Anti-GARP-TGF-β1 / PD-1 combination therapy

Abstract

The present disclosure provides a method for treating cancer by combining an anti-TGF-β1 / GARP complex antibody and an anti-PD-1 antibody.

Description

Technical Field

[0001] 1. Sequence Listing This application includes a sequence listing submitted electronically in XML format, the entire content of which is incorporated herein by reference. The XML copy was created on July 7, 2022, with the file name SeqList_350794-50100 and a size of 22,691 bytes.

[0002] 2. Technical Field This application relates to the combined use of an antibody capable of inhibiting the activation of TGF-β1 and a checkpoint inhibitor for the treatment of cancer.

Background Art

[0003] 3. Background Art Glycoprotein-A repetitions predominant (GARP) binds to membrane-bound latent transforming growth factor β1 (TGF-β1) to control its availability and regulate its activation. The GARP-TGF-β1 complex is expressed by several cell types including activated B cells, activated regulatory T lymphocytes, activated monocytes, and activated platelets. When active TGF-β1 is released from the GARP-TGF-β1 complex on activated regulatory T cells (Tregs), the TGF-β1 receptor on Tregs signals to enhance Treg immunosuppressive activity, while the receptor on tumor-infiltrating lymphocytes (TILs) acts to suppress cytotoxic activity. Thus, TGF-β1 can act in an autocrine or paracrine manner, can have various effects and functional consequences on immune cells, and ultimately leads to immunosuppression. Furthermore, TGF-β1 has a multifaceted impact on tumor and other cell types where receptors are localized in the surrounding tissue (de Streel and Lucas, 2021, Biochemical Pharmacology: 192:114697).

[0004] WO2015 / 015003 and WO2016 / 125017 disclose monoclonal antibodies that can interfere with the activation of mature TGF-β1 and its release from the GARP / TGF-β1 complex. These antibodies have been shown to interfere with the immunosuppressive effects of Tregs in vitro and in vivo. WO2018 / 206790 describes the humanization of ABBV-151 (ribmoprimab), a monoclonal antibody that specifically binds to the GARP-TGF-β1 complex and blocks the release of active TGF-β1.

[0005] Preclinical data in a mouse model using a surrogate antibody specific for the mouse GARP-TGF-β1 complex support the hypothesis that preventing the release of TGF-β1 from the GARP-TGF-β1 complex reduces active TGF-β1 in tumors and tissues where cells expressing the TGF-β1 receptor are thought to be present (de Streel, et al., 2020, Nature Communications, 11:4545).

[0006] To determine whether ABBV-151 can blunt the immunosuppressive effects of TGF-β1 and induce a more effective anti-tumor immune response when combined with antibodies targeting other immune checkpoint molecules, a Phase 1 trial was designed to determine the recommended Phase 2 dose (RP2D) when ABBV-151 is administered as a single agent and when administered in combination with bdurigamab (ABBV-181), a monoclonal anti-PD-1 antibody (see ClinicalTrials.gov Identifier NCT03821935).

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Literature

[0008]

Non-Patent Literature 1

Non-Patent Literature 2

Non-Patent Literature 3

Summary of the Invention

Means for Solving the Problems

[0009] 4. Summary In certain embodiments, an antibody (e.g., Ab1) that binds to a complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 and an anti-PD-1 antibody are co-administered to a subject having a cancer that at least partially evades host immune surveillance by TGF-β1 expression and release. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the treatment of the cancer is front-line treatment, second-line treatment, or third-line or later treatment.

[0010] In certain embodiments, an antibody (e.g., Ab1) that binds to a complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 and an anti-PD-1 antibody are co-administered to a subject having hepatocellular carcinoma. In certain embodiments, the treatment of hepatocellular carcinoma is front-line treatment, second-line treatment, or third-line or later treatment.

[0011] In certain embodiments, an antibody (e.g., Ab1) that binds to a complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 and an anti-PD-1 antibody are co-administered to a subject having pancreatic cancer.

[0012] In certain embodiments, an antibody that binds to the complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 (e.g., Ab1) and an anti-PD-1 antibody are co-administered to a subject having urothelial cancer.

[0013] In certain embodiments, an antibody that binds to the complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 (e.g., Ab1) and an anti-PD-1 antibody are co-administered to a subject having muscle-invasive urothelial cancer.

[0014] In certain embodiments, an antibody that binds to the complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 (e.g., Ab1) and an anti-PD-1 antibody are co-administered to a subject having head and neck squamous cell carcinoma.

[0015] In certain embodiments, an antibody that binds to the complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 (e.g., Ab1) and an anti-PD-1 antibody are co-administered to a subject having microsatellite stable colorectal cancer. In certain embodiments, the microsatellite stable colorectal cancer is non-selective. In other embodiments, the microsatellite stable colorectal cancer is of the CMS4 subtype.

[0016] In certain embodiments, an antibody that binds to the complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 (e.g., Ab1) and an anti-PD-1 antibody are co-administered to a subject having non-small cell lung cancer (NSCLC). In certain embodiments, the treatment of NSCLC is front-line treatment that combines Ab1, an anti-PD-1 antibody, and chemotherapy. In certain embodiments, the chemotherapy is a platinum doublet regimen using carboplatin and pemetrexed. In other embodiments, Ab1 and an anti-PD-1 antibody are combined to treat recurrent / refractory NSCLC regardless of the presence or absence of liver metastasis.

[0017] In certain embodiments, an antibody that binds to a complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1 (e.g., Ab1) and an anti-PD-1 antibody are co-administered to a subject having granulosa cell tumor of the ovary. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] 5. BRIEF DESCRIPTION OF THE DRAWINGS

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Mode for Carrying Out the Invention

[0019] 6. Detailed Description 6.1. Antibody In one embodiment, a method for treating cancer is provided, the method comprising administering to a patient in need of said treatment: (1) an antibody that binds to a complex of human repetitive dominant glycoprotein A (hGARP) and TGF-β1, and (2) an anti-PD-1 antibody.

[0020] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is Ab1. As used herein, Ab1 means an antibody having the CDR sequences shown in Table 1. In certain embodiments, Ab1 is a human immunoglobulin G4 (IgG4; S228P) / κ monoclonal antibody (mAb) that specifically binds to the GARP-TGF-β1 complex and blocks the release of active TGF-β1. In certain embodiments, Ab1 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. In certain embodiments, Ab1 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. For the amino acid sequences of the CDRs, variable regions and full-length sequences of Ab1, see Table 1. In one embodiment, the heavy chain sequence of Ab1 includes a terminal lysine (K) residue in addition to the full-length heavy chain of SEQ ID NO: 9 (SEQ ID NO: 22).

[0021] In certain embodiments, Ab1 is ABBV-151. As used herein, ABBV-151 refers to an antibody comprising the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 10.

[0022] In certain embodiments, Ab1 is riba moniprimab. As used herein, riba moniprimab refers to an antibody comprising the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 10, and a formulation containing such an antibody, and the antibody or formulation has a name with or without an FDA-specified suffix attached to the core name riba moniprimab.

[0023]

Table 1

[0024] The anti-PD-1 antibody can be an antibody that binds to PD-1. The anti-PD-1 antibody may also be an antibody that binds to PD-L1. An antibody that binds to PD-1 can interfere with the binding of PD-1 to PD-L1 and PD-L2, and an antibody that binds to PD-L1 can interfere with the binding of PD-1 to PD-L1.

[0025] In certain embodiments, the antibody that binds to PD-1 is ABBV-181. As used herein, ABBV-181 refers to an antibody having the CDR sequences shown in Table 2. In certain embodiments, as used herein, ABBV-181 refers to an antibody having the heavy chain of SEQ ID NO: 19 or SEQ ID NO: 21 and the light chain of SEQ ID NO: 20. For the amino acid sequences of the CDR, variable region, and heavy chain sequence of ABBV-181, see Table 2.

[0026] In certain embodiments, ABBV-181 is bimagrumab. As used herein, bimagrumab refers to an antibody comprising a heavy chain (HC) of SEQ ID NO: 19 or SEQ ID NO: 21 and a light chain of SEQ ID NO: 20, and a formulation containing such an antibody, and the antibody or formulation has a name with or without an FDA-designated suffix attached to the core name bimagrumab.

[0027]

Table 2

[0028] In one embodiment, a method of treating cancer is provided, the method comprising administering to a patient in need of such treatment (1) an antibody that binds to the complex of hGARP and TGF-β1 (e.g., Ab1), and (2) an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody binds to PD-1 and is selected from the group consisting of pembrolizumab, nivolumab, semaprilumab, dostarlimab, and bimagrumab. In one embodiment, the method of treating cancer comprises administering to a patient in need of such treatment (1) an antibody that binds to the complex of hGARP and TGF-β1 (e.g., Ab1), and (2) an antibody that binds to PD-L1, and an antibody selected from the group consisting of atezolizumab, durvalumab, and avelumab.

[0029] 6.2. Administration of an antibody that binds to the complex of hGARP and TGF-β1 and an anti-PD-1 antibody The present application provides a method for treating cancer patients by combining an antibody that binds to the complex of hGARP and TGF-β1 and an anti-PD-1 antibody. In certain embodiments, the cancer is a solid tumor. Non-limiting examples of the administration timing and dosage of the antibody that binds to the complex of hGARP and TGF-β1 and is suitable for combination with an anti-PD-1 antibody, non-limiting examples of the administration timing and dosage of the anti-PD-1 antibody that is suitable for combination with an antibody that binds to the complex of hGARP and TGF-β1, and non-limiting examples of the administration of both antibodies are given below.

[0030] 6.2.1. Administration of an Antibody that Binds to the Complex of hGARP and TGF-β1 In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0031] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 200 mg to 1500 mg Q2W. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg, 1000 mg, or 1500 mg Q2W. In still other embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 1500 mg Q2W.

[0032] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 200 mg to 1200 mg Q3W. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg Q3W. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 400 mg Q3W. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 1200 mg Q3W.

[0033] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 250 mg to 1600 mg Q4W. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 250 mg, 500 mg, 550 mg, 600 mg, 750 mg, 1000 mg, or 1500 mg Q4W. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 600 mg Q4W. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a fixed dose of 1500 mg Q4W.

[0034] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered in an amount and schedule sufficient to improve the therapeutic efficacy of the anti-PD-1 antibody. In certain embodiments, (1) the antibody that binds to the complex of hGARP and TGF-β1 is administered at a dose that achieves a tumor site concentration of 0.8 ug / mL, which is the minimum required to inhibit TGF-β1 signaling at the site of action (e.g., the tumor site), and (2) the antibody that binds to the complex of hGARP and TGF-β1 is administered at a dose of 0.319 ug / mL that achieves 95 the EC of GARP / TGF-β1 target engagement in the tumor microenvironment in the majority of subjects.

[0035] In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Ab1. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Ab1, and Ab1 comprises CDRH1, CDRH2, and CDRH3 of SEQ ID NOs: 1, 2, and 3, and CDRL1, CDRL2, and CDRL3 of SEQ ID NOs: 4, 5, and 6, respectively. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Ab1, and Ab1 comprises the heavy chain variable region of SEQ ID NO: 7 and the light chain variable region of SEQ ID NO: 8. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Ab1, and Ab1 comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Ab1, and Ab1 comprises the heavy chain of SEQ ID NO: 22 and the light chain of SEQ ID NO: 10.

[0036] In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Ab1, and Ab1 is ABBV-151 comprising the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 10.

[0037] In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Ab1, and Ab1 is ribomuniprimab comprising the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 10.

[0038] 6.2.2. Administration of Anti-PD-1 Antibody In certain embodiments, the anti-PD-1 antibody is administered at a dose of 1 to 10 mg / kg once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In certain embodiments, the anti-PD-1 antibody is administered at a fixed dose of 240 mg to 1680 mg once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), or once every six weeks (Q6W).

[0039] In certain embodiments, the anti-PD-1 antibody is administered at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In certain embodiments, the anti-PD-1 antibody is administered at a fixed dose of 240 mg Q2W, 250 mg Q2W, 840 mg Q2W, 200 mg Q3W, 360 mg Q3W, 375 mg Q3W, 1200 mg Q3W, 480 mg Q4W, 500 mg Q4W, 1680 mg Q4W, or 400 mg Q6W once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), or once every six weeks (Q6W). In certain embodiments, the anti-PD-1 antibody is administered at a fixed dose of 375 mg Q3W only to subjects in the combination cohort. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience an infusion-related reaction during the first administration, the infusion time for the second administration can be shortened to 60 minutes, and the infusion time for subsequent administrations can be shortened to 30 minutes.

[0040] 6.2.2.1. Administration of ABBV-181 In certain embodiments, the anti-PD-1 antibody is ABBV-181 and is administered at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In certain embodiments, the anti-PD-1 antibody is administered at a fixed dose of 250 mg Q2W, 375 mg Q3W, or 500 mg Q4W.

[0041] In certain embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every two weeks (Q2W) at a dose of 1 mg / kg, 3 mg / kg or 10 mg / kg. In certain embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every two weeks (Q2W) at a fixed dose of 250 mg, 375 mg or 500 mg. In certain embodiments, ABBV-181 is administered at a fixed dose of 250 mg Q2W only to subjects in the combination cohort. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience an infusion-related reaction during the first administration, the infusion time for the second administration can be shortened to 60 minutes and the infusion time for subsequent administrations can be shortened to 30 minutes.

[0042] In certain embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every three weeks (Q3W) at a dose of 1 mg / kg, 3 mg / kg or 10 mg / kg. In certain embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every three weeks (Q3W) at a fixed dose of 250 mg, 375 mg or 500 mg. In certain embodiments, ABBV-181 is administered at a fixed dose of 375 mg Q3W only to subjects in the combination cohort. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience an infusion-related reaction during the first administration, the infusion time for the second administration can be shortened to 60 minutes and the infusion time for subsequent administrations can be shortened to 30 minutes.

[0043] In certain embodiments, ABBV-181 is administered once every four weeks (Q4W) at a dose of 1 mg / kg, 3 mg / kg or 10 mg / kg or at a fixed dose of 250 mg, 375 mg or 500 mg. In certain embodiments, ABBV-181 is administered at a fixed dose of 500 mg Q4W only to subjects in the combination cohort. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience an infusion-related reaction during the first administration, the infusion time for the second administration can be shortened to 60 minutes and the infusion time for subsequent administrations can be shortened to 30 minutes.

[0044] 6.2.2.2. Administration of Budigalimab In certain embodiments, the anti-PD-1 antibody is budigalimab and is administered once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg. In certain embodiments, the anti-PD-1 antibody is administered at a fixed dose of 250 mg once every two weeks (Q2W), 375 mg once every three weeks (Q3W), or 500 mg once every four weeks (Q4W).

[0045] In certain embodiments, the anti-PD-1 antibody is budigalimab and is administered once every two weeks (Q2W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg. In certain embodiments, the anti-PD-1 antibody is budigalimab and is administered once every two weeks (Q2W) at a fixed dose of 250 mg, 375 mg, or 500 mg. In certain embodiments, budigalimab is administered at a fixed dose of 250 mg Q2W only to subjects in the combination cohort. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience an infusion-related reaction during the first administration, the infusion time for the second administration can be shortened to 60 minutes, and the infusion time for subsequent administrations can be shortened to 30 minutes.

[0046] In certain embodiments, the anti-PD-1 antibody is budigalimab and is administered once every three weeks (Q3W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg or at a fixed dose of 250 mg, 375 mg, or 500 mg. In certain embodiments, budigalimab is administered at a fixed dose of 375 mg Q3W only to subjects in the combination cohort. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience an infusion-related reaction during the first administration, the infusion time for the second administration can be shortened to 60 minutes, and the infusion time for subsequent administrations can be shortened to 30 minutes.

[0047] In certain embodiments, budigalimab is administered once every four weeks (Q4W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg. In certain embodiments, budigalimab is administered once every four weeks (Q4W) at a fixed dose of 250 mg, 375 mg, or 500 mg. In certain embodiments, budigalimab is administered at a fixed dose of 500 mg Q4W only to subjects in the combination cohort. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience an infusion-related reaction during the first administration, the infusion time for the second administration can be shortened to 60 minutes, and the infusion time for subsequent administrations can be shortened to 30 minutes.

[0048] 6.2.2.3. Administration of Pembrolizumab, Nivolumab, and Atezolizumab In certain embodiments, the anti-PD-1 antibody is pembrolizumab and is administered once every three weeks (Q3W) at a fixed dose of 200 mg. In certain embodiments, the anti-PD-1 antibody is pembrolizumab and is administered once every six weeks (Q6W) at a fixed dose of 400 mg. The dosage and frequency of administration of pembrolizumab are known in the art, for example, as specified in the KEYTRUDA (R) prescribing information.

[0049] In certain embodiments, the anti-PD-1 antibody is nivolumab and is administered once every two weeks (Q2W) at a fixed dose of 240 mg. In certain embodiments, the anti-PD-1 antibody is nivolumab and is administered once every two weeks (Q2W) at a dose of 3 mg / kg. In certain embodiments, the anti-PD-1 antibody is nivolumab and is administered once every three weeks (Q3W) at a fixed dose of 360 mg. In certain embodiments, the anti-PD-1 antibody is nivolumab and is administered once every four weeks (Q4W) at a fixed dose of 480 mg. The dosage and frequency of administration of nivolumab are known in the art, for example, as specified in the OPDIVO (R) prescribing information.

[0050] In certain embodiments, the anti-PD-1 antibody is atezolizumab, an antibody that binds to PD-L1, and is administered at a fixed dose of 840 mg once every two weeks (Q2W). In certain embodiments, the anti-PD-1 antibody is atezolizumab, an antibody that binds to PD-L1, and atezolizumab is administered at a fixed dose of 1200 mg once every three weeks (Q3W). In certain embodiments, the anti-PD-1 antibody is atezolizumab, an antibody that binds to PD-L1, and is administered at a fixed dose of 1680 mg once every four weeks (Q4W). The dosage and frequency of administration of atezolizumab are known in the art, for example, as specified in the prescribing information for TECENTRIQ(R).

[0051] 6.2.3. Combination Regimen The following are non-limiting examples of combination regimens. Even if a particular combination of administration timing and dosage is not mentioned, it does not mean that the combination is not clearly contemplated or that it is not within the scope of the invention disclosed in this application.

[0052] In one embodiment, (1) the antibody that binds to the complex of hGARP and TGF-β1 and (2) the anti-PD-1 antibody are administered simultaneously.

[0053] In one embodiment, (1) the antibody that binds to the complex of hGARP and TGF-β1 and (2) the anti-PD-1 antibody are administered sequentially. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered first, followed by the anti-PD-1 antibody. In certain embodiments, a time interval of up to 15 minutes, up to 30 minutes, up to 45 minutes, or up to 60 minutes is allowed before administering the anti-PD-1 antibody.

[0054] In one embodiment, (1) the antibody that binds to the complex of hGARP and TGF-β1 and (2) the anti-PD-1 antibody are administered non-simultaneously within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 2 days, or within 1 day of each other.

[0055] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 200 mg to 1500 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg, 1000 mg, or 1500 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 400 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 600 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 1500 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W).

[0056] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 200 mg to 1200 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 375 mg (Q3W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 375 mg (Q3W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 400 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 375 mg (Q3W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 600 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 375 mg (Q3W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 1200 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 375 mg (Q3W).

[0057] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 250 mg to 1600 mg Q4W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at fixed doses of 250 mg, 500 mg, 550 mg, 600 mg, 750 mg, 1000 mg, 1500 mg, 1600 mg Q4W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 600 mg Q4W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W). In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a fixed dose of 1500 mg Q4W, and the anti-PD-1 antibody is ABBV-181 or bdurigamab and is administered at a fixed dose of 500 mg (Q4W).

[0058] In certain embodiments, the order of drug administration is such that the antibody that binds to the complex of hGARP and TGF-β1 is administered first, followed by the anti-PD-1 antibody. In certain embodiments, after completion of the infusion of the antibody that binds to the complex of hGARP and TGF-β1, the subject waits for up to 60 minutes before starting the infusion of the anti-PD-1 antibody.

[0059] In certain embodiments, the combined administration of the antibody that binds to the complex of hGARP and TGF-β1 and the anti-PD-1 antibody is continued until disease progression or unacceptable toxicity occurs. In certain embodiments, the combined administration of the antibody that binds to the complex of hGARP and TGF-β1 and the anti-PD-1 antibody is continued for 4 months, 5 months, 6 months, 7 months, 8 months, 12 months, 18 months, 24 months, or longer.

[0060] The efficacy of the combination of the antibody that binds to the complex of hGARP and TGF-β1 and the anti-PD-1 antibody is evaluated by various clinical endpoints. In certain embodiments, the subject administered the antibody that binds to the complex of hGARP and TGF-β1 and the anti-PD-1 antibody in combination has a higher objective response rate (ORR) than the standard treatment. In certain embodiments, the subject administered the antibody that binds to the complex of hGARP and TGF-β1 and the anti-PD-1 antibody in combination has a higher objective response rate (ORR) than that observed with the administration of the anti-PD-1 antibody alone. In certain embodiments, the subject administered the antibody that binds to the complex of hGARP and TGF-β1 and the anti-PD-1 antibody in combination has an objective response rate (ORR) of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more. In certain embodiments, the efficacy of the treatment includes that the median duration of response (DoR) is 4 months or more (e.g., at least 4 months, at least 6 months, at least 8 months, and / or at least 10 months). Other efficacy endpoints include disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and an acceptable safety and tolerability profile.

[0061] In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Ab1. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Ab1, and Ab1 comprises CDRH1, CDRH2, and CDRH3 of SEQ ID NOs: 1, 2, and 3, and CDRL1, CDRL2, and CDRL3 of SEQ ID NOs: 4, 5, and 6, respectively. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Ab1, and Ab1 comprises the heavy chain variable region of SEQ ID NO: 7 and the light chain variable region of SEQ ID NO: 8. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Ab1, and Ab1 comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10. In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Ab1, and Ab1 comprises the heavy chain of SEQ ID NO: 22 and the light chain of SEQ ID NO: 10.

[0062] In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Ab1, and Ab1 is ABBV-151 comprising the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 10.

[0063] In one embodiment, the antibody that binds to the complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Ab1, and Ab1 is ribomomab comprising the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 10.

[0064] In one embodiment, the anti-PD-1 antibody in this section (Section 5.2.3) is ABBV-181. In one embodiment, the anti-PD-1 antibody in this section (Section 6.2.3) is budigalimab. In one embodiment, the anti-PD-1 antibody in this section (Section 6.2.3) is nivolumab. In one embodiment, the anti-PD-1 antibody in this section (Section 6.2.3) is pembrolizumab. In one embodiment, the anti-PD-1 antibody in this section (Section 6.2.3) is atezolizumab.

[0065] 6.3. Selection of Tumor Types Cancer immune phenotypes are proposed to have three basic phenotypes: desert (characterized by no immune infiltration into the tumor or surrounding stroma), excluded (immune cells are present in the stroma but cannot access the tumor microenvironment), and inflamed (immune cells are present in the stroma and tumor microenvironment). Furthermore, the success of immunotherapy targeting T cell co-stimulation, such as anti-PD-1 agents, appears to depend on the amount and location of T cell infiltration (Chen DS, Mellman I. Nature. 2017;541(7637):321-30).

[0066] Using gene expression analysis, immune infiltration markers and TGF-β1-related signaling were compared in multiple cohorts constructed from The Cancer Genome Atlas (TCGA) database. Bulk RNAseq data from primary tumor samples were evaluated for enrichment of immune gene signatures (e.g., immunologic constant of rejection, a set of 20 genes representing the coordinated activation of natural and adaptive responses downstream of immune-mediated tissue destruction). Similar gene expression signatures have also been found to be predictors of response to anti-PD-1 therapy (Ayers M, Lunceford J, Nebozhyn M, et al. J Clin Invest. 2017;127(8):2930-40). Other signatures representing T cells and PD-1 signaling have also been evaluated (Hendrickx W, Simeone I, Anjum S, et al. Oncoimmunology. 2017;6(2):e1253654; Bindea G, Mlecnik B, Tosolini M, et al. Immunity. 2013;39(4):782-95; Yoshihara K, Shahmoradgoli M, Martinez E, et al. Nat Commun. 2013;4:2612; and Quigley M, Pereyra F, Nilsson B, et al. Nat Med. 2010;16(10):1147-51).

[0067] Next, samples were evaluated for TGF-β1-related gene signatures and stromal gene signatures, including the signatures identified by Mariathasan et al., to predict atezolizumab non-responsiveness. Finally, samples were evaluated for GARP (LRRC32) expression. At sites where gene expression profiles of pancreatic cancer, urothelial cancer (UC), hepatocellular cancer (HCC), head and neck squamous cell cancer (HNSCC), microsatellite stable colorectal cancer (MSS-CRC), and non-small cell lung cancer (NSCLC) were obtained, it was suggested that there is an overlap between markers of T cell infiltration that appears to correlate with the efficacy of anti-PD-1 therapy and TGF-β1-related gene signatures, and it is considered that the release of TGF-β1 may be an immune evasion mechanism in these patients. In these tumor indications, GARP (LRRC32) expression is associated with TGF-β1-related gene signatures, so it is thought that inhibiting GARP-TGF-β1 may regulate TGF-β1-related gene signatures.

[0068] In certain embodiments, an Ab1 and an anti-PD-1 antibody are co-administered to a subject having a cancer (e.g., a solid tumor) that at least partially evades host immune surveillance by expression and release of active TGF-β1. In certain embodiments, a therapeutically effective amount of an anti-PD-1 antibody and an antibody that binds to a complex of hGARP and TGF-β1 in a therapeutically effective schedule to improve the therapeutic efficacy of the anti-PD-1 antibody are administered to a subject having a cancer that at least partially evades host immune surveillance by expression and release of active TGF-β1. In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is Ab1. In certain embodiments, Ab1 is ABBV-151. In certain embodiments, Ab1 is administered as ribomnimab at a dose of about 200 mg to about 1500 mg once every two weeks, once every three weeks, or once every four weeks, and the anti-PD-1 antibody is administered as bdurigamab at a dose of 375 mg once every three weeks or at a dose of 500 mg once every four weeks.

[0069] In certain embodiments, when administered as described above to a subject having cancer that at least partially evades host immune surveillance by expression and release of active TGF-β1, a higher ORR is obtained than that obtained by administration of the anti-PD-1 antibody alone. In certain embodiments, when administered as described above to a subject having cancer that at least partially evades host immune surveillance by expression and release of active TGF-β1, an ORR of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more is obtained.

[0070] In certain embodiments, Ab1 treatment is added to the anti-PD-1 therapy of the cancer, and Ab1 is also administered to all subjects to whom an anti-PD-1 antibody (e.g., an antibody that binds to PD-1 or PD-L1) is administered for treatment of the cancer.

[0071] In certain embodiments, the subject has not received systemic treatment for their cancer, i.e., has not received first-line systemic treatment. In certain embodiments, the subject has progressed after receiving first-line systemic treatment. In certain embodiments, the subject has recurrent or refractory cancer. In certain embodiments, the subject has acquired resistance to therapy with checkpoint inhibitors. In certain embodiments, the subject has acquired resistance to therapy with one or more of a PD-1 inhibitor or a PD-L1 inhibitor. In certain embodiments, the subject has no history of treatment with checkpoint inhibitors, i.e., is checkpoint inhibitor-naïve. In certain embodiments, the subject has not previously received therapy with one or more of a PD-1 inhibitor or a PD-L1 inhibitor.

[0072] In certain embodiments, when Ab1 and an anti-PD-1 antibody are co-administered to tumors that have historically been unresponsive to immunotherapeutic agents, i.e., cold tumors such as pancreatic cancer and microsatellite stable colorectal cancer, an ORR of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more can be obtained. In one embodiment, the Ab1 is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, the Ab1 is ribmoniprimab and the anti-PD-1 antibody is budigalimab.

[0073] In other embodiments, when Ab1 and an anti-PD-1 antibody are co-administered to inflamed or hot tumors such as urothelial cancer (UC), HCC, HNSCC, and NSCLC, an ORR of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more can be obtained. In one embodiment, the Ab1 is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, the Ab1 is ribmoniprimab and the anti-PD-1 antibody is budigalimab.

[0074] In certain embodiments, the cancer is a solid tumor selected from the group consisting of pancreatic cancer, urothelial cancer (UC) including muscle-invasive urothelial cancer (MIUC), hepatocellular cancer (HCC), head and neck squamous cell carcinoma, colorectal cancer (CRC, including microsatellite stable colorectal cancer (MSS-CRC)), non-small cell lung cancer (NSCLC), ovarian cancer, ovarian granulosa cell tumor (GCT), breast cancer, or gastroesophageal junction adenocarcinoma, and when Ab1 and the anti-PD-1 are co-administered to the cancer, an ORR of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more can be obtained. In one embodiment, the Ab1 is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, the Ab1 is ribmoniprimab and the anti-PD-1 antibody is budigalimab.

[0075] In certain embodiments, the cancer is selected from the group consisting of pancreatic cancer, urothelial cancer including muscle-invasive urothelial cancer, hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma, colorectal cancer (CRC, including microsatellite stable colorectal cancer (MSS-CRC)), non-small cell lung cancer (NSCLC), ovarian cancer, ovarian granulosa cell tumor, breast cancer, or gastroesophageal junction adenocarcinoma, and when Ab1 and the anti-PD-1 antibody are used in combination for treating a metastatic cancer, an ORR of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more is obtained. In one embodiment, the Ab1 is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, the Ab1 is ribomunoprimab and the anti-PD-1 antibody is budigalimab.

[0076] The present application provides a method for treating cancer in a subject in need of cancer treatment, comprising co-administering 1) an anti-PD-1 antibody and 2) Ab1 in a therapeutically effective amount, wherein the cancer is selected from the group consisting of muscle-invasive urothelial cancer, hepatocellular carcinoma, microsatellite stable colorectal cancer, non-small cell lung cancer, and ovarian granulosa cell tumor.

[0077] In one embodiment, the Ab1 in this section (Section 6.3) is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, the Ab1 in this section (Section 6.3) is ribomunoprimab and the anti-PD-1 antibody is budigalimab.

[0078] Table 3 shows examples of subjects having cancer treated with the combination of Ab1 and an anti-PD-1 antibody, therapeutically effective dosing regimens of these antibodies, and examples of the overall response rate (ORR) of these regimens. In certain embodiments, a subpopulation of individuals having a specified cancer is selected for treatment, and said selection is based on one or more of the selection criteria listed in the lower column for each cancer. Contradictory criteria (e.g., treatment-naïve vs. progressive after prior therapy) are not used in combination for the purpose of defining the subpopulation.

[0079]

Table 3

[0080] In one embodiment, Ab1 in Table 3 is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, Ab1 in Table 3 is ribomuniprimab and the anti-PD-1 antibody is budigalimab. The dose selection is set based on the proposed mechanism of action, clinical efficacy and safety, and clinical PK / PD modeling of ribomuniprimab. Furthermore, preclinical evidence has demonstrated that ribomuniprimab can inhibit the release of active TGF-β1 from the GARP-TGF-β1 complex depending on its concentration, and it is expected to inhibit subsequent signaling within the TME, and thus the dose selection is also set based on such evidence.

Example

[0081] 7. Example 7.1. Example 1: Objectives of the M19-345 Phase 1 First-in-Human Multicenter Open-Label Dose Escalation Study to Examine the Safety, Tolerability, Pharmacokinetics, and RP2D of ABBV-151 as Monotherapy and in Combination with ABBV-181 in Subjects with Locally Advanced or Metastatic Solid Tumors This study is a Phase 1, open-label, dose escalation, dose expansion, PK, biomarker / PD, and proof-of-activity study. This study aims to evaluate the safety, PK, PD, and preliminary efficacy of ABBV-151 as monotherapy and in combination with budigalimab.

[0082] Approximately 257 subjects with locally advanced or metastatic solid tumors will be enrolled in this FIH study. As shown in Figure 1 and described below, this study consists of 2 parts. Approximately 46 subjects with solid tumors will be enrolled in the dose escalation cohort. Approximately 138 - 191 subjects with pancreatic cancer, urothelial cancer, HCC, HNSCC, MSS-CRC, and NSCLC will be enrolled in the expansion cohort.

[0083] Subjects will be administered ABBV-151 and / or budigalimab (in the combination cohort only) until disease progression or intolerable toxicity occurs.

[0084] 7.1.1. Dose Escalation Cohort: The dose escalation will be the FIH evaluation of ABBV-151 as a single agent administered to the escalating dose cohorts according to the Bayesian optimal interval (BOIN) design. First, initiate the ABBV-151 single-agent therapy dose escalation arm. Administer ABBV-151 by 60-minute intravenous (IV) infusion Q2W. Eligible subjects shall be those with advanced solid tumors who are considered refractory or intolerant to all existing therapies that have been shown to have a clinical effect in their respective disease states (i.e., subjects progressing on standard therapies that have been shown to have a clinical effect). One cycle is defined as 28 days. The single-agent therapy dose escalation will lead to the characterization of the safety profile, PK profile, and target engagement of ABBV-151 when used as described below, and the selection of the single-agent therapy RP2D. Collect efficacy data as an exploratory endpoint during dose escalation.

[0085] If it is determined that two or more dose levels from the beginning of the ABBV-151 single-agent therapy are safe, initiate the ABBV-151 and budigalimab combination therapy dose escalation arm. The starting dose of ABBV-151 under combination with budigalimab shall be at least two dose levels lower than the highest dose level of the ABBV-151 single-agent therapy that has been determined to be safe, and before initiating the combination therapy dose escalation, administer to at least three subjects with the ABBV-151 single-agent therapy. The dose escalation combination therapy of ABBV-151 and budigalimab is implemented according to the BOIN design with a minimum cohort size of three subjects. The dose of budigalimab is fixed at 500 mg (fixed dose) as an IV infusion Q4W.

[0086] 7.1.2. Eligibility Criteria: Adult subjects with solid tumors who are considered refractory or intolerant to all existing therapies that have been found to have a clinical effect on their respective disease states (i.e., subjects who have progressed on standard therapies that have been found to have a clinical effect). Additionally, subjects who have been offered standard therapy and have refused it or are considered ineligible for standard therapy may, on a case-by-case basis, be eligible for this trial. Subjects with pancreatic cancer, urothelial cancer, HCC, or HNSCC who are considered to belong to the dose-escalation cohort must also meet the histology-specific eligibility criteria described below for dose expansion.

[0087] 7.1.3. Dose Expansion Cohort: Dose expansion is to further evaluate the safety and tolerability of ABBV-151 when administered using the RP2D determined in the dose-escalation administered under combination with bimagrumab. All dose-expansion arms will only be initiated after the RP2D / MTD or MAD has been determined for both ABBV-151 monotherapy and ABBV-151 + bimagrumab combination therapy.

[0088] The RP2D selected for dose expansion is 1500 mg of ABBV-151 Q2W, which will be administered either as monotherapy or in combination with bimagrumab.

[0089] Dose expansion includes six cohorts with six types of tumor types to be evaluated (pancreatic cancer, urothelial cancer, HCC, HNSCC, MSS-CRC, and NSCLC). The expansion cohorts will evaluate the following indications: · ABBV-151 in combination with bimagrumab in pancreatic cancer · ABBV-151 in combination with bimagrumab in urothelial cancer · ABBV-151 in combination with bimagrumab in HCC · ABBV-151 in combination with bimagrumab in HNSCC · ABBV-151 in combination with bimagrumab in MSS-CRC · ABBV-151 in combination with bimagrumab in NSCLC.

[0090] The dose escalation provides the characterization of the safety profile, PK / PD, and preliminary efficacy of ABBV-151 in combination with budigalimab.

[0091] 7.1.4. Eligibility Criteria: All subjects with HCC, pancreatic cancer, or MSS-CRC must not have had prior exposure to a PD-1 / PD-L1 antagonist on any line of therapy.

[0092] Subjects with pancreatic cancer must have disease progression during or after the administration of one systemic therapy (gemcitabine monotherapy or combination therapy with other agents, FOLFIRINOX therapy [or another regimen including both 5-fluorouracil and oxaliplatin], capecitabine monotherapy or combination therapy with other agents) administered in the adjuvant setting, locally advanced setting, or metastatic setting. Progression on two or more prior systemic therapies is not allowed in this cohort. If the therapy was used in the adjuvant setting, disease progression must have occurred within 6 months of completion of adjuvant therapy.

[0093] Subjects with urothelial carcinoma of the bladder and urinary tract must have disease progression after treatment with a platinum-based regimen (regardless of the line of therapy administered) and a PD-1 / PD-L1 antagonist administered in the recurrent or metastatic setting (progression after PD-1 / PD-L1 antagonist administration is defined as overt progression within 3 months of the last dose of anti-PD-1 or anti-PD-L1 therapy).

[0094] Subjects with hepatocellular carcinoma must not have disease progression during or after one line of prior systemic therapy. Progression on two or more prior systemic therapies is not allowed in this cohort. Subjects must have a Child-Pugh classification of A and must not require chronic therapy for ascites (i.e., do not require diuretics, repeated paracentesis, or indwelling catheter). Subjects with varices are eligible as long as they have received appropriate prophylaxis / intervention according to local guidelines. Subjects must also meet specific requirements regarding their viral hepatitis status.

[0095] Subjects with head and neck squamous cell carcinoma (primary in the oral cavity, oropharynx, hypopharynx, or larynx) must not have disease progression after treatment with a platinum-based regimen (regardless of the line of administration) and a PD-1 / PD-L1 antagonist administered in a recurrent or metastatic setting (progression after PD-1 / PD-L1 antagonist administration is defined as overt progression within 3 months of the last dose of anti-PD-1 or anti-PD-L1 therapy).

[0096] CRC subjects with microsatellite stability or mismatch repair proficient colorectal adenocarcinoma (when determined by PCR / NGS or IHC, respectively) who have received a prior fluorouracil-based combination chemotherapy regimen that includes oxaliplatin and irinotecan (with or without concomitant use of VEGF and / or EGFR targeted agents).

[0097] Subjects with histologically or cytologically confirmed advanced or metastatic NSCLC who have received one line of prior chemotherapy administered concomitantly or sequentially in a metastatic setting and one prior anti-PD-(L)1 antibody treatment. Prior chemotherapy and immunotherapy in the neoadjuvant / adjuvant setting are permitted, but subjects who have received two or more lines of chemotherapy in the metastatic setting and / or two or more prior anti-PD-(L)1s in the metastatic setting are ineligible. Progression after PD-1 / PD-L1 antagonist administration is defined as overt progression within three months of the last administration of anti-PD-1 or anti-PD-L1 therapy. NSCLC subjects with known EGFR mutations or ALK / ROS1 gene rearrangements are ineligible.

[0098] Subjects must further meet the following requirements.

[0099] The Eastern Cooperative Oncology Group (ECOG) performance status is 0 - 1, and bone marrow, renal, hepatic, and coagulation functions are adequate. Subjects must not have received anti-cancer therapy, including chemotherapy, immunotherapy, radiotherapy, biologic / phyto-therapy, or any investigational therapy, within five half-lives or 28 days (whichever is shorter) prior to the first administration of the investigational drug. There are no grade >1 unhealed AEs attributable to prior anti-cancer therapy, except alopecia. There are no clinically significant uncontrolled pathologies, no active bacterial, fungal, or viral infections, and no active autoimmune diseases, except vitiligo, type I diabetes, hypothyroidism, and psoriasis. There is no history of a past clinical diagnosis of primary immunodeficiency syndrome, bone marrow transplantation, solid organ transplantation, or tuberculosis. There is no history of inflammatory bowel disease, interstitial lung disease or pneumonia, myocarditis, Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS). There are no known uncontrolled metastases to the central nervous system (except for specified exceptions).

[0100] For all subjects other than those with HCC, the viral hepatitis status of the subject must be confirmed to be negative on tests for active hepatitis A, B, or C.

[0101] Have not used immunosuppressive drugs currently or have not used them previously within 14 days before the first dose of the test drug.

[0102] Have not received live vaccines within 28 days before the first dose of the test drug.

[0103] 7.2. Example 2: Results of the M19-345 Phase 1 First-in-Human Multicenter Open-Label Dose Escalation Study to Examine the Safety, Tolerability, Pharmacokinetics, and RP2D of ABBV-151 as Monotherapy and in Combination with ABBV-181 in Subjects with Locally Advanced or Metastatic Solid Tumors 7.2.1. Overview As of June 1, 2022, 157 subjects are registered. Among these subjects, 57 belong to the dose escalation cohort, of which 23 belong to the monotherapy cohort and 34 belong to the combination therapy cohort. 100 subjects are registered in the dose expansion cohort and are receiving ABBV-151 in combination with budigalimab.

[0104] Subjects with progressive solid tumors who are considered refractory or intolerant to all existing therapies with known clinical efficacy for their respective conditions were enrolled in the dose escalation cohort. 23 subjects were enrolled in the monotherapy dose escalation cohort, and ABBV-151 at 7 dose levels from 3 mg to 1500 mg was administered intravenously every 2 weeks (Q2W) as monotherapy. 34 subjects were enrolled in the combination therapy dose escalation cohort, and ABBV-151 at 6 dose levels from 10 mg to 1500 mg Q2W was administered under the combination with the fixed-dose anti-PD-1 antibody budigalimab (500 mg Q4W). The RP2D selected for ABBV-151 was determined to be 1500 mg every 2 weeks (Q2W) as monotherapy or in combination with budigalimab.

[0105] The objective response rate was 0% in the subjects treated with monotherapy and 12% in the combination therapy dose-escalation cohort. The response rate regardless of confirmation was 0% in the monotherapy dose-escalation cohort and 15% in the combination therapy dose-escalation cohort, and 26.5% of the subjects treated with combination therapy showed the best response of disease stabilization. The subjects enrolled in the dose-escalation cohort included both those with a history of anti-PD-1 therapy and PD-1 naive subjects, and included multiple tumor types such as non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer (both triple-negative breast cancer and hormone receptor-positive breast cancer), colorectal cancer, urothelial cancer, endometrial cancer, renal cell cancer, gastric cancer and esophagogastric junction cancer, prostate cancer, uterine adenocarcinoma, mesothelioma, perivascular epithelioid cell tumor, as well as several low-frequency adenocarcinomas, carcinomas, and sarcomas.

[0106] Subjects treated with the combination therapy of ABBV-151 + buparlisib were enrolled in the dose-expansion cohort. The cancer types included PD-1 relapsed / refractory urothelial cancer, PD-1 relapsed / refractory head and neck squamous cell carcinoma (HNSCC), and PD-1 relapsed / refractory non-small cell lung cancer (NSCLC), as well as PD-1 naive microsatellite stable colorectal cancer (MSS-CRC), PD-1 naive hepatocellular carcinoma (HCC), and PD-1 naive pancreatic cancer and ovarian granulosa cell tumor.

[0107] The subjects who responded to the administration of ABBV-151 + buparlisib included 1 subject with esophagogastric junction adenocarcinoma, 4 subjects with colorectal cancer (3 out of 4 had MSS-CRC), 2 subjects with ovarian cancer (granulosa cell subtype), 1 subject with pancreatic cancer, 7 subjects with urothelial cancer, 5 subjects with hepatocellular cancer, and 3 subjects with ovarian granulosa cell tumor. Additionally, several other subjects had stable disease lasting for more than 6 months. Therefore, it is clear that the combination of ABBV-151 + buparlisib has a sustained antitumor effect not only on PD-1 relapsed / refractory subjects with various previous treatment histories but also on PD-1 naive subjects.

[0108] 7.2.2. Results of dose escalation of ABBV-151 monotherapy: Twenty-three subjects were enrolled in the monotherapy escalation cohort. Sixty-five percent were naïve to anti-PD-(L)1, and the median number of prior therapy lines was 4. Tumor types were 4 cases of NSCLC, 3 cases of ovarian cancer, 1 case of pancreatic cancer, 3 cases of CRC, 2 cases of TNBC, 1 case of breast cancer (non-TNBC), and 9 cases of other solid tumors (2 cases of endometrial cancer, osteosarcoma, mesothelioma, 2 cases of gastric cancer, rhabdomyosarcoma, papillary adenocarcinoma, perivascular epithelioid cell tumor).

[0109] The results are shown in Figure 2. There were no responders in the monotherapy cohort. The objective response rate (ORR) was 0%, the best overall response rate (including unconfirmed) was 0%, and the number of patients with stable disease (SD) lasting more than about 6 months was 0.

[0110] 7.2.3. Results of ABBV-151 + ABBV-181 dose-escalation combination therapy: Thirty-four subjects were enrolled in the combination therapy dose-escalation cohort. Seventy percent were naïve to anti-PD-(L)1, and the median number of prior therapy lines was 3. Tumor types were 1 case of NSCLC, 7 cases of ovarian cancer, 4 cases of pancreatic cancer, 8 cases of CRC, 1 case of urothelial cancer, 2 cases of breast cancer (non-TNBC), and 11 cases of other solid tumors (renal cell cancer, adrenocortical cancer, prostate cancer, esophagogastric junction adenocarcinoma, sebaceous gland cancer (eyelid sebaceous gland cancer), uterine adenocarcinoma, leiomyosarcoma, duodenal papilla adenocarcinoma, clear cell sarcoma, alveolar soft part sarcoma, and endometrial adenocarcinoma).

[0111] The results are shown in Figure 2. The objective response rate was 4 / 34 (11.8%), and the best overall response rate (including unconfirmed) was 5 / 34 (14.7%). Furthermore, the number of subjects who did not respond but had stable disease lasting more than about 6 months was 4 / 34 (11.8%).

[0112] The responders were 1 subject with gastroesophageal junction adenocarcinoma who was PD-1 naive (20004 in the 30 mg ABBV-151 combination cohort), 2 subjects with colorectal cancer (12010 who was PD-1 naive and treated in the 30 mg ABBV-151 combination cohort, and 20007 who had a previous treatment history with a PD-1 inhibitor and was treated in the 100 mg ABBV-151 combination cohort), and 1 subject with ovarian cancer who was PD-1 naive (10015 treated in the 1500 mg ABBV-151 combination cohort). One subject with PD-1 naive ovarian cancer (10017 treated in the 1500 mg ABBV-151 combination cohort) achieved unconfirmed PR at the final disease assessment. Additionally, 4 subjects (12007 with PD-1 refractory colorectal cancer in the 10 mg ABBV-151 combination cohort, 40007 with PD-1 naive alveolar soft part sarcoma in the 1500 mg ABBV-151 combination cohort, 10019 with PD-1 naive ovarian cancer in the 1500 mg ABBV-151 combination cohort, and 30012 with PD-1 refractory urothelial cancer in the 1500 mg ABBV-151 combination cohort) had stable disease for 6 months or more at the data cutoff time.

[0113] 7.2.4. Dose Escalation of ABBV-151 + ABBV-181 in PD-1 R / R Urothelial Cancer: Subjects with histologically or cytologically confirmed urothelial cancer of the bladder and urinary tract were enrolled who had progressed after treatment with a platinum-based regimen (regardless of the line of administration) and a PD-1 / PD-L1 antagonist administered in a recurrent or metastatic setting (progression after PD-1 / PD-L1 antagonist administration is defined as overt progression within 3 months of the last dose of anti-PD-1 or anti-PD-L1 therapy).

[0114] As of May 2022, 32 patients were registered, the median number of pre-treatment lines was 3, several of whom had a previous treatment history with enfortumab vedotin, including 1 responder who did not respond to previous treatment for EV. The results are shown in Figure 3. The objective response rate to date is 5 / 32 patients (15.6%). The best overall response rate to date (including unconfirmed) is 6 / 32 patients (18.8%). As of July 26, 7 out of 36 registered patients were responders (6 confirmed). Additionally, 1 other subject had stable disease for more than about 6 months.

[0115] As of March 30, 2023, 48 patients were registered, 45 were evaluable for response, and the confirmed ORR based on RECIST 1.1 was 18%.

[0116] 7.2.5. Dose Escalation of ABBV-151 + ABBV-181 in PD-1 Naive Hepatocellular Carcinoma (HCC): Subjects with histologically confirmed advanced HCC who had disease progression during or after one line of prior systemic therapy were enrolled. Progression on more than two prior systemic therapies was not allowed in this cohort. Subjects had to be Child-Pugh class A and not require chronic therapy for ascites. Subjects with venous aneurysms were eligible as long as they received appropriate prophylaxis / intervention according to local guidelines. Additionally, viral status eligibility was included in the protocol.

[0117] 12 subjects were enrolled, most of whom had a previous treatment history with sorafenib, while several had a previous treatment history with lenvatinib or other tyrosine kinase inhibitors (TKIs). The median number of pre-treatment lines was 1.

[0118] The results are shown in Figure 4. The objective response rate was 3 / 12 subjects (25%). As of July 2022, there were 5 confirmed responders. The best overall response rate (including unconfirmed) was 4 / 12 subjects (33.3%). 2 other subjects had stable disease for more than about 6 months.

[0119] As of March 30, 2023, 12 patients were registered, all of whom were evaluable for efficacy, and the confirmed ORR based on iRECIST was 42%.

[0120] 7.2.6. Dose Escalation of ABBV-151 + ABBV-181 in PD-1 Naïve Pancreatic Cancer: Subjects with histologically or cytologically confirmed advanced or metastatic pancreatic cancer who had disease progression during or after one systemic therapy were enrolled. As of May 2022, 23 subjects were enrolled, and the median number of pre-treatment lines was 2.

[0121] The results are shown in Figure 5. The objective response rate was 0%. The best overall response rate (including unconfirmed) was 1 / 23 (4.3%). Another subject had stable disease for approximately 6 months.

[0122] As of March 30, 2023, 23 patients were registered, all of whom were evaluable for efficacy, and the confirmed ORR based on RECIST 1.1 was 0%.

[0123] 7.2.7. Dose Escalation of ABBV-151 + ABBV-181 in PD-1 Naïve Microsatellite Stable Colorectal Adenocarcinoma: Subjects with microsatellite stability or proficient mismatch repair colorectal adenocarcinoma (when determined by PCR / NGS or IHC respectively), who had received 1-2 prior chemotherapy regimens and had refused or were ineligible for other approved therapies were enrolled. Subjects progressing on more than 3 prior systemic therapies were not eligible for this cohort. Subjects must have access to their past microsatellite instability or mismatch repair test results or have accessible archival tissue suitable for the expected tests at prescreening. Subjects known to have a high tumor mutational burden (defined as ≥10 mutations per megabase) based on past results were not eligible.

[0124] The results are shown in Figure 6. As of July 2022, 25 subjects were registered. The objective response rate was 1 / 25 (4%). The best overall response rate (including unconfirmed) was 2 / 25 (8%). Another subject had stable disease for approximately 6 months.

[0125] As of March 30, 2023, 25 patients were registered, 24 were evaluable for response, and the confirmed ORR based on RECIST 1.1 was 8%.

[0126] 7.2.8. Dose Escalation of ABBV-151 + ABBV-181 in NSCLC As of March 30, 2023, 3 patients were registered, all 3 were evaluable for response, and the confirmed ORR was 0%. Since this cohort was recently started, the results are immature and more patient data are needed to fully evaluate the efficacy of the combination in NSCLC.

[0127] 7.2.9. Dose Escalation of ABBV-151 + ABBV-181 in Ovarian Granulosa Cell Tumor As of March 30, 2023, 4 patients were registered, and the unconfirmed ORR was 75%.

[0128] 7.3. Example 3: PK / PD Analysis, Modeling, and Dose Optimization 7.3.1. Pharmacodynamic Biomarkers Using a validated method, GARP / TGF-β1 target engagement of ABBV-151 on activated platelets isolated from clinical samples was measured.

[0129] 7.3.2. Pharmacokinetics and Pharmacodynamics Pharmacokinetic samples were collected at the designated hospital visit and at the designated time points. Using a validated method, the serum concentration of ABBV-151 was measured.

[0130] A non-linear mixed effects modeling approach was used to estimate population PK parameters such as clearance (CL) and volume of distribution (V) of ABBV-151. Emax Using the model to model pharmacodynamics and extrapolating to the tumor microenvironment after estimating the concentration (EC 95 ) required to achieve 95% target engagement of platelet GARP / TGF-β1 in circulation.

[0131] 7.3.3. Clinical PK / PD Modeling and Dose Optimization In the treatment where ribmoniprimab was administered as monotherapy and in combination with budigalimab, the tolerance was good, and there were no major safety issues at all doses tested in the dose escalation (Study M19-345). The maximum administered dose (MAD) was 1500 mg Q2W in combination with budigalimab, and it is being evaluated for multiple solid tumor indications in the expansion phase. In combination with budigalimab, a clinical response (confirmed response according to the RECIST criteria) was observed at a low dose of 30 mg Q2W during dose escalation and at 1500 mg Q2W during dose expansion.

[0132] According to preclinical and clinical PK / PD evaluations, the doses that are predicted to exert sufficient pharmacological effects at the tumor site in the majority of subjects in the treatment population and potentially exhibit clinical efficacy include 500 mg Q4W or more or 375 mg Q3W or more. As evidenced by the clinical activity during the dose escalation part and the dose expansion part of M19-345, it seems that even lower doses are effective.

[0133] (1) Based on clinical PK / PD data, the C 95 value (28-day cycle for Q4W, 21-day cycle for Q3W) required to reach above the upper limit of the 95% prediction interval (PI) of GARP / TGF-β1 target engagement in the tumor microenvironment of the majority of subjects, and (2) after maximally inhibiting the release of TGF-β1 from the GARP-TGF-β1 complex, the minimum C min,C1 required to inhibit the autocrine and paracrine signaling of TGF-β1 in the tumor microenvironment min,C1The specific target concentrations at the tumor site were used, and the identification of the pharmacologically and clinically effective dosage ranges was carried out using the achievement of these concentrations as an indicator. It has been demonstrated by preclinical in vitro assays that ribomuniprimab at a minimum concentration of 0.8 μg / mL maximally inhibits TGF-β1 release and signal transduction. Therefore, the latter target concentration was set based on this.

[0134] Table 4 summarizes the percentage of subjects who achieved these two target concentrations at the tumor site with the specified Q4W dosage. Table 5 summarizes the results of Q3W administration corresponding to an exposure equivalent to the Q4W regimen. As is clear from the table, with ribomuniprimab 500 mg Q4W or 375 mg Q3W, more than 95% of the subjects, including those with the lower limit of the PI of the predicted ribomuniprimab tumor exposure (C min,C1 ) are likely to achieve complete target saturation at the tumor site and inhibition of TGF-β1 release and signal transduction. Therefore, ribomuniprimab 500 mg Q4W or 375 mg Q3W is the predicted minimum dosage required for maximum pharmacological activity in most subjects with all solid tumor indications treated starting from cycle 1. If the dosage is less than 500 mg Q4W or 375 mg Q3W, exposure may be insufficient in some of the subjects treated in cycle 1, and the achievement of the goal of providing pharmacological activity and potentially clinical efficacy as early as possible may be at risk.

[0135] In addition to the model-predicted effective dosage range (500 mg Q4W or more; 375 mg Q3W or more), the clinically confirmed effective dosage range of 30 mg Q2W or more will also be considered in the future.

[0136] [Table 4]

[0137] [Table 5]

[0138] 8. Typical Embodiments The above has specifically described various specific embodiments, and representative examples are given below. Of course, various modifications can be made without departing from the spirit and scope of the present invention.

[0139] 8.1. Embodiments of solid tumors expressing TGF-β1 1. A method for treating cancer that at least partially evades host immune surveillance by expressing and releasing active TGF-β1, the method comprising administering to a human subject having said tumor a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks or once every three weeks at a dose of about 200 mg to about 1600 mg. 2. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1500 mg. 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 5. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg, and 1600 mg. 6. The method according to embodiment 2, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 8. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 9. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 13. A method for treating cancer that at least partially evades host immune surveillance by the expression and release of active TGF-β1, the method comprising administering to a human subject having said cancer a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1200 mg. 14. The method according to embodiment 12, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 15. The method according to embodiment 12, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 16. The method according to embodiment 12, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 17. A method for treating cancer that at least partially evades host immune surveillance by the expression and release of active TGF-β1, the method comprising administering to a human subject having said cancer a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, The method of administering the anti-TGF-β1 / GARP complex antibody once every four weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 550 mg, 600 mg, 1000 mg, 1500 mg, and 1600 mg. 18. The method according to embodiment 17, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 19. The method according to embodiment 17, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 20. The method according to embodiment 17, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 21. A method for treating cancer that evades host immune surveillance by at least partially expressing and releasing active TGF-β1 in a population of human subjects, comprising administering to the human subject having the cancer that evades host immune surveillance by at least partially expressing and releasing active TGF-β1 a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg, and the overall response rate (ORR) is higher than that of standard treatment, for example, 5% or more, 15% or more, 20% or more, 30% or more, or 40% or more. 22. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody in the treatment of cancer that at least partially evades host immune surveillance by the expression and release of active TGF-β1, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each composed of the amino acid sequence of SEQ ID NO: 9 and two light chains each composed of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg, and the anti-PD-1 antibody is administered once every three weeks at a dose of 375 mg or once every four weeks at a dose of 500 mg.

[0140] 8.2. Embodiments of hepatocellular carcinoma 1. A method for treating hepatocellular carcinoma (HCC), comprising administering to a human subject having the HCC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each composed of the amino acid sequence of SEQ ID NO: 9 and two light chains each composed of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. 2. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1600 mg. 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 5. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg, and 1600 mg. 6. The method according to embodiment 2, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 8. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 9. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 13. The method according to embodiment 1, wherein the subject having HCC has previously received first-line treatment for HCC and has experienced disease progression during the first-line treatment. 14. The method according to embodiment 13, wherein the first-line treatment comprises a checkpoint inhibitor. 15. The method according to embodiment 1, wherein the subject having HCC has progressed on two or more previous lines of treatment. 16. The method according to embodiment 1, wherein the subject having HCC has not previously been treated with a tyrosine kinase inhibitor, has no untreated brain metastases, and has not had prior exposure to a PD-1 or PD-L1 antagonist. 17. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is intravenously administered prior to intravenous administration of the anti-PD-1 antibody, and the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered on the same day. 18. The method according to embodiment 1, wherein the anti-PD-1 antibody is pembrolizumab. 19. The method according to embodiment 2, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 500 mg once every 4 weeks. 20. The method according to embodiment 3, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every three weeks at a dose of 375 mg. 21. The method according to embodiment 4, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every four weeks at a dose of 500 mg. 22. The method according to embodiment 1, wherein the subject having the HCC has not received previous treatment for HCC. 23. A method for treating hepatocellular carcinoma (HCC), comprising administering to a human subject having the HCC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each composed of the amino acid sequence of SEQ ID NO: 9 and two light chains each composed of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1200 mg, and the subject having the HCC has previously received first-line treatment for HCC and has experienced disease progression during the first-line treatment. 24. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 25. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 26. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 27. A method for treating hepatocellular carcinoma (HCC), comprising administering to a human subject having the HCC a) an anti-PD-1 antibody, b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each composed of the amino acid sequence of SEQ ID NO: 9 and two light chains each composed of the amino acid sequence of SEQ ID NO: 10, and c) bevacizumab in combination at a therapeutically effective amount, The anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose selected from the group consisting of 400 mg, 600 mg, 800 mg, and 1200 mg, the anti-PD-1 antibody is administered once every three weeks at a dose of 375 mg, and bevacizumab is administered once every three weeks at a dose of 15 mg / kg. The method, wherein the subject with HCC has not received previous treatment for HCC. 28. A method for treating hepatocellular carcinoma (HCC), comprising administering to a human subject having the HCC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, The method, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose selected from the group consisting of 500 mg, 550 mg, 600 mg, 1000 mg, 1500 mg, and 1600 mg. 29. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 30. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1000 mg. 31. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 32. A method for treating hepatocellular carcinoma (HCC) in a population of human subjects, comprising administering to the human subject having the HCC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, The method, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. 33. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody in the treatment of HCC, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

[0141] 8.3. Embodiments of urothelial cancer 1. A method for treating urothelial cancer (UC), comprising administering to a human subject having the UC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. 2. The method according to embodiment 1, wherein the UC is muscle-invasive urothelial cancer (MIUC). 3. The method according to embodiment 2, wherein the MIUC is classified as MIUC pT2-PT4a or ypT4. 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1600 mg. 5. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 6. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 7. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, and 1500 mg. 8. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 9. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 10. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 11. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 12. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 13. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 14. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 15. The method according to embodiment 1, wherein the subject having urothelial cancer or MIUC has received a previous treatment line for their respective cancer and has experienced disease progression in the previous treatment line. 16. The method according to embodiment 15, wherein the previous treatment line is treatment with a platinum-based regimen and / or a PD-1 / PD-L1 antagonist administered in a recurrent or metastatic setting. 17. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered intravenously on the same day, and the anti-TGF-β1 / GARP complex antibody is administered prior to the administration of the anti-PD-1 antibody. 18. The method according to embodiment 1, wherein the anti-PD-1 antibody is pembrolizumab. 19. The method according to embodiment 2, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 500 mg once every 4 weeks. 20. The method according to embodiment 5, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every three weeks at a dose of 375 mg. 21. The method according to embodiment 6, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every four weeks at a dose of 500 mg. 22. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered intravenously. 23. The method according to embodiment 1, wherein the subject having urothelial cancer or MIUC has not received prior treatment for urothelial cancer or MIUC. 24. A method for treating urothelial cancer, comprising administering to a human subject having said cancer: a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, and 1200 mg. 25. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 26. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 27. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 28. A method for treating urothelial cancer, comprising administering to a human subject having said cancer: a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, in combination, The method of administering the anti-TGF-β1 / GARP complex antibody once every four weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 550 mg, 600 mg, 1000 mg, 1500 mg, and 1600 mg. 29. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 30. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 31. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 32. A method for treating urothelial cancer in a population of human subjects, comprising administering to the human subject having the urothelial cancer a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg, and the overall response rate (ORR) is higher than that of standard treatment, for example, 5% or more, 10% or more, 15% or more, or 20% or more. 33. The method according to embodiment 32, wherein the UC is MIUC. 34. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody in the treatment of urothelial cancer, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

[0142] 8.4. Embodiments of non-small cell lung cancer 1. A method for treating non-small cell lung cancer (NSCLC), comprising administering to a human subject having said NSCLC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein said anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. 2. The method according to embodiment 1, wherein said combination further comprises carboplatin and pemetrexed. 3. The method according to embodiment 1, wherein said anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1500 mg. 4. The method according to embodiment 1, wherein said anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 5. The method according to embodiment 1, wherein said anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 6. The method according to embodiment 4, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg, and 1600 mg. 7. The method according to embodiment 3, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 8. The method according to embodiment 4, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 9. The method according to embodiment 4, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 10. The method according to embodiment 4, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 11. The method according to embodiment 5, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 12. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 13. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 14. The method according to embodiment 1 or 2, wherein the administration is first-line treatment. 15. The method according to embodiment 1 or 2, wherein the NSCLC has a PD-L1 TPS ≧ 1%. 16. The method according to embodiment 1 or 2, wherein the NSCLC has a PD-L1 TPS ≧ 50%. 17. The method according to embodiment 1, wherein the subject has received two or more previous lines of treatment and the subject's NSCLC is recurrent / refractory. 18. The method according to embodiment 1 or 2, wherein the subject's NSCLC has a PD-L1 TPS ≧ 50% and the subject has liver metastases. 19. The method according to embodiment 1 or 2, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered intravenously on the same day, and the anti-TGF-β1 / GARP complex antibody is administered prior to the administration of the anti-PD-1 antibody. 20. The method according to embodiment 1 or 2, wherein the anti-PD-1 antibody is pembrolizumab. 21. The method according to embodiment 3, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 500 mg once every 4 weeks. 22. The method according to embodiment 4, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 375 mg once every 3 weeks. 23. The method according to embodiment 5, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 500 mg once every 4 weeks. 24. A method for treating non-small cell lung cancer ("NSCLC"), comprising administering to a human subject having the NSCLC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering, said anti-TGF-β1 / GARP complex antibody at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1200 mg, once every three weeks, said method. 25. The method according to embodiment 24, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 26. The method according to embodiment 24, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 27. The method according to embodiment 24, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 28. A method for treating non-small cell lung cancer ("NSCLC"), comprising administering to a human subject having said NSCLC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody consisting of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering, said anti-TGF-β1 / GARP complex antibody at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 550 mg, 600 mg, 1000 mg, 1500 mg, and 1600 mg, once every four weeks, said method. 29. The method according to embodiment 28, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 30. The method according to embodiment 28, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 31. The method according to embodiment 28, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 32. A method for treating non-small cell lung cancer ("NSCLC") in a population of human subjects, comprising administering to said human subject having said NSCLC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) An anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering the anti-TGF-β1 / GARP complex antibody at a dose of about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks, wherein the overall response rate (ORR) is higher than that of standard treatment, for example, 20% or more, 30% or more, or 40% or more, said method. 33. The method according to embodiment 32, wherein said co-administration further comprises carboplatin and pemetrexed. 34. A TGF-β1 / GARP complex antibody for co-administration with an anti-PD-1 antibody in the treatment of NSCLC, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered at a dose of about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks, said complex antibody.

[0143] 8.5. Embodiments of microsatellite stable colorectal cancer 1. A method for treating microsatellite stable colorectal cancer (MSS-CRC), comprising administering to a human subject having said MSS-CRC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering the anti-TGF-β1 / GARP complex antibody at a dose of about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks, said method. 2. The method according to embodiment 1, wherein said MSS-CRC is of the CMS4 subtype. 3. The method according to embodiment 1, wherein said MSS-CRC is non-selective for the CMS4 subtype. 4. The method according to any one of Embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1500 mg. 5. The method according to any one of Embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 6. The method according to any one of Embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 7. The method according to any one of Embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, and 1400 mg. 8. The method according to Embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 9. The method according to Embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 10. The method according to Embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 11. The method according to Embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 12. The method according to Embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 13. The method according to Embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 14. The method according to Embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 15. The method according to any one of Embodiments 1 to 3, wherein the subject having MSS-CRC has previously received a previous treatment line for microsatellite stable colorectal cancer and has experienced disease progression in the first-line treatment. 16. The method according to embodiment 15, wherein the previous treatment line is fluorouracil-based combination chemotherapy and the subject has not received prior exposure to anti-PD-1 or anti-PD-L1 antibody therapy. 17. The method according to embodiment 16, wherein the previous treatment line comprises oxaliplatin or irinotecan. 18. The method according to any one of embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered intravenously on the same day, and the anti-TGF-β1 / GARP complex antibody is administered prior to the administration of the anti-PD-1 antibody. 19. The method according to any one of embodiments 1 to 3, wherein the anti-PD-1 antibody is pembrolizumab. 20. The method according to embodiment 4, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every 4 weeks at a dose of 500 mg. 21. The method according to embodiment 5, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every 3 weeks at a dose of 375 mg. 22. The method according to embodiment 6, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every 4 weeks at a dose of 500 mg. 23. The method according to any one of embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered intravenously. 24. The method according to any one of embodiments 1 to 3, wherein the subject having MSS-CRC has not received prior treatment for MSS-CRC. 25. A method for treating MSS-CRC, comprising administering to a human subject having MSS-CRC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, The method, wherein the anti-TGF-β1 / GARP complex antibody is administered once every 3 weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1200 mg. 26. The method according to embodiment 25, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 27. The method according to embodiment 25, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 28. The method according to embodiment 25, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 29. The method according to embodiment 25, wherein the MSS-CRC is of the CMS4 subtype. 30. The method according to embodiment 25, wherein the MSS-CRC is non-selective for the CMS4 subtype. 31. A method for treating MSS-CRC, comprising administering to a human subject having the MSS-CRC a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every 4 weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 550 mg, 600 mg, 1000 mg, 1500 mg, and 1600 mg. 32. The method according to embodiment 31, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 33. The method according to embodiment 31, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 34. The method according to embodiment 31, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 35. The method according to embodiment 31, wherein the MSS-CRC is of the CMS4 subtype. 36. The method according to embodiment 31, wherein the MSS-CRC is non-selective for the CMS4 subtype. 37. A method for treating MSS-CRC in a population of human subjects, comprising administering to the human subject having the MSS-CRC a) A therapeutically effective amount of an anti-PD-1 antibody, and b) An anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering, administering the anti-TGF-β1 / GARP complex antibody once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg, The method, wherein the overall response rate (ORR) is higher than that of standard treatment, for example, 5% or more, 15% or more, 20% or more, 30% or more, or 40% or more. 38. The method according to embodiment 37, wherein the MSS-CRC is of the CMS4 subtype. 39. The method according to embodiment 37, wherein the MSS-CRC is non-selective for the CMS4 subtype. 34. A TGF-β1 / GARP complex antibody for co-administration with an anti-PD-1 antibody in the treatment of MSS-CRC, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

[0144] 8.6. Embodiments of ovarian granulosa cell tumors 1. A method for treating ovarian granulosa cell tumor (GCT), comprising administering to a human subject having the GCT a) A therapeutically effective amount of an anti-PD-1 antibody, and b) An anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering, administering the anti-TGF-β1 / GARP complex antibody once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. 2. The method according to embodiment 1, wherein the GCT comprises a FOXL2 gene mutation. 3. The method according to embodiment 2, wherein the FOXL2 mutation is a C134W mutation. 4. The method according to any one of embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1500 mg. 5. The method according to any one of embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 6. The method according to any one of embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 7. The method according to any one of embodiments 1 to 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg, and 1600 mg. 8. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 9. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 10. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 11. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 12. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 13. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 14. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 15. The method according to any one of Embodiments 1 to 3, wherein the subject having the GCT has undergone unilateral salpingo - oophorectomy or bilateral salpingo - oophorectomy within 120 days before the administration of the anti - TGF - β1 / GARP complex antibody. 16. The method according to any one of Embodiments 1 to 3, wherein the anti - TGF - β1 / GARP complex antibody and the anti - PD - 1 antibody are intravenously administered on the same day, and the anti - TGF - β1 / GARP complex antibody is administered prior to the administration of the anti - PD - 1 antibody. 17. The method according to any one of Embodiments 1 to 3, wherein the anti - PD - 1 antibody is pembrolizumab. 18. The method according to Embodiment 2, wherein the anti - PD - 1 antibody is pembrolizumab and is administered once every 4 weeks at a dose of 500 mg. 19. The method according to Embodiment 5, wherein the anti - PD - 1 antibody is pembrolizumab and is administered once every 3 weeks at a dose of 375 mg. 20. The method according to Embodiment 6, wherein the anti - PD - 1 antibody is pembrolizumab and the anti - PD - 1 antibody is administered once every 4 weeks at a dose of 500 mg or 600 mg. 21. The method according to any one of Embodiments 1 to 3, wherein the anti - TGF - β1 / GARP complex antibody and the anti - PD - 1 antibody are intravenously administered. 22. The method according to any one of Embodiments 1 to 3, wherein the subject having the GCT has not received prior systemic treatment for GCT. 23. A method for treating granulosa cell tumor (GCT) containing FOXL2 C134W mutation, comprising administering to a human subject having the GCT a) a therapeutically effective amount of an anti - PD - 1 antibody, and b) an anti - TGF - β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti - TGF - β1 / GARP complex antibody is administered once every 3 weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, and 1200 mg. The method wherein the subject having the GCT has undergone unilateral salpingo - oophorectomy or bilateral salpingo - oophorectomy within 120 days before administration of the anti - TGF - β1 / GARP complex antibody. 24. The method according to embodiment 23, wherein the anti - TGF - β1 / GARP complex antibody is administered at a dose of 400 mg. 25. The method according to embodiment 23, wherein the anti - TGF - β1 / GARP complex antibody is administered at a dose of 600 mg. 26. The method according to embodiment 23, wherein the anti - TGF - β1 / GARP complex antibody is administered at a dose of 1200 mg. 27. A method for treating granulosa cell tumor (GCT) containing FOXL2 C134W mutation, comprising administering to a human subject having the GCT a) an anti - PD - 1 antibody in a therapeutically effective amount, b) an anti - TGF - β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and c) bevacizumab in combination, wherein the anti - TGF - β1 / GARP complex antibody is administered once every 3 weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1200 mg, The method wherein the subject having the GCT has not received prior systemic treatment for GCT. 28. A method for treating granulosa cell tumor (GCT) containing FOXL2 C134W mutation, comprising administering to a human subject having the GCT a) an anti - PD - 1 antibody in a therapeutically effective amount, and b) an anti - TGF - β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, The method of administering the anti-TGF-β1 / GARP complex antibody once every four weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 550 mg, 600 mg, 1000 mg, 1500 mg, and 1600 mg. 29. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 30. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 31. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 32. A method for treating ovarian granulosa cell tumor (GCT) containing the FOXL2 C134W mutation in a population of human subjects, comprising administering to the human subject having the GCT a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1500 mg, the overall response rate (ORR) is higher than that of standard treatment, for example, 5% or more, about 10% or more, about 15% or more, 20% or more, 30% or more, or 40% or more, said method. 33. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody in the treatment of GCT, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1500 mg.

[0145] 8.7. Embodiments of head and neck squamous cell carcinoma 1. A method for treating head and neck squamous cell carcinoma, comprising administering to a human subject having said head and neck squamous cell carcinoma, a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein said anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. 2. The method according to embodiment 1, wherein said anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1500 mg. 3. The method according to embodiment 1, wherein said anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 4. The method according to embodiment 1, wherein said anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 5. The method according to embodiment 1, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg, and 1600 mg. 6. The method according to embodiment 2, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 7. The method according to embodiment 3, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 8. The method according to embodiment 3, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 9. The method according to embodiment 3, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 10. The method according to embodiment 4, wherein said anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 13. The method according to embodiment 1, wherein the head and neck squamous cell carcinoma originates from the oral cavity, oropharynx, hypopharynx, or larynx. 14. The method according to embodiment 1, wherein the subject having the head and neck squamous cell carcinoma has received prior treatment before first-line treatment of the head and neck squamous cell carcinoma and has experienced disease progression in the prior treatment. 15. The method according to embodiment 14, wherein the prior treatment line is a platinum-based regimen and an anti-PD-1 or anti-PD-L1 antibody administered in a recurrent or metastatic setting. 16. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is intravenously administered prior to the intravenous administration of the anti-PD-1 antibody, and the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered on the same day. 17. The method according to embodiment 1, wherein the anti-PD-1 antibody is pembrolizumab. 18. The method according to embodiment 2, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every 4 weeks at a dose of 500 mg. 19. The method according to embodiment 3, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every 3 weeks at a dose of 375 mg. 20. The method according to embodiment 4, wherein the anti-PD-1 antibody is pembrolizumab and is administered once every 4 weeks at a dose of 500 mg. 21. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are intravenously administered. 22. The method according to embodiment 1, wherein the subject having the head and neck squamous cell carcinoma has not received prior treatment for the head and neck squamous cell carcinoma. 23. A method for treating head and neck squamous cell carcinoma, comprising administering to a human subject having the head and neck squamous cell carcinoma, a) a therapeutically effective amount of an anti-PD-1 antibody, and b) An anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering the anti-TGF-β1 / GARP complex antibody at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, and 1200 mg once every 3 weeks, and the anti-PD-1 antibody at a dose of 375 mg once every 3 weeks, wherein the subject having the head and neck squamous cell carcinoma has received a previous treatment line for head and neck squamous cell carcinoma and has experienced disease progression in the previous treatment line, the method. 24. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 25. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 26. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 27. A method for treating head and neck squamous cell carcinoma, comprising administering to a human subject having the head and neck squamous cell carcinoma a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering the anti-TGF-β1 / GARP complex antibody at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 550 mg, 600 mg, 1000 mg, 1500 mg, and 1600 mg once every 4 weeks, and the anti-PD-1 antibody at a dose of 500 mg once every 4 weeks, the method. 28. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 29. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 30. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 31. A method for treating head and neck squamous cell carcinoma in a population of human subjects, comprising administering to the human subject having the head and neck squamous cell carcinoma a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1500 mg, and the overall response rate (ORR) is higher than that of standard treatment, for example, 5% or more, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more. 33. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody in the treatment of head and neck squamous cell carcinoma, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

[0146] 8.8. Embodiments of pancreatic cancer 1. A method for treating pancreatic cancer, comprising administering to a human subject having the pancreatic cancer a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. 2. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose of about 200 mg to about 1500 mg. 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose of about 200 mg to about 1200 mg. 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose of about 200 mg to about 1600 mg. 5. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, and 1500 mg. 6. The method according to embodiment 2, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 8. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 9. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 13. The method according to embodiment 1, wherein the subject having pancreatic cancer has received previous treatment of one line or less of pancreatic cancer and has experienced disease progression in the first-line treatment. 14. The previous treatment line is a) gemcitabine monotherapy or combination therapy with other agents; b) FOLFIRINOX therapy or another regimen comprising both 5-fluorouracil and oxaliplatin; or c) Capecitabine monotherapy or combination therapy with other agents which is administered in an adjuvant setting, a locally advanced setting, or a metastatic setting, and wherein the subject has not had prior exposure to a PD-1 or PD-L1 antagonist, the method according to embodiment 13. 15. The method according to embodiment 14, wherein the previous treatment line is in an adjuvant setting and disease progression has occurred within 6 months from the completion of adjuvant therapy. 16. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered on the same day. 17. The method according to embodiment 1, wherein the anti-PD-1 antibody is pembrolizumab. 18. The method according to embodiment 2, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 500 mg once every 4 weeks. 19. The method according to embodiment 3, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 375 mg once every 3 weeks. 20. The method according to embodiment 4, wherein the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 500 mg once every 4 weeks. 21. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody are administered intravenously. 22. The method according to embodiment 1, wherein the subject having pancreatic cancer has not received prior treatment for pancreatic cancer. 23. A method for treating pancreatic cancer, comprising administering to a human subject having pancreatic cancer a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in combination, The anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose selected from the group consisting of 400 mg, 500 mg, 600 mg, 800 mg, and 1200 mg, and the anti-PD-1 antibody is administered once every three weeks at a dose of 375 mg. The method, wherein the subject having pancreatic cancer has received a previous treatment line for pancreatic cancer and has experienced disease progression in the previous treatment line. 24. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg. 25. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 26. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg. 27. A method for treating pancreatic cancer, comprising administering to a human subject having pancreatic cancer a) an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 in a therapeutically effective amount in combination, The anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose selected from the group consisting of 200 mg, 400 mg, 500 mg, 550 mg, 600 mg, 1000 mg, and 1500 mg, and the anti-PD-1 antibody is administered once every four weeks at a dose of 500 mg. 28. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg. 29. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg. 30. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg. 31. A method for treating pancreatic cancer in a population of human subjects, comprising administering to the human subject having pancreatic cancer a) a therapeutically effective amount of an anti-PD-1 antibody, and b) an anti-TGF-β1 / GARP complex antibody composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10 comprising co-administering the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1500 mg, and the anti-PD-1 antibody is administered once every three weeks at a dose of 375 mg or once every four weeks at a dose of 500 mg, the method, wherein the overall response rate (ORR) is higher than that of standard treatment, for example, 5% or more, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more. 32. A TGF-β1 / GARP complex antibody for co-administering with an anti-PD-1 antibody in the treatment of pancreatic cancer, wherein the anti-TGF-β1 / GARP complex antibody is composed of two heavy chains each consisting of the amino acid sequence of SEQ ID NO: 9 and two light chains each consisting of the amino acid sequence of SEQ ID NO: 10, and the anti-TGF-β1 / GARP complex antibody is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

Claims

**Claim 1** A method for treating microsatellite stable colorectal cancer rich in CMS4, comprising administering to a human subject having said cancer a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, wherein said ribmoniprimab is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. **Claim 2** The method according to claim 1, wherein said anti-PD-1 antibody is bdurigamab, and said bdurigamab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg. **Claim 3** A method for treating microsatellite stable colorectal cancer, comprising administering to a human subject having said cancer a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, wherein said ribmoniprimab is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. **Claim 4** The method according to claim 3, wherein said anti-PD-1 antibody is bdurigamab, and said bdurigamab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg. **Claim 5** A method for treating non-small cell lung cancer (NSCLC), comprising administering to a human subject having said NSCLC a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, wherein said ribmoniprimab is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. **Claim 6** The method according to claim 5, further comprising administering carboplatin and pemetrexed. **Claim 7** The method according to claim 5 or 6, wherein said anti-PD-1 antibody is bdurigamab, and said bdurigamab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg. **Claim 8** A method for treating recurrent / refractory non-small cell lung cancer (NSCLC), comprising administering to a human subject having said cancer a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, The method of administering the ribmoniprimab once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. **Claim 9** The method according to claim 1, wherein the anti-PD-1 antibody is bdurigamab, and the bdurigamab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg. **Claim 10** A method for treating pancreatic cancer, comprising administering to a human subject having the pancreatic cancer a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, The method of administering the ribmoniprimab once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. **Claim 11** The method according to claim 10, wherein the anti-PD-1 antibody is bdurigamab, and the bdurigamab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg. **Claim 12** The method according to claim 10 or 11, further comprising administering paclitaxel or nab-paclitaxel and gemcitabine. **Claim 13** A method for treating muscle-invasive bladder cancer, comprising administering to a human subject having the cancer a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in combination, The method of administering the ribmoniprimab once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. **Claim 14** The method according to claim 13, wherein the anti-PD-1 antibody is bdurigamab, and the bdurigamab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg. **Claim 15** A method for treating granulosa cell tumor (GCT) containing FOXL2 C134W mutation, comprising administering to a human subject having the tumor a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in combination, The method of administering the ribmoniprimab once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg. **Claim 16** The method according to claim 15, wherein the anti-PD-1 antibody is pembrolizumab, and the pembrolizumab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg.

17. A method for treating head and neck squamous cell carcinoma, comprising administering to a human subject having said carcinoma a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, wherein the ribmoniprimab is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

18. The method according to claim 1, wherein the anti-PD-1 antibody is pembrolizumab, and the pembrolizumab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg.

19. A method for treating hepatocellular carcinoma (HCC), comprising administering to a human subject having said carcinoma a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, wherein the ribmoniprimab is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

20. The method according to claim 18, wherein the anti-PD-1 antibody is pembrolizumab, and the pembrolizumab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg.

21. The method according to claim 19 or 20, wherein the subject has not received a previous treatment line for HCC.

22. The method according to claim 19 or 20, wherein the subject has received one previous treatment for HCC.

23. The method according to claim 19 or 20, wherein the subject has received two or more previous treatments for HCC.

24. A method for treating urothelial carcinoma, comprising administering to a human subject having said carcinoma a) a therapeutically effective amount of an anti-PD-1 antibody under a therapeutically effective schedule, and b) ribmoniprimab in a therapeutically effective amount in combination, wherein the ribmoniprimab is administered once every two weeks, once every three weeks, or once every four weeks at a dose of about 200 mg to about 1600 mg.

25. The method according to claim 1, wherein the anti-PD-1 antibody is bdurigamab, and the bdurigamab is administered once every two weeks at a dose of 250 mg, once every three weeks at a dose of 375 mg, or once every four weeks at a dose of 500 mg.

26. The method according to any one of claims 1 to 25, wherein the combined administration of ribmoniprimab and the anti-PD-1 antibody is more effective than when the anti-PD-1 antibody is used as a monotherapy.

27. The method according to any one of claims 1 to 25, wherein the combined administration of ribmoniprimab and the anti-PD-1 antibody results in a higher overall response rate than when the anti-PD-1 antibody is used as a monotherapy.

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