9-2] A list of selected monoclonal antibody properties is presented. [Figure 10A-1]A chart of antibody sequences is presented, with sequence divisions reflecting NT numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. [Figure 10A-2] A chart of antibody sequences is presented, with sequence divisions reflecting NT numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. [Figure 10A-3] A chart of antibody sequences is presented, with sequence divisions reflecting NT numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. [Figure 10A-4] A chart of antibody sequences is presented, with sequence divisions reflecting NT numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. [Figure 10B-1]A chart of antibody sequences (corresponding to the sequence chart in Figure 10A) is presented, with sequence divisions reflecting ImMunoGeneTics (IMGT) numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. [Figure 10B-2] A chart of antibody sequences (corresponding to the sequence chart in Figure 10A) is presented, with sequence divisions reflecting ImMunoGeneTics (IMGT) numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. [Figure 10B-3] A chart of antibody sequences (corresponding to the sequence chart in Figure 10A) is presented, with sequence divisions reflecting ImMunoGeneTics (IMGT) numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. [Figure 10B-4]A chart of antibody sequences (corresponding to the sequence chart in Figure 10A) is presented, with sequence divisions reflecting ImMunoGeneTics (IMGT) numbering. Highlighted amino acids in the CDR sequences indicate mutations from the germline-encoded sequence. As will be apparent to one of skill in the art, antibody numbering, including determination of CDR sequences, framework sequences, etc., can be performed in a number of art-recognized ways, including via the NT and IMGT numbering systems presented in Figures 10A and 10B and employed elsewhere herein. DETAILED DESCRIPTION OF THE INVENTION

[0218] The present disclosure provides, at least in part, antibody molecules that bind to human IL-27 with high affinity and specificity. In one embodiment, human antibodies that bind to IL-27 are disclosed herein. As used herein, the terms "IL-27" and "IL27" interchangeably refer to IL-27, a heterodimeric cytokine composed of two distinct subunits encoded by two different genes: Epstein-Barr virus-induced gene 3 (EBI3) and IL-27p28. IL-27 has both pro- and anti-inflammatory properties and has diverse effects on hematopoietic and non-hematopoietic cells.

[0219] Thus, in one aspect, the present disclosure provides a monoclonal antibody or antigen-binding portion thereof that specifically binds to and antagonizes human IL-27, wherein the antibody or antigen-binding portion thereof has the following properties: (i) Human IL-27 has an equilibrium dissociation constant (K) of 15 nM or less D ) to join; (ii) blocking the binding of IL-27 to the IL-27 receptor; (iii) inhibiting or reducing STAT1 and / or STAT3 phosphorylation in cells; (iv) inhibiting or reducing IL-27-mediated inhibition of CD161 expression in cells; (v) inhibiting or reducing IL-27-mediated PD-L1 and / or TIM-3 expression in cells; (vi) inducing or enhancing PD-1-mediated secretion of one or more cytokines from cells; and (vii) exhibiting at least one or more of the combinations of (i) to (vi).

[0220] In other aspects, the disclosure provides monoclonal antibodies, or antigen-binding portions thereof, that specifically bind to human IL-27 and inhibit or reduce IL-27 biological activity or IL-27 signaling.

[0221] Additional aspects of the present invention include nucleic acid molecules encoding the antibody molecules, expression vectors, host cells, and methods of making the antibody molecules. Immunoconjugates, multi- or bispecific molecules, and pharmaceutical compositions comprising the antibody molecules are also provided. The anti-IL-27 antibody molecules disclosed herein can be used to treat, prevent, and / or diagnose cancerous or malignant disorders, such as solid and liquid tumors (e.g., leukemia, e.g., lymphoma, e.g., AML), lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, breast cancer (e.g., triple-negative breast cancer), melanoma, testicular cancer, sarcoma, head and neck cancer (e.g., squamous cell head and neck cancer), liver cancer (e.g., hepatocellular carcinoma (HCC)), colorectal cancer, ovarian cancer, brain cancer (e.g., glioblastoma multiforme), or kidney cancer (e.g., renal cell carcinoma, e.g., clear cell renal carcinoma).

[0222] Anti-IL-27 antibodies and antigen-binding fragments thereof The present disclosure provides antibodies and antigen-binding portions thereof that specifically bind to and antagonize IL-27, particularly human IL-27. Provided herein are isolated monoclonal antibodies or antigen-binding portions thereof that specifically bind to human IL-27, comprising the heavy chain and light chain CDRs and variable sequences set forth in Table 12.

[0223] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, has the following properties: (i) an equilibrium dissociation constant (K D(ii) block the binding of IL-27 to the IL-27 receptor; (iii) inhibit or reduce STAT1 and / or STAT3 phosphorylation in the cell; (iv) inhibit or reduce inhibition of CD161 expression in the cell; (v) inhibit or reduce PD-L1 and / or TIM-3 expression in the cell; (vi) induce or enhance PD-1-mediated secretion of one or more cytokines from the cell; and (vii) exhibit at least one or more combinations of (i)-(vi).

[0224] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, binds to human IL-27 with an equilibrium dissociation constant (K D ) to join them.

[0225] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, binds to recombinant human IL-27 or murine IL-27.

[0226] In some embodiments, the isolated monoclonal antibody or antigen-binding portion thereof inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell. In some embodiments, the cell is an immune cell. In some embodiments, the cell is a cancer cell.

[0227] In some embodiments, the isolated monoclonal antibody or antigen-binding portion thereof inhibits or reduces inhibition of CD161 expression in the cell (e.g., restores or alleviates inhibition of CD161 expression in the cell). In some embodiments, the cell is an immune cell.

[0228] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, inhibits or reduces PD-L1 and / or TIM-3 expression in a cell. In some embodiments, PD-L1 expression is inhibited or reduced. In some embodiments, TIM-3 expression is inhibited or reduced. In some embodiments, both PD-L1 expression and TIM-3 expression are reduced. In some embodiments, the cell is an immune cell.

[0229] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, induces or enhances PD-1-mediated secretion of one or more cytokines from a cell. In some embodiments, the one or more cytokines are TNFα. In some embodiments, the one or more cytokines are IL-6. In some embodiments, the one or more cytokines are TNFα and IL-6. In some embodiments, the cell is an immune cell.

[0230] In some embodiments, the isolated monoclonal antibody, or antigen-binding portion thereof, is selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibodies. In some embodiments, the antibody is an IgG1 antibody or an IgG4 antibody. In some embodiments, the antibody comprises a wild-type IgG1 heavy chain constant region. In some embodiments, the antibody comprises a wild-type IgG4 heavy chain constant region. In some embodiments, the antibody comprises an Fc domain comprising at least one mutation. In some embodiments, the antibody comprises a mutated IgG1 heavy chain constant region. In some embodiments, the antibody comprises a mutated IgG4 heavy chain constant region. In some embodiments, the mutated IgG4 heavy chain constant region comprises any one of the substitutions S228P, L235E, L235A, or a combination thereof, according to EU numbering.

[0231] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that binds to substantially the same epitope on IL-27 as an antibody, or antigen-binding portion thereof, of any one of the preceding embodiments.

[0232] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that binds to at least one of the amino acid residues comprising IL-27 to which the antibody, or antigen-binding portion thereof, of any one of the preceding embodiments binds.

[0233] In some embodiments, the present disclosure provides an isolated monoclonal antibody or antigen-binding portion thereof, wherein a mutation in the epitope on IL-27 to which the antibody or antigen-binding portion thereof binds inhibits, reduces, or blocks binding to both the antibody or antigen-binding portion thereof and the antibody or antigen-binding portion thereof according to any one of the preceding embodiments.

[0234] In some embodiments, the present disclosure provides isolated monoclonal antibodies or antigen-binding portions thereof that bind to an epitope on IL-27, which epitope is the same as or similar to an epitope bound by an antibody molecule listed in Table 12.

[0235] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (i) heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 51, 52 and 53, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 59, 60 and 61, respectively; (ii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 73, 74, and 75, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 81, 82, and 83, respectively; (iii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 95, 96, and 97, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 103, 104, and 105, respectively; (iv) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 117, 118, and 119, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 161, 162, and 163, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 169, 170, and 171, respectively; (vii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 185, 186, and 187, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 193, 194, and 195, respectively; (viii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 207, 208, and 209, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 215, 216, and 217, respectively; (ix) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 229, 230, and 231, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 237, 238, and 239, respectively; (x) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 251, 252, and 253, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 295, 296, and 297, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 303, 304, and 305, respectively; (xiii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 317, 318, and 319, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 361, 362, and 363, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 369, 370, and 371, respectively; and (xvi) comprises heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 383, 384, and 385, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 391, 392, and 393, respectively.

[0236] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises heavy chain CDRs and light chain CDRs, wherein the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 161, 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.

[0237] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (i) heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 54, 55 and 56, respectively, and light chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 62, 63 and 64, respectively; (ii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 76, 77, and 78, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 84, 85, and 86, respectively; (iii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 98, 99, and 100, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 106, 107, and 108, respectively; (iv) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 120, 121, and 122, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 128, 129, and 130, respectively; (v) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 142, 143, and 144, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 188, 189, and 190, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 196, 197, and 198, respectively; (viii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 210, 211, and 212, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 218, 219, and 220, respectively; (ix) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 232, 233, and 234, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 240, 241, and 242, respectively; (x) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 254, 255, and 256, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 298, 299, and 300, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 306, 307, and 308, respectively; (xiii) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 320, 321, and 322, respectively, and 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) heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 364, 365, and 366, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 372, 373, and 374, respectively; and (xvi) comprises heavy chain CDRs and light chain CDRs selected from the group consisting of heavy chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 386, 387, and 388, respectively, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 394, 395, and 396, respectively.

[0238] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises heavy chain and light chain CDRs, wherein 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.

[0239] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain CDR and a light chain CDR, wherein the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 are SYSMS (SEQ ID NO: 23), YISYDGGSAYYPDTVKG (SEQ ID NO: 24), and HGDYDDDDAMDY (SEQ ID NO: 25), respectively, and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 are RASENIYSYLA (SEQ ID NO: 26), NAETLTE (SEQ ID NO: 27), and QHHYGTPLT (SEQ ID NO: 28), respectively.

[0240] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 367, and 389, and the light chain variable region comprises 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.

[0241] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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, respectively; and (xvi) comprising a heavy chain variable region and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 389 and 397, respectively.

[0242] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 57, 79, 101, 123, 145, 167, 191, 213, 235, 257, 279, 301, 323, 345, 367, and 389, and the light chain variable region comprises an amino acid sequence at least 90% identical to 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.

[0243] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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, respectively; and (xvi) comprises a heavy chain variable region and a light chain variable region comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 389 and 397, respectively.

[0244] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively.

[0245] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 167 and 175, respectively.

[0246] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 67, 89, 111, 133, 155, 177, 201, 223, 245, 267, 289, 311, 333, 355, 377, and 399, and the light chain comprises an 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.

[0247] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 67, 89, 111, 133, 155, 177, 201, 223, 245, 267, 289, 311, 333, 355, 377, and 399, and the light chain comprises an amino acid sequence at least 90% identical to an 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.

[0248] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 93, 115, 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381, and 403, and the light chain comprises an 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.

[0249] In some embodiments, the disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, the antibody, or antigen-binding portion thereof, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 71, 93, 115, 137, 159, 181, 205, 227, 249, 271, 293, 315, 337, 359, 381, and 403, and the light chain comprises an amino acid sequence at least 90% identical to an 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.

[0250] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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: 223 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) comprising a heavy chain and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 399 and 401, respectively.

[0251] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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: 223 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) comprises a heavy chain and a light chain comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 399 and 401, respectively.

[0252] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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) comprising a heavy chain and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 403 and 401, respectively.

[0253] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (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) heavy and light chains comprising amino acid sequences at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 403 and 401, respectively.

[0254] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively.

[0255] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 177 and 179, respectively.

[0256] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively.

[0257] In some embodiments, the present disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, that specifically binds to and antagonizes human IL-27, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain comprising amino acid sequences that are at least 90% identical to the amino acid sequences set forth in SEQ ID NOs: 181 and 179, respectively.

[0258] Methods for producing anti-IL-27 antibodies and antigen-binding fragments thereof The present disclosure also relates to methods for producing any of the anti-IL-27 antibodies or antigen-binding fragments thereof described herein. In some embodiments, methods for preparing an antibody described herein can include immunizing a subject (e.g., a non-human mammal) with a suitable immunogen. Suitable immunogens for generating any of the antibodies described herein are described herein. For example, to generate an antibody that binds to IL-27, one skilled in the art can immunize a suitable subject (e.g., a non-human mammal such as a rat, mouse, gerbil, hamster, dog, cat, pig, goat, horse, or non-human primate) with IL-27. In some embodiments, a full-length human IL-27 EBI3 monomer polypeptide comprising the amino acid sequence set forth in SEQ ID NO:97 is used as the immunogen. In some embodiments, a full-length human IL-27p28 monomer polypeptide comprising the amino acid sequence set forth in SEQ ID NO:98 is used as the immunogen.

[0259] A suitable subject (e.g., a non-human mammal) can be immunized with an appropriate antigen, with subsequent boosts, a number of times sufficient to induce the production of antibodies by the mammal. The immunogen can be administered to the subject (e.g., a non-human mammal) with an adjuvant. Adjuvants useful for producing antibodies in a subject include, but are not limited to, protein adjuvants; bacterial adjuvants, such as whole bacteria (BCG, Corynebacterium parvum, or Salmonella minnesota) and bacterial components, such as cell wall skeleton, trehalose dimycolate, monophosphoryl lipid A, methanol extract residue of tubercle bacillus (MER), complete or incomplete Freund's adjuvant; viral adjuvants; chemical adjuvants, such as aluminum hydroxide, and iodoacetate and cholesteryl hemisuccinate. Other adjuvants that can be used in methods to induce an immune response include, for example, cholera toxin and parapoxvirus proteins. See also Bieg et al. (1999) Autoimmunity 31(1):15-24. See also, e.g., Lodmell et al. (2000) Vaccine 18:1059-1066; Johnson et al. (1999) J Med Chem 42:4640-4649; Baldridge et al. (1999) Methods 19:103-107; and Gupta et al. (1995) Vaccine 13(14):1263-1276.

[0260] In some embodiments, the method involves preparing a hybridoma cell line secreting a monoclonal antibody that binds to the immunogen. For example, a suitable mammal, e.g., a laboratory mouse, is immunized with an IL-27 polypeptide as described above. Antibody-producing cells (e.g., splenic B cells) from the immunized mammal can be isolated 2-4 days after at least one booster immunization with the immunogen, then briefly expanded in culture and fused with cells of a suitable myeloma cell line. These cells can be fused in the presence of a fusion promoter, e.g., vaccinia virus or polyethylene glycol. The hybrid cells resulting from the fusion are cloned, and cell clones secreting the desired antibody are selected. For example, spleen cells from a Balb / c mouse immunized with a suitable immunogen can be fused with cells of the myeloma cell line PAI or the myeloma cell line Sp2 / 0-Ag14. After fusion, the cells are expanded in a suitable culture medium supplemented with a selective medium, e.g., HAT medium, at regular intervals to prevent overgrowth of the desired hybridoma cells by normal myeloma cells. The resulting hybrid cells are then screened for secretion of a desired antibody, e.g., an antibody that binds to human IL-27; in some embodiments, one skilled in the art can identify anti-IL-27 antibodies from non-immune biased libraries, as described, for example, in U.S. Pat. No. 6,300,064 (Knappik et al.; Morphosys AG) and Schoonbroodt et al. (2005) Nucleic Acids Res 33(9):e81.

[0261] In some embodiments, the methods described herein utilize antibody screening techniques such as, for example, phage display, bacterial display, yeast surface display, eukaryotic viral display, mammalian cell display, and cell-free (e.g., ribosome display) antibody screening techniques (e.g., Etz et al. (2001) J Bacteriol 183:6924-6935; Cornelis (2000) Curr Opin Biotechnol 11:450-454; Klemm et al. (2000) Microbiology 146:3025-3032; Kieke et al. (1997) Protein Eng 10:1303-1310; Yeung et al. (2002) Biotechnol Prog 18:212-220; Boder et al. (2000) Methods Enzymology 328:430-444; Grabherr et al. al. (2001) Comb Chem High Throughput Screen 4:185-192; Michael et al. (1995) Gene Ther 2:660-668; Pereboev et al. (2001) J Virol 75:7107-7113; Schaffitzel et al. (1999) J Immunol Methods 231:119-135; and Hanes et al. (2000) Nat Biotechnol 18:1287-1292).

[0262] Methods for identifying antibodies using various phage display methods are known in the art. In phage display, functional antibody domains are displayed on the surface of phage particles carrying the polynucleotide sequences encoding them. Such phages can be used to display antigen-binding domains of antibodies, such as Fab, Fv, or disulfide-stabilized Fv antibody fragments, expressed from repertoire or combinatorial antibody libraries (e.g., human or murine). The phages used in these methods are typically filamentous phages such as fd and M13. The antigen-binding domain is expressed as a recombinantly fused protein to one of the phage coat proteins pIII, pVIII, or pIX. See, e.g., Shi et al. (2010) JMB 397:385-396. Examples of phage display methods that can be used to generate the immunoglobulins or fragments thereof described herein include those described in Brinkman et al. (1995) J Immunol Methods 182:41-50; Ames et al. (1995) J Immunol Methods 184:177-186; Kettleborough et al. (1994) Eur J Immunol 24:952-958; Persic et al. (1997) Gene 187:9-18; Burton et al. (1994) Advances in Immunology 57:191-280; and those disclosed in PCT Publication Nos. WO90 / 02809, WO91 / 10737, WO92 / 01047, WO92 / 18619, WO93 / 11236, WO95 / 15982, and WO95 / 20401. Suitable methods are also described, for example, in U.S. Patent Nos. 5,698,426, 5,223,409, 5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698, 5,427,908, 5,516,637, 5,780,225, 5,658,727, 5,733,743, and 5,969,108.

[0263] In some embodiments, phage display antibody libraries can be generated using mRNA collected from B cells from immunized mammals. For example, a spleen cell sample containing B cells can be isolated from a mouse immunized with an IL-27 polypeptide as described above. The mRNA can be isolated from the cells and converted to cDNA using standard molecular biology techniques. See, for example, Sambrook et al. (1989) "Molecular Cloning: A Laboratory Manual, 2 nd See, e.g., "The Immunoglobulin ... 62(1-2):213-9; Di Niro et al. (2005) Biochem J 388(Pt3):889-894; and Engberg et al. (1995) Methods Mol Biol 51:355-376.

[0264] In some embodiments, a combination of selection and screening can be employed to identify antibodies of interest, for example, from a population of hybridoma-derived antibodies or a phage display antibody library. Suitable methods are known in the art and are described, for example, in Hoogenboom (1997) Trends in Biotechnology 15:62-70; Brinkman et al. (1995), supra; Ames et al. (1995), supra; Kettleborough et al. (1994), supra; Persic et al. (1997), supra; and Burton et al. (1994), supra. For example, multiple phagemid vectors, each encoding a fusion protein of a bacteriophage coat protein (e.g., pIII, pVIII, or pIX of M13 phage) and a different antigen complex domain, are produced using standard molecular biology techniques and introduced into a population of bacteria (e.g., E. coli). Expression of bacteriophage in bacteria may, in some embodiments, require the use of helper phage. In some embodiments, helper phage is not required (see, for example, Chasteen et al., (2006) Nucleic Acids Res 34(21):e145). The phage produced from the bacteria is recovered and contacted with a target antigen, for example, bound to a solid support (immobilized). The phage may be contacted with the antigen in solution, and the complex is then bound to a solid support.

[0265] Subpopulations of antibodies screened using the above methods can be characterized for their specificity and binding affinity for a particular antigen (e.g., human IL-27) using any immunological or biochemical-based method known in the art. For example, the specific binding of an antibody to IL-27 can be determined using immunological or biochemical-based methods, such as, but not limited to, the above-mentioned ELISA assays, SPR assays, immunoprecipitation assays, affinity chromatography, and equilibrium dialysis. Immunoassays that can be used to analyze the immunospecific binding and cross-reactivity of antibodies include, but are not limited to, competitive and non-competitive assay systems using techniques such as Western blots, RIAs, ELISAs (enzyme-linked immunosorbent assays), "sandwich" immunoassays, immunoprecipitation assays, immunodiffusion assays, agglutination assays, complement fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays. Such assays are conventional and well known in the art.

[0266] It is understood that the above methods can also be used to determine, for example, whether an anti-IL-27 antibody does not bind to full-length, human IL-27 and / or IL-27 protein.

[0267] In embodiments where the selected CDR amino acid sequence is a short sequence (e.g., less than 10-15 amino acids in length), the nucleic acid encoding the CDR can be chemically synthesized, for example, as described in Shiraishi et al. (2007) Nucleic Acids Symposium Series 51(1):129-130 and U.S. Pat. No. 6,995,259. For a given nucleic acid sequence encoding an acceptor antibody, the region of the nucleic acid sequence encoding the CDR can be replaced with a chemically synthesized nucleic acid using standard molecular biology techniques. The 5' and 3' ends of the chemically synthesized nucleic acid can be synthesized to include sticky-end restriction enzyme sites for use in cloning the nucleic acid into a nucleic acid encoding the variable region of a donor antibody.

[0268] In some embodiments, the anti-IL-27 antibodies described herein comprise an altered heavy chain constant region that exhibits reduced (or no) effector function compared to the corresponding unaltered constant region. Effector functions associated with the constant region of an anti-IL-27 antibody can be modulated by modifying the properties of the constant or Fc region. Altered effector functions include, for example, modulation of one or more of the following activities: antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), apoptosis, binding to one or more Fc receptors, and pro-inflammatory responses. Modulation refers to an increase, reduction, or elimination of the effector function activity exhibited by a subject antibody containing an altered constant region compared to the activity of the unaltered form of the constant region. In certain embodiments, modulation includes situations in which an activity is abolished or completely absent.

[0269] In one embodiment, an anti-IL-27 antibody described herein comprises an IgG4 heavy chain constant region. In one embodiment, the IgG4 heavy chain constant region is a wild-type IgG4 heavy chain constant region. In another embodiment, the IgG4 constant region comprises mutations, e.g., S228P and one or both of L235E or L235A, according to EU numbering (Kabat, EA, et al., supra). Representative sequences of wild-type and mutated IgG4 constant regions for use in antibodies of the disclosure are set forth in Table 12. In one embodiment, an anti-IL-27 antibody described herein comprises an IgG1 constant region. In one embodiment, the IgG1 heavy chain constant region is a wild-type IgG1 heavy chain constant region. In another embodiment, the IgG1 heavy chain constant region comprises mutations. Representative sequences of wild-type and mutated IgG4 constant regions for use in antibodies of the disclosure are set forth in Table 12.

[0270] An altered constant region with altered FcR binding affinity and / or ADCC activity and / or altered CDC activity is a polypeptide that has enhanced or decreased FcR binding activity and / or ADCC activity and / or CDC activity compared to the unaltered form of the constant region. An altered constant region that exhibits increased binding to an FcR binds at least one FcR with greater affinity than the unaltered polypeptide. An altered constant region that exhibits decreased binding to an FcR binds at least one FcR with lower affinity than the unaltered form of the constant region. Such variants that exhibit reduced binding to FcR may have little or no appreciable binding to FcR, for example, 0-50% (e.g., less than 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%) binding to FcR compared to the binding level of a native sequence immunoglobulin constant region or Fc region to FcR. Similarly, an altered constant region that displays modulated ADCC and / or CDC activity may exhibit increased or decreased ADCC and / or CDC activity compared to the unaltered constant region. For example, in some embodiments, an anti-IL-27 antibody comprising an altered constant region may exhibit approximately 0-50% (e.g., less than 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%) of the ADCC and / or CDC activity of the unaltered form of the constant region. Anti-IL-27 antibodies described herein that comprise altered constant regions that exhibit reduced ADCC and / or CDC may exhibit reduced or no ADCC and / or CDC activity.

[0271] In some embodiments, the anti-IL-27 antibodies described herein exhibit reduced or no effector function. In some embodiments, the anti-IL-27 antibodies comprise a hybrid constant region or portion thereof, e.g., a G2 / G4 hybrid constant region (see, e.g., Burton et al. (1992) Adv Immun 51:1-18; Canfield et al. (1991) J Exp Med 173:1483-1491; and Mueller et al. (1997) Mol Immunol 34(6):441-452). See supra.

[0272] In some embodiments, anti-IL-27 antibodies may contain modified constant regions that exhibit enhanced or reduced complement-dependent cytotoxicity (CDC). Modulated CDC activity may be achieved by introducing one or more amino acid substitutions, insertions, or deletions into the Fc region of the antibody. See, for example, U.S. Patent No. 6,194,551. Alternatively or additionally, cysteine ​​residue(s) may be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved or reduced internalization capability and / or increased or reduced complement-mediated cell killing. See, e.g., Caron et al. (1992) J Exp Med 176:1191-1195 and Shopes (1992) Immunol 148:2918-2922; PCT Publication Nos. WO 99 / 51642 and WO 94 / 29351; Duncan and Winter (1988) Nature 322:738-40; and U.S. Pat. Nos. 5,648,260 and 5,624,821.

[0273] Recombinant antibody expression and purification The antibodies or antigen-binding fragments thereof described herein can be produced using a variety of techniques known in the art of molecular biology and protein chemistry. For example, nucleic acids encoding one or both of the antibody heavy and light chain polypeptides can be inserted into an expression vector containing transcriptional and translational control sequences, including, for example, promoter sequences, ribosomal binding sites, transcriptional start and stop sequences, translational start and stop sequences, transcriptional terminator signals, polyadenylation signals, and enhancer or activator sequences. Control sequences include promoters and transcriptional start and stop sequences. In addition, the expression vector can contain multiple replication systems so that it can be maintained in two different organisms, for example, in mammalian or insect cells for expression and in a prokaryotic host for cloning and amplification.

[0274] Several potential vector systems are available for the expression of cloned heavy and light chain polypeptides from nucleic acids in mammalian cells. One class of vectors relies on integration of the desired gene sequence into the host cell genome. Cells with stably integrated DNA can be selected by co-introducing a drug resistance gene such as E. coli gpt (Mulligan and Berg (1981) Proc Natl Acad Sci USA 78:2072) or Tn5neo (Southern and Berg (1982) Mol Appl Genet 1:327). The selectable marker gene can either be linked to the DNA gene sequence to be expressed or introduced into the same cell by co-transfection (Wigler et al. (1979) Cell 16:77). A second class of vectors utilizes DNA elements that confer autonomous replication capability to extrachromosomal plasmids. These vectors can be derived from animal viruses, such as bovine papillomavirus (Sarver et al. (1982) Proc Natl Acad Sci USA, 79:7147), cytomegalovirus, polyomavirus (Deans et al. (1984) Proc Natl Acad Sci USA 81:1292), or SV40 virus (Lusky and Botchan (1981) Nature 293:79).

[0275] The expression vector can be introduced into cells in a manner suitable for subsequent expression of the nucleic acid. The introduction method depends largely on the type of target cell, as described below. Exemplary methods include CaPO precipitation, liposome fusion, cationic liposomes, electroporation, viral infection, dextran-mediated transfection, polybrene-mediated transfection, protoplast fusion, and direct microinjection.

[0276] Suitable host cells for expression of antibodies or antigen-binding fragments thereof include yeast, bacteria, insect, plant, and mammalian cells. Of particular interest are bacteria such as E. coli, fungi such as Saccharomyces cerevisiae and Pichia pastoris, insect cells such as SF9, mammalian cell lines (e.g., human cell lines), and primary cell lines.

[0277] In some embodiments, antibodies or fragments thereof can be expressed in and purified from transgenic animals (e.g., transgenic mammals). For example, antibodies can be produced in transgenic non-human mammals (e.g., rodents) and isolated from their milk, as described, for example, in Houdebine (2002) Curr Opin Biotechnol 13(6):625-629; van Kuik-Romeijn et al. (2000) Transgenic Res 9(2):155-159; and Pollock et al. (1999) J Immunol Methods 231(1-2):147-157.

[0278] Antibodies and fragments thereof can be produced from host cells transformed with an expression vector containing nucleic acid encoding the antibody or fragment by culturing the cells under conditions and for an amount of time sufficient to allow expression of the protein. Such conditions for protein expression will vary with the choice of expression vector and host cell, and will be readily ascertained by one of ordinary skill in the art through routine experimentation. For example, antibodies expressed in E. coli can be refolded from inclusion bodies (see, e.g., Hou et al., J. Immunol. 1999, 123:111-112). (See, e.g., Kaszubska et al. (1998) Cytokine 10:319-30). Bacterial expression systems and methods for their use are well known in the art (see, Current Protocols in Molecular Biology, Wiley & Sons, and Molecular Cloning--A Laboratory Manual--3rd Ed., Cold Spring Harbor Laboratory Press, New York (2001)). The selection of codons, suitable expression vectors, and suitable host cells can vary depending on several factors and can be readily optimized as needed. The antibodies (or fragments thereof) described herein can be expressed in mammalian cells or other expression systems, including but not limited to, yeast, baculovirus, and in vitro expression systems (see, e.g., Kaszubska et al. (2000) Protein Expression and Purification 18:213-220).

[0279] After expression, antibodies and their fragments can be isolated. Antibodies or their fragments can be isolated or purified in a variety of ways known to those skilled in the art, depending on other components present in the sample. Standard purification methods include electrophoretic, molecular, immunological, and chromatographic techniques, such as ion exchange, hydrophobic, affinity, and reverse-phase HPLC chromatography. For example, antibodies can be purified using a standard anti-antibody column (e.g., a Protein A or Protein G column). Ultrafiltration and diafiltration techniques, combined with protein concentration, are also useful. See, for example, Scopes (1994) "Protein Purification, 3 rd edition,”Springer-Verlag,New York City,New See, York. The degree of purification required will vary depending on the desired use. In some instances, purification of the expressed antibody or fragment thereof will not be necessary.

[0280] Methods for determining the yield or purity of a purified antibody or fragment thereof are known in the art and include, for example, Bradford assay, ultraviolet spectroscopy, biuret protein assay, Lowry protein assay, amido black protein assay, high pressure liquid chromatography (HPLC), mass spectrometry (MS), and gel electrophoresis (e.g., using a protein stain such as Coomassie blue or colloidal silver stain).

[0281] Modification of antibodies or antigen-binding fragments thereof Antibodies or antigen-binding fragments thereof can be modified after their expression and purification. Modifications can be covalent or non-covalent. Such modifications can be introduced into antibodies or fragments, for example, by reacting targeted amino acid residues of the polypeptide with organic derivatizing agents capable of reacting with selected side chains or terminal residues. Suitable sites for modification can be selected using any of a variety of criteria, including, for example, structural analysis or amino acid sequence analysis of the antibody or fragment.

[0282] In some embodiments, an antibody or antigen-binding fragment thereof can be conjugated to a heterologous moiety, which can be, for example, a heterologous polypeptide, a therapeutic agent (e.g., a toxin or drug), or a detectable label, for example, but not limited to, a radioactive label, an enzymatic label, a fluorescent label, a heavy metal label, a luminescent label, or an affinity tag such as biotin or streptavidin. Suitable heterologous polypeptides include, for example, antigen tags (FLAG (DYKDDDDK (SEQ ID NO: 405)), polyhistidine (6-His; HHHHHH (SEQ ID NO: 406), hemagglutinin (HA; YPYDVPDYA (SEQ ID NO: 407)), glutathione-S-transferase (GST), or maltose binding protein (MBP)) for use in purifying the antibody or fragment. Heterologous polypeptides also include polypeptides (e.g., enzymes) that are useful as diagnostic or detectable markers, such as luciferase, fluorescent proteins (e.g., green fluorescent protein (GFP)), or chloramphenicol acetyltransferase (CAT). Suitable radiolabels include, for example, 32 P, 33 P, 14 C. 125 I, 131 I, 35 S, and 3 H. Suitable fluorescent labels include, but are not limited to, fluorescein, fluorescein isothiocyanate (FITC), green fluorescent protein (GFP), DyLight™ 488, phycoerythrin (PE), propidium iodide (PI), PerCP, PE-Alexa Fluor® 700, Cy5, allophycocyanin, and Cy7. Luminescent labels include, for example, any of a variety of luminescent lanthanide (e.g., europium or terbium) chelates. For example, suitable europium chelates include the europium chelates of diethylenetriaminepentaacetic acid (DTPA) or tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Enzymatic labels include, for example, alkaline phosphatase, CAT, luciferase, and horseradish peroxidase.

[0283] Two proteins (e.g., an antibody and a heterologous moiety) can be crosslinked using any of several known chemical crosslinkers. Examples of such crosslinkers are those that link two amino acid residues via a linkage containing a "hindered" disulfide bond. In these linkages, the disulfide bond within the crosslinking unit is protected (by hindering groups on both sides of the disulfide bond) from reduction, e.g., by the action of reduced glutathione or the enzyme disulfide reductase. One suitable reagent, 4-succinimidyloxycarbonyl-α-methyl-α(2-pyridyldithio)toluene (SMPT), utilizes a terminal lysine on one protein and a terminal cysteine ​​on the other to form such a bond between two proteins. Heterobifunctional reagents that crosslink via different coupling moieties on each protein can also be used. Other useful cross-linking agents include, but are not limited to, reagents that link two amino groups (e.g., N-5-azido-2-nitrobenzoyloxysuccinimide), reagents that link two sulfhydryl groups (e.g., 1,4-bis-maleimidobutane), reagents that link amino and sulfhydryl groups (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester), reagents that link amino and carboxyl groups (e.g., 4-[p-azidosalicylamido]butylamine), and reagents that link amino and guanidinium groups present in the side chain of arginine (e.g., p-azidophenylglyoxal monohydrate).

[0284] In some embodiments, the radiolabel can be conjugated directly to the amino acid backbone of the antibody. Alternatively, the radiolabel can be attached to a larger molecule (e.g., meta-[ 125 Iodophenyl-N-hydroxysuccinimide ([ 125 I]mIPNHS) 125I) (see, e.g., Rogers et al. (1997) J Nucl Med 38:1221-1229) or as part of a chelate (e.g., DOTA or DTPA), which is then attached to the protein backbone. Methods for conjugating radiolabels or larger molecules / chelates containing them to the antibodies or antigen-binding fragments described herein are known in the art. Such methods involve incubating the protein with the radiolabel under conditions (e.g., pH, salt concentration, and / or temperature) that promote binding of the radiolabel or chelate to the protein (see, e.g., U.S. Pat. No. 6,001,329).

[0285] Methods for conjugating fluorescent labels (sometimes referred to as "fluorophores") to proteins (e.g., antibodies) are known in the field of protein chemistry. For example, fluorophores can be conjugated to free amino groups (e.g., of lysines) or sulfhydryl groups (e.g., of cysteines) of proteins using succinimidyl (NHS) ester or tetrafluorophenyl (TFP) ester moieties attached to the fluorophore. In some embodiments, fluorophores can be conjugated to heterobifunctional crosslinker moieties such as sulfo-SMCC. A suitable conjugation method involves incubating an antibody, or a fragment thereof, with the fluorophore under conditions that promote binding of the fluorophore to the protein. See, for example, Welch and Redvanly (2003) "Handbook of Radiopharmaceuticals: Radiochemistry and Applications," John Wiley and Sons (ISBN 0471495603).

[0286] In some embodiments, the antibody or fragment can be modified with a moiety that improves stabilization and / or retention of the antibody in circulation, e.g., in blood, serum, or other tissues. For example, the antibody or fragment can be PEGylated or HESylated, e.g., as described in Lee et al. (1999) Bioconjug Chem 10(6):973-8; Kinstler et al. (2002) Advanced Drug Deliveries Reviews 54:477-485; and Roberts et al. (2002) Advanced Drug Delivery Reviews 54:459-476 (Fresenius Kabi, Germany; e.g., Pavisic et al. (2010) Int J Pharm 387(1-2):110-119.) The stabilizing moiety can improve the stability or retention of the antibody (or fragment) by at least 1.5-fold (e.g., at least 2, 5, 10, 15, 20, 25, 30, 40, or 50 or more).

[0287] In some embodiments, the antibodies or antigen-binding fragments thereof described herein can be glycosylated. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can be subjected to enzymatic or chemical treatment or produced from cells so that the antibodies or fragments have reduced or no glycosylation. Methods for producing antibodies with reduced glycosylation are known in the art and are described, for example, in U.S. Pat. No. 6,933,368; Wright et al. (1991) EMBO J 10(10):2717-2723; and Co et al. (1993) Mol Immunol 30:1361.

[0288] Pharmaceutical Compositions and Formulations In certain embodiments, the present invention provides pharmaceutical compositions comprising an anti-IL-27 antibody together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and / or adjuvant.

[0289] In certain embodiments, acceptable formulation materials are preferably non-toxic to recipients at the dosages and concentrations employed. In certain embodiments, the formulation material(s) are for subcutaneous and / or intravenous administration. In certain embodiments, pharmaceutical compositions can contain formulation materials to modify, maintain, or preserve, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or penetration of the composition.In certain embodiments, suitable formulation materials include amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrate, phosphate, or other organic acids); bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose, or dextrins); proteins (such as serum albumin, gelatin, or immunoglobulins); colorants; flavoring agents and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium). etc.); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as Pluronic®, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal, etc.); stability enhancers (such as sucrose or sorbitol); tonicity enhancers (such as alkali metal halides, preferably sodium chloride or potassium chloride, mannitol sorbitol, etc.); delivery vehicles; diluents; excipients, and / or pharmaceutical adjuvants. (Remington's Pharmaceutical Sciences, 18th Edition, A.R. Gennaro, ed., Mack Publishing Company (1995). In certain embodiments, the formulation comprises PBS; 20 mM NaOAC, pH 5.2, 50 mM NaCl; and / or 10 mM NAOAC, pH 5.2, 9% sucrose.In certain embodiments, optimal pharmaceutical compositions will be determined by one of skill in the art depending on, for example, the intended route of administration, delivery format, and desired dosage. See, e.g., Remington's Pharmaceutical Sciences, supra. In certain embodiments, such compositions may influence the physical state, stability, rate of in vivo release, and / or rate of in vivo clearance of the anti-IL-27 antibody.

[0290] In certain embodiments, the primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, in certain embodiments, a suitable vehicle or carrier can be water for injection, saline solution, or artificial cerebrospinal fluid, possibly supplemented with other ingredients common in compositions for parenteral administration. In certain embodiments, the saline solution comprises isotonic phosphate-buffered saline. In certain embodiments, neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In certain embodiments, the pharmaceutical composition comprises Tris buffer of about pH 7.0-8.5 or acetate buffer of about pH 4.0-5.5, which may further comprise sorbitol or a suitable substitute. In certain embodiments, compositions comprising anti-IL-27 antibodies can be prepared for storage by mixing a selected composition having the desired purity with optional formulation agents (Remington's Pharmaceutical Sciences, supra) in the form of a lyophilized cake or aqueous solution. Additionally, in certain embodiments, compositions comprising anti-IL-27 antibodies can be formulated as a lyophilizate using appropriate excipients such as sucrose.

[0291] In certain embodiments, pharmaceutical compositions can be selected for parenteral delivery. In certain embodiments, compositions can be selected for delivery via inhalation or the digestive tract, e.g., oral administration. The preparation of such pharmaceutically acceptable compositions is within the capabilities of those skilled in the art.

[0292] In certain embodiments, formulation components are present in concentrations that are acceptable to the site of administration. In certain embodiments, buffering agents are used to maintain the composition at physiological pH or slightly lower, typically within a pH range of about 5 to about 8.

[0293] In certain embodiments, when parenteral administration is intended, the therapeutic composition may be in the form of a pyrogen-free, parenterally acceptable aqueous solution containing an anti-IL-27 antibody in a pharmaceutically acceptable vehicle. In certain embodiments, the vehicle for parenteral injection is sterile distilled water, in which the anti-IL-27 antibody is formulated as a sterile, isotonic solution and properly stored. In certain embodiments, the preparation involves formulating the desired molecule with an agent that can provide controlled or sustained release of the product, such as injectable microspheres, bioerodible particles, polymeric compounds (e.g., polylactic acid or polyglycolic acid), beads, or liposomes, which can then be delivered via depot injection. In certain embodiments, hyaluronic acid can also be used and can have the effect of promoting sustained duration in the circulation. In certain embodiments, an implantable drug delivery device can be used to introduce the desired molecule.

[0294] In certain embodiments, the pharmaceutical composition can be formulated for inhalation. In certain embodiments, the anti-IL-27 antibody can be formulated as a dry powder for inhalation. In certain embodiments, an inhalation solution containing the anti-IL-27 antibody can be formulated with a propellant for aerosol delivery. In certain embodiments, the solution can be nebulized. Pulmonary administration is further described in PCT Application No. PCT / US94 / 001875, which describes pulmonary delivery of chemically modified proteins.

[0295] It is contemplated that in certain embodiments, the formulation can be administered orally. In certain embodiments, anti-IL-27 antibodies administered in this manner can be formulated with or without carriers customarily used in compounding solid dosage forms such as tablets and capsules. In certain embodiments, capsules can be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. In certain embodiments, at least one additional agent can be included to promote absorption of the anti-IL-27 antibody. In certain embodiments, diluents, flavorings, low-melting waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.

[0296] In certain embodiments, pharmaceutical compositions can involve an effective amount of anti-IL-27 antibody in a mixture with non-toxic excipients suitable for the manufacture of tablets. In certain embodiments, tablets can be prepared in unit dosage form by dissolving the solution in sterile water or another suitable vehicle. In certain embodiments, suitable excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate or sodium bicarbonate, lactose, or calcium phosphate; or binders such as starch, gelatin, or gum arabic; or lubricants such as magnesium stearate, stearic acid, or talc.

[0297] Additional pharmaceutical compositions, including formulations involving anti-IL-27 antibodies in sustained- or controlled-delivery formulations, will be apparent to those skilled in the art. In certain embodiments, techniques for formulating various other sustained- or controlled-delivery means, such as liposome carriers, bioerodible microparticles or porous beads, and depot injections, are also known to those skilled in the art. See, e.g., PCT Application No. PCT / US93 / 00829, which describes the controlled release of porous polymeric microparticles for the delivery of pharmaceutical compositions. In certain embodiments, sustained-release preparations may comprise semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include polyesters, hydrogels, polylactides (U.S. Pat. No. 3,773,919 and EP 058,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers, 22:547-556 (1983)), poly(2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed. Mater. Res., 15:167-277 (1981) and Langer, Chem. Tech., 12:98-105 (1982)), ethylene vinyl acetate (Langer et al., supra), or poly-D(-)-3-hydroxybutyrate (EP 133,988). In certain embodiments, sustained-release compositions can also contain liposomes, which can be prepared by any of several methods known in the art. See, for example, Eppstein et al., Proc. Natl. Acad. Sci. USA, 82:3688-3692 (1985); EP 036,676; EP 088,046 and EP 143,949.

[0298] Pharmaceutical compositions used for in vivo administration are typically sterile. In certain embodiments, this can be achieved by filtration through a sterile filtration membrane. In certain embodiments, when the composition is lyophilized, sterilization using this method can be carried out before or after lyophilization and reconstitution. In certain embodiments, compositions for parenteral administration can be stored in lyophilized form or in a solution. In certain embodiments, parenteral compositions are generally placed into a container with a sterile access port, for example, an intravenous infusion bag or vial with a stopper that can be pierced by a hypodermic injection needle.

[0299] In certain embodiments, once formulated, the pharmaceutical compositions can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. In certain embodiments, such formulations can be stored either in a ready-to-use form or in a form that is reconstituted (e.g., lyophilized) prior to administration.

[0300] In certain embodiments, the kit is provided for producing single-dose units.In certain embodiments, the kit can contain both the first container with dry protein and the second container with aqueous formulation.In certain embodiments, the kit includes the kit that contains single-chamber and multi-chamber pre-filled syringe (for example, liquid syringe and lyosyringe).

[0301] In certain embodiments, the effective amount of a pharmaceutical composition comprising an anti-IL-27 antibody employed therapeutically will depend, for example, on the context and purpose of the treatment. One of skill in the art will understand that appropriate dosage levels for treatment according to certain embodiments will vary depending, in part, on the molecule being delivered, the indication for which the anti-IL-27 antibody is being used, the route of administration, and the size (weight, body surface area, or organ size) and / or condition (age and general health) of the patient. In certain embodiments, a clinician can titrate the dosage and modify the route of administration to obtain the optimal therapeutic effect.

[0302] In certain embodiments, the frequency of dosing will take into account the pharmacokinetic parameters of the anti-IL-27 antibody in the formulation used. In certain embodiments, the clinician will administer the composition until a dosage that achieves the desired effect is reached. In certain embodiments, the composition may be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implanted device or catheter. Further refinement of the appropriate dosage is routinely performed by those skilled in the art and is within the scope of their routinely performed tasks. In certain embodiments, the appropriate dosage can be ascertained through the use of appropriate dose-response data.

[0303] In certain embodiments, the administration route of the pharmaceutical composition is according to known methods, for example, oral, intravenous, intraper...

Claims

1. 1. A composition for treating cancer in a subject, comprising an isolated monoclonal antibody or antigen-binding portion thereof that specifically binds to human IL-27, wherein the antibody or antigen-binding portion thereof comprises heavy chain and light chain CDRs; (i) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 161, 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; (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; (iii) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 73, 74, and 75, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 81, 82, and 83, respectively; (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; (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 set forth in SEQ ID NOs: 103, 104, and 105, respectively; (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; (vii) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 117, 118, and 119, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 125, 126, and 127, respectively; (viii) the heavy chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 120, 121, and 122, respectively, and the light chain CDR1, CDR2, and CDR3 sequences are set forth in SEQ ID NOs: 128, 129, and 130, respectively; (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; (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 set forth in SEQ ID NOs: 150, 151, and 152, respectively; (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; or (xii) The composition, wherein 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.

2. 2. The composition of claim 1, wherein the cancer is selected from lung cancer, sarcoma, testicular cancer, ovarian cancer, pancreatic cancer, breast cancer, melanoma, head and neck cancer, colorectal cancer, bladder cancer, endometrial cancer, prostate cancer, thyroid cancer, hepatocellular carcinoma, gastric cancer, brain cancer, lymphoma, leukemia, and renal cancer.

3. The composition of claim 1 , wherein the cancer is non-small cell lung cancer.

4. The composition of claim 1 , wherein the cancer is hepatocellular carcinoma.

5. The composition of claim 1 , wherein the cancer is renal cell carcinoma.

6. The composition of claim 1 , wherein the cancer is gastric cancer.

7. The composition of claim 1 , wherein the cancer is gastroesophageal cancer.

8. The composition of claim 1, wherein the isolated monoclonal antibody or antigen-binding portion thereof is: (i) SEQ ID NO: 167 and SEQ ID NO: 175, respectively; (ii) SEQ ID NO:57 and SEQ ID NO:65, respectively; (iii) SEQ ID NO: 79 and SEQ ID NO: 87, respectively; (iv) SEQ ID NO: 101 and SEQ ID NO: 109, respectively; (v) SEQ ID NO: 123 and SEQ ID NO: 131, respectively; and (vi) SEQ ID NO: 145 and SEQ ID NO: 153, respectively A composition comprising heavy and light chain variable regions comprising amino acid sequences that are at least 90% identical to an amino acid sequence selected from the group consisting of:

9. 9. The composition of any one of claims 1 to 8 for use in combination with one or more additional therapeutic agents or procedures, wherein the one or more additional therapeutic agents or procedures are selected from the group consisting of chemotherapy, targeted anti-cancer therapy, oncolytic agents, cytotoxic agents, immune system therapy, cytokines, surgical procedures, radiation procedures, activators of costimulatory molecules, inhibitors of inhibitory molecules, vaccines, cellular immunotherapy, and combinations thereof.

10. 10. The composition of claim 9, wherein the one or more additional therapeutic agents is a PD-1 antagonist, a PD-L1 inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, a CD112R inhibitor, a TAM inhibitor, a STING agonist, a 4-1BB agonist, or a combination thereof.

11. The composition of claim 10, wherein the one or more additional therapeutic agents is a PD-1 antagonist.

12. 12. The composition of claim 11, wherein the PD-1 antagonist is selected from the group consisting of PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, and AMP-224.

13. 11. The composition of claim 10, wherein the PD-L1 inhibitor is selected from the group consisting of FAZ053, atezolizumab, avelumab, durvalumab, and BMS-936559.

14. The one or more additional therapeutic agents may be sunitinib, cabozantinib, axitinib, lenvatinib, everolimus, bevacizumab, epacadostat, NKTR-214, tivozanib, abexinostat, ipilimumab, tremelimumab, pazopanib, sorafenib, temsirolimus, ramucirumab, niraparib, savolitinib, boranib, regorafenib, donafenib, camrelizumab, pexil 11. The composition of claim 10, wherein the compound is selected from the group consisting of sustimodin debasilepvec, ramucirumab, apatinib, encapsulated doxorubicin, tivantinib, ADI-PEG20, binimetinib, apatinib mesylate, nintedanib, lirilumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab-rwlc, tislelizumab, and spartalizumab.

15. The composition of claim 10, wherein the one or more additional therapeutic agents is a TIM-3 inhibitor.

16. The composition of claim 15, wherein the TIM-3 inhibitor is MGB453 or TSR-022.

17. The composition of claim 10, wherein the one or more additional therapeutic agents is a LAG-3 inhibitor.

18. 18. The composition of claim 17, wherein the LAG-3 inhibitor is selected from the group consisting of LAG525, BMS-986016, and TSR-033.

19. The composition of claim 10, wherein the one or more additional therapeutic agents is a TIGIT inhibitor.

20. The composition of claim 10, wherein the one or more additional therapeutic agents is a CD112R inhibitor.

21. 11. The composition of claim 10, wherein the one or more additional therapeutic agents is a TAM (Axl, Mer, Tyro) inhibitor.

22. The composition of claim 10, wherein the one or more additional therapeutic agents is a 4-1BB agonist.

23. 11. The composition of claim 10, wherein the one or more additional therapeutic agents is a tyrosine kinase inhibitor (TKI).

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