ANTI-GARP-TGF-beta1 / PD-1 COMBINATION THERAPY

Abstract

The present disclosure provides methods of treating cancer with a combination of an anti-TGF-beta 1 / GARP complex antibody and an anti-PD-1 antibody.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 369,931, filed on July 29, 2022, which is hereby incorporated by reference in its entirety.

[0003] 1. Sequence Listing

[0004] This application contains a sequence listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy was created on July 7, 2022, is named SeqList_350794-50100 and is 22,691 bytes in size. Technical Field

[0005] The present application relates to the use of an antibody capable of inhibiting TGF-β1 activation in combination with a checkpoint inhibitor for treating cancer. Background Art

[0006] Glycoprotein A repeat dominant protein (GARP) binds to and regulates the availability of membrane-bound latent transforming growth factor β-1 (TGF-β1) and regulates 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) is used to suppress cytotoxic activity. Therefore, TGF-β1 can act in an autocrine or paracrine manner and can have different effects and functional results on immune cells, ultimately leading to immunosuppression. In addition, TGF-β1 has pleiotropic effects on other cell types carrying this receptor in tumors and peripheral tissues (deStreel and Lucas, 2021, Biochemical Pharmacology: 192: 114697).

[0007] Monoclonal antibodies capable of interfering with the activation and release of mature TGF-β1 from the GARP / TGF-β1 complex are disclosed in WO2015 / 015003 and WO2016 / 125017. These antibodies have been shown to interfere with the immunosuppressive effects of Tregs in vitro and in vivo. WO 2018 / 206790 describes the humanization of the ABBV-151 (livmoniplimab) monoclonal antibody that specifically binds to the GARP-TGF-β1 complex, thereby blocking the release of active TGF-β1.

[0008] Preclinical data in mouse models using a surrogate antibody specific for the mouse GARP-TGF-β1 complex support the hypothesis that blocking the release of TGF-β1 from the GARP-TGF-β1 complex leads to a loss of active TGF-β1 in tumors and tissues in which cells expressing the TGF-β1 receptor may be present (de Streel et al., 2020, Nature Communications, 11:4545).

[0009] To determine whether ABBV-151 can attenuate the immunosuppressive effects of TGF-β1 and enable a more effective anti-tumor immune response when used in combination with antibodies targeting other immune checkpoint molecules, a Phase 1 study was designed to determine the recommended Phase 2 dose (RP2D) of ABBV-151 administered as monotherapy and in combination with the anti-PD-1 monoclonal antibody budigalimab (ABBV-181) (see ClinicalTrials.govIdentifier NCT03821935). Summary of the invention

[0010] In embodiments, a subject with a cancer that escapes host immune surveillance at least in part through the expression and release of TGF-β1 is treated with a combination of an antibody (e.g., Ab1) that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 and an anti-PD-1 antibody. In some embodiments, the cancer is a solid tumor. In embodiments, the treatment of cancer is first-line treatment, second-line treatment, or second-line plus treatment.

[0011] In an embodiment, a subject with hepatocellular carcinoma is treated with a combination of an antibody that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 (e.g., Ab1) and an anti-PD-1 antibody. In an embodiment, the treatment of hepatocellular carcinoma is first-line treatment, second-line treatment, or second-line plus treatment.

[0012] In an embodiment, a subject having pancreatic adenocarcinoma is treated with a combination of an antibody that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 (eg, Abl) and an anti-PD-1 antibody.

[0013] In an embodiment, a subject having urothelial carcinoma is treated with a combination of an antibody that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 (eg, Abl) and an anti-PD-1 antibody.

[0014] In an embodiment, a subject having muscle-invasive urothelial carcinoma is treated with a combination of an antibody that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 (eg, Abl) and an anti-PD-1 antibody.

[0015] In an embodiment, a subject having head and neck squamous cell carcinoma is treated with a combination of an antibody that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 (eg, Abl) and an anti-PD-1 antibody.

[0016] In an embodiment, a subject with microsatellite stable colorectal cancer is treated with a combination of an antibody (e.g., Ab1) that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 and an anti-PD-1 antibody. In an embodiment, the microsatellite stable colorectal cancer is unselected. In other embodiments, the microsatellite stable colorectal cancer is a CMS4 subtype.

[0017] In the embodiment, a subject with non-small cell lung cancer (NSCLC) is treated with a combination of an antibody (e.g., Abl) that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 and an anti-PD-1 antibody. In the embodiment, the treatment of NSCLC is a first-line treatment using a combination of Abl, anti-PD-1 antibodies and chemotherapy. In the embodiment, chemotherapy is a platinum-containing double-drug regimen using carboplatin plus pemetrexed. In other embodiments, the combination of Abl and anti-PD-1 antibodies is used to treat recurrent / refractory NSCLC with or without liver metastases.

[0018] In an embodiment, a subject having an ovarian granulosa cell tumor is treated with a combination of an antibody that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1 (eg, Abl) and an anti-PD-1 antibody. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Study illustration and enrollment status of the ongoing clinical trial NCT03821935.

[0020] Figure 2A and Figure 2B .Dose escalation results for ABBV-151 monotherapy and ABBV-151 + brigatinib combination therapy. Monotherapy: No responders. Combination cohort: 4 confirmed responders and 1 unconfirmed responder; 4 with durable stable disease ≥6 months. Indications include esophagogastric junction adenocarcinoma (GEJ adenocarcinoma), colorectal cancer (CRC), ovarian cancer, alveolar sarcoma, and urothelial carcinoma.

[0021] Figure 3 Dose expansion results for the PD-1 relapsed / refractory (R / R) urothelial carcinoma cohort: 5 confirmed responders and 1 unconfirmed responder; 5 best responses with stable disease.

[0022] Figure 4 .PD-1 primordial Dose expansion results for the hepatocellular carcinoma cohort: 5 confirmed PRs (including 1 PR per iRECIST and 1 requiring data clearance); 3 had a best response of SD.

[0023] Figure 5 Dose expansion results for the PD-1 naive pancreatic adenocarcinoma cohort: 1 unconfirmed PR (new lesions on second scan); 6 with best response of SD.

[0024] Figure 6 Dose expansion results for the PD-1 naive microsatellite stable colorectal cancer cohort: 1 confirmed PR (overall response with site entry into SD, but PR based on lesion measurements): 7 with best response of SD.

[0025] Figure 7 Dose expansion results in 4 patients with ovarian granulosa cell tumors: 3 of 4 patients had a confirmed PR.

[0026] Figure 2A , Figure 2B , Figure 3 , Figure 4 , Figure 5 and Figure 6 : Shows subjects with at least 1 post-baseline disease assessment. DETAILED DESCRIPTION

[0027] Antibodies

[0028] In one embodiment, a method of treating cancer is provided, comprising administering to a patient in need thereof (1) an antibody that binds to a complex of human glycoprotein A repeat dominant protein (hGARP) and TGF-β1, and (2) an anti-PD-1 antibody.

[0029] In certain embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is Ab1. As used herein, Ab1 refers to an antibody having a CDR sequence shown in Table 1. In an embodiment, Ab1 is a human immunoglobulin G4 (IgG4; S228P) / k monoclonal antibody (mAb) that specifically binds to the GARP-TGF-β1 complex, thereby blocking the release of active TGF-β1. In an embodiment, 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 an embodiment, Ab1 comprises a heavy chain (HC) of SEQ ID NO:9 and a light chain (LC) of SEQ ID NO:10. The amino acid sequences of Ab1's CDRs, variable sequences, and full-length sequences are shown in Table 1. In one embodiment, the heavy chain sequence of Ab1 comprises a full-length heavy chain SEQ ID NO:9 (SEQ ID NO:22) having a lysine (K) residue at the other end.

[0030] In some embodiments, Abl is ABBV- 151. As used herein, ABBV-151 refers to an antibody comprising a heavy chain (HC) of SEQ ID NO:9 and a light chain (LC) of SEQ ID NO:10.

[0031] In an embodiment, Abl is lemonilimumab. As used herein, lemonilimumab refers to an antibody comprising a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10, and products containing such antibodies, wherein the antibody or product has a name comprising the core name lemonilimumab, with or without an FDA-designated suffix.

[0032] Table 1. Abl, ABBV-151 and Lemonilimab sequences. CDRs are underlined. Constant regions are in italics .

[0033]

[0034] The anti-PD-1 antibody may be an antibody that binds to PD-1. The anti-PD-1 antibody may be an antibody that binds to PD-L1. The antibody that binds to PD-1 may disrupt the binding of PD-1 to PD-L1 and PD-L2, and the antibody that binds to PD-L1 may disrupt the binding of PD-1 to PD-L1.

[0035] In certain embodiments, the antibody that binds to PD-1 is ABBV-181. As used herein, ABBV-181 refers to an antibody having a CDR sequence shown in Table 2. In an embodiment, ABBV-181 as used herein refers to an antibody having a heavy chain of SEQ ID NO: 19 or SEQ ID NO: 21 and a light chain of SEQ ID NO: 20. The amino acid sequences of the CDR, variable and heavy chain sequences of ABBV-181 are shown in Table 2.

[0036] In an embodiment, ABBV-181 is bruglimab. As used herein, bruglimab 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 products containing such antibodies, wherein the antibody or product has a name comprising the core name bruglimab, with or without an FDA-designated suffix.

[0037] Table 2. ABBV-181 and brigatinib sequences. CDRs are underlined. Constant regions are in italics.

[0038]

[0039]

[0040] In one embodiment, a method for treating cancer is provided, the method comprising administering to a patient in need thereof (1) an antibody (e.g., Ab1) that binds to a complex of hGARP and TGF-β1 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, cemiplimab, dostarlimab, and bruglimab. In one embodiment, the method for treating cancer comprises administering to a patient in need thereof (1) an antibody that binds to a complex of hGARP and TGF-β1, e.g., Ab1, and (2) an antibody that binds to PD-L1 selected from the group consisting of atezolizumab, durvalumab, and avelumab.

[0041] 6.2. Administration of Antibodies Binding to the Complex of hGARP and TGF-β1 and Anti-PD-1 Antibodies

[0042] Provided herein are methods for treating cancer patients with a combination of an antibody that binds to a complex of hGARP and TGF-β1 and an anti-PD-1 antibody. In some embodiments, the cancer is a solid tumor. Provided below are non-limiting examples of timing and dosage of an antibody that binds to a complex of hGARP and TGF-β1 suitable for use in combination with an anti-PD-1 antibody, non-limiting examples of timing and dosage of an anti-PD-1 antibody suitable for use in combination with an antibody that binds to a complex of hGARP and TGF-β1, and non-limiting examples of administration of both types of antibodies.

[0043] 6.2.1. Administration of Antibodies Binding to the Complex of hGARP and TGF-β1

[0044] In some 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 2 weeks (Q2W), once every 3 weeks (Q3W), or once every 4 weeks (Q4W).

[0045] In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as a steady dose of 200 mg to 1500 mg Q2W. In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as a steady dose of 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg, 1000 mg or 1500 mg Q2W. In other embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as a steady dose of 1500 mg Q2W.

[0046] In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 200 mg to 1200 mg Q3W. In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 200 mg, 400 mg, 600 mg, 800 mg or 1200 mg Q3W. In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 400 mg Q3W. In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 1200 mg Q3W.

[0047] In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 250mg to 1600mg Q4W. In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 250mg, 500mg, 550mg, 600mg, 750mg, 1000mg or 1500mgQ4W. In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 600mg Q4W. In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered as an IV infusion at a steady dose of 1500mg Q4W.

[0048] In 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 some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a dose that achieves: (1) a concentration of 0.8 ug / mL at the tumor site, which is minimally required to inhibit TGF-β1 signaling at the site of action (e.g., the tumor site); and (2) a dose of 0.319 ug / mL of the antibody that binds to the complex of hGARP and TGF-β1, which achieves EC of GARP / TGF-β1 target engagement in the tumor microenvironment of most subjects. 95 .

[0049] 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, wherein Ab1 comprises CDRH1, CDRH2, and CDRH3 of SEQ ID NOs: 1, 2, and 3, respectively, 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, wherein 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, wherein Ab1 comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10. In one embodiment, the antibody of this section (Section 6.2.1) that binds to a complex of hGARP and TGF-β1 is Abl, wherein Abl comprises a heavy chain of SEQ ID NO:22 and a light chain of SEQ ID NO:10.

[0050] In one embodiment, the antibody that binds to a complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Abl, wherein Abl is ABBV-151, which comprises the heavy chain (HC) of SEQ ID NO:9 and the light chain (LC) of SEQ ID NO:10.

[0051] In one embodiment, the antibody that binds to a complex of hGARP and TGF-β1 in this section (Section 6.2.1) is Abl, wherein Abl is lemonilimumab, which comprises the heavy chain (HC) of SEQ ID NO:9 and the light chain (LC) of SEQ ID NO:10.

[0052] 6.2.2. Administration of anti-PD-1 antibodies

[0053] In some embodiments, the anti-PD-1 antibody is administered at a dose of 1-10 mg / kg once every 2 weeks (Q2W), once every three weeks (Q3W), or once every 4 weeks (Q4W). In some embodiments, the anti-PD-1 antibody is administered at a steady dose of 240 mg-1680 mg once every 2 weeks (Q2W), once every three weeks (Q3W), once every 4 weeks (Q4W), or once every 6 weeks (Q6W).

[0054] In some embodiments, the anti-PD-1 antibody is administered at a dose of 1 mg / kg, 3 mg / kg or 10 mg / kg once every 2 weeks (Q2W), once every three weeks (Q3W) or once every 4 weeks (Q4W). In some embodiments, the anti-PD-1 antibody is administered at a steady dose of 240 mg once every 2 weeks (Q2W), 250 mg once every two weeks (Q2W), 840 mg once every 2 weeks (Q2W), 200 mg once every 3 weeks (Q3W), 360 mg once every 3 weeks (Q3W), 375 mg once every three weeks (Q3W), 1200 mg once every 3 weeks (Q3W), 480 mg once every 4 weeks (Q4W), 500 mg once every 4 weeks (Q4W), 1680 mg once every 4 weeks (Q4W) or 400 mg once every 6 weeks (Q6W). In some embodiments, the anti-PD-1 antibody is administered to subjects in the combined cohort only at a steady dose of 375 mg Q3W. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience any infusion-related reactions during the first dose, the infusion duration for the second dose can be shortened to 60 minutes, and the infusion duration for subsequent doses can be shortened to 30 minutes.

[0055] 6.2.2.1. Administration of ABBV-181

[0056] In some 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 2 weeks (Q2W), once every three weeks (Q3W), or once every 4 weeks (Q4W). In some embodiments, the anti-PD-1 antibody is administered at a steady dose of 250 mg once every two weeks (Q2W), 375 mg once every three weeks (Q3W), or 500 mg once every 4 weeks (Q4W).

[0057] In some embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every 2 weeks (Q2W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg. In some embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every 2 weeks (Q2W) at a steady dose of 250 mg, 375 mg, or 500 mg. In some embodiments, ABBV-181 is administered to subjects in only the combined cohort at a steady dose of 250 mg Q2W. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience any infusion-related reactions during the first dose, the infusion duration of the second dose can be shortened to 60 minutes, and the infusion duration of the subsequent dose can be shortened to 30 minutes.

[0058] In some embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every 3 weeks (Q3W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg. In some embodiments, the anti-PD-1 antibody is ABBV-181 and is administered once every 3 weeks (Q3W) at a steady dose of 250 mg, 375 mg, or 500 mg. In some embodiments, ABBV-181 is administered to subjects in only the combined cohort at a steady dose of 375 mg Q3W. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience any infusion-related reactions during the first dose, the infusion duration of the second dose can be shortened to 60 minutes, and the infusion duration of the subsequent dose can be shortened to 30 minutes.

[0059] In some embodiments, ABBV-181 is administered once every 4 weeks (Q4W) at a dosage of 1 mg / kg, 3 mg / kg or 10 mg / kg or a steady dose of 250 mg, 375 mg or 500 mg. In some embodiments, ABBV-181 is administered to subjects in only the combined cohort at a steady dose of 500 mg Q4W. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience any infusion-related reactions during the first dose, the infusion duration of the second dose can be shortened to 60 minutes, and the infusion duration of the subsequent dose can be shortened to 30 minutes.

[0060] 6.2.2.2. Administration of brigatinib

[0061] In some embodiments, the anti-PD-1 antibody is brigatinib and is administered at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg once every 2 weeks (Q2W), once every three weeks (Q3W), or once every 4 weeks (Q4W). In some embodiments, the anti-PD-1 antibody is administered at a steady dose of 250 mg once every two weeks (Q2W), 375 mg once every three weeks (Q3W), or 500 mg once every 4 weeks (Q4W).

[0062] In some embodiments, the anti-PD-1 antibody is bruglimab and is administered once every 2 weeks (Q2W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg. In some embodiments, the anti-PD-1 antibody is bruglimab and is administered once every 2 weeks (Q2W) at a steady dose of 250 mg, 375 mg, or 500 mg. In some embodiments, bruglimab is administered to subjects in only the combined cohort at a steady dose of 250 mg Q2W. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience any infusion-related reactions during the first dose, the infusion duration of the second dose can be shortened to 60 minutes, and the infusion duration of the subsequent dose can be shortened to 30 minutes.

[0063] In some embodiments, the anti-PD-1 antibody is brigatinib and is administered once every 3 weeks (Q3W) at a dose of 1 mg / kg, 3 mg / kg, or 10 mg / kg or a steady dose of 250 mg, 375 mg, or 500 mg. In some embodiments, brigatinib is administered to subjects in the combined cohort only at a steady dose of 375 mg Q3W. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience any infusion-related reactions during the first dose, the infusion duration of the second dose can be shortened to 60 minutes, and the infusion duration of the subsequent dose can be shortened to 30 minutes.

[0064] In some embodiments, bugli monob is administered once every 4 weeks (Q4W) at a dose of 1 mg / kg, 3 mg / kg, 10 mg / kg. In some embodiments, bugli monob is administered once every 4 weeks (Q4W) at a steady dose of 250 mg, 375 mg, or 500 mg. In some embodiments, bugli monob is administered to subjects in only the combined cohort at a steady dose of 500 mgQ4W. In one embodiment, the first infusion is administered over 90 minutes. If the subject does not experience any infusion-related reactions during the first dose, the infusion duration of the second dose can be shortened to 60 minutes, and the infusion duration of the subsequent dose can be shortened to 30 minutes.

[0065] 6.2.2.3. Administration of pembrolizumab, nivolumab, and atezolizumab

[0066] In some embodiments, the anti-PD-1 antibody is pembrolizumab and is administered at a steady dose of 200 mg once every 3 weeks (Q3W). In some embodiments, the anti-PD-1 antibody is pembrolizumab and is administered at a steady dose of 400 mg once every 6 weeks (Q6W). Doses and administration frequencies of pembrolizumab are known in the art, e.g., as as specified in the prescribing information.

[0067] In some embodiments, the anti-PD-1 antibody is nivolumab and is administered at a steady dose of 240 mg once every 2 weeks (Q2W). In some embodiments, the anti-PD-1 antibody is nivolumab and is administered at 3 mg / kg once every 2 weeks (Q2W). In some embodiments, the anti-PD-1 antibody is nivolumab and is administered at a steady dose of 360 mg once every 3 weeks (Q3W). In some embodiments, the anti-PD-1 antibody is nivolumab and is administered at a steady dose of 480 mg once every 4 weeks (Q4W). Doses and administration frequencies of nivolumab are known in the art, for example, as as specified in the prescribing information.

[0068] In some embodiments, the anti-PD-1 antibody binds to PD-L1, is atezolizumab, and is administered at a steady dose of 840 mg once every 2 weeks (Q2W). In some embodiments, the anti-PD-1 antibody binds to PD-L1, is atezolizumab, and is atezolizumab and is administered at a steady dose of 1200 mg once every 3 weeks (Q3W). In some embodiments, the anti-PD-1 antibody binds to PD-L1, is atezolizumab, and is administered at a steady dose of 1680 mg once every 4 weeks (Q4W). Doses and administration frequencies of atezolizumab are known in the art, for example, as as specified in the prescribing information.

[0069] 6.2.3. Combination scheme

[0070] The following combination regimens are provided as non-limiting examples, and the omission of a particular combination of timing and dosage does not indicate that the combination is not expressly contemplated or is not within the scope of the invention disclosed herein.

[0071] In one embodiment, (1) an antibody that binds to the complex of hGARP and TGF-β1 and (2) an anti-PD-1 antibody are administered simultaneously.

[0072] In one embodiment, (1) an antibody that binds to a complex of hGARP and TGF-β1 and (2) an anti-PD-1 antibody are administered sequentially. In certain embodiments, the antibody that binds to a complex of hGARP and TGF-β1 is administered first, followed by the anti-PD-1 antibody. In embodiments, a maximum of 15 minutes, 30 minutes, 45 minutes, or 60 minutes elapses prior to administration of the anti-PD-1 antibody.

[0073] In one embodiment, (1) an antibody that binds to a complex of hGARP and TGF-β1 and (2) an anti-PD-1 antibody are administered non-simultaneously within 4 weeks, 3 weeks, 2 weeks, 1 week, 2 days, or 1 day of each other.

[0074] In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 200 mg to 1500 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or brigalimab and is administered at a steady dose of 500 mg (Q4W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady 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 brigalimab and is administered at a steady dose of 500 mg (Q4W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 400 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bruglimab and is administered at a steady dose of 500 mg (Q4W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 600 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bruglimab and is administered at a steady dose of 500 mg (Q4W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 1500 mg Q2W, and the anti-PD-1 antibody is ABBV-181 or bruglimab and is administered at a steady dose of 500 mg (Q4W).

[0075] In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 200 mg to 1200 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bruglimab and is administered at a steady dose of 375 mg (Q3W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 200 mg, 400 mg, 600 mg, 800 mg or 1200 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bruglimab and is administered at a steady dose of 375 mg (Q3W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 400 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or bruglimab and is administered at a steady dose of 375 mg (Q3W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 600 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or brigalimab and is administered at a steady dose of 375 mg (Q3W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 1200 mg Q3W, and the anti-PD-1 antibody is ABBV-181 or brigalimab and is administered at a steady dose of 375 mg (Q3W).

[0076] In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 250 mg to 1600 mg Q4W, and the anti-PD-1 antibody is ABBV-181 or brigalimab and is administered at a steady dose of 500 mg (Q4W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose 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 brigalimab and is administered at a steady dose of 500 mg (Q4W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 600 mg Q4W, and the anti-PD-1 antibody is ABBV-181 or brigalimab and is administered at a steady dose of 500 mg (Q4W). In some embodiments, the antibody that binds to the complex of hGARP and TGF-β1 is administered at a steady dose of 1500 mg Q4W, and the anti-PD-1 antibody is ABBV-181 or brigalimab and is administered at a steady dose of 500 mg (Q4W).

[0077] In an embodiment, the order of drug administration is to first administer the antibody that binds to the complex of hGARP and TGF-β1, and then administer the anti-PD-1 antibody. In an embodiment, after the infusion of the antibody that binds to the complex of hGARP and TGF-β1 is completed, the subject waits up to 60 minutes before starting the anti-PD-1 antibody infusion.

[0078] In embodiments, the combination of an antibody that binds to a complex of hGARP and TGF-β1 and an anti-PD-1 antibody is administered continuously until progressive disease or unacceptable toxicity occurs. In embodiments, the combination of an antibody that binds to a complex of hGARP and TGF-β1 and an anti-PD-1 antibody is administered for 4 months, 5 months, 6 months, 7 months, 8 months, 12 months, 18 months, 24 months or longer.

[0079] The efficacy of the combination of antibodies and anti-PD-1 antibodies that bind to the complex of hGARP and TGF-β1 is evaluated by various clinical endpoints. In the embodiment, the subject treated with the combination of antibodies and anti-PD-1 antibodies that bind to the complex of hGARP and TGF-β1 has a higher objective response rate (ORR) than the standard of care. In the embodiment, the subject treated with the combination of antibodies and anti-PD-1 antibodies that bind to the complex of hGARP and TGF-β1 has a higher objective response rate (ORR) than that observed in the case of anti-PD-1 antibodies administered alone. In the embodiment, the subject treated with the combination of antibodies and anti-PD-1 antibodies that bind to the complex of hGARP and TGF-β1 has an objective response rate (ORR) greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60% or greater than or equal to 70%. In embodiments, the efficacy of treatment includes a median duration of response (DoR) of 4 months or longer (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 acceptable safety and tolerability profiles.

[0080] 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, wherein Ab1 comprises CDRH1, CDRH2, and CDRH3 of SEQ ID NOs: 1, 2, and 3, respectively, 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, wherein 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, wherein Ab1 comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10. In one embodiment, the antibody of this section (Section 6.2.3) that binds to a complex of hGARP and TGF-β1 is Abl, wherein Abl comprises a heavy chain of SEQ ID NO:22 and a light chain of SEQ ID NO:10.

[0081] In one embodiment, the antibody that binds to a complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Abl, wherein Abl is ABBV-151, which comprises the heavy chain (HC) of SEQ ID NO:9 and the light chain (LC) of SEQ ID NO:10.

[0082] In one embodiment, the antibody that binds to a complex of hGARP and TGF-β1 in this section (Section 6.2.3) is Abl, wherein Abl is lemonilimumab, which comprises the heavy chain (HC) of SEQ ID NO:9 and the light chain (LC) of SEQ ID NO:10.

[0083] 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 bruglimumab. 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.

[0084] 6.3. Selection of tumor type

[0085] It has been proposed that there may be three basic cancer immune phenotypes: desert type (characterized by the absence of immune infiltrates in the tumor or surrounding stroma), exclusion type (in which immune cells are present in the stroma but cannot enter the tumor microenvironment), and inflammatory type (in which immune cells are present in both the stroma and the tumor microenvironment). In addition, the success of immunotherapies targeting T cell co-stimulation (such as anti-PD-1 agents) may depend on the content and location of T cell infiltrates (Chen DS, Mellman I. Nature. 2017; 541(7637): 321-30).

[0086] Gene expression analysis was used to compare markers of immune infiltration and TGF-β1-related signaling in multiple cohorts from the Cancer Genome Atlas (TCGA) database. A large amount of RNAseq data from primary tumor samples was evaluated for the enrichment of immune gene signatures, such as immune rejection constants, which are a set of 20 genes representing the consistent activation of innate and adaptive responses downstream of immune-mediated tissue destruction. Similar gene expression signatures have been found to predict responses 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, Martínez E et al. Nat Commun. 2013; 4: 2612; and Quigley M, Pereyra F, Nilsson B et al. Nat Med. 2010; 16(10): 1147-51).

[0087] The samples were then evaluated for stromal and TGF-β1-associated gene signatures, including the signature identified by Mariathasan et al., to predict lack of response to atezolizumab. Finally, the samples were evaluated for GARP (LRRC32) expression. The resulting gene expression profiles of pancreatic adenocarcinoma, urothelial carcinoma (UC), hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma (HNSCC), microsatellite-stable colorectal cancer (MSS-CRC), and non-small cell lung cancer (NSCLC) showed overlap between markers of T cell infiltration that may be associated with responsiveness to anti-PD-1 therapy and the TGF-β1-associated gene signature, suggesting that release of TGF-β1 may be a mechanism of immune escape in these patients. In these tumor indications, GARP (LRRC32) expression was associated with the TGF-β1-associated gene signature, suggesting that blockade of GARP-TGF-β1 could modulate the TGF-β1-associated gene signature.

[0088] In some embodiments, a subject with a cancer (such as a solid tumor) that escapes host immune surveillance at least in part by the expression and release of active TGF-β1 is treated with a combination of Ab1 and an anti-PD-1 antibody. In an embodiment, a subject with a cancer that escapes host immune surveillance at least in part by the expression and release of active TGF-β1 is administered a therapeutically effective amount of an anti-PD-1 antibody in a therapeutically effective schedule and an antibody that binds to a complex of hGARP and TGF-β1 in a schedule sufficient to improve the therapeutic efficacy of the anti-PD-1 antibody. In certain embodiments, the antibody that binds to a complex of hGARP and TGF-β1 is Ab1. In certain embodiments, Ab1 is ABBV-151. In certain embodiments, Ab1 is lemonilimumab administered once every two weeks, once every three weeks, or once every four weeks at a dose ranging from about 200 mg to about 1500 mg, and the anti-PD-1 antibody is bruglimumab administered at a dose of 375 mg once every three weeks or 500 mg once every four weeks.

[0089] In embodiments, administration to subjects with cancer that escapes host immune surveillance at least in part through expression and release of active TGF-β1 achieves an ORR greater than that obtained with administration of an anti-PD-1 antibody alone. In embodiments, administration to subjects with cancer that escapes host immune surveillance at least in part through expression and release of active TGF-β1 achieves an ORR of greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, or greater than or equal to 70%.

[0090] In some embodiments, Abl treatment is added to anti-PD-1 therapy for the cancer, such that Abl is also administered to any subject administered an anti-PD-1 antibody (e.g., an antibody that binds PD-1 or PD-L1) for treatment of the cancer.

[0091] In some embodiments, the subject has not received systemic treatment for his cancer, i.e., has not received first-line systemic treatment. In embodiments, the subject has progressed after receiving first-line systemic treatment. In embodiments, the subject suffers from recurrent or refractory cancer. In some embodiments, the subject has acquired resistance to therapy using check point inhibitors. In embodiments, the subject has acquired resistance to therapy using one or more of PD-1 inhibitors or PD-L1 inhibitors. In embodiments, the subject has not been treated with check point inhibitors, i.e., is naive to check point inhibitors. In embodiments, the subject has not previously received therapy using one or more of PD-1 inhibitors or PD-L1 inhibitors.

[0092] In some embodiments, tumors that have not responded to immunotherapy agents in the past, i.e., cold tumors, such as pancreatic cancer and microsatellite stable colorectal cancer, are treated with a combination of Abl and an anti-PD-1 antibody to achieve an ORR of greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, or greater than or equal to 70%. In one embodiment, Abl is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, Abl is lemonilimumab and the anti-PD-1 antibody is bruglimumab.

[0093] In other embodiments, inflammatory or hot tumors, such as urothelial carcinoma (UC), HCC, HNSCC, and NSCLC, are treated with a combination of Abl and an anti-PD-1 antibody to achieve an ORR of greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, or greater than or equal to 70%. In one embodiment, Abl is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, Abl is lemonilimumab and the anti-PD-1 antibody is bruglimumab.

[0094] In embodiments, the cancer is a solid tumor selected from the group consisting of pancreatic adenocarcinoma, urothelial carcinoma (UC) (including muscle-invasive urothelial carcinoma (MIUC)), hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma, colorectal cancer (CRC, including microsatellite stable (MSS-CRC)), non-small cell lung cancer (NSCLC), ovarian cancer, ovarian granulosa cell tumor cancer (GCT), breast cancer, or esophageal gastric junction adenocarcinoma, and these cancers are treated with a combination of Abl and anti-PD-1 to achieve an ORR of greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, or greater than or equal to 70%. In one embodiment, Abl is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, Abl is lemonilimumab and the anti-PD-1 antibody is brigalimumab.

[0095] In an embodiment, a combination of Abl and an anti-PD-1 antibody is used to treat a cancer selected from the group consisting of pancreatic adenocarcinoma, urothelial carcinoma (including muscle-invasive urothelial carcinoma), hepatocellular carcinoma (HCC), head and neck squamous cell carcinoma, colorectal cancer (CRC, including microsatellite stable (MSS-CRC)), non-small cell lung cancer (NSCLC), ovarian cancer, ovarian granulosa cell tumor cancer, breast cancer, or esophageal gastric junction adenocarcinoma to achieve an ORR of greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, or greater than or equal to 70%. In one embodiment, Abl is ABBV-151 and the anti-PD-1 antibody is ABBV-181. In one embodiment, Abl is lemonilimumab and the anti-PD-1 antibody is brigalimumab.

[0096] Provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of 1) an anti-PD-1 antibody and 2) a combination of Ab1, wherein the cancer is selected from the group consisting of muscle-invasive urothelial carcinoma, hepatocellular carcinoma, microsatellite-stable colorectal cancer, non-small cell lung cancer, and ovarian granulosa cell tumor cancer.

[0097] In one embodiment, Abl in this section (Section 6.3) is ABBV-151 and the anti-PD-1 antibody is ABBV- 181. In one embodiment, Abl in this section (Section 6.3) is lemonilimab and the anti-PD-1 antibody is brigalimab.

[0098] Table 3 provides examples of subjects with cancer treated with a combination of Ab1 and anti-PD-1 antibodies, therapeutically effective dosing regimens for antibodies, and examples of overall response rates (ORRs) for those regimens. In the embodiments, a subpopulation of individuals with the indicated cancer is selected and treated, wherein the selection is based on one or more of the selection criteria listed below each cancer. For the purpose of defining subpopulations, criteria that are inconsistent with each other (e.g., treatment naivety relative to progression after previous therapy) are not merged.

[0099] Table 3

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] 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 lemonilimumab and the anti-PD-1 antibody is bruglimumab. The choice of dose depends on the proposed mechanism of action of lemonilimumab, clinical efficacy and safety, clinical PK / PD modeling, and preclinical evidence demonstrating the concentration-dependent ability of lemonilimumab to inhibit the release of active TGF-β1 from the GARP-TGF-β1 complex (expected to inhibit subsequent signaling within the TME).

[0108] 7. Examples

[0109] 7.1. Example 1: Evaluation of the efficacy of ABBV-151 as a single agent and in combination with ABBV-181 in patients with locally advanced Phase 1 M19-3451 first-in-human study to evaluate safety, tolerability, pharmacokinetics, and RP2D in subjects with solid tumors or metastatic solid tumors Study objectives:

[0110] This is a Phase 1, open-label, dose-escalation, dose-expansion, PK, biomarker / PD, and activity validation study that will evaluate the safety, PK, PD, and preliminary efficacy of ABBV-151 as monotherapy and in combination with brigatinib.

[0111] Approximately 257 subjects with locally advanced or metastatic solid tumors will be enrolled in this FIH study. The trial will consist of 2 parts, such as Figure 1 Approximately 46 subjects with solid tumors will be enrolled in the dose escalation cohort. Approximately 138-191 subjects with pancreatic adenocarcinoma, urothelial carcinoma, HCC, HNSCC, MSS-CRC, and NSCLC will be enrolled in the expansion cohort.

[0112] Subjects will receive ABBV-151 and / or brigatinib (combination cohort only) until disease progression or unacceptable toxicity.

[0113] 7.1.1. Dose escalation cohort :

[0114] Dose escalation will be the FIH assessment of ABBV-151 administered as a single agent in the ascending dose cohort guided by Bayesian optimal interval (BOIN) design.First, the ABBV-151 monotherapy dose escalation group will be started. ABBV-151 will be administered by 60 minutes intravenous (IV) infusion Q2W. Eligible subjects will suffer from advanced solid tumors, which are considered to be refractory or intolerant to all existing therapies known to provide clinical benefits for their symptom (i.e., subjects progressing in the standard therapy known to provide clinical benefits). The cycle is defined as 28 days. Monotherapy dose escalation will result in the characterization of safety profile, PK profile and target engagement, and result in the selection of the monotherapy RP2D of ABBV-151 to be used as described below. Efficacy data will be collected as the exploratory endpoint during dose escalation.

[0115] The combination therapy dose escalation group of ABBV-151 and brigatinib will start when the first two or more dose levels of ABBV-151 monotherapy are declared safe. The starting dose of ABBV-151 combined with brigatinib will be at least 2 dose levels lower than the highest ABBV-151 monotherapy dose level shown to be safe, and at least 3 subjects will be treated with ABBV-151 monotherapy before starting the combination dose escalation. The dose escalation combination of ABBV-151 and brigatinib will be guided by a BOIN design with a minimum cohort size of 3 subjects. The dose of brigatinib will be fixed at 500mg (steady dose) by IV infusion Q4W.

[0116] 7.1.2. Entry and Exclusion Criteria :

[0117] Adult subjects with advanced solid tumors who are considered refractory or intolerant to all existing therapies known to provide clinical benefits for their condition (i.e., subjects who progress in standard therapies known to provide clinical benefits). In addition, subjects who have been offered standard therapy and rejected or subjects who are considered not to meet the conditions of standard therapy may meet the conditions of this study on a case-by-case basis. Subjects with pancreatic adenocarcinoma, urothelial carcinoma, HCC or HNSCC who are being considered for inclusion in the dose escalation cohort must also meet the histology-specific inclusion criteria described below for dose expansion.

[0118] 7.1.3. Dose Expansion Cohort :

[0119] Dose expansion will further evaluate the safety and tolerability of ABBV-151 given at the RP2D determined in dose escalation in combination with brigatinib. All dose expansion cohorts will start only after the RP2D / MTD or MAD has been defined for ABBV-151 monotherapy and ABBV-151 + brigatinib combination therapy.

[0120] The RP2D selected for dose expansion is 1500 mg ABBV-151 Q2W administered as monotherapy or in combination with brigatinib.

[0121] Dose expansion will include 6 cohorts with 6 tumor types to be evaluated (pancreatic adenocarcinoma, urothelial carcinoma, HCC, HNSCC, MSS-CRC, and NSCLC). The expansion cohorts will evaluate the following:

[0122] Combination of ABBV-151 and brigatinib in pancreatic adenocarcinoma

[0123] Combination of ABBV-151 and brigatinib in urothelial carcinoma

[0124] Combination of ABBV-151 and brigatinib in HCC

[0125] Combination of ABBV-151 and brigatinib in HNSCC

[0126] Combination of ABBV-151 and brigatinib in MSS-CRC

[0127] Combination of ABBV-151 and brigatinib in NSCLC

[0128] Dose expansion will provide characterization of the safety profile, PK / PD, and preliminary efficacy of the combination of ABBV-151 and brigatinib.

[0129] 7.1.4. Entry and Exclusion Criteria :

[0130] All subjects with HCC, pancreatic adenocarcinoma, or MSS-CRC must not have been previously exposed to previous PD-1 / PD-L1 antagonists in any line of therapy.

[0131] Pancreatic adenocarcinoma subjects must have progressive disease during or after 1 systemic therapy (gemcitabine monotherapy or in combination with other agents, FOLFIRINOX [or another regimen including 5-fluorouracil and oxaliplatin], capecitabine monotherapy or in combination with other agents) administered in the adjuvant, locally advanced, or metastatic setting. Progression on more than 1 prior systemic therapy is not allowed in this cohort. If this therapy is used in the adjuvant setting, progressive disease must occur within 6 months of completion of adjuvant therapy.

[0132] Urothelial carcinoma of the bladder and urinary tract subjects must have progressed following treatment with a platinum-based regimen (administered in any line of therapy) and a PD-1 / PD-L1 antagonist administered in the recurrent or metastatic setting (progression following a PD-1 / PD-L1 antagonist was defined as unequivocal progression on or within 3 months of the last dose of anti-PD-1 or anti-PD-L1 therapy).

[0133] Hepatocellular carcinoma subjects must have progressive disease during or after 1 previous systemic therapy line. Progression is not allowed in more than 1 previous systemic therapy in this cohort. Subjects must have Child-Pugh A classification and must not have ascites requiring long-term therapy (i.e., no diuretics, repeated punctures or indwelling catheters are required). Subjects with varicose veins are eligible as long as they receive appropriate prevention / intervention according to local guidance. Subjects must also meet specific requirements for viral hepatitis status.

[0134] Subjects with head and neck squamous cell carcinoma (originating from the oral cavity, oropharynx, hypopharynx, or larynx) must have progressed following treatment with a platinum-based regimen (administered in any line of therapy) and a PD-1 / PD-L1 antagonist administered in the recurrent or metastatic setting (progression following a PD-1 / PD-L1 antagonist was defined as unequivocal progression on or within 3 months of the last dose of anti-PD-1 or anti-PD-L1 therapy).

[0135] CRC subjects with microsatellite-stable or mismatch repair-proficient colorectal adenocarcinoma (determined by PCR / NGS or IHC, respectively) who have received a prior fluorouracil-based combination chemotherapy regimen including oxaliplatin and irinotecan (with or without VEGF and / or EGFR-targeting agents).

[0136] Subjects with histologically or cytologically confirmed advanced or metastatic NSCLC who have received 1 prior line of chemotherapy and 1 prior anti-PD-(L)1 antibody administered concurrently or sequentially in the metastatic setting. Prior chemotherapy and immunotherapy in the neoadjuvant / adjuvant setting are allowed, but subjects who have progressed on more than 1 line of chemotherapy in the metastatic setting and / or more than 1 prior anti-PD-(L)1 in the metastatic setting will not be eligible. Progression after PD-1 / PD-L1 antagonists is defined as unequivocal progression on or within 3 months of the last dose of anti-PD-1 or anti-PD-L1 therapy. NSCLC subjects with known EGFR mutations or ALK / ROS1 gene rearrangements are not eligible.

[0137] Subjects must also have:

[0138] Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, adequate bone marrow, kidney, liver and coagulation function. No anticancer therapy, including chemotherapy, immunotherapy, radiotherapy, biological therapy, herbal therapy or any investigational therapy, must have been received within a period of 5 half-lives or 28 days (whichever is shorter) before the first dose of study drug. No unresolved >1 grade AEs caused by previous anticancer therapy except alopecia. No clinically significant uncontrolled conditions; no active bacterial, fungal or viral infections; and no active autoimmune diseases except vitiligo, type I diabetes, hypothyroidism and psoriasis. No history of primary immunodeficiency, bone marrow transplantation, solid organ transplantation or previous clinical diagnosis of tuberculosis. 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 CNS metastases (with certain exceptions).

[0139] Viral Hepatitis Status of All Subjects Without HCC: Subjects must be confirmed to have tested negative for active hepatitis A, B, or C.

[0140] No current or past use of immunosuppressive medications within 14 days prior to the first dose of study drug.

[0141] No live vaccines were administered ≤28 days before the first dose of study drug.

[0142] 7.2. Example 2: Evaluation of the efficacy of ABBV-151 as a single agent and in combination with ABBV-181 in patients with locally advanced Phase 1 M19-3451 first-in-human study to evaluate safety, tolerability, pharmacokinetics, and RP2D in subjects with solid tumors or metastatic solid tumors Results of a multicenter, open-label, dose-escalation study

[0143] 7.2.1. Overview :

[0144] As of June 1, 2022, 157 subjects have been enrolled. Of those subjects, 57 are in the dose escalation cohort, 23 are in the monotherapy cohort, and 34 are in the combination therapy cohort. In the dose expansion cohort, 100 subjects are enrolled and treated with the combination of ABBV-151 + brigatinib.

[0145] Dose escalation enrolled subjects with advanced solid tumors who were considered refractory or intolerant to all existing therapies known to provide clinical benefits for their condition. In the monotherapy dose escalation cohort, 23 subjects were enrolled, and they received seven dose levels of ABBV-151 as a monotherapy in the range of 3mg to 1500mg administered intravenously every 2 weeks (Q2W). Combination dose escalation had 34 subjects enrolled, who received six dose levels of ABBV-151 (ranging from 10mg to 1500mgQ2W) combined with a fixed dose of anti-PD-1 antibody bruglimab (500mgQ4W). As a monotherapy or in combination with bruglimab, the selected RP2D of ABBV-151 was determined to be 1500mg every two weeks (Q2W).

[0146] The objective response rate of subjects treated with monotherapy was 0%, and the objective response rate was 12% in combined dose escalation. Regardless of the confirmed results, the response rate was 0% in monotherapy dose escalation and 15% in combined dose escalation, and another 26.5% of subjects treated with combination therapy had the best response of stable disease. Subjects enrolled in dose escalation include those who have received anti-PD-1 therapy and those who are PD-1 primary, and include several tumor types, including non-small cell lung cancer, ovarian cancer, pancreatic adenocarcinoma, breast cancer (triple-negative breast cancer and hormone receptor-positive breast cancer), colorectal cancer, urothelial carcinoma, endometrial cancer, renal cell carcinoma, gastric and esophagogastric junction cancer, prostate adenocarcinoma, uterine adenocarcinoma, mesothelioma, hemangiopericytoma, and several less common adenocarcinomas, carcinomas, and sarcomas.

[0147] The dose expansion cohort enrolled subjects treated with the ABBV-151 + brigatinib combination therapy. Cancer types included PD-1 relapsed / refractory urothelial carcinoma, 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 adenocarcinoma and ovarian granulosa cell tumor.

[0148] Subjects who responded to ABBV-151 + brigatinib treatment included 1 subject with esophagogastric junction adenocarcinoma, 4 subjects with colorectal cancer (3 of 4 had MSS-CRC), 2 subjects with ovarian cancer (granulosa subtype), 1 subject with pancreatic adenocarcinoma, 7 subjects with urothelial carcinoma, and 5 subjects with hepatocellular carcinoma and 3 subjects with ovarian granulosa cell tumors. Several additional subjects experienced durable stable disease for 6 months or longer. Thus, the combination of ABBV-151 + brigatinib demonstrated durable antitumor activity in heavily pretreated PD-1 relapsed and refractory subjects as well as PD-1 naive subjects.

[0149] 7.2.2. ABBV-151 Monotherapy Dose Escalation Results :

[0150] Twenty-three subjects were enrolled in the monotherapy escalation cohort. 65% were anti-PD-(L)1 naive and had received a median of 4 prior lines of therapy. Tumor types included 4 NSCLC, 3 ovarian cancers, 1 pancreatic cancer, 3 CRC, 2 TNBC, 1 breast cancer (non-TNBC), and 9 other solid tumors (endometrial (N=2), osteosarcoma, mesothelioma, gastric (N=2), rhabdomyosarcoma, papillary adenosarcoma, hemangiopericytoma).

[0151] 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 durable stable disease (SD) lasting approximately 6 months or longer was 0.

[0152] 7.2.3. Results of ABBV-151+ABBV-181 Dose-Escalation Combination Therapy :

[0153] Thirty-four subjects were enrolled in the combination therapy dose escalation cohort. 70% were anti-PD-(L)1 naive and had received a median of 3 prior lines of therapy. Tumor types included: 1 NSCLC, 7 ovarian cancers, 4 pancreatic cancers, 8 CRCs, 1 urothelial carcinoma, 2 breast cancers (non-TNBC), 11 other solid tumors (renal cell carcinoma, adrenocortical carcinoma, prostate adenocarcinoma, esophagogastric junction adenocarcinoma, sebaceous gland carcinoma (orbital sebaceous gland carcinoma), uterine adenocarcinoma, leiomyosarcoma, ampullary adenocarcinoma, clear cell sarcoma, alveolar soft tissue sarcoma, and endometrial adenocarcinoma).

[0154] 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%). Additional subjects who did not respond but had durable stable disease lasting approximately 6 months or longer were 4 / 34 (11.8%).

[0155] Responders included 1 subject with esophagogastric junction adenocarcinoma who was PD-1 naive (20004, 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 prior PD-1 inhibitor therapy and was treated in the 100 mg ABBV-151 combination cohort), and a subject with PD-1 naive ovarian cancer (10015, treated in the 1500 mg ABBV-151 combination cohort). One subject with PD-1 naive ovarian cancer achieved an unconfirmed PR at the last disease assessment (10017, treated in the 1500 mg ABBV-151 combination cohort). An additional 4 subjects had stable disease lasting 6 months or longer as of data cutoff (12007, with PD-1 recurrent colorectal cancer in the 10 mg ABBV-151 combination cohort; 40007, with PD-1 naïve alveolar sarcoma in the 1500 mg ABBV-151 combination cohort; 10019, with PD-1 naïve ovarian cancer in the 1500 mg ABBV-151 combination cohort; and 30012, with PD-1 recurrent urothelial carcinoma in the 1500 mg ABBV-151 combination cohort).

[0156] 7.2.4. ABBV-151 + ABBV-181 Dose Expansion - PD-1R / R Urothelial Carcinoma :

[0157] Subjects were enrolled with histologically or cytologically confirmed urothelial carcinoma of the bladder and urinary tract that had progressed following treatment with a platinum-based regimen (administered in any line of therapy) and a PD-1 / PD-L1 antagonist administered in the recurrent or metastatic setting (progression after PD-1 / PD-L1 antagonist was defined as unequivocal progression on or within 3 months of the last dose of anti-PD-1 or anti-PDL-1 therapy).

[0158] As of May 2022, 32 patients have been enrolled with a median of 3 prior lines of therapy, including several patients who received prior enfortumab and vedotin, including 1 responder who had failed prior EV. Results are shown in Figure 3 So far, the objective response rate is 5 / 32 (15.6%). So far, the best overall response rate (including unconfirmed) is 6 / 32 (18.8%). As of July 26, there are 7 responders (6 confirmed) out of 36 enrolled. In addition, another subject has durable stable disease lasting approximately 6 months or more.

[0159] As of March 30, 2023, 48 patients have been enrolled and 45 are response-evaluable, with a confirmed ORR of 18% by RECIST1.1.

[0160] 7.2.5. ABBV-151 + ABBV-181 Dose Expansion - PD-1 Primary Hepatocellular Carcinoma (HCC) :

[0161] Subjects had histologically confirmed advanced HCC at enrollment who had progressive disease during or after 1 prior line of systemic therapy. Progression on more than 1 prior systemic therapy was not allowed in this cohort. Subjects must have Child-Pugh A grade and must not have ascites requiring long-term therapy. Subjects with varicose veins are eligible, provided they have received appropriate prophylaxis / intervention according to local guidance. Other viral status in the protocol is eligible.

[0162] Twelve subjects were enrolled, most with prior sorafenib treatment, and a few with prior lenvatinib or other tyrosine kinase inhibitors (TKIs). The median number of prior lines of therapy was 1.

[0163] The results are shown in Figure 4 The objective response rate was 3 / 12 (25%). As of July 2022, there are now 5 confirmed responders. The best overall response rate (including unconfirmed) was 4 / 12 (33.3%). Two additional subjects had durable stable disease lasting approximately 6 months or longer.

[0164] As of March 30, 2023, 12 patients have been enrolled, all of whom are response evaluable, with a confirmed ORR of 42% by iRECIST.

[0165] 7.2.6. ABBV-151 + ABBV-181 Dose Expansion - PD-1 Naïve Pancreatic Adenocarcinoma :

[0166] Subjects enrolled had histologically or cytologically confirmed advanced or metastatic pancreatic adenocarcinoma with progressive disease during or after 1 systemic therapy. As of May 2022, 23 subjects have been enrolled, with a median of 2 prior lines of therapy.

[0167] 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%). One additional subject had durable stable disease lasting approximately 6 months.

[0168] As of March 30, 2023, 23 patients have been enrolled, all of whom were response evaluable, with a confirmed ORR of 0% by RECIST1.1.

[0169] 7.2.7. ABBV-151 + ABBV-181 Dose Expansion - PD-1-naïve microsatellite-stable colorectal adenocarcinoma :

[0170] Subjects will have microsatellite stable or mismatch repair normal colorectal adenocarcinoma (determined by PCR / NGS or IHC, respectively) at enrollment who have received 1-2 prior chemotherapy regimens and have refused or are ineligible for other approved therapies. Subjects with progression on more than 2 prior systemic therapies will not be eligible for this cohort. Subjects must have available historical microsatellite instability or mismatch repair test results, or have available archived tissue suitable for prospective testing at prescreening. Subjects known to have a high tumor mutational burden (defined as ≥10 mutations / megabase) based on historical results will not be eligible.

[0171] The results are shown in Figure 6 In. As of July 2022, 25 subjects have been enrolled. The objective response rate was 1 / 25 (4%). The best overall response rate (including unconfirmed) was 2 / 25 (8%). One additional subject had durable stable disease lasting approximately 6 months.

[0172] As of March 30, 2023, 25 patients have been enrolled and 24 are response-evaluable, with a confirmed ORR of 8% by RECIST1.1.

[0173] 7.2.8. ABBV-151+ABBV-181 Dose Expansion-NSCLC

[0174] As of March 30, 2023, 3 patients have been enrolled, all 3 are response evaluable, with a confirmed ORR of 0%. This cohort has only recently begun enrolling, so the results are immature and more patient data are needed to fully evaluate the efficacy of this combination in NSCLC.

[0175] 7.2.9. ABBV-151 + ABBV-181 Dose Expansion - Ovarian Granulosa Cell Tumors

[0176] As of March 30, 2023, 4 patients have been enrolled, with an unconfirmed ORR of 75%.

[0177] 7.3. Example 3: PK / PD analysis, modeling and dose optimization

[0178] 7.3.1. Pharmacodynamic biomarkers

[0179] A validated method was used to determine GARP / TGF-β1 target engagement of ABBV-151 on activated platelets from clinical samples.

[0180] 7.3.2. Pharmacokinetics and pharmacodynamics

[0181] Pharmacokinetic samples were obtained at specific visits and time points. Serum concentrations of ABBV-151 were determined using a validated method.

[0182] A nonlinear mixed-effects modeling approach was used to estimate population PK parameters of ABBV-151, such as clearance (CL) and volume (V). max The pharmacodynamics were modeled to estimate the concentration required in the circulation to achieve 95% platelet GARP / TGF-β1 target engagement (EC 95 ) and subsequently extrapolated to the tumor microenvironment.

[0183] 7.3.3. Clinical PK / PD Modeling and Dose Optimization

[0184] Lemonilimab is administered as a monotherapy, and the combination with brigatinib is well tolerated, with no major safety issues at the doses tested in dose escalation (study M19-345). The maximum administered dose (MAD) is 1500mg Q2W in combination with brigatinib and is currently being evaluated for multiple solid tumor indications in the expansion phase. During dose escalation, clinical responses were observed when combined with brigatinib at as low as 30mg Q2W (confirming responses according to RECIST criteria), and in dose expansion, clinical responses were observed at 1500mg Q2W.

[0185] Based on preclinical and clinical PK / PD assessments, it is predicted that doses that provide adequate pharmacological activity and potential clinical efficacy at the tumor site in most subjects in the treated population include 500 mg Q4W and above or 375 mg Q3W and above. As demonstrated by the clinical activity during the dose escalation and expansion parts of M19-345, lower doses may also be effective.

[0186] The determination of a pharmacologically and clinically active dose range is guided by achieving specific target concentrations at the tumor site: (1) Achieving an EC greater than or equal to GARP / TGF-β1 target engagement in the tumor microenvironment of the majority of subjects based on clinical PK / PD data 95 The upper limit of the 95% prediction interval (PI) required for C min,C1 (2) The minimum C value required to maximally inhibit the release of TGFβ1 from the GARP-TGF-β1 complex and subsequently inhibit the autocrine and paracrine signaling of TGF-β1 in the tumor microenvironment. min,C1 This target concentration was derived from preclinical in vitro assays that demonstrated that lemnisimab at a minimum concentration of 0.8 ug / mL maximally inhibited TGF-β1 release and signaling.

[0187] The percentages of subjects achieving these two target concentrations at the tumor site at the indicated Q4W doses are summarized in Table 4. Results from Q3W dosing, which also resulted in similar exposures to the Q4W regimen, are summarized in Table 5. As shown, lemnisimab 500 mg Q4W or 375 mg Q3W will enable ≥95% of subjects to achieve complete target saturation and blockade of TGF-β1 release and signaling at the tumor site, including for subjects at the lower end of the PI for lemnisimab predicted tumor exposure (C min,C1 ). Therefore, lemnisumab 500 mg Q4W or 375 mg Q3W is the predicted minimum dose required to achieve maximal pharmacological activity across solid tumor indications in the majority of subjects treated starting in Cycle 1, and doses lower than 500 mg Q4W or 375 mg Q3W may result in inadequate exposure in a subset of subjects treated in Cycle 1, which may compromise the goal of providing pharmacological activity as quickly as possible and potentially providing clinical efficacy.

[0188] In addition to the model-predicted active dose range (500 mg Q4W and above; 375 mg Q3W and above), the observed clinically active dose range of 30 mg Q2W and above will be studied.

[0189] Table 4. Predicted serum and tumor lemnisimab trough concentrations and median C after Q4W dosing (28-day cycle) min ,C1 ECs that achieve GARP / TGF-β1 target engagement 95 The percentage of subjects with 95% PI upper limit and complete blockade of TGF-β1 release Minimum concentration required for release and signaling

[0190] a. The predicted tumor lemnisimab concentrations are based on the assumption of at least 5% tumor penetration of the monoclonal antibody reported in clinical studies. Guolan Lu et al. Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers. Clin Cancer Res 2020;26:2582–94; Andrew M. Scott et al. A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake. Clin Cancer Res 2005;11:4810-17; Li et al. Clin Pharmacol Ther. 2021 Jul;110(1):200-209

[0191] b. Estimated EC of target engagement95 Preliminary clinical PK / pharmacodynamic modeling based on GARP / TGF-β1 target engagement data on platelets from clinical samples.

[0192] c. The in vitro efficacy of lemnisimab in blocking the release of TGF-β1 from the GARP-TGF-β1 complex was measured by a reporter gene assay in human GARP-TGF-β1 expressed on HEK293T cells.

[0193] d. Using the predictions obtained from the updated model, the dose selection was consistent between the original model and the updated model.

[0194] Table 5. Predicted serum and tumor lemnisimab trough concentrations and median C after Q3W dosing (21-day cycle) min ,C1 ECs that achieve GARP / TGF-β1 target engagement 95 The percentage of subjects with 95% PI upper limit and complete blockade of TGF-β1 release Minimum concentration required for release and signaling

[0195]

[0196] a. The predicted tumor lemnisimab concentrations are based on the assumption of at least 5% tumor penetration of the monoclonal antibody reported in clinical studies. Guolan Lu et al. Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers. Clin Cancer Res 2020;26:2582–94; Andrew M. Scott et al. A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake. Clin Cancer Res 2005;11:4810-17; Li et al. Clin Pharmacol Ther. 2021 Jul;110(1):200-209

[0197] b. Estimated EC of target engagement 95 It is preliminary clinical PK / pharmacodynamic modeling based on GARP / TGF-β1 target engagement data on platelets.

[0198] c. The in vitro efficacy of lemnisimab in blocking the release of TGF-β1 from the GARP-TGF-β1 complex was measured by a reporter gene assay in human GARP-TGF-β1 expressed on HEK293T cells.

[0199] d. Using the predictions obtained from the updated model, the dose selection was consistent between the original model and the updated model.

[0200] 8. Exemplary embodiments

[0201] While various specific embodiments have been illustrated and described, and some are shown below by way of example, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention.

[0202] 8.1. Solid Tumors Expressing TGF-β1

[0203] 1. A method of treating a cancer that evades host immune surveillance at least in part through the expression and release of active TGF-β1, the method comprising administering to a human subject having said tumor a combination of

[0204] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0205] 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,

[0206] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks or once every three weeks.

[0207] 2. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose ranging from about 200 mg to about 1500 mg.

[0208] 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose ranging from about 200 mg to about 1200 mg.

[0209] 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose ranging from about 200 mg to about 1600 mg.

[0210] 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.

[0211] 6. The method according to embodiment 2, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0212] 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0213] 8. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0214] 9. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0215] 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0216] 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0217] 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0218] 13. A method of treating a cancer that evades host immune surveillance at least in part through the expression and release of active TGF-β1, the method comprising administering to a human subject suffering from said cancer a combination of

[0219] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0220] 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,

[0221] 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.

[0222] 14. The method according to embodiment 12, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0223] 15. The method according to embodiment 12, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0224] 16. The method according to embodiment 12, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0225] 17. A method of treating a cancer that evades host immune surveillance at least in part through the expression and release of active TGF-β1, the method comprising administering to a human subject suffering from said cancer a combination of

[0226] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0227] 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,

[0228] wherein 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, 1500 mg and 1600 mg.

[0229] 18. The method according to embodiment 17, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0230] 19. The method according to embodiment 17, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0231] 20. The method according to embodiment 17, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0232] 21. A method of treating a population of human subjects for a cancer that evades host immune surveillance at least in part through expression and release of active TGF-β1, the method comprising administering to said human subjects having said cancer that evades host immune surveillance at least in part through expression and release of active TGF-β1 a combination of

[0233] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0234] 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,

[0235] wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks,

[0236] wherein the overall response rate (ORR) is greater than the standard of care, such as 5% or greater, 15% or greater, 20% or greater, 30% or greater, or 40% or greater.

[0237] 22. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat cancer that evades host immune surveillance at least in part through the expression and release of active TGF-β1, wherein the anti-TGF-β1 / GARP complex antibody consists 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 wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks, and the anti-PD-1 antibody is administered at a dose of 375 mg once every three weeks or 500 mg once every four weeks.

[0238] 8.2. Hepatocellular Carcinoma Implementation Plan

[0239] 1. A method for treating hepatocellular carcinoma (HCC), the method comprising administering to a patient suffering from

[0240] Human subjects with HCC are administered a combination of

[0241] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0242] 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,

[0243] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0244] 2. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose ranging from about 200 mg to about 1600 mg.

[0245] 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose ranging from about 200 mg to about 1200 mg.

[0246] 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose ranging from about 200 mg to about 1600 mg.

[0247] 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.

[0248] 6. The method according to embodiment 2, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0249] 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0250] 8. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0251] 9. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0252] 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0253] 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0254] 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0255] 13. A method according to embodiment 1, wherein the subject suffering from the HCC has previously received a first-line treatment for HCC and experienced progressive disease during the first-line treatment.

[0256] 14. The method of embodiment 13, wherein the first-line treatment comprises a checkpoint inhibitor.

[0257] 15. The method of embodiment 1, wherein the subject with the HCC has progressed on more than one prior line of treatment.

[0258] 16. The method of embodiment 1, wherein the subject with the HCC has not received prior treatment with a tyrosine kinase inhibitor, has no untreated brain metastases, and has not been previously exposed to a PD-1 or PD-L1 antagonist.

[0259] 17. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is intravenously administered before 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 as each other.

[0260] 18. The method according to embodiment 1, wherein the anti-PD-1 antibody is brigatinib.

[0261] 19. The method according to embodiment 2, wherein the anti-PD-1 antibody is brigatinib, administered at a dose of 500 mg once every four weeks.

[0262] 20. The method according to embodiment 3, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 375 mg once every three weeks.

[0263] 21. The method according to embodiment 4, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0264] 22. The method of embodiment 1, wherein the subject suffering from the HCC has not received prior treatment for HCC.

[0265] 23. A method of treating hepatocellular carcinoma (HCC), the method comprising administering to a human subject suffering from said HCC a combination of

[0266] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0267] 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,

[0268] 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,

[0269] wherein the subject having the HCC has previously received a first-line treatment for HCC and experienced progressive disease on the first-line treatment.

[0270] 24. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0271] 25. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0272] 26. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0273] 27. A method of treating hepatocellular carcinoma (HCC), the method comprising administering to a human subject suffering from said HCC a therapeutically effective amount of a combination of

[0274] a) Anti-PD-1 Antibodies

[0275] 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, and

[0276] c) bevacizumab,

[0277] wherein 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,

[0278] wherein said subject having said HCC has not received prior treatment for HCC.

[0279] 28. A method of treating hepatocellular carcinoma (HCC), the method comprising administering to a human subject suffering from said HCC a combination of

[0280] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0281] 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,

[0282] 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.

[0283] 29. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0284] 30. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1000 mg.

[0285] 31. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0286] 32. A method of treating hepatocellular carcinoma (HCC) in a population of human subjects, the method comprising administering to said human subjects suffering from said HCC a combination of

[0287] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0288] 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,

[0289] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0290] 33. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat HCC, wherein the anti-TGF-β1 / GARP complex antibody consists 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 wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0291] 8.3. Urothelial Carcinoma Implementation Plan

[0292] 1. A method of treating urothelial carcinoma (UC), the method comprising administering to a human subject suffering from said UC a combination of

[0293] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0294] 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,

[0295] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0296] 2. The method according to embodiment 1, wherein the UC is muscle invasive urothelial carcinoma (MIUC).

[0297] 3. The method of embodiment 2, wherein the MIUC is classified as MIUCpT2-PT4a or ypT4.

[0298] 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose ranging from about 200 mg to about 1600 mg.

[0299] 5. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose ranging from about 200 mg to about 1200 mg.

[0300] 6. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose ranging from about 200 mg to about 1600 mg.

[0301] 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.

[0302] 8. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0303] 9. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0304] 10. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0305] 11. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0306] 12. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0307] 13. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0308] 14. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0309] 15. The method of embodiment 1, wherein the subject having the urothelial carcinoma or MIUC has received a prior line of treatment for their cancer and experienced progressive disease in the prior line of treatment.

[0310] 16. The method of embodiment 15, wherein the prior line of treatment was treatment with a platinum-based regimen and / or a PD-1 / PD-L1 antagonist administered in the recurrent or metastatic setting.

[0311] 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 as each other, and the anti-TGF-β1 / GARP complex antibody is administered before the anti-PD-1 antibody.

[0312] 18. The method according to embodiment 1, wherein the anti-PD-1 antibody is brigatinib.

[0313] 19. The method according to embodiment 2, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0314] 20. The method according to embodiment 5, wherein the anti-PD-1 antibody is brigatinib administered once every three weeks at a dose of 375 mg.

[0315] 21. The method according to embodiment 6, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0316] 22. The method according to embodiment 1, wherein the administration of the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody is intravenous.

[0317] 23. The method of embodiment 1, wherein the subject having the urothelial carcinoma or MIUC has not received prior treatment for urothelial carcinoma or MIUC.

[0318] 24. A method of treating urothelial carcinoma, the method comprising administering to a human subject suffering from said cancer a combination of

[0319] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0320] 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,

[0321] 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.

[0322] 25. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0323] 26. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0324] 27. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0325] 28. A method of treating urothelial carcinoma, the method comprising administering to a human subject suffering from said cancer a combination of

[0326] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0327] 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,

[0328] wherein 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, 1500 mg and 1600 mg.

[0329] 29. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0330] 30. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0331] 31. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0332] 32. A method of treating urothelial carcinoma in a population of human subjects, the method comprising administering to said human subjects suffering from said urothelial carcinoma a combination of

[0333] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0334] 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,

[0335] wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks,

[0336] wherein the overall response rate (ORR) is greater than the standard of care, such as 5% or greater, 10% or greater, 15% or greater, or 20% or greater.

[0337] 33. The method of embodiment 32, wherein the UC is MIUC.

[0338] 34. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat urothelial carcinoma, wherein the anti-TGF-β1 / GARP complex antibody consists 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 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 ranging from about 200 mg to about 1600 mg.

[0339] 8.4. Non-small cell lung cancer implementation plan

[0340] 1. A method of treating non-small cell lung cancer (NSCLC), the method comprising administering to a human subject suffering from said NSCLC a combination of

[0341] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0342] 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,

[0343] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0344] 2. The method according to embodiment 1, wherein the combination further comprises carboplatin and pemetrexed.

[0345] 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose ranging from about 200 mg to about 1500 mg.

[0346] 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose ranging from about 200 mg to about 1200 mg.

[0347] 5. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose ranging from about 200 mg to about 1600 mg.

[0348] 6. The method according to embodiment 4, 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.

[0349] 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0350] 8. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0351] 9. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0352] 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0353] 11. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0354] 12. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0355] 13. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0356] 14. The method of embodiment 1 or 2, wherein the administration is first-line treatment.

[0357] 15. The method according to embodiment 1 or 2, wherein the NSCLC has PD-L1 TPS ≥ 1%.

[0358] 16. The method according to embodiment 1 or 2, wherein the NSCLC has a PD-L1 TPS ≥ 50%.

[0359] 17. The method according to embodiment 1, wherein the subject has received more than one prior line of treatment and the subject's NSCLC is relapsed / refractory.

[0360] 18. The method of embodiment 1 or 2, wherein the subject's NSCLC has a PD-L1 TPS ≥ 50% and the subject has liver metastasis.

[0361] 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 as each other, and the anti-TGF-β1 / GARP complex antibody is administered before the anti-PD-1 antibody.

[0362] 20. The method according to embodiment 1 or 2, wherein the anti-PD-1 antibody is brigatinib.

[0363] 21. The method according to embodiment 3, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0364] 22. The method according to embodiment 4, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 375 mg once every three weeks.

[0365] 23. The method of embodiment 5, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0366] 24. A method of treating non-small cell lung cancer ("NSCLC"), the method comprising administering to a human subject suffering from said NSCLC a combination of

[0367] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0368] 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,

[0369] 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.

[0370] 25. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0371] 26. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0372] 27. The method according to embodiment 24, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0373] 28. A method of treating non-small cell lung cancer ("NSCLC") comprising administering to a human subject suffering from said NSCLC a combination of

[0374] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0375] 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,

[0376] wherein 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, 1500 mg and 1600 mg.

[0377] 29. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0378] 30. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0379] 31. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0380] 32. A method of treating non-small cell lung cancer ("NSCLC") in a population of human subjects, the method comprising administering to said human subjects suffering from said NSCLC a combination of

[0381] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0382] 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,

[0383] wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks,

[0384] wherein the overall response rate (ORR) is greater than the standard of care, such as 20% or greater, 30% or greater, or 40% or greater.

[0385] 33. The method of embodiment 32, wherein the combination further comprises carboplatin and pemetrexed.

[0386] 34. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat NSCLC, wherein the anti-TGF-β1 / GARP complex antibody consists 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 wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0387] 8.5. Implementation Plan for Microsatellite Stable Colorectal Cancer

[0388] 1. A method of treating microsatellite stable colorectal cancer (MSS-CRC), the method comprising administering to a human subject suffering from said MSS-CRC a combination of

[0389] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0390] 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,

[0391] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0392] 2. The method according to embodiment 1, wherein the MSS-CRC is of CMS4 subtype.

[0393] 3. A method according to embodiment 1, wherein the MSS-CRC is unselected for the CMS4 subtype.

[0394] 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 ranging from about 200 mg to about 1500 mg.

[0395] 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 ranging from about 200 mg to about 1200 mg.

[0396] 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 ranging from about 200 mg to about 1600 mg.

[0397] 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.

[0398] 8. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0399] 9. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0400] 10. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0401] 11. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0402] 12. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0403] 13. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0404] 14. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0405] 15. A method according to any one of embodiments 1 to 3, wherein the subject suffering from the MSS-CRC has previously received a prior line of treatment for microsatellite stable colorectal cancer and experienced progressive disease on the first-line treatment.

[0406] 16. The method of embodiment 15, wherein the prior line of treatment is fluorouracil-based combination chemotherapy and the subject has no prior exposure to anti-PD-1 or anti-PD-L1 antibody treatment.

[0407] 17. The method of embodiment 16, wherein the prior line of treatment comprises oxaliplatin or irinotecan.

[0408] 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 as each other, and the anti-TGF-β1 / GARP complex antibody is administered before the anti-PD-1 antibody.

[0409] 19. The method according to any one of embodiments 1 to 3, wherein the anti-PD-1 antibody is brigatinib.

[0410] 20. The method of embodiment 4, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0411] 21. The method according to embodiment 5, wherein the anti-PD-1 antibody is brigatinib administered once every three weeks at a dose of 375 mg.

[0412] 22. The method according to embodiment 6, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0413] 23. The method according to any one of embodiments 1 to 3, wherein the administration of the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody is intravenous.

[0414] 24. The method of any one of embodiments 1 to 3, wherein the subject suffering from the MSS-CRC has not received prior treatment for MSS-CRC.

[0415] 25. A method of treating MSS-CRC, the method comprising administering to a human subject suffering from said MSS-CRC a combination of

[0416] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0417] 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,

[0418] 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.

[0419] 26. The method according to embodiment 25, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0420] 27. The method according to embodiment 25, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0421] 28. The method according to embodiment 25, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0422] 29. A method according to embodiment 25, wherein the MSS-CRC is CMS4 subtype.

[0423] 30. A method according to embodiment 25, wherein the MSS-CRC is unselected for the CMS4 subtype.

[0424] 31. A method of treating MSS-CRC, the method comprising administering to a human subject suffering from said MSS-CRC a combination of

[0425] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0426] 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,

[0427] wherein 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, 1500 mg and 1600 mg.

[0428] 32. The method according to embodiment 31, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0429] 33. The method according to embodiment 31, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0430] 34. The method according to embodiment 31, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0431] 35. A method according to embodiment 31, wherein the MSS-CRC is CMS4 subtype.

[0432] 36. A method according to embodiment 31, wherein the MSS-CRC is unselected for the CMS4 subtype.

[0433] 37. A method of treating MSS-CRC in a population of human subjects, the method comprising administering to said human subjects suffering from said MSS-CRC a combination of

[0434] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0435] 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,

[0436] wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks,

[0437] wherein the overall response rate (ORR) is greater than the standard of care, such as 5% or greater, 15% or greater, 20% or greater, 30% or greater, or 40% or greater.

[0438] 38. A method according to embodiment 37, wherein the MSS-CRC is CMS4 subtype.

[0439] 39. A method according to embodiment 37, wherein the MSS-CRC is unselected for the CMS4 subtype.

[0440] 34. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat MSS-CRC, wherein the anti-TGF-β1 / GARP complex antibody consists 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 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 ranging from about 200 mg to about 1600 mg.

[0441] 8.6. Implementation Plan for Ovarian Granulosa Cell Tumors

[0442] 1. A method of treating ovarian granulosa cell tumor (GCT), the method comprising administering to a human subject having said GCT a combination of

[0443] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0444] 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,

[0445] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0446] 2. The method according to embodiment 1, wherein the GCT contains a FOXL2 gene mutation.

[0447] 3. The method according to embodiment 2, wherein the FOXL2 mutation is a C134W mutation.

[0448] 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 ranging from about 200 mg to about 1500 mg.

[0449] 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 ranging from about 200 mg to about 1200 mg.

[0450] 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 ranging from about 200 mg to about 1600 mg.

[0451] 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.

[0452] 8. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0453] 9. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0454] 10. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0455] 11. The method according to embodiment 5, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0456] 12. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0457] 13. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0458] 14. The method according to embodiment 6, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0459] 15. The method of any one of embodiments 1 to 3, wherein the subject with the GCT has previously undergone a unilateral salpingo-oophorectomy or a bilateral salpingo-oophorectomy within 120 days prior to treatment with the anti-TGF-β1 / GARP complex antibody.

[0460] 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 administered intravenously on the same day as each other, and the anti-TGF-β1 / GARP complex antibody is administered before the anti-PD-1 antibody.

[0461] 17. The method according to any one of embodiments 1 to 3, wherein the anti-PD-1 antibody is brigatinib.

[0462] 18. The method according to embodiment 2, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0463] 19. The method according to embodiment 5, wherein the anti-PD-1 antibody is brigatinib administered once every three weeks at a dose of 375 mg.

[0464] 20. The method according to embodiment 6, wherein the anti-PD-1 antibody is brigatinib, and the anti-PD-1 antibody is administered at a dose of 500 mg or 600 mg once every four weeks.

[0465] 21. The method according to any one of embodiments 1 to 3, wherein the administration of the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody is intravenous.

[0466] 22. The method of any one of embodiments 1 to 3, wherein the subject suffering from the GCT has not received prior systemic treatment for the GCT.

[0467] 23. A method of treating an ovarian granulosa cell tumor (GCT) containing a FOXL2C134W mutation, the method comprising administering to a human subject having the GCT a combination of

[0468] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0469] 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,

[0470] 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,

[0471] wherein said subject having said GCT has previously undergone unilateral salpingo-oophorectomy or bilateral salpingo-oophorectomy within 120 days prior to treatment with said anti-TGF-β1 / GARP complex antibody.

[0472] 24. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0473] 25. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0474] 26. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0475] 27. A method of treating an ovarian granulosa cell tumor (GCT) containing a FOXL2C134W mutation, the method comprising administering to a human subject having the GCT a combination of

[0476] a) A therapeutically effective amount of an anti-PD-1 antibody

[0477] 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, and

[0478] c) Bevacizumab,

[0479] 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,

[0480] wherein said subject having said GCT has not received prior systemic treatment for the GCT.

[0481] 28. A method of treating an ovarian granulosa cell tumor (GCT) containing a FOXL2C134W mutation, the method comprising administering to a human subject having the GCT a combination of

[0482] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0483] 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,

[0484] wherein 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, 1500 mg and 1600 mg.

[0485] 29. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0486] 30. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0487] 31. The method according to embodiment 28, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0488] 32. A method of treating a population of human subjects for ovarian granulosa cell tumors (GCTs) containing a FOXL2C134W mutation, the method comprising administering to said human subjects having said GCTs a combination of

[0489] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0490] 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,

[0491] wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1500 mg once every two weeks, once every three weeks, or once every four weeks,

[0492] wherein the overall response rate (ORR) is greater than the standard of care, such as 5% or greater, about 10% or greater, about 15% or greater, 20% or greater, 30% or greater, or 40% or greater.

[0493] 33. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat GCT, wherein the anti-TGF-β1 / GARP complex antibody consists 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 wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1500 mg once every two weeks, once every three weeks, or once every four weeks.

[0494] 8.7. Head and Neck Squamous Cell Carcinoma Implementation Plan

[0495] 1. A method of treating head and neck squamous cell carcinoma, the method comprising administering to a human subject suffering from said head and neck squamous cell carcinoma a combination of

[0496] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0497] 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,

[0498] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0499] 2. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose ranging from about 200 mg to about 1500 mg.

[0500] 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose ranging from about 200 mg to about 1200 mg.

[0501] 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose ranging from about 200 mg to about 1600 mg.

[0502] 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.

[0503] 6. The method according to embodiment 2, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0504] 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0505] 8. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0506] 9. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0507] 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0508] 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0509] 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0510] 13. The method of embodiment 1, wherein the head and neck squamous cell carcinoma originates from the oral cavity, oropharynx, hypopharynx, or larynx.

[0511] 14. A method according to embodiment 1, wherein the subject suffering from the head and neck squamous cell carcinoma has received prior treatment for first-line treatment of head and neck squamous cell carcinoma and experienced progressive disease during the prior treatment.

[0512] 15. The method of embodiment 14, wherein the prior line of treatment was a platinum-based regimen and an anti-PD-1 or anti-PD-L1 antibody administered in the recurrent or metastatic setting.

[0513] 16. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered intravenously before 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 as each other.

[0514] 17. The method according to embodiment 1, wherein the anti-PD-1 antibody is brigatinib.

[0515] 18. The method according to embodiment 2, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0516] 19. The method according to embodiment 3, wherein the anti-PD-1 antibody is brigatinib, and the anti-PD-1 antibody is administered once every three weeks at a dose of 375 mg.

[0517] 20. The method of embodiment 4, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0518] 21. The method according to embodiment 1, wherein the administration of the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody is intravenous.

[0519] 22. The method of embodiment 1, wherein the subject suffering from the head and neck squamous cell carcinoma has not received prior treatment for head and neck squamous cell carcinoma.

[0520] 23. A method of treating head and neck squamous cell carcinoma, the method comprising administering to a human subject suffering from said head and neck squamous cell carcinoma a combination of

[0521] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0522] 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,

[0523] 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 anti-PD-1 antibody is administered once every three weeks at a dose of 375 mg,

[0524] wherein the subject having the head and neck squamous cell carcinoma has received a prior line of treatment for head and neck squamous cell carcinoma and experienced progressive disease in the prior line of treatment.

[0525] 24. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0526] 25. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0527] 26. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0528] 27. A method of treating head and neck squamous cell carcinoma, the method comprising administering to a human subject suffering from said head and neck squamous cell carcinoma a combination of

[0529] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0530] 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,

[0531] wherein 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, 1500 mg and 1600 mg, and the anti-PD-1 antibody is administered once every four weeks at a dose of 500 mg.

[0532] 28. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0533] 29. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0534] 30. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0535] 31. A method of treating head and neck squamous cell carcinoma in a population of human subjects, the method comprising administering to said human subjects suffering from said head and neck squamous cell carcinoma a combination of

[0536] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0537] 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,

[0538] wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1500 mg once every two weeks, once every three weeks, or once every four weeks, wherein the overall response rate (ORR) is greater than the standard of care, such as 5% or greater, 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater.

[0539] 33. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat head and neck squamous cell carcinoma, wherein the anti-TGF-β1 / GARP complex antibody consists 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 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 ranging from about 200 mg to about 1600 mg.

[0540] 8.8. Pancreatic Adenocarcinoma Implementation Plan

[0541] 1. A method of treating pancreatic adenocarcinoma, the method comprising administering to a human subject suffering from said pancreatic adenocarcinoma a combination of

[0542] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0543] 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,

[0544] The anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

[0545] 2. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every two weeks at a dose ranging from about 200 mg to about 1500 mg.

[0546] 3. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every three weeks at a dose ranging from about 200 mg to about 1200 mg.

[0547] 4. The method according to embodiment 1, wherein the anti-TGF-β1 / GARP complex antibody is administered once every four weeks at a dose ranging from about 200 mg to about 1600 mg.

[0548] 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.

[0549] 6. The method according to embodiment 2, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0550] 7. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0551] 8. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0552] 9. The method according to embodiment 3, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0553] 10. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0554] 11. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0555] 12. The method according to embodiment 4, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0556] 13. The method of embodiment 1, wherein the subject having the pancreatic adenocarcinoma has received no more than one prior line of treatment for pancreatic adenocarcinoma and experienced progressive disease on the first-line treatment.

[0557] 14. The method according to embodiment 13, wherein the previous line of treatment is

[0558] a) Gemcitabine monotherapy or in combination with other agents;

[0559] b) FOLFIRINOX or another regimen that includes 5-fluorouracil and oxaliplatin; or

[0560] c) Capecitabine monotherapy or in combination with other agents,

[0561] Administration in the adjuvant, locally advanced, or metastatic setting, and the subject has not been previously exposed to a PD-1 or PD-L1 antagonist.

[0562] 15. The method of embodiment 14, wherein the prior line of treatment was in the adjuvant setting and progressive disease occurred within six months of completion of adjuvant therapy.

[0563] 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 as each other.

[0564] 17. The method according to embodiment 1, wherein the anti-PD-1 antibody is brigatinib.

[0565] 18. The method according to embodiment 2, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0566] 19. The method according to embodiment 3, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 375 mg once every three weeks.

[0567] 20. The method of embodiment 4, wherein the anti-PD-1 antibody is brigatinib administered at a dose of 500 mg once every four weeks.

[0568] 21. The method according to embodiment 1, wherein the administration of the anti-TGF-β1 / GARP complex antibody and the anti-PD-1 antibody is intravenous.

[0569] 22. The method of embodiment 1, wherein the subject suffering from the pancreatic adenocarcinoma has not received prior treatment for pancreatic adenocarcinoma.

[0570] 23. A method of treating pancreatic adenocarcinoma, the method comprising administering to a human subject suffering from said pancreatic adenocarcinoma a combination of

[0571] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0572] 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,

[0573] wherein 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,

[0574] wherein said subject having said pancreatic adenocarcinoma has received a prior line of treatment for pancreatic adenocarcinoma and has experienced progressive disease in said prior line of treatment.

[0575] 24. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 400 mg.

[0576] 25. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0577] 26. The method according to embodiment 23, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1200 mg.

[0578] 27. A method of treating pancreatic adenocarcinoma, the method comprising administering to a human subject suffering from said pancreatic adenocarcinoma a therapeutically effective amount of a combination of

[0579] a) Anti-PD-1 antibodies and

[0580] 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,

[0581] wherein 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.

[0582] 28. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 500 mg.

[0583] 29. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 600 mg.

[0584] 30. The method according to embodiment 27, wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose of 1500 mg.

[0585] 31. A method of treating pancreatic adenocarcinoma in a population of human subjects, the method comprising administering to said human subjects suffering from said pancreatic adenocarcinoma a combination of

[0586] a) a therapeutically effective amount of an anti-PD-1 antibody, and

[0587] 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,

[0588] wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from 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 at a dose of 375 mg once every three weeks or 500 mg once every four weeks,

[0589] wherein the overall response rate (ORR) is greater than the standard of care, such as 5% or greater, 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater.

[0590] 32. A TGF-β1 / GARP complex antibody for use in combination with an anti-PD-1 antibody to treat pancreatic adenocarcinoma, wherein the anti-TGF-β1 / GARP complex antibody consists 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 wherein the anti-TGF-β1 / GARP complex antibody is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

Claims

1. A method for treating CMS4-enriched microsatellite-stable colorectal cancer, the method comprising administering to a human subject suffering from said cancer a therapeutically effective amount of a combination of the following a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

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

3. A method of treating microsatellite stable colorectal cancer, the method comprising administering to a human subject suffering from said cancer a therapeutically effective amount of a combination of a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

4. The method of claim 3, wherein the anti-PD-1 antibody is brigatinib, and wherein the brigatinib is administered at a dose of 250 mg once every two weeks, 375 mg once every three weeks, or 500 mg once every four weeks.

5. A method of treating non-small cell lung cancer (NSCLC), the method comprising administering to a human subject suffering from said NSCLC a therapeutically effective amount of a combination of a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

6. The method of claim 5, further comprising administering carboplatin and pemetrexed.

7. The method of claim 5 or claim 6, wherein the anti-PD-1 antibody is brigatinib, and wherein the brigatinib is administered at a dose of 250 mg once every two weeks, 375 mg once every three weeks, or 500 mg once every four weeks.

8. A method of treating relapsed / refractory non-small cell lung cancer (NSCLC), the method comprising administering to a human subject suffering from said cancer a therapeutically effective amount of a combination of a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

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

10. A method of treating pancreatic adenocarcinoma, the method comprising administering to a human subject suffering from said pancreatic adenocarcinoma a therapeutically effective amount of a combination of a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

11. The method of claim 10, wherein the anti-PD-1 antibody is brigatinib, and wherein the brigatinib is administered at a dose of 250 mg once every two weeks, 375 mg once every three weeks, or 500 mg once every four weeks.

12. The method of claim 10 or claim 11 further comprising administering paclitaxel or nab-paclitaxel and gemcitabine.

13. A method of treating muscle-invasive bladder cancer, the method comprising administering to a human subject suffering from said cancer a combination of a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

14. The method of claim 13, wherein the anti-PD-1 antibody is brigatinib, and wherein the brigatinib is administered at a dose of 250 mg once every two weeks, 375 mg once every three weeks, or 500 mg once every four weeks.

15. A method of treating an ovarian granulosa cell tumor (GCT) containing a FOXL2 C134W mutation, the method comprising administering to a human subject having the tumor a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

16. The method of claim 15, wherein the anti-PD-1 antibody is brigatinib, and wherein the brigatinib is administered at a dose of 250 mg once every two weeks, 375 mg once every three weeks, or 500 mg once every four weeks.

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

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

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

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

21. The method of claim 19 or claim 20, wherein the subject has no prior line of treatment for HCC 22. The method of claim 19 or claim 20, wherein the subject has one prior line of treatment for HCC.

23. The method of claim 19 or claim 20, wherein the subject has more than one prior line of treatment for HCC.

24. A method of treating urothelial cancer, the method comprising administering to a human subject suffering from said cancer a therapeutically effective amount of a combination of a) a therapeutically effective amount of an anti-PD-1 antibody on a therapeutically effective schedule, and b) Lemonilimab wherein the lemnisumab is administered at a dose ranging from about 200 mg to about 1600 mg once every two weeks, once every three weeks, or once every four weeks.

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

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

27. The method of any one of claims 1 to 25, wherein administration of the combination of lemnisumab 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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