Methods and compositions for treating cancer

Abstract

The present invention provides methods and compositions for treating cancer in a subject (e.g., locally advanced, recurrent, or metastatic solid tumors) by administering an anticancer therapy comprising, for example, an anti-latent TGF-beta 1 antibody to the subject. Compositions for use in treating cancer in a subject (e.g., anti-latent TGF-beta 1 antibodies, their pharmaceutical compositions, their kits, and their manufacturing articles) are also provided.

Description

[Technical Field]

[0001] Sequence List This application includes a sequence listing submitted electronically in XML format, the entirety of which is incorporated herein by reference. The XML copy, created on 29 April 2024, is named "50474-323WO2_Sequence_Listing_4_29_24" and has a size of 62,842 bytes.

[0002] Field of Invention The present invention relates to methods and compositions for use in treating cancer in a subject (e.g., locally advanced, recurrent, or metastatic solid tumors) by administering, for example, an anticancer therapy comprising an anti-latent transforming growth factor (TGF)-beta 1 antibody to the subject. [Background technology]

[0003] Background of the Invention Cancer remains one of the deadliest threats to human health. In the United States, approximately 1.3 million people are newly diagnosed with cancer each year, making it the second leading cause of death after heart disease and accounting for about a quarter of all deaths. Cancer is also projected to surpass cardiovascular disease as the leading cause of death within five years. Solid tumors account for the majority of these deaths. While significant progress has been made in treating certain types of cancer, the five-year overall survival rate for all cancers has improved by only about 10% in the last 20 years. Malignant solid tumors, in particular, are extremely difficult to detect and treat in a timely manner because they metastasize and grow rapidly without control.

[0004] Despite significant advances in cancer treatment, improved anti-cancer therapies are still needed. [Overview of the project]

[0005] Summary of the Invention The present invention provides, in particular, a method for treating cancer (e.g., locally advanced, recurrent, or metastatic solid tumors), as well as related compositions and manufactured articles for use.

[0006] In one embodiment, the present invention provides a method for treating a subject having locally advanced, recurrent, or metastatic solid tumors, the method comprising administering an anticancer therapy comprising an anti-latent transforming growth factor (TGF)-beta-1 antibody to the subject at a dose of 1800 mg, wherein the anti-latent TGF-beta-1 antibody comprises the following six hypervariable regions (HVRs): (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. 1) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of HVR-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively.

[0007] In another embodiment, the present invention provides anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors, the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1800 mg, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of R-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively.

[0008] In some embodiments, the anti-latent TGF-beta 1 antibody is administered to the subject in a drug regimen that includes one or more 21-day drug cycles.

[0009] In some embodiments, the anti-latent TGF-beta 1 antibody is administered to the subject on day 1 of each 21-day drug cycle.

[0010] In another embodiment, the present invention provides a method for treating subjects having locally advanced, recurrent, or metastatic solid tumors, the method comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W), wherein the anti-latent TGF-beta-1 antibody comprises the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR- (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively.

[0011] In another embodiment, the present invention provides anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors, the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W), the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. (c) HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of H1, HVR-H2, and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively.

[0012] In another embodiment, the present invention provides a method for treating a subject having locally advanced, recurrent, or metastatic solid tumors, the method comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and (c) HVR-H3, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0013] In another embodiment, the present invention provides anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors, the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of R-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively.

[0014] In some embodiments, the anti-latent TGF-beta 1 antibody is administered to the subject in a drug regimen that includes one or more 28-day drug cycles.

[0015] In some embodiments, the anti-latent TGF-beta 1 antibody is administered to the subject on day 1 and day 15 of each 28-day drug cycle.

[0016] In another embodiment, the present invention provides a method for treating subjects having locally advanced, recurrent, or metastatic solid tumors, the method comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W), the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of sequence numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of sequence numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of sequence numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of sequence numbers 28, 29, and 30, respectively.

[0017] In another embodiment, the present invention provides anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors, the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W), the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. (c) HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of H1, HVR-H2, and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively.

[0018] In some embodiments, the anti-latent TGF-beta 1 antibody is administered intravenously to the subject.

[0019] In some embodiments, the anti-latent TGF-beta 1 antibody is administered intravenously to the subject by infusion.

[0020] In some embodiments, tumor samples derived from the subject have been determined to have detectable levels of PD-L1 expression.

[0021] In some cases, the target age is 18 years or older.

[0022] In some aspects, anti-cancer therapy is the first-line treatment.

[0023] In some aspects, anti-cancer therapy is a second-line or third-line therapy.

[0024] In some embodiments, the subjects have not been previously treated with checkpoint inhibitors.

[0025] In some cases, solid tumors are metastatic.

[0026] In some aspects, locally advanced, recurrent, or metastatic solid tumors include non-small cell lung cancer (NSCLC), gastric cancer, pancreatic ductal adenocarcinoma (PDAC), urothelial carcinoma (UC), gastrointestinal stromal tumor (GIST), skin cancer, colorectal cancer, ovarian (OV) cancer, kidney cancer, or gallbladder cancer.

[0027] In some aspects, locally advanced, recurrent, or metastatic solid tumors are considered NSCLCs.

[0028] In some embodiments, NSCLC is histologically or cytologically confirmed metastatic non-squamous NSCLC or metastatic squamous NSCLC.

[0029] In some embodiments, subjects had disease progression during or after treatment for metastatic or locally advanced, unresectable NSCLC, which was given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order, comprising a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist.

[0030] In some embodiments, the subjects had previously received combination therapy including a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist.

[0031] In some embodiments, the subjects had previously received platinum-containing chemotherapy regimens and PD-1 axis-coupled antagonists as separate regimens.

[0032] In some cases, the subjects had experienced disease progression or relapse within 6 months of curative treatment for locally progressive NSCLC.

[0033] In some embodiments, tumor samples derived from the subject have been determined to have detectable levels of PD-L1 expression.

[0034] In some aspects, locally advanced, recurrent, or metastatic solid tumors are gastric cancer.

[0035] In some embodiments, the subjects have unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be adenocarcinoma.

[0036] In some embodiments, gastric cancer includes cancer of the esophagogastric junction.

[0037] In some aspects, gastric cancer is HER2-negative gastric cancer.

[0038] In some embodiments, the subjects have not been previously treated for gastric cancer and / or have not been previously treated with checkpoint inhibitors.

[0039] In some embodiments, locally advanced, recurrent, or metastatic solid tumors are PDACs.

[0040] In some embodiments, the subject has histologically or cytologically confirmed metastatic PDAC.

[0041] In some embodiments, the subjects have not been previously treated for PDAC and / or have not been previously treated with checkpoint inhibitors.

[0042] In some aspects, locally advanced, recurrent, or metastatic solid tumors are ulcerative colitis (UC).

[0043] In some embodiments, the subjects have histologically demonstrated locally progressive (T4b, any N; or any T, N2-N3) UC or metastatic UC (M1, stage 4).

[0044] In some cases, the subjects have not been previously treated for UC.

[0045] In some cases, the subjects are ineligible for cisplatin-containing chemotherapy.

[0046] In some aspects, subjects are ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) renal impairment in terms of glomerular filtration rate (GFR) of 30 mL / min or more and less than 60 mL / min, as assessed by direct measurement or calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two adjacent frequencies, as measured by audiometry; (iii) grade 2 peripheral neuropathy; or (iv) ineligibility for cisplatin-containing chemotherapy as defined by one of the following: East Coast Cancer Clinical Trials Group (ECOG) Performance Status 2.

[0047] In some embodiments, the subject has previously received at least one platinum-containing chemotherapy regimen.

[0048] In some embodiments, the subjects had disease progression during or after treatment with at least one platinum-containing chemotherapy regimen.

[0049] In some embodiments, at least one platinum-containing chemotherapy regimen comprises (i) gemcitabine and cisplatin or carboplatin, or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin.

[0050] In some aspects, the subjects had received prior adjuvant or neoadjuvant chemotherapy and their disease progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.

[0051] In some embodiments, subjects received one cycle of platinum-containing chemotherapy regimen but discontinued it due to grade 4 hematological toxicity or grade 3–4 non-hematological toxicity.

[0052] In some aspects, the subjects received two or fewer prior treatment lines for locally advanced or metastatic UC.

[0053] In some aspects, the subjects had not received prior treatment with T-cell costimulation therapy or checkpoint inhibitors.

[0054] In some embodiments, the anti-latent TGF-beta 1 antibody is administered to the subject in combination with one or more additional therapeutic agents.

[0055] In some embodiments, one or more additional therapeutic agents include checkpoint inhibitors.

[0056] In some embodiments, the checkpoint inhibitor comprises a PD-1 axis-binding antagonist or a CTLA4 antagonist.

[0057] In some embodiments, checkpoint inhibitors include PD-1 axis-binding antagonists.

[0058] In some embodiments, the PD-1 axis-coupled antagonist includes a PD-L1-coupled antagonist, a PD-1-coupled antagonist, or a PD-L2-coupled antagonist.

[0059] In some embodiments, the PD-1 axis-coupled antagonist includes the PD-L1-coupled antagonist.

[0060] In some embodiments, the PD-L1-binding antagonist includes an anti-PD-L1 antibody.

[0061] In some embodiments, the anti-PD-L1 antibody includes atezolizumab, durvalumab, avelumab, or MDX-1105.

[0062] In some embodiments, the anti-PD-L1 antibody comprises atezolizumab.

[0063] In some embodiments, atezolizumab is administered to the subject in a drug regimen that includes one or more drug cycles.

[0064] In some embodiments, one or more medication cycles include a 21-day medication cycle.

[0065] In some embodiments, atezolizumab is administered to the subject on day 1 of each 21-day drug cycle.

[0066] In some embodiments, atezolizumab is administered to the subject at a dose of 1200 mg.

[0067] In some embodiments, one or more medication cycles include either a 14-day medication cycle or a 28-day medication cycle.

[0068] In some embodiments, one or more drug cycles consist of 14-day drug cycles in which atezolizumab is administered to the subject at a dose of 840 mg.

[0069] In some embodiments, atezolizumab is administered to the subject on day 1 of each 14-day drug cycle.

[0070] In some embodiments, one or more drug cycles consist of a 28-day drug cycle in which atezolizumab is administered to the subject at a dose of 1680 mg.

[0071] In some embodiments, atezolizumab is administered to the subject on day 1 of each 28-day drug cycle.

[0072] In some embodiments, atezolizumab is administered intravenously to the subject.

[0073] In some embodiments, atezolizumab is administered intravenously to the subject by infusion.

[0074] In some embodiments, the PD-1 axis-coupled antagonist includes a PD-1-binding antagonist.

[0075] In some embodiments, the PD-1 conjugated antagonist includes an anti-PD-1 antibody.

[0076] In some embodiments, the anti-PD-1 antibody includes nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiprimab, prorugolimab, camrelizumab, cintilimab, tislerizumab, tripalimab, dostalimab, retifanlimab, sasanlimab, penprimab, zinbererimab, valstilimab, genolimusumab, cetrelimab, or buzigalimab.

[0077] In some embodiments, the anti-PD-1 antibody comprises nivolumab.

[0078] In some embodiments, nivolumab is administered to the subject in a drug regimen that includes one or more drug cycles.

[0079] In some embodiments, one or more medication cycles include a 21-day medication cycle.

[0080] In some embodiments, nivolumab is administered to the subject on day 1 of each 21-day drug cycle.

[0081] In some embodiments, nivolumab is administered to the subject at a dose of 360 mg.

[0082] In some embodiments, nivolumab is administered intravenously to the subject.

[0083] In some embodiments, nivolumab is administered intravenously to the subject by infusion.

[0084] In some embodiments, one or more additional therapeutic agents are selected from chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, anti-angiogenic agents, and any combination thereof.

[0085] In some embodiments, one or more additional therapeutic agents include one or more chemotherapeutic agents.

[0086] In some embodiments, one or more chemotherapeutic agents include platinum-based chemotherapeutic agents, antimetabolites, cytotoxic agents, growth inhibitors, taxanes, folic acid analogs, or any combination thereof.

[0087] In some embodiments, the platinum-based chemotherapeutic agent includes oxaliplatin, cisplatin, or carboplatin.

[0088] In some embodiments, the platinum-based chemotherapeutic agent includes oxaliplatin.

[0089] In some embodiments, oxaliplatin is administered to the subject in a drug regimen that includes one or more drug cycles.

[0090] In some embodiments, one or more medication cycles include a 21-day medication cycle.

[0091] In some embodiments, oxaliplatin is administered to the subject on day 1 of each 21-day drug cycle.

[0092] In some embodiments, oxaliplatin is 130 mg / m² 2 It is administered to the target in the specified dose.

[0093] In some embodiments, oxaliplatin is administered intravenously to the subject.

[0094] In some embodiments, the antimetabolite includes capecitabine, gemcitabine, 5-fluorouracil, or tegafur.

[0095] In some embodiments, the antimetabolite includes capecitabine.

[0096] In some embodiments, capecitabine is administered to a subject in a drug regimen that includes one or more drug cycles.

[0097] In some embodiments, one or more medication cycles include a 21-day medication cycle.

[0098] In some embodiments, capecitabine is administered to subjects on days 1 through 14 of each 21-day medication cycle.

[0099] In some embodiments, capecitabine is administered to subjects at a dose of 1000 mg / m². 2 It is administered twice a day at this dose.

[0100] In some embodiments, capecitabine is administered orally to the subject.

[0101] In some embodiments, the antimetabolite includes gemcitabine.

[0102] In some embodiments, gemcitabine is administered to a subject in a drug regimen that includes one or more drug cycles.

[0103] In some embodiments, one or more medication cycles include a 28-day medication cycle.

[0104] In some embodiments, gemcitabine is administered to subjects on days 1, 8, and 15 of each 28-day drug cycle.

[0105] In some embodiments, gemcitabine is administered to the subject at a dose of 1000 mg / m². 2 It is administered twice a day at this dose.

[0106] In some embodiments, gemcitabine is administered intravenously to the subject.

[0107] In some embodiments, the antimetabolite includes tegafur.

[0108] In some embodiments, the antimetabolite includes S-1 (tegafur, gimeracil, oteracil potassium).

[0109] In some embodiments, S-1 is administered to the subject in a drug regimen that includes one or more drug cycles.

[0110] In some embodiments, one or more medication cycles include a 21-day medication cycle.

[0111] In some embodiments, S-1 is administered to the subject on days 1 through 14 of each 21-day medication cycle.

[0112] In some embodiments, S-1 is administered to the subject at a dose of 40 mg / m². 2 It is administered twice a day at this dose.

[0113] In some embodiments, S-1 is administered orally to the subject.

[0114] In some embodiments, the taxane includes nab-paclitaxel or paclitaxel.

[0115] In some embodiments, the taxane includes nab-paclitaxel.

[0116] In some embodiments, nab-paclitaxel is administered to the subject in a drug regimen that includes one or more drug cycles.

[0117] In some embodiments, one or more medication cycles include a 28-day medication cycle.

[0118] In some embodiments, nab-paclitaxel is administered to subjects on days 1, 8, and 15 of each 28-day drug cycle.

[0119] In some embodiments, nab-paclitaxel is administered at 125 mg / m². 2 It is administered to the target in the specified dose.

[0120] In some embodiments, nab-paclitaxel is administered intravenously to the subject.

[0121] In some embodiments, the folic acid analog comprises leucovorin.

[0122] In another embodiment, the present invention provides a method for treating a subject having locally advanced, recurrent, or metastatic NSCLC, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of HVR-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (e) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0123] In another embodiment, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic NSCLC, the treatment comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) sequence (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively.

[0124] In some embodiments, NSCLC is histologically or cytologically confirmed metastatic non-squamous NSCLC or metastatic squamous NSCLC.

[0125] In some embodiments, subjects had disease progression during or after treatment for metastatic or locally advanced, unresectable NSCLC, which was given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order, comprising a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist.

[0126] In some embodiments, the subjects had previously received combination therapy including a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist.

[0127] In some embodiments, the subjects had previously received platinum-containing chemotherapy regimens and PD-1 axis-coupled antagonists as separate regimens.

[0128] In some cases, the subjects had experienced disease progression or relapse within 6 months of curative treatment for locally progressive NSCLC.

[0129] In some embodiments, tumor samples derived from the subject have been determined to have detectable levels of PD-L1 expression.

[0130] In another embodiment, the present invention provides a method for treating a subject having locally advanced, recurrent, or metastatic gastric cancer, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and sequence number (i) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively; and (ii) nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day treatment cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1 to 14 of each 21-day treatment cycle. 2 (b) capecitabine at the prescribed dosage, or (b) 40 mg / m² orally twice daily on days 1-14 of each 21-day medication cycle. 2 S-1 at the dosage of (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle; and (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. 2 Oxaliplatin at the prescribed dosage.

[0131] In another embodiment, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic gastric cancer, the treatment comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) sequence number (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively.

[0132] In some embodiments, the subjects have unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be adenocarcinoma.

[0133] In some embodiments, gastric cancer includes cancer of the esophagogastric junction.

[0134] In some aspects, gastric cancer is HER2-negative gastric cancer.

[0135] In some embodiments, the subjects have not been previously treated for gastric cancer and / or have not been previously treated with checkpoint inhibitors.

[0136] In another aspect, the present invention provides a method of treating a subject having locally advanced, recurrent, or metastatic PDAC, the method comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, the anti-cancer therapy comprising: (i) an anti-latent TGF-beta 1 antibody at a dose of 1200 mg intravenously on days 1 and 15 of each 28-day dosing cycle, the anti-latent TGF-beta 1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 each comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 each comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 each comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 each comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 each comprising the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 each comprising the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 each comprising the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 each comprising the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively; and (ii) atezolizumab at a dose of 840 mg intravenously on days 1 and 15 of each 28-day dosing cycle; (iii) nab-paclitaxel at a dose of 125 mg / m 2 of the dose on days 1, 8, and 15 of each 28-day dosing cycle; and (iv) gemcitabine at a dose of 1000 mg / m 2 intravenously on days 1, 8, and 15 of each 28-day dosing cycle.

[0137] In another embodiment, the present invention provides anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic PDAC, the treatment comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, the anticancer therapy comprising: (i) anti-latent TGF-beta-1 antibodies administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, comprising the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (b) HVR-H1, HVR-H2 and HVR- (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of H3 and SEQ ID NOs. 16, 17, and 18, respectively; (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (ii) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively; (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8, and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at this dosage.

[0138] In some embodiments, the subject has histologically or cytologically confirmed metastatic PDAC.

[0139] In some embodiments, the subjects have not been previously treated for PDAC and / or have not been previously treated with checkpoint inhibitors.

[0140] In another embodiment, the present invention provides a method for treating a subject having locally advanced, recurrent, or metastatic UC, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HV (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of R-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0141] In another embodiment, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic UC, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-L2, HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of VR-H1, HVR-H2, and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0142] In some embodiments, the subjects have histologically demonstrated locally progressive (T4b, any N; or any T, N2-N3) UC or metastatic UC (M1, stage 4).

[0143] In some cases, the subjects have not been previously treated for UC.

[0144] In some cases, the subjects are ineligible for cisplatin-containing chemotherapy.

[0145] In some embodiments, subjects are ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) renal impairment in terms of glomerular filtration rate (GFR) of 30 mL / min or more and less than 60 mL / min, as assessed by direct measurement or calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two adjacent frequencies, as measured by audiometry; (iii) grade 2 peripheral neuropathy; or (iv) ECOG performance status 2.

[0146] In some embodiments, the subject has previously received at least one platinum-containing chemotherapy regimen.

[0147] In some embodiments, the subjects had disease progression during or after treatment with at least one platinum-containing chemotherapy regimen.

[0148] In some embodiments, at least one platinum-containing chemotherapy regimen comprises (i) gemcitabine and cisplatin or carboplatin, or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin.

[0149] In some aspects, the subjects had received prior adjuvant or neoadjuvant chemotherapy and their disease progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.

[0150] In some embodiments, subjects received one cycle of platinum-containing chemotherapy regimen but discontinued it due to grade 4 hematological toxicity or grade 3–4 non-hematological toxicity.

[0151] In some aspects, the subjects had received two or fewer prior treatment regimens for locally advanced or metastatic UC.

[0152] In some aspects, the subjects had not received prior treatment with T-cell costimulation therapy or checkpoint inhibitors.

[0153] In another embodiment, the present invention provides a method for treating a subject having metastatic non-squamous NSCLC or metastatic squamous NSCLC, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3) -H3;(d)HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4);(e)HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and(f)HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); and (ii)atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who had disease progression during or after treatment of metastatic or locally advanced unresectable NSCLC, which was given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order).

[0154] In another embodiment, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of a subject having metastatic non-squamous NSCLC or metastatic squamous NSCLC, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H2 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3) (d) HVR-H3 containing the sequence; (e) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who had disease progression during or after treatment of metastatic or locally advanced unresectable NSCLC, including a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist, which was administered in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order).

[0155] In another embodiment, the present invention provides a method for treating a subject having locally advanced, unresectable, or metastatic HER2-negative gastric cancer, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTYRANWARG (SEQ ID NO: 1) (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day treatment cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1-14 of each 21-day treatment cycle. 2 (b) capecitabine at the prescribed dosage, or (b) 40 mg / m² orally twice daily on days 1-14 of each 21-day medication cycle. 2 S-1 at the dosage of (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. 2 Oxaliplatin at the specified dosage (for patients with locally advanced, unresectable, or metastatic HER2-negative gastric cancer who have not been previously treated).

[0156] In another embodiment, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, unresectable, or metastatic HER2-negative gastric cancer, the treatment comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTYRANWA (i) HVR-H2 containing the amino acid sequence of RG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day treatment cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1-14 of each 21-day treatment cycle. 2 (b) capecitabine at the prescribed dosage, or (b) 40 mg / m² orally twice daily on days 1-14 of each 21-day medication cycle. 2 S-1 at the dosage of (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. 2 Oxaliplatin at the specified dosage (for patients with locally advanced, unresectable, or metastatic HER2-negative gastric cancer who have not been previously treated).

[0157] In another embodiment, the present invention provides a method for treating a subject having metastatic PDAC, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2) (i) HVR-H2 containing (c) the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8 and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at the specified dosage (for patients with metastatic PDAC who have not been previously treated).

[0158] In another embodiment, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of a subject having metastatic PDAC, the treatment comprising administering an anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTYRANWARG (SEQ ID NO: 2) (i) HVR-H2 containing the amino acid sequence of (c)GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8 and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at the specified dosage (for patients with metastatic PDAC who have not been previously treated).

[0159] In another embodiment, the present invention provides a method for treating a subject having locally advanced or metastatic UC, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) GTGIYDYYYWVMD (d) HVR-H3 containing the amino acid sequence of L (SEQ ID NO: 3); (e) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (f) HVR-L3 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (the subject is not previously treated for locally advanced UC or metastatic UC and is ineligible for cisplatin-containing chemotherapy; or the subject has previously received at least one platinum-containing chemotherapy regimen).

[0160] In another embodiment, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced or metastatic UC, the treatment comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) GTGIYD (d) HVR-H3 containing the amino acid sequence YYYWVMDL (SEQ ID NO: 3); (e) HVR-L1 containing the amino acid sequence QASQSISTYLA (SEQ ID NO: 4); (f) HVR-L3 containing the amino acid sequence QSYSDGDSVG (SEQ ID NO: 6); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who have not been previously treated for locally advanced or metastatic UC and are ineligible for cisplatin-containing chemotherapy; or individuals who have previously received at least one platinum-containing chemotherapy regimen).

[0161] In another embodiment, the present invention provides a method for treating cancer in a subject having locally advanced or recurrent tumors, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 300 mg to 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (b) HVR-H comprising the amino acid sequences of SEQ ID NOs: 13, 14 and 15, respectively. 1) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of HVR-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively, and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0162] In some cases, the subjects had previously received treatment with atezolizumab at an intravenous dose of 1200 mg.

[0163] In some embodiments, the anticancer therapy includes an anti-latent TGF-beta-1 antibody at a dosage of 300 mg. In some embodiments, the anticancer therapy includes an anti-latent TGF-beta-1 antibody at a dosage of 600 mg. In some embodiments, the anticancer therapy includes an anti-latent TGF-beta-1 antibody at a dosage of 900 mg. In some embodiments, the anticancer therapy includes an anti-latent TGF-beta-1 antibody at a dosage of 1200 mg. In some embodiments, the anticancer therapy includes an anti-latent TGF-beta-1 antibody at a dosage of 1500 mg. In some embodiments, the anticancer therapy includes an anti-latent TGF-beta-1 antibody at a dosage of 1800 mg.

[0164] In some embodiments, the anti-latent TGF-beta 1 antibody is administered intravenously to the subject. In some embodiments, the anti-latent TGF-beta 1 antibody is administered intravenously to the subject by infusion.

[0165] In some embodiments, it has been determined that the organism has detectable levels of PD-L1 expression.

[0166] In some cases, the target age is 18 years or older.

[0167] In some aspects, anticancer therapy is a first-line treatment. In other aspects, anticancer therapy is a second-line or third-line treatment.

[0168] In some embodiments, the subjects have not been previously treated with checkpoint inhibitors.

[0169] In some embodiments, cancer is NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer.

[0170] In another embodiment, the present invention provides anti-latent TGF-beta-1 for use in the treatment of cancer in subjects having locally advanced or recurrent tumors, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 300 mg to 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3 respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5 and 6 respectively; (b) the amino acid sequences of SEQ ID NOs: 13, 14 and 15 respectively (c) HVR-H1, HVR-H2, and HVR-H3, and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (d) HVR-H1, HVR-H2, and HVR-H3, each containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively; and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (e) HVR-H1, HVR-H2, and HVR-H3, each containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively; and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0171] In some embodiments, subjects are administered anti-latent TGF-beta-1 antibodies until clinical benefit is lost or unacceptable toxicity occurs.

[0172] In some embodiments, the method includes 1 to 20 drug administration cycles (e.g., 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, or 20 cycles).

[0173] In some embodiments, the anti-latent TGF-beta 1 antibody comprises HVR-H1, HVR-H2, and HVR-H3, each containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

[0174] In some embodiments, the anti-latent TGF-beta 1 antibody comprises: (a) (i) a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7, (ii) a light chain variable domain (VL) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8, or (iii) the VH sequence defined in (i) and the VL sequence defined in (ii); (b) (i) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 31, (ii) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 32, or (iii) defined in (i) (i) a VH sequence and a VL sequence defined in (ii); (c) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 33, (ii) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 34, (iii) a VH sequence defined in (i) and a VL sequence defined in (ii); or (d) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 35, (ii) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 36, or (iii) a VH sequence defined in (i) and a VL sequence defined in (ii).

[0175] In some embodiments, the anti-latent TGF-beta 1 antibody comprises: (a) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 8; (b) the VH sequence of SEQ ID NO: 31 and the VL sequence of SEQ ID NO: 32; (c) the VH sequence of SEQ ID NO: 33 and the VL sequence of SEQ ID NO: 34; (d) the VH sequence of SEQ ID NO: 35 and the VL sequence of SEQ ID NO: 36.

[0176] In some embodiments, the anti-latent TGF-beta 1 antibody comprises the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 8.

[0177] In some embodiments, anti-latent TGF-beta 1 antibodies are chimeric antibodies.

[0178] In some embodiments, the anti-latent TGF-beta 1 antibody is a humanized antibody.

[0179] In some embodiments, the anti-latent TGF-beta 1 antibody is a full-length antibody.

[0180] In some embodiments, the anti-latent TGF-beta 1 antibody comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 38; (b) a heavy chain containing the amino acid sequence of SEQ ID NO: 39 and a light chain containing the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain containing the amino acid sequence of SEQ ID NO: 41 and a light chain containing the amino acid sequence of SEQ ID NO: 42; (d) a heavy chain containing the amino acid sequence of SEQ ID NO: 43 and a light chain containing the amino acid sequence of SEQ ID NO: 44; (e) a heavy chain containing the amino acid sequence of SEQ ID NO: 45 and a light chain containing the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain containing the amino acid sequence of SEQ ID NO: 47 and a light chain containing the amino acid sequence of SEQ ID NO: 48; (g) a heavy chain containing the amino acid sequence of SEQ ID NO: 49 and a light chain containing the amino acid sequence of SEQ ID NO: 50; or (h) a heavy chain containing the amino acid sequence of SEQ ID NO: 51 and a light chain containing the amino acid sequence of SEQ ID NO: 52.

[0181] In some embodiments, the anti-latent TGF-beta 1 antibody includes a modified IgG1 Fc region having reduced effector function compared to the wild-type IgG1 Fc region.

[0182] In some embodiments, the modified IgG1 Fc region includes a stationary weight (CH) region containing one or more of the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, and / or S440E (EU numbering).

[0183] In some embodiments, the CH region includes the amino acid sequence of SEQ ID NO: 9.

[0184] In some embodiments, the modified IgG1 Fc region includes a constant light (CL) domain containing the amino acid sequence of SEQ ID NO: 10.

[0185] In some embodiments, the anti-latent TGF-beta 1 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 11 and a light chain sequence containing the amino acid sequence of SEQ ID NO: 12.

[0186] In some embodiments, an anti-latent TGF-beta 1 antibody is an antibody fragment that binds to latent TGF-beta 1.

[0187] In some cases, the subject is a human being. [Brief explanation of the drawing]

[0188] [Figure 1] The flowchart for the study design described in Example 1 is shown. 1L = First-line treatment; 2L = Second-line treatment; 3L = Third-line treatment; GC = Gastric cancer; IMC = Internal Monitoring Committee; NSCLC = Non-small cell lung cancer; PDAC = Pancreatic ductal adenocarcinoma; SOC = Standard care. a = After approximately 15 patients enrolled from the safety introduction and expansion phases have completed at least one tumor assessment in a given cohort, an efficacy analysis will be performed for each cohort. [Figure 2] As discussed in Example 1, a flowchart outlining the conditions for continuing treatment beyond disease progression is shown. ECOG = East Coast Cancer Clinical Trials Group; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1. [Figure 3]The flowchart for the study design described in Example 2 is shown. 1L = First-line; 2L = Second-line; IMC = Internal Monitoring Committee; UC = Urothelial carcinoma. a = After approximately 15 patients enrolled from the safety introduction and expansion phases have completed at least one tumor assessment in a given cohort, an efficacy analysis will be performed for each cohort. [Figure 4] This figure shows an overview of the drug regimen treatments for cohorts 1-6 described in Example 3. Atezo = atezolizumab. [Figure 5A] The time course of plasma SOF10 concentration (μg / mL) in patients from cohorts 1-5 described in Example 3 is shown. [Figure 5B] The time course of plasma SOF10 concentration (μg / mL) in patients from Cohort 6 described in Example 3 is shown. [Figure 6] This shows the time course of tumor size relative to baseline in various cancers after combination therapy with SOF10 and atezolizumab as described in Example 3. [Figure 7A] This shows the time course of total plasma TGF-β1 concentration after the first dose of the combination therapy of SOF10 and atezolizumab described in Example 3. [Figure 7B] This shows the time course of the 1% change in TGF-β relative to baseline after the first dose of the combination therapy of SOF10 and atezolizumab described in Example 3. [Modes for carrying out the invention]

[0189] Detailed description of the invention The present invention provides therapeutic methods and compositions for treating cancer, such as locally advanced, recurrent, or metastatic solid tumors (e.g., non-small cell lung cancer (NSCLC), gastric cancer, pancreatic ductal adenocarcinoma (PDAC), urothelial carcinoma (UC), gastrointestinal stromal tumor (GIST), skin cancer, colorectal cancer, ovarian (OV) cancer, renal cancer, or gallbladder cancer). The present invention is at least in part based on the development of dosages and administration regimens for the anti-latent TGF-beta 1 antibodies described herein, designed to provide significant antitumor activity. In some cases, while we do not wish to be bound by any particular theory, the methods and compositions disclosed herein are expected to target key resistance mechanisms to checkpoint inhibitors and improve the efficacy of these agents in cancer patients by altering the immunosuppressive tumor microenvironment.

[0190] I. Definition For the purposes of this specification, “acceptor human framework” means a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “derived” from a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain a modification of the amino acid sequence. In some examples, the number of amino acid modifications is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some examples, a VL acceptor human framework is sequence-identical to a VL human immunoglobulin framework sequence or a human consensus framework sequence.

[0191] The term “antibody” as used herein is used in its broadest sense and encompasses a wide range of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and their antibody fragments. The term “antibody” also includes any antigen-binding molecule containing a variable heavy chain and / or variable light chain structure of an immunoglobulin.

[0192] The terms "anti-latent TGF-beta 1 antibody" and "antibody capable of binding to latent TGF-beta 1" refer to antibodies capable of binding to latent TGF-beta 1 with sufficient binding activity to be useful as diagnostic and / or therapeutic agents when the antibody targets latent TGF-beta 1. For example, an "antibody capable of binding to latent TGF-beta 1" is an antibody that specifically binds to latent TGF-beta 1. For example, the degree of binding activity of an anti-latent TGF-beta 1 antibody against unrelated non-latent TGF-beta 1 protein is less than 10% of the binding activity of the antibody against latent TGF-beta 1 when measured, for example, by radioimmunoassay (RIA). In specific examples, an antibody capable of binding to TGF-beta 1 may have a micromolar or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 It has a dissociation constant (KD) of M). In certain cases, the anti-latent TGF-beta-1 antibody binds to a latent TGF-beta-1 epitope that is conserved among latent TGF-beta-1 from different species. In some cases, the anti-latent TGF-beta-1 antibody is the anti-latent TGF-beta-1 antibody disclosed in International Publication No. 2021 / 039945, which is incorporated herein by reference in its entirety. In some cases, the anti-latent TGF-beta-1 antibody is SOF10.

[0193] An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0194] A "reference antibody" and an "antibody that binds to the same epitope" refer to an antibody that blocks the reference antibody from binding to its antigen by 50% or more in a competitive assay, and conversely, a reference antibody that blocks the antibody from binding to its antigen by 50% or more in a competitive assay. An example of a competitive assay is provided in International Publication No. 2021 / 039945.

[0195] For the purposes of this specification, “atezolizumab” is a PD-L1-binding Fc-modified humanized nonglycosylated IgG1 kappa immunoglobulin. Atezolizumab contains a single amino acid substitution (asparagine to alanine) (N297A) at position 297 on the heavy chain using EU numbering of Fc region amino acid residues, resulting in a nonglycosylated antibody with minimal binding to the Fc receptor. Atezolizumab is also listed in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances (proposed INN)) List 112, Vol.28, No.4, 2014, p.488.

[0196] The term "binding activity" refers to the sum of the non-covalent interactions between one or more binding sites on a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Here, "binding activity" is not strictly limited to 1:1 interactions between members of a binding pair (e.g., an antibody and an antigen). For example, if the members of a binding pair reflect a monovalent 1:1 interaction, the binding activity is specifically called intrinsic binding affinity (affinity). If the members of a binding pair are capable of both monovalent and polyvalent binding, the binding activity is the sum of the individual binding strengths. The binding activity of molecule X to its partner Y can generally be expressed by the dissociation constant (KD) or the "amount of analyte bound per unit amount of ligand" (hereinafter sometimes referred to as "amount bound"). Those skilled in the art will understand that, generally, a lower value of the dissociation constant (KD) indicates higher binding activity, and a higher value of the "amount of analyte bound per unit amount of ligand" or "amount bound" indicates higher binding activity. Binding activity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary examples for measuring binding activity are described below.

[0197] "Binding activity matured" and "affinity matured" antigen-binding molecules or antibodies, and "increased binding activity" or "increased affinity" antigen-binding molecules or antibodies refer to antibodies that have one or more modifications (e.g., substitutions) in one or more hypervariable regions (HVRs) compared to the parent antigen-binding molecule or a parent antibody without modifications, resulting in improved binding activity of the antigen-binding molecule or antibody to the antigen.

[0198] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. Forms of cancer include solid tumors and non-solid tumors. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies.More specific examples of such cancers include, but are not limited to, skin cancer, gallbladder cancer, bladder cancer (e.g., urothelial carcinoma (UC) (including metastatic UC (mUC)); muscle-invasive bladder cancer (MIBC), and non-muscle-invasive bladder cancer (NMIBC)); kidney cancer or renal cancer (e.g., renal cell carcinoma (RCC)); lung cancer, including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung; cancers of the urinary tract; breast cancer (e.g., HER2+ breast cancer and estrogen receptor (E) Triple-negative breast cancer (TNBC) that is R-, progesterone receptor (PR-), and HER2 (HER2-) negative; prostate cancer, e.g., castration-resistant prostate cancer (CRPC); peritoneal cancer; hepatocellular carcinoma; gastric cancer or stomach cancer including gastrointestinal cancer and gastrointestinal stromal cancer (GIST); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)); glioblastoma; cervical cancer; ovarian cancer (OV); liver cancer (e.g., hepatocellular carcinoma (HCC)); liver cancer; colon cancer; rectal cancer; colorectal cancer; endometrial cancer or Uterine cancer; salivary gland cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; penile cancer; melanoma (including superficial spreading melanoma, lentigo malignant melanoma, acral lentigo melanoma, and nodular melanoma); multiple myeloma and B-cell lymphoma (including low-grade / follicular non-Hodgkin lymphoma (NHL)); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small unsevered cell NHL; giant Large-lesion NHL; mantle cell lymphoma; AIDS-associated lymphoma; and Waldenström macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myoblastic leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndromes (MDS), as well as nevus disorders, edema (such as that associated with brain tumors), Meigs syndrome, brain cancer, head and neck cancer and associated metastases. In one example, cancer is a locally advanced, recurrent, or metastatic solid tumor (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer). Cancer can be locally advanced or metastatic.In some cases, cancer is locally advanced. In other cases, cancer is metastatic. In some cases, cancer may be unresectable (e.g., unresectable locally advanced or metastatic cancer). In some cases, cancer may recur.

[0199] As used herein, the term “checkpoint inhibitor” refers to a therapeutic agent that antagonizes an immune checkpoint protein, for example, by blocking its binding to one or more of its binding partners. Exemplary checkpoint inhibitors include, but are not limited to, PD-1 axis-binding antagonists (e.g., PD-L1-binding antagonists (e.g., anti-PD-L1 antibodies (e.g., atezolizumab)) or PD-1-binding antagonists (e.g., anti-PD-1 antibodies (e.g., nivolumab)), CTLA-4 antagonists (e.g., anti-CTLA-4 antibodies (e.g., ipilimumab)), and LAG-3 antagonists (e.g., anti-LAG-3 antibodies (e.g., relatrimab)).

[0200] As used herein, the term “chemotherapeutic agent” refers to a compound useful in treating locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer). Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer) Inc.); ZD1839, Gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM105180 ((6-amino-4-(3-methylphenylamino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluorophenyl)-N2-(1-methylpiperidine-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidine-6-yl]phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine; CL-387785(N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butinamide); EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano N-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth); AG1478(Pfizer); AG1571(SU5271; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine));Tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, e.g., TAK165 (Takeda); CP-724, 714; oral selective inhibitors of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, e.g., EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2-overexpressing and EGFR-overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors, e.g., canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, e.g., antisense agents that inhibit Raf-1 signaling, ISIS-5132 (ISIS Pharmaceuticals); non-HER-targeted tyrosine kinase inhibitors, e.g., imatinib mesylate (GLEEVEC®, Glaxo) SmithKline); multi-targeted tyrosine kinase inhibitors, e.g., sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors, e.g., batalanib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulatory kinase I inhibitor CI-1040 (Pharmacia); Quinazoline, e.g., PD153035,4-(3-chloroanilino)quinazoline; Pyridopyrimidine; Pyrimidopyrimidine; Pyrrolopyrimidine, e.g., CGP59326, CGP60261 and CGP62706; Pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; Curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); Tyrophostine containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); Antisense molecules (e.g., those that bind to nucleic acids encoding HER); Quinoxaline (US Patent No. 5,804,396); Triphostine (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, e.g., CI-1033 (Pfizer); Affinitac (ISIS3521; Isis / Lilly); PKI166 (Novartis); GW2016 (Glaxo SmithKline);CI-1033 (Pfizer); EKB-569 (Wyeth); semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®); proteasome inhibitors, e.g., bortezomib (VELCADE®, Millennium); Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasnate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; ronafamib (SCH66336); sorafenib (NEXAVAR®, Bayer) Labs); AG1478, thiotepa and alkylating agents such as CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and pigosulfan; aziridines such as benzodopa, carbocron, metredopa and uredopa; ethyleneimines and methylmelamines such as altoretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide and trimethylmelamine; acetogenins (especially bratacin and bratacinone); Ampothecines (topotecan and irinotecan); bryostatins; karystatins; CC-1065 (including its synthetic analogues adzeresin, karzeresin, and bizeresin); cryptophycines (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductases including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mosetinostat, dorastatin;Aldesleukin, talc duocalmycin (including synthetic analogs, KW-2189 and CB1-TM1); eletarobine; pancratistatin; sarcodictin; spongistatin, chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimustine, trophosphamide, nitrogenous mustards such as uracil mustard; carmustine, chlorozotocin, fotemustine, Nitrosoureas such as lomustine, nimustine, and ranimustine; antibiotics such as enediene antibiotics (e.g., calichemycin, especially calichemycin γ1 and calichemycin ω1); dynemycin including dynemycin A; bisphosphonates such as clodronate; espermycin; similarly, neocardinostatin chromophores and related chromophores (enediene antibiotic chromophores), acrasinomycins, actinomycin, autoramycin, azaserin, kakuchinomycin, carabicin, kaminomycin, car Dinophylline, chromomycin, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, keramycin, rhodorubicin, streptonigrin , streptozocin, tubercidine, ubenimex, dinostatin, zolubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfridine, enocitabine, and phloxlysine;Androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiosteine, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as floric acid; acegraton; aldofsphamide glycosides; aminolevulinic acid; enyluracil; amsacrin; bestrabusil; bisantren; edatraxate; defofamine; demecolsin; diazykion; e Rufomitin; eriptinium acetate; epotilon; etoglucide; gallium nitrate; hydroxyurea; lentinan; ronidynin; mytansinoids such as mytansin and ansamitosin; mitogwazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; fenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural) Products); Lazoxane; Rhizoxin; Schizofuran; Spirogermanium; Tenuazonic acid; Triazione; 2,2',2”-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, Veraculine A, Loridine A and Anguidine); Urethane; Vindesine; Dacarbazine; Mannomustine; Maitobronitol; Maitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil, GEMZAR® (Gemcitabine), Examples include 6-thioguanine, mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; maitoxantrone; nobandron; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, as well as any pharmaceutically acceptable salts, acids, prodrugs, and derivatives of the above.

[0201] Furthermore, as chemotherapeutic agents, (i) anti-hormone agents that act to modulate or inhibit the hormonal effects on tumors, such as anti-estrogen drugs including tamoxifen (NOLVADEX®; including tamoxifen citrate), raloxifene, droloxifene, iodoxifene, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and FARESTON® (toremifine citrate), and selective estrogen receptor mo (ii) Aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production in the adrenal gland, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozol, RIVISOR® (borozol), FEMARA® (letrozole; Novartis) and A (iii) Antiandrogens, e.g., flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, trypterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide and troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) Protein kinase inhibitors; (v) Lipids (vi) Kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Ralf, and H-Ras; (vii) Ribozymes, e.g., VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) Vaccines, such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, and VAXID®;(ix) Growth inhibitors comprising vinca (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin) and DNA alkylating agents (e.g., tamoxigen, prednisone, dacarbazine, mechloretamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0202] As used herein, the term “cytotoxic agent” refers to any agent that is harmful to cells (e.g., causes cell death, inhibits proliferation, or otherwise interferes with cellular function). Cytotoxic agents include radioisotopes (e.g., At). 211 , I 131 , I 125 , Y 90 Re 186 Re 188 Sm 153 , Bi 212 , P 32 Pb 212Examples of cytotoxic agents include, but are not limited to, low molecular weight toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including radioisotopes of Lu; chemotherapeutic agents; enzymes and their fragments, such as nucleases; and toxins, such as low molecular weight toxins or enzymatically active toxins, of bacterial, fungal, plant or animal origin, including their fragments and / or variants. Exemplary cytotoxic agents may be selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signaling pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, apoptosis promoters, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors. In one example, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one case, the cytotoxic agent is an EGFR antagonist, e.g., N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (e.g., erlotinib). In another case, the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and / or CRAF inhibitor. In yet another case, the RAF inhibitor is vemurafenib. In yet another case, the cytotoxic agent is a PI3K inhibitor.

[0203] Chemotherapy agents also include "platinum-based" chemotherapeutic agents, which contain organic compounds with platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are platinum coordination complexes. Platinum-based chemotherapeutic agents are sometimes referred to as "platins" in the art. Examples of platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, and satraplatin. Platinum-based chemotherapeutic agents (e.g., cisplatin or carboplatin) may be administered in combination with one or more additional chemotherapeutic agents, such as an antimetabolite (e.g., gemcitabine).

[0204] In this specification, “effective dose” refers to the amount of a therapeutic agent (e.g., an anti-latent TGF-beta-1 antibody) or a combination of therapeutic agents (e.g., an anti-latent TGF-beta-1 antibody and one or more additional therapeutic agents, e.g., a checkpoint inhibitor (e.g., a PD-1 axis antagonist (e.g., an anti-PD-L1 antibody (e.g., atezolizumab) or an anti-PD-1 antibody (e.g., nivolumab)) and / or one or more chemotherapeutic agents) that achieves a therapeutic outcome. In some examples, the effective dose of a therapeutic agent or combination of therapeutic agents is the amount of the active agent or combination of active agents that achieves the clinical endpoints of improved overall response rate (ORR), complete response (CR), pathological complete response (pCR), partial response (PR), improved survival (e.g., disease-free survival (DFS), progression-free survival (PFS), and / or overall survival (OS)), and / or improved duration of response (DOR). Improvement (e.g., with respect to response rate (e.g., ORR, CR and / or PR), survival (e.g., PFS and / or OS), or DOR) may be due to appropriate reference therapy, e.g., therapy without anti-latent TGF-beta-1 antibodies and / or one or more additional therapeutic agents, e.g., checkpoint inhibitors (e.g., PD-1 axis antagonists (e.g., anti-PD-L1 antibodies (e.g., atezolizumab) or anti-PD-1 antibodies (e.g., nivolumab))) and / or therapy without one or more chemotherapeutic agents.

[0205] As used herein, “complete response” and “CR” refer to the disappearance of all target lesions.

[0206] As used herein, “partial response” and “PR” refer to a reduction of at least 30% in the sum of the longest diameters (SLD) of the target lesions, with reference to baseline SLD before treatment.

[0207] As used herein, “overall response rate,” “objective response rate,” and “ORR” are interchangeable terms for the sum of the complete response (CR) rate and the partial response (PR) rate. For example, ORR may be defined as the percentage of patients who have a CR or PR in two consecutive opportunities separated by four weeks or more, as determined by the investigator in accordance with RECIST v1.1.

[0208] As used herein, “progression-free survival” and “PFS” refer to the length of time during and after treatment in which the cancer does not progress. PFS may include the amount of time a subject experiences complete response (CR) or partial response (PR), and the amount of time a subject experiences stable disease. In some cases, PFS is defined as the time from the date of the first anti-TGF-beta-1 antibody treatment to the first occurrence of disease progression or death from any cause during the study (whichever occurs first), as determined by the principal investigator in accordance with RECIST v1.1.

[0209] As used herein, “overall survival” and “OS” refer to the length of time from the date of diagnosis or the date of commencement of treatment for the disease (e.g., cancer) during which the subject is still alive.

[0210] As used herein, the terms “duration of response” and “DOR” refer to the length of time from the first occurrence of tumor response to the first occurrence of disease progression or death from any cause. In some cases, DOR is defined as the time from the date of the first anti-TGF-beta-1 antibody treatment to the first occurrence of disease progression or death from any cause during the study, as determined by the principal investigator in accordance with RECIST v1.1.

[0211] The term "ineligible for cisplatin-containing chemotherapy" means that, at the discretion of the attending physician, or according to standardized criteria for eligibility for platinum-based chemotherapy described herein or known in the art, the subject is not eligible for treatment with cisplatin-based chemotherapy. For example, the criteria described in Galsky et al. Lancet Oncol. 12(3):211-4, 2011 may be used to determine whether a subject is eligible for cisplatin-based chemotherapy. Galsky et al. describe a consensus definition of patients with metastatic ulcerative ulcerative colitis (mUC) who are considered unsuitable for cisplatin-based chemotherapy if they meet at least one of the following criteria: (i) World Health Organization (WHO) or East Coast Clinical Oncology Group (ECOG) performance status 2, or Karnofsky performance status 60-70%; (ii) creatinine clearance (calculated or measured) less than 1 mL / s; (iii) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade ≥2 hearing loss; (iv) CTCAE v4.0 grade ≥2 peripheral neuropathy; and / or New York Cardiology Association (NYHA) class III heart failure. For example, a patient is ineligible for cisplatin-based chemotherapy if they have one or more of the following: renal impairment (e.g., glomerular filtration rate (GFR) > 30 but < 60 mL / min); GFR may be assessed by direct measurement (i.e., creatinine clearance or ethyldiamine tetraacetate) or, if unavailable, by calculation from serum / plasma creatinine (e.g., Cockcroft-Gault formula); hearing loss (e.g., National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade ≥ 2, hearing loss of 25 decibels at two consecutive frequencies); peripheral neuropathy (e.g., NCI CTCAE v4.0 grade ≥ 2 peripheral neuropathy (i.e., sensory changes or paresthesia including stabbing pain)); and / or ECOG performance status assessment (see Oken et al. Am.J.Clin.Oncol. 5:649-655, 1982) (e.g., ECOG performance status of 2).

[0212] As used herein, “taxane” refers to a drug (e.g., diterpene) that binds to tubulin and promotes microtubule assembly and stabilization, and / or prevents microtubule depolymerization. Exemplary taxanes include, but are not limited to, paclitaxel (i.e., TAXOL®, CAS#33069-62-4), docetaxel (i.e., TAXOTERE®, CAS#114977-28-5), larotaxel, cabazitaxel, mirataxel, tesetaxel, and / or orataxel. Taxanes included herein also include taxoid 10-deacetylbaccatin III and / or its derivatives. In some examples, the taxane is albumin-coated nanoparticles (e.g., nano-albumin-bound (nab)-paclitaxel, i.e., ABRAXANE® and / or nab-docetaxel, ABI-008). In some cases, the taxane is nab-paclitaxel (ABRAXANE®). In some cases, the taxane is formulated with CREMAPHOR® (e.g., TAXOL®) and / or TWEEN®, e.g., polysorbate 80 (e.g., TAXOTERE®). In some cases, the taxane is liposome-encapsulated taxane. In some cases, the taxane is in the form of a prodrug and / or a conjugate form of the taxane (e.g., paclitaxel, paclitaxel polygrumex, and / or DHA covalently conjugated to linoleyl carbonate-paclitaxel). In some cases, paclitaxel is formulated substantially without surfactants (e.g., in the absence of CREMAPHOR® and / or TWEEN®, such as TOCOSOL® paclitaxel).

[0213] The term "chimeric" antibody refers to an antibody in which part of the heavy chain and / or light chain originates from a specific source or species, while the rest of the heavy chain and / or light chain originates from a different source or species.

[0214] The "class" of an antibody refers to the type of constant domain or constant region held by its heavy chain. Antibodies exist in five main classes: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into "subclasses" (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.

[0215] As used herein, “in combination with” means the administration of an anticancer therapy comprising, in addition to another mode of treatment, one mode of treatment, e.g., an anti-latent TGF-beta 1 antibody and one or more additional therapeutic agents, e.g., a checkpoint inhibitor (e.g., a PD-1 axis antagonist (e.g., an anti-PD-L1 antibody (e.g., atezolizumab) or an anti-PD-1 antibody (e.g., nivolumab))) and / or one or more chemotherapeutic agents. Thus, “in combination with” means the application of one mode of treatment to a subject before, during, or after the administration of another mode of treatment.

[0216] Drugs administered "concurrently" with one or more other drugs are administered on the same treatment day as one or more of the other drugs, and optionally at the same time as one or more of the other drugs, within the same treatment cycle. For example, in cancer therapy administered every three weeks, each drug administered concurrently is given on day 1 of the three-week cycle.

[0217] "Effector function" refers to the biological activity resulting from the Fc region of an antibody, and it varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0218] As used herein, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. For example, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) or glycine-lysine (residues 446-447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0219] The "framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0220] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein synonymously to refer to antibodies having a structure substantially similar to that of a native antibody or having a heavy chain containing an Fc region as defined herein.

[0221] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acids have been introduced, and cells including the offspring of such cells. Host cells include “transformed organisms” and “transformed cells,” and these cells include primary transformed cells and their offspring, regardless of passage number. Offspring may contain mutations, although they may not be completely identical to the parent cells in terms of nucleic acid content. In this specification, mutant offspring having the same function or biological activity as those screened or selected in the initially transformed cells are included.

[0222] A "human antibody" is an antibody produced by a human or human cell, or an antibody that has an amino acid sequence corresponding to a non-human antibody that utilizes a sequence encoding a human antibody, such as the human antibody repertoire. This definition of a human antibody explicitly excludes humanized antibodies that contain non-human antigen-binding residues.

[0223] The "Human Consensus Framework" is a framework representing the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences derives from subgroups of variable domain sequences. Generally, the sequence subgroups are those described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. For example, for VL, the subgroup is subgroup Kappa I, as described in Kabat et al. For example, for VH, the subgroup is subgroup III, as described in Kabat et al.

[0224] A "humanized" antibody refers to a chimeric antibody containing amino acid residues derived from non-human HVR and amino acid residues derived from human FR. In certain examples, a humanized antibody contains substantially all of at least one, typically two, variable domains, where all or substantially all of the HVR (e.g., CDR) corresponds to the non-human antibody and all or substantially all of the FR corresponds to the human antibody. A humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0225] As used herein, the terms “hypervariable region” or “HVR” refer to each region of the antibody variable domain that contains a sequence that is hypervariable (“complementarity-determining region” or “CDR”), and / or forms a structurally defined loop (“hypervariable loop”), and / or an antigen contact residue (“antigen contact”). Generally, an antibody contains a total of six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Illustrative HVRs as used herein include: (a) Hypervariable loops arising from amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J.Mol.Biol.196:901-917(1987)); (b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) Antigen contact occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J.Mol.Biol.262:732-745 (1996)); and (d) A combination of (a), (b) and / or (c) including HVR amino acid residues 46-56(L2), 47-56(L2), 48-56(L2), 49-56(L2), 26-35(H1), 26-35b(H1), 49-65(H2), 93-102(H3), and 94-102(H3).

[0226] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein in accordance with Kabat et al.

[0227] An "immune conjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to cytotoxic agents.

[0228] An "isolated" antibody is one that has been separated from its natural environment. In some cases, antibodies are purified to a purity of over 95% or over 99%, as determined by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For an overview of methods for evaluating antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0229] "Isolated nucleic acid encoding an anti-latent TGF-beta-1 antibody" or "nucleic acid encoding an anti-latent TGF-beta-1 antibody" means one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an antibody, including such nucleic acid molecules(s) in a single vector or separate vectors, and such nucleic acid molecules(s) are located at one or more locations within a host cell.

[0230] The Kabat numbering system is generally used when referring to residues within the variable domain (approximately light chain residues 1-107 and heavy chain residues 1-113) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally used when referring to residues in the constant region of the immunoglobulin heavy chain (e.g., the EU index reported by Kabat et al. above). "EU index as in Kabat" refers to the residue numbering of human IgG1 EU antibodies.

[0231] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies constituting that population are identical and / or bind to the same epitope, with the exception of possible variant antibodies, such as those containing naturally occurring mutations or arising during the production of a monoclonal antibody preparation, which are generally present in small amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed toward different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed toward a single determinant on an antigen. Therefore, the modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous collection of antibodies and should not be interpreted as requiring antibody production by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus, and such and other exemplary methods for producing monoclonal antibodies are described herein.

[0232] A "naked antibody" refers to an antibody that is not conjugated with a heterogeneous portion (e.g., a cytotoxic portion) or a radioactive label. Naked antibodies may be present in pharmaceutical formulations.

[0233] "Native antibodies" refer to naturally occurring immunoglobulin molecules with diverse structures. For example, a native IgG antibody is a heterotetrameric glycoprotein with approximately 150,000 daltons, composed of two identical light chains and two identical heavy chains linked by disulfide bonds. Each heavy chain from the N-terminus to the C-terminus has a variable region (VH), also called a variable heavy chain domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, each light chain from the N-terminus to the C-terminus has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. Based on the amino acid sequence of its constant domain, the light chains of an antibody may be assigned to one of two types called kappa or lambda.

[0234] The term “packaging insert” is used to refer to the instructions typically included in the commercial packaging of a therapeutic product, which contain information about the indications, use, dosage, administration, combination therapies, contraindications, and / or warnings regarding the use of such therapeutic product.

[0235] The term "PD-1 axis-binding antagonist" refers to a molecule that inhibits the interaction between a PD-1 axis-binding partner and one or more of its binding partners in order to eliminate T cell dysfunction caused by signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, a PD-1 axis-binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some cases, a PD-1 axis-binding antagonist includes either a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred embodiment, a PD-1 axis-binding antagonist is a PD-L1 binding antagonist.

[0236] The term “PD-L1-binding antagonist” refers to a molecule that reduces, blocks, inhibits, represses, or interferes with signaling resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In some cases, a PD-L1-binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In specific embodiments, a PD-L1-binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some cases, a PD-L1-binding antagonist includes anti-PD-L1 antibodies, their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, repress, or interfere with signaling resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In one case, PD-L1-binding antagonists reduce negative costimulatory signaling mediated by or via cell surface proteins expressed on T lymphocytes via PD-L1-mediated signaling, thereby reducing dysfunction in dysfunctional T cells (e.g., enhancing the effector response to antigen recognition). In some cases, PD-L1-binding antagonists bind to PD-L1. In some cases, PD-L1-binding antagonists are anti-PD-L1 antibodies (e.g., anti-PD-L1 antagonist antibodies). Examples of anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, emvafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosivelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one specific embodiment, the PD-L1-binding antagonist is MDX-1105. In another specific embodiment, the PD-L1-binding antagonist is MEDI4736 (durvalumab). In yet another specific embodiment, the PD-L1-binding antagonist is MSB0010718C (avelumab). In other embodiments, the PD-L1-binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041, which may be administered orally in some cases. Other exemplary PD-L1-binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred embodiment, the PD-L1-binding antagonist is atezolizumab.

[0237] The term “PD-1 binding antagonist” refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signaling resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. PD-1 (programmed cell death 1) is also known in the art as “programmed cell death 1,” “PDCD1,” “CD279,” and “SLEB2.” An exemplary human PD-1 is shown in UniProtKB / Swiss-Prot accession number Q15116. In some cases, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In specific embodiments, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1-binding antagonists include anti-PD-1 antibodies, their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or interfere with signaling resulting from the interaction between PD-1 and PD-L1 and / or PD-L2. In one case, a PD-1-binding antagonist reduces negative costimulatory signaling mediated by or via cell surface proteins expressed on T lymphocytes via PD-1-mediated signaling, thereby reducing dysfunction in dysfunctional T cells (e.g., enhancing the effector response to antigen recognition). In some cases, PD-1-binding antagonists bind to PD-1. In some cases, a PD-1-binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody).Examples of anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (semiprimab), BGB-108, prorugolimab, camrelizumab, cintilimab, tislerizumab, tripalimab, dostalimab, retifanlimab, sasanlimab, penprimab, CS1003, HLX10, and SCT-I10A. Examples include zinbererimab, valstilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, buzigalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM244C8, ENUM388D4, STI-1110, AK-103, and hAb21. In a specific embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In yet another specific embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, such as AMP-224. In another specific embodiment, the PD-1 binding antagonist is MED1-0680. In another specific embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another specific embodiment, the PD-1 binding antagonist is REGN2810 (semiprimab). In another specific embodiment, the PD-1 binding antagonist is BGB-108. In another specific embodiment, the PD-1 binding antagonist is prorugolimab. In another specific embodiment, the PD-1 binding antagonist is camrelizumab. In another specific embodiment, the PD-1 binding antagonist is cintilimab. In another specific embodiment, the PD-1 binding antagonist is tislerizumab. In another specific embodiment, the PD-1 binding antagonist is tripalimab. Other example PD-1-binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0238] The term “PD-L2-binding antagonist” refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signaling resulting from the interaction of PD-L2 with one or more of its binding partners, such as PD-1. PD-L2 (programmed cell death ligand 2) is also referred to in the art as “programmed cell death ligand 12,” “PDCD1LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.” An exemplary human PD-L2 is shown in UniProtKB / Swiss-Prot accession number Q9BQ51. In some cases, a PD-L2-binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In specific embodiments, a PD-L2-binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or interfere with signaling resulting from the interaction of PD-L2 with one or more of its binding partners, such as PD-1. In one embodiment, a PD-L2-binding antagonist reduces negative costimulatory signaling mediated by or via cell surface proteins expressed on T lymphocytes via PD-L2-mediated signaling, thereby reducing dysfunction in dysfunctional T cells (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-L2-binding antagonist binds to PD-L2. In some embodiments, the PD-L2-binding antagonist is an immunoadhesin. In other embodiments, the PD-L2-binding antagonist is an anti-PD-L2 antagonist antibody.

[0239] In this specification, the terms “programmed cell death ligand 1” and “PD-L1” refer to the native sequence human PD-L1 polypeptide. The native sequence PD-L1 polypeptide is provided under Uniprot accession number Q9NZQ7. For example, the native sequence PD-L1 may have the amino acid sequence described in Uniprot accession number Q9NZQ7-1 (isoform 1). In another example, the native sequence PD-L1 may have the amino acid sequence described in Uniprot accession number Q9NZQ7-2 (isoform 2). In yet another example, the native sequence PD-L1 may have the amino acid sequence described in Uniprot accession number Q9NZQ7-3 (isoform 3). PD-L1 is also referred to in the art as “programmed cell death ligand 1,” “PDCD1LG1,” “CD274,” “B7-H,” and “PDL1.”

[0240] The "amino acid sequence identity percentage (%)" for a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues of the reference polypeptide, after the sequences have been aligned and gaps introduced if necessary to obtain the maximum percentage of sequence identity, and assuming that no conservative substitutions are considered part of the sequence identity. Alignment for the purpose of determining the amino acid sequence identity percentage can be achieved in various ways within the scope of the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) software, or GENETYX® (Genetyx Co., Ltd.). A person skilled in the art can determine appropriate parameters for sequence alignment, including any algorithm necessary to achieve the maximum alignment over the full length of the sequences being compared.

[0241] The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and its source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington DC, 20559, and is registered under U.S. Copyright Registration Number TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from its source code. The ALIGN-2 program should be compiled for use with UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged. In situations where ALIGN-2 is used for amino acid sequence comparison, the amino acid sequence identity % of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (or can be described as a given amino acid sequence A having or containing a certain amino acid sequence identity % to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y In the formula, X is the number of amino acid residues scored as identical matches in the alignment of A and B by the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the amino acid sequence identity % for A to B will not be equal to the amino acid sequence identity % for B to A. Unless otherwise specified, all amino acid sequence identity % values ​​used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0242] The term "subject" refers to a human subject. For example, a subject could be an adult. A subject could also be a patient.

[0243] As used herein, the term “TGF-beta-1” refers to any native TGF-beta-1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length” unprocessed TGF-beta-1, as well as any form of TGF-beta-1 resulting from processing in cells. The term also encompasses naturally occurring variants of TGF-beta-1, such as splice variants or allele variants. The amino acid sequence of an exemplary human TGF-beta-1 preproprotein is shown in SEQ ID NO: 53 (NCBI RefSeq: NP_000651.3), and the nucleic acid sequence encoding an exemplary human TGF-beta-1 is shown in SEQ ID NO: 54 (NCBI RefSeq: NM_000660.6). The amino acid sequence of an exemplary mouse TGF-beta-1 preproprotein is shown in SEQ ID NO: 55 (NCBI RefSeq: NP_035707.1), and the nucleic acid sequence encoding an exemplary mouse TGF-beta-1 is shown in SEQ ID NO: 56 (NCBI RefSeq: NM_011577.2). The amino acid sequence of an exemplary cynomolgus monkey TGF-beta-1 preproprotein is shown in SEQ ID NO: 57 (NCBI RefSeq: XP_005589396.1), and the nucleic acid sequence encoding an exemplary cynomolgus monkey TGF-beta-1 is shown in SEQ ID NO: 58 (NCBI RefSeq: XM_005589339.2). The term "TGF-beta-1" encompasses both latent TGF-beta-1 and mature TGF-beta-1.

[0244] As used herein, the term “latent TGF-beta-1” refers to any TGF-beta-1 that forms a latent TGF-beta-1 complex (“cell surface latent TGF-beta-1”, LLC or SLC (see below)) and / or cannot bind to its receptor. Transforming growth factor-beta-1 (TGF-beta-1) is a member of the TGF-beta superfamily. Like other members of the TGF-beta superfamily, TGF-beta is synthesized as a precursor protein and forms homodimers that interact with its latent association peptide (LAP) and latent TGF-beta binding protein (LTBP) to form a larger complex called a large latent complex (LLC). The amino acid sequence of an exemplary latent human TGF-beta-1 (TGF-beta homodimer and its LAP) is amino acids 30-390 of SEQ ID NO: 53. The amino acid sequence of an exemplary mouse latent TGF-beta-1 (TGF-beta homodimer and its LAP) is amino acids 30-390 of SEQ ID NO: 55. The amino acid sequence of an example latent cynomolgus monkey TGF-beta-1 (TGF-beta homodimer and its LAP) is amino acids 30-390 of SEQ ID NO: 57.

[0245] The complex formed from TGF-beta homodimers and their LAP is called the small latent complex (SLC). This latent complex keeps TGF-beta in an inactive form that cannot bind to its receptor. The SLC can covalently bind to another protein, latent TGF-beta binding protein (LTBP), to form the large latent complex (LLC). There are four known distinct LTBP isoforms: LTBP-1, LTBP-2, LTBP-3, and LTBP-4. LTBP-1, LTBP-3, and LTBP-4 have been reported to bind to SLC (see, e.g., Rifkin et al., J Biol Chem. 2005 Mar 4;280(9):7409-12). The SLC can also covalently bind to other additional proteins, such as glycoprotein A repeat dominant (GARP) or leucine-rich repeat-containing protein 33 (LRRC33). GARP and LRRC have transmembrane domains and associate with LAP on the cell surface (see, e.g., Wang et al., Mol Biol Cell. 2012 Mar;23(6):1129-39). Regarding LLC, it has been reported that LLC covalently associates with the extracellular matrix (ECM) via the N-terminus of LTBP (see, e.g., Saharinen et al., Cytokine Growth Factor Rev. 1999 Jun;10(2):99-117). In some cases, latent TGF-beta 1 that associates with the ECM on the cell surface is called "cell surface latent TGF-beta 1".

[0246] As used herein, the terms “active TGF-beta-1,” “mature TGF-beta-1,” or “active mature TGF-beta-1” refer to any TGF-beta-1 homodimer that does not form a latent TGF-beta-1 complex (LLC or SLC) and is capable of binding to its receptor. The TGF-beta-1 activation process involves the release of LLC from the ECM, followed by further proteolysis of LAP to release active TGF-beta to its receptor. A broad range of proteases, including plasmin (PLN), prekallikrein (PLK), matrix metalloproteinase (MMP) 2, MMP9, MMP13, MMP14, thrombin, tryptase, and calpain, are known to cleave latent TGF-beta and release active TGF-beta. These proteases may be collectively referred to as “(latent) TGF-beta cleaving proteases” or “(latent) TGF-beta-1 cleaving proteases” in the context of the present invention. In addition to proteases, thrombospondin 1 (TSP-1), neuropilin-1 (Nrp1), ADAMSTS1, and F-spondin activate latent TGF-beta. Alternatively, during mechanical stretching, integrins (preferably integrin alpha-V-beta 8 and / or integrin alpha-V-beta 6) can activate TGF-beta by binding to the RGD motif present in LAP and inducing the release of mature TGF-beta from its latent complex form.

[0247] As used herein, “treating” includes effective cancer treatment with an effective dose of a therapeutic agent (e.g., an anti-latent TGF-beta-1 antibody) or a combination of therapeutic agents (e.g., an anti-latent TGF-beta-1 antibody and one or more additional therapeutic agents, e.g., a checkpoint inhibitor (e.g., a PD-1 axis antagonist (e.g., an anti-PD-L1 antibody (e.g., atezolizumab) or an anti-PD-1 antibody (e.g., nivolumab))) and / or one or more chemotherapeutic agents). Treatments as used herein include, among other things, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy) and metastatic cancer therapy. Treatment may be first-line treatment (e.g., the subject may be previously untreated or have not previously received systemic therapy), or second-line or later treatment (e.g., third-line, fourth-line, fifth-line, or later).

[0248] As used herein, “tumor” refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as they appear herein.

[0249] As used herein, the term “unresectable” refers to cancer that cannot be surgically removed or that cannot be safely performed.

[0250] The "variable region" or "variable domain" refers to the domain of the heavy or light chain of an antibody that is involved in the binding of the antibody to an antigen. The variable domains of the heavy and light chains of a native antibody (VH and VL, respectively) generally have a similar structure, and each domain includes four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). A single VH domain or VL domain may be sufficient to confer antigen-binding specificity. Further, an antibody that binds a specific antigen can be isolated using the VH domain or VL domain of an antibody that binds that antigen, and libraries of complementary VL domains or VH domains, respectively, can be screened. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0251] The terms "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refer to the numbering system used for the heavy chain variable domain or light chain variable domain of the compilation of antibodies in Kabat et al., (supra). Using this numbering system, the actual linear amino acid sequence may include fewer amino acids or additional amino acids corresponding to deletions or insertions in the FR or HVR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion (residue 52a according to Kabat) after residue 52 of H2, and residues inserted after residue 82 of the heavy chain FR (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment in the homologous regions between the sequence of the antibody and the sequence numbered by "standard" Kabat.

[0252] II. Methods and Compositions for Treating Cancer For example, provided herein are treatment methods and compositions for use in treating cancer (e.g., locally advanced, recurrent, or metastatic solid tumors) in a subject, including administering to the subject an anti-cancer therapy comprising a latent TGF-beta1 antibody.

[0253] In one example, provided herein is a method of treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors), the method comprising administering to the subject an anti-cancer therapy comprising a latent TGF-beta1 antibody at a dosage of 1800 mg.

[0254] In another example, provided herein is latent TGF-beta1 for use in treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors), the treatment comprising administering to the subject an anti-cancer therapy comprising a latent TGF-beta1 antibody at a dosage of 1800 mg.

[0255] In another example, provided herein is the use of latent TGF-beta1 in the manufacture of a medicament for treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors), the treatment comprising administering to the subject an anti-cancer therapy comprising a latent TGF-beta1 antibody at a dosage of 1800 mg.

[0256] In some examples, the latent TGF-beta1 antibody is administered to the subject in a dosing regimen comprising one or more 21-day dosing cycles. For example, the latent TGF-beta1 antibody can be administered to the subject on day 1 of each 21-day dosing cycle.

[0257] In another example, provided herein is a method of treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors), the method comprising administering to the subject an anti-cancer therapy comprising a latent TGF-beta1 antibody at a dosage of 1800 mg every three weeks (Q3W).

[0258] In another example, an anti-latent TGF-beta 1 for use in the treatment of a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors) is provided herein, the treatment comprising administering an anticancer therapy containing an anti-latent TGF-beta 1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W).

[0259] In another example, the use of anti-latent TGF-beta 1 in the manufacture of a pharmaceutical product for treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors) is provided herein, the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W).

[0260] In another example, a method for treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumor) is provided herein, the method comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject at a dose of 1200 mg.

[0261] In another example, an anti-latent TGF-beta 1 for use in the treatment of a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors) is provided herein, the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject in a dose of 1200 mg.

[0262] In another example, the use of anti-latent TGF-beta 1 in the manufacture of a pharmaceutical product for treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors) is provided herein, the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject in a dose of 1200 mg.

[0263] In some cases, the anti-latent TGF-beta-1 antibody is administered to the subject in a drug regimen that includes one or more 28-day drug cycles. For example, the anti-latent TGF-beta-1 antibody may be administered to the subject on day 1 and day 15 of each 28-day drug cycle.

[0264] In another embodiment, the present invention provides a method for treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumor), the method comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W).

[0265] In another embodiment, the present invention provides anti-latent TGF-beta-1 for use in the treatment of subjects having cancer (e.g., locally advanced, recurrent, or metastatic solid tumors), the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W).

[0266] In another embodiment, the present invention provides the use of anti-latent TGF-beta 1 in the manufacture of a pharmaceutical for treating a subject having cancer (e.g., locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W).

[0267] Any suitable cancer can be treated. In some cases, the cancer is a locally advanced, recurrent, or metastatic solid tumor. In some cases, the cancer is NSCLC, gastric cancer, PDAC, or UC.

[0268] Any suitable anti-latent TGF-beta-1 antibody, including any anti-latent TGF-beta-1 antibody disclosed herein or in International Publication No. 2021 / 039945 or in Section III below, may be administered to the subject.

[0269] In some examples, the anti-latent TGF-beta 1 antibody contains the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 4, 5, and 6 respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18 respectively. VR-L2 and HVR-L3; (c) HVR-H1, HVR-H2 and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20 and 21, respectively, and HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23 and 24, respectively; or (d) HVR-H1, HVR-H2 and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26 and 27, respectively, and HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29 and 30, respectively. In a specific example, the anti-latent TGF-beta 1 antibody contains the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 1, 2 and 3, respectively, and HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 4, 5 and 6, respectively.

[0270] In some cases, cancer is a locally advanced, recurrent, or metastatic solid tumor.

[0271] For example, a method for treating a subject having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer) is provided herein, the method comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1800 mg, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) the amino acid sequences of SEQ ID NOs: 13, 14, and 15 (c) HVR-H1, HVR-H2, and HVR-H3 each containing the amino acid sequence, and HVR-L1, HVR-L2, and HVR-L3 each containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 each containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, and HVR-L1, HVR-L2, and HVR-L3 each containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24; or (d) HVR-H1, HVR-H2, and HVR-H3 each containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, and HVR-L1, HVR-L2, and HVR-L3 each containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30.

[0272] In another example, anti-latent TGF-beta-1 is provided herein for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer), the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1800 mg, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) SEQ ID NOs: 13, 1 (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of 4 and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0273] In another example, provided herein is the use of anti-latent TGF-beta1 in the manufacture of a medicament for treating a subject having a locally advanced, recurrent, or metastatic solid tumor (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer), wherein the treatment comprises administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta1 antibody at a dosage of 1800 mg, and the anti-latent TGF-beta1 antibody comprises the following six HVRS: (a) HVR-H1, HVR-H2, and HVR-H3, each comprising the amino acid sequence of SEQ ID NO: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3, each comprising the amino acid sequence of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3, each comprising the amino acid sequence of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3, each comprising the amino acid sequence of SEQ ID NO: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3, each comprising the amino acid sequence of SEQ ID NO: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3, each comprising the amino acid sequence of SEQ ID NO: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3, each comprising the amino acid sequence of SEQ ID NO: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3, each comprising the amino acid sequence of SEQ ID NO: 28, 29, and 30, respectively.

[0274] In some examples, the anti-latent TGF-beta1 antibody is administered to the subject in a dosing regimen comprising one or more 21-day dosing cycles. For example, the anti-latent TGF-beta1 antibody can be administered to the subject on day 1 of each 21-day dosing cycle.

[0275] In another example, a method for treating a subject having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer) is provided herein, the method comprising administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody at a dose of 1800 mg every three weeks (Q3W) to the subject, the anti-latent TGF-beta-1 antibody containing the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) SEQ ID NOs: 13, 14 (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of (sequences 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of (sequences 19, 20, and 21, respectively; and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of (sequences 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of (sequences 25, 26, and 27, respectively; and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of (sequences 28, 29, and 30, respectively.

[0276] In another example, anti-latent TGF-beta 1 is provided herein for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer), the treatment comprising administering an anticancer therapy containing an anti-latent TGF-beta 1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W), the anti-latent TGF-beta 1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) sequence number (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively.

[0277] In another example, the use of anti-latent TGF-beta 1 in the manufacture of a pharmaceutical product for treating subjects having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer), the treatment comprising administering an anticancer therapy containing an anti-latent TGF-beta 1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W), the anti-latent TGF-beta 1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0278] In another example, a method for treating a subject having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer) is provided herein, the method comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) the amino acid sequences of SEQ ID NOs: 13, 14, and 15 (c) HVR-H1, HVR-H2, and HVR-H3 each containing the amino acid sequence, and HVR-L1, HVR-L2, and HVR-L3 each containing the amino acid sequence of SEQ ID NOs. 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 each containing the amino acid sequence of SEQ ID NOs. 19, 20, and 21, and HVR-L1, HVR-L2, and HVR-L3 each containing the amino acid sequence of SEQ ID NOs. 22, 23, and 24; or (d) HVR-H1, HVR-H2, and HVR-H3 each containing the amino acid sequence of SEQ ID NOs. 25, 26, and 27, and HVR-L1, HVR-L2, and HVR-L3 each containing the amino acid sequence of SEQ ID NOs. 28, 29, and 30.

[0279] In another example, anti-latent TGF-beta 1 is provided herein for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer), the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject at a dose of 1200 mg, the anti-latent TGF-beta 1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) SEQ ID NOs: 13, 1 (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of 4 and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0280] In another example, the use of anti-latent TGF-beta 1 in the manufacture of a pharmaceutical product for treating subjects having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer) is provided herein, and the treatment comprises administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody to the subject at a dose of 1200 mg, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) SEQ ID NOs: (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0281] In some cases, the anti-latent TGF-beta-1 antibody is administered to the subject in a drug regimen that includes one or more 28-day drug cycles. For example, the anti-latent TGF-beta-1 antibody may be administered to the subject on day 1 and day 15 of each 28-day drug cycle.

[0282] In another example, a method for treating a subject having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer) is provided herein, the method comprising administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody at a dose of 1200 mg every two weeks (Q2W) to the subject, the anti-latent TGF-beta-1 antibody containing the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) SEQ ID NOs: 13, 14 (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of (sequences 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of (sequences 19, 20, and 21, respectively; and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of (sequences 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of (sequences 25, 26, and 27, respectively; and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of (sequences 28, 29, and 30, respectively.

[0283] In another example, anti-latent TGF-beta 1 is provided herein for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer), the treatment comprising administering an anticancer therapy containing an anti-latent TGF-beta 1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W), the anti-latent TGF-beta 1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) sequence number (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively.

[0284] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical product for treating subjects having locally advanced, recurrent, or metastatic solid tumors (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer), the treatment comprising administering an anticancer therapy comprising an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W), wherein the anti-latent TGF-beta-1 antibody comprises the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0285] Anti-latent TGF-beta 1 antibodies can be administered by any suitable route. In some cases, anti-latent TGF-beta 1 antibodies are administered intravenously to the subject. In some cases, anti-latent TGF-beta 1 antibodies are administered intravenously to the subject by infusion.

[0286] In some cases, tumor samples derived from the subject have been determined to have detectable levels of PD-L1 expression. Any suitable approach for detecting PD-L1 expression may be used, including any approach described herein (see, for example, Section V below).

[0287] In some cases, the target age is 18 years or older. The target may also be adults.

[0288] Anti-cancer therapy can represent any appropriate line of treatment. In some cases, anti-cancer therapy is the first-line treatment. In other cases, anti-cancer therapy is the second-line or third-line treatment.

[0289] In some cases, chemotherapy is the first-line treatment. For example, the patient may not have been treated previously. In some cases, the subject has not been previously treated with checkpoint inhibitors.

[0290] In some cases, solid tumors are metastatic. In other cases, solid tumors are locally advanced. In yet another case, solid tumors are recurrent.

[0291] Any suitable solid tumor can be treated. In some cases, locally advanced, recurrent, or metastatic solid tumors include NSCLC, gastric cancer, PDAC, or UC.

[0292] In some cases, locally advanced, recurrent, or metastatic solid tumors are NSCLC. For example, NSCLC may be histologically or cytologically confirmed metastatic non-squamous NSCLC or metastatic squamous NSCLC. In some cases, subjects had disease progression during or after treatment for metastatic or locally advanced, unresectable NSCLC, including platinum-containing chemotherapy regimens and PD-1 axially coupled antagonists, given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order. In some cases, subjects had previously received combination therapy including platinum-containing chemotherapy regimens and PD-1 axially coupled antagonists. In some cases, subjects had previously received platinum-containing chemotherapy regimens and PD-1 axially coupled antagonists as separate regimens. In some cases, subjects had disease progression or recurrence within six months of curative treatment for locally advanced NSCLC. In some cases, tumor samples derived from the target organism have been determined to have detectable levels of PD-L1 expression.

[0293] In some cases, locally advanced, recurrent, or metastatic solid tumors are gastric cancer. In some cases, subjects have unresectable locally advanced or metastatic gastric cancer histologically confirmed to be adenocarcinoma. In some cases, gastric cancer includes esophagogastric junction cancer. In some cases, gastric cancer is HER2-negative gastric cancer. In some cases, subjects have not been previously treated for gastric cancer and / or have not been previously treated with checkpoint inhibitors.

[0294] In some cases, locally advanced, recurrent, or metastatic solid tumors are PDACs. In some cases, subjects have histologically or cytologically confirmed metastatic PDACs. In some cases, subjects have not been previously treated for PDACs and / or have not been previously treated with checkpoint inhibitors.

[0295] In some cases, locally advanced, recurrent, or metastatic solid tumors are UC. In some cases, subjects have histologically demonstrated locally advanced (T4b, any N; or any T, N2-N3) UC or metastatic UC (M1, stage 4). In some cases, subjects have not been previously treated for UC. In some cases, subjects are ineligible for cisplatin-containing chemotherapy. In some cases, subjects are ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) renal impairment in terms of glomerular filtration rate (GFR) of 30 mL / min or greater and less than 60 mL / min, assessed by direct measurement or calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two adjacent frequencies, measured by audiometry; (iii) grade 2 peripheral neuropathy; or (iv) performance status 2 of the East Coast Clinical Oncology Group (ECOG). In some cases, subjects have previously received at least one platinum-containing chemotherapy regimen. In some cases, subjects experienced disease progression during or after treatment with at least one platinum-containing chemotherapy regimen. In some cases, at least one platinum-containing chemotherapy regimen included (i) gemcitabine and cisplatin or carboplatin, or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin. In some cases, subjects received prior adjuvant or neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen. In some cases, subjects received one cycle of a platinum-containing chemotherapy regimen but discontinued it due to grade 4 hematological toxicity or grade 3–4 non-hematological toxicity. In some cases, subjects received two or fewer prior lines of treatment for locally advanced UC or metastatic UC. In some cases, subjects had not received prior treatment with T-cell costimulation therapy or checkpoint inhibitors.

[0296] In some examples, anti-latent TGF-beta-1 antibodies include: (a) (i) a heavy chain variable domain (VH) sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 8; (ii) at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 8 A light chain variable domain (VL) sequence having sequence identity of 9%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more; (iii) The VH sequence defined in (i) and the VL sequence defined in (ii); (b) At least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) of the amino acid sequence of (i) Sequence ID No. 31 (ii) A VH sequence having (ii) a sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) with the amino acid sequence of (ii); (iii) A VH sequence defined in (i) and a VL sequence defined in (ii); (c) A sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 8) with the amino acid sequence of (i) 33; (ii) A VH sequence having sequence identity of 7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more; (ii) A VL sequence having sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) with the amino acid sequence of SEQ ID NO: 34; (iii) A VH sequence defined in (i) and a VL sequence defined in (ii);Or (d)(i) a VH sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 35, (ii) a VL sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 36, or (iii) a VH sequence defined in (i) and a VL sequence defined in (ii). ;

[0297] In some examples, anti-latent TGF-beta 1 antibodies include: (a) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 8; (b) the VH sequence of SEQ ID NO: 31 and the VL sequence of SEQ ID NO: 32; (c) the VH sequence of SEQ ID NO: 33 and the VL sequence of SEQ ID NO: 34; (d) the VH sequence of SEQ ID NO: 35 and the VL sequence of SEQ ID NO: 36.

[0298] In certain cases, the anti-latent TGF-beta 1 antibody contains the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 8.

[0299] In some cases, anti-latent TGF-beta 1 antibodies are chimeric antibodies.

[0300] In some cases, anti-latent TGF-beta 1 antibodies are humanized antibodies.

[0301] In some cases, anti-latent TGF-beta 1 antibodies are full-length antibodies.

[0302] In some examples, an anti-latent TGF-beta 1 antibody may include: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 38; (b) a heavy chain containing the amino acid sequence of SEQ ID NO: 39 and a light chain containing the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain containing the amino acid sequence of SEQ ID NO: 41 and a light chain containing the amino acid sequence of SEQ ID NO: 42; (d) a heavy chain containing the amino acid sequence of SEQ ID NO: 43 and a light chain containing the amino acid sequence of SEQ ID NO: 44; (e) a heavy chain containing the amino acid sequence of SEQ ID NO: 45 and a light chain containing the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain containing the amino acid sequence of SEQ ID NO: 47 and a light chain containing the amino acid sequence of SEQ ID NO: 48; (g) a heavy chain containing the amino acid sequence of SEQ ID NO: 49 and a light chain containing the amino acid sequence of SEQ ID NO: 50; or (h) a heavy chain containing the amino acid sequence of SEQ ID NO: 51 and a light chain containing the amino acid sequence of SEQ ID NO: 52.

[0303] In some cases, anti-latent TGF-beta 1 antibodies contain a modified IgG1 Fc region with reduced effector function compared to the wild-type IgG1 Fc region.

[0304] In some examples, the modified IgG1 Fc region contains a stationary weight (CH) region that includes one or more of the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, and / or S440E (EU numbering).

[0305] In some examples, the CH region contains the amino acid sequence of SEQ ID NO: 9.

[0306] In some examples, the modified IgG1 Fc region contains a constant light (CL) domain with the amino acid sequence of SEQ ID NO: 10.

[0307] In some cases, anti-latent TGF-beta 1 antibodies include a heavy chain containing the amino acid sequence of SEQ ID NO: 11 and a light chain containing the amino acid sequence of SEQ ID NO: 12.

[0308] In some cases, anti-latent TGF-beta 1 antibodies are antibody fragments that bind to latent TGF-beta 1.

[0309] In some cases, anti-latent TGF-beta 1 antibodies are administered to the patient as monotherapy.

[0310] In some cases, an anti-latent TGF-beta 1 antibody is administered to the subject in combination with one or more additional therapeutic agents. Any suitable additional therapeutic agent or combination of additional therapeutic agents, including any of those described herein, may be administered. In some cases, one or more additional therapeutic agents include a checkpoint inhibitor. In some cases, the checkpoint inhibitor includes a PD-1 axis-binding antagonist or a CTLA4 antagonist. In some cases, the checkpoint inhibitor includes a PD-1 axis-binding antagonist, including any PD-1 axis-binding antagonist disclosed herein (see, for example, Section IV). In some cases, the PD-1 axis-binding antagonist includes a PD-L1-binding antagonist, a PD-1-binding antagonist, or a PD-L2-binding antagonist.

[0311] In some cases, the PD-1 axis-conjugated antagonist includes a PD-L1-conjugated antagonist. In some cases, the PD-L1-conjugated antagonist includes an anti-PD-L1 antibody. Any suitable anti-PD-L1 antibody may be used. In some cases, the anti-PD-L1 antibody includes atezolizumab, durvalumab, avelumab, or MDX-1105.

[0312] In certain cases, the anti-PD-L1 antibody includes atezolizumab. In some cases, atezolizumab is administered to the subject in a drug regimen consisting of one or more drug cycles. In some cases, one or more drug cycles consist of 21-day drug cycles. In some cases, atezolizumab is administered to the subject on day 1 of each 21-day drug cycle. In some cases, atezolizumab is administered to the subject at a dose of 1200 mg. In some cases, one or more drug cycles consist of either 14-day or 28-day drug cycles. In some cases, one or more drug cycles consist of 14-day drug cycles, and atezolizumab is administered to the subject at a dose of 840 mg. In some cases, atezolizumab is administered to the subject on day 1 of each 14-day drug cycle. In some cases, one or more drug cycles consist of 28-day drug cycles in which atezolizumab is administered to the subject at a dose of 1680 mg. In some cases, atezolizumab is administered to the subject on day 1 of each 28-day drug cycle. In some cases, atezolizumab is administered to the subject intravenously. In some cases, atezolizumab is administered to the subject intravenously by infusion.

[0313] In some cases, atezolizumab is administered intravenously to patients at doses of approximately 840 mg every two weeks, approximately 1200 mg every three weeks, or approximately 1680 mg every four weeks.

[0314] In other examples, a PD-1 axis-conjugated antagonist includes a PD-1-binding antagonist. In some examples, a PD-1-binding antagonist includes an anti-PD-1 antibody. Any suitable anti-PD-1 antibody may be used. In some examples, the anti-PD-1 antibody includes nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiprimab, prorugolimab, camrelizumab, cintilimab, tislerizumab, tripalimab, dostarimab, retifanlimab, sasanlimab, penprimab, zinbererimab, valstilimab, genolimuzumab, cetrelimab, or buzigalimab.

[0315] In certain cases, the anti-PD-1 antibody includes nivolumab. In some cases, nivolumab is administered to the subject in a drug regimen consisting of one or more drug cycles. In some cases, one or more drug cycles consist of 21-day drug cycles. In some cases, nivolumab is administered to the subject on day 1 of each 21-day drug cycle. In some cases, nivolumab is administered to the subject at a dose of 360 mg. In some cases, nivolumab is administered to the subject intravenously. In some cases, nivolumab is administered to the subject intravenously by infusion.

[0316] In some cases, one or more additional therapeutic agents are selected from chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, anti-angiogenic agents, and any combination thereof.

[0317] In some examples, one or more additional therapeutic agents include agonists against activating costimulatory molecules. In some examples, the activating costimulatory molecules may include CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some examples, one or more additional therapeutic agents include agonist antibodies that bind to CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some examples, one or more additional therapeutic agents include antagonists against inhibitory costimulatory molecules. In some embodiments, the inhibitory costimulatory molecules may include CTLA-4 (also known as CD152), TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, or arginase. In some embodiments, the antagonist to the inhibitory costimulatory molecule is CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, or an antagonist antibody that binds to arginase.

[0318] In some examples, one or more additional therapeutic agents include one or more chemotherapeutic agents. Any suitable chemotherapeutic agent may be used, including any chemotherapeutic agent or combination of chemotherapeutic agents disclosed herein (see, for example, Section VI below). In some examples, one or more chemotherapeutic agents include platinum-based chemotherapeutic agents, antimetabolites, cytotoxic agents, growth inhibitors, taxanes, folic acid analogs, or any combination thereof.

[0319] In some cases, the platinum-based chemotherapy agent includes oxaliplatin, cisplatin, or carboplatin. In some cases, the platinum-based chemotherapy agent includes oxaliplatin. In some cases, oxaliplatin is administered to the subject in a drug regimen consisting of one or more drug cycles. In some cases, one or more drug cycles consist of 21-day drug cycles. In some cases, oxaliplatin is administered to the subject on day 1 of each 21-day drug cycle. In some cases, oxaliplatin is administered at 130 mg / m². 2 It is administered to the subject at the specified dose. In some cases, oxaliplatin is administered intravenously to the subject.

[0320] In some cases, the antimetabolites include capecitabine, gemcitabine, 5-fluorouracil, or tegafur.

[0321] In some cases, the antimetabolite includes capecitabine. In some cases, capecitabine is administered to the subject in a drug regimen that includes one or more drug cycles. In some cases, one or more drug cycles include 21-day drug cycles. In some cases, capecitabine is administered to the subject on days 1 through 14 of each 21-day drug cycle. In some cases, capecitabine is administered to the subject at a dose of 1000 mg / m². 2 It is administered twice daily at this dose. In some cases, capecitabine is administered orally to the subject.

[0322] In other examples, the antimetabolite includes gemcitabine. In some examples, gemcitabine is administered to the subject in a drug regimen that includes one or more drug cycles. In some examples, one or more drug cycles include a 28-day drug cycle. In some examples, gemcitabine is administered to the subject on day 1, day 8, and day 15 of each 28-day drug cycle. In some examples, gemcitabine is administered to the subject at a dose of 1000 mg / m². 2 It is administered twice daily at this dose. In some cases, gemcitabine is administered intravenously to the patient.

[0323] In some cases, the antimetabolites include tegafur.

[0324] In some cases, the antimetabolite includes S-1 (tegafur / gimeracil / oteracil potassium). In some cases, S-1 is administered to the subject in a drug regimen that includes one or more drug cycles. In some cases, one or more drug cycles include 21-day drug cycles. In some cases, S-1 is administered to the subject on days 1-14 of each 21-day drug cycle. In some cases, S-1 is administered to the subject at a dose of 40 mg / m². 2 It is administered twice daily at this dose. In some cases, S-1 is administered orally to the subject.

[0325] In some cases, taxanes include nab-paclitaxel or paclitaxel.

[0326] In some cases, the taxane includes nab-paclitaxel. In some cases, nab-paclitaxel is administered to the subject in a drug regimen that includes one or more drug cycles. In some cases, one or more drug cycles include 28-day drug cycles. In some cases, nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day drug cycle. In some cases, nab-paclitaxel is administered at 125 mg / m². 2 It is administered to the subject at the specified dose. In some cases, nab-paclitaxel is administered intravenously to the subject.

[0327] In some cases, folate analogs include leucovorin.

[0328] In another example, a method for treating a subject having locally advanced, recurrent, or metastatic NSCLC is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively. (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of HVR-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (e) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0329] In another example, an anti-latent TGF-beta-1 for use in the treatment of a subject having locally advanced, recurrent, or metastatic NSCLC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) sequence (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively.

[0330] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical for treating subjects having locally advanced, recurrent, or metastatic NSCLC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0331] In some cases, NSCLC is histologically or cytologically confirmed metastatic non-squamous NSCLC or metastatic squamous NSCLC.

[0332] In some cases, subjects had disease progression during or after treatment for metastatic or locally advanced, unresectable NSCLC, which was given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order, including platinum-containing chemotherapy regimens and PD-1 axis-coupled antagonists.

[0333] In some cases, the subjects had previously received combination therapy including platinum-containing chemotherapy regimens and PD-1 axis-coupled antagonists.

[0334] In some cases, the subjects had previously received platinum-containing chemotherapy regimens and PD-1 axis-coupled antagonists as separate regimens.

[0335] In some cases, the subjects experienced disease progression or relapse within 6 months of curative treatment for locally progressive NSCLC.

[0336] In some cases, tumor samples derived from the target organism have been determined to have detectable levels of PD-L1 expression.

[0337] In another example, a method for treating a subject having locally advanced, recurrent, or metastatic gastric cancer is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and sequence number (i) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively; and (ii) nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day treatment cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1 to 14 of each 21-day treatment cycle. 2 (b) capecitabine at the prescribed dosage, or (b) 40 mg / m² orally twice daily on days 1-14 of each 21-day medication cycle. 2 S-1 at the dosage of (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle; and (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. 2 Oxaliplatin at the prescribed dosage.

[0338] In another example, an anti-latent TGF-beta-1 for use in the treatment of a subject having locally advanced, recurrent, or metastatic gastric cancer, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) sequence number (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of numbers 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of numbers 28, 29, and 30, respectively.

[0339] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical product for treating subjects having locally advanced, recurrent, or metastatic gastric cancer is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively.

[0340] In some cases, the subjects have unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be adenocarcinoma.

[0341] In some cases, gastric cancer includes cancer at the esophagogastric junction.

[0342] In some cases, the gastric cancer is HER2-negative gastric cancer.

[0343] In some cases, the subjects had not been previously treated for gastric cancer and / or had not been previously treated with checkpoint inhibitors.

[0344] In another example, a method for treating a subject having locally advanced, recurrent, or metastatic PDAC is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (b) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 13, 14 and 15, respectively, and sequence (i) HVR-L1, HVR-L2, and HVR-L3 containing amino acid sequences 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing amino acid sequences 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing amino acid sequences 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing amino acid sequences 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing amino acid sequences 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8, and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at this dosage.

[0345] In another example, an anti-latent TGF-beta-1 for use in the treatment of a subject having locally advanced, recurrent, or metastatic PDAC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 28-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (b) HVR-H1, HVR-H2 and HVR- (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of H3 and SEQ ID NOs. 16, 17, and 18, respectively; (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (ii) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively; (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8, and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at this dosage.

[0346] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical for treating subjects having locally advanced, recurrent, or metastatic PDAC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 28-day dosing cycles, the anticancer therapy comprising: (i) anti-latent TGF-beta-1 antibodies in a dosing dose of 1200 mg intravenously on days 1 and 15 of each 28-day dosing cycle, the anti-latent TGF-beta-1 antibodies comprising the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3 respectively, and HVR-L1, HVR-L2 and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5 and 6 respectively; (b) HVR-H1, HVR-H2 and (c) HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17 and 18, respectively; (d) HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 19, 20 and 21, respectively, and HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23 and 24, respectively; or (d) SEQ ID NOs. 25, 26 and (ii) HVR-H1, HVR-H2, and HVR-H3 containing 27 amino acid sequences, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively; (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8, and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at this dosage.

[0347] In some cases, the subjects have histologically or cytologically confirmed metastatic PDACs.

[0348] In some cases, the subjects had not been previously treated for PDAC and / or had not been previously treated with checkpoint inhibitors.

[0349] In another example, a method for treating a subject having locally advanced, recurrent, or metastatic UC is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HV (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of R-H2 and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0350] In another example, an anti-latent TGF-beta-1 for use in the treatment of a subject having locally advanced, recurrent, or metastatic UC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) HVR-L2, HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 13, 14, and 15 respectively. (c) HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of VR-H1, HVR-H2, and HVR-H3, respectively, and SEQ ID NOs: 16, 17, and 18; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0351] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical for treating subjects having locally advanced, recurrent, or metastatic UC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively; (b) the amino acid sequences of SEQ ID NOs: 13, 14, and 15 respectively (c) HVR-H1, HVR-H2, and HVR-H3, and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18, respectively; (d) HVR-H1, HVR-H2, and HVR-H3, each containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively; and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (e) HVR-H1, HVR-H2, and HVR-H3, each containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively; and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively; and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle.

[0352] In some cases, the subjects have histologically demonstrated locally progressive (T4b, any N; or any T, N2-N3) UC or metastatic UC (M1, stage 4).

[0353] In some cases, the subjects had not previously been treated for UC.

[0354] In some cases, the subjects are ineligible for cisplatin-containing chemotherapy.

[0355] In some cases, the subjects are ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) renal impairment in terms of glomerular filtration rate (GFR) of 30 mL / min or more but less than 60 mL / min, as assessed by direct measurement or calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two adjacent frequencies, as measured by audiometry; (iii) grade 2 peripheral neuropathy; or (iv) ECOG performance status 2.

[0356] In some cases, the subjects had previously received at least one platinum-containing chemotherapy regimen.

[0357] In some cases, subjects experienced disease progression during or after treatment with at least one platinum-containing chemotherapy regimen.

[0358] In some cases, at least one platinum-containing chemotherapy regimen included (i) gemcitabine and cisplatin or carboplatin, or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin.

[0359] In some cases, the subjects had received prior adjuvant or neoadjuvant chemotherapy and their disease progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.

[0360] In some cases, subjects received one cycle of platinum-containing chemotherapy regimens, but treatment was discontinued due to grade 4 hematological toxicity or grade 3–4 non-hematological toxicity.

[0361] In some cases, the subjects had received two or fewer prior treatment regimens for locally advanced or metastatic UC.

[0362] In some cases, the subjects had not received prior treatment with T-cell costimulation therapy or checkpoint inhibitors.

[0363] In another example, a method for treating a subject having metastatic non-squamous NSCLC or metastatic squamous NSCLC is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3) -H3;(d)HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4);(e)HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and(f)HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); and (ii)atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who had disease progression during or after treatment of metastatic or locally advanced unresectable NSCLC, which was given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order).

[0364] In another example, an anti-latent TGF-beta-1 for use in the treatment of a subject having metastatic non-squamous NSCLC or metastatic squamous NSCLC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H2 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3) (d) HVR-H3 containing the sequence; (e) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who had disease progression during or after treatment of metastatic or locally advanced unresectable NSCLC, including a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist, which was administered in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order).

[0365] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical for treating a subject having metastatic non-squamous NSCLC or metastatic squamous NSCLC is provided herein, the treatment comprising administering an anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) GTGIYDYYYWVMDL (SEQ ID NO: 3) (d) HVR-H3 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who had disease progression during or after treatment of metastatic or locally advanced unresectable NSCLC, which was administered in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order).

[0366] In another example, a method for treating a subject having locally advanced, unresectable, or metastatic HER2-negative gastric cancer is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTYRANWARG (SEQ ID NO: 1). (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day treatment cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1-14 of each 21-day treatment cycle. 2 (b) capecitabine at the prescribed dosage, or (b) 40 mg / m² orally twice daily on days 1-14 of each 21-day medication cycle. 2 S-1 at the dosage of (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. 2 Oxaliplatin at the specified dosage (for patients with locally advanced, unresectable, or metastatic HER2-negative gastric cancer who have not been previously treated).

[0367] In another example, an anti-latent TGF-beta-1 for use in the treatment of a subject having locally advanced, unresectable, or metastatic HER2-negative gastric cancer is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTYRANWA (i) HVR-H2 containing the amino acid sequence of RG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day treatment cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1-14 of each 21-day treatment cycle. 2 (b) capecitabine at the prescribed dosage, or (b) 40 mg / m² orally twice daily on days 1-14 of each 21-day medication cycle. 2 S-1 at the dosage of (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. 2 Oxaliplatin at the specified dosage (for patients with locally advanced, unresectable, or metastatic HER2-negative gastric cancer who have not been previously treated).

[0368] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical product for treating subjects having locally advanced, unresectable, or metastatic HER2-negative gastric cancer is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTY (i) HVR-H2 containing the amino acid sequence of RANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day treatment cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1-14 of each 21-day treatment cycle. 2 (b) capecitabine at the prescribed dosage, or (b) 40 mg / m² orally twice daily on days 1-14 of each 21-day medication cycle. 2 S-1 at the dosage of (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. 2 Oxaliplatin at the specified dosage (for patients with locally advanced, unresectable, or metastatic HER2-negative gastric cancer who have not been previously treated).

[0369] In another example, a method for treating a subject with metastatic PDAC is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2) (i) HVR-H2 containing (c) the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8 and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at the specified dosage (for patients with metastatic PDAC who have not been previously treated).

[0370] In another example, the present invention provides an anti-latent TGF-beta-1 for use in the treatment of a subject having metastatic PDAC, the treatment comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTYRANWARG (SEQ ID NO: 2) (i) HVR-H2 containing the amino acid sequence of (c)GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8 and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at the specified dosage (for patients with metastatic PDAC who have not been previously treated).

[0371] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical for treating a subject having metastatic PDAC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 28-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody in a dosing dose of 1200 mg intravenously on days 1 and 15 of each 28-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) YIYTSGTTYRANWARG ( (ii) HVR-H2 containing the amino acid sequence of (c) GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6); (ii) atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day drug cycle; (iii) 125 mg / m² on days 1, 8 and 15 of each 28-day drug cycle. 2 (iv) nab-paclitaxel at the dose of (iv) 1000 mg / m² intravenously on days 1, 8 and 15 of each 28-day medication cycle. 2 Gemcitabine at the specified dosage (for patients with metastatic PDAC who have not been previously treated).

[0372] In another example, a method for treating a subject with locally advanced or metastatic UC is provided herein, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) GTGIYDYYYWVMD (d) HVR-H3 containing the amino acid sequence of L (SEQ ID NO: 3); (e) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (f) HVR-L3 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (the subject is not previously treated for locally advanced UC or metastatic UC and is ineligible for cisplatin-containing chemotherapy; or the subject has previously received at least one platinum-containing chemotherapy regimen).

[0373] In another example, an anti-latent TGF-beta-1 for use in the treatment of a subject having locally advanced or metastatic UC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) GTGIYD (d) HVR-H3 containing the amino acid sequence YYYWVMDL (SEQ ID NO: 3); (e) HVR-L1 containing the amino acid sequence QASQSISTYLA (SEQ ID NO: 4); (f) HVR-L3 containing the amino acid sequence QSYSDGDSVG (SEQ ID NO: 6); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who have not been previously treated for locally advanced or metastatic UC and are ineligible for cisplatin-containing chemotherapy; or individuals who have previously received at least one platinum-containing chemotherapy regimen).

[0374] In another example, the use of anti-latent TGF-beta-1 in the manufacture of a pharmaceutical for treating a subject with locally advanced or metastatic UC is provided herein, the treatment comprising administering anticancer therapy to the subject in a dosing regimen comprising one or more 21-day dosing cycles, the anticancer therapy comprising: (i) an anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day dosing cycle, the anti-latent TGF-beta-1 antibody comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) G (d) HVR-H3 containing the amino acid sequence TGIYDYYYWVMDL (SEQ ID NO: 3); (e) HVR-L1 containing the amino acid sequence QASQSISTYLA (SEQ ID NO: 4); (f) HVR-L3 containing the amino acid sequence QSYSDGDSVG (SEQ ID NO: 6); and (ii) atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day drug cycle (individuals who have not been previously treated for locally advanced UC or metastatic UC and are ineligible for cisplatin-containing chemotherapy; or individuals who have previously received at least one platinum-containing chemotherapy regimen).

[0375] In any of the examples described above, subjects may be administered anti-latent TGF-beta-1 antibodies to the extent that clinical benefit is lost or unacceptable toxicity occurs.

[0376] In any of the examples above, each medication cycle may have any appropriate length, for example, about 7 days, about 14 days, about 21 days, about 28 days, or longer. In some cases, each medication cycle is about 21 days. In some cases, each medication cycle is 21 days. In some cases, each medication cycle is about 28 days. In some cases, each medication cycle is 28 days.

[0377] In some cases, this method involves 1 to 40 medication cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 medication cycles).

[0378] In some cases, the subjects include a total of 1 to 50 doses, for example, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 5 0 dose, 3~45 dose, 3~40 dose, 3~35 dose, 3~30 dose, 3~25 dose, 3~20 dose, 3~15 dose, 3~10 dose, 3~5 dose, 4~50 dose, 4~45 dose, 4~40 amount, 4-35 doses, 4-30 doses, 4-25 doses, 4-20 doses, 4-15 doses, 4-10 doses, 4-5 doses, 5-50 doses, 5-45 doses, 5-40 doses, 5-35 doses, 5-30 doses, 5-25 doses, 5-20 doses, 5-15 doses, 5-10 doses, 10-50 doses, 10-45 doses, 10-40 doses, 10-35 doses, 10-30 doses, 10-25 doses, 10-20 doses, 1 For 0~15 doses, 15~50 doses, 15~45 doses, 15~40 doses, 15~35 doses, 15~30 doses, 15~25 doses, 15~20 doses, 20~50 doses, 20~45 doses, 20~40 The following doses of anti-latent TGF-beta 1 antibody are administered: 20-35 doses, 20-30 doses, 20-25 doses, 25-50 doses, 25-45 doses, 25-40 doses, 25-35 doses, 25-30 doses, 30-50 doses, 30-45 doses, 30-40 doses, 30-35 doses, 35-50 doses, 35-45 doses, 35-40 doses, 40-50 doses, 40-45 doses, or 45-50 doses. In certain cases, the dose may be administered intravenously.

[0379] Anti-latent TGF-beta-1 antibodies and / or any additional therapeutic agents (e.g., checkpoint inhibitors (e.g., PD-1 axis antagonists (e.g., anti-PD-L1 antibodies (e.g., atezolizumab) or anti-PD-1 antibodies (e.g., nivolumab))) and / or one or more chemotherapeutic agents) may be administered in any suitable manner known in the art. For example, anti-latent TGF-beta-1 antibodies and / or any additional therapeutic agents may be administered sequentially (on different days) or simultaneously (on the same day or during the same treatment cycle). In some cases, anti-latent TGF-beta-1 antibodies are administered before additional therapeutic agents. In other cases, anti-latent TGF-beta-1 antibodies are administered after additional therapeutic agents. In some cases, anti-latent TGF-beta-1 antibodies and / or any additional therapeutic agents may be administered on the same day. In some cases, anti-latent TGF-beta-1 antibodies may be administered before additional therapeutic agents administered on the same day. For example, anti-latent TGF-beta-1 antibodies may be administered before chemotherapy on the same day. In another example, an anti-latent TGF-beta-1 antibody may be administered on the same day before both chemotherapy and another drug (e.g., a checkpoint inhibitor (e.g., a PD-1 axis antagonist (e.g., an anti-PD-L1 antibody (e.g., atezolizumab) or an anti-PD-1 antibody (e.g., nivolumab))) and / or one or more chemotherapeutic agents). In yet another example, an anti-latent TGF-beta-1 antibody may be administered after an additional therapeutic agent administered on the same day. In yet another example, an anti-latent TGF-beta-1 antibody is administered concurrently with an additional therapeutic agent. In some cases, the PD anti-latent TGF-beta-1 antibody is in a separate composition from the additional therapeutic agent. In some cases, the anti-latent TGF-beta-1 antibody is in the same composition as the additional therapeutic agent. In some cases, the anti-latent TGF-beta-1 antibody is administered via a separate intravenous line from any other therapeutic agents administered to the subject on the same day.

[0380] Anti-latent TGF-beta 1 antibodies and any additional therapeutic agents may be administered by the same or different routes of administration. In some cases, anti-latent TGF-beta 1 antibodies are administered intravenously, intramuscularly, subcutaneously, topically, orally, percutaneously, intraperitoneally, intraorbitally, implantably, by inhalation, intrathecally, intraventricularly, or intranasally. In some cases, additional therapeutic agents are administered intravenously, intramuscularly, subcutaneously, topically, orally, percutaneously, intraperitoneally, intraorbitally, implantably, by inhalation, intrathecally, intraventricularly, or intranasally.

[0381] In preferred cases, the anti-latent TGF-beta 1 antibody is administered intravenously.

[0382] Methods for treating cancer in a subject are also provided herein, comprising administering an anticancer therapy comprising an effective amount of an anti-latent TGF-beta-1 antibody and / or a checkpoint inhibitor (e.g., a PD-1 axis antagonist (e.g., an anti-PD-L1 antibody (e.g., atezolizumab) or an anti-PD-1 antibody (e.g., nivolumab)) and / or one or more chemotherapeutic agents) to the subject in combination with another anticancer agent or cancer therapy. For example, an anti-latent TGF-beta-1 antibody may be administered in combination with additional chemotherapy or chemotherapeutic agents (see definition above); targeted therapy or targeted therapeutic agents; immunotherapy or immunotherapeutic agents, e.g., monoclonal antibodies; one or more cytotoxic agents (see definition above); or a combination thereof.

[0383] In some cases, treatment may further include additional treatments. Any suitable additional treatment known in the art or described herein may be used. Additional treatments may include radiotherapy, surgery, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, gamma irradiation, or a combination thereof.

[0384] In some cases, additional treatment involves the administration of side effect limiting agents (e.g., medications intended to reduce the occurrence and / or severity of side effects of treatment, such as anti-nausea agents, corticosteroids (e.g., prednisone or equivalent, e.g., at doses of 1-2 mg / kg / day), hormone replacement therapy, etc.).

[0385] III. Anti-latent TGF-beta 1 antibody A. Exemplary anti-latent TGF-beta 1 antibody Anti-latent TGF-beta-1 antibodies that can be used in the methods and compositions described herein are provided herein. Any suitable anti-latent TGF-beta-1 antibody may be used, including any anti-latent TGF-beta-1 antibody disclosed in International Publication No. 2021 / 039945 or herein.

[0386] In some examples, the anti-latent TGF-beta 1 antibody contains at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 1, 2, and 3 respectively, and / or HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 4, 5, and 6 respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15 respectively, and / or HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18 (c) HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 19, 20 and 21, respectively, and / or HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23 and 24, respectively; or (d) HVR-H1, HVR-H2 and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26 and 27, respectively, and / or HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29 and 30, respectively. In a specific example, the anti-latent TGF-beta 1 antibody comprises at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1, HVR-H2, and HVR-H3, each containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and / or HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

[0387] In some examples, the anti-latent TGF-beta 1 antibody contains the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 1, 2, and 3 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 4, 5, and 6 respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 13, 14, and 15 respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 16, 17, and 18 respectively. VR-L2 and HVR-L3; (c) HVR-H1, HVR-H2 and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20 and 21, respectively, and HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23 and 24, respectively; or (d) HVR-H1, HVR-H2 and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26 and 27, respectively, and HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29 and 30, respectively. In a specific example, the anti-latent TGF-beta 1 antibody contains the following six HVRs: (a) HVR-H1, HVR-H2 and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 1, 2 and 3, respectively, and HVR-L1, HVR-L2 and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 4, 5 and 6, respectively.

[0388] In some examples, anti-latent TGF-beta-1 antibodies include: (a) (i) a heavy chain variable domain (VH) sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 8; (ii) at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 8 A light chain variable domain (VL) sequence having sequence identity of 9%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more; (iii) The VH sequence defined in (i) and the VL sequence defined in (ii); (b) At least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) of the amino acid sequence of (i) Sequence ID No. 31 (ii) A VH sequence having (ii) a sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) with the amino acid sequence of (ii); (iii) A VH sequence defined in (i) and a VL sequence defined in (ii); (c) A sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 8) with the amino acid sequence of (i) 33; (ii) A VH sequence having sequence identity of 7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more; (ii) A VL sequence having sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) with the amino acid sequence of SEQ ID NO: 34; (iii) A VH sequence defined in (i) and a VL sequence defined in (ii);Or (d)(i) a VH sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 35, (ii) a VL sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 36, or (iii) a VH sequence defined in (i) and a VL sequence defined in (ii). ;

[0389] Any of the aforementioned anti-latent TGF-beta 1 antibodies described above may comprise at least one, two, three, four, five, or six HVRs disclosed above.

[0390] In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity includes substitutions (e.g., conservative substitutions), insertions, or deletions relative to a reference sequence, but an anti-latent TGF-beta 1 antibody containing such a sequence retains the ability to bind to latent TGF-beta 1.

[0391] In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity includes substitutions (e.g., conservative substitutions), insertions, or deletions relative to a reference sequence, but an anti-latent TGF-beta 1 antibody containing such a sequence retains the ability to bind to latent TGF-beta 1.

[0392] In some examples, anti-latent TGF-beta 1 antibodies include: (a) the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 8; (b) the VH sequence of SEQ ID NO: 31 and the VL sequence of SEQ ID NO: 32; (c) the VH sequence of SEQ ID NO: 33 and the VL sequence of SEQ ID NO: 34; (d) the VH sequence of SEQ ID NO: 35 and the VL sequence of SEQ ID NO: 36.

[0393] In certain cases, the anti-latent TGF-beta 1 antibody contains the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 8.

[0394] In some cases, anti-latent TGF-beta 1 antibodies are chimeric antibodies.

[0395] In some cases, anti-latent TGF-beta 1 antibodies are humanized antibodies.

[0396] In some cases, anti-latent TGF-beta 1 antibodies are full-length antibodies.

[0397] In some examples, an anti-latent TGF-beta 1 antibody includes: (a) a heavy chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 37, and (b) a heavy chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 8) sequence identity with the amino acid sequence of SEQ ID NO: 38. (b) A light chain containing an amino acid sequence having sequence identity of 4%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more; (b) A light chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) of sequence identity with the amino acid sequence of SEQ ID NO: 39 (c) A heavy chain containing an amino acid sequence having the amino acid sequence of (c) 41, and a light chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of (c) 41, and at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, A heavy chain containing an amino acid sequence having sequence identity of 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more; and a light chain containing an amino acid sequence having sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) with the amino acid sequence of SEQ ID NO: 42;(d) A heavy chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 43 and a light chain containing the amino acid sequence of SEQ ID NO: 44; (e) At least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 8) sequence identity with the amino acid sequence of SEQ ID NO: 45 (f) A heavy chain containing an amino acid sequence having sequence identity of 7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, and a light chain containing the amino acid sequence of SEQ ID NO: 46; (f) At least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) of the amino acid sequence of SEQ ID NO: 47. (g) A heavy chain containing an amino acid sequence having sequence identity with the amino acid sequence of SEQ ID NO: 48 and a light chain containing an amino acid sequence having sequence identity with at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) of the amino acid sequence of SEQ ID NO: 49; (g) A heavy chain containing an amino acid sequence having sequence identity with at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 8 A heavy chain containing an amino acid sequence having sequence identity of 7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more; and a light chain containing an amino acid sequence having sequence identity of at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) with the amino acid sequence of SEQ ID NO: 50;Or (h) a heavy chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 51, and a light chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 52.

[0398] In some examples, an anti-latent TGF-beta 1 antibody may include: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 38; (b) a heavy chain containing the amino acid sequence of SEQ ID NO: 39 and a light chain containing the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain containing the amino acid sequence of SEQ ID NO: 41 and a light chain containing the amino acid sequence of SEQ ID NO: 42; (d) a heavy chain containing the amino acid sequence of SEQ ID NO: 43 and a light chain containing the amino acid sequence of SEQ ID NO: 44; (e) a heavy chain containing the amino acid sequence of SEQ ID NO: 45 and a light chain containing the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain containing the amino acid sequence of SEQ ID NO: 47 and a light chain containing the amino acid sequence of SEQ ID NO: 48; (g) a heavy chain containing the amino acid sequence of SEQ ID NO: 49 and a light chain containing the amino acid sequence of SEQ ID NO: 50; or (h) a heavy chain containing the amino acid sequence of SEQ ID NO: 51 and a light chain containing the amino acid sequence of SEQ ID NO: 52.

[0399] In some cases, anti-latent TGF-beta 1 antibodies contain a modified IgG1 Fc region with reduced effector function compared to the wild-type IgG1 Fc region.

[0400] In some examples, the modified IgG1 Fc region contains a stationary weight (CH) region with one or more of the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, and / or S440E (EU numbering).

[0401] In some examples, the CH region contains the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 9.

[0402] In some examples, the CH region contains the amino acid sequence of SEQ ID NO: 9.

[0403] In some examples, the modified IgG1 Fc region includes a constant light chain (CL) domain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 10.

[0404] In some examples, the modified IgG1 Fc region includes a CL domain containing the amino acid sequence of SEQ ID NO: 10.

[0405] In some examples, an anti-latent TGF-beta 1 antibody comprises a heavy chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 11, and a light chain containing an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity with the amino acid sequence of SEQ ID NO: 12.

[0406] In a specific example, the anti-latent TGF-beta 1 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 11 and a light chain containing the amino acid sequence of SEQ ID NO: 12.

[0407] In some cases, anti-latent TGF-beta 1 antibodies are antibody fragments that bind to latent TGF-beta 1.

[0408] Any of the anti-latent TGF-beta 1 antibodies disclosed herein may contain one or more post-translational modifications. Post-translational modifications include, but are not limited to, pyroglutamylation, which converts glutamine or glutamic acid at the N-terminus of the heavy or light chain to pyroglutamic acid.

[0409] In some cases, an anti-latent TGF-beta 1 antibody is an antibody that competes for binding to latent TGF-beta 1 and / or binds to the same epitope as any of the anti-latent TGF-beta 1 antibodies disclosed herein.

[0410] In further embodiments, anti-latent TGF-beta 1 antibodies disclosed herein or according to any of the above examples may incorporate any of the features, either alone or in combination, as described in Sections 1 to 7 below.

[0411] 1.Antibody binding activity In certain embodiments, the antibodies provided herein have a concentration of 1 micromolar or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (for example, 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 It has a dissociation constant (KD) of M.

[0412] In one embodiment, the antibody binding activity is measured by radiolabeled antigen binding assay (RIA) and expressed by KD. In one embodiment, the RIA is performed using the Fab version of the antibody of interest and its antigen. For example, the solution binding activity of Fab to the antigen is measured in the presence of a titration series of the unlabeled antigen at a minimum concentration. 125 I) Fab is equilibrated with labeled antigen and then measured by capturing the bound antigen with a plate coated with anti-Fab antibody (see, e.g., Chen et al., J.Mol.Biol.293:865-881 (1999)). To establish conditions for the assay, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 micrograms / ml of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), followed by blocking with 2% (w / v) bovine serum albumin in PBS for 2 to 5 hours at room temperature (approximately 23 degrees Celsius (C)). In non-adsorbent plates (Nunc#269620), 100 pM or 26 pM ( 125I) Mix the antigen with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of the anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). Then incubate the Fab of interest overnight, but incubation can be extended for a longer period (e.g., about 65 hours) to ensure equilibrium is reached. Then transfer the mixture to a capture plate for incubation at room temperature (e.g., 1 hour). Remove the solution and wash the plate eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plate is dry, add 150 microliters / well of scintillant (MICROSCINT-20®, Packard) and count the plate for 10 minutes with a TOPCOUNT® gamma counter (Packard). Select concentrations of each Fab that yield less than 20% of maximum binding for use in competitive binding assays.

[0413] In one embodiment, a ligand capture method is used to measure antibody binding activity, for example, using BIACORE® T200 or BIACORE® 4000 (GE Healthcare, Uppsala, Sweden), which relies on surface plasmon resonance spectroscopy as the measurement principle. BIACORE® Control Software is used to operate the device. In one embodiment, an amine coupling kit (GE Healthcare, Uppsala, Sweden) is used according to the manufacturer's instructions to immobilize molecules for ligand capture, such as anti-tagged antibodies, anti-IgG antibodies, protein A, etc., onto a sensor chip (GE Healthcare, Uppsala, Sweden) coated with carboxymethyl dextran. The ligand capture molecules are diluted in a 10 mM sodium acetate solution at an appropriate pH and injected at an appropriate flow rate and injection time. Binding activity is measured using a buffer containing 0.05% polysorbate 20 (Tween®-20) as the measurement buffer at a flow rate of 10-30 microliters / min, preferably at a measurement temperature of 25°C or 37°C. In measurements using an antibody captured by a ligand-capturing molecule as the ligand, the antibody is injected to capture a target amount of antibody, and then serial dilutions of the antigen and / or Fc receptor (analyte) prepared with the measurement buffer are injected.

[0414] In one embodiment, the measurement results are analyzed using BIACORE® Evaluation Software. Kinetic parameters are calculated by simultaneously fitting association and dissociation sensorgrams using a 1:1 coupling model, and the association velocity (k on or k a ), dissociation rate (k off or k dThe binding activity and the equilibrium dissociation constant (KD) can be calculated. If the binding activity is weak, especially if the dissociation is fast and it is difficult to calculate the kinetic parameters, the equilibrium dissociation constant (KD) can be calculated using a steady-state model. As an additional parameter related to binding activity, the "amount of analyte bound per unit amount of ligand" can be calculated by dividing the amount of analyte (resonance unit: RU) bound at a particular concentration by the amount of captured ligand.

[0415] 2. Antibody fragment In certain embodiments, the antibodies provided herein are antibody fragments. Examples of antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, and other fragments described below. For an overview of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For an overview of scFv fragments, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); also see International Publication No. 93 / 16185; and U.S. Patents 5571894 and 5587458. For a discussion of Fab and F(ab')2 fragments containing salvage receptor-binding epitope residues and exhibiting increased in vivo half-lives, see U.S. Patent No. 5,869,046.

[0416] Diabodies are antibody fragments having two antigen-binding sites that may be bivalent or bispecific. See, for example, EP404,097, International Publication No. 1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003), and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0417] A single-domain antibody is an antibody fragment that contains all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (see Domantis, Inc., Waltham, MA, e.g., U.S. Patent No. 6,248,516).

[0418] Antibody fragments can be produced by various techniques, including but not limited to production by recombinant host cells (e.g., Escherichia coli or phages) as described herein, as well as protein digestion of intact antibodies.

[0419] The present invention also relates to antigen-binding molecules that bind to TGF-beta 1, and includes, for example, minibodies (low molecular weight antibodies) and scaffold proteins. In this disclosure, any scaffold protein is acceptable as long as it has a stable three-dimensional structure and is at least a peptide capable of binding to an antigen. Such peptides include, for example, fragments of antibody variable regions, fibronectin, protein A domains, LDL receptor A domains, lipocalin, and other molecules described in Nygren et al. (Current Opinion in Structural Biology, (1997) 7:463-469; Journal of Immunol Methods, (2004) 290:3-28), Binz et al. (Nature Biotech. (2005) 23:1257-1266), and Hosse et al. (Protein Science, (2006) 15:14-27). When referring to such antibodies, for example, "anti-latent TGF-beta 1 antibody" should be replaced with "anti-latent TGF-beta 1 antigen-binding molecule" in the context of this specification.

[0420] 3. Chimeric antibodies and humanized antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and in Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from mouse, rat, hamster, rabbit, or non-human primate, e.g., monkey) and a human constant region. In further examples, a chimeric antibody is a “class-switched” antibody in which the class or subclass is changed from those of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0421] In certain embodiments, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce its immunogenicity to humans while retaining the specificity and binding activity of the parent non-human antibody. Generally, a humanized antibody contains one or more variable domains in which the HVR, e.g., CDR (or part thereof), is derived from a non-human antibody and the FR (or part thereof) is derived from a human antibody sequence. The humanized antibody also optionally contains at least a portion of the human constant region. In some embodiments, some FR residues of the humanized antibody are substituted with corresponding residues derived from a non-human antibody (e.g., the antibody from which the HVR residues are derived) to restore or improve antibody specificity or binding activity, for example.

[0422] Humanized antibodies and their manufacturing methods have been reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further, for example, Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989), U.S. Patents 5,821,337, 7527791, 6982321, and 7087409; Kashmiri et al., Methods This is described in 36:25-34 (2005) (grafting of the specificity determination region (SDR)), Padlan, Mol.Immunol.28:489-498 (1991) ("resurfacing" is described), Dall'Acqua et al., Methods 36:43-60 (2005) ("FR shuffling" is described), as well as in Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br.J.Cancer,83:252-260 (2000) ("inducible selection" approach to FR shuffling is described).

[0423] Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best fit" method (see, e.g., Sims et al. J.Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of specific subgroups of light chain or heavy chain variable regions (see, e.g., Carter et al. Proc.Natl.Acad.Sci.USA, 89:4285 (1992); and Presta et al. J.Immunol., 151:2623 (1993)); human maturation (somatic mutation) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front.Biosci. 13:1619-1633 (2008)); and framework regions derived from FR library screening (see, e.g., Baca et al., J.Biol.Chem. 272:10678-10684 (1997) and Rosok et al. (See al., J. Biol. Chem. 271:22611-22618 (1996))

[0424] 4. Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0425] Human antibodies may be prepared by administering an immunogen to a transgenic animal modified to produce intact human antibodies or intact antibodies with a human variable region in response to an antigenic challenge. Such animals typically contain all or some human immunoglobulin loci that replace endogenous immunoglobulin loci or are extrachromosomal or randomly incorporated into the animal's chromosomes. In such transgenic mice, endogenous immunoglobulin loci are generally inactivated. For an overview of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE® technology; U.S. Patent No. 5,770,429 describing HUMAB® technology; U.S. Patent No. 7,041,870 describing KM MOUSE® technology; and U.S. Patent Application Publication 2007 / 0061900 describing VELOCIMOUSE® technology. Such human variable regions derived from intact antibodies produced by animals may be further modified, for example, by combining them with different human constant regions.

[0426] Human antibodies can also be produced by hybridoma-based methods. Human myeloma cell lines and mouse-human xenomyeloma cell lines for producing human monoclonal antibodies have been described. (See, for example, Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991).) Human antibodies produced via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Further methods include, for example, those described in U.S. Patent No. 7,189,826 (production of monoclonal human IgM antibody from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0427] Human antibodies can also be produced by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0428] 5. Antibodies derived from libraries The antibodies of the present invention can be isolated by screening a combinatorial library for antibodies having desired activity(s). For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies having desired binding properties. Such methods are reviewed, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and further, for example, McCafferty et al., Nature 348:552-554; Clackson et al, Nature 352:624-628 (1991); Marks et al, J.Mol.Biol.222:581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al, J.Mol.Biol.338(2):299-310 (2004); Lee et This is described in al, J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al, J. Immunol. Methods 284(1-2):119-132 (2004).

[0429] In certain phage display methods, the VH and VL gene repertoires can be cloned separately by polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for antigen-binding phages as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). The phages typically present antibody fragments either as single-stranded Fv (scFv) fragments or as Fab fragments. Libraries from immunization sources provide highly binding antibodies to immunogens without the need to construct hybridomas. Alternatively, naive repertoires can be cloned (e.g., from humans) as described by Griffiths et al., EMBO J, 12:725-734 (1993) to provide a single antibody source against a wide range of non-self and autoantigens without any immunization. Finally, naive libraries can be synthetically constructed by cloning an unrearranged V gene segment derived from stem cells and encoding a highly variable CDR3 region using PCR primers containing random sequences to achieve in vitro rearrangement, as described in Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Examples of patent publications describing human antibody phage libraries include: U.S. Patent No. 5,750,373, and U.S. Patent Application Publications 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0430] Antibodies or antibody fragments isolated from a human antibody library are considered human antibodies or human antibody fragments in this specification.

[0431] 6. Multispecific antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, for example, bispecific antibodies. A multispecific antibody is a monoclonal antibody having binding specificity to at least two different sites. In certain embodiments, one binding specificity is to TGF-beta 1 and the other is to any other antigen. In certain embodiments, a bispecific antibody may bind to two different epitopes of TGF-beta 1. Bispecific antibodies may also be used to localize cytotoxic agents to cells expressing TGF-beta 1. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0432] Methods for producing multispecific antibodies include, but are not limited to, the recombinant co-expression of two immunoglobulin heavy-light chain pairs with different specificities (see Milstein and Cuello, Nature 305:537 (1983)), International Publication No. 93 / 08829, and Traunecker et al., EMBO J.10:3655 (1991)), and the "knob-in-hole" technique (see, for example, U.S. Patent No. 5,731,168). Furthermore, multispecific antibodies are produced by manipulating the electrostatic steering effect to create antibody Fc heterodimer molecules (International Publication No. 2009 / 089004A1); crosslinking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980 and Brennan et al., Science, 229:81 (1985)); using leucine zippers to produce bispecific antibodies (see, e.g., Kostelny et al., J.Immunol., 148(5):1547-1553 (1992)); using "diabody" techniques to produce bispecific antibody fragments (see, e.g., Hollinger et al., Proc.Natl.Acad.Sci.USA, 90:6444-6448 (1993)); and using single-chain Fv (scFv) dimers (see, e.g., Gruber et al.) See al., J.Immunol., 152:5368 (1994); and it can also be prepared by the preparation of a triplicate antibody as described, for example, Tutt et al. J.Immunol. 147:60 (1991).

[0433] Modified antibodies having three or more functional antigen-binding sites, including "octopus antibodies," are also included herein (see, for example, U.S. Patent Application Publication 2006 / 0025576A1).

[0434] Furthermore, the antibodies or fragments described herein also include “dual-acting Fabs” or “DAFs” that contain antigen-binding sites that bind to TGF-beta 1 and another different antigen (see, for example, U.S. Patent Application Publication No. 2008 / 0069820).

[0435] 7. Antibody variants In certain embodiments, amino acid sequence variants of antibodies provided herein are intended. For example, it may be desirable to improve the binding activity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from residues in the amino acid sequence of the antibody, and / or insertions into residues in the amino acid sequence of the antibody, and / or substitutions of residues in the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be carried out so as to reach the final construct, insofar as the final construct has the desired characteristics (e.g., antigen binding).

[0436] a) Substitution, insertion, and deletion variants In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest with respect to mutagenesis by substitution include HVR and FR. Conservative substitutions are shown in Table A under the heading “Preferred Substitutions.” More substantial changes are shown in Table A under the heading “Exemplary Substitutions” and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the product can be screened for desired activity, e.g., retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. (Table A) TIFF2026517896000001.tif136128

[0437] Amino acids can be classified as follows according to the common side-chain characteristics: (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basicity: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0438] Non-conservative substitution involves swapping one member of one of these classes with one of another.

[0439] One type of substitution variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized antibody or a human antibody). Generally, the resulting variant(s) selected for further study have altered (e.g., improved) specific biological properties (e.g., increased binding activity, decreased immunogenicity) and / or substantially retained specific biological properties of the parent antibody compared to the parent antibody. Exemplary substitution variants are binding activity matured antibodies, which may be readily prepared, for example, using phage display-based binding activity maturation techniques as described herein. Briefly, one or more HVR residues are mutated, the variant antibody is presented on a phage, and screened for specific biological activity (e.g., binding activity).

[0440] Modifications (e.g., substitutions) may be made, for example, in HVR to improve antibody binding activity. Such modifications may be made in HVR "hot spots," i.e., residues encoded by codons that frequently mutate during somatic cell maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or residues in contact with the antigen, and the binding activity of the resulting variant VH or VL is tested. Binding activity maturation by constructing a secondary library and then re-selecting from it is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of binding activity maturation, diversity is introduced into the variable genes selected for maturation by one of various methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). Next, a secondary library is prepared. This library is then screened to identify antibody variants with the desired binding activity. Another method for introducing diversity involves an HVR-targeted approach, which randomizes several HVR residues (e.g., 4-6 residues at a time). HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3, in particular, are often targeted.

[0441] In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such modifications do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative modifications that do not substantially reduce binding activity (e.g., conservative substitutions provided herein) may be made within an HVR. Such modifications may be, for example, outside the antigen-contact residue within the HVR. In certain embodiments of the variant VH and VL sequences provided above, each HVR is either unmodified or contains one, two, or three or fewer amino acid substitutions.

[0442] A useful method for identifying antibody residues or regions that may be targets for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or target residue groups (e.g., charged residues, e.g., Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the antibody-antigen interaction is affected. Further substitutions may be introduced at the positions of amino acids that exhibit functional sensitivity to the initial substitution. Alternatively, or in addition to this, the crystal structure of the antigen-antibody complex may be analyzed to identify contact points between the antibody and antigen. Such contact residues and adjacent residues may be targeted as candidates for substitution or excluded. Variants may be screened to determine whether they contain the desired properties.

[0443] Amino acid insertions include amino-terminus and / or carboxyl-terminus fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertion variants of antibody molecules include fusion of an enzyme (e.g., in the case of ADEPT) or a polypeptide that increases the plasma half-life of the antibody to the N-terminus or C-terminus of the antibody.

[0444] b) Glycosylated variants In certain embodiments, the antibodies provided herein are modified to increase or decrease the degree to which the antibody is glycosylated. The addition or deletion of glycosylation sites to an antibody can be conveniently achieved by modifying the amino acid sequence so that one or more glycosylation sites are created or removed.

[0445] If the antibody contains an Fc region, the carbohydrate attached to it may be modified. Native antibodies produced by mammalian cells typically contain branched oligosaccharides that are commonly bound to Asn297 of the CH2 domain of the Fc region by an N-bond. See, for example, Wright et al. TIBTECH 15:26-32 (1997). Oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose bound to the GlcNAc of the "stem" of the branched oligosaccharide structure. In some embodiments, modification of the oligosaccharide in the antibody of the present invention may be performed to create antibody variants having specific improved properties.

[0446] In one embodiment, the antibody variant is provided having a glycan structure lacking fucose attached (directly or indirectly) to the Fc region. The amount of fucose in such an antibody may be, for example, 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycans at Asn297 relative to the sum of all glycan structures attached to Asn297 (e.g., complex structures, hybrid structures, and high-mannose structures), as measured by MALDI-TOF mass spectrometry, as described in, for example, International Publication No. 2008 / 077546. Asn297 refers to the asparagine residue located approximately at position 297 (EU numbering of Fc region residues) within the Fc region, although Asn297 may also be located + / - 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to slight variations in the antibody sequence. Such fucosylated variants may possess improved ADCC function. See, for example, U.S. Patent Application Publication No. 2003 / 0157108 (Presta, L.); and No. 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include U.S. Patent Application Publication No. 2003 / 0157108; International Publication No. 2000 / 61739; International Publication No. 2001 / 29246; U.S. Patent Application Publication No. 2003 / 0115614; International Publication No. 2002 / 0164328; International Publication No. 2004 / 0093621; International Publication No. 2004 / Examples include publications No. 0132140; No. 2004 / 0110704; No. 2004 / 0110282; No. 2004 / 0109865; International Publication No. 2003 / 085119; No. 2003 / 084570; No. 2005 / 035586; No. 2005 / 035778; No. 2005 / 053742; No. 2002 / 031140; Okazaki et al. J.Mol.Biol.336:1239-1249(2004); Yamane-Ohnuki et al. Biotech.Bioeng.87:614(2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells with protein fucosylation deletion (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application Publication No. 2003 / 0157108A1, Presta, L; and International Publication No. 2004 / 056312A1, Adams et al., particularly in Example 11), as well as knockout cell lines such as those containing the alpha-1,6-fucosyltransferase gene, FUT8, and knockout CHO cells (e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al.). See also al., Biotechnol. Bioeng, 94(4):680-688(2006); and International Publication No. 2003 / 085107.

[0447] For example, antibody variants having a bifid oligosaccharide are provided, in which a bifid oligosaccharide attached to the Fc region of the antibody is bifid by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in International Publication 2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and U.S. Patent Application Publication 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in International Publication No. 1997 / 30087 (Patel et al.); International Publication No. 1998 / 58964 (Raju, S.); and International Publication No. 1999 / 22764 (Raju, S.).

[0448] c) Fc region variant In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibodies presented herein to create an Fc region variant. The Fc region variant may include a human Fc region sequence (e.g., human IgG1, IgG2, IgG3, or IgG4 Fc region) containing amino acid modifications (e.g., substitutions) at one or more amino acid positions. In other embodiments, the human Fc variant may include a chimeric human Fc region sequence (e.g., human IgG1 / 4 or human IgG2 / 4 Fc region), or a chimeric human Fc region sequence further containing amino acid modifications (e.g., substitutions) at one or more amino acid positions.

[0449] In certain embodiments, the present invention aims to provide antibody variants that, by possessing some, but not all, effector functions, are desirable candidates for applications where the half-life of the antibody in vivo is important, but certain effector functions (such as complement and ADCC) are unnecessary or detrimental. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / depletion of CDC and / or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to confirm that the antibody lacks Fc gamma-R binding (and therefore is likely to lack ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only Fc gamma-RIII, while monocytes express Fc gamma-RI, Fc gamma-RII, and Fc gamma-RIII. FcR expression on hematopoietic cells is summarized in Table 3, p. 464, Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating the ADCC activity of the molecule of interest are described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); and U.S. Patent No. 5,821,337 (see, e.g., Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (e.g., flow cytometry (CellTechnology, Inc. Mountain View, ACT1® non-radioactive cytotoxicity assay for CA, and CytoTox® 96 non-radioactive cytotoxicity assay (Promega, Madison, WI))). Effector cells useful for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells.Alternatively or additionally, the ADCC activity of the molecule of interest may be evaluated in vivo in animal models, such as those disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay may also be performed to confirm that the antibody is unable to bind to C1q and therefore lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in International Publication Nos. 2006 / 029879 and 2005 / 100402. To evaluate complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J.Immunol.Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life can also be determined using methods known in the art (see, for example, Petkova, S B et al., Int'l.Immunol. 18(12):1759-1769 (2006)).

[0450] Antibodies with reduced effector function include those having one or more substitutions at residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (U.S. Patent No. 6,737,056). Such Fc mutants include the so-called "DANA" Fc mutant, which has substitutions at residues 265 and 297 of alanine, and Fc mutants having substitutions at two or more amino acid positions 265, 269, 270, 297, and 327 (U.S. Patent No. 7,332,581).

[0451] Specific antibody variants exhibiting increased or decreased binding to FcR are described. (See, for example, U.S. Patent No. 6,737,056; International Publication No. 2004 / 056312; and Shields et al., J. Biol. Chem. 9(2):6591-6604(2001).)

[0452] In certain embodiments, the antibody variant includes an Fc region having one or more amino acid substitutions that improve ADCC, for example, substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region.

[0453] In some embodiments, modifications are made to the Fc region that alter (i.e., increase or decrease) C1q binding and / or complement-dependent cytotoxicity (CDC), as described, for example, in U.S. Patent No. 6,194,551, International Publication No. 99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0454] Antibodies with increased half-life and increased binding to the neonatal Fc receptor (FcRn), which plays a role in the transfer of maternal IgG to the fetus (Guyer et al., J.Immunol.117:587 (1976) and Kim et al., J.Immunol.24:249 (1994)) are described in U.S. Patent Application Publication No. 2005 / 0014934 (Hinton et al.). These antibodies contain an Fc region having one or more substitutions that increase the binding of the Fc region to FcRn. Such Fc variants include substitutions in one or more of the Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, for example, those having a substitution in Fc region residue 434 (U.S. Patent No. 7,371,826).

[0455] For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988), U.S. Patent Nos. 5,648,260, 5,624,821, and International Publication No. 94 / 29351.

[0456] d) Cysteine-modified antibody variants In certain embodiments, it may be desirable to create cysteine-modified antibodies, e.g., “thioMAbs”, in which one or more residues of the antibody are substituted with cysteine ​​residues. In certain embodiments, the substituted residues are located in an accessible site of the antibody. By substituting these residues with cysteine, a reactive thiol group is positioned in an accessible site of the antibody, which can be used to create an immunoconjugate by conjugating the antibody to other parts, such as a drug moiety or a linker-drug moiety, as further described herein. In certain embodiments, one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain, A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of the heavy chain Fc region. Cysteine-modified antibodies can be produced, for example, as described in U.S. Patent No. 7521541.

[0457] e) Antibody derivative In certain embodiments, the antibodies provided herein may be further modified to include further non-proteinoid moieties known and readily available in the art. Suitable sites for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous in production due to its stability in water. The polymers may have any molecular weight and may be branched or unbranched. The number of polymers attached to an antibody varies, and if multiple polymers are attached, they may be the same molecule or different molecules. Generally, the number and / or type of polymers used for derivatization is not limiting, but can be determined based on considerations such as the specific properties or functions of the antibody being improved, and whether the antibody derivative will be used for therapeutic purposes under defined conditions.

[0458] In another embodiment, an antibody-nonprotein conjugate is provided that can be selectively heated by exposure to radiation. In one embodiment, the nonprotein portion is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation may be of any wavelength and may not harm normal cells, but may include, but is not limited to, wavelengths that heat the nonprotein portion to a temperature that kills cells proximal to the antibody nonprotein portion.

[0459] B. Recombination methods and compositions The antibody may be produced using, for example, the recombinant method and composition described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an anti-latent TGF-beta 1 antibody as described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL of the antibody and / or the VH of the antibody (e.g., the light chain and / or heavy chain of the antibody). In a further embodiment, one or more vectors (e.g., an expression vector) comprising such nucleic acid are provided. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, the host cell comprises (e.g., transformed with): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a nucleic acid encoding an amino acid sequence comprising the VH of the antibody, or (2) a vector comprising a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is a eukaryotic cell, e.g., a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., a Y0, NS0, Sp2 / 0 cell). In one embodiment, a method is provided for producing an anti-latent TGF-beta 1 antibody, which comprises culturing host cells containing nucleic acids encoding the antibody under conditions suitable for antibody expression, and optionally recovering the antibody from the host cells (or host cell culture medium), as provided above.

[0460] For recombinant production of anti-latent TGF-beta 1 antibodies, for example, nucleic acids encoding the antibody, such as those described above, are isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids may be readily isolated and sequenced using conventional procedures (for example, by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the antibody).

[0461] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly when glycosylation and effector function are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patents 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKCLo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in Escherichia coli (E. coli).) After expression, the antibodies of the present invention may be isolated from the bacterial cell paste in a soluble fraction and further purified.

[0462] In addition to prokaryotes, eukaryotes such as filamentous fungi and yeasts are suitable as cloning or expression hosts for antibody-encoding vectors, including strains of fungi and yeast with "humanized" glycosylation pathways, resulting in the production of antibodies with partially or completely human glycosylation patterns. See Gerngross, Nat. Biotech. 22:1409-1414 (2004) and Li et al., Nat. Biotech. 24:210-215 (2006).

[0463] Furthermore, suitable host cells for expressing glycosylated antibodies are derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Many baculovirus strains have been identified, and these may be used in combination with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0464] Plant cell cultures can also be used as hosts. For example, see U.S. Patents 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe PLANTIBODIES® technology for antibody production in transgenic plants).

[0465] Vertebrate cells may also be used as hosts. For example, mammalian cell lines adapted to grow in suspensions may be useful. Other examples of useful mammalian host cell lines include the monkey kidney CV1 cell line transformed with SV40 (COS-7); human fetal kidney lineage (e.g., 293 cells or 293 cells as described in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells as described in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical tumor cells (HELA); canine kidney cells (MDCK); buffalo rat hepatocytes (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor cells (MMT 060562); e.g., Mather et al., Annals These include TRI cells; MRC5 cells; and FS4 cells, as described in NYAcad.Sci.383:44-68(1982). Other useful mammalian host cell lines include DHFR - This includes Chinese hamster ovary (CHO) cells, including CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)), as well as myeloma cell lines, such as Y0, NS0, and Sp2 / 0. For an overview of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKCLo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0466] IV. Evaluation of PD-L1 expression PD-L1 expression may be evaluated in subjects treated according to any of the methods and compositions for use described herein or known in the art. Methods and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., tumor sample) obtained from the subject. In other examples, the expression level of PD-L1 in a biological sample (e.g., tumor sample) obtained from the subject is determined before or after the initiation of treatment. PD-L1 expression may be determined using any suitable approach. For example, PD-L1 expression may be determined as described in U.S. Patent Application No. 15 / 787,988 or U.S. Patent No. 11,535,671. Any suitable tumor sample, such as formalin-fixed paraffin-embedded (FFPE) tumor sample, stored tumor sample, fresh tumor sample, or frozen tumor sample may be used.

[0467] For example, PD-L1 expression can be determined as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable level of PD-L1, and / or as the percentage of tumor cells in a tumor sample expressing a detectable level of PD-L1, with respect to the percentage of tumor-infiltrating immune cells in the tumor sample expressing a detectable level of PD-L1. In any of the above examples, it should be understood that the percentage of tumor sample composed of tumor-infiltrating immune cells may be with respect to the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject (e.g., as assessed by IHC using an anti-PD-L1 antibody (e.g., SP142 antibody)). For example, any suitable anti-PD-L1 antibody may be used, including SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11. In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263.

[0468] In some cases, tumor samples obtained from subjects have detectable PD-L1 expression levels in less than 1% of tumor cells, more than 1% of tumor cells, 1% to less than 5% of tumor cells, more than 5% of tumor cells, 5% to less than 50% of tumor cells, or more than 50% of tumor cells.

[0469] In some cases, tumor samples obtained from subjects have detectable PD-L1 expression levels in tumor-infiltrating immune cells that constitute less than 1% of the tumor sample, more than 1% of the tumor sample, 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

[0470] In some cases, tumor specimens may be scored for PD-L1 positivity in tumor-infiltrating immune cells and / or tumor cells, according to the diagnostic assessment criteria shown in Table B and / or Table C, respectively. (Table B) Tumor-infiltrating immune cell (IC) IHC diagnostic criteria TIFF2026517896000002.tif91128 (Table C) Tumor Cell (TC) IHC Diagnostic Criteria TIFF2026517896000003.tif54128

[0471] V.PD-1 axial coupling antagonist In some cases, an anti-latent TGF-beta 1 antibody is administered in combination with a PD-1 axis-conjugated antagonist. PD-1 axis-conjugated antagonists may include PD-L1-conjugated antagonists, PD-1-conjugated antagonists, and PD-L2-conjugated antagonists. Any suitable PD-1 axis-conjugated antagonist may be used.

[0472] A. PD-L1 binding antagonist In some cases, PD-L1-binding antagonists inhibit the binding of PD-L1 to one or more of its ligand-binding partners. In other cases, PD-L1-binding antagonists inhibit the binding of PD-L1 to PD-1. In yet another case, PD-L1-binding antagonists inhibit the binding of PD-L1 to B7-1. In some cases, PD-L1-binding antagonists inhibit the binding of PD-L1 to both PD-1 and B7-1. PD-L1-binding antagonists may be, but are not limited to, antibodies, their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, or small molecules. In some cases, PD-L1-binding antagonists are small molecules that inhibit PD-L1 (e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041). In some cases, the PD-L1-binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some cases, the PD-L1-binding antagonist is CA-170 (also known as AUPM-170). In some cases, the PD-L1-binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some cases, the small molecule is a compound described in International Publication No. 2015 / 033301 and / or No. 2015 / 033299.

[0473] In some cases, the PD-L1 conjugated antagonist is an anti-PD-L1 antibody. Various anti-PD-L1 antibodies are intended and described herein. In any case herein, an isolated anti-PD-L1 antibody can conjugate to human PD-L1, e.g., human PD-L1 as shown in UniProtKB / Swiss-Prot accession number Q9NZQ7-1, or a variant thereof. In some cases, the anti-PD-L1 antibody can inhibit the binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1. In some cases, the anti-PD-L1 antibody is a monoclonal antibody. In some cases, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab fragment, Fab'-SH fragment, Fv fragment, scFv fragment, and (Fab')2 fragment. In some cases, the anti-PD-L1 antibody is a humanized antibody. In some cases, the anti-PD-L1 antibody is a human antibody. Examples of anti-PD-L1 antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, emvafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosivelimab, rhodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. Examples of anti-PD-L1 antibodies useful in the methods of the present invention and methods for producing them are described in International Patent Application Publication No. 2010 / 077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

[0474] In some cases, the anti-PD-L1 antibody is atezolizumab.

[0475] In some cases, the anti-PD-L1 antibody is avelumab (CAS registry number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

[0476] In some cases, the anti-PD-L1 antibody is durvalumab (CAS Registry No.: 1428935-60-7). Also known as MEDI4736, durvalumab is an Fc-optimized human monoclonal IgG1 kappa anti-PD-L1 antibody (MedImmune, AstraZeneca) described in International Publication No. 2011 / 066389 and U.S. Patent Application Publication No. 2013 / 034559.

[0477] In some cases, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007 / 005874.

[0478] In some cases, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

[0479] In some cases, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody.

[0480] In some cases, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single-domain antibody (dAB) generated from a camel phage display library.

[0481] In some cases, anti-PD-L1 antibodies consist of cleavable moieties or linkers that, when cleaved (e.g., by proteases in the tumor microenvironment), activate the antibody-antigen-binding domain, enabling it to bind to the antigen, for example, by removing an unbinding stereomolecule. In some cases, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0482] In some cases, the anti-PD-L1 antibody comprises six HVR sequences (e.g., three heavy-chain HVRs and three light-chain HVRs), and / or heavy-chain variable domains and light-chain variable domains from the anti-PD-L1 antibody described in U.S. Patent Application Publication 20160108123, International Publication 2016 / 000619, International Publication 2012 / 145493, U.S. Patent No. 9,205,148, International Publication 2013 / 181634, or International Publication 2016 / 061142.

[0483] In more specific embodiments, anti-PD-L1 antibodies have reduced or minimal effector function. In more specific embodiments, minimal effector function results from "effector-less Fc mutations" or aglycosylation mutations. In further cases, effector-less Fc mutations are N297A or D265A / N297A substitutions within the constant region. In further cases, effector-less Fc mutations are N297A substitutions within the constant region. In some cases, isolated anti-PD-L1 antibodies are aglycosylated. Antibody glycosylation is typically either N-linked or O-linked. N-linked refers to binding to the side chain of the asparagine residue in the carbohydrate moiety. The asparagine-X-serine and asparagine-X-threonine (where X is any amino acid other than proline) in the tripeptide sequence are recognition sequences for enzymatic binding of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the binding of one of the sugars, N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Removal of glycosylation sites from antibodies is conveniently achieved by modifying the amino acid sequence so that one of the aforementioned tripeptide sequences is removed (for N-linked glycosylation sites). This modification can be carried out by substituting an asparagine, serine, or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

[0484] In a further embodiment, the anti-PD-L1 antibody may incorporate any of the features individually or in combination, as described in Sections 1-7 of Section III(A) above.

[0485] B. PD-1 binding antagonist In some cases, a PD-1 axis-binding antagonist is a PD-1-binding antagonist. For example, in some cases, a PD-1-binding antagonist inhibits the binding of PD-1 to one or more of its ligand-binding partners. In some cases, a PD-1-binding antagonist inhibits the binding of PD-1 to PD-L1. In other cases, a PD-1-binding antagonist inhibits the binding of PD-1 to PD-L2. In yet another case, a PD-1-binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. A PD-1-binding antagonist may be, but is not limited to, an antibody, its antigen-binding fragment, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some cases, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin containing an extracellular or PD-1 binding moiety of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence)). For example, in some cases, the PD-1 binding antagonist is an Fc fusion protein. In some cases, the PD-1 binding antagonist is AMP-224. Also known as B7-DCIg, AMP-224 is a PD-L2-Fc fusion soluble receptor described in International Publication No. 2010 / 027827 and International Publication No. 2011 / 066342. In some cases, the PD-1 binding antagonist is a peptide or small molecule compound. In some cases, the PD-1 binding antagonist is AUNP-12 (Pierre Fabre / Aurigene). See, for example, International Publications 2012 / 168944, 2015 / 036927, 2015 / 044900, 2015 / 033303, 2013 / 144704, 2013 / 132317, and 2011 / 161699. In some cases, PD-1-binding antagonists are small molecules that inhibit PD-1.

[0486] In some cases, the PD-1 conjugated antagonist is an anti-PD-1 antibody. Various anti-PD-1 antibodies may be used in the methods and uses disclosed herein. In any of the examples herein, the PD-1 antibody can conjugate to human PD-1 or a variant thereof. In some cases, the anti-PD-1 antibody is a monoclonal antibody. In some cases, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some cases, the anti-PD-1 antibody is a humanized antibody. In other cases, the anti-PD-1 antibody is a human antibody. Examples of anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (semiprimab), BGB-108, prorugolimab, camrelizumab, cintilimab, tislerizumab, tripalimab, dostarimab, retifanlimab, sasanlimab, penprimab, CS1003, HLX10, SCT-I10A, zinbererimab, valstilimab, genolimusumab, and BI. Examples include 754091, cetrerimab, YBL-006, BAT1306, HX008, buzigalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21.

[0487] In some cases, the anti-PD-1 antibody is nivolumab (CAS registry number: 946414-94-4). Nivolumab (Bristol-Myers Squibb / Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in International Publication No. 2006 / 121168.

[0488] In some cases, the anti-PD-1 antibody is pembrolizumab (CAS registry number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in International Publication No. 2009 / 114335.

[0489] In some cases, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

[0490] In some cases, the anti-PD-1 antibody is PDR001 (CAS registry number 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

[0491] In some cases, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

[0492] In some cases, the anti-PD-1 antibody is BGB-108 (BeiGene).

[0493] In some cases, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0494] In some cases, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

[0495] In some cases, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

[0496] In some cases, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

[0497] In some cases, the anti-PD-1 antibody is PF-06801591 (Pfizer).

[0498] In some cases, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro / AnaptysBio).

[0499] In some cases, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

[0500] In some cases, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking the binding of PD-L1 to PD-1.

[0501] In some cases, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

[0502] In some cases, anti-PD-1 antibodies are listed in International Publication Nos. 2015 / 112800, 2015 / 112805, 2015 / 112900, U.S. Patent Application Publication No. 20150210769, 2016 / 089873, 2015 / 035606, 2015 / 085847, 2014 / 206107, 2012 / 145493, and U.S. Patent No. 9,205. It comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or heavy chain variable domains and light chain variable domains derived from anti-PD-1 antibodies described in International Publication No. 148, International Publication No. 2015 / 119930, International Publication No. 2015 / 119923, International Publication No. 2016 / 032927, International Publication No. 2014 / 179664, International Publication No. 2016 / 106160, and International Publication No. 2014 / 194302, derived from anti-PD-1 antibodies.

[0503] In more specific embodiments, the anti-PD-1 antibody has reduced or minimal effector function. In even more specific embodiments, minimal effector function results from an "effector-less Fc mutation" or an aglycosylation mutation. In further cases, the effector-less Fc mutation is an N297A or D265A / N297A substitution within the constant region. In some cases, the isolated anti-PD-1 antibody is aglycosylated.

[0504] In a further embodiment, the anti-PD-1 antibody may incorporate any of the features individually or in combination, as described in Sections 1-7 of Section III(A) above.

[0505] C.PD-L2 binding antagonist In some cases, the PD-1 axis-binding antagonist is a PD-L2-binding antagonist. In some cases, the PD-L2-binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand-binding partner. In specific embodiments, the PD-L2-binding ligand partner is PD-1. The PD-L2-binding antagonist may be, but is not limited to, an antibody, its antigen-binding fragment, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.

[0506] In some cases, the PD-L2-binding antagonist is an anti-PD-L2 antibody. In any of the cases described herein, the anti-PD-L2 antibody can bind to human PD-L2 or a variant thereof. In some cases, the anti-PD-L2 antibody is a monoclonal antibody. In some cases, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some cases, the anti-PD-L2 antibody is a humanized antibody. In other cases, the anti-PD-L2 antibody is a human antibody. In further specific embodiments, the anti-PD-L2 antibody has reduced or minimal effector function. In further specific embodiments, minimal effector function results from an "effectorless Fc mutation" or an aglycosylation mutation. In further cases, the effectorless Fc mutation is an N297A or D265A / N297A substitution within the constant region. In some cases, isolated anti-PD-L2 antibodies are aglycosylated.

[0507] In a further embodiment, the anti-PD-L2 antibody may incorporate any of the features individually or in combination, as described in Sections 1-7 of Section III(A) above.

[0508] VI. Chemotherapy agents and chemotherapy Methods for treating cancer in a subject are provided herein, comprising administering an anticancer therapy comprising an anti-latent TGF-beta 1 antibody and one or more chemotherapeutic agents to the subject. Related compositions for use (e.g., pharmaceutical compositions), kits and manufactured articles are also provided. Any of the methods, compositions for use, kits or manufactured articles described herein may contain or be associated with any of the agents described herein.

[0509] Any suitable chemotherapeutic agent, including any chemotherapeutic agent or combination thereof disclosed herein, may be used. In some examples, one or more chemotherapeutic agents include platinum-based chemotherapeutic agents, antimetabolites, cytotoxic agents, growth inhibitors, taxanes, folic acid analogs, or any combination thereof.

[0510] In some cases, chemotherapy agents or combinations of chemotherapy agents may constitute standard care (SOC) therapy for cancer.

[0511] Any suitable platinum-based chemotherapeutic agent may be used. Exemplary platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, and satraplatin. In some examples, the platinum-based chemotherapeutic agent includes oxaliplatin, cisplatin, or carboplatin. In some examples, the platinum-based chemotherapeutic agent includes oxaliplatin. In some examples, oxaliplatin is administered to the subject in a dosing regimen comprising one or more dosing cycles. In some examples, one or more dosing cycles comprise 21-day dosing cycles. In some examples, oxaliplatin is administered to the subject on day 1 of each 21-day dosing cycle. In some examples, oxaliplatin is administered at 130 mg / m². 2 It is administered to the subject at the specified dose. In some cases, oxaliplatin is administered intravenously to the subject.

[0512] Any suitable antimetabolite may be used. In some examples, the antimetabolite may include capecitabine, gemcitabine, 5-fluorouracil, or tegafur.

[0513] In some cases, the antimetabolite includes capecitabine. In some cases, capecitabine is administered to the subject in a drug regimen that includes one or more drug cycles. In some cases, one or more drug cycles include 21-day drug cycles. In some cases, capecitabine is administered to the subject on days 1 through 14 of each 21-day drug cycle. In some cases, capecitabine is administered to the subject at a dose of 1000 mg / m². 2 It is administered twice daily at this dose. In some cases, capecitabine is administered orally to the subject.

[0514] In other examples, the antimetabolite includes gemcitabine. In some examples, gemcitabine is administered to the subject in a drug regimen that includes one or more drug cycles. In some examples, one or more drug cycles include a 28-day drug cycle. In some examples, gemcitabine is administered to the subject on day 1, day 8, and day 15 of each 28-day drug cycle. In some examples, gemcitabine is administered to the subject at a dose of 1000 mg / m². 2 It is administered twice daily at this dose. In some cases, gemcitabine is administered intravenously to the patient.

[0515] In some cases, the antimetabolites include tegafur.

[0516] In some cases, the antimetabolite includes S-1 (tegafur / gimeracil / oteracil potassium). In some cases, S-1 is administered to the subject in a drug regimen that includes one or more drug cycles. In some cases, one or more drug cycles include 21-day drug cycles. In some cases, S-1 is administered to the subject on days 1-14 of each 21-day drug cycle. In some cases, S-1 is administered to the subject at a dose of 40 mg / m². 2 It is administered twice daily at this dose. In some cases, S-1 is administered orally to the subject.

[0517] Any suitable taxane may be used. Exemplary taxanes include, but are not limited to, paclitaxel (i.e., TAXOL®, CAS#33069-62-4), docetaxel (i.e., TAXOTERE®, CAS#114977-28-5), larotaxel, cabazitaxel, mirataxel, tesetaxel, and / or orataxel. In some examples, the taxane includes nab-paclitaxel or paclitaxel.

[0518] In some cases, the taxane includes nab-paclitaxel. In some cases, nab-paclitaxel is administered to the subject in a drug regimen that includes one or more drug cycles. In some cases, one or more drug cycles include 28-day drug cycles. In some cases, nab-paclitaxel is administered to the subject on days 1, 8, and 15 of each 28-day drug cycle. In some cases, nab-paclitaxel is administered at 125 mg / m². 2 It is administered to the subject at the specified dose. In some cases, nab-paclitaxel is administered intravenously to the subject.

[0519] Any suitable folate analog may be used. Exemplary, non-limiting folate analogs include leucovorin and levoleucovorin. In some examples, the folate analog includes leucovorin.

[0520] VII. Pharmaceutical Compositions and Formulations Pharmaceutical compositions and formulations comprising an anti-latent TGF-beta 1 antibody and optionally a pharmaceutically acceptable carrier are also provided herein. The disclosure also provides pharmaceutical compositions and formulations comprising one or more additional therapeutic agents, e.g., checkpoint inhibitors (e.g., PD-1 axis antagonists (e.g., anti-PD-L1 antibodies (e.g., atezolizumab) or anti-PD-1 antibodies (e.g., nivolumab))) and / or one or more chemotherapeutic agents and optionally a pharmaceutically acceptable carrier.

[0521] The pharmaceutical compositions and formulations described herein may be prepared, for example, in the form of lyophilized formulations or aqueous solutions, by mixing an active ingredient having a desired purity (e.g., a PD-1 axially coupled antagonist) with one or more pharmaceutically acceptable carriers (see, for example, Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)).

[0522] An exemplary atezolizumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20, and sucrose, and has a pH of 5.8. For example, atezolizumab may be supplied in a 20 mL vial containing 1200 mg of atezolizumab formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821.6 mg), with a pH of 5.8. In another example, atezolizumab may be supplied in a 14 mL vial containing 840 mg of atezolizumab formulated in glacial acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg), with a pH of 5.8.

[0523] VIII. Manufactured articles or kits In another embodiment, manufactured articles or kits comprising an anti-latent TGF-beta-1 antibody are provided herein. In some cases, the manufactured article or kit further includes a package insert containing instructions for using the anti-latent TGF-beta-1 antibody to treat or delay the progression of cancer in a subject. In some cases, the manufactured article or kit further includes a package insert containing instructions for using the anti-latent TGF-beta-1 antibody in combination with one or more additional therapeutic agents (e.g., checkpoint inhibitors (e.g., PD-1 axis antagonists (e.g., anti-PD-L1 antibodies (e.g., atezolizumab) or anti-PD-1 antibodies (e.g., nivolumab))) and / or one or more chemotherapeutic agents) to treat or delay the progression of cancer in a subject. Any of the anti-latent TGF-beta-1 antibodies and additional therapeutic agents (e.g., checkpoint inhibitors, e.g., PD-1 axis-conjugated antagonists and / or one or more chemotherapeutic agents) described herein may be included in the manufactured article or kit.

[0524] In some cases, the anti-latent TGF-beta-1 antibody and one or more additional therapeutic agents (e.g., checkpoint inhibitors (e.g., PD-1 axis antagonists (e.g., anti-PD-L1 antibodies (e.g., atezolizumab) or anti-PD-1 antibodies (e.g., nivolumab))) and / or one or more chemotherapeutic agents) are contained in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and ...

Claims

1. A method for treating a subject having locally advanced, recurrent, or metastatic solid tumor, the method comprising administering an anticancer therapy containing an anti-latent transforming growth factor (TGF)-beta-1 antibody to the subject at a dose of 1800 mg, wherein the anti-latent TGF-beta-1 antibody comprises the following six hypervariable regions (HVRs): (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Methods that include...

2. The method according to claim 1, wherein the anti-latent TGF-beta 1 antibody is administered to the subject in a drug regimen comprising one or more 21-day drug cycles.

3. The method according to claim 2, wherein the anti-latent TGF-beta 1 antibody is administered to the subject on the first day of each 21-day drug administration cycle.

4. A method for treating a subject having locally advanced, recurrent, or metastatic solid tumor, the method comprising administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W), wherein the anti-latent TGF-beta-1 antibody is one of the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Methods that include...

5. A method for treating a subject having locally advanced, recurrent, or metastatic solid tumor, the method comprising administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg, wherein the anti-latent TGF-beta-1 antibody is found to be one of the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Methods that include...

6. The method according to claim 5, wherein the anti-latent TGF-beta 1 antibody is administered to the subject in a drug regimen comprising one or more 28-day drug cycles.

7. The method according to claim 6, wherein the anti-latent TGF-beta 1 antibody is administered to the subject on day 1 and day 15 of each 28-day drug administration cycle.

8. A method for treating a subject having locally advanced, recurrent, or metastatic solid tumors, the method comprising administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W), wherein the anti-latent TGF-beta-1 antibody is one of the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Methods that include...

9. The method according to any one of claims 1 to 8, wherein the anti-latent TGF-beta 1 antibody is administered intravenously to the subject.

10. The method according to claim 9, wherein the anti-latent TGF-beta 1 antibody is administered intravenously to the subject by injection.

11. The method according to any one of claims 1 to 10, wherein the tumor sample derived from the subject is determined to have a detectable level of PD-L1 expression.

12. The method according to any one of claims 1 to 11, wherein the age of the subject is 18 years or older.

13. The method according to any one of claims 1 to 12, wherein the anticancer therapy is the first-line therapy.

14. The method according to any one of claims 1 to 12, wherein the anticancer therapy is a second-line or third-line therapy.

15. The method according to any one of claims 1 to 14, wherein the subject has not been previously treated with a checkpoint inhibitor.

16. The method according to any one of claims 1 to 15, wherein the solid tumor is metastatic.

17. The method according to any one of claims 1 to 16, wherein the locally advanced, recurrent, or metastatic solid tumor is non-small cell lung cancer (NSCLC), gastric cancer, pancreatic ductal adenocarcinoma (PDAC), urothelial carcinoma (UC), gastrointestinal stromal tumor (GIST), skin cancer, colorectal cancer, ovarian (OV) cancer, kidney cancer, or gallbladder cancer.

18. The method according to claim 17, wherein the locally progressive, recurrent, or metastatic solid tumor is NSCLC.

19. The method according to claim 18, wherein the NSCLC is histologically or cytologically confirmed metastatic non-squamous NSCLC or metastatic squamous NSCLC.

20. The method according to claim 18 or 19, wherein the subject had disease progression during or after treatment of metastatic or locally advanced, unresectable NSCLC comprising a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist, which are given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order.

21. The method according to claim 20, wherein the subject has previously received combination therapy including a platinum-containing chemotherapy regimen and a PD-1 axis-binding antagonist.

22. The method according to claim 20, wherein the subject has previously received a platinum-containing chemotherapy regimen and a PD-1 axis-binding antagonist as separate regimens.

23. The method according to any one of claims 20 to 22, wherein the subject had disease progression or recurrence within six months of curative treatment for locally progressive NSCLC.

24. The method according to any one of claims 18 to 23, wherein the tumor sample derived from the subject is determined to have a detectable level of PD-L1 expression.

25. The method according to claim 17, wherein the locally advanced, recurrent, or metastatic solid tumor is gastric cancer.

26. The method according to claim 25, wherein the subject has an unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be an adenocarcinoma.

27. The method according to claim 25 or 26, wherein the gastric cancer includes esophagogastric junction cancer.

28. The method according to any one of claims 25 to 27, wherein the gastric cancer is HER2-negative gastric cancer.

29. The method according to any one of claims 25 to 28, wherein the subject has not been previously treated for gastric cancer and / or has not been previously treated with a checkpoint inhibitor.

30. The method according to claim 17, wherein the locally progressive, recurrent, or metastatic solid tumor is a PDAC.

31. The method according to claim 30, wherein the subject has histologically or cytologically confirmed metastatic PDAC.

32. The method according to claim 30 or 31, wherein the subject has not been previously treated with the PDAC and / or the subject has not been previously treated with a checkpoint inhibitor.

33. The method according to claim 17, wherein the locally progressive, recurrent, or metastatic solid tumor is UC.

34. The method according to claim 33, wherein the subject has histologically demonstrated locally progressive (T4b, any N; or any T, N2-N3) UC or metastatic UC (M1, stage 4).

35. The method according to claim 33 or 34, wherein the subject has not been previously treated for UC.

36. The method according to any one of claims 33 to 35, wherein the subject is unsuitable for cisplatin-containing chemotherapy.

37. The above-mentioned subjects meet the following criteria: (i) Renal impairment as assessed by direct measurement or by calculation from serum or plasma creatinine, in terms of glomerular filtration rate (GFR) of 30 mL / min or more but less than 60 mL / min; (ii) Hearing loss of 25 dB at two adjacent frequencies as measured by a hearing test; (iii) Grade 2 peripheral neuropathy; or (iv) East Coast Cancer Group (ECOG) Performance Status 2 The method according to claim 36, which is unsuitable for cisplatin-containing chemotherapy as defined by any one of the following:

38. The method according to any one of claims 33 to 35, wherein the subject has previously received at least one platinum-containing chemotherapy regimen.

39. The method according to claim 38, wherein the subject had disease progression during or after treatment with at least one platinum-containing chemotherapy regimen.

40. The method according to claim 39, wherein the at least one platinum-containing chemotherapy regimen comprises (i) gemcitabine and cisplatin or carboplatin, or (ii) methotrexate, vinblastine, doxorubicin and cisplatin.

41. The method according to claim 38, wherein the subject has received prior adjuvant or neoadjuvant chemotherapy and has progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.

42. The method according to claim 38, wherein the subject received one cycle of platinum-containing chemotherapy regimen but was discontinued due to grade 4 hematological toxicity or grade 3-4 non-hematological toxicity.

43. The method according to any one of claims 33 to 42, wherein the subject has received two or fewer prior treatment lines for the locally progressive ulcerative colitis or metastatic ulcerative colitis.

44. The method according to any one of claims 33 to 43, wherein the subject has not received prior treatment with T-cell costimulation therapy or a checkpoint inhibitor.

45. The method according to any one of claims 1 to 44, wherein the anti-latent TGF-beta 1 antibody is administered to the subject in combination with one or more additional therapeutic agents.

46. The method according to claim 45, wherein the one or more additional therapeutic agents include a checkpoint inhibitor.

47. The method according to any one of claims 15, 29, 32, 44, and 46, wherein the checkpoint inhibitor comprises a PD-1 axis-binding antagonist or a CTLA4 antagonist.

48. The method according to claim 47, wherein the checkpoint inhibitor comprises a PD-1 axis-binding antagonist.

49. The method according to any one of claims 20 to 22, 47, and 48, wherein the PD-1 axial coupling antagonist includes a PD-L1 coupling antagonist, a PD-1 coupling antagonist, or a PD-L2 coupling antagonist.

50. The method according to claim 49, wherein the PD-1 axis-coupled antagonist includes a PD-L1-coupled antagonist.

51. The method according to claim 50, wherein the PD-L1-binding antagonist comprises an anti-PD-L1 antibody.

52. The method according to claim 51, wherein the anti-PD-L1 antibody comprises atezolizumab, durvalumab, avelumab, or MDX-1105.

53. The method according to claim 52, wherein the anti-PD-L1 antibody comprises atezolizumab.

54. The method according to claim 53, wherein the atezolizumab is administered to the subject in a drug regimen comprising one or more drug cycles.

55. The method according to claim 54, wherein the one or more drug administration cycles include a 21-day drug administration cycle.

56. The method according to claim 55, wherein the atezolizumab is administered to the subject on the first day of each 21-day drug cycle.

57. The method according to any one of claims 53 to 56, wherein the atezolizumab is administered to the subject at a dose of 1200 mg.

58. The method according to claim 54, wherein the one or more drug administration cycles include a 14-day drug administration cycle or a 28-day drug administration cycle.

59. The method according to claim 58, wherein the one or more drug cycles comprise a 14-day drug cycle, and the atezolizumab is administered to the subject at a dose of 840 mg.

60. The method according to claim 59, wherein the atezolizumab is administered to the subject on the first day of each 14-day drug cycle.

61. The method according to claim 58, wherein the one or more drug cycles include a 28-day drug cycle, and the atezolizumab is administered to the subject at a dose of 1680 mg.

62. The method according to claim 61, wherein the atezolizumab is administered to the subject on the first day of each 28-day drug cycle.

63. The method according to any one of claims 53 to 62, wherein the atezolizumab is administered intravenously to the subject.

64. The method according to claim 63, wherein the atezolizumab is administered intravenously to the subject by infusion.

65. The method according to claim 49, wherein the PD-1 axially coupled antagonist includes a PD-1 binding antagonist.

66. The method according to claim 65, wherein the PD-1 conjugated antagonist comprises an anti-PD-1 antibody.

67. The method according to claim 66, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiprimab, prorugolimab, camrelizumab, cintilimab, tislerizumab, tripalimab, dostalimab, retifanlimab, sasanlimab, penprimab, zinbererimab, valstilimab, genolimuzumab, cetrelimab, or buzigalimab.

68. The method according to claim 67, wherein the anti-PD-1 antibody comprises nivolumab.

69. The method according to claim 68, wherein the nivolumab is administered to the subject in a drug regimen comprising one or more drug cycles.

70. The method according to claim 69, wherein the one or more drug administration cycles include a 21-day drug administration cycle.

71. The method according to claim 70, wherein the nivolumab is administered to the subject on the first day of each 21-day drug cycle.

72. The method according to any one of claims 68 to 71, wherein the nivolumab is administered to the subject in a dose of 360 mg.

73. The method according to any one of claims 68 to 72, wherein the nivolumab is administered intravenously to the subject.

74. The method according to claim 73, wherein the nivolumab is administered intravenously to the subject by injection.

75. The method according to any one of claims 1 to 74, wherein the one or more additional therapeutic agents are selected from chemotherapeutic agents, immunotherapeutic agents, radiotherapy agents, anti-angiogenic agents, and any combination thereof.

76. The method according to claim 75, wherein the one or more additional therapeutic agents comprise one or more chemotherapeutic agents.

77. The method according to claim 76, wherein the one or more chemotherapeutic agents include platinum-based chemotherapeutic agents, antimetabolites, cytotoxic agents, growth inhibitors, taxanes, folic acid analogs, or any combination thereof.

78. The method according to claim 77, wherein the platinum-based chemotherapeutic agent comprises oxaliplatin, cisplatin, or carboplatin.

79. The method according to claim 78, wherein the platinum-based chemotherapeutic agent comprises oxaliplatin.

80. The method according to claim 79, wherein the oxaliplatin is administered to the subject in a drug regimen comprising one or more drug cycles.

81. The method according to claim 80, wherein the one or more drug administration cycles include a 21-day drug administration cycle.

82. The method according to claim 81, wherein the oxaliplatin is administered to the subject on the first day of each 21-day drug cycle.

83. The aforementioned oxaliplatin is 130 mg / m² ２ The method according to any one of claims 79 to 82, wherein the subject is administered the dose of the dose of the subject.

84. The method according to any one of claims 79 to 83, wherein the oxaliplatin is administered intravenously to the subject.

85. The method according to claim 84, wherein the antimetabolite comprises capecitabine, gemcitabine, 5-fluorouracil, or tegafur.

86. The method according to claim 85, wherein the antimetabolite comprises capecitabine.

87. The method according to claim 86, wherein the capecitabine is administered to the subject in a drug regimen comprising one or more drug cycles.

88. The method according to claim 87, wherein the one or more drug administration cycles include a 21-day drug administration cycle.

89. The method according to claim 88, wherein the capecitabine is administered to the subject on days 1 to 14 of each 21-day drug cycle.

90. The capecitabine was administered to the subject at a dose of 1000 mg / m². ２ The method according to any one of claims 86 to 89, administered twice daily at the specified dose.

91. The method according to any one of claims 86 to 90, wherein the capecitabine is orally administered to the subject.

92. The method according to claim 85, wherein the antimetabolite comprises gemcitabine.

93. The method according to claim 92, wherein gemcitabine is administered to the subject in a drug regimen comprising one or more drug cycles.

94. The method according to claim 93, wherein the one or more drug administration cycles include a 28-day drug administration cycle.

95. The method according to claim 94, wherein gemcitabine is administered to the subject on day 1, day 8, and day 15 of each 28-day drug cycle.

96. The gemcitabine was administered to the subject at a dose of 1000 mg / m². ２ The method according to any one of claims 92 to 95, administered twice daily in the specified dose.

97. The method according to any one of claims 92 to 96, wherein gemcitabine is administered intravenously to the subject.

98. The method according to claim 85, wherein the antimetabolite comprises tegafur.

99. The method according to claim 98, wherein the antimetabolite contains S-1 (tegafur, gimeracil, oteracil potassium).

100. The method according to claim 99, wherein S-1 is administered to the subject in a drug regimen comprising one or more drug cycles.

101. The method according to claim 100, wherein the one or more drug administration cycles include a 21-day drug administration cycle.

102. The method according to claim 101, wherein S-1 is administered to the subject on the 1st to 14th days of each 21-day drug administration cycle.

103. The aforementioned S-1 is administered to the subject at a concentration of 40 mg / m². ２ The method according to any one of claims 99 to 102, administered twice daily in the specified dose.

104. The method according to any one of claims 99 to 103, wherein S-1 is administered orally to the subject.

105. The method according to claim 77, wherein the taxane comprises nab-paclitaxel or paclitaxel.

106. The method according to claim 105, wherein the taxane comprises nab-paclitaxel.

107. The method according to claim 106, wherein the nab-paclitaxel is administered to the subject in a drug regimen comprising one or more drug cycles.

108. The method according to claim 107, wherein the one or more drug administration cycles include a 28-day drug administration cycle.

109. The method according to claim 108, wherein the nab-paclitaxel is administered to the subject on day 1, day 8, and day 15 of each 28-day drug cycle.

110. The aforementioned nab-paclitaxel is 125 mg / m². ２ The method according to any one of claims 105 to 109, administered to the subject in the dose of [specified dose].

111. The method according to any one of claims 105 to 110, wherein the nab-paclitaxel is administered intravenously to the subject.

112. The method according to claim 77, wherein the folic acid analog comprises leucovorin.

113. A method for treating a subject having locally advanced, recurrent, or metastatic NSCLC, wherein the method comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Methods that include...

114. The method according to claim 113, wherein the NSCLC is histologically or cytologically confirmed metastatic non-squamous NSCLC or metastatic squamous NSCLC.

115. The method according to claim 113 or 114, wherein the subject had disease progression during or after treatment of metastatic or locally advanced, unresectable NSCLC comprising a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist, which are given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order.

116. The method according to claim 115, wherein the subject has previously received combination therapy including a platinum-containing chemotherapy regimen and a PD-1 axis-binding antagonist.

117. The method according to claim 115, wherein the subject has previously received a platinum-containing chemotherapy regimen and a PD-1 axis-binding antagonist as separate regimens.

118. The method according to any one of claims 113 to 117, wherein the subject had disease progression or recurrence within six months of curative treatment for locally progressive NSCLC.

119. The method according to any one of claims 113 to 118, wherein the tumor sample derived from the subject is determined to have a detectable level of PD-L1 expression.

120. A method for treating a subject having locally advanced, recurrent, or metastatic gastric cancer, wherein the method comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy is (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; and (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day medication cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ Capecitabine at the dosage, or (b) 40 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ S-1 at the dosage of the drug; and (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. ２ Oxaliplatin at the dosage Methods that include...

121. The method according to claim 120, wherein the subject has an unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be an adenocarcinoma.

122. The method according to claim 120 or 121, wherein the gastric cancer includes esophagogastric junction cancer.

123. The method according to any one of claims 120 to 122, wherein the gastric cancer is HER2-negative gastric cancer.

124. The method according to any one of claims 120 to 123, wherein the subject has not been previously treated for gastric cancer and / or has not been previously treated with a checkpoint inhibitor.

125. A method for treating a subject having locally advanced, recurrent, or metastatic PDAC, wherein the method comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, and the anticancer therapy comprises (i) Anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; (ii) Atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day medication cycle; (iii) nab-paclitaxel at a dose of 125 mg / m ２ on days 1, 8, and 15 of each 28-day dosing cycle; and (iv) 1000 mg / m³ intravenously on days 1, 8, and 15 of each 28-day medication cycle. ２ gemcitabine at the dosage Methods that include...

126. The method according to claim 125, wherein the subject has histologically or cytologically confirmed metastatic PDAC.

127. The method according to claim 125 or 126, wherein the subject has not been previously treated with the PDAC and / or the subject has not been previously treated with a checkpoint inhibitor.

128. A method for treating a subject having locally advanced, recurrent, or metastatic ulcerative colitis, wherein the method comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Methods that include...

129. The method according to claim 128, wherein the subject has histologically demonstrated locally progressive (T4b, any N; or any T, N2-N3) UC or metastatic UC (M1, stage 4).

130. The method according to claim 128 or 129, wherein the subject has not been previously treated for UC.

131. The method according to any one of claims 128 to 130, wherein the subject is unsuitable for cisplatin-containing chemotherapy.

132. The above-mentioned subjects meet the following criteria: (i) Renal impairment as assessed by direct measurement or by calculation from serum or plasma creatinine, in terms of glomerular filtration rate (GFR) of 30 mL / min or more but less than 60 mL / min; (ii) Hearing loss of 25 dB at two adjacent frequencies as measured by a hearing test; (iii) Grade 2 peripheral neuropathy; or (iv) ECOG Performance Status 2 The method according to claim 131, which is unsuitable for cisplatin-containing chemotherapy as defined by any one of the following.

133. The method according to any one of claims 128 to 130, wherein the subject has previously received at least one platinum-containing chemotherapy regimen.

134. The method according to claim 133, wherein the subject had disease progression during or after treatment with at least one platinum-containing chemotherapy regimen.

135. The method according to claim 134, wherein the at least one platinum-containing chemotherapy regimen comprises (i) gemcitabine and cisplatin or carboplatin, or (ii) methotrexate, vinblastine, doxorubicin and cisplatin.

136. The method according to claim 133, wherein the subject has received prior adjuvant or neoadjuvant chemotherapy and has progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.

137. The method according to claim 133, wherein the subject received one cycle of platinum-containing chemotherapy regimen but was discontinued due to grade 4 hematological toxicity or grade 3-4 non-hematological toxicity.

138. The method according to any one of claims 128 to 137, wherein the subject has received two or fewer prior treatment regimens for the locally progressive ulcerative colitis or metastatic ulcerative colitis.

139. The method according to any one of claims 128 to 138, wherein the subject has not received prior treatment with T-cell costimulation therapy or a checkpoint inhibitor.

140. A method for treating a subject having metastatic non-squamous NSCLC or metastatic squamous NSCLC, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, wherein the anticancer therapy is (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibodies including; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Includes, A method in which the subject had disease progression during or after treatment of metastatic or locally advanced, unresectable NSCLC comprising a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist, which is given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in either order.

141. A method for treating a subject having locally advanced, unresectable, or metastatic HER2-negative gastric cancer, wherein the method comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibody containing; (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day medication cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ Capecitabine at the dosage, or (b) 40 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ S-1 at the dosage of the drug; and (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. ２ Oxaliplatin at the dosage Includes, The method wherein the subject has not been previously treated for locally advanced, unresectable, or metastatic HER2-negative gastric cancer.

142. A method for treating a subject having metastatic PDA, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, wherein the anticancer therapy is (i) Anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibody containing; (ii) Atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day medication cycle; (iii) 125 mg / m² on days 1, 8, and 15 of each 28-day medication cycle. ２ Nab-paclitaxel at the dose of; and (iv) 1000 mg / m³ intravenously on days 1, 8, and 15 of each 28-day medication cycle. ２ gemcitabine at the dosage Includes, The subject has not been previously treated for the metastatic PDAC.

143. A method for treating a subject having locally advanced UC or metastatic UC, wherein the method comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibodies including; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Includes, Here: The subject is one who has not been previously treated for the locally advanced UC or metastatic UC and is ineligible for cisplatin-containing chemotherapy; or The subjects mentioned above are methods that have previously received at least one platinum-containing chemotherapy regimen.

144. The method according to any one of claims 1 to 143, wherein the subject is administered the anti-latent TGF-beta 1 antibody until loss of clinical benefit or unacceptable toxicity occurs.

145. The method according to any one of claims 1 to 144, comprising 1 to 20 medication cycles.

146. The method according to any one of claims 1 to 145, wherein the anti-latent TGF-beta 1 antibody comprises HVR-H1, HVR-H2, and HVR-H3, each containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3, each containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively.

147. A method according to any one of claims 1 to 146, wherein the anti-latent TGF-beta 1 antibody is (a) (i) a heavy chain variable domain (VH) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7, (ii) a light chain variable domain (VL) sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8, or (iii) the VH sequence defined in (i) and the VL sequence defined in (ii); (b) (i) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 31, (ii) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 32, or (iii) the VH sequence defined in (i) and the VL sequence defined in (ii); (c) (i) a VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 33, (ii) a VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 34, or (iii) the VH sequence defined in (i) and the VL sequence defined in (ii); or (d) (i) A VH sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 35, (ii) A VL sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 36, or (iii) A VH sequence defined in (i) and a VL sequence defined in (ii). Methods that include...

148. A method according to any one of claims 1 to 147, wherein the anti-latent TGF-beta 1 antibody is (a) The VH sequence of sequence number 7 and the VL sequence of sequence number 8; (b) The VH sequence of sequence number 31 and the VL sequence of sequence number 32; (c) the VH sequence of sequence number 33 and the VL sequence of sequence number 34; or (d) VH sequence of SEQ ID NO: 35 and VL sequence of SEQ ID NO: 36 Methods that include...

149. The method according to any one of claims 1 to 148, wherein the anti-latent TGF-beta 1 antibody comprises the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO:

8.

150. The method according to any one of claims 1 to 149, wherein the anti-latent TGF-beta 1 antibody is a chimeric antibody.

151. The method according to any one of claims 1 to 150, wherein the anti-latent TGF-beta 1 antibody is a humanized antibody.

152. The method according to any one of claims 1 to 151, wherein the anti-latent TGF-beta 1 antibody is a full-length antibody.

153. A method according to any one of claims 1 to 152, wherein the anti-latent TGF-beta 1 antibody is (a) A heavy chain containing the amino acid sequence of SEQ ID NO: 37 and a light chain containing the amino acid sequence of SEQ ID NO: 38; (b) A heavy chain containing the amino acid sequence of SEQ ID NO: 39 and a light chain containing the amino acid sequence of SEQ ID NO: 40; (c) A heavy chain containing the amino acid sequence of SEQ ID NO: 41 and a light chain containing the amino acid sequence of SEQ ID NO: 42; (d) A heavy chain containing the amino acid sequence of SEQ ID NO: 43 and a light chain containing the amino acid sequence of SEQ ID NO: 44; (e) A heavy chain containing the amino acid sequence of SEQ ID NO: 45 and a light chain containing the amino acid sequence of SEQ ID NO: 46; (f) A heavy chain containing the amino acid sequence of SEQ ID NO: 47 and a light chain containing the amino acid sequence of SEQ ID NO: 48; (g) A heavy chain containing the amino acid sequence of SEQ ID NO: 49 and a light chain containing the amino acid sequence of SEQ ID NO: 50; or (h) Heavy chain containing the amino acid sequence of SEQ ID NO: 51 and light chain containing the amino acid sequence of SEQ ID NO: 52 Methods that include...

154. The method according to any one of claims 1 to 152, wherein the anti-latent TGF-beta 1 antibody comprises a modified IgG1 Fc region having reduced effector function compared to the wild-type IgG1 Fc region.

155. The method according to claim 154, wherein the modified IgG1 Fc region includes a steady weight (CH) region containing one or more of the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, S440E (EU numbering).

156. The method according to claim 155, wherein the CH region includes the amino acid sequence of SEQ ID NO:

9.

157. The method according to any one of claims 152 to 156, wherein the modified IgG1 Fc region includes a constant light (CL) domain containing the amino acid sequence of SEQ ID NO:

10.

158. The method according to any one of claims 1 to 157, wherein the anti-latent TGF-beta 1 antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 11 and a light chain sequence containing the amino acid sequence of SEQ ID NO:

12.

159. The method according to any one of claims 1 to 151, wherein the anti-latent TGF-beta 1 antibody is an antibody fragment that binds to latent TGF-beta 1.

160. The method according to any one of claims 1 to 159, wherein the subject is a human.

161. Anti-latent TGF-beta 1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors, wherein the treatment comprises administering an anticancer therapy containing an anti-latent TGF-beta 1 antibody to the subject at a dose of 1800 mg, and the anti-latent TGF-beta 1 antibody is one of the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Includes anti-latent TGF-beta 1.

162. Anti-latent TGF-beta-1 for use in the treatment of subjects with locally advanced, recurrent, or metastatic solid tumors, wherein the treatment comprises administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody to the subject at a dose of 1800 mg every three weeks (Q3W), wherein the anti-latent TGF-beta-1 antibody is one of the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Includes anti-latent TGF-beta 1.

163. Anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic solid tumors, wherein the treatment comprises administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg, and the anti-latent TGF-beta-1 antibody is one of the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Includes anti-latent TGF-beta 1.

164. Anti-latent TGF-beta-1 for use in the treatment of subjects with locally advanced, recurrent, or metastatic solid tumors, wherein the treatment comprises administering an anticancer therapy containing an anti-latent TGF-beta-1 antibody to the subject at a dose of 1200 mg every two weeks (Q2W), wherein the anti-latent TGF-beta-1 antibody is one of the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Includes anti-latent TGF-beta 1.

165. Anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic NSCLC, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises, (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Includes anti-latent TGF-beta 1.

166. Anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic gastric cancer, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises, (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day medication cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ Capecitabine at the dosage, or (b) 40 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ S-1 at the dosage of the drug; and (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. ２ Oxaliplatin at the dosage Includes anti-latent TGF-beta 1.

167. Anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic PDAC, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, and the anticancer therapy comprises (i) Anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; (ii) Atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day medication cycle; (iii) 125 mg / m² on days 1, 8, and 15 of each 28-day medication cycle. ２ Nab-paclitaxel at the dose of; and (iv) 1000 mg / m³ intravenously on days 1, 8, and 15 of each 28-day medication cycle. ２ gemcitabine at the dosage Includes anti-latent TGF-beta 1.

168. Anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, recurrent, or metastatic UC, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises, (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Includes anti-latent TGF-beta 1.

169. Anti-latent TGF-beta-1 for use in the treatment of subjects having metastatic non-squamous NSCLC or metastatic squamous NSCLC, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises, (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibodies including; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Includes, The subject had disease progression during or after treatment of metastatic or locally advanced, unresectable NSCLC comprising a platinum-containing chemotherapy regimen and a PD-1 axis-coupled antagonist, which is given in combination as one therapy line for up to two preceding systemic therapy lines or as two separate therapy lines in any order.

170. Anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced, unresectable, or metastatic HER2-negative gastric cancer, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises, (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibody containing; (ii) Nivolumab administered intravenously at a dose of 360 mg on day 1 of each 21-day medication cycle; (iii) (a) 1000 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ Capecitabine at the dosage, or (b) 40 mg / m² orally twice daily on days 1 to 14 of each 21-day medication cycle. ２ S-1 at the dosage of the drug; and (iv) 130 mg / m³ intravenously on day 1 of each 21-day medication cycle. ２ Oxaliplatin at the dosage Includes, The subject is an anti-latent TGF-beta 1 patient who has not been previously treated for locally advanced, unresectable, or metastatic HER2-negative gastric cancer.

171. Anti-latent TGF-beta 1 for use in the treatment of subjects having metastatic PDAC, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 28-day drug cycles, and the anticancer therapy comprises, (i) Anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg on days 1 and 15 of each 28-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibody containing; (ii) Atezolizumab administered intravenously at a dose of 840 mg on days 1 and 15 of each 28-day medication cycle; (iii) 125 mg / m² on days 1, 8, and 15 of each 28-day medication cycle. ２ Nab-paclitaxel at the dose of; and (iv) 1000 mg / m³ intravenously on days 1, 8, and 15 of each 28-day medication cycle. ２ gemcitabine at the dosage Includes, The subject is an anti-latent TGF-beta 1 that has not been previously treated for the metastatic PDAC.

172. Anti-latent TGF-beta-1 for use in the treatment of subjects having locally advanced UC or metastatic UC, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises, (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1800 mg on day 1 of each 21-day drug cycle, for the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SEAMN (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence GTGIYDYYYWVMDL (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence of QASQSISTYLA (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of AASTLES (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QSYSDGDSVG (SEQ ID NO: 6) Anti-latent TGF-beta 1 antibodies including; and (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Includes, Here: The subject is one who has not been previously treated for the locally advanced UC or metastatic UC and is ineligible for cisplatin-containing chemotherapy; or The subjects mentioned above are anti-latent TGF-beta 1 patients who have previously received at least one platinum-containing chemotherapy regimen.

173. A method for treating cancer in a subject having a locally advanced or recurrent tumor, the method comprising administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, wherein the anticancer therapy is (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg to 1800 mg on day 1 of each 21-day drug cycle, comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing, (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Methods that include...

174. The method according to claim 173, wherein the subject has previously received treatment with atezolizumab at a dose of 1200 mg intravenously.

175. The method according to claim 173 or 174, wherein the anticancer therapy comprises the anti-latent TGF-beta 1 antibody in a dosage of 1200 mg.

176. The method according to any one of claims 173 to 175, wherein the anticancer therapy comprises the anti-latent TGF-beta 1 antibody in a dosage of 1500 mg.

177. The method according to any one of claims 173 to 176, wherein the anticancer therapy comprises the anti-latent TGF-beta 1 antibody in a dosage of 1800 mg.

178. The method according to any one of claims 173 to 177, wherein the anti-latent TGF-beta 1 antibody is administered intravenously to the subject.

179. The method according to claim 178, wherein the anti-latent TGF-beta 1 antibody is administered intravenously to the subject by injection.

180. The method according to any one of claims 173 to 179, wherein the above is determined to have a detectable level of PD-L1 expression.

181. The method according to any one of claims 173 to 180, wherein the age of the subject is 18 years or older.

182. The method according to any one of claims 173 to 181, wherein the anti-cancer therapy is the first-line therapy.

183. The method according to any one of claims 173 to 181, wherein the anti-cancer therapy is a second-line or third-line therapy.

184. The method according to any one of claims 173 to 183, wherein the subject has not been previously treated with a checkpoint inhibitor.

185. The method according to any one of claims 173 to 184, wherein the cancer is NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, kidney cancer, or gallbladder cancer.

186. The method according to claim 185, wherein the cancer is GIST, skin cancer, colorectal cancer, ovarian cancer, kidney cancer, or gallbladder cancer.

187. Anti-latent TGF-beta-1 for use in the treatment of cancer in subjects with locally advanced or recurrent tumors, wherein the treatment comprises administering anticancer therapy to the subject in a drug regimen comprising one or more 21-day drug cycles, and the anticancer therapy comprises (i) An anti-latent TGF-beta-1 antibody administered intravenously at a dose of 1200 mg to 1800 mg on day 1 of each 21-day drug cycle, comprising the following six HVRs: (a) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (b) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs: 13, 14, and 15, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively; (c) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 19, 20, and 21, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 22, 23, and 24, respectively; or (d) HVR-H1, HVR-H2, and HVR-H3 containing the amino acid sequences of SEQ ID NOs. 25, 26, and 27, respectively, and HVR-L1, HVR-L2, and HVR-L3 containing the amino acid sequences of SEQ ID NOs. 28, 29, and 30, respectively. Anti-latent TGF-beta 1 antibody containing, (ii) Atezolizumab administered intravenously at a dose of 1200 mg on day 1 of each 21-day medication cycle. Includes anti-latent TGF-beta 1.

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