Combinations of Anti-il-27 antibodies with toripalimab and bevacizumab

Abstract

The present application relates to methods of stimulating an immune response in a subject by administering to the subject (i) an antibody that binds human IL-27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) toripalimab, and (iii) bevacizumab. Methods of treating a cancer by administering (i) an antibody that binds human IL-27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) toripalimab, and (iii) bevacizumab are provided.

Description

COMBINATIONS OF ANTI-IL-27 ANTIBODIES WITH TORIPALIMAB ANDBEVACIZUMABCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of U.S. Provisional application number 63 / 716,483, filed November 5, 2024, the disclosure of which is incorporated herein by reference in its entirety.REFERENCE TO SEQUENCE LISTING

[0002] The present application contains a Sequence Listing which has been submitted electronically in XML format. Said XML copy, created on October 31. 2024, is named “4494- 173-SEQ-Listing.xml” and is 296,824 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.FIELD

[0003] The present disclosure relates generally to methods for treating a subject afflicted with a cancer by administering to the subject an anti-IL-27 antibody, toripalimab, and bevacizumab.BACKGROUND

[0004] In recent years, an increasing body of evidence suggests that the immune system operates as a significant barrier to tumor formation and progression. The principle that naturally occurring T cells with anti -tumor potential or activity exist in a patient with cancer has rationalized the development of immunotherapeutic approaches in oncology. Immune cells, such as T cells, macrophages, and natural killer cells, can exhibit anti-tumor activity and effectively control the occurrence and growth of malignant tumors. Tumor-specific or -associated antigens can induce immune cells to recognize and eliminate malignancies (Chen & Mellman, (2013) Immunity 39(1): 1-10). In spite of the existence of tumor-specific immune responses, malignant tumors often evade or avoid immune attack through a variety of immunomodulatory mechanisms resulting in the failure to control tumor occurrence and progression (Motz & Coukos, (2013) Immunity 39( 1 ):61 -730). Indeed, an emerging hallmark of cancer is the exploitation of these immunomodulatory mechanisms and the disablement of anti-tumor immune responses, resulting in tumor evasion and escape from immunological killing (Hanahan and Weinberg (2011) Cell 144(5):646-674).

[0005] Despite the significant advances being made in cancer treatment and management, there is still an ongoing need for new and effective therapies for treating and managing cancer. There remains a long-felt and unmet clinical need for the majority of cancer patients who do not experience an objective response or who progress after receiving existing therapy options.SUMMARY OF THE DISCLOSURE

[0006] Some aspects of the present disclosure are directed to a method of stimulating an immune response in a subject, the method comprising administering to the subject (i) an antibody that binds human IL-27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), (ii) toripalimab, and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0007] Some aspects of the present disclosure are directed to a method of treating a cancer in a subject in need thereof comprising administering to the subject (i) an antibody that binds human IL-27 or an antigen binding portion thereof ("an anti -IL-27 antibody"),(ii) toripalimab. and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0008] In some aspects, the anti-IL-27 antibody is administered at a dose of at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1100 mg, at least about 1200 mg, at least about 1300 mg, at least about 1400 mg, at least about 1500 mg, at least about 1600 mg, at least about 1700 mg, at least about 1800 mg, at least about 1900 mg, or about 2000 mg.

[0009] In some aspects, the anti-IL-27 antibody is administered once about every week, once about every two weeks, once about every three weeks, once about every four weeks, once about every 6 weeks, once about every 8 weeks, or once about every 12 weeks.

[0010] In some aspects, the anti-IL-27 antibody is administered at a flat dose. In some aspects, the anti-IL-27 antibody is administered once about every three weeks. In some aspects, the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks. In some aspects, the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every three weeks. In some aspects, the anti-IL-27 antibody is administered once about every four weeks. In some aspects, the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks. In some aspects, the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks.

[0011] In some aspects, toripalimab is administered at a flat dose. In some aspects, toripalimab is administered at a dose of about 120 mg to about 720 mg, about 240 mg to about 480 mg, or about 240 mg to about 360 mg, e.g., 240 mg or 340 mg. In some aspects, toripalimab is administered once about every week, once about every two weeks, once about every three weeks, or once about every four weeks. In some aspects, toripalimab is administered at a dose of about 240 mg once about every three weeks. In some aspects, toripalimab is administered at a dose of about 340 mg once about every four weeks.

[0012] In some aspects, bevacizumab is administered at a dose of at least about 0.003 mg / kg, at least about 0.006 mg / kg, at least about 0.009 mg / kg, at least about 0.03 mg / kg, at least about 0.06 mg / kg, at least about 0.09 mg / kg, at least about 0.3 mg / kg, at least about 0.6 mg / kg, at least about 0.9 mg / kg, at least about 1.0 mg / kg, at least about 2 mg / kg, at least about 3 mg / kg, at least about 4 mg / kg, at least about 5 mg / kg, at least about 6 mg / kg, at least about 7 mg / kg, at least about 8 mg / kg, at least about 9 mg / kg, at least about 10 mg / kg, at least about 11 mg / kg, at least about 12 mg / kg, at least about 13 mg / kg, at least about 14 mg / kg, at least about 15 mg / kg, at least about 16 mg / kg, at least about 17 mg / kg, at least about 18 mg / kg, at least about 19 mg / kg, at least about 20 mg / kg, at least about 21 mg / kg, at least about 22 mg / kg, at least about 23 mg / kg, at least about 24 mg / kg, at least about 25 mg / kg, or at least about 30 mg / kg. In some aspects, bevacizumab is administered once about every week, once about every two weeks, once about every three weeks, or once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0013] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks.

[0014] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks.

[0015] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0016] In some aspects, (i) the anti -IL- 27 antibody is administered at a dose of about 1400 mg once about every' three weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0017] In some aspects, (i) the anti -IL- 27 antibody is administered at a dose of about 1000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks.

[0018] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks.

[0019] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0020] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0021] In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are administered on the same day. In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are administered concurrently, for example, during the same treatment session. In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are administeredsequentially. In some aspects, the anti-IL-27 antibody is administered first, toripalimab is administered second, and bevacizumab is administered third. In some aspects, (i) the anti-IL-27 antibody and (ii) toripalimab and bevacizumab are administered on different days.

[0022] In some aspects, the anti-IL-27 antibody comprises a heavy chain variable region comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 11. In some aspects, the anti-IL-27 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11. In some aspects, the anti -IL-27 antibody comprises a light chain variable region comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the anti-IL-27 antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the anti-IL-27 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19.

[0023] In some aspects, the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21. In some aspects, the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25. In some aspects, the anti-IL-27 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0024] In some aspects, the subject is afflicted with a cancer. In some aspects, the cancer is a hepatocellular carcinoma (HCC).

[0025] In some aspects, the cancer is advanced. In some aspects, the cancer is locally advanced. In some aspects, the cancer is metastatic. In some aspects, the cancer is refractory. In some aspects, the cancer is unresectable.

[0026] In some aspects, the cancer is unresectable and / or locally advanced or metastatic hepatocellular carcinoma.

[0027] In some aspects, the cancer is previously untreated.

[0028] In some aspects, the subject previously received at least one, at least two, at least three, at least four, or at least five prior anticancer therapies. In some aspects, the prior anticancer therapy comprises a prior anti-PD-1 antibody therapy or a prior anti-PD-Ll antibody therapy.

[0029] Some aspects of the present disclosure are directed to a composition comprising (i) an antibody that binds human IL- 27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) a surfactant, and (iii) one or more stabilizer; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0030] In some aspects, the surfactant is polysorbate 80. In some aspects the one or more stabilizers comprise histidine and sucrose. In some aspects, the composition has a pH of about 4 to about 7, about 4.5 to about 6.5, about 5 to about 6, or about 5.5.BRIEF DESCRIPTION OF DRAWINGS

[0031] FIGs. 1A-1D are schematics of a phase 1 / lb dose-escalation and expansion study for an anti-IL-27 antibody. ccRCC = clear cell renal cell carcinoma; CR = complete response; HCC = hepatocellular carcinoma; N = number; PR = partial response; pts = patients, RP2D = recommended Phase 2 dose; 2L = second line. Dose level 1 = 0.003 mg / kg; Dose level 2 = 0.03 mg / kg; Dose level 3 = 0.1 mg / kg; Dose level 4 = 0.3 mg / kg; Dose level 5 = 1.0 mg / kg; Dose level 6 = 3.0 mg / kg; Dose level 7 = 10.0 mg / kg; Dose level 8 = 20.0 mg / kg; NSCLC = nonsmall cell lung cancer; Q4W = administered every 4 weeks; Q3W = administered every 3 weeks.

[0032] FIG. 2 is a Swimmer’s plot depicting time on study and RECIST response grouped by starting dose of the 29 patients enrolled in a dose escalation study. The median time on study was 9 weeks (with a range of 1 to 71 weeks).

[0033] FIGs. 3A-3B show target lesion changes over time. FIG. 3A is a waterfall plot depicting the best percentage change in target lesions from baseline (n=27). FIG. 3B is a spider plot depicting the target lesion change from baseline over time.

[0034] FIGs. 4A-4B are graphical representations of anti-IL-27 Abl monotherapy dose escalation response. FIG. 4A is a waterfall plot depicting the best percentage change in sum of target lesions. FIG. 4B is a spider plot depicting the lesion change over time.

[0035] FIGs. 5A-5B are graphical representations of the anti -IL-27 Abl pharmacokinetic profile. FIG. 5A shows Cycle 1 anti -IL-27 Abl PK by dose regimen, irrespective of tumor type. FIG. 5B shows the PK of anti -IL-27 Abl when given once every four weeks as monotherapy in the dose escalation phase of the study (mixed solid tumors) and in the HCC and ccRCC expansions.

[0036] FIGs. 6A-6B are graphical representations of anti-IL-27 Abl ccRCC monotherapy dose escalation response. FIG. 6A is a waterfall plot depicting the best percentage change in sum of target lesions. FIG. 6B is a spider plot depicting the lesion change over time.

[0037] FIGs. 7A-7B are graphical representations of anti-IL-27 Ab 1 HCC monotherapy response. FIG. 7A is a waterfall plot depicting the best percentage change in sum of target lesions. FIG. 7B is a spider plot depicting the lesion change over time.

[0038] FIGs. 8A-8B are graphs depicting time on study and RECIST response. FIG. 8A is a Swimmer’s plot indicating the tumor histology (adeno or squamous) for 44 patients enrolled in the dose expansion study. The median time on study was 9 weeks (with a range of 1 to 91 weeks). FIG. 8B is a spider plot depicting lesion change over time for patients with NSCLC of different histology (adeno or squamous) receiving anti -IL-27 Abl monotherapy at different dose levels.

[0039] FIGs. 9A-9C are graphical representations of the simulated pharmacokinetics of anti -IL- 27 Abl. FIGs. 9A-9C show the calculated maximum concentration (FIG. 9A), exposure (as normalized area under the curve at 3 weeks, FIG. 9B), and trough concentration (FIG. 9C) for anti-IL-27 administered to virtual subjects at 700 mg vs 10 mg / kg Q3W and Q4W.

[0040] FIG. 10 depicts graphs showing changes in biomarker expression upon treatment of activated human peripheral blood mononuclear cell (PBMC) cultures with CHS-388 and / or an anti-PD- 1 antibody. Panel A is scatter plots showing the normalized fold change of TNFa and IFNy upon treatment with CHS-388 and / or an anti-PD- 1 antibody. Panel B is scatter plots showing the normalized fold change of TNFa and IFNv upon treatment with CHS-388 and / ortoripalimab. Panel C is a bar graph showing PD-L1 expression upon treatment with IL-27, alone and in combination with CHS -388. HCC = hepatocellular carcinoma; RCC = renal cell carcinoma.

[0041] FIGs. 11A-11D show graphical representations of simulated pharmacokinetic parameters for different toripalimab dosing regimens. FIG. 11A depicts average concentration (Cave), FIG. 11B depicts area under the curve (AUC), FIG. 11C depicts trough concentration levels (Ctrough), and FIG. HD depicts maximum concentration (Cmax). Q3W = once every 3 weeks. Q4W = once every 4 weeks. Q6W = once every 6 weeks.

[0042] FIG. 12 is a schematic of a phase 2 clinical study for CHS-388 in combination with toripalimab plus bevacizumab. HCC = hepatocellular carcinoma; N = number; ECOG-PS = Eastern Cooperative Oncology Group performance score; HBV = hepatitis B virus; HCV = hepatitis C virus; R = randomization; PE = primary endpoint; ORR = objective response rate; DoR = duration of response; PFS = progression-free survival; OS = overall survival; DCR = disease control rate; AE = adverse event; SAE = serious adverse event; AESI = adverse event of special interest; PK = pharmacokinetics; ADA = antidrug antibody; IL = first line.

[0043] FIG. 13 is a chart detailing the schedule of assessments for clinical trial CHS-388- 202. ADA = antidrug antibody; AE = adverse event; AESI = adverse event of special interest; AFP = alpha-fetoprotein; [3hCG = beta human chorionic gonadotropin; C = cycle; cfDNA = cell- free DNA; D or d = day; EBNA = Epstein-Barr nuclear antigen; EBV = Epstein-Barr virus; ECOG = Eastern Cooperative Oncology7Group; EoT = End of Treatment; HBV = hepatitis B virus; HCV = hepatitis C virus; IgG = immunoglobulin G; IgM = immunoglobulin M; PBMC = peripheral blood mononuclear cell; PD = progressive disease; PK = pharmacokinetics; Q3W = once every 3 weeks; SAE = serious adverse event; T4 = free thyroxine 4; TSH = thyroid stimulating hormone.

[0044] FIG. 14 is a chart detailing the schedule of pharmacokinetic and anti drug antibody assessments for clinical trial CHS-388-202. ADA = antidrug antibody; AE = adverse event; EoT = End of Treatment; hr = hour(s); min = minutes; PK = pharmacokinetics.DETAILED DESCRIPTION

[0045] While aspects of the subject matter of the present disclosure may be embodied in a variety of forms, the following description is merely intended to disclose some of these forms as specific examples of the subject matter encompassed by the present disclosure. Accordingly, thesubject matter of this disclosure is not intended to be limited to the forms or aspects so described.

[0046] As used herein, a plurality of compounds, elements, uses or method steps may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. Furthermore, certain molecules, constructs, compositions, elements, moieties, excipients, disorders, conditions, properties, uses, method steps, or the like may be discussed in the context of one specific aspect or aspect or in a separate paragraph or section of this disclosure. It is understood that this is merely for convenience and brevity, and any such disclosure is equally applicable to and intended to be combined with any other aspects or aspects found anywhere in the present disclosure and claims, which all form the application and claimed invention at the filing date. For example, a list of constructs, molecules, method steps, kits, or compositions described with respect to an antibody, molecule, polypeptide, composition, or method is intended to and does find direct support for aspects related to antibodies, molecules, polypeptides, compositions, formulations, and methods described in any other part of this disclosure, even if those method steps, active agents, kits, or compositions are not re-listed in the context or section of that aspect or aspects.

[0047] Some aspects of the present disclosure are directed to methods of stimulating an immune response in a subject, the method comprising administering to the subject (i) an antibody that binds human IL- 27 or an antigen binding portion thereof ("an anti -IL- 27 antibody"), (ii), toripalimab, and (iii) bevacizumab. Some aspects of the present disclosure are directed to methods of treating a cancer in a subject in need thereof comprising administering to the subject (i) an antibody that binds human IL- 27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), (ii) toripalimab, and (iii) bevacizumab. In some aspects, the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15. In some aspects, the anti-IL-27antibody is administered at a dose of about 500 mg to about 2000 mg. In some aspects, toripalimab is administered at a dose of about 240 mg. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg. In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are administered once about every three weeks.I. Definitions

[0048] Terms used in the claims and specification are defined as set forth below unless otherwise specified.

[0049] It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise.

[0050] As used herein, "about" will be understood by persons of ordinary skill and will vary to some extent depending on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill given the context in which it is used, "about" will mean up to plus or minus 10% of the particular value.

[0051] As used herein, the term "amount" or "level" is used in the broadest sense and refers to a quantity, concentration or abundance of a substance (e.g., a metabolite, a small molecule, a protein, an mRNA, a 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. "Elevated levels" or "increased levels" refers to an increase in the quantity, concentration or abundance of a substance within a sample relative to a control sample, such as from an individual or individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control. In some aspects, the 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). "Reduced levels" refers to a decrease in the quantity, concentration or abundance of a substance (e.g., a drug) in an individual relative to a control, such as from an individual or individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control. In some aspects, a reduced level is little or no detectable quantity, concentration or abundance. In some aspects, the reduced level of a substance (e.g., a drug) in a sample refers to a decrease 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).

[0052] When referring to a protein, mRNA or a marker, such as those described herein, the terms "level of expression" or "expression level" in general are used interchangeably and generally refer to a detectable amount of a protein, mRNA, or marker in a biological sample. In some aspects, a detectable amount or detectable level of a protein, mRNA or a marker is associated with a likelihood of a response to an agent, such as those described herein. "Expression" generally refers to the process by which information contained within a gene is converted into the structures (e.g., a protein marker, such as PD-L1) present and operating in the cell. Therefore, as used herein, "expression" may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide). Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide) shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., by proteolysis. "Expressed genes" include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs). "Elevated expression," "elevated expression levels," or "elevated levels" refers to an increased expression or increased levels of a substance within a sample relative to a control sample, such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control. In some aspects, the 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). "Reduced expression," "reduced expression levels," or "reduced levels" refers to a decrease expression or decreased levels of a substance (e.g., a protein marker) in an individual relative to a control, such as an individual or individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control. In some aspects, reduced expression is little or no expression. In some aspects, the reduced expression of a substance (e.g., a protein marker) ina sample refers to a decrease 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).

[0053] As used herein, the phrase "antibody that antagonizes human IL-27, or an antigen binding portion thereof 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), for example, relating to a decrease (or reduction) in human IL-27 activity that is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. Additional examples of IL- 27 biological activities and / or downstream pathway (s) mediated by IL-27 signaling or other IL- 27 -mediated function are described in additional detail below and elsewhere herein.

[0054] As used herein, the term "anti-IL-27 antagonist antibody" (interchangeably termed "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. An anti-IL-27 antagonist antibody encompasses antibodies that block, antagonize, suppress, inhibit or reduce an IL-27 biological activity (e.g., ligand binding, enzymatic activity), including downstream pathways mediated by IL- 27 signaling or function, such as receptor binding and / or elicitation of a cellular response to IL-27 or its metabolites. In some aspects, an anti-IL-27 antagonist antibody provided by the disclosure binds to human IL- 27 and prevents, blocks, or inhibits binding of human IL- 27 to its cognate or normal receptor (e.g., IL-27 receptor), or one or more receptor subunits (e.g., gpl30 and / or IL-27Ra (also known as WSX1 / TCCR)). In some aspects, the anti-IL-27 antagonist antibody prevents, blocks, or inhibits the binding of human IL-27 to the gpl30. In some aspects, the anti-IL-27 antagonist antibody prevents, blocks, or inhibits the binding of human IL-27 to the IL-27Ra. In some aspects, the anti- IL-27 antagonist antibody prevents, blocks, or inhibits the dimerization of IL- 27 monomers. In some aspects, the anti-IL-27 antibody does not specifically bind to the EBB monomer. In some aspects, the anti-IL-27 antibody specifically binds to the IL-27p28 monomer. In some aspects, the anti-IL-27 antibody specifically binds to a non-contiguous epitope comprising p28, but does not bind to the EBI3 monomer. In some aspects, the anti-IL-27 antibody inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell. In some aspects, the anti-IL-27 antibody inhibits or reduces inhibition of CD161 expression in a cell (e.g.,ameliorates or relieves IL- 27 mediated inhibition of CD161 expression in a cell). In some aspects, the anti-IL-27 antibody inhibits or reduces PD-L1 expression in a cell. In some aspects, the anti-IL-27 induces or enhances PD-1- mediated secretion of one or more cytokines from a cell. In some aspects, the anti-IL-27 antibody alters the expression of TIM-3 in a cell. In some aspects, an anti-IL-27 antagonist antibody binds to human IL- 27 and stimulates or enhances an anti-tumor response. In some aspects, the anti-IL- 27 antagonist antibody binds to human IL-27 with an affinity of 15 nM or less. In some aspects, the anti-IL-27 antagonist antibody binds to human IL- 27 and comprises a wild type or mutant IgGl 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.

[0055] “Casdozokitug,” as used herein, refers to a fully human, antagonistic IgGl monoclonal antibody targeting the p28 subunit of IL- 27. Casdozokitug (also known as “CHS- 388” or “CHS388” or “SRF388”) is a new drug under development by Coherus Oncology, Inc.

[0056] “Toripalimab," as used herein, refers to a recombinant humanized IgG4 monoclonal antibody that binds to programmed cell death protein 1 (PD-1). Toripalimab is marketed by Coherus Oncology, Inc. under the name LOQTORZI®.

[0057] Bevacizumab," as used herein, refers to a recombinant humanized monoclonal IgGl antibody that binds human vascular endothelial growth factor (VEGF) and neutralizes VEGF’s biologic activity.

[0058] The term "carcinoma" is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas. The anti-IL-27 antibodies and combinations described herein can be used to treat patients who have, who are suspected of having, or who may be at high risk for developing any type of cancer, including renal carcinoma 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 carcinosarcomas, which include malignant tumors composed of carcinomatous and sarcomatous tissues. An "adenocarcinoma" refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.

[0059] As used herein, the term "CD112R" refers to a member of poliovirus receptor-like proteins and is a co-inhibitory receptor for human T cells. CD112R is an inhibitory receptorprimarily expressed by T cells and NK cells and competes for CD112 binding with the activating receptor CD226. The interaction of CD112 with CD112R is of higher affinity than with CD226 and thereby effectively regulates CD226 mediated cell activation. Anti-CDl 12R antagonists that block the interaction with CD112 limit inhibitory signaling directly downstream of CD 112R while simultaneously promoting greater immune cell activation by increasing CD226 interactions with CD112. As used herein the term "CD112R inhibitor" refers to an agent that disrupts, blocks or inhibits the biological function or activity of CD112R.

[0060] As used herein, the term "CD137" (alternatively "4-1BB") refers to a member of the tumor necrosis factor (TNF) receptor superfamily. 4- IBB is a co-stimulatory immune checkpoint molecule, primarily for activated T cells. Crosslinking 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 function of 4-1BB. An exemplary 4- IBB agonist is Utomilumab (PF-05082566), a fully human IgG2 monoclonal antibody that targets this 4-1BB to stimulate T cells.

[0061] As used herein, the term "CD161" (alternatively 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 of T cells and CD161 expression has been associated with T cell infiltration into the tumor microenvironment for a number of different cancer types. CD161 is further described in Fergusson et al., (2014) Cell Reports 9(3):1075- 1088, which is incorporated herein by reference it its entirety.

[0062] 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 families, and is a heterodimeric cytokine that comprises a first subunit known as Epstein-Barr Virus Induced Gene 3 (EBI3; also known as IL- 27 subunit P and IL-27B) and a second subunit known as IL-27p28 (also known as IL30, IL-27 subunit a and IL-27 A). IL-27 is predominantly synthesized by activated antigen-presenting cells including monocytes, endothelial cells and dendritic cells (Jankowski et al. (2010) Arch Immunol. The Exp. 58:417-425, Diakowski et al. (2013) Adv. Clin. Exp. Med. (2013) 22(5): 683-691). Although IL- 27 can have proinflammatory effects, many studies suggest an important role of IL-27 as an immunosuppressive agent (Shimizu et al. (2006) J. Immunol. 176:7317- 7324, Hisada et al. (2004) Cancer Res. 64: 1152-1156, Diakowski (2013) supra).

[0063] IL-27 signals through a heterodimeric type I cytokine receptor (the IL- 27 receptor or IL-27R) that comprises a first subunit known as WSX1 (also known as IL-27 receptor subunita, IL-27RA, T-Cell Cytokine Receptor Type 1 (TCCR), and Cytokine Receptor-Like 1 (CRL1)) and a second subunit known as gpl30 (also known as Interleukin-6 Signal Transducer (IL6ST), Interleukin-6 Receptor Subunit P (IL-6RB), and Oncostatin M Receptor). gpl30 is also a receptor subunit for the 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.

[0064] EBB is also believed to have biological functions independent of p28 or the IL-27 heterodimer. For example, EBB 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).

[0065] An amino acid sequence of an exemplary human EBB protein is provided in SEQ ID NO: 1 (NCBI Reference Sequence: NP_005746.2; N- mtpqlllalvlwascppcsgrkgppaaltlprvqcrasrypiavdcswtlppapnstspvsfiatyrlgmaarghswpclqqtptstscti tdvqlfsmapyvlnvtavhpwgssssfvpfitehiikpdppegvrlsplaerqlqvqweppgswpfpeifslkywirykrqgaarfhr v gpieatsfilravrpraryyvqvaaqdltdygelsdwslpatatmslgk-C). An amino acid sequence of an exemplary human p28 protein is provided in SEQ ID NO: 2 (NCBI Reference Sequence: NP_663634.2; N- mgqtagdlgwrlsllllplllvqagvwgfprppgrpqlslqelrreftvslhlarkllsevrgqahrfaeshlpgvnlyllplgeqlpdvsltf qawrrlsdperlcfisttlqpfhallgglgtqgrwtnmermqlwamrldlrdlqrhlrfqvlaagfnlpeeeeeeeeeeeeerkgllpgal g salqgpaqvswpqllstyrllhslelvlsravrellllskaghsvwplgfptlspqp-C). An amino acid sequence of an exemplary human WSX1 protein is provided in SEQ ID NO: 3 (NCBI Reference Sequence: NP_004834.1; N- mrggrgapfwlwplpklallpllwvlfqrtrpqgsagplqcygvgplgdlncsweplgdlgapselhlqsqkyrsnktqtvavaagrs wvaipreqltmsdkllvwgtkagqplwppvfvnletqmkpnaprlgpdvdfseddpleatvhwapptwpshkvlicqfhyrrcqe aawtllepelktipltpveiqdlelatgykvygrcmiekeedlwgewspilsfqtppsapkdvwvsgnlcgtpggeeplllwkapgp cvqvsykvwfwvggrelspegitcccslipsgaewarvsavnatswepltnlslvcldsasaprsvavssiagstellvtwqpgpgepl ehvvdwardgdpleklnwvrlppgnlsallpgnftvgvpyritvtavsasglasassvwgfreelaplvgptlwrlqdappgtpaiaw gevprhqlrghlthytlcaqsgtspsvcmnvsgntqsvtlpdlpwgpcelwvtastiagqgppgpilrlhlpdntlrwkvlpgilflwgl fUgcglslatsgrcyhlrhkvlprwvwekvpdpansssgqphmeqvpeaqplgdlpileveemepppvmessqpaqatapldsg yekhf Iptpeelgllgpprpqvla-C). An amino acid sequence of an exemplary human gpBO protein is provided in SEQ ID NO: 4 (NCBI Reference Sequence: NP_002175.2; N-mltlqtwlvqalfiflttestgelldpcgyispespvvqlhsnftavcvlkekcmdyfhvnanyivwktnhftipkeqytiinrtassvtft diaslniqltcniltfgqleqnvygitiisglppekpknlscivnegkkmrcewdggrethletnftlksewathkfadckakrdtptsctv dystvyfvnievwveaenalgkvtsdhinfdpvykvkpnpphnlsvinseelssilkltwtnpsiksviilkyniqyrtkdastwsqip pedtastrssftvqdlkpfteyvfrircmkedgkgywsdwseeasgityedrpskapsfwykidpshtqgyrtvqlvwktlppfeang kildyevtltrwkshlqnytvnatkltvnltndrylatltvmlvgksdaavltipacdfqathpvmdlkafpkdnmlwvewttpresvk kyilewcvlsdkapcitdwqqedgtvhrtylrgnlaeskcylitvtpvyadgpgspesikaylkqappskgptvrtkkvgkneavle wdqlpvdvqngfimytifyrtiignetavnvdsshteytlssltsdtlymvrmaaytdeggkdgpeftfttpkfaqgeieaivvpvclaf llttllgvlfcfnkrdlikkhiwpnvpdpskshiaqwsphtpprhnfnskdqmysdgnftdvsvveieandkkpfpedlksldlfkke kinteghssgiggsscmsssrpsisssdenessqntsstvqystvvhsgyrhqvpsvqvfsrsestqplldseerpedlqlvdhvdggd gilprqqyfkqncsqhesspdishferskqvssvneedfvrlkqqisdhisqscgsgqmkmfqevsaadafgpgtegqverfetvg meaatdegmpksylpqtvrqggympq-C).

[0066] As used herein, the tern "Programmed Cell Death Protein 1" or "PD-1" refers to the Programmed Cell Death Protein 1 polypeptide, an immune-inhibitory receptor belonging to the CD28 family and is encoded by the PDCD1 gene in humans. Alternative names or synonyms for PD-1 include: PDCD1, PD1, CD279 and SLEB2. PD-1 is expressed predominantly on previously activated T cells, B cells, and myeloid cells in vivo, and binds to two ligands, PD-L1 and PD-L2. The term "PD-1 " as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank Accession No. AAC51773.

[0067] As used herein, the term "Programmed Death Ligand-1 " or "PD-L1 " is one of two cell surface glycoprotein ligands for PD- 1 (the other being PD-L2) that downregulates T cell activation and cytokine secretion upon binding to PD-1. Alternative names and synonyms for PD- LI include: PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H. The term "PD-L1" as used herein includes human PD-L1 (hPD-Ll), variants, isoforms, and species homologs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll. The complete hPD-Ll sequence can be found under GenBank Accession No. Q9NZQ7.

[0068] PD-1 is known as an immune-inhibitory protein that negatively regulates TCR signals (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 act as an immune checkpoint, which can lead to a decrease in 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 et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can bereversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99: 12293-7; Brown et al. (2003) J. Immunol. 170: 1257-66).

[0069] For several cancers, tumor survival and proliferation is sustained by tumor- mediated immune checkpoint modulation. This modulation can result in the disruption of anticancer immune system functions. For example, recent studies have indicated that the expression of immune checkpoint receptors ligands, such as PD-L1 or PD-L2, by tumor cells can downregulate immune system activity in the tumor microenvironment and promote cancer immune evasion, particularly by suppressing T cells. PD-L1 is abundantly expressed by a variety of human cancers (Dong et al., (2002) Nat Med 8:787-789). The receptor for PD-L1 , 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 cognate PD-L1 ligands on tumor cells, the resulting T cell suppression contributes to an impaired immune response against the tumor (e.g., a decrease in tumor infiltrating lymphocytes or the establishment of immune evasion by cancer cells).

[0070] In large sample sets of e.g. ovarian, renal, colorectal, pancreatic, liver cancers and melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment (see 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) IntJ 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 was found to mark 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). PD-1 / PD-L1 antagonists, such as those that affect the function of the PD-1 / PD-L1 / PD-L2 signaling axis and / or disrupt the interaction between PD-1 and PD-L1 and / or PD-L2, for example, have been developed and represent a novel class of antitumor inhibitors that function via modulation of immune cell-tumor cell interaction. In some aspects, the PD-1 antagonist comprises toripalimab.

[0071] A polypeptide can comprise an amino acid sequence that is not naturally occurring. Such variants necessarily have less than 100% sequence identity or similarity with the starting molecule. In certain aspects, a variant will have an amino acid sequence from about 75% to less than 100% amino acid sequence identity or similarity with the amino acid sequence of the starting polypeptide, more preferably from about 80% to less than 100%, more preferably from about 85% to less than 100%, more preferably from about 90% to less than 100% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) and most preferably from about 95% to less than 100%, e.g., over the length of the variant molecule.

[0072] In certain aspects, the antibodies of the disclosure are encoded by a nucleotide sequence. Nucleotide sequences of the disclosure can be useful for a number of applications, including: cloning, gene therapy, protein expression and purification, mutation introduction, DNA vaccination of a host in need thereof, antibody generation for, e.g., passive immunization, PCR, primer and probe generation, and the like.

[0073] It will also be understood by one of ordinary skill in the art that the antibodies suitable for use in the methods disclosed herein may be altered such that they vary in sequence from the naturally occurring or native sequences from which they were derived, while retaining the desirable activity of the native sequences. For example, nucleotide or amino acid substitutions leading to conservative substitutions or changes at "non-essential" amino acid residues may be made. Mutations may be introduced by standard techniques, such as site- directed mutagenesis and PCR-mediated mutagenesis.

[0074] As used herein, the term "cross-reacts" refers to the ability of an antibody of the disclosure to bind to IL-27 from a different species. For example, an antibody of the present disclosure which binds human IL-27 may also bind another species of IL-27. As used herein, cross-reactivity is measured by detecting a specific reactivity with purified antigen in binding assays (e.g., SPR, ELISA) or binding to, or otherwise functionally interacting with, cells physiologically expressing IL- 27. Methods for determining cross-reactivity include standard binding assays as described herein, for example, by Biacore™ surface plasmon resonance (SPR) analysis using a Biacore™ 2000 SPR instrument (Biacore AB, Uppsala, Sweden), or flow cytometric techniques.

[0075] As used herein, the term "effective dose" or "effective dosage" is defined as an amount sufficient to achieve or at least partially achieve the desired effect. The term "therapeutically effective dose" is defined as an amount sufficient to cure or at least partiallyarrest the disease and its complications in a patient already suffering from the disease. Amounts effective for this use will depend upon the severity of the disorder being treated and the general state of the patient’s own immune system.

[0076] As used herein, the term "epitope" or "antigenic determinant" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds.

[0077] As used herein, the term "Fc-mediated effector functions" or "Fc effector functions" refer to the biological activities of an antibody other than the antibody’s primary function and purpose. For example, the effector functions of a therapeutic agnostic antibody are the biological activities other than the activation of the target protein or pathway. Examples of antibody effect functions include Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibody -dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e g., B cell receptor); lack of activation of platelets that express Fc receptor; and B cell activation. Many effector functions begin with Fc binding to an Fey receptor. In some aspects, the tumor antigen-targeting antibody has effector function, e.g., ADCC activity. In some aspects, a tumor antigen-targeting antibody described herein comprises a variant constant region having increased effector function (e.g. increased ability to mediate ADCC) relative to the unmodified form of the constant region.

[0078] As used herein, the term "Fc receptor" refers to a polypeptide found on the surface of immune effector cells, which is bound by the Fc region of an antibody. In some aspects, the Fc receptor is an Fey receptor. There are three subclasses of Fey receptors, FcyRI (CD64), FcyRII (CD32) and FcyRIII (CD 16). All four IgG isotypes (IgGl , IgG2, IgG3 and IgG4) bind and activate Fc receptors FcyRI, FcyRIIA and FcyRIIIA. FcyRIIB is an inhibitory receptor, and therefore antibody binding to this receptor does not activate complement and cellular responses. FcyRI is a high affinity receptor that binds to IgG in monomeric form, whereas FcyRIIA and FcyRIIA are low affinity receptors that bind IgG only in multimeric form and have slightly lower affinity. The binding of an antibody to an Fc receptor and / or Clq is governed by specific residues or domains within the Fc regions. Binding also depends on residues located within the hinge region and within the CH2 portion of the antibody. In some aspects, the agonistic and / or therapeutic activity of the antibodies described herein is dependent on binding of the Fc region to the Fc receptor (e.g., FcyR). In some aspects, the agonistic and / or therapeutic activity of the antibodies described herein is enhanced by binding of the Fc region to the Fc receptor (e.g., FcyR).

[0079] A list of certain Fc receptor sequences employed in the instant disclosure is set forth as Table IB below.

[0080] As used herein, the term "glycosylation pattern" is defined as the pattern of carbohydrate units that are covalently attached to a protein, more specifically to an immunoglobulin protein. A glycosylation pattern of a heterologous antibody can be characterized as being substantially similar to glycosylation patterns which occur naturally on antibodies produced by the species of the nonhuman transgenic animal, when one of ordinary skill in the art would recognize the glycosylation partem of the heterologous antibody as being more similar to said pattern of glycosylation in the species of the nonhuman transgenic animal than to the species from which the CH genes of the transgene were derived.

[0081] As used herein, the term "human antibody" includes antibodies having variable and constant regions (if present) of human germline immunoglobulin sequences. Human antibodies of the disclosure can include amino acid residues not encoded by human gemiline 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. N. Y. 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).

[0082] As used herein, the term a "heterologous antibody" is defined in relation to the transgenic non-human organism producing such an antibody. This term refers to an antibody having an amino acid sequence or an encoding nucleic acid sequence corresponding to that found in an organism not consisting of the transgenic non-human animal, and generally from a species other than that of the transgenic non-human animal.

[0083] The terms "inducing an immune response" and "enhancing an immune response" are used interchangeably and refer to the stimulation of an immune response (i.e., either passive or adaptive) to a particular antigen. The terms "induce" as used with respect to inducing CDC or ADCC refer to the stimulation of particular direct cell killing mechanisms.

[0084] As used herein, the terms "inhibits", "reduces" or "blocks" (e.g., referring to inhibition or reduction of human IL-27-mediated phosphorylation of STAT1 and / or STAT3 in a cell) are used interchangeably and encompass both partial and complete inhibition / blocking. Theinhibition / blocking of IL-27 and / or PD-1 reduces or alters the normal level or type of activity that occurs without inhibition or blocking. Inhibition and blocking are also intended to include any measurable decrease in the binding affinity of target protein, e.g., IL- 27 or PD-1 when in contact with an antibody, e.g., an anti -IL-27 antibody or toripalimab, respectively, as compared to the target protein not in contact with a corresponding antibody, e.g., inhibits binding of IL-27 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%.

[0085] As used herein, a subject "in need of prevention," "in need of treatment," or "in need thereof," refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of nonhuman mammals), would reasonably benefit from a given treatment (such as treatment with an anti-IL- 27 antibody disclosed herein, toripalimab, and bevacizumab).

[0086] The term "in vivo" refers to processes that occur in a living organism.

[0087] As used herein, the term "isolated antibody" is intended to refer to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to human IL-27 is substantially free of antibodies that specifically bind antigens other than IL-27). An isolated antibody that specifically binds to an epitope may, however, have cross-reactivity to other proteins, e.g., other IL-27 proteins, from different species. However, the antibody continues to display specific binding to human IL-27 in a specific binding assay as described herein. In addition, an isolated antibody is typically substantially free of other cellular material and / or chemicals.

[0088] As used herein, the term "isolated nucleic acid molecule" refers to nucleic acids encoding antibodies or antibody portions (e.g., VH, VL, CDR3) that bind to IL- 27, is intended to refer to a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free of other nucleotide sequences encoding antibodies or antibody portions that bind antigens other than IL- 27, which other sequences may naturally flank the nucleic acid in human genomic DNA.

[0089] As used herein, "isotype" refers to the antibody class (e.g., IgM or IgGl) that is encoded by heavy chain constant region genes. In some aspects, a human monoclonal antibody of the disclosure is of the IgGl isotype. In some aspects, a human monoclonal antibody of the disclosure is of the IgG2 isotype. In some aspects, a human monoclonal antibody of the disclosure is of the IgG3 isotype. In some aspects, a human monoclonal antibody of thedisclosure is of the IgG4 isotype. As is apparent to a skilled artisan, identification of antibody isotypes (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl IgA2, IgD, and IgE) is routine in the art and commonly involves a combination of sequence alignments with known antibodies, published Fc variant sequences and conserved sequences.

[0090] As used herein, the term "isotype switching" refers to the phenomenon by which the class, or isotype, of an antibody changes from one Ig class to one of the other Ig classes.

[0091] As used herein, the term "lymphocytes" refers to a type of leukocyte or white blood cell that is involved in the immune defenses of the body. There are two main types of lymphocytes: B-cells and T-cells.

[0092] As used herein, "local administration" or "local delivery," refers to delivery that does not rely upon transport of the composition or agent to its intended target tissue or site via the vascular system. For example, the composition may 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 in the vicinity of a target tissue or site, the composition or agent, or one or more components thereof, may diffuse to the intended target tissue or site.

[0093] As used herein, the term "monocyte" refers to a type of leukocyte and can differentiate into macrophages and dendritic cells to affect an immune response.

[0094] As used herein, the term "natural killer (NK) cell" refers to a type of cytotoxic lymphocyte. These are large, usually granular, non-T, non-B lymphocytes, which kill certain tumor cells and play an important role in innate immunity to viruses and other intracellular pathogens, as well as in antibody-dependent cell-mediated cytotoxicity (ADCC).

[0095] As used herein, the term "naturally occurring" as applied to an object refers to the fact that an 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 source in nature, and which has not been intentionally modified by man in the laboratory is naturally occurring.

[0096] As used herein, "parenteral administration," "administered parenterally," and other grammatically equivalent phrases, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, intraocular, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrastemal injection and infusion.

[0097] The term "percent identity," in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., BLAST? and BLASTN or other algorithms available to persons of skill) or by visual inspection. Depending on the application, the "percent identity" can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared. For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, 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 for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0098] Optimal alignment of sequences for comparison can be conducted, e.g., 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).

[0099] 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 National Center for Biotechnology Information website. As generally used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0100] As used herein, a "pharmaceutically acceptable carrier" refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0101] As used herein, the term "recombinant host cell" (or simply "host cell") is intended to refer to a cell into which a recombinant expression vector has been introduced. It should be 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 in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term "host cell" as used herein.

[0102] As used herein, the term "recombinant human antibody" includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, (b) antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies comprise variable and constant regions that utilize particular human germline immunoglobulin sequences are encoded by the germline genes, but include subsequent rearrangements and mutations which occur, for example, during antibody maturation. As known in the art (see, e.g., Lonberg (2005) Nature Biotech. 23(9): 1117-1125), the variable region contains the antigen binding domain, which is encoded by various genes that rearrange to form an antibody specific for a foreign antigen. In addition to rearrangement, the variable region can be further modified by multiple single amino acid changes (referred to as somatic mutation or hypermutation) to increase the affinity of the antibody to the foreign antigen. The constant region will change in further response to an antigen (i.e., isotype switch). Therefore, the rearranged and somatically mutated nucleic acid molecules that encode the light chain and heavy chain immunoglobulin polypeptides in response to an antigen may not have sequence identity with the original nucleic acid molecules, but instead will be substantially identical or similar (i.e., have at least 80% identity).

[0103] As used herein, the terms "specific binding," "selective binding," "selectively binds," and "specifically binds," refer to antibody binding to an epitope on a predetermined antigen. Typically, the antibody binds with an equilibrium dissociation constant (KD) of approximately less than 106M, such as approximately less than 107, 108M, 109M or 1010M or even lower when determined by surface plasmon resonance (SPR) technology in a BIACORE 2000 instrument using recombinant human IL- 27 as the analyte and the antibody as the ligand and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely- related antigen. In certain aspects, an antibody that specifically binds to IL- 27 binds with an equilibrium dissociation constant (KD) of approximately less than 100 nM (10‘7M), optionally approximately less than 50 nM (5 x 10’8M), optionally approximately less than 15 nM (1.5 x 10’8M), optionally approximately less than 10 nM (IO-8M), optionally approximately less than 5 nM (5 x 109M), optionally approximately less than 1 nM (109M), optionally approximately less than 0.1 nM (IO10M), optionally approximately less than 0.01 nM (10-11M), or even lower, when determined by surface plasmon resonance (SPR) technology in a BIACORE 2000 instrument using recombinant human IL-27 as the analyte and the antibody as the ligand, where binding to the predetermined antigen occurs with an affinity that is at least two-fold greater than the antibody’s affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen The phrases "an antibody recognizing an antigen" and "an antibody specific for an antigen" are used interchangeably herein with the term "an antibody which binds specifically to an antigen."

[0104] 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, that cause activation and dimerization by forming homo- or heterodimers which translocate to the nucleus to work as transcription factors. STAT1 can be activated (i.e., phosphorylated) in response to signaling via several ligands, including IL-27. IL- 27 signaling through the IL-27R results in phosphorylation of STAT1 (pSTATl). STAT1 has a key role in gene expression involved in survival of the cell, viability or pathogen response. Methods to determine STAT1 phosphorylation as a result of IL-27 signaling include, but are not limited to, flow cytometric analysis of cells labeled with antibodies that specifically recognize phosphorylated STAT1 (see e.g., Tochizawa et al., (2006) J Immunol Methods 313(l-2):29-37).

[0105] 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 a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. Methods to determine STAT3 phosphorylation as a result of IL-27 signaling include, but are not limited to, analysis of cells or cell extracts labeled with antibodies that specifically recognize phosphorylated STAT3 (see e.g., Fursov et al., (2011) Assay Drug Dev Technol 9(4):420-429).

[0106] As used herein, the terms "therapeutically effective amount" or "therapeutically effective dose," or similar terms used herein are intended to mean an amount of an agent (e.g., an anti-IL-27 antibody or an antigen-binding fragment thereof) that will elicit the desired biological or medical response (e.g., an improvement in one or more symptoms of a cancer).

[0107] As used herein, the term "TAM receptor" refers to the TAM receptor protein tyrosine kinases (TYR03, AXL and MER). TAM receptors are involved in the regulation of immune system homeostasis. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti -tumor responses of diverse immune cells. Further description of TAM receptors is 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.

[0108] As used herein, the term "TIGIT" or "T-cell immunoreceptor with 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 domaincontaining protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1.

[0109] 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 pertains. 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 ortesting of the presently disclosed methods and compositions. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.IL Methods of the Disclosure

[0110] Some aspects of the present disclosure are directed to methods of stimulating an immune response in a subject, the method comprising administering to the subject (i) an antibody that binds human IL- 27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), (ii) toripalimab, and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15. Some aspects of the present disclosure are directed to methods of treating a cancer in a subject in need thereof comprising administering to the subject (i) an antibody that binds human IL-27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), (ii) toripalimab, and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0111] The methods described herein can be used in the treatment of various types of cancer. In some aspects, the cancer is selected from Kaposi's sarcoma, leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblasts promyelocyte myelomonocytic monocytic erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, primary central nervous system lymphoma, Burkitt’s lymphoma and marginal zone B cell lymphoma, Polycythemia vera Lymphoma, Hodgkin’s disease, non-Hodgkiris disease, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, solid tumors, sarcomas, and carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chrondrosarcoma, osteogenic sarcoma, osteosarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon sarcoma, colorectal carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, retinoblastoma, nasopharyngeal carcinoma, esophageal carcinoma, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system (CNS) cancer, cervical cancer, choriocarcinoma, colorectal cancers, connective tissue cancer, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, gastric cancer, intraepithelial neoplasm, kidney cancer, larynx cancer, liver cancer, lung cancer (small cell, large cell), melanoma, neuroblastoma; oral cavity cancer (for example lip. tongue, mouth and pharynx), ovarian cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer; cancer of the respiratory system, sarcoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, cancer of the urinary system, and any combination thereof. In some aspects, the cancer comprises lung cancer (e.g., non-small cell lung cancer), sarcoma, testicular cancer, ovarian cancer, pancreas cancer, breast cancer (e.g., triple-negative breast cancer), melanoma, head and neck cancer (e.g., squamous 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), renal cancer (e.g., renal cell carcinoma, e.g., clear cell RCC and / or non-clear cell RCC), or any combination thereof. In some aspects, the cancer comprises a non-small cell lung cancer (NSCLC). In some aspects, the NSCLC is a squamous NSCLC. In some aspects, the cancer comprises a renal cancer. In some aspects, the renal cancer is a renal cell carcinoma (RCC). In some aspects, the RCC is a clear cell RCC. In some aspects, the RCC is a non-clear cell RCC. In some aspects, the cancer comprises a hepatocellular carcinoma(HCC). In some aspects, the cancer is unresectable. In some aspects, the cancer is locally advanced or metastatic.

[0112] In some aspects, the methods can be performed in conjunction with other therapies for cancer. For example, the antibodies can be administered to a subject at the same time, prior to, or after, radiation, surgery, targeted or cytotoxic chemotherapy, chemoradiotherapy, hormone therapy, immunotherapy, gene therapy, cell transplant therapy, precision medicine, genome editing therapy, or other pharmacotherapy.

[0113] In some aspects, the methods disclosed herein comprise administering an anti-IL- 27 antibody disclosed herein, toripalimab, bevacizumab, and a chemotherapeutic agent. Chemotherapeutic agents suitable for combination and / or co-administration with antibodies of the present disclosure include, for example: taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxyanthrancindione, mitoxantrone, mithramycin, actinomycin D, 1- dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Further agents include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5 -fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioTEPA, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlordiamine platinum (II)(DDP), procarbazine, altretamine, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, or triplatin tetranitrate), anthracycline (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomcin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine) and temozolomide.

[0114] In some aspects, the antibodies disclosed herein are administered to a subject, e.g., a human subject, using a variety of methods that depend, in part, on the route of administration. The route can be, e.g., intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneal (IP) injection, intramuscular injection (IM), or intrathecal injection (IT). The injection can be in a bolus or a continuous infusion.

[0115] Administration can be achieved by, e.g., local infusion, injection, or by means of an implant. The implant can be of a porous, non-porous, or gelatinous material, including membranes, such as silastic membranes, or fibers. The implant can be configured for sustained or periodic release of the composition to the subject. See, e.g., U.S. Patent ApplicationPublication No. 20080241223; U.S. Patent Nos. 5,501,856; 4,863,457; and 3,710,795;EP488401; and EP 430539, the disclosures of each of which are incorporated herein by reference in their entirety. The antibodies can be delivered to the subject by way of an implantable device based on, e.g., diffusive, erodible, or convective systems, e.g., osmotic pumps, biodegradable implants, electrodiffusion systems, electroosmosis systems, vapor pressure pumps, electrolytic pumps, effervescent pumps, piezoelectric pumps, erosion-based systems, or electromechanical systems.

[0116] In some aspects, the anti-IL-27 antibody, toripalimab, and / or bevacizumab is therapeutically delivered to a subject by way of local administration.

[0117] In certain aspects, the route of administration is in accord with known methods, e.g. orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, subcutaneously, intra-ocular, intraarterial, intraportal, or intralesional routes; by sustained release systems or by implantation devices. In certain aspects, the antibodies can be administered by bolus injection or continuously by infusion, or by implantation device. In certain aspects, individual elements of the combination therapy may be administered by different routes.

[0118] In certain aspects, the anti-IL-27 antibody, toripalimab, and / or bevacizumab is administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. In certain aspects, where an implantation device is used, the device is implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous administration. In certain aspects, it is desirable to use a pharmaceutical composition comprising the anti-IL-27 antibody, toripalimab, and / or bevacizumab in an ex vivo manner. In such instances, cells, tissues and / or organs that have been removed from the patient are exposed to a pharmaceutical composition comprising the anti-IL-27 antibody, toripalimab, and / or bevacizumab after which the cells, tissues and / or organs are subsequently implanted back into the patient.

[0119] In certain aspects, the anti-IL-27 antibody, toripalimab, and / or bevacizumab is delivered by implanting certain cells that have been generically engineered, using methods such as those described herein, to express and secrete the polypeptides. In certain aspects, such cells are animal or human cells, and can be autologous, heterologous, or xenogeneic. In certain aspects, the cells are immortalized. In certain aspects, in order to decrease the chance of animmunological response, the cells are encapsulated to avoid infiltration of surrounding tissues. In certain aspects, the encapsulation materials are typically biocompatible, semi -permeable polymeric enclosures or membranes that allow the release of the protein product(s) but prevent the destruction of the cells by the patient's immune system or by other detrimental factors from the surrounding tissues.

[0120]

[0149] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of one or more biomarkers selected from the group consisting of Eotaxin-1 (CCL11), TARC (CCL17), VEGF-A, IL-7, IL-8, MCP-L MCP-4, and any combination thereof; wherein the increased expression of the one or more biomarkers is relative to the expression of the one or more biomarker prior to the administration.

[0121] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of Eotaxin-1 (CCL11), wherein the increased expression of Eotaxin-1 (CCL11) is relative to the expression of Eotaxin-1 (CCL11) prior to the administration.

[0122] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of TARC (CCL17), wherein the increased expression of TARC (CCL17) is relative to the expression of TARC (CCL17) prior to the administration.

[0123] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of VEGF-A, wherein the increased expression of VEGF-A is relative to the expression of VEGF-A prior to the administration.

[0124] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of IL-7, wherein the increased expression of IL-7 is relative to the expression of IL-7 prior to the administration.

[0125] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of IL-8, wherein the increased expression of IL-8 is relative to the expression of IL-8 prior to the administration.

[0126] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of MCP-1, wherein the increased expression of MCP-1 is relative to the expression of MCP-1 prior to the administration.

[0127] In some aspects, following administration of the anti-IL-27 antibody, toripalimab, and / or bevacizumab, the subject exhibits increased expression of MCP-4, wherein the increased expression of MCP-4 is relative to the expression of MCP-4 prior to the administration.A. Anti-IL-27 Antibodies and Antigen-Binding Portions Thereof

[0128] In some aspects, an anti-IL-27 antibody comprising a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15 may also be known as casdozokitug.

[0129] Casdozokitug refers to a fully human, antagonistic IgGl monoclonal antibody targeting the p28 subunit of IL- 27. Casdozokitug comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21 and light chain comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0130] In some aspects, casdozokitug is provided as a liquid formulation. For example, a casdozokitug formulation may be provided at a target concentration of 50 mg / mL in 20 mM histidine, 8% sucrose, 0.02% polysorbate 80, pH 5.5.

[0131] In some aspects, the anti-IL-27 antibody comprising a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15 is administered at a dose of at least about 500 mg to about 2000 mg. In some aspects, the anti-IL-27 antibody is administered at a dose that is sufficient to maintain IC90 of pSTATl inhibition level for the duration of the treatment.

[0132] In some aspects, the antibody or antigen binding portion thereof is administered at a dose of at least about 500 mg to about 2000 mg, at least about 600 mg to about 2000 mg, at least about 700 mg to about 2000 mg, at least about 800 mg to about 2000 mg, at least about 900 mg to about 2000 mg, at least about 1000 mg to about 2000 mg, at least about 1100 mg to about 2000 mg, at least about 1200 mg to about 2000 mg, at least about 1300 mg to about 2000 mg, atleast about 1400 mg to about 2000 mg, at least about 1500 mg to about 2000 mg, at least about 1600 mg to about 2000 mg, at least about 1700 mg to about 2000 mg, at least about 1800 mg to about 2000 mg, at least about 1900 mg to about 2000 mg, at least about 500 mg to at least about1900 mg, at least about 500 mg to at least about 1800 mg, at least about 500 mg to at least about1700 mg, at least about 500 mg to at least about 1600 mg, at least about 500 mg to at least about1500 mg, at least about 500 mg to at least about 1400 mg, at least about 600 mg to at least about1400 mg, or about 700 mg to about 1400 mg.

[0133] In some aspects, the antibody or antigen binding portion thereof is administered at a dose of at least about 500 mg, at least about 600 mg, at least 700 mg, at least about 800 mg, at least about 900mg, at least about 1000 mg, at least about 1 100 mg, at least about 1200 mg, at least about 1300 mg, at least about 1400 mg, at least about 1500 mg, at least about 1600 mg, at least about 1700 mg, at least about 1800 mg, at least about 1900 mg, or about 2000 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of at least about 500mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 600 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 700 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 800 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 900 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1000 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1100 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1200 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1300 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1400 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1500 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1600 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1700 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1800 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1900 mg. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 2000 mg.

[0134] In some aspects, the antibody or antigen binding portion thereof is administered once about every week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every 6 weeks, once about every 7 weeks, once about every 8 weeks, or once about every 12 weeks. In some aspects, the antibody or antigen binding portion thereof is administered once about every two weeks. In some aspects, the antibody or antigen binding portion thereof is administered once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered once about every four weeks.

[0135] In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 500 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 600 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 700 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 800 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 900 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1000 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1100 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1200 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1300 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1400 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1500 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1600 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1700 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1800 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1900 mg once about every three weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 2000 mg once about every three weeks.

[0136] In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 500 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 600 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 700 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 800 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 900 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1000 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1100 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1200 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1300 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1400 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1500 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1600 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1700 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1800 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1900 mg once about every four weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 2000 mg once about every four weeks.

[0137] In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 500 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 600 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 700 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 800 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 900 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereofis administered at a dose of about 1000 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1100 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1200 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1300 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1400 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1500 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1600 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1700 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1800 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 1900 mg once about every six weeks. In some aspects, the antibody or antigen binding portion thereof is administered at a dose of about 2000 mg once about every six weeks.

[0138] In some aspects, the anti-IL-27 antibody or antigen binding portion thereof disclosed herein (i.e., comprising a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15) inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell in the subject. In some aspects, the anti- IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL- 27 mediated pSTATl signaling). In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 25%, at least about 50%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the antibody or antigen binding portion thereof (e.g., an anti-IL-27 antibodydisclosed herein). In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 90% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the antibody or antigen binding portion thereof (e.g., an anti-IL-27 antibody disclosed herein). In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 91% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti-IL-27 antibody or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 92% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti- IL-27 antibody or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 93% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti-IL-27 antibody or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 94% relative to PSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti- IL- 27 antibody or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 95% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti-IL-27 antibody or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 96% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti- IL-27 antibody or antigen binding portion thereof e.g., an anti-IL-27 antibody disclosed herein). In some aspects, the anti- IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL- 27 mediated pSTATl signaling) by at least about 97% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti-IL- 27 antibody or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 98% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior toadministration of the anti-IL-27 antibody or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) by at least about 99% relative to pSTATl signaling (e.g., IL-27 mediated pSTATl signaling) prior to administration of the anti-IL- 27 antibody or antigen binding portion thereof.

[0139] In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces inhibition of CD161 expression in a cell in the subject. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof inhibits or reduces PD-L1 expression in a cell in the subject. In some aspects, the anti-IL-27 antibody or antigen binding portion thereof induces or enhances PD-1 mediated secretion of one or more cytokines from a cell in the subject. In some aspects, the anti-IL- 27 antibody or antigen binding portion thereof alters TIM-3 expression in a cell in the subject. In some aspects, the cell is a tumor cell or an immune cell.

[0140] Accordingly, in one aspect, the anti-IL- 27 antibody or an antigen binding portion thereof exhibits at least one or more of the following properties: (i) binds to human IL-27 with an equilibrium dissociation constant (KD) of 15 nM or less; (ii) blocks binding of IL- 27 to IL-27 receptor; (iii) inhibits or reduces STAT1 and / or STAT3 phosphorylation in a cell; (iv) inhibits or reduces IL-27 mediated inhibition of CD 161 expression in a cell; (v) inhibits or reduces IL-27 mediated PD-L1 expression in a cell; (vi) induces or enhances PD-1 mediated secretion of one or more cytokines from a cell; (vii) alters TIM-3 expression in a cell; and (viii) a combination of (i)- (vii).

[0141] In some aspects, the antibody or the antigen binding portion thereof comprises a heavy chain variable region comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 11. In some aspects, the antibody or the antigen binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0142] In some aspects, the antibody or the antigen binding portion thereof comprises a light chain variable region comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the antibody or the antigen binding portion thereof comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19.

[0143] In some aspects, the antibody or the antigen binding portion thereof comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19.

[0144] In some aspects, the methods described herein comprise administering(i) toripalimab, (ii) bevacizumab, and (iii) a dose of at least about 500 mg to about 2000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of at least about 500 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 700 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 1000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 1400 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19. In some aspects, the method comprises(i) toripalimab, (ii) bevacizumab, and (iii) administering a dose of about 2000 mg of an anti-IL- 27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19.

[0145] In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a heavy chain comprising an amino acid sequence that has at least about 85%, at leastabout 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 21. In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21.

[0146] In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a heavy chain comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 25. In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25.

[0147] In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a light chain comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0148] In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the methods described herein comprise administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of at least about 500 mg to about 2000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of at least about 500 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 700 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In someaspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 1000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 1400 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 2000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0149] In some aspects, the anti-IL-27 antibody or the antigen binding portion thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the methods described herein comprise administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of at least about 500 mg to about 2000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of at least about 500 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 700 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 1000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 1400 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23. In some aspects, the method comprises administering (i) toripalimab, (ii) bevacizumab, and (iii) a dose of about 2000 mg of an anti-IL-27 antibody or antigen binding portion thereof comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 23.

[0150] In some aspects, the anti-IL-27 antibody or antigen-binding portion thereof comprises an amino acid sequence set forth in Table 1A.Table 1A: Anti-IL-27 Antibody Sequences

[0151] In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, comprises an Fc sequence set forth in Table IB. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, comprises a heavy chain, wherein the heavy chain comprises an Fc region having an amino acid at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to the sequence set forth in SEQ ID NO: 27, 28, 29, or 30. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, comprises a heavy chain, wherein the heavy chain comprises an Fc region comprising the amino acid sequence set forth in SEQ ID NO: 27. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, comprises a heavy chain, wherein the heavy chain comprises an Fc region comprising the amino acid sequence set forth in SEQ ID NO: 28. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, comprises a heavy chain, wherein the heavy chain comprises an Fc region comprising the amino acid sequence set forth in SEQ ID NO: 29. In some aspects, the anti-IL-27 antibody, or antigenbinding portion thereof, comprises a heavy chain, wherein the heavy chain comprises an Fc region comprising the amino acid sequence set forth in SEQ ID NO: 30.Table IB: Fc Sequences (=CH2+CH3)

[0152] In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 and STAT3 phosphorylation in a cell. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by 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%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, relative to the STAT1phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 50%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 60%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 70%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 75%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 80%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 85%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 90%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT1 phosphorylation in a cell by at least about 95%, relative to the STAT1 phosphorylation in the cell prior to contacting the cell with the antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, eliminates STAT1 phosphorylation in the cell.

[0153] In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by 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 leastabout 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 50%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 60%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 70%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 75%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 80%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 85%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti- IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 90%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces STAT3 phosphorylation in a cell by at least about 95%, relative to the STAT3 phosphorylation in the cell prior to contacting the cell with the anti-IL-27 antibody, or antigen binding portion thereof. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, eliminates STAT3 phosphorylation in the cell.

[0154] In some aspects, the cell is an immune cell. In some aspects, the cell is a cancer cell.

[0155] In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces inhibition of CD161 expression in a cell (e.g. ameliorates or relieves the inhibition of CD161 expression in a cell). In some aspects, the cell is an immune cell.

[0156] In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, inhibits or reduces PD-L1 expression in a cell. In some aspects, PD-L1 expression is inhibited or reduced. In some aspects, TIM-3 expression is altered. In some aspects, both PD-L1 expression and TIM-3 expression is altered. In some aspects, the cell is an immune cell.

[0157] In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, induces or enhances the PD-1 -mediated secretion of one or more cytokines from a cell. In some aspects, the one or more cytokines is TNFa. In some aspects, the one or more cytokine is IL-6. In some aspects, the one or more cytokine is TNFa and IL-6. In some aspects, the cell is an immune cell.

[0158] In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, is selected from the group consisting of an IgGl, an IgG2, an IgG3, an IgG4, an IgM, an IgAl an IgA2, an IgD, and an IgE antibody. In some aspects, the anti-IL-27 antibody is an IgGl antibody or an IgG4 antibody. In some aspects, the anti-IL-27 antibody comprises a wild type IgGl heavy chain constant region. In some aspects, the anti-IL-27 antibody comprises a wild type IgG4 heavy chain constant region. In some aspects, the anti-IL-27 antibody comprises an Fc domain comprising at least one mutation. In some aspects, the anti-IL-27 antibody comprises a mutant IgGl heavy chain constant region. In some aspects, the anti-IL-27 antibody comprises a mutant IgG4 heavy chain constant region. In some aspects, the mutant IgG4 heavy chain constant region comprises any one of the substitutions S228P, L235E, L235A, or a combination thereof, according to EU numbering.B. Toripalimab

[0159] Some aspects of the present disclosure are directed to methods of stimulating an immune response in a subject, the method comprising administering to the subject (i) an antibody that binds human IL- 27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), (ii) toripalimab, and (iii) bevacizumab, wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0160] Toripalimab (also known as LOQTORZI®; toripalimab-tpzi) is a recombinant humanized IgG4 monoclonal antibody that binds to programmed cell death protein 1 (PD- 1). Toripalimab comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 33 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 34. Toripalimab comprises a variable heavy domain comprising the amino acid sequence set forth in SEQ ID NO: 31 and a variable light domain comprising the amino acid sequence set forth in SEQ ID NO: 32.Table 2A: Toripalimab Sequences

[0161] In some aspects, toripalimab is administered at a dose of at least about 1 mg / kg to at least about 10 mg / kg. In some aspects, toripalimab is administered at a dose of at least about 1 mg / kg, at least about 2 mg / kg, at least about 3 mg / kg, at least about 4 mg / kg, at least about 5 mg / kg, at least about 6 mg / kg, at least about 7 mg / kg, at least about 8 mg / kg, at least about 9mg / kg, or at least about 10 mg / kg. In some aspects, toripalimab is administered at a flat dose. In some aspects toripalimab is administered at a flat dose of at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, at least about 220 mg, at least about 230 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 270 mg, at least about 280 mg, at least about 290 mg, at least about 300 mg, at least about 310 mg, at least about 320 mg, at least about 340 mg, at least about 350 mg, at least about 360 mg, at least about 370 mg, at least about 380 mg, at least about 390 mg, at least about 400 mg, at least about 410 mg, at least about 420 mg, at least about 430 mg, at least about 440 mg, at least about 450 mg, at least about 460 mg, at least about 470 mg, at least about 480 mg, at least about 490 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 720 mg, at least about 800 mg, at least about 900 mg, or at least about 1000 mg.

[0162] In some aspects, toripalimab is administered at a dose of about 120 mg to about 720 mg, or about 240 mg to about 480 mg, or about 240 mg to about 360 mg. In some aspects, toripalimab is administered at a dose of about 240 mg. In some aspects, toripalimab is administered at a dose of about 340 mg.

[0163] In some aspects, toripalimab is administered once about every week, once about every two weeks, once about every three weeks, or once about every four weeks. In some aspects, toripalimab is administered once about every three weeks. In some aspects, toripalimab is administered once about every four weeks.

[0164] In some aspects, toripalimab is administered at a dose of about 120 mg once about every four weeks, about 240 mg once about every four weeks, about 340 mg once about every four weeks, about 360 mg once about every four weeks, about 480 mg once about every four weeks, about 600 mg once about every four weeks, or about 720 mg once about every four weeks. In some aspects, toripalimab is administered at a dose of about 240 mg once about every four weeks. In some aspects, toripalimab is administered at a dose of about 340 mg once about every four weeks.

[0165] In some aspects, toripalimab is administered at a dose of about 120 mg once about every three weeks, about 240 mg once about every three weeks, about 340 mg once about every three weeks, about 360 mg once about every three weeks, about 480 mg once about every threeweeks, about 600 mg once about every three weeks, or about 720 mg once about every three weeks. In some aspects, toripalimab is administered at a dose of about 240 mg once about every three weeks.

[0166] In some aspects, toripalimab is provided as a liquid medicament, which comprises 40 mg / mL toripalimab, 0.51 mg / mL citric acid monohydrate, 25 mg / mL mannitol, 0.2 mg / mL polysorbate 80, 2.92 mg / mL sodium chloride, 4.65 mg / mL sodium citrate, and water for injection, with a pH of 6.0.

[0167] In some aspects, the selected dose of toripalimab is administered by IV infusion over a time period of between 30 and 60 minutes, or about 30 minutes, or about 60 minutes.C. Bevacizumab

[0168] Some aspects of the present disclosure are directed to methods of stimulating an immune response in a subject, the method comprising administering to the subject (i) an antibody that binds human IL- 27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), (ii) toripalimab. and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0169] Bevacizumab (also know n as AVASTIN®; biosimilar MVASI®) is a recombinant humanized monoclonal IgGl antibody that binds human vascular endothelial growth factor (VEGF) and neutralizes VEGF’s biologic activity. Bevacizumab comprises a variable heavy domain comprising the amino acid sequence set forth in SEQ ID NO: 35 and a variable light domain comprising the amino acid sequence set forth in SEQ ID NO: 36.Table 2B: Bevacizumab Sequences

[0170] In some aspects, bevacizumab is administered at a dose of at least about 0.1 mg / kg to about 30 mg / kg. In some aspects, bevacizumab is administered at a dose of at least about 1 mg / kg to at least about 20 mg / kg. In some aspects, bevacizumab is administered at a dose of at least about 10 mg / kg to at least about 20 mg / kg, at least about 10 mg / kg to at least about 19 mg / kg, at least about 10 mg / kg to at least about 18 mg / kg, at least about 10 mg / kg to at least about 17 mg / kg, at least about 10 mg / kg to at least about 16 mg / kg, at least about 10 mg / kg to at least about 15 mg / kg, at least about 11 mg / kg to at least about 20 mg / kg, at least about 12 mg / kg to at least about 20 mg / kg, at least about 13 mg / kg to at least about 20 mg / kg, at least about 14 mg / kg to at least about 2000 mg / kg, at least about 15 mg / kg to at least about 20 mg / kg, at least about 11 mg / kg to at least about 19 mg / kg, at least about 12 mg / kg to at least about 18 mg / kg, at least about 13 mg / kg to at least about 17 mg / kg, at least about 14 mg / kg to at least about 16 mg / kg, at least about 15 mg / kg to at least about 16 mg / kg, or at least about 14 mg / kg to at least about 15 mg / kg.

[0171] In some aspects, bevacizumab is administered at a dose of about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg. In some aspects, bevacizumab is administered at a dose of about 10 mg / kg. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg. In some aspects, bevacizumab is administered at a dose of about 20 mg / kg.

[0172] In some aspects, bevacizumab is administered at a dose of about 10 mg / kg once about every three weeks, about 11 mg / kg once about every three weeks, about 12 mg / kg once about every three weeks, about 13 mg / kg once about every three weeks, about 14 mg / kg once about every three weeks, about 15 mg / kg once about every three weeks, about 16 mg / kg once about every three weeks, about 17 mg / kg once about every three weeks, about 18 mg / kg once about every three weeks, about 19 mg / kg once about every three weeks, or about 20 mg / kg once about every three weeks. In some aspects, bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks. In some aspects, bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks.

[0173] In some aspects, bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks, about 16 mg / kg once about every four weeks, about 17 mg / kg once about every four weeks, about 18 mg / kg once about every four weeks, about 19 mg / kg once about every four weeks, about 20 mg / kg once about every four weeks, about 21 mg / kg once about every four weeks, about 22 mg / kg once about every four weeks, about 23 mg / kg once about every four weeks, about 24 mg / kg once about every four weeks, or about 25 mg / kg once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 19 mg / kg once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 17 mg / kg once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 19 mg / kg once about every four weeks. In some aspects, bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks.

[0174] In some aspects, bevacizumab may be provided as a liquid medicament, which comprises 25 mg / mL bevacizumab, 60 mg / mL a,a-trehalose dihydrate, 0.4 nig / mL polysorbate 20, 1.2 mg / mL sodium phosphate dibasic, anhydrous, and 5.8 mg / mL sodium phosphate monobasic, monohydrate, at pH 6.2.

[0175] In some aspects, the selected dose of bevacizumab is administered by IV infusion over a time period of between 50 and 70 minutes, or about 60 minutes. In some aspects, the selected dose of bevacizumab is administered by IV infusion over a time period of between 80 and 100 minutes, or about 90 minutes.D. Combination Therapy

[0176] Some aspects of the present disclosure are directed to methods of treating a cancer in a subject in need thereof, the method comprising administering to the subject (i) an antibody that binds human IL- 27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), (ii) toripalimab. and (iii) bevacizumab,: wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the aminoacid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

[0177] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every7three weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0178] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every7three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0179] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0180] In some aspects, (i) the anti -IL- 27 antibody is administered at a dose of about 1000 mg once about every7three weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks. In some aspects, (i) the anti -IL-27 antibody is administered at a dose of about 2000 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every7three weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every three weeks.

[0181] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks: (ii) toripalimab is administered at a dose of about 240 mgonce about every three weeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks.

[0182] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every7three weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks.

[0183] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks.

[0184] In some aspects, (i) the anti -IL- 27 antibody is administered at a dose of about 1000 mg once about every7three weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every three yveeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks.

[0185] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks; (ii) toripalimab is administered at a dose of about340 mg or 360 mg once about every three yveeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every three weeks; and (ii) toripalimab isadministered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks.

[0186] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every7three weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 14 mg / kg once about every three weeks.

[0187] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks.

[0188] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every three weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks. In some aspects, (i) the anti -IL-27 antibody is administered at a dose of about 2000 mg once about every three weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every three weeks; and (iii) bevacizumab is administered at a dose of about 16 mg / kg once about every three weeks.

[0189] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks: and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks.

[0190] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks.

[0191] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks: and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks. In some aspects, (i) the anti -IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks.

[0192] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks. In some aspects, (i) the anti -IL- 27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 15 mg / kg once about every four weeks.

[0193] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks: and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks.

[0194] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered ata dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks.

[0195] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks. In some aspects, (i) the anti -IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks.

[0196] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks.

[0197] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 18 mg / kg once about every four weeks.

[0198] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 17 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 17 mg / kg once about every four weeks.

[0199] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg onceabout every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks.

[0200] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 240 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks.

[0201] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 17 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 17 mg / kg once about every four weeks.

[0202] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 17 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 17 mg / kg once about every four weeks.

[0203] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 700 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1400 mg once about every four weeks; and (ii) toripalimab isadministered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks.

[0204] In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 1000 mg once about every four weeks; (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks. In some aspects, (i) the anti-IL-27 antibody is administered at a dose of about 2000 mg once about every four weeks; and (ii) toripalimab is administered at a dose of about 340 mg or 360 mg once about every four weeks; and (iii) bevacizumab is administered at a dose of about 20 mg / kg once about every four weeks.

[0205] In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are administered on the same day. In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are administered concurrently. In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are administered sequentially. In some aspects, the anti- IL-27 antibody is administered before toripalimab and bevacizumab. In some aspects, the anti- IL-27 antibody is administered after toripalimab and bevacizumab. In some aspects, (i) the anti- IL-27 antibody and (ii) toripalimab and bevacizumab are administered on different days.

[0206] In some aspects, the disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) an antibody that binds human IL- 27 or an antigen binding portion thereof ("an anti-IL-27 antibody"), provided by the disclosure, (ii) toripalimab, and (iii) bevacizumab, in combination with one or more additional therapeutic agents or procedure, wherein the one or more additional therapeutic agent or procedure is selected from the group consisting of; a chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy, a biologic agent, or a combination thereof.

[0207] In some aspects, the one or more additional therapeutic agents is 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. In some aspects, the one or more additional therapeutic agents is a CD39 antagonist, a CD73 antagonist, a CCR8 antagonist, or a combination thereof. In some aspects, the anti-CD73 is any anti-CD73 antibody disclosed in, e.g., U.S. Publication No. 2019 / 0031766 Al, which is incorporated by reference herein in itsentirety. In some aspects, the anti-CD39 is any anti-CD39 antibody disclosed in, e.g., Int'l Publication No. WO 2019 / 178269 A2, which is incorporated by reference herein in its entirety.

[0208] In some aspects, the one or more additional therapeutic agents is a TIM-3 inhibitor, optionally wherein the TIM-3 inhibitor is MGB453 or TSR-022.

[0209] In some aspects, 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.

[0210] In some aspects, the one or more additional therapeutic agents is a TIGIT inhibitor. In some aspects, the one or more additional therapeutic agents is a CD112R inhibitor. In some aspects, the one or more additional therapeutic agents is a TAM (Axl, Mer, Tyro) inhibitor. In some aspects, the one or more additional therapeutic agents is a STING agonist. In some aspects, the one or more additional therapeutic agents is a 4-1BB agonist.

[0211] In some aspects, the one or more additional therapeutic agents is a tyrosine kinase inhibitor, an agent targeting the adenosine axis (for example a CD39 antagonist, a CD73 antagonist or a A2AR, A2BR or dual A2AR / A2BR antagonist), a CCR8 antagonist, a CTLA4 antagonist, a VEG-F inhibitor or a combination thereof.1. Combination with Chemotherapeutic Agents

[0212] In some aspects, the methods disclosed herein comprise administering (i) an anti- IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a chemotherapeutic agent. Chemotherapeutic agents suitable for combination and / or coadministration with compositions of the present disclosure include, for example: taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxyanthrancindione, mitoxantrone, mithramycin, actinomycin D, 1 -dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Further agents include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6- thioguanine, cytarabine, 5 -fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioTEPA, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cisdichlordiamine platinum (II)(DDP), procarbazine, altretamine, cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, or triplatin tetranitrate), anthracycline (e.g., daunombicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomcin (formerly actinomycin),bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine) and temozolomide.2. Combinations with TIM-3 Inhibitors

[0213] In some aspects, the methods disclosed herein comprise administering (i) an anti- IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a TIM-3 inhibitor. The TIM-3 inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. In some aspects, the TIM-3 inhibitor is chosen from MGB453 (Novartis), TSR-022 (Tesaro), or LY3321367 (Eli Lilly). In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, is administered in combination with MGB453. In some aspects, the anti-IL-27 antibody, or antigen binding portion thereof, is administered in combination with TSR-022.3. Combinations with LAG-3 Inhibitor

[0214] In some aspects, the methods disclosed herein comprise administering (i) an anti- IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a LAG-3 inhibitor. In some aspects, the LAG-3 inhibitor is an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or any combination thereof. In some aspects, the LAG-3 inhibitor is chosen from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), TSR-033 (Tesaro), MK-4280 (Merck & Co), or REGN3767 (Regeneron).4. Other Combinations

[0215] In some aspects, the methods disclosed herein comprise administering (i) an anti- IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a TIGIT inhibitor. In some aspects, the methods disclosed herein comprise administering (i) an anti-IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a kinase inhibitor (e.g., a tyrosine kinase inhibitor (TKI)). In some aspects, the methods disclosed herein comprise administering (i) an anti-IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a CD112R inhibitor. In some aspects, the methods disclosed herein comprise administering (i) an anti-IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a TAM receptor inhibitor. In some aspects, the methods disclosed herein comprise administering (i) an anti-IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a STING agonist and / or a 4-1BB agonist. In some aspects, a composition provided by the disclosure is combined(e.g., administered in combination) with a tyrosine kinase inhibitor, an agent targeting the adenosine axis (for example a CD39 antagonist, a CD73 antagonist or a A2AR, A2BR or dual A2AR / A2BR antagonist), a CCR8 antagonist, a CTLA4 antagonist, a VEG-F inhibitor or a combination thereof.

[0216] In some aspects, the methods disclosed herein comprise administering (i) an anti- IL-27 antibody or antigen-binding portion thereof, (ii) toripalimab, (iii) bevacizumab, and (iv) a cell therapy. In some aspects, the cell therapy comprises a modified immune cell therapy. In some aspects, the cell therapy comprises a chimeric antigen receptor (CAR) modified immune cell therapy, e.g., CAR T therapy. In some aspects, the cell therapy comprises an engineered T cell receptor (TCR) immune cell therapy. In some aspects, the cell therapy comprises an allogeneic tumor infiltrating lymphocyte (TIL) therapy.E. Pharmaceutical Compositions and Formulations

[0217] In some aspects, an antibody, or antigen-binding portion thereof, useful in the methods and compositions disclosed herein is present in a pharmaceutical composition. As such, some aspects of the present disclosure are directed to a pharmaceutical composition comprising an anti-IL-27 antibody with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and / or adjuvant. In some aspects, the anti-IL-27 antibody, toripalimab, and bevacizumab are present in separate pharmaceutical compositions. In some aspects, the anti- IL-27 antibody, toripalimab, and bevacizumab are present in a single fonnulation, i.e., a coformulation of the anti-IL-27 antibody, toripalimab, and bevacizumab.

[0218] In certain aspects, acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed. In certain aspects, the formulation material(s) are for s.c. and / or I.V. administration. In certain aspects, the pharmaceutical composition comprises formulation materials for modifying, maintaining or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In certain aspects, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen- sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic 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); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); 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 pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, fyloxapal); stability’ enhancing agents (such as histidine, sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants. (Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company (1995).

[0219] In certain aspects, the primary vehicle or carrier in a pharmaceutical composition is either aqueous or non-aqueous in nature. For example, in certain aspects, a suitable vehicle or carrier is water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. In certain aspects, the saline comprises isotonic phosphate -buffered saline. In certain aspects, neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In certain aspects, pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5. In some aspects, the pharmaceutical composition further comprises sorbitol or a suitable substitute therefore. In certain aspects, a composition comprising an antibody of the present disclosure is prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (Remington's Pharmaceutical Sciences, supra) in the form of a lyophilized cake or an aqueous solution. Further, in certain aspects, a composition comprising an antibody of the present disclosure is formulated as a lyophilizate using appropriate excipients such as sucrose.

[0220] In certain aspects, the pharmaceutical composition is selected for parenteral delivery. In certain aspects, the compositions is selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the ability of one skilled in the art.

[0221] In certain aspects, the formulation components are present in concentrations that are acceptable to the site of administration. In certain aspects, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.

[0222] In certain aspects, when parenteral administration is contemplated, a therapeutic composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising an anti-IL-27 antibody, in a pharmaceutically acceptable vehicle. In certain aspects, a vehicle for parenteral injection is sterile distilled water in which an anti-IL-27 antibody is formulated as a sterile, isotonic solution, and properly preserved. In certain aspects, the preparation involves the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that can provide for the controlled or sustained release of the product which can then be delivered via a depot injection. In certain aspects, hyaluronic acid is also used. Hyaluronic acid, when present, can have the effect of promoting sustained duration in the circulation. In certain aspects, implantable drug delivery devices are used to introduce the desired molecule.

[0223] In certain aspects, a pharmaceutical composition is formulated for inhalation. In certain aspects, an anti-IL-27 antibody is formulated as a dry powder for inhalation. In certain aspects, an inhalation solution comprising an anti-IL-27 antibody is formulated with a propellant for aerosol delivery. In certain aspects, solutions are nebulized. Pulmonary administration is further described in PCT application No. PCT / US94 / 001875, which describes pulmonary delivery of chemically modified proteins.

[0224] In certain aspects, the pharmaceutical composition disclosed herein is formulated for oral administration. In some aspects, the pharmaceutical composition is administered orally. In certain aspects, an anti-IL-27 antibody that is administered in this fashion is formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. In certain aspects, a capsule is designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and presystemic degradation is minimized. In certain aspects, at least one additional agent is included to facilitate absorption of an anti-IL-27 antibody. In certain aspects, diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders are also employed.

[0225] In certain aspects, a pharmaceutical composition involves an effective quantity of an anti -IL- 27 antibody in a mixture with non-toxic excipients which are suitable for the manufacture of tablets. In certain aspects, by dissolving the tablets in sterile water, or another appropriate vehicle, solutions are prepared in unit-dose form. In certain aspects, suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

[0226] Additional pharmaceutical compositions will be evident to those skilled in the art, including formulations involving an anti-IL-27 antibody in sustained- or controlled-delivery formulations. In certain aspects, techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. See for example, PCT Application No. PCT / US93 / 00829 which describes the controlled release of porous polymeric microparticles for the delivery of pharmaceutical compositions. In certain aspects, sustained- release preparations can include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices can 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-hydroxybutyric acid (EP 133,988). In certain aspects, sustained release compositions can also include liposomes, which can be prepared by any of several methods known in the art. See, e.g., Eppstein et al, Proc. Natl. Acad. Sci. USA, 82:3688-3692 (1985); EP 036,676; EP 088,046 and EP 143,949.

[0227] The pharmaceutical composition to be used for in vivo administration typically is sterile. In certain aspects, this is accomplished by filtration through sterile filtration membranes. In certain aspects, where the composition is lyophilized, sterilization using this method is conducted either prior to or following lyophilization and reconstitution. In certain aspects, the composition for parenteral administration is stored in lyophilized form or in a solution. In certain aspects, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0228] In certain aspects, once the pharmaceutical composition has been formulated, it is stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. In certain aspects, such formulations are stored either in a ready -to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration. In certain aspects, kits are provided for producing a single-dose administration unit. In certain aspects, the kit comprises both a first container having a dried protein and a second container having an aqueous formulation. In certain aspects, kits comprising single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are included.

[0229] In some aspects, the present disclosure is directed to a pharmaceutical composition comprising (i) 50 mg / mL of an antibody that binds human IL- 27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) 0.02% polysorbate 80, (iii) 20 mM histidine, and (iv) 8% sucrose. In some aspects, the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15. In some aspects, the pharmaceutical composition has a pH of about 5.5.F. Kits

[0230] A kit can include an anti-IL-27 antibody as disclosed herein, and instructions for use. In some aspects, the kit may comprise, in a suitable container, an anti-IL-27 antibody, one or more controls, and various buffers, reagents, enzymes and other standard ingredients well known in the art. In some aspects, the kit may comprise, in a suitable container, an anti-IL-27 antibody, toripalimab, bevacizumab, one or more controls, and various buffers, reagents, enzymes and other standard ingredients well known in the art. In some aspects, the disclosure provides a kit comprising an anti-IL-27 antibody or antigen-binding portion as disclosed herein, and instructions for use in stimulating an immune response in a subject, or treating cancer in a subject, optionally with instructions for use in combination with one or more additional therapeutic agents or procedure as disclosed herein. In some aspects, the disclosure provides a kit comprising an anti-IL-27 antibody, toripalimab, bevacizumab, and instructions for use in stimulating an immune response in a subject, or treating cancer in a subject, optionally withinstmctions for use in combination with one or more additional therapeutic agents or procedure as disclosed herein.

[0231] In some aspects, the container can include at least one vial, well, test tube, flask, bottle, syringe, or other container means, into which an anti-IL-27 antibody may be placed, and in some instances, suitably aliquoted. In some aspects, the container can include at least one vial, well, test tube, flask, bottle, syringe, or other container means, for each of (i) an anti-IL-27 antibody, (ii) toripalimab, and (iii) bevacizumab. Where an additional component is provided, the kit can contain additional containers into which this component may be placed. The kits can also include a means for containing an anti-IL-27 antibody and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow-molded plastic containers into which the desired vials are retained. Containers and / or kits can include labeling with instmctions for use and / or warnings.III. Administration of Anti-IL-27 Antibodies i. CHS388-101 Study Plan

[0232] A Phase 1 / lb, open-label, FIH, dose-escalation, safety, and expansion study (CHS388-101) is ongoing to analyze the effects of in vivo administration of anti-IL-27 antibodies disclosed herein in the treatment of solid tumors. Part A consists of the anti-IL-27 monotherapy dose-escalation portion of the study and enrolled 29 patients with advanced solid tumors. This dose escalation part employed an Accelerated Phase (single patient) for Dose Levels 1-3, followed by a Standard Phase (3+3) for Dose Levels 4-8.

[0233] Part B has enrolled patients with advanced or metastatic ccRCC (any clear cell component in the histologic definition), NSCLC or HCC into indication-specific monotherapy expansion cohorts, to further examine the safety, efficacy, tolerability, PK, and pharmacodynamics of the anti-IL-27 antibody as a monotherapy using a 2-stage design. Stage 1 of each expansion cohort enrolled at least 17 patients. If > 1 of the 17 patients in Stage 1 has a confirmed radiographic response (complete response [CR] or partial response [PR]), then approximately 23 additional patients are enrolled in Stage 2. Approximately 12 patients (out of approximately 40 patients) in each of the indication-specific cohorts are required to have a soft tissue metastasis or primary tumor that is accessible for biopsy. The total number of patients enrolled in Part B is 84 (approximately 28 in each expansion cohort).

[0234] Part C enrolls approximately 40 patients with RCC, NSCLC or HCC into indication-specific combination therapy cohorts. The combination therapy consists of the anti-IL-27 antibody and the anti-PD-1 antibody pembrolizumab administered once about every 3 weeks.

[0235] Part D enrolls approximately 40 patients with NSCLC to test the safety and preliminary efficacy of the anti -IL- 27 antibody in combination with the anti-PD-1 antibody toripalimab.

[0236] The study design is presented in FIGs. 1A-1D.

[0237] Part A: Anti-IL-27 Antibody Monotherapy Dose Escalation

[0238] The starting dose of the anti-IL-27 antibody monotherapy was 0.003 mg / kg givenIV q4 week. Subsequent anti-IL-27 antibody dose levels for monotherapy dose escalation are detailed in Table 3 below.Table 3: Proposed dose levels for monotherapy dose escalation.

[0239] Monotherapy dose escalation began with an Accelerated Phase, whereby 1 patient each was enrolled in Dose Levels 1 -3 and DLTs and AEs were monitored during the first cycle of study treatment (a cycle is defined as 4 weeks [28 days] from Day 1). Had a patient in the Accelerated Phase experienced a DLT or any > Grade 2 treatment-related adverse event during the first cycle, dose escalation would have converted to Standard Phase at that dose level. As no DLTs were observed at Dose Levels 1-3, no conversion from Accelerated Phase to Standard Phase was required.

[0240] A RP2D was determined by the SRC for the anti-IL-27 antibody monotherapy. A minimum of 6 patients must be treated at a particular dose level and schedule for it to be considered the RP2D. The RP2D is based upon cumulative safety, PK, and pharmacodynamic data.

[0241] If not initiated on treatment at the recommended Phase 2 dose (RP2D), patients may have their dose escalated to a higher dose or changed to a different dosing schedule if they have received their current dose level for at least 3 cycles, if no toxicities > Grade 1 on theircurrent dose level are reported, and if they have not had a dose reduction. If any treatment- related > Grade 3 toxicity occurs at any level, no intrapatient dose escalation will be allowed at that level for any patient. Patients may only have their dose escalated or moved to an alternative dosing schedule at a dose level that has already been evaluated and is at or below the RP2D for the anti-IL-27 antibody monotherapy. There is no limit to how many dose levels a patient can be escalated (if below RP2D) as long as they meet the above criteria. Toxicities that occur during the first cycle of a higher dose for such a patient would not be considered DLTs.

[0242] Dose-limiting toxicities were evaluated during the first treatment cycle (28 days) using NCI-CTCAE version 5.0 or higher and defined for Part A and Part C of the study. Patients must have received at least 50% of the prescribed dose of the anti-IL-27 antibody and have not discontinued study therapy in the first 28 days (Cycle 1) for reasons other than drug -related adverse events to be evaluable for DLTs.

[0243] Toxicities (regardless of Grade) considered clearly related to disease progression, intercurrent illness, or concomitant medications are not considered DLTs. Grade 3 or Grade 4 non-hematologic laboratory abnormalities without clinical sequelae, resolving within 72 hours, and not requiring treatment, are not considered DLTs.

[0244] The occurrence of any certain toxicities during Cycle 1 may be considered a DLT, if related to study treatment.

[0245] Part B: Anti-IL-27 Antibody Monotherapy Expansion

[0246] The Part B monotherapy expansion cohorts evaluate the safety, efficacy, tolerability, PK, and pharmacodynamics of the anti-IL-27 antibody monotherapy at the RP2D in patients with ccRCC (any clear cell component in the histologic definition), HCC and non-small cell lung cancer (NSCLC) in indication-specific cohorts using a 2-stage design. Stage 1 of each expansion cohort enrolled approximately 17 patients. As > 1 of the 17 patients in Stage 1 had a confirmed radiographic response (CR or PR), then up to 23 additional patients wereenrolled in Stage 2. Approximately 12 patients (out of approximately 40 patients) in each of the indicationspecific cohorts are required to have a soft tissue metastasis or primary tumor that is accessible for biopsy. The total number of patients enrolled in Part B is 84 (27 patients with ccRCC, 17 patients with HCC, and 40 patients with NSCLC).

[0247] Part C: Anti-IL-27 Antibody Combination with Pembrolizumab

[0248] The Part C combination dose expansion cohorts evaluate the safety, efficacy, tolerability, PK, and pharmacodynamics of the anti-IL-27 antibody in combination withpembolizumab at 200 mg Q3W in patients with ccRCC, HCC and NSCLC in indication-specific cohorts using a 2-stage design. Patients are administered anti-IL-27 Abl at a dose of about 10 mg / kg Q3W, about 700 mg Q3W, about 20 mg / kg Q3W, or about 1400 mg Q3W.

[0249] Part D: Anti-IL-27 Antibody Combination with Toripalimab

[0250] The Part D combination dose expansion evaluates the safety, efficacy, tolerability, PK, and pharmacodynamics of the anti-IL-27 antibody in combination with toripalimab at 240 mg Q3W in patients with NSCLC using a 2-stage design. Patients are administered anti-IL-27 Abl at a dose of about 10 mg / kg Q3W, about 700 mg Q3W, about 20 mg / kg Q3W, or about 1400 mg Q3W.Part A and Part B Inclusion Criteria

[0251] All patients for Part A and Part B must meet the following criteria for inclusion:1. Patients must be > 18 years of age.2. Locally advanced or metastatic (Stage IV) solid tumor that has progressed during or after standard therapy, and for whom no available therapies are appropriate.3. Patients in Part B with advanced or metastatic ccRCC, HCC or NSCLC must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.4. Patients with HCC in Part B must have at least 1 measurable target lesion according to modified RECIST (mRECIST) meeting the following criteria. Lesion(s) should be suitable for repeat measurement.• Hepatic target lesion(s) should be at least > 1.0 cm (for typical, i.e., arterial enhancing lesions, this should be of the viable tumor, whereas for atypical lesions, the longest diameter should be used).• Nonhepatic target lesion(s) can include the following:- Lymph node (LN) lesion measuring > 1.5 cm in the short axis, unless it is a porta hepatis LN, which should be at least > 2.0 cm in the short axis.- Non-nodal lesion measuring > 1.0 cm in the longest diameter. Bone lesions are not eligible.• Lesions previously treated with radiation or other forms of locoregional therapy must show radiographic evidence of disease progression to be used as a target lesion.5. Patients with HCC must have unresectable disease, Barcelona Clinic Liver Cancer5Stage B (not eligible for transcatheter arterial chemoembolization) or Stage C.For patients in Part B with ccRCC, demonstrated progressive disease (PD) during or after the most recent treatment regimen. Prior treatment history must include progression during or after treatment with regimen(s) that have included a vascular endothelial growth factor (VEGF) -targeted agent and a programmed death receptor-1 (PD-l) / programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor. Patients who did not progress on but discontinued the VEGF-targeted agent for toxicity or intolerability are permitted. For patients in Part B with HCC, demonstrated PD during or after the most recent treatment regimen. Prior treatment history must include progression during or after treatment with a VEGF-targeted agent. Patients who did not progress on but discontinued the VEGF-targeted agent for toxicity or intolerability are permitted. For Part B patients in the tumor biopsy subsets only, must have tumor tissue that is accessible for pretreatment and on-treatment tumor biopsy in the opinion of the Investigator and be willing to undergo pretreatment and on-treatment biopsies per protocol. Washout period from the last dose of previous anticancer therapy (chemotherapy, biologic, or other investigational agent) to the initiation of study drug must be > 5 times the half-life of the agent or > 21 days (whichever is shorter).• Note: The washout period for palliative radiotherapy to non-central nervous system disease is 7 days. Resolution of non-immune related AEs secondary to prior anticancer therapy (excluding alopecia and peripheral neuropathy) to < Grade 1 per NCI-CTCAE version 5.0 or higher, and complete resolution of immune-related AEs secondary to prior checkpoint inhibitor therapy.• Note: Patients with other clinically stable and / or nonsignificant AEs related to prior therapy may be enrolled (e.g., controlled thyroid disorders, vitiligo, asymptomatic elevated amylase / lipase, type 1 diabetes on insulin, < Grade 2 controlled rash, < Grade 2 electrolyte abnormalities on a stable dose of supplementation). Serum creatinine clearance > 30 mL / min per Cockcroft-Gault formula or serum creatinine < 2.0 X the upper limit of normal (ULN). Total bilirubin < 1.5 X ULN (< 3 x ULN if elevated because of Gilbert’s syndrome, and <2 X ULN for patients with HCC or patients with known liver metastases).Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST / SGOT) and alanine aminotransferase (ALT / SGPT) < 2.5 X ULN (< 5 X ULN if liver metastasis or for patients with HCC). For patients with HCC, Child-Pugh class A or B7 with a serum albumin > 2.8 g / dL (> 28 g / L). Adequate hematologic function, defined as absolute neutrophil count (ANC)> 1.0 x 109 / L, hemoglobin > 9.0 g / dL, and platelet count > 100 x 109 / L. For patients with HCC, platelet count > 75 x 109 / L without transfusion. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Ejection fraction > 50%, as measured by echocardiogram or multigated acquisition scan at Screening. For women of childbearing potential (WCBP): negative serum f> human chorionic gonadotropin pregnancy test within 1 week before first treatment (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months for women > 55 years of age). Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of the study treatment period, including 75 days after the last dose of SRF388; male patients must refrain from donating sperm during this period. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception. Azoospermic male patients and WCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, female patients must still undergo pregnancy testing as described in this section. Ability to adhere to the study visit schedule and all protocol requirements. Signed and dated institutional review board / independent ethics committee-approved informed consent form before any screening procedures are performed. Patients with NSCLC must have histologically confirmed locally advanced and / or metastatic Stage IV NSCLC. Patients with NSCLC must have demonstrated PD during or after the most recent treatment regimen. Prior treatment history must include progression during or after treatment with (1) anti-PD-(L)l if disease has no driver alterations and (2) a targetedtherapy if the patient has disease with driver alterations. Patients who did not progress on but discontinued the targeted agent for toxicity or intolerability are permitted.Note: Patients with driver alterations are not required to have had prior anti-PD-(L)l therapy.Part A and Part B Exclusion Criteria

[0252] Patients were excluded from Part A and Part B of the study if they met any of the following criteria:1. Previously received an anti-IL-27 antibody or anti-IL-27 targeted therapy.2. For patients in Part B with renal cell carcinoma (RCC), non-clear cell RCC histology.3. For patients in Part B, received > 4 prior systemic regimens for Stage IV disease.4. For patients with HCC, known fibrolamellar or mixed hepatocellular cholangiocarcinoma.5. For patients with HCC, moderate or severe ascites.6. Receiving chronic anti-coagulation therapy (e.g., warfarin, enoxaparin) that cannot be safely discontinued temporarily for the required biopsies (only if in the applicable tumor biopsy subset).7. History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy, or any excipient in the study drugs.8. Major surgery within 4 weeks prior to Screening.9. Symptomatic or untreated brain metastases (including leptomeningeal metastases). Patients previously treated for brain metastases must be > 28 days from completion of radiation treatment with follow-up imaging showing no progression.10. Primary central nervous system malignancy.11. Prior autologous stem cell transplant < 3 months before the first dose of SRF388.12. Prior allogeneic hematopoietic cell transplant within 6 months of the first dose of SRF388 or with a history of or current clinical Graft-Versus-Host Disease.13. Known infection with HIV.14. Known infection with hepatitis B virus (HBV) or hepatitis C vims (HCV). The following exceptions are permitted:Patients with HCC: controlled active HBV or fully treated HCV infection is permitted. Antiviral therapy as per local standard of care should be continued.- For patients with HCC with active HBV, controlled disease is considered HBV DNA < 500 lU / mL during the Screening Period with willingness to continue antiviral treatment during length of study. The patient must be on anti-HBV treatment (per local standard of care: e.g., entecavir) for a minimum of 14 days prior to study entry.- For patients with HCC with HCV, only cured disease or HCV considered fully treated and no longer requiring antiviral therapy for control is permitted.- No co-infection with HCV and HBV is allowed. Co-infection is defined as HCV RNA positive and hepatitis B surface antigen (HBsAg) positive. However, a patient who is HCV Ab+, hepatitis B core antibody (HBcAb) + but negative HBsAg is not considered co-infected and is permitted.• Patients with any solid tumor who have a history of cured HCV are permitted. Active autoimmune disease requiring steroids or immunosuppressive (e.g., cyclosporine) therapy or medical conditions requiring chronic steroid (i.e., > 10 mg / day prednisone or equivalent) or immunosuppressive therapy.• Note: Topical, intranasal, or inhaled corticosteroids are permitted. Physiologic replacement for patients with thyroid, adrenal, or pituitary insufficiency (e.g., thyroxine, physiologic corticosteroids [< 10 mg / day of prednisone or its equivalent], or insulin) is allowed. Patients with a history of autoimmune disease may be eligible following discussion with the Medical Monitor. Ongoing uncontrolled systemic bacterial, fungal, or viral infections at Screening.• Note: Oral antibiotics for a controlled infection are permitted. Patients on antimicrobial, antifungal, or antiviral prophylaxis are not specifically excluded if all other inclusion / exclusion criteria are met. Administration of a live attenuated vaccine within 6 weeks before the first dose of study drag. Baseline QT interval corrected (QTc) with Fridericia’s method (QTcF) > 480 ms.• Note: If 1 elevated QTc reading, the screening requirement can be met with the average of triplicate ECGs. Criterion does not apply to patients with a right or left bundle branch block. Female patients who are pregnant or breastfeeding.20. Another malignancy, other than those with negligible risk of death, including but not limited to non-melanoma skin cancer, low risk localized or cured prostate cancer, ductal carcinoma in situ, or carcinoma in situ of the cervix, within 2 years before Screening.21. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within 6 months before Screening.22. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition including pneumonitis and / or interstitial lung disease, uncontrolled diabetes, symptomatic fistula) or any important medical illness or abnonnal laboratory finding that would, in the Investigator’s judgment, increase the risk to the patient associated with his or her participation in the study.23. For patients with NSCLC, any component of small cell histology.Part C and Part D Inclusion Criteria

[0253] All patients for Part C and Part D must meet the following criteria for inclusion:1. Patients must be > 18 years of age.2. For patients in Part C, advanced RCC of any histology or advanced HCC previously treated with at least one systemic anticancer therapy OR histologically or cytologically confirmed metastatic or unresectable adenocarcinoma or squamous cell NSCLC.3. Patients in Part C with HCC must have unresectable disease, Barcelona Clinic Liver Cancer (BCLC) Stage B (not eligible for transcatheter arterial chemoembolization) or Stage C.4. For patients in Part D, histologically or cytologically confirmed metastatic or unresectable adenocarcinoma or squamous cell NSCLC.5. For patients in Part D, no more than 3 prior lines of systemic therapy for unresectable or metastatic disease with prior radiologic progression on or following platinum-based chemotherapy and prior anti-PD-(L)l therapy whether given alone or in combination.6. At least 1 measurable lesion per RECIST 1.1.7. Patients with HCC must have at least 1 measurable target lesion according to modified RECIST (mRECIST).8. ECOG performance status of 0-1.9. ANC >1500 / gL (1.5 x 109 / L).10. Platelets >100 000 / pL (> 100 x 109 / L).11. Hemoglobin for participants with RCC: >9.0 g / dL; for participants with HCC: >8.5 g / dL.Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) <1.5 x ULN OR >30 mL / min for participant with creatinine levels >1.5 x institutional ULN. Total bilirubin <1.5 x ULN OR direct bilirubin <ULN for participants with total bilirubin levels >1.5 x ULN. AST (SGOT) and ALT (SGPT) <2.5 x ULN (<5 x ULN for participants with liver metastases). International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) <1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants. For patients in Part C with HCC, Child-Pugh Class A or B7 with a serum albumin > 2.8 g / dL (> 28 g / L). Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of the study drag period (or beginning 14 days before the initiation of pembrolizumab for oral contraception), including 75 days after the last dose of CHS-388 or 120 days after the last dose of pembrolizumab; male patients must refrain from donating sperm during this period. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception with spermicide. Azoospermic male patients and WCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, female patients must still undergo pregnancy testing as described in this section. Patients from Part A or Part B with RCC or HCC must have progressed on monotherapy by RECIST 1.1. Patients from Part A or Part B with RCC of HCC must not have experienced prior Grade >3 toxicity related to monotherapy. Patients from Part A or Part B with RCC or HCC must be willing to undergo pretreatment core or excisional biopsy if deemed safe and tumor is accessible. Patients from Part A or Part B with RCC or HCC must have received no systemic anticancer therapies between monotherapy doses.22. For patients with NSCLC, no more than 3 prior lines of systemic therapy for unresectable or metastatic disease with prior radiologic progression on or following platinum-based chemotherapy and prior anti-PD-(L) 1 therapy whether given alone or in combination.Part C and Part D Exclusion Criteria

[0254] Patients were excluded from Part C and Part D of the study if they met any of the following criteria:1 . Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study drug.2. Previously received an anti-IL 27 antibody or anti-IL 27 targeted therapy (exception to patients who received monotherapy in Part A or Part B).3. No prior systemic therapy for unresectable or metastatic disease.4. Received > 4 prior systemic regimens for unresectable or metastatic disease (prior PD- (L)l inhibitors are allowed if the patient did not discontinue therapy due to > Grade 3 drug-related toxicity).5. For patients in Part C with HCC, fibrolamellar histology or mixed hepatocellular cholangiocarcinoma.6. For patients in Part C with HCC, moderate or severe ascites.7. For patients in Part C with HCC, inability to undergo disease evaluation with triphasic computed tomography or magnetic resonance imaging because of contrast allergy or other contraindication.8. For patients in Part C with HCC, imaging findings consistent with > 50% liver occupation by HCC tumors.9. For patients in Part D, has received prior therapy with an anti-PD-1, anti-PD-Ll, or anti- PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a > Grade 3 irAE because of contrast allergy or other contraindication.10. History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs.11. Surgeries that required general anesthesia must be completed at least 2 weeks before first study drug administration.12. Prior autologous stem cell transplant < 3 months before the first dose.13. Prior allogeneic hematopoietic cell transplant within 6 months of the first dose or with a history of or current clinical Graft-Versus-Host Disease.14. Has had an allogenic tissue / solid organ transplant.15. Other unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would increase the risk to the patient associated with his or her participation in the study.Biomarker Assessments

[0255] Samples were collected for biomarker analysis to investigate the biological effects of anti-IL-27 at the molecular and cellular level, as well as to evaluate how changes in the markers and immune cell populations may relate to exposure and clinical outcomes. The goal of the biomarker assessments is to provide supportive data for the clinical trial. There may be circumstances when a decision is made to stop a collection, not perform, or discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample number, sample quality issues precluding analysis, etc.).

[0256] Additional biomarker samples may be requested (when feasible) at the time of any unusual safety event (i.e. , an AE different in type and severity from that which is expected in the setting of anti-IL-27 use), or if a sample is found to be compromised.

[0257] The following biomarker samples may be analyzed: blood (whole blood and PBMCs) for immunophenotyping and immune monitoring (to monitor the effects of treatment on various peripheral blood immune cell populations; subsets may include, but are not limited to, monocytes, neutrophils, myeloid-derived suppressor cells, and T / NK / myeloid-cell populations); blood serum for cytokine / chemokine / soluble factors (for profiling of potential predictive and pharmacodynamic biomarkers of response and / or resistance to anti-IL-27; serum levels of soluble factors associated with cancer and immunological function will be assessed. Examples include but are not limited to: EBB, IL-27, TNFa, MIP-la (CCL3), IFNy, IL-10, and IL-6. ii. CHS388-101 Study Results

[0258] Patients with advanced solid tumors refractory to standard therapy were enrolled in a phase 1 dose-escalation study (accelerated single patient followed by standard 3+3) to establish the preliminary safety of anti-IL-27 antibody monotherapy and to identify a dose suitable for expansion (NCT04374877). The anti-IL-27 antibody was administered intravenously every 4 weeks on day one of each four-week cycle (FIG. ID). Anti-IL-27 antibody monotherapyexpansions (Part B) enrolled patients with advanced ccRCC, HCC and NSCLC in Simon 2-stage designs, anti-IL-27 antibody in combination with pembrolizumab (Part C) has enrolled patients with advanced ccRCC and HCC, and anti-IL-27 antibody in combination with toripalimab (Part D) enrolls patients with NSCLC (FIGs. 1A-1D).

[0259] In Part A, the dose escalation component, the primary end points were rate of dose limiting toxicities (DLTs), safety, and tolerability with overarching objective of RP2D determination. Key secondary end points included objective response rate (ORR) per RECIST vl.l and iRECIST (if HCC, by mRECIST), pharmacokinetics, pharmacodynamic assessments (phosphorylated signal transducer and activator of transcription- 1 (pSTATl) levels in immune cell subsets), and serum concentrations of EBI3. Exploratory analyses planned to identify potential biomarkers of response and resistance. The safety analysis set included all patients who received any amount of study medication. The response evaluable analysis set included all patients with measurable disease at baseline who received at least one dose of anti -IL-27 Abl and had one postbaseline response assessment or who discontinued study treatment within 6 weeks (± 2 weeks) of first dose. For the primary pharmacodynamic marker, fresh whole blood samples were analyzed by flow cytometry to monitor inhibition of pSTATl.

[0260] Study Results

[0261] In Part A, twenty-nine (29) patients received the anti-IL-27 antibody at doses ranging from 0.003 to 20 mg / kg. Median age was 64 years, 62% were female, and ECOG PS was 0 / 1 (24% / 76%) (Table 4). 62% of patients had received 3 or more lines off prior therapy, and 79% were anti-PD-(L)l experienced (n=23). The only treatment-related adverse events observed across dose levels at >=10% was low-grade fatigue (n=3). No dose-limiting toxicities (DLTs), > Grade 3 related toxicity have occurred at any dose level. There have been 6 reported related TEAEs, which were all low grade, including fatigue (n=3), nausea (n=2), excess salivation (n=l), cough (n=l), and hyperthyroidism (n=l).Table 4: Part A, Dose Escalation Demographics and Baseline Characteristics (All patients, N = 21)

[0262] Mean time on study for Part A was 9 weeks (range 1-71), as measured by the days from the first dose to the last visit, including safety follow-up visits (FIG. 2). Six patients were escalated to higher doses on study, as depicted by changing of the lane color at the time of dose increase. Disease assessment was performed at week 8 and then every 12 weeks thereafter. Of the 27 evaluable patients, approximately 40% experienced clinical benefit in the form of disease stabilization or partial response, with 28% of disease stabilization persisting beyond 16 weeks. One patient (3.7%) exhibited a confirmed partial response, 10 patients (37%) exhibited stable disease, and 16 patients (59%) exhibited progressive disease, as measured by RECIST vl.l (FIGs. 3A-3B). Three patients with RCC, cecal adenocarcinoma, and appendiceal adenocarcinoma who received prior anti-PD-1 had prolonged stable disease at 9 months or beyond. One patient with NSCLC whose disease was primarily refractory to 3 prior therapies including platinum and taxane chemotherapies and PD-1 blockade was treated at 10 mg / kg and experienced a rapid partial response evident at the first response assessment at 8 weeks, which was confirmed at 12 weeks.

[0263] A review of the subset of ccRCC patients enrolled in Part A of the study was performed. Of the 29 patients in Part A, 7 were ccRCC patients. The majority were men (71%) and of intermediate risk (80%). This subset of patients was heavily pretreated with 29% having 3-4 prior lines of therapy and 43% having 5 or more prior lines. All had received prior PD-1 pathway blockade. Of these 7 patients, 43% (n=3) experienced disease stabilization for >20 weeks (range: 20-32) (FIGs. 4A-4B).

[0264] A subsequent PK analysis of patient samples who were administered 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg and 20 mg / kg doses of anti-IL-27 antibody in Part A of the study was performed, confirming that anti-IL-27 antibody PK are linear and dose proportional from 0.03 to 20 mg / kg. The terminal elimination half-life was estimated to be approximately 10 days, ranging from 6 to 13 days. Steady state was attained by Cycle 4, with an Accumulation Index of 1.2. Exposures (Cmax and AUC) in patients with ccRCC or HCC treatedwith 10 mg / kg anti-IL27 antibody as monotherapy were similar to those observed in the 10 mg / kg dose escalation cohort (FIGs. 5A-5B). Pre-existing low-titer anti-drug antibodies (ADA) were identified in the Cycle 1 pre-dose samples of 7 out of 63 patients; none were significantly boosted (increase in titer of > 4-fold) post-treatment. Two out of 65 patients developed ADA after initiation of treatment.

[0265] The confirmed partial response in a 64-year NSCLC patient receiving the anti-IL- 27 antibody at 10 mg / kg intravenously once every four weeks deepened to a 74% decrease in target lesions at cycle 6 response assessment.

[0266] The anti-IL-27 antibody is well-tolerated at all tested doses to date in patients with advanced solid tumors. Preliminary results of IL-27 pathway blockade with a first-in-class therapeutic study of the anti-IL-27 antibody shows evidence of single-agent activity even in heavily pre-treated patients, including a confirmed partial response in a patient with squamous cell NSCLC whose disease was resistant to three prior regimens including chemotherapy and PD- 1 blockade, and multiple patients have experienced disease stabilization. PK are linear and doseproportional with maximal target inhibition of downstream IL- 27 -mediated pSTATl maintained throughout the dosing interval. Preliminary results of IL-27 pathway blockade with a first-in-class immunotherapy support further evaluation of the anti-IL-27 antibody as monotherapy and in combination with standard and investigational regimens in both immune checkpoint naive and experienced patients with the initial focus planned in HCC, RCC, and NSCLC.

[0267] The Part B Simon 2 Stage studies are ongoing with the primary endpoint of objective response. No concerning new safety signals have been identified thus far.

[0268] In the clear cell RCC cohort, 21 patients have been enrolled. Most of the population was male (91%), intermediate risk (57%) by International Metastatic RCC Database Consortium Risk Score (“IDMC”) and had lung (71%) and nodal (100%) metastases. Close to 40% had liver (n=8) and bone disease (n=7) which generally correlate with worse prognosis. All patients were required to have had prior VEGF targeted therapy and PD-1 blockade alone or in combination (Table 5). Thirteen (13) patients were evaluable for RECISTvl. l response (FIGs. 6A-6B). Disease control rate defined as CR / PR + SD was 31 % including one patient with a confirmed partial response. Progressive disease was best response in 71 %. The patient with a partial response experienced target lesion tumor shrinkage of 45%, which was confirmed at C6 and the patient remains on study at cycle 9.Table 5: Part B, ccRCC Demographics and Baseline Characteristics (All patient, N = 21)

[0269] In the treatment-refractory HCC cohort, 17 patients were enrolled in a monotherapy expansion. It was an advanced treatment refractory population with a median progression free survival (PFS) of 7.2 weeks (6.3, NE). Of the 16 response evaluable patients, 31% (n=5) experienced stable disease and 69% (n=l 1 ) progressive disease as best response by RECIST vl.l (FIGs. 7A-7B). Interrogation of baseline demographics highlights the advanced nature of the population enrolled: 53 % 3-4 lines of prior therapy, 18% Child Pugh B7, 77% BCLC Stage C, 94% with ECOG 1, 59% AFP >=400. Only 18% ever had prior PR and 18% were primary treatment refractory to all prior lines of therapy (Table 6).Table 6: Part B, HCC Demographics and Baseline Characteristics (All patients, N = 17)

[0270] Monotherapy TEAE results of the clinical trial in 45 human patients with NSCLC administered the anti-IL-27 antibody are summarized below:

[0271] Mean time on study for Part B NSCLC cohort is 8 weeks (range 2-91), as measured by the days from the first dose to the last visit, including safety follow-up visits (FIG. 8A). Disease assessment was performed at week 8 and then every 12 weeks thereafter. Of the 44 evaluable patients, approximately 31% experienced clinical benefit in the form of disease stabilization or partial response. Two patients (5%) exhibited a confirmed partial response, 11 patients (26%) exhibited stable disease, and 29 patients (69%) exhibited progressive disease, as measured by RECISTvl. l (FIGs. 8A-8B).

[0272] The Part C Simon 2 Stage studies are ongoing and have enrolled 21 patients. In the combination cohorts receiving the anti-IL-27 antibody at 10 mg / kg and pembrolizumab at 200 mg Q3W, the most common (occurring in > 20% patients) TEAE was anaemia in 5 (23.8%) patients. Grade 3 or higher TEAEs occurred in a total of 7 (33.3%) patients. One (4.8%) patient had an event of Grade 3 fatigue that was assessed as related to study drug. No TEAEs led to treatment discontinuation. Treatment-emergent SAEs were reported in 5 (23.8%) patients; none were reported in > 1 patient or considered related to study drug. One TEAE of pneumonia with anoutcome of death was assessed as not related to study drug. A confirmed partial response was observed in one patient with HCC.

[0273] Combined Preliminary Safety Results

[0274] Atotal of 129 unique patients have received anti-IL-27 Abl in Study CHS388-101, including 29 patients in the completed monotherapy dose escalation part, 84 patients in monotherapy dose expansion, and 21 patients received anti-IL-27 Abl in combination with pembrolizumab, 5 of whom had received treatment with anti-IL-27 Abl monotherapy and then crossed over to receive combination therapy. Summary of the TEAEs for Study Part A, B and C are provided below.

[0275] The most frequently reported (> 15%) TEAEs in monotherapy dose escalation (Part A) included fatigue (7 patients, 24.1 %), hyponatraemia (6 patients, 20.7 %), and cough (5 patients, 17.2%). The most frequently reported TEAEs in monotherapy dose expansion (Part B) included fatigue (21 patients, 25.0%), dyspnoea (16 patients, 19.0%), and anaemia (13 patients, 15.5%). The most frequently reported TEAEs in combination therapy (Part C) included anaemia (5 patients, 23.8%) and aspartate aminotransferase increased (4 patients, 19.0%).

[0276] The incidence of Grade > 3 TEAEs was similar across monotherapy and combination therapy groups and treatment-related Grade > 3 TEAEs were uncommon (< 6.0% of all patients).

[0277] Treatment-emergent SAEs were reported more frequently in monotherapy expansion (36.9%) with low incidence of treatment-related SAEs (3.6%). There were no treatment-related SAEs in monotherapy dose escalation or combination therapy.

[0278] TEAEs leading to discontinuation were reported in < 10% of all patients and no patients receiving combination therapy discontinued study treatment due to AEs.

[0279] No DLTs were reported. No adverse events of special interest have been defined for anti-IL-27 Abl. Fatal TEAEs were reported in < 10% of all patients and all but 1 event were assessed as not related to study treatment; 1 event of Respiratory’ failure in monotherapy expansion was assessed as possibly related to the anti-IL-27 antibody; this event occurred in a patient with NSCLC in the context of a differential diagnosis that included bacteremia and disease progression.

[0280] The immunogenicity of the anti-IL-27 antibody, as assessed by the development of antidrug antibodies (ADA), is ongoing. To date, the incidence of treatment-emergent ADA (TE- ADA) has been low. In CHS388-10L the incidence of TE-ADAin Part A was 4% (1 of 29) acrossall dosing groups; in Part B the incidence was 1.6% (1 of 84) across all disease cohorts; and in Part C the incidence to date is 0% (0 of 21) across all cohorts.

[0281] Flat Doing of the Anti-IL-27 Antibody

[0282] To examine the differences in exposure between dosing at 10 mg / kg Q3W, and flat dosing of 700 mg, simulations were performed in a virtual population of 1000 subjects. Simulations were conducted to identify a flat dose that results in a Ctrough level above 14 pg / mL and similar Cmax.ss, Ctrough, ss- and AUCtau.ss (point estimate and 90% CI) as compared to the 10 mg / kg dose, for both body weight adjusted and flat dose Q3W administration. Further, simulations were conducted to identify an additional (higher) flat dose for Q4W administration that would meet the Ctrough criteria with minimal overlap in simulated exposure (Cmax and AUC) to the anti- IL-27 antibody.

[0283] Simulations of a dose of 700 mg resulted in comparable exposure to 10 mg / kg (FIGs. 9A-9C), irrespective of the dosing frequency (Q3W and Q4W), although with slightly higher variability in Cmax and AUC in the flat dosing population. This is commensurate with the median body weight of ~70 kg in the virtual population.

[0284] Flat dosing of the anti-IL-27 antibody is tested in Part D of CHS388-101. Part D evaluates safety, efficacy, tolerability, PK, and pharmacodynamics of the anti-IL-27 antibody in combination with toripalimab at 240 mg Q3W in patients with NSCLC using a 2-stage design. Patients are administered anti -IL-27 Abl at a dose of about 10 mg / kg Q3W, about 700 mg Q3W, about 20 mg / kg Q3W, or about 1400 mg Q3W. The total number of patients enrolled in Part D is approximately 40. The primary outcome measure is objective response rate (CR or PR) per RECIST v 1.1. Serum is collected to assess EBI3 correlation with clinical outcomes. Serum is also collected to assess the development of anti-drug antibodies (AD As) to the anti-IL-27 antibody and toripalimab. iii. CHS388-201 Study Plan

[0285] A randomized Phase 2 trial (CHS388-201) is conducted to evaluate the efficacy and safety of a fully human IgGl blocking antibody to IL- 27 ("anti-IL-27 antibody") in combination with atezolizumab (TECENTRIQ®) plus bevacizumab (AVASTIN®) compared to placebo in combination with atezolizumab plus bevacizumab in patients with first-line advanced or metastatic hepatocellular carcinoma (HCC).

[0286] After a Safety Lead-In of 30 patients to receive open-label anti-IL-27 antibody+ atezolizumab + bevacizumab, patients are randomized with a 1 : 1 allocation into one of twoarms. Central treatment allocation / randomization occurs using Interactive Response Technology (IRT). Patients enrolled in Arm A (n ~ 52) receive anti-IL-27 antibody + atezolizumab + bevacizumab. Patients enrolled in Am B (n ~ 52) receive placebo + atezolizumab + bevacizumab.

[0287] Patients remain on study drug (defined as anti-IL-27 antibody / placebo, atezolizumab, bevacizumab) for up to 2 years or until documented disease progression or unacceptable toxicity.

[0288] Thirty patients are enrolled in a Safety Lead-In to assess the preliminary safety, tolerability and activity of the triplet combination. Patient dosing is staggered by 48 hours during the Safety Lead-In, and all patients receive the anti-IL-27 antibody + atezolizumab + bevacizumab intravenously (IV) once every 3 weeks (q3 weeks) on Day 1 of a 21 -day cycle. 10 mg / kg IV of the anti-IL-27 antibody is administered first during an approximately 20 to 60 minute infusion duration. After an observation period of 30 minutes, the other study drugs are administered; atezolizumab 1200 mg IV is administered prior to bevacizumab 15 mg / kg IV. The atezolizumab infusion occurs over 60 + 15 minutes for the first infusion and then 30 + 10 minutes for subsequent infusions, if tolerated. There is a minimum of 5 minutes between the atezolizumab infusion and the start of the bevacizumab infusion. The bevacizumab infusion occurs over 90 ± 15 minutes for the first infusion, 60 minutes for the second infusion, and 30 ± 10 minutes for subsequent infusions, if tolerated.

[0289] During the Safety Lead-In, the first 6 patients receive 1 cycle of the triplet combination, during which safety stopping rules are applied for safety evaluation. If 2 or more of these 6 patients experience a Grade D3 related adverse event (AE; with the exception of toxicities listed below), any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1 , or prolonged delay (defined as > 14-day delay in initiating Cycle 2 due to toxicity), the trial will be halted for safety review with consideration given for evaluating an additional 6 patients at a reduced dose of the anti-IL-27 antibody in conjunction with atezolizumab plus bevacizumab. If < 2 patients experience a Grade > 3 related AE as defined by the safety stopping rules, any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1, or prolonged delay (defined as > 14-day delay in initiating Cycle 2 due to toxicity), then the study will move forward into the Randomized Phase.

[0290] The following toxicities considered at least possibly related to study treatment would not be considered to meet criteria for a safety stopping rule: any Grade > 3 event responding to supportive treatment within 3 days (e.g., nausea, vomiting, and diarrhea); a Grade > 3 eventlasting < 7 days (e.g., fatigue); a Grade 3 event lasting any duration if it can be controlled with treatment (e.g., hypertension); a Grade D3 event lasting < 14 days (e.g., proteinuria); a Grade D3 event lasting any during if asymptomatic for / showing no clinical signs of pancreatitis (e.g., asymptomatic amylase / lipase elevations); a Grade > 3 event lasting any duration if can be controlled with treatment such as thyroid supplementation or beta blockade (e.g., thyroid function abnormalities including hypo- or hyperthyroidism); a Grade D3 event recovering to Grade 1 with treatment (e.g., steroids) within 7 days (e.g., rash); a Grade < 2 event lasting any duration (e.g., alopecia); or clinically nonsignificant, treatable, or reversible non-hematologic laboratory abnormalities (e.g., liver function tests, electrolytes, uric acid, etc.).

[0291] To be considered evaluable for the Safety Lead-In, patients must have completed at least 50% of the prescribed doses of all 3 drugs during the review period (Days 1-21 = Cycle 1) and must not have discontinued treatment during Cycle 1 for reasons other than drug-related AEs. For example, patients who discontinued study treatment during Cycle 1 for progressive disease (PD) or for patient or physician preference but without experiencing a Grade > 3 related toxicity would not be considered fully evaluable for the Safety Lead-In and would be replaced. A ‘related’ toxicity is defined as those toxicities related to any study drug.

[0292] Patients receive anti-IL-27 antibody / placebo, atezolizumab, and bevacizumab Q3W until documented PD or unacceptable toxicity through C35. Doses of the anti -IL- 27 antibody / placebo, atezolizumab, and / or bevacizumab are administered within a ± 3-day window; otherwise, they are skipped for that cycle.

[0293] The anti-IL-27 antibody drug product is a sterile filtered liquid, aseptically filled into a single-use stoppered glass vial and sealed with a flip-off seal and stored at -20°C. The drug product contains at least 2.0 mL at a target concentration of 50 mg / mL (nominal dose of 100 mg) in 20 mM histidine, 8% sucrose, 0.02% polysorbate 80, pH 5.5 for IV infusion. All lots of drag product are tested to ensure product identity, strength, quality, purity, and potency. The drag product is diluted in normal saline (0.9%, Sodium Chloride for Injection, United States Pharmacopeia) as diluent prior to IV infusion.

[0294] The anti -IL-27 antibody is administered as an IV infusion at a dose of 10 mg / kg body weight.

[0295] For the first administration of the anti-IL-27 antibody / placebo (Cycle 1 Day 1 (C1D1)), no pre-infusion medication is required. If a Grade > 1 infusion-related AE is recorded at any dose, then for all subsequent doses for that patient, antipyretics (oral acetaminophen 650 to1000 mg) and an antihistamine (oral or IV diphenhydramine 25 to 50 mg or equivalent) may be administered.

[0296] Patients with a Grade > 2 infusion-related reaction (IRR) may also be administered a glucocorticoid (IV 20 mg dexamethasone or 80 mg methylprednisolone) for all subsequent infusions.

[0297] In both the Safety Lead-In and Randomized Phases, the disease response assessments employing computed tomography (CT) or magnetic resonance imaging (MRI) scans are performed at baseline and every 9 weeks thereafter (± 7 days) for the trial duration or until disease progression, patient withdrawal, or initiation of additional anticancer therapy. Additional disease assessments such as focused physical examinations and alpha-fetoprotein (AFP) monitoring are also performed.Inclusion Criteria:

[0298] Inclusion and exclusion criteria will be reviewed for each potential patient. All patients must meet the following criteria for inclusion:1. Patients must be > 18 years of age on day of signing informed consent.2. Patients must have unresectable locally advanced or metastatic HCC with diagnosis confirmed by histology / cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria (see Appendix 1) in cirrhotic patients. Patients without cirrhosis require histological confirmation of diagnosis.3. Patients must not have had prior systemic treatment for unresectable locally advanced or metastatic HCC.4. Patients must have BCLC Stage B (not eligible for transcatheter arterial chemoembolization) or Stage C disease.5. Patients must have Child-Pugh Class A disease.6. Patients must have > 1 measurable lesion per RECIST vl. l and > 1 measurable target lesion per mRECIST (see Appendix 2 for more details). Lesion(s) should be suitable for repeat measurement, a) For mRECIST, the following criteria apply: i. Hepatic target lesion(s) > 1.0 cm (for typical (i.e., arterial enhancing lesions) this should be of the viable tumor, whereas for atypical lesions, the longest diameter should be used), ii. Nonhepatic target lesion(s) can include the following: Lymph node (LN) lesion measuring > 1.5 cm in the short axis, unless it is a porta hepatis LN, which should be > 2.0 cm in the short axis. Non- nodal lesion measuring > 1.0 cm in the longest diameter. Bone lesions are noteligible, b) Lesions previously treated with radiation or other forms of locoregional therapy must show radiographic evidence of PD to be designated as a target lesion.7. Patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1.8. Patients must have laboratory values indicative of adequate organ function (see Table 7).Table 7: Laboratory Values Indicative of Adequate Organ Function9. For women of childbearing potential (WCBP): patients must have a negative serum human chorionic gonadotropin pregnancy test within 1 week prior to first dose of study drug (WCBP defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for > 12 consecutive months without an alternative medical cause).10. WCBP patients must be willing to refrain from heterosexual intercourse or use acceptable methods of birth control while they are receiving study drug and for 6 months after the last dose of any study drug. WCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, female patients must still undergo pregnancy testing.11. Male patients must be willing to refrain from heterosexual intercourse with a partner of childbearing potential or a pregnant partner or use acceptable methods of birth control while they are receiving study drug and for 6 months after the last dose of any study drug to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Azoospermic male patients are exempt from contraceptive requirements.12. Patients must have the ability to adhere to the trial visit schedule and all protocol requirements.13. Patients must provide signed and dated institutional review board / independent ethics committee-approved informed consent form before any Screening procedures are performed.Exclusion Criteria:

[0299] Patients are to be excluded from the trial if they meet any of the following criteria:1. The patient is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.2. The patient previously received an anti-interleukin (IL)-27 antibody (Ab) or anti-IL-27- targeted therapy.3. The patient received prior systemic therapy for unresectable or metastatic disease, unless the prior systemic therapy was administered for neoadjuvant, adjuvant, or curative intent (localized disease) > 1 year prior to the development of recurrent or metastatic disease.4. The patient received prior local, neoadjuvant, or adjuvant anticancer therapy > 1 year ago but has not had resolution of any non-immune-related AEs (irAEs) secondary to prior anticancer therapy to Grade < 1 per NCI-CTCAE version 5.0 or higher and / or complete resolution of any irAEs secondary to prior immune checkpoint inhibitor therapy, with the following exceptions: a) Patients with non-irAEs of alopecia, peripheral neuropathy, stable thyroid dysfunction, Grade < 2 controlled rash, and Grade < 2 electrolyte abnormalities on a stable dose of supplementation are eligible even if these AEs have not resolved to Grade < 1 per NCI- CTCAE version 5.0 or higher, b) Patients with the following clinically stable or clinically nonsignificant irAEs are eligible: controlled thyroid disorders, vitiligo, asymptomatic elevated amylase / lipase, type 1 diabetes on insulin, Grade < 2 controlled rash, and Grade < 2 electrolyte abnormalities on a stable dose of supplementation, c) Patients with other clinically stable or nonsignificant AEs from past therapy may be eligible, d) Patients who discontinued prior treatment due to a Grade > 3 irAE are excluded even if the event has resolved.5. The patient has known fibrolamellar HCC histology, sarcomatoid HCC, or mixed holangiocarcinoma and HCC.6. The patient has moderate or severe ascites.The patient has uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX™) are eligible. The patient has a history of or current hepatic encephalopathy. The patient is unable to undergo disease evaluation with a triphasic CT or MRI because of contrast allergy or other contraindication. The patient has imaging findings consistent with > 50% liver occupation by HCC tumors. The patient has untreated or incompletely treated varices with bleeding or high risk for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone EGD within 6 months of study treatment initiation do not need to repeat the procedure. The patient has a history of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs. The patient has undergone a major surgical procedure, other than for diagnosis, within 28 days prior to initiation of study treatment, or anticipates the need for a major surgical procedure during the trial. The patient has not fully recovered from surgical resection or ablation within 4 weeks prior to randomization. The patient has symptomatic or untreated brain metastases or leptomeningeal carcinomatosis. Patients previously treated for brain metastases must be > 28 days from completion of radiation treatment, with follow-up imaging showing no progression, and have no ongoing steroid requirement. The patient received a prior allogeneic hematopoietic cell transplant or solid tumor organ transplant. The patient received prior radiotherapy within 28 days or abdominal / pelvic radiotherapy within 60 days prior study treatment initiation. A 7-day washout is permitted for palliative radiation (< 2 weeks of radiotherapy) to bone lesions. The patient received prior radiotherapy and has any ongoing radiation-related toxicity, an ongoing corticosteroid requirement, or a history of radiation pneumonitis. The patient has an active or history of autoimmune disease or immune deficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemiclupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: a) Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study, b) Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study, c) Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (j.e., patients with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met: Rash must cover < 10% of body surface area. Disease is well controlled at baseline and requires only low-potency topical corticosteroids. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. The patient has medical conditions requiring chronic steroid therapy (i.e., > 10 mg / day of prednisone or its equivalent) or anticipates the need for systemic immunosuppressive medications during treatment with study drug, with the following exceptions: a) Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed, b) Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible, c) Patients who received corticosteroids for chronic obstructive pulmonary disease or asthma or low-dose corticosteroids for orthostatic hypotension are eligible. The patient has a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on Screening chest CT scan. A history of radiation pneumonitis in the radiation field (fibrosis) is permitted as long as resolved / asymptomatic. The patient has an uncontrolled infection requiring active antimicrobial treatment. The patient has active tuberculosis. The patient has received a live or live-attenuated vaccine within 4 weeks prior to the first dose of study treatment or anticipates the need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab. Administration of killed vaccines and approved COVID-19 vaccines is allowed.The patient has known active infection with HIV. The patient has known infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), except for controlled active HBV or fully treated HCV infection, which are eligible and are defined as follows: a) For patients with active HBV, controlled disease is considered HBV DNA < 500 lU / mL during the Screening Period with willingness to continue antiviral treatment during the length of the trial. The patient must be on anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to trial entry, b) For patients with HCV, only cured disease or HCV considered fully treated and no longer requiring antiviral therapy for control is permitted, c) Patients with co-infection with HCV and HBV, defined as HCV RNA positive and hepatitis B surface antigen (HBsAg) positive, are not eligible; however, patients who are HCV Ab+ and HBV core antibody positive but HBsAg- are not considered to have co-infection and are eligible. The patient has inadequately controlled arterial hypertension (defined as systolic blood pressure [BP] > 150 mmHg and / or diastolic BP > 100 mmHg). Anti-hypertensive therapy to achieve eligibility criteria is permitted. If one session’s BP reading is exclusionary, an average of 3 BP readings across 2 sessions can be used to meet eligibility. The patient has a prior history of hypertensive crisis or hypertensive encephalopathy. The patient has had significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment. The patient has had a history of hemoptysis (defined as > 2.5 mb of bright red blood per episode) within 1 month prior to initiation of study treatment. The patient shows evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anti coagulation). The patient is currently using or recently (within 10 days of first dose of study treatment) used aspirin (> 325 mg / day) or been treated with dipyridamole, ticlopidine, clopidogrel, or cilostazol. The patient is currently receiving chronic daily treatment with a nonsteroidal antiinflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed. The patient is currently using or recently (within 10 days prior to study treatment start) used full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (asopposed to prophylactic) purposes. Prophylactic anti coagulation for the patency of venous access devices is allowed provided the activity of the agent results in an international normalized ratio < 1.5 x upper limit of normal and activated partial thromboplastin time is within normal limits within 14 days prior to initiation of study treatment. For prophylactic use of anticoagulants or thrombolytic therapies, the approved dose as described by the local label may be used. The patient has had a core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab. The patient has had a history of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment. The patient has had a history of intestinal obstruction and / or clinical signs or symptoms of GI obstruction including subocclusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months prior to initiation of study treatment. Patients with signs / symptoms of subocclusive syndrome / intestinal obstruction at time of initial diagnosis may be enrolled if they have received definitive (surgical) treatment for symptom resolution. The patient shows evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure. The patient has a serious, nonhealing or dehiscing wound, active ulcer, or untreated bone fracture. The patient has metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses (< 30 mm from the carina) of large volume. Patients with vascular invasion of the portal or hepatic veins are eligible. The patient has had a history of intra-abdominal inflammatory process within 6 months prior to initiation of study treatment, including but not limited to peptic ulcer disease, diverticulitis, or colitis. The patient has had another malignancy, other than those with negligible risk of death, including but not limited to nonmelanoma skin cancer, low-risk localized or cured prostate cancer, ductal carcinoma in situ, or carcinoma in situ of the cervix, within 2 years prior to Screening.43. The patient has had a history of significant cardiovascular disease such as stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within 6 months prior to Screening.44. The patient has known New York Heart Association congestive heart failure with Grade > II.45. The patient has another unstable or severely uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition, or uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would increase the risk to the patient associated with his or her participation in the trial.

[0300] Each patient’s complete medical history is obtained, including demographics, cancer history, and documentation of all previous treatments and treatment results (i.e., best response). Disease characterization includes but is not limited to Child-Pugh score and BCLC stage.

[0301] At Screening, concomitant and previous medications and procedures are assessed including all medications / procedures that have occurred within the previous 30 days (previous 6 weeks for live attenuated vaccines). In addition, any cancer treatment procedures from any time in the past (e.g., radiation, surgical resection) are captured under prior procedures. Assessment of any change in concomitant medications or procedures since the last visit occurs at all patient visits through Safety Follow-up.

[0302] Following Screening, physical examination is symptom-directed and includes evaluation of disease-relevant systems and capture of vital signs. Patient weight is taken predose on Day 1 of each cycle to calculate the appropriate doses of the anti-IL-27 antibody / placebo and bevacizumab to be administered on that cycle. Alternatively, sites may follow their institutional practice of using the Cycle 1 Day 1 (C1D1) weight to dose throughout the study unless there is a > 5% change. While Day 1 physical examinations must be conducted in person or per institutional standards, physical examinations on all other visit days may be done by telemedicine following institutional procedures.

[0303] Eastern Cooperative Oncology Group (ECOG) Performance Status is assessed at Screening and serially during the study treatment period, as well as at the EoT Visit and 30-day Safety Follow-up Visit. A standard 12-lead electrocardiogram (ECG) is also conducted at screening, as well as an esophagogastroduodenoscopy (EGD), clinical laboratory tests (e.g., serum pregnancy test in WCBP, blood chemistry and liver function tests, hematology tests, afasting lipid panel, coagulation measurements, completely urinalysis, thyroid function tests, and Alpha Fetoprotein measurement), HIV and Hepatitis testing, and tumor evaluation with triphasic computerized tomography (CT) or Magnetic Resonance Imaging (MRI) to quantify disease burden.

[0304] Pharmacokinetic (PK) samples are collected at time points shown in Table 8. Serum samples are analyzed for the anti-IL-27 antibody and atezolizumab concentrations. An additional PK sample, beyond those listed in Table 8, should be drawn at the time of any unusual safety event (z.e., an AE different in type and severity from that which is expected in the setting of the anti-IL- 27 antibody, atezolizumab or bevacizumab use). An additional blood sample for the anti-IL-27 anti body / placebo PK and anti-drug antibody (ADA) assessments should be drawn at the time of any unusual safety event (i.e., an AE different in type and severity from that which is expected in the setting of the anti -IL-27 antibody, atezolizumab, or bevacizumab use). After cycle 4, atezolizumab PK and ADA samples should only be collected on Day 1 of Cycle 8, Cycle 12, and Cycle 16, as well as End of Treatment.Table 8. Schedule of Pharmacokinetic and Anti-Drug Antibody (ADA) Assessments: the anti-IL- 27 antibody / Placebo + Atezolizumab + Bevacizumab, Q3W Dosing

[0305] Samples are also collected for biomarker analysis to investigate the biological effects of the anti-IL-27 antibody at the molecular and cellular level, as well as to evaluate how changes in the markers and immune cell populations may relate to exposure and clinical outcomes. Blood serum are collected for EBI3 biomarker and cytokine / chemokine / soluble factor measurement. Whole blood and peripheral blood mononuclear cells (PBMCs) are collected for immunophenotyping and immune monitoring. The goal of the biomarker assessments is to provide supportive data for the clinical trial. There may be circumstances when a decision is made to stop a collection, not perform, or discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample number, sample quality issues precluding analysis, etc.).

[0306] Additional biomarker samples may be requested (when feasible) at the time of any unusual safety event (i.e. , an AE different in type and severity from that which is expected in the setting of the anti -IL-27 antibody, atezolizumab, or bevacizumab use).

[0307] A buccal swab is collected from all patients for phamiacogenomics assessment at Screening or prior to dosing at C1D1 (Table 7). This sample may be used to study how polymorphisms in germline DNA affect PK and metabolism of the anti-IL-27 antibody, as well as clinical response to the anti-IL-27 antibody. This sample may also serve as a germline DNA control to help interpret sequencing and gene copy number variation data obtained from patient tumor samples.

[0308] Hematologic toxicities attributed to the anti-IL-27 antibody may require dose hold, dose modification, or discontinuation of the anti-IL-27 antibody / Placebo. In the case of neutropenia, for Grade 3 (Absolute Neutrophil Count (ANC) < 1000 / pL; 1 x 109 / L) with a single temperature of > 38.3°C (101°F) or a sustained temperature of > 38°C (100.4 °F) for > 1 hour, the anti-IL-27 antibody / placebo dose should be held until toxicity recovers to Baseline and then resumed at a reduced dose. If Grade > 3 neutropenia recurs, the anti-IL-27 antibody / placebo should be permanently discontinued. For Grade 4 neutropenia (ANC < 500 / pL; < 0.5 x 109 / L) persisting for > 7 days, and / or complicated by infection and for Grade 4 neutropenia with life threatening consequences, the anti-IL-27 antibody / placebo should be discontinued.

[0309] The anti-IL-27 antibody / placebo should also be discontinued in the case of Grade3 low platelet count with associated clinically significant bleeding or Grade 4 with any duration of bleeding. Discontinuation of the anti-IL-27 antibody / placebo is also recommended for Grade4 anemia, any Grade 4 or recurrent Grade 3 hematologic toxicity. For non-recunent Grade 3 orintolerable or recurrent Grade 2 hematologic toxicity, the anti-IL-27 antibody / placebo treatment should be held until symptoms resolve to baseline and then resumed at a reduced dose.

[0310] Steroids may be used to manage severe (Grade > 3) hematologic toxicity if thought to be immune-related.

[0311] In some aspects, a bone marrow biopsy may be performed.

[0312] In some aspects, anti-IL-27 antibody treatment is discontinued or decreased in dose in cases of hepatotoxicity; Grade 3 or 4 electrolyte disturbance; Grade 3 or 4 gastrointestinal symptoms; Grades 2-4 pneumonitis, colitis, or nephritis; Grade 3 or 4 skin toxicity; Grade 4 infusion-related reactions (IRRs); Grade 3 or 4 endocrinopathies; other Grade 4 or recurrent Grade 3 nonhematologic toxicities; and some Grade 2 or 3 AEs that require dose reduction. Additionally, the anti-IL-27 antibody / placebo may be discontinued if there are treatment delays > 42 days because of study drug-related toxicities or if there is an inability to taper the corticosteroid dose to < 10 mg per day of prednisone or its equivalent for > 42 days after the last dose of the anti-IL- 27 antibody / placebo.

[0313] In the case of infusion related reactions (IRRs) of any grade / severity, the anti-IL-27 antibody / placebo infusion may be interrupted to manage symptoms. Management of IRRs may require reduction in the rate of infusion, or treatment discontinuation of the anti-IL-27 antibody / placebo. For Grade 1 to 2 (mild or moderate) reactions, once reaction symptoms resolve, the infusion may be resumed at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 100 mL / hour. For Grade 3 (severe) reactions, once reaction symptoms resolve, the infusion may be restarted at no more than half the rate at which the reaction occurred and the anti-IL-27 antibody / placebo should be permanently discontinued upon the second occurrence of a Grade > 3 IRR. For Grade 4 (life threatening) reactions, the anti-IL-27 antibody / placebo may be permanently discontinued.

[0314] For any patient who has a Grade > 2 IRR with the anti-IL-27 antibody / placebo, steroidal premedication may be used for all subsequent infusions.

[0315] The dose of the anti-IL-27 antibody / placebo may be reduced from the initial dose of 10 mg / kg to 7.5 mg / kg. Any patient who requires > 1 dose-level reduction or requires holding of the anti-IL-27 antibody / placebo for > 42 days may be discontinued from the anti-IL-27 antibody / placebo. Patients who have a dose reduction because of a toxicity may not re-escalate the dose.

[0316] Atezolizumab is administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21 -day cycle. Bevacizumab is administered by IV infusion at a fixed dose of 15 mg / kg on Day 1 of each 21 -day cycle.

[0317] An ADA assay for the anti-IL-27 antibody / placebo is performed at a central laboratory for immunogenicity testing. The time points for the collection of this assessment are detailed in Table 8. An additional ADA sample may be requested at the time of any unusual safety event (i.e., an AE different in type and severity from that which is expected in the setting of the anti-IL-27 antibody, atezolizumab, or bevacizumab use). Patients who test positive for the anti- IL-27 antibody or atezolizumab ADA are tested throughout the study or until the EoT visit.

[0318] At a minimum, assessments include a triphasic CT or MRI scan of chest, abdomen, and pelvis. Other scans may be performed (e.g., brain MRI) if clinically indicated or if the area is a site of known disease. The MRI may be substituted if clinically indicated, but the modality chosen to evaluate each site of disease for an individual patient may be the same throughout the duration of the study. Imaging is also performed at the end of treatment if the patient is discontinued for reasons other than disease progression and a previous assessment has not been performed within 30 days.

[0319] For patients who experience an objective response or who progress on therapy and continue treatment past progression, confirmatory scans may be done a minimum of 4 weeks and a maximum of 9 weeks later.

[0320] Local assessment of objective response is evaluated using RECIST vl.l and mRECIST, as well as clinical decision making. These evaluations are conducted on treatment or following treatment discontinuation until the patient experiences PD or discontinues the study.

[0321] Note that pseudoprogression or delayed response may occur in patients treated with immune -modulating agents such as the anti-IL-27 antibody and atezolizumab, and therefore patients may continue on treatment past progression.

[0322] Patients may continue on treatment past radiologic progression if the following criteria are met: absence of symptoms and signs indicating clinically significant progression of disease, no decline in ECOG performance status from study entry, and absence of symptomatic rapid disease progression requiring urgent medical intervention.

[0323] Herbal therapies are cautionary therapies and are not recommended because their PK profiles, safety profiles, and drug-drug-interaction potential are generally unknown. However, herbal therapies not intended for the treatment of cancer may be used.

[0324] Additionally, systemic corticosteroids and TNFa inhibitors may attenuate potentially beneficial immunologic effects of atezolizumab. Therefore, in situations in which systemic corticosteroids or TNFa inhibitors would be routinely administered, alternatives (e.g., antihistamines) may be considered. If the alternatives are not feasible, systemic corticosteroids and TNFa inhibitors may be administered.

[0325] Radiation therapy to a symptomatic or progressing solitary lesion including the brain may be performed.

[0326] Objectives and Endpoints

[0327] The primary objective of the trial is the efficacy of the anti-IL-27 antibody in combination with atezolizumab + bevacizumab compared to placebo in combination with atezolizumab + bevacizumab as measured by progression-free survival (PFS). The primary efficacy endpoint of the trial is PFS, defined as time from randomization to occurrence of progressive disease (PD) or death from any cause (whichever occurs first), as determined by Investigator review according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST vl.l).

[0328] A secondary efficacy objective is additional measures of efficacy of the anti-IL-27 antibody in combination with atezolizumab + bevacizumab compared to placebo in combination with atezolizumab + bevacizumab. The endpoints for this objective are PFS, defined as time from randomization to occurrence of PD or death from any cause (whichever occurs first) according to HCC modified RECIST (mRECIST); objective response rate (ORR) as determined by Investigator review according to RECIST vl.l or HCC mRECIST; duration of response (DoR), defined as time from initial documented objective response to PD or death from any cause (whichever occurs first), as determined by Investigator review according to RECIST v 1.1 or HCC mRECIST; disease control rate (DCR), defined as the proportion of patients who experience best overall response of complete response (CR), partial response (PR), or stable disease (SD); time to progression (TTP), defined as time from randomization to occurrence of disease progression, as determined by Investigator review according to RECIST vl .1 or HCC mRECIST; overall survival (OS), defined as time from randomization to death from any cause; time to response, defined as time from randomization to initial documented objective response, as determined by Investigator review according to RECIST vl. l or HCC mRECIST; and time on therapy, defined as time from randomization to last treatment.

[0329] Another secondary efficacy objective is efficacy of the anti -IL-27 antibody in combination with atezolizumab + bevacizumab compared to placebo in combination with atezolizumab + bevacizumab according to serum Epstein-Barr vims induced gene 3 (EBI3) levels. The endpoints for this objective are PFS, ORR, TTP, and OS by serum EBI3 concentrations.

[0330] The safety objective is safety and tolerability of the anti-IL-27 antibody in combination with atezolizumab + bevacizumab compared to placebo in combination with atezolizumab + bevacizumab. The safety endpoints are determined by the nature, frequency, and severity of AEs per NCI-CTCAE version 5.0 or higher and the timing of AEs.

[0331] The immunogenicity objectives are to characterize the immunogenicity of the anti- IL-27 antibody and atezolizumab and to explore potential correlations between immunogenicity and efficacy, safety, and pharmacokinetic (PK) outcomes. The immunogenicity endpoints are the incidence of the anti-IL-27 antibody anti-drug antibodies (ADAs), incidence of atezolizumab ADAs, and the efficacy, safety, and PK endpoints.

[0332] The pharmacokinetic objectives are to characterize the PK profile of the anti -IL-27 antibody when given in combination with atezolizumab + bevacizumab and to explore the potential PK impact from drug interaction. The pharmacokinetic endpoints are determined by serum concentrations of the anti-IL-27 antibody and serum concentrations of atezolizumab.

[0333] The exploratory biomarker objectives are to identify and evaluate potential blood or tissue biomarkers of response, resistance, and / or safety and to evaluate the effects of the anti- IL-27 antibody in combination with atezolizumab + bevacizumab on peripheral blood immune cell subsets and circulating cytokines and chemokines. One exploratory biomarker endpoint is an assessment of selected blood-based and tumor tissue biomarkers, which may include cytokines, immune cell population subset enumeration and evaluation, programmed death-ligand 1 (PD-L1) expression, gene and protein expression levels, DNA mutation and copy number variations, and correlation of Baseline levels and changes in these markers with clinical outcomes (e.g., PFS, ORR). A second exploratory biomarker endpoint is determined by changes in peripheral blood immune cell populations by flow cytometry and gene expression.EXAMPLES

[0334] While the present disclosure has been described with reference to the specific aspects thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of thedisclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the disclosure.Example 1: In vitro Administration of Casdozokitug in Combination with Anti-PD-1 Antibodies

[0335] Fresh human peripheral blood mononuclear cells (PBMCs) were activated with 0.25 pg / mL anti-CD3 antibody in the presence of IgG4 isoty pe (1 pg / mL), toripalimab (1 pg / mL), casdozokitug (10 pg / mL), or toripalimab (1 pg / mL) and casdozokitug (10 pg / mL). Supernatants collected on day 5 were quantified for concentrations of IFNy and TNF by ELISA profiling. Casdozokitug increased production of TNFa and IFNy from activated PBMCs from healthy donors and patients with cancer. When casdozokitug was tested in combination with an anti-PD- 1 antibody, the combination treatment led to a significantly higher concentration of TNFa and IFNy production (FIG. 10, panel A) compared with either antibody treatment alone. In addition, casdozokitug in combination with toripalimab demonstrated a similar upregulation of these inflammatory cytokines in activated healthy human PBMCs (FIG. 10, panel B). Furthermore, casdozokitug significantly downregulated the levels of IL-27-induced inhibitory receptor expression by immune cells such as PD-L1, TIM-3, CD161, and C-C chemokine receptor type 6 (CCR6). Downregulation of PD-L1 on CD8+ cells is shown in FIG. 10, panel C. In vivo, casdozokitug blocked murine IL-27 signaling and demonstrated antitumor activity in mouse models of HCC and lung metastases.Example 2: Pharmacokinetic modeling supports a novel dosing regimen for toripalimab

[0336] The population pharmacokinetic (PK) model of toripalimab was utilized to simulatePK parameters in individual patients. The database included a total of 1,554 participants with 12,464 PK observations. For each participant, area under the serum concentration time curve over the dosing interval (AUC o- , average serum concentration time curve over dosing interval (Cave), maximum serum concentration (Cmax), and trough semm concentration (Cuough) were simulated at early treatment (weeks 1-12) and at steady state (weeks 25 to 36) for 240 mg Q3W, 340 mg Q4W, 480 mg Q6W, and 480 mg Q2W (Table 9). Values are reported as geometric mean in pg / mL (%CV) [minimum, maximum], 1 indicates early treatment cycle (weeks 1 to 12) and ss indicates steady state (weeks 25-36).Table 9: Toripalimab population PK model parameters for Q2W, QW, Q4W, and Q6W

[0337] At steady state, the Cavg(FIG. 11 A) or AUCo-c(FIG. 11 B) for the 340 mg Q4W dose is predicted to be similar (~6% higher) to that of 240 mg Q3 W dose. Additionally, the mean Ctrough for 340 mg Q4W is predicted to be lower than 240 mg Q3W by 28.4% and 23.7% for early treatment and steady state, respectively (FIG. 11C). However, for majority of the participants (99.7%), the Ctrough at steady state for 340 mg Q4W was within the reference range of 240 mg Q3W. The maximum serum concentration at steady state (Cmax ss) for 340 mg Q4W (155 pg / mL) (FIG. 11 D) is well below the Cmax ss for the 480 mg Q2W dosing (simulated value: 287 pg / mL; clinical value: 303 pg / mL), a clinically administered dose that has shown a similar safety profile as the regulatory approved 240 mg Q3W dose. Thus, a toripalimab dosing regimen of 340 mg Q4W is included in the methods of the disclosure.Example 3: In vivo Administration of Casdozokitug in Combination with Toripalimab Plus Bevacizumab

[0338] A Phase 2, open-label, randomized clinical trial (CHS388-202) is conducted to evaluate the preliminary efficacy, safety, and tolerability of casdozokitug in combination with toripalimab + bevacizumab and to define the recommended dose for the triplet combination in participants with first-line unresectable and / or locally advanced or metastatic HCC. Up to 72 participants are randomized to 1 of 3 treatment arms in a 1: 1:1 ratio:• Arm A: casdozokitug 700 mg + toripalimab 240 mg + bevacizumab 15 mg / kg IV Q3W on Day 1 of a 21 -day cycle (n ~ 24).• Arm B: casdozokitug 1400 mg + toripalimab 240 mg + bevacizumab 15 mg / kg IV Q3W on Day 1 of a 21 -day cycle (n ~ 24).• Arm C: toripalimab 240 mg + bevacizumab 15 mg / kg IV Q3W on Day 1 of a 21 -day cycle (n ~ 24).Participants are also stratified by two baseline factors:• Geographic region: Asia, excluding Japan, versus the rest of the world.• Macrovascular invasion or extrahepatic spread of disease (presence vs. absence).

[0339] The study design is presented in FIG. 12.

[0340] For the triplet combination, i.e., Ann A and Arm B, casdozokitug is administered first. After a 30-minute observation period, toripalimab 240 mg IV followed by bevacizumab 15 mg / kg IV is then administered.

[0341] Safety Run-in evaluation is conducted after the first approximately 6 participants have enrolled in Ann A (casdozokitug [700 mg] + toripalimab 240 mg + bevacizumab 15 mg / kg IV Q3W) and Arm B (casdozokitug [1400 mg] + toripalimab 240 mg + bevacizumab 15 mg / kg IV Q3W) and at least 3 participants each in Arm A and Arm B have completed the first cycle of treatment. If < 2 of 3 participants in each arm of the Safety Run-in experiences a DLT, enrollment continues with an additional 3 participants to confirm a DLT rate < 33%. If the DLT rate is > 33% in 6 participants in each arm, the study is paused for safety review. If > 2 of these 3 participants within a treatment arm experiences a DLT, the study is paused for safety review.

[0342] Evaluation of safety with the initial 6 participants (3 each in Arm A and Arm B) is conducted based on the following criteria used for DLT evaluation in the casdozokitug Phase 1 dose escalation study (CHS388-101). Participants may have received at least 50% of theprescribed doses of casdozokitug, toripalimab, and bevacizumab and not discontinued from study treatment in the first 21 days (Cycle 1) for reasons other than drug- related AEs.

[0343] The occurrence of any of the following hematologic toxicities during the first 21- day cycle is considered a DLT in the triplet combination regimen if assessed to be related to study treatment administration.1. Grade 5 toxicity2. Grade 4 neutrophil count decreased (absolute neutrophil count [ANC] < 0.5 x 109 / L) persisting for > 7 days and / or complicated by infection.3. Grade >3 febrile neutropenia. a. Grade 3 is defined as ANC < 1000 / mm3with a single temperature of > 38.3°C (101°F) or a sustained temperature of > 38°C (100.4°F) for more than 1 hour. b. Grade 4 is defined as life-threatening consequences; urgent intervention indicated.4. Grade > 3 Platelet count decreased. a. Grade 3 is defined as platelets < 25,000 to 50,000 / mm3(< 25.0 to 50.0 x 109 / L) with associated clinically significant bleeding. b. Grade 4 is defined as platelets < 25,000 / mm3(< 25.0 x 109 / L) for any duration.5. Grade 4 anemia is defined as life-threatening consequences; urgent intervention indicated (any duration).6. Any nonhematologic AE Grade > 3 during the first 21 -day cycle will be considered a DLT except the following: a. Grade > 3 event of nausea, vomiting, or diarrhea responding to supportive treatment within 3 days b. Grade > 3 fatigue lasting < 7 days c. Grade > 3 rash recovering to Grade 1 with treatment (e.g.. steroids) within 7 days d. Any Grade >3 thyroid function abnormality (i.e.. hypo- or hyperthyroidism) lasting any duration if controlled with treatment such as thyroid supplementation or beta blockers e. Any Grade > 3 amylase / lipase elevation if asymptomatic and / or no clinical signs of pancreatitis f. Isolated Grade 3 laboratory abnormalities that are not associated with clinical sequelae and are corrected with supplementation or appropriate management within 72 hours of onsetg. Grade 3 infusion related reaction (IRR), allergic reactions, or anaphylaxis will not be considered DLTs but may lead to discontinuation.7. Confirmed drug -induced liver injury meeting Hy’s Law (concomitant ALT / AST > 3 x upper limit of normal (ULN) with bilirubin > 2 x ULN without an alternative cause (e.g., cholestasis).For participants with Grade 2 hepatic transaminase at baseline as a result of HCC, a hepatic transaminase level > 10 x ULN will be used for this criterion.8. Concomitant ALT / AST > 10 x ULN with clinical jaundice regardless of duration or ALT / AST 8 to 10 x ULN that persists for > 3 weeks.9. A treatment delay of > 14 days will be considered a DLT.

[0344] An End of Treatment (EoT) visit is conducted within 7 days after the last dose of study treatment. FIG. 13 provides the assessments to be completed at the EoT visit.

[0345] A Safety Follow-up (SFU) visit is conducted 30 (+ 5) days after the last dose of study drug (casdozokitug, toripalimab, or bevacizumab, whichever is later). FIG. 13 provides the assessments to be completed at the SFU visit.

[0346] A Long-Term Follow-up (LTFU) visit is conducted 90 (+ 5) days after the last dose of study drug (casdozokitug, toripalimab, or bevacizumab, whichever is later). FIG. 13 provides the assessments to be completed at the LTFU visit.

[0347] Survival Follow-up visits are conducted every 6 months (± 4 weeks). FIG. 13 provides the assessments to be completed at Survival Follow-up visits. This assessment may be conducted by telephone interview or medical chart review. Information on initiation of other anticancer therapy (including start date, therapy type, and response on treatment) will also be collected.Inclusion Criteria

[0348] All participants must meet the following criteria for inclusion in this study.1. Male or female > 18 years of age on day of signing informed consent.2. Unresectable locally advanced or metastatic HCC with diagnosis confirmed by histology / cytology or clinically by American Association for the Study of Liver Diseases criteria in cirrhotic participants.• Note: Participants without cirrhosis require histological confirmation of diagnosis.3. Disease that is not amenable to curative surgical and / or locoregional therapies or PD aftersurgical and / or locoregional therapies.Participants who received prior locoregional therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, trans-arterial embolization including chemo- and radio-embolization) are eligible, provided the target lesion(s) within the field of local therapy have subsequently progressed per RECIST vl.l. > 1 measurable lesion (per RECIST vl.l) that is untreated. An ECOG performance status of 0 or 1. Participant has laboratory values indicative of adequate organ function. a. HematologicalAbsolute neutrophil count: > 1500 / pL (1.5 x 109 / L)Absolute lymphocyte count: > 500 / pL (0.5 x 109 / L)Platelets: > 75,000 / pL (> 75 x 109 / L) without platelet transfusionHemoglobin: > 9.0 g / dL (without packed red blood cell transfusion within the prior 2 weeks; participants can be on a stable dose of erythropoietin [> approximately 3 months]). b. RenalCreatinine OR creatinine clearance (CrCl) (glomerular filtration rate can be used in place of creatinine or CrCl): < 1.5 x upper limit of normal (ULN) OR > 50 mL / min for participants with creatinine levels > 1.5 x institutional ULN. CrCl should be calculated using the Cockcroft-Gault formula:(140-age [years] x weight [kg]) / serum creatinine (mg / dL) x 72 Urinalysis for proteinuria: < 2+ (within 7 days prior to initiation of study treatment). If > 2+ proteinuria at Baseline, participant should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours. c. HepaticTotal bilirubin: < 3 x ULNAST (SGOT) and ALT (SGPT): < 5 x ULNAlkaline phosphatase: < 5 x ULNSerum albumin: > 2.8 g / dL (> 28 g / L) d. CoagulationInternational normalized ratio (INR) or prothrombin time: < 2 x ULN unless noparticipant is receiving anticoagulant therapy. For participants receiving anticoagulant therapy activated partial thromboplastin time or INR should be within the therapeutic range of anticoagulants e. EndocrineCalcium: ionized calcium < 1.5 mmol / L or calcium < 12 mg / dL, and corrected serum calcium < ULN Child-Pugh Class A Documented serology test for hepatitis by HBsAg, antibody to hepatitis B core antigen (anti-HBc Ab), and antibody to hepatitis C virus (anti-HCV Ab). Participants with active hepatitis B virus (HBV) infection characterized by positive HBsAg, detectable HBV DNA, and / or positive anti-HBc Ab are eligible if they have received antiviral therapy for at least 2 weeks and have controlled disease status defined by HBV DNA < 1000 lU / mL within 28 days prior to study treatment.Note: Participants should remain on antiviral treatment throughout study treatment and follow local guidance for HBV antiviral therapy post completion of study treatment for the length of the study. For women of childbearing potential (WCBP): negative urine P human chorionic gonadotropin ( hCG) pregnancy test within 7 days prior to the first dose of study treatment.• Note: WCBP defined as sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for > 12 consecutive months without an alternative medical cause. WCBP must be willing to refrain from heterosexual intercourse or use acceptable methods of birth control while they are receiving study treatment and for 6 months after the last dose of study treatment. WCBP who are continuously not heterosexually active are exempt from contraceptive requirements; however, female participants must still undergo pregnancy testing as described in the Schedule of Assessments (FIG. 13). Male participants must be willing to refrain from heterosexual intercourse with a partner of childbearing potential or a pregnant partner or use acceptable methods of birth control while they are receiving study treatment and for 6 months after the last dose of any study drug to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Azoospermic male participants are exempt from contraceptiverequirements.13. Has the ability to adhere to the study visit schedule and all protocol requirements.14. Has provided signed and dated institutional review board / independent ethics committee- approved informed consent form before any screening procedures are performed.15. A baseline tumor tissue sample is mandatory. An archival tumor tissue sample (block or 10-15 slides with associated pathology report) is acceptable. If archival tumor tissue is not available, a baseline fresh biopsy sample (up to 3 core needle samples) will be required, avoiding measurable target or irradiated lesions.• Note: Archival tissue samples collected within 2 years of screening are acceptable.Exclusion Criteria

[0349] Participants who meet any of the following criteria are not eligible to participate in this study.1. Has received prior systemic therapy for HCC.2. Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the initiation of study treatment.3. Has previously received an anti-IL-27 antibody (Ab) or anti-IL-27-targeted therapy.4. Has known fibrolamellar HCC histology, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.5. Has moderate or severe ascites.6. Has uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).• Note: Participants with indwelling catheters (e.g., PleurX™) are eligible.7. Has a history of or current hepatic encephalopathy.8. Unable to undergo disease evaluation with a triphasic computed tomography (CT) or multiple resonance imaging (MRI) because of contrast allergy or other contraindication.9. Has untreated or incompletely treated varices with bleeding or high risk for bleeding.• Note: Participants must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Participants who have undergone EGD within 6 monthsof the initiation of the first dose of study treatment do not need to repeat the procedure unless clinically indicated. History of Grade 4 allergic or anaphylactic reaction to any mAb therapy or any excipient in the study drugs. Has undergone a major surgical procedure, other than for diagnosis, within 28 days prior to initiation of study treatment, or anticipates the need for a major surgical procedure during the study. Locoregional therapy to HCC within 28 days prior to initiation of study treatment or nonrecovery from complications due to the procedure (radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity, focused ultrasound, trans -arterial embolization including chemo- and radio-embolization). Symptomatic or untreated brain metastases or leptomeningeal carcinomatosis.• Note: Participants previously treated for brain metastases must be > 28 days from completion of radiation treatment, with follow-up imaging showing no progression, and have no ongoing steroid requirement for central nervous system (CNS) disease. Stable dose of anticonvulsant therapy for CNS disease is allowed. Has received a prior allogeneic hematopoietic cell transplant or solid tumor organ transplant. Has received prior radiotherapy within 28 days or abdominal / pelvic radiotherapy within 60 days prior study treatment initiation.• Note: A 7-day washout is permitted for palliative radiation (< 2 weeks of radiotherapy) to bone lesions. Has any ongoing radiation-related toxicity or an ongoing corticosteroid requirement due to radiation. Active or history of autoimmune disease or immune deficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: a. Participants with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.b. Participants with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. c. Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met:• Rash must cover < 10% of body surface area.• Disease is well controlled at baseline and requires only low-potency topical corticosteroids.• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. Has medical conditions requiring chronic steroid therapy (ie, > 10 mg / day of prednisone or its equivalent) or anticipates the need for systemic immunosuppressive medications during treatment with study drug, with the following exceptions: a. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed. b. Participants who received acute, low-dose systemic immunosuppressant medication or a 1-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible. c. Participants who received corticosteroids for chronic obstructive pulmonary disease or asthma or low-dose corticosteroids for orthostatic hypotension are eligible. Baseline QT interval corrected with Frederica’s formula (QTcF) 480 ms.Note: If participant has 1 elevated QTcF reading, the screening requirement can be met with the average of triplicate ECGs. Criterion does not apply to participants with right or left bundle branch block. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, interstitial pneumonitis, or evidence of active pneumonitis on screening chest CT scan. Has an uncontrolled infection requiring active antimicrobial treatment. Has active tuberculosis. Has received a live or live-attenuated vaccine within 4 weeks prior to the first dose ofstudy treatment or anticipates the need for such a vaccine during toripalimab treatment or within 5 months after the last dose of toripalimab. History of HIV infection. Co-infection with hepatitis C virus (HCV) and HBV.Note: Participants with history of HCV infection but who are negative for HCV RNA by polymerase chain reaction (PCR) will be considered noninfected with HCV. Has inadequately controlled arterial hypertension (defined as systolic blood pressure [BP] > 150 mmHg and / or diastolic BP > 100 mmHg).• Note: Antihypertensive therapy to achieve eligibility criteria is permitted. If the BP reading from 1 session is exclusionary, an average of 3 BP readings across 2 sessions can be used to meet eligibility. Prior history of hypertensive crisis or hypertensive encephalopathy. Has had significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment. History of hemoptysis (defined as > 2.5 mL of bright red blood per episode) within 1 month prior to initiation of study treatment. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). Current or recent (within 10 days of first dose of study treatment) use of aspirin (> 325 mg / day) or treatment with dipyridamole, ticlopidine, clopidogrel, or cilostazol. Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID) with the exception of chronic low-dose aspirin (< 325 mg / day). Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purposes. Has had a core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab. History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment. History of intestinal obstruction and / or clinical signs or symptoms of GI obstruction including subocclusive disease related to the underlying disease or requirement forroutine parenteral hydration, parenteral nutrition, or tube feeding within 6 months prior to initiation of study treatment.• Note: Participants with signs / symptoms of subocclusive syndrome / intestinal obstruction at time of initial diagnosis may be enrolled if they have received definitive (surgical) treatment for symptom resolution.37. Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure.38. Has a serious, nonhealing or dehiscing wound, active ulcer, or untreated bone fracture.39. Has metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses (< 30 mm from the carina) of large volume.• Note: Participants with vascular invasion of the portal or hepatic veins are eligible.40. History of intra-abdominal inflammatory event within 6 months prior to initiation of study treatment, including but not limited to peptic ulcer disease, diverticulitis, or colitis.41 . Has had another malignancy, other than those with negligible risk of death, including but not limited to nonmelanoma skin cancer, low risk localized or cured prostate cancer, ductal carcinoma in situ, or carcinoma in situ of the cervix, within 2 years prior to screening.42. History of significant cardiovascular disease such as stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within 6 months prior to screening.43. Has known New York Heart Association congestive heart failure Grade > II.44. Has another unstable or severely uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator’s judgment, increase the risk to the participant associated with his or her participation in the study.

[0350] Patient Screening

[0351] A full physical examination is performed at screening and includes vital signs (temperature, BP [sitting for 5 minutes], pulse rate, and respiratory rate), height, and weight, as well as a systematic physical examination; this constitutes the Baseline examination.

[0352] Following screening, physical examination is symptom-directed and includes evaluation of disease-relevant systems and capture of vital signs. Participant weight is taken predose on Day 1 of each cycle to calculate the appropriate dose of bevacizumab to be administered on that cycle. Alternatively, sites may follow their institutional practice of using the CID 1 weight to dose throughout the study unless there is a > 5% change.

[0353] Results from the symptom-directed physical examinations are used for assessment of disease response. Any new clinically-significant abnormality from Baseline should be recorded as an AE. If the physical examination at screening is performed within 7 days of the first dose (C1D1), the screening assessment may be used and does not need to be repeated. The symptom- directed physical examination may be done within a 48-hour window prior to dosing in all subsequent cycles.

[0354] Vitals signs may be recorded at the end of infusion and 60 (± 15) minutes after infusion of toripalimab; if clinically indicated, or if the participant experienced symptoms during previous infusions, vital signs may be recorded during toripalimab infusion. Vital signs may be recorded 2 (± 1) hours after the infusion of bevacizumab. If the participant experienced an IRR with any previous bevacizumab infusion, vital signs may be recorded 60 minutes prior to the infusion, at the end of the infusion, and 2 (± 1) hours after the infusion of bevacizumab.

[0355] At screening, a standard 12-lead ECG is conducted to determine a baseline following an approximately 10-minute rest period. QTc measurements will use QTcF. During screening, 1 individual tracing will be collected. If there is 1 elevated QTc reading, the screening requirement may be met with the average of triplicate ECGs; triplicate ECGs are taken 5 minutes apart.

[0356] At screening, participants undergo an EGD, and all size of varices (small to large) are assessed and treated per local standard of care prior to enrollment.

[0357] ECOG performance status is assessed at screening and serially during the study treatment period, as well as at the EoT Visit and 30-day SFU Visit. If the ECOG performance status assessed at screening is performed within 7 days of the first dose (C1D1), the screening assessment can be used and does not need to be repeated. The ECOG performance status assessment should be done within a 48-hour window prior to dosing in all subsequent cycles.

[0358] At screening, concomitant and previous medications and procedures are assessed including all medications / procedures that have occurred within the previous 28 days (previous 30 days for live attenuated vaccines). In addition, any cancer treatment procedures from any time inthe past (e.g., radiation, surgical resection) should be captured under prior procedures. Assessment of any change in concomitant medications or procedures since the last visit will occur at all participant visits through SFU.

[0359] Monitoring and recording of AEs is conducted throughout the study. AEs are captured once the ICF has been signed until 30 days after the final dose of study treatment (casdozokitug, toripalimab, or bevacizumab, whichever is later). An AE is followed until it is either resolved, has returned to baseline, or is determined to be a stable or chronic condition.

[0360] Antibody Administration and Safety Assessments

[0361] Casdozokitug is administered as an IV infusion. Casdozokitug drug product is a sterile filtered liquid, aseptically filled into a single-use stoppered glass vial and sealed with a flip- off seal should be stored frozen (below -15 °C [5 °F]) or refrigerated at 2 to 8 °C (36 to 46 °F) and protected from light. The drug product contains at least 2.0 mL at a target concentration of 50 mg / mL (nominal dose of 100 mg) in 20 mM histidine, 8% sucrose, 0.02% polysorbate 80, pH 5.5 for IV infusion. The drug product is diluted in normal saline (0.9%, Sodium Chloride for Injection, United States Pharmacopeia) as diluent prior to IV infusion.

[0362] Participants receive 240 mg toripalimab by IV infusion on Day 1 of each 21 -day cycle in a monitored setting where there is immediate access to trained personnel and adequate equipment / medicine to manage potentially serious reactions. Toripalimab is administered in 100- mL 0.9% NaCl infusion bags at the dose of 240 mg as an IV over 60 (± 15) minutes followed by a 60-minute observation period (only required in the first 2 cycles). If no clinically significant infusion reactions are observed during or after the first 2 cycles, toripalimab will be administered as a 30-minute IV infusion (± 10 minutes is permitted). Toripalimab is given on the first day of each cycle.

[0363] Bevacizumab drag product may be supplied as a sterile liquid in single -use 100-mg and 400-mg preservative-free glass vials to deliver 4 mL or 16 mL of bevacizumab (25 mg / mL). Bevacizumab is administered by IV infusion at a fixed dose of 15 mg / kg on Day 1 of each 21 -day cycle.

[0364] Participants are monitored continuously for toxicity while on study drag. Toxicity severity is assessed using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CRCAE) Version 5.0 or higher. For any toxicity between cycles, the next cycle administration may be delayed due to persisting toxicity when a new cycle is due to start. Only for non-immune related adverse events (irAEs) and AEs, including infusion related reaction (IRR)and cytokine release syndrome, dose reduction for casdozokitug (Arm B) may be required in a subsequent cycle based on toxicity experienced in the previous cycle.

[0365] Participants experiencing Grade 3 or 4 toxicity or intolerable Grade 2 toxicity despite supportive care may have their treatment interrupted. Treatment is discontinued for any AE, recurring AE, laboratory abnormality, or intercurrent illness which, in the Investigator’s clinical judgement, presents a substantial risk to the participant with continued study treatment. If any AE that led to the treatment interruption recovers within the same cycle, then dosing is allowed to continue in the cycle. Doses omitted for toxicity are not replaced within the same cycle. If scheduled dosing coincides with a holiday that precludes dosing, dosing may commence on the nearest following date.

[0366] Reduction in the dose of casdozokitug due to toxicity follows the criteria described in Table 10. Dose reduction is applicable to participants treated with casdozokitug 1400 mg (Arm B).Table 10: Dose Reduction of Casdozokitug

[0367] Hematologic toxicities that are not clearly related to disease progression, intercurrent illness, or concomitant medications are managed according to the guidelines in Table 11.Table 11: Hematologic Toxicities Attributed to Casdozokitug Lading to Dose Hold, Dose Modification, or Discontinuation

[0368] Steroids may be used to manage severe (Grade > 3) hematologic toxicity if thought to be immune -related.

[0369] Nonhematologic toxicities that occur during treatment with casdozokitug that are not clearly related to disease progression, intercurrent illness, or concomitant medications, are managed according to the guidelines in Table 12.Table 12: Nonhematologic Toxicities Leading to Dose Hold, Modification, or Discontinuation of CasdozokitugAbbreviations: AE = adverse event; ALT = alanine aminotransferase: AST = aspartate aminotransferase; IRR = infusion-related reaction; ULN = upper limit of normal.aOther than laboratory abnormalities that Investigator deems clinically insignificant and that last < 48 hours.

[0370] For IRRs of any grade / severity, infusion of casdozokitug may be interrupted and the symptoms managed. Management of IRRs may require a reduction in the rate of infusion or treatment discontinuation of casdozokitug as outlined below:• Grade 1 or 2 (mild or moderate): Once reaction symptoms resolve, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at increments and intervals as clinically appropriate up to the maximum rate of 100 mL / hour.• Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more than half the rate at which the reaction occurred. Permanently discontinue casdozokitug upon the second occurrence of a Grade > 3 IRR.• Grade 4 (life threatening): Permanently discontinue casdozokitug.

[0371] No dose reductions of casdozokitug for unresolved IRRs are recommended. For any participant who has a Grade > 2 IRR with casdozokitug, steroidal premedication may be used for all subsequent infusions.

[0372] Discontinuation of toripalimab may not have an immediate therapeutic effect and, in severe cases, immune -mediated toxicides may require acute management with IVcorticosteroids, and / or mycophenolate, or TNFa inhibitors. Toripalimab is permanently discontinued in participants with life-threatening immune -mediated AEs. Recommended dose modifications for toripalimab are provided in Table 13.Table 13: Recommended Dose Modifications for Toripalimab Adverse ReactionsAbbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; DRESS = drug rash with eosinophilia and systemic symptoms; SJS = Stevens Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normalaNational Cancer Institute Common Terminology for Adverse Events Version 5.0bResume toripalimab in participants with resolution to Grade 0 or Grade 1 after corticosteroid taper or stable on hormone replacement therapy. Permanently discontinue if the adverse reaction does not resolve to Grade 0 or Grade 1 within 12 weeks of initiating steroids or inability reduce prednisone to equal or less than 10 mg per day (or equivalent) within 12 weeks.

[0373] Guidelines for dose modification of bevacizumab for the medical management of IRRs are provided in Table 14.Table 14: Management Guidelines for Adverse Events Associated with BevacizumabAbbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRS = cytokine release syndrome; GI = gastrointestinal; IRR = infusion-related reaction; IV = intravenous(ly); LFT = liver function test; MR1 = magnetic resonance imaging; TSH = thyroid stimulating hormone; UA = urinalysis; ULN = upper limit of normal.3Resumption of treatment may be considered if the Investigator believes the participant is likely to derive clinical benefit and the Medical Monitor is in agreement.bInstitutional protocols acceptable.

[0374] Efficacy and Biomarker Assessments

[0375] Disease response assessments employing CT or MRI scans are performed at screening and every 9 weeks (± 7 days) after C1D1 and thereafter for the duration of the study or until disease progression, participant withdrawal, or initiation of additional anticancer therapy, and may include imaging consistent with anatomic areas and modality used at screening.Additional disease assessments such as focused physical examinations and AFP monitoring are also performed.

[0376] RECIST vl.l and HCC mRECIST are applied at the time points specified in FIG. 13. RECIST vl.l is the primary method of outcomes assessment. HCC mRECIST outcomes are secondary.

[0377] Assessments include a liver CT or MRI (optimized for precontrast, arterial, and portal venous phase [e.g., triphasic or other institutional HCC protocol adequate for HCC mRECIST evaluation]) and contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. Other scans may be performed (e.g., brain MRI, bone scan) if clinically indicated or if the area is a site of known disease. Imaging is also performed at the end of treatment if the participant is discontinued for reasons other than disease progression and a previous assessment has not been performed within 30 days.

[0378] Local assessment of objective response is evaluated using RECIST vl. l and HCC mRECIST, as well as clinical decision making.

[0379] PK sample collection timepoints are shown in FIG. 12. Serum samples are analyzed for casdozokitug and toripalimab concentrations. The date and time of each sample collection and the date and time of the prior study drug dose are recorded for all collected samples. An additional PK sample may be drawn at the time of any unusual safety event (i.e., an AE different in type and severity from that which is expected in the setting of casdozokitug, toripalimab, or bevacizumab use).

[0380] Samples are collected for biomarker analysis to investigate the biological effects of casdozokitug in combination with toripalimab and bevacizumab at the cellular, proteomic, genomic, and metabolic level, as well as to evaluate how changes in the markers and immune cell populations may relate to exposure and clinical outcomes. The exploratory biomarker objectives of this study are to identify biomarkers associated with immuno-oncology study drug by assessing tumor tissue and blood, including, but not limited to, DNA, RNA, enzymes, growth factors, cytokines, antibodies, and immune cells. Evaluation of baseline levels and / or changes with study drug may be performed to determine association with treatment and / or clinical outcomes, including clinical response and resistance, as well as study drug tolerability. There may be circumstances when a decision is made to stop a collection, not perform, or discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample number, sample quality issues precluding analysis). The timing of collection of these assessments is outlined in FIGs. 13 and 14.Additional biomarker samples may be requested (when feasible) at the time of any unusual safety event (i.e., an AE different in type and severity from that which is expected in the setting of casdozokitug, toripalimab, or bevacizumab use), or if a sample is found to be compromised.

[0381] The following biomarker samples may be analyzed at a central laboratory or a specialized laboratory vendor:• Blood (PBMCs) for immunophenotyping and immune monitoring: o To monitor the effects of treatment on various peripheral blood immune cell populations. Subsets may include, but are not limited to, monocytes, neutrophils, myeloid-derived suppressor cells, and T / NK / myeloid-cell populations.• Blood for circulating soluble factors: o For profiling of potential predictive and pharmacodynamic circulating biomarkers (including but not limited to EBI3 and IL-27) of drug treatment, response and / or resistance, and / or safety.• Blood for cell-free DNA biomarkers: o For profiling circulating tumor DNA as a measure of monitoring disease response to casdozokitug in combination with toripalimab + bevacizumab.

[0382] A baseline tumor tissue sample (archival or fresh) is obtained for participants enrolled in Study CHS388-202. An archival tumor tissue sample (block or 10-15 slides with associated pathology report) collected within 2 years is acceptable. If archival tumor tissue is not available, a baseline fresh biopsy sample (up to 3 core needle samples) is obtained, avoiding measurable target or irradiated lesions.

[0383] Additional on-treatment tumor biopsies (3 to 5 core needle, incisional, or excisional) are collected when medically feasible. If the participant is willing, the on-treatment biopsies are obtained during Cycle 2 (i.e., after the second dose of study treatment preferably between C2D1 and C2D15).

[0384] Baseline archival tumor tissue / fresh tumor biopsy and on-treatment tumor biopsy samples when available are analyzed at a central laboratory or a specialized laboratory vendor to assess the following:In situ examination of potential predictive and / or correlative biomarkers on tumor cells and nontumoral cells within the tumor (such as immune cells, Kuepfer cells, endothelial cells, and stromal cells) by immunohistochemistry or immunofluorescence that mayinclude, but are not limited to, IL- 27, IL-27RA and related proteins, PD-L1, and markers of immune cell subpopulations.• Gene expression evaluation of tumor-specific and immune-related genes and / or gene signatures that correlate with response or resistance.• Exploratory analysis depending on sample availability may include identifying potential biomarkers (cellular, proteomic, genomic, and metabolic) of drug treatment, response, resistance, and / or safety of casdozokitug in combination with toripalimab + bevacizumab.

[0385] Validated ADA assays for casdozokitug and toripalimab are used for immunogenicity testing. The time points for the collection of this assessment are detailed in FIG. 14. An additional ADA sample, beyond those listed, should be drawn (when feasible) at the time of any unusual safety event (i.e., an AE different in type and severity from that which is expected in the setting of casdozokitug, toripalimab, or bevacizumab use). PK and ADA samples collected for casdozokitug or toripalimab at a specific time point may be used interchangeably if needed.

[0386] Expected Results

[0387] The study objectives and endpoints are detailed in Table 15.Table 15: Study Objectives and EndpointsAbbreviations: Objective response rate (ORR): the proportion of participants who experience best overall response of complete response (CR) and partial response (PR).Progression-free survival (PFS): time from initiation of study treatment to occurrence of progressive disease (PD), or death from any cause (whichever occurs first).Duration of response (DoR): time from initial documented objective response to PD or death from any cause (whichever occurs first).Disease control rate (DCR): the proportion of participants who experience best overall response of CR, PR, or stable disease.Overall survival (OS): time from initiation of study treatment to death from any cause.Time to progression: time from initiation of study treatment to occurrence of PD.Time to response: time from initiation of study treatment to initial documented objective response. Time on therapy: time from initiation of study treatment to last treatment.

[0388] The primary efficacy endpoint of objective response rate (ORR) based on RECIST vl.l is expected to be higher for casdozokitug in combination with toripalimab + bevacizumab (Arm A and Arm B) vs. toripalimab + bevacizumab without casdozokitug (Arm C). Similarly, the secondary efficacy endpoints of disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS) are expected to be higher for casdozokitug in combination with toripalimab + bevacizumab (Arm A and Ann B) vs. toripalimab + bevacizumab without casdozokitug (Arm C). All tumor-based endpoints are assessed according to RECIST vl.l and HCC mRECIST. In some aspects, the ORR of Arm A and / or Arm B is at least 30%. In some aspects, the ORR of Arm A and / or Arm B is at least 40%. In some aspects, the median PFS in Arm A and / or Arm B is at least 6 months, at least 7 months, or at least 8 months. In some aspects, the DCR is at least 10%, at least 12%, or at least 15%.NUMBERED ITEMSThe following non-limiting numbered items form part of the disclosure.1. A method of stimulating an immune response in a subject, the method comprising administering to the subject (i) an antibody that binds human IL-27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) toripalimab, and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.2. A method of treating a cancer in a subject in need thereof comprising administering to the subject (i) an antibody that binds human IL-27 or an...

Claims

We Claim:

1. A method of stimulating an immune response in a subject, the method comprising administering to the subject (i) an antibody that binds human IL-27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) toripalimab, and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

2. A method of treating a cancer in a subject in need thereof comprising administering to the subject (i) an antibody that binds human IL-27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) toripalimab, and (iii) bevacizumab; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

3. The method of claim 1 or 2, comprising administering the anti-IL-27 antibody at a dose of about 500 mg to about 2000 mg.

4. The method of any one of claims 1 to 3, comprising administering the anti-IL-27 antibody at a dose of at least about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.

5. The method of any one of claims 1 to 4, comprising administering the anti-IL-27 antibody once about every week, once about every two weeks, once about every three weeks, once about every four weeks, once about every 6 weeks, once about every 8 weeks, or once about every 12 weeks.

6. The method of any one of claims 1 to 5, comprising administering the anti-IL-27 antibody at a dose of about 1000 mg once about every four weeks.

7. The method of any one of claims 1 to 5, comprising administering the anti-IL-27 antibody at a dose of about 2000 mg once about every four weeks.

8. The method of any one of claims 1 to 5, comprising administering the anti-IL-27 antibody at a dose of about 700 mg once about every three weeks.

9. The method of any one of claims 1 to 5, comprising administering the anti-IL-27 antibody at a dose of about 1400 mg once about every three weeks.

10. The method of any one of claims 1 to 9, comprising administering the toripalimab at a flat dose.

11. The method of any one of claims 1 to 10, comprising administering the toripalimab at a dose of about 120 mg to about 720 mg, or about 240 mg to about 480 mg, or about 240 mg to about 360 mg.

12. The method of any one of claims 1 to 11, comprising administering the toripalimab once about every week, once about every two weeks, once about every three weeks, or once about every four weeks.

13. The method of any one of claims 1 to 12, comprising administering the toripalimab at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks.

14. The method of any one of claims 1 to 13, comprising administering the bevacizumab at a dose of at least about 0.003 mg / kg, about 0.006 mg / kg, about 0.009 mg / kg, about 0.03 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, or about 30 mg / kg.

15. The method of any one of claims 1 to 14, comprising administering the bevacizumab once about every week, once about every two weeks, once about every three weeks, or once about every four weeks.

16. The method of any one of claims 1 to 15, comprising administering the bevacizumab at a dose of about 15 mg / kg once about every three weeks.

17. The method of any one of claims 1 to 5, comprising:(i) administering the anti-IL-27 antibody at a dose of about 700 mg once about every three weeks; and(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks.

18. The method of any one of claims 1 to 5, comprising:(i) administering the anti -IL-27 antibody at a dose of about 1400 mg once about every three weeks; and(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks.

19. The method of any one of claims 1 to 5, comprising:(i) administering the anti-IL-27 antibody at a dose of about 700 mg once about every three weeks;(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks; and(iii) administering the bevacizumab at a dose of about 15 mg / kg once about every three weeks.

20. The method of any one of claims 1 to 5, comprising:(i) administering the anti -IL-27 antibody at a dose of about 1400 mg once about every three weeks;(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks; and(iii) administering the bevacizumab at a dose of about 15 mg / kg once about every three weeks.

21. The method of any one of claims 1 to 5, comprising:(i) administering the anti -IL-27 antibody at a dose of about 1000 mg once about every four weeks; and(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks.

22. The method of any one of claims 1 to 5, comprising:(i) administering the anti-IL-27 antibody at a dose of about 2000 mg once about every four weeks; and(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks.

23. The method of any one of claims 1 to 5, comprising:(i) administering the anti -IL-27 antibody at a dose of about 1000 mg once about every four weeks;(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks; and(iii) administering the bevacizumab at a dose of about 15 mg / kg once about every three weeks.

24. The method of any one of claims 1 to 5, comprising:(i) administering the anti-IL-27 antibody at a dose of about 2000 mg once about every four weeks;(ii) administering the toripalimab at a dose of about 240 mg once about every three weeks or about 340 mg once about every four weeks; and(iii) administering the bevacizumab at a dose of about 15 mg / kg once about every three weeks.

25. The method of any one of claims 1 to 24, comprising administering the anti-IL-27 antibody, toripalimab, and bevacizumab on the same day.

26. The method of any one of claims 1 to 25, comprising administering the anti-IL-27 antibody, toripalimab, and bevacizumab concurrently.

27. The method of any one of claims 1 to 25, comprising administering the anti-IL-27 antibody, toripalimab, and bevacizumab sequentially.

28. The method of any one of claims 1 to 25, comprising administering the anti-IL-27 antibody first, administering toripalimab second, and administering bevacizumab third.

29. The method of any one of claims 1 to 24, wherein (i) the anti -IL-27 antibody and (ii) toripalimab and bevacizumab are administered on different days.

30. The method of any one of claims 1 to 29, wherein the anti-IL-27 antibody comprises a heavy chain variable region comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 11.

31. The method of any one of claims 1 to 30, wherein the anti -IL- 27 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11.

32. The method of any one of claims 1 to 31, wherein the anti -IL- 27 antibody comprises a light chain variable region comprising an amino acid sequence that has at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 19.

33. The method of any one of claims 1 to 32, wherein the anti -IL- 27 antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19.

34. The method of any one of claims 1 to 33, wherein the anti-IL-27 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 19.

35. The method of any one of claims 1 to 34, wherein the anti-IL-27 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23.

36. The method of any one of claims 1 to 35, wherein the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21.

37. The method of any one of claims 1 to 35, wherein the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25.

38. The method of any one of claims 1 to 36, wherein the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23.

39. The method of any one of claims 1 to 35 or 37, wherein the anti-IL-27 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 23.

40. The method of any one of claims 2 to 39, wherein the cancer is a hepatocellular carcinoma (HCC).

41. The method of any one of claims 2 to 40, wherein the cancer is advanced.

42. The method of any one of claims 2 to 41, wherein the cancer is locally advanced.

43. The method of any one of claims 2 to 42, wherein the cancer is metastatic.

44. The method of any one of claims 2 to 43, wherein the cancer is refractory.

45. The method of any one of claims 2 to 44, wherein the cancer is unresectable.

46. The method of any one of claims 2 to 45, wherein the cancer is unresectable and / or locally advanced or metastatic hepatocellular carcinoma.

47. The method of any one of claims 2 to 39, wherein the cancer is a non-small cell lung cancer (NSCLC).

48. The method of claim 47, wherein the cancer is a squamous NSCLC.

49. The method of any one of claims 2 to 39, wherein the cancer is a liver cancer.

50. The method of any one of claims 2 to 39, wherein the cancer is a head and neck cancer.

51. The method of any one of claims 2 to 39, wherein the cancer is a gastric cancer.

52. The method of any one of claims 2 to 39, wherein the cancer is a cervical cancer.

53. The method of any preceding claim, wherein the anti -IL-27 antibody is Casdozokitug.

54. The method of any preceding claim, wherein the method comprises administering 700 mg Casdozokitug, 240 mg or 340 mg toripalimab, and 15 mg / kg bevacizumab.

55. The method of any preceding claim, wherein the method comprises administering 1400 mg Casdozokitug, 240 mg or 340 mg toripalimab, and 15 mg / kg bevacizumab.

56. The method of any preceding claim, wherein the method comprises administering Casdozokitug, toripalimab, and bevacizumab intravenously.

57. The method of any preceding claim, wherein the method comprises administering Casdozokitug, toripalimab, and bevacizumab intravenously every 3 weeks or every 4 weeks.

58. The method of any preceding claim, wherein the subject has:(i) an absolute neutrophil count: > 1500 / pL (1.5 x 109 / L),(ii) an absolute lymphocyte count: > 500 / pL (0.5 x 109 / L),(iii) platelets: > 75,000 / pL (> 75 x 109 / L) without platelet transfusion, and(iv) hemoglobin: > 9.0 g / dL.

59. A composition comprising (i) an antibody that binds human IL-27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) a surfactant, and (iii) one or more stabilizer; wherein the anti -IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15.

60. The composition of claim 59, comprising about 50 mg / mL of the anti-IL-27 antibody.

61. The composition of claim 59 or 60, wherein the emulsifier is polysorbate 80.

62. The composition of claim 61 , comprising 0.02% polysorbate.

63. The composition of any one of claims 59 to 62, wherein the one or more stabilizer is sucrose and histidine.

64. The composition of claim 63, comprising 20 mM histidine and 8% sucrose.

65. The composition of any one of claims 59 to 64, wherein the composition has a pH of about 5.5.

66. A composition comprising (i) 50 mg / mL of an antibody that binds human IL- 27 or an antigen binding portion thereof (an anti-IL-27 antibody), (ii) 0.02% polysorbate 80, (iii) 20 mM histidine, and (iv) 8% sucrose; wherein the anti-IL-27 antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15; and wherein the composition has a pH of about 5.5.

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