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WO2024233646A1 - Méthodes et compositions pour le traitement du cancer - Google Patents

Méthodes et compositions pour le traitement du cancer Download PDF

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Publication number
WO2024233646A1
WO2024233646A1 PCT/US2024/028339 US2024028339W WO2024233646A1 WO 2024233646 A1 WO2024233646 A1 WO 2024233646A1 US 2024028339 W US2024028339 W US 2024028339W WO 2024233646 A1 WO2024233646 A1 WO 2024233646A1
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WIPO (PCT)
Prior art keywords
hvr
seq
amino acid
subject
acid sequences
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/US2024/028339
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English (en)
Inventor
Colby Sasson SHEMESH
David VOONG
Yulei Wang
Eunpi CHO
Stevan Nicholas DJAKOVIC
Eisuke Ueda
Takaaki Ishida
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chugai Pharmaceutical Co Ltd
Genentech Inc
Original Assignee
Chugai Pharmaceutical Co Ltd
Genentech Inc
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Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd, Genentech Inc filed Critical Chugai Pharmaceutical Co Ltd
Priority to AU2024268933A priority Critical patent/AU2024268933A1/en
Publication of WO2024233646A1 publication Critical patent/WO2024233646A1/fr
Priority to MX2025013394A priority patent/MX2025013394A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • This invention relates to methods and compositions for use in treating cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor) in a subject, for example, by administering to the subject an anti-cancer therapy that includes an anti-latent transforming growth factor (TGF)-beta 1 antibody.
  • cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • an anti-cancer therapy that includes an anti-latent transforming growth factor (TGF)-beta 1 antibody.
  • TGF anti-latent transforming growth factor
  • Cancer remains one of the deadliest threats to human health. In the U.S., cancer affects nearly 1 .3 million new patients each year and is the second leading cause of death after heart disease, accounting for approximately 1 in 4 deaths. It is also predicted that cancer may surpass cardiovascular diseases as the number one cause of death within 5 years. Solid tumors are responsible for most of those deaths. Although there have been significant advances in the medical treatment of certain cancers, the overall 5-year survival rate for all cancers has improved only by about 10% in the past 20 years. Malignant solid tumors, in particular, metastasize and grow rapidly in an uncontrolled manner, making their timely detection and treatment extremely difficult.
  • the invention provides, inter alia, methods for treating cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), and related compositions for use and articles of manufacture.
  • cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor, the method comprising administering to the subject an anti-cancer therapy comprising an anti-latent transforming growth factor (TGF)-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO:
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic solid tumor, the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO
  • the anti-latent TGF-beta 1 antibody is administered to the subject in a dosing regimen comprising one or more 21 -day dosing cycles.
  • the anti-latent TGF-beta 1 antibody is administered to the subject on Day 1 of each 21 -day dosing cycle.
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor, the method comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 16, 17, and 18,
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic solid tumor, the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor, the method comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 16, 17, and 18, respectively; (c) HVR-H
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic solid tumor, the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO:
  • the anti-latent TGF-beta 1 antibody is administered to the subject in a dosing regimen comprising one or more 28-day dosing cycles.
  • the anti-latent TGF-beta 1 antibody is administered to the subject on Days 1 and 15 of each 28-day dosing cycle.
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor, the method comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg every two weeks (Q2W), wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs:
  • HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively;
  • HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 16, 17, and 18, respectively;
  • HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 19, 20, and 21 , respectively, and HVR-L1 , HVR-L2, and HVR- L3 comprising the amino acid sequences of SEQ ID NO: 22, 23, and 24, respectively; or
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic solid tumor, the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino
  • the anti-latent TGF-beta 1 antibody is administered to the subject intravenously.
  • the anti-latent TGF-beta 1 antibody is administered to the subject intravenously by infusion.
  • a tumor sample from the subject has been determined to have a detectable level of PD-L1 expression.
  • the subject’s age is 18 years or older.
  • the anti-cancer therapy is a first-line therapy.
  • the anti-cancer therapy is a second-line therapy or a third-line therapy.
  • the subject has not been previously treated with a checkpoint inhibitor.
  • the solid tumor is metastatic.
  • 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, renal cancer, or gallbladder cancer.
  • NSCLC non-small cell lung cancer
  • PDAC pancreatic ductal adenocarcinoma
  • UC pancreatic ductal adenocarcinoma
  • GIST gastrointestinal stromal tumor
  • skin cancer colorectal cancer
  • OV ovarian cancer
  • renal cancer or gallbladder cancer.
  • the locally advanced, recurrent, or metastatic solid tumor is NSCLC.
  • the NSCLC is histologically or cytological ly confirmed metastatic nonsquamous NSCLC or metastatic squamous NSCLC.
  • the subject has had disease progression during or following treatment for metastatic or locally advanced, inoperable NSCLC that comprised a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist, given in combination as one line of therapy or as two separate lines of therapy, in either order, for a maximum of two prior lines of systemic therapy.
  • the subject has previously received a combination therapy comprising a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist.
  • the subject has previously received a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist as individual regimens.
  • the subject had disease progression or recurrence within 6 months of definitive therapy for locally advanced NSCLC.
  • a tumor sample from the subject has been determined to have a detectable level of PD-L1 expression.
  • the locally advanced, recurrent, or metastatic solid tumor is gastric cancer.
  • the subject has unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be adenocarcinoma.
  • the gastric cancer comprises esophagogastric junction cancer.
  • the gastric cancer is HER2-negative gastric cancer.
  • the subject is previously untreated for gastric cancer and/or the subject has not been previously treated with a checkpoint inhibitor.
  • the locally advanced, recurrent, or metastatic solid tumor is PDAC.
  • the subject has histologically or cytologically confirmed metastatic PDAC.
  • the subject is previously untreated for the PDAC and/or the subject has not been previously treated with a checkpoint inhibitor.
  • the locally advanced, recurrent, or metastatic solid tumor is UC.
  • the subject has histologically documented, locally advanced (T4b, any N; or any T, N2-N3) UC, or metastatic UC (M1 , Stage 4).
  • the subject is previously untreated for UC.
  • the subject is ineligible for cisplatin-containing chemotherapy.
  • the subject is ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) impaired renal function in terms of glomerular filtration rate (GFR) of > 30 mL/min but ⁇ 60 mL/min as assessed by direct measurement or by calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two contiguous frequencies as measured by audiometry; (iii) Grade 2 peripheral neuropathy; or (iv) Eastern Cooperative Oncology Group (ECOG) Performance Status of 2.
  • GFR glomerular filtration rate
  • COG Eastern Cooperative Oncology Group
  • the subject has previously received at least one platinum-containing chemotherapy regimen.
  • the subject had disease progression during or following treatment with at least one platinum-containing chemotherapy regimen.
  • the at least one platinum-containing chemotherapy regimen comprised (i) gemcitabine and cisplatin or carboplatin or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin.
  • the subject received prior adjuvant or neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.
  • the subject received one cycle of a platinum-containing chemotherapy regimen but discontinued because of a Grade 4 hematologic toxicity or a Grade 3-4 non-hematologic toxicity. In some aspects, the subject received no more than two prior lines of treatment for the locally advanced or metastatic UC.
  • the subject has not received prior treatment with a T-cell co-stimulating therapy or a checkpoint inhibitor.
  • the anti-latent TGF-beta 1 antibody is administered to the subject in combination with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents comprises a checkpoint inhibitor.
  • the checkpoint inhibitor comprises a PD-1 axis binding antagonist or a CTLA4 antagonist.
  • the checkpoint inhibitor comprises a PD-1 axis binding antagonist.
  • the PD-1 axis binding antagonist comprises a PD-L1 binding antagonist, a PD-1 binding antagonist, or a PD-L2 binding antagonist.
  • the PD-1 axis binding antagonist comprises a PD-L1 binding antagonist.
  • the PD-L1 binding antagonist comprises an anti-PD-L1 antibody.
  • the anti-PD-L1 antibody comprises atezolizumab, durvalumab, avelumab, or MDX-1105.
  • the anti-PD-L1 antibody comprises atezolizumab.
  • the atezolizumab is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the atezolizumab is administered to the subject on Day 1 of each 21 -day dosing cycle.
  • the atezolizumab is administered to the subject at a dose of 1200 mg.
  • the one or more dosing cycles comprise 14-day dosing cycles or 28-day dosing cycles.
  • the one or more dosing cycles comprise 14-day dosing cycles, and the atezolizumab is administered to the subject at a dose of 840 mg.
  • the atezolizumab is administered to the subject on Day 1 of each 14-day dosing cycle.
  • the one or more dosing cycles comprise 28-day dosing cycles, and the atezolizumab is administered to the subject at a dose of 1680 mg.
  • the atezolizumab is administered to the subject on Day 1 of each 28-day dosing cycle.
  • the atezolizumab is administered to the subject intravenously.
  • the atezolizumab is administered to the subject intravenously by infusion.
  • the PD-1 axis binding antagonist comprises a PD-1 binding antagonist.
  • the PD-1 binding antagonist comprises an anti-PD-1 antibody.
  • the anti-PD-1 antibody comprises nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, zimberelimab, balstilimab, genolimzumab, cetrelimab, or budigalimab.
  • the anti-PD-1 antibody comprises nivolumab.
  • the nivolumab is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the nivolumab is administered to the subject on Day 1 of each 21 -day dosing cycle.
  • the nivolumab is administered to the subject at a dose of 360 mg.
  • the nivolumab is administered to the subject intravenously.
  • the nivolumab is administered to the subject intravenously by infusion.
  • the one or more additional therapeutic agents is selected from a chemotherapeutic agent, an immunotherapy agent, a radiation therapy agent, an anti-angiogenic agent, and any combination thereof.
  • the one or more additional therapeutic agents comprise one or more chemotherapeutic agents.
  • the one or more chemotherapeutic agents comprise a platinum-based chemotherapeutic agent, an antimetabolite, a cytotoxic agent, a growth inhibitory agent, a taxane, a folate analog, or any combination thereof.
  • the platinum-based chemotherapeutic agent comprises oxaliplatin, cisplatin, or carboplatin.
  • the platinum-based chemotherapeutic agent comprises oxaliplatin.
  • the oxaliplatin is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the oxaliplatin is administered to the subject on Day 1 of each 21 -day dosing cycle.
  • the oxaliplatin is administered to the subject at a dose of 130 mg/m 2 .
  • the oxaliplatin is administered to the subject intravenously.
  • the antimetabolite comprises capecitabine, gemcitabine, 5-fluorouracil, or tegafur.
  • the antimetabolite comprises capecitabine.
  • the capecitabine is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the capecitabine is administered to the subject on Days 1 -14 of each 21 -day dosing cycle.
  • the capecitabine is administered to the subject at a dose of 1000 mg/m 2 twice daily.
  • the capecitabine is administered to the subject orally.
  • the antimetabolite comprises gemcitabine.
  • the gemcitabine is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 28-day dosing cycles.
  • the gemcitabine is administered to the subject on Days 1 , 8, and 15 of each 28- day dosing cycle.
  • the gemcitabine is administered to the subject at a dose of 1000 mg/m 2 twice daily.
  • the gemcitabine is administered to the subject intravenously.
  • the antimetabolite comprises tegafur.
  • the antimetabolite comprises S-1 (tegafur-gimeracil-oteracil potassium).
  • the S-1 is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the S-1 is administered to the subject on Days 1 -14 of each 21 -day dosing cycle.
  • the S-1 is administered to the subject at a dose of 40 mg/m 2 twice daily.
  • the S-1 is administered to the subject orally.
  • the taxane comprises nab-paclitaxel or paclitaxel.
  • the taxane comprises nab-paclitaxel.
  • the nab-paclitaxel is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 28-day dosing cycles.
  • the nab-paclitaxel is administered to the subject on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the nab-paclitaxel is administered to the subject at a dose of 125 mg/m 2 .
  • the nab-paclitaxel is administered to the subject intravenously.
  • the folate analog comprises leucovorin.
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic NSCLC, the method comprising administering to the subject an anticancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anticancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14,
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic NSCLC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the
  • the NSCLC is histologically or cytological ly confirmed metastatic nonsquamous NSCLC or metastatic squamous NSCLC.
  • the subject has had disease progression during or following treatment for metastatic or locally advanced, inoperable NSCLC that comprised a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist, given in combination as one line of therapy or as two separate lines of therapy, in either order, for a maximum of two prior lines of systemic therapy.
  • the subject has previously received a combination therapy comprising a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist.
  • the subject has previously received a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist as individual regimens.
  • the subject had disease progression or recurrence within 6 months of definitive therapy for locally advanced NSCLC.
  • a tumor sample from the subject has been determined to have a detectable level of PD-L1 expression.
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic gastric cancer, the method comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anticancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13,
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic gastric cancer, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the
  • the subject has unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be adenocarcinoma.
  • the gastric cancer comprises esophagogastric junction cancer.
  • the gastric cancer is HER2-negative gastric cancer.
  • the subject is previously untreated for gastric cancer and/or the subject has not been previously treated with a checkpoint inhibitor.
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic PDAC, the method comprising administering to the subject an anticancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anticancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14,
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic PDAC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 compris
  • the subject has histologically or cytologically confirmed metastatic PDAC.
  • the subject is previously untreated for the PDAC and/or the subject has not been previously treated with a checkpoint inhibitor.
  • the invention provides a method of treating a subject having a locally advanced, recurrent, or metastatic UC, the method comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13,
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic UC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising
  • the subject has histologically documented, locally advanced (T4b, any N; or any T, N2-N3) UC, or metastatic UC (M1 , Stage 4).
  • the subject is previously untreated for UC.
  • the subject is ineligible for cisplatin-containing chemotherapy.
  • the subject is ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) impaired renal function in terms of glomerular filtration rate (GFR) of > 30 mL/min but ⁇ 60 mL/min as assessed by direct measurement or by calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two contiguous frequencies as measured by audiometry; (iii) Grade 2 peripheral neuropathy; or (iv) ECOG Performance Status of 2.
  • GFR glomerular filtration rate
  • the subject has previously received at least one platinum-containing chemotherapy regimen.
  • the subject had disease progression during or following treatment with at least one platinum-containing chemotherapy regimen.
  • the at least one platinum-containing chemotherapy regimen comprised (i) gemcitabine and cisplatin or carboplatin or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin.
  • the subject received prior adjuvant or neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.
  • the subject received one cycle of a platinum-containing chemotherapy regimen but discontinued because of a Grade 4 hematologic toxicity or a Grade 3-4 non-hematologic toxicity.
  • the subject received no more than two prior regimens of treatment for the locally advanced or metastatic UC.
  • the subject has not received prior treatment with a T-cell co-stimulating therapy or a checkpoint inhibitor.
  • the invention provides a method of treating a subject having a metastatic non- squamous NSCLC or a metastatic squamous NSCLC, the method comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 compris
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a metastatic non-squamous NSCLC or a metastatic squamous NSCLC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti- latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID
  • the invention provides a method of treating a subject having a locally advanced, unresectable, or metastatic HER2-negative gastric cancer, the method comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF- beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, unresectable, or metastatic HER2-negative gastric cancer, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti- latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d
  • the invention provides a method of treating a subject having a 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, wherein the anti-cancer therapy comprises: (i) an anti- latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR- H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of QASQSISTYLA (SEQ ID NO:
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a metastatic PDAC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence
  • the invention provides a method of treating a subject having a locally advanced or metastatic UC, the method comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of QASQSISTYLA (SEQ ID NO:
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced or metastatic UC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino
  • the invention provides a method of treating cancer in a subject having a locally advanced or recurrent tumor, the method comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 300 mg to 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13,
  • the subject has previously received treatment with atezolizumab at a dosage of 1200 mg intravenously.
  • the anti-cancer therapy comprises the anti-latent TGF-beta 1 antibody at a dosage of 300 mg. In some aspects, the anti-cancer therapy comprises the anti-latent TGF-beta 1 antibody at a dosage of 600 mg. In some aspects, the anti-cancer therapy comprises the anti-latent TGF- beta 1 antibody at a dosage of 900 mg. In some aspects, the anti-cancer therapy comprises the anti- latent TGF-beta 1 antibody at a dosage of 1200 mg. In some aspects, the anti-cancer therapy comprises the anti-latent TGF-beta 1 antibody at a dosage of 1500 mg. In some aspects, the anti-cancer therapy comprises the anti-latent TGF-beta 1 antibody at a dosage of 1800 mg.
  • the anti-latent TGF-beta 1 antibody is administered to the subject intravenously. In some aspects, the anti-latent TGF-beta 1 antibody is administered to the subject intravenously by infusion.
  • the subject’s age is 18 years or older.
  • the anti-cancer therapy is a first-line therapy. In some aspects, the anti-cancer therapy is a second-line therapy or a third-line therapy.
  • the subject has not been previously treated with a checkpoint inhibitor.
  • the cancer is NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, renal cancer, or gallbladder cancer. In some aspects, the cancer is GIST, skin cancer, colorectal cancer, OV cancer, renal cancer, or gallbladder cancer.
  • the invention provides an anti-latent TGF-beta 1 for use in a treatment of cancer in a subject having a locally advanced or recurrent tumor, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 300 mg to1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H
  • the subject is administered the anti-latent TGF-beta 1 antibody until loss of clinical benefit or unacceptable toxicity.
  • the method comprises between 1 and 20 dosing cycles (e.g., 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10, cycles, 1 1 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, or 20 cycles).
  • dosing cycles e.g., 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10, cycles, 1 1 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, or 20 cycles.
  • the anti-latent TGF-beta 1 antibody comprises HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively.
  • the anti-latent TGF-beta 1 antibody comprises: (a) (i) a heavy chain variable domain (VH) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7, (ii) a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8, or (Hi) a VH sequence as defined in (i) and a VL sequence as defined in (ii); (b) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 31 , (ii) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 32, or (Hi) a VH sequence as defined in (i) and a VL sequence as defined in (ii); (c) (i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 33, (ii) a VL sequence having at least 95% sequence identity to the
  • the anti-latent TGF-beta 1 antibody comprises: (a) a VH sequence of SEQ ID NO: 7 and a VL sequence of SEQ ID NO: 8; (b) a VH sequence of SEQ ID NO: 31 and a VL sequence of SEQ ID NO: 32; (c) a VH sequence of SEQ ID NO: 33 and a VL sequence of SEQ ID NO: 34; or (d) a VH sequence of SEQ ID NO: 35 and a VL sequence of SEQ ID NO: 36.
  • the anti-latent TGF-beta 1 antibody comprises a VH sequence of SEQ ID NO: 7 and a VL sequence of SEQ ID NO: 8.
  • the anti-latent TGF-beta 1 antibody is a chimeric antibody.
  • the anti-latent TGF-beta 1 antibody is a humanized antibody.
  • the anti-latent TGF-beta 1 antibody is a full-length antibody.
  • the anti-latent TGF-beta 1 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 38; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 and a light chain comprising the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising the amino acid sequence of SEQ ID NO: 42; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 44; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain comprising the amino acid sequence of SEQ
  • the anti-latent TGF-beta 1 antibody comprises a modified IgG 1 Fc region having reduced effector function compared with a wild-type IgG 1 Fc region.
  • the modified IgG 1 Fc region comprises a constant heavy (CH) region comprising one or more of the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, and/or S440E (EU numbering).
  • CH constant heavy
  • the CH region comprises the amino acid sequence of SEQ ID NO: 9.
  • the modified IgG 1 Fc region comprises a constant light (CL) domain comprising the amino acid sequence of SEQ ID NO: 10.
  • the anti-latent TGF-beta 1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 1 and a light chain sequence comprising the amino acid sequence of SEQ ID NO: 12.
  • the anti-latent TGF-beta 1 antibody is an antibody fragment that binds to latent TGF-beta 1 .
  • the subject is a human.
  • FIG. 1 shows a flow diagram of the study design described in Example 1 .
  • a Efficacy analysis is performed for each cohort after approximately 15 patients enrolled from the safety run-in and expansion stages have completed at least one tumor assessment in a given cohort.
  • FIG. 2 shows a flow diagram outlining the conditions for continuing treatment beyond disease progression, as discussed in Example 1 .
  • ECOG Eastern Cooperative Oncology Group
  • RECIST v1 .1 Response Evaluation Criteria in Solid Tumors, Version 1 .1 .
  • FIG. 3 shows a flow diagram of the study design described in Example 2.
  • a Efficacy analysis is performed for each cohort after approximately 15 patients enrolled from the safety run-in and expansion stages have completed at least one tumor assessment in a given cohort.
  • FIG. 4 shows a diagram outlining the dosing regimen treatments for Cohorts 1 -6 described in Example 3.
  • Atezo atezolizumab.
  • FIG. 5A shows a time course of plasma SOF10 concentration (pg/mL) in patients from Cohorts 1 - 5 described in Example 3.
  • FIG. 5B shows a time course of plasma SOF10 concentration (pg/mL) in patients from Cohort 6 described in Example 3.
  • FIG. 6 shows a time course of tumor size, relative to baseline, in various cancers following the SOF10 and atezolizumab combinatorial treatment described in Example 3.
  • FIG. 7A shows a time course of TGF-p1 total plasma concentrations following the first dose of the SOF10 and atezolizumab combinatorial treatment described in Example 3.
  • FIG. 7B shows a time course of TGF-p1 percent change, relative to baseline, following the first dose of the SOF10 and atezolizumab combinatorial treatment described in Example 3.
  • the present invention provides therapeutic methods and compositions for treating cancer, for example, a locally advanced, recurrent, or metastatic solid tumor (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).
  • NSCLC non-small cell lung cancer
  • PDAC pancreatic ductal adenocarcinoma
  • UC pancreatic ductal adenocarcinoma
  • GIST gastrointestinal stromal tumor
  • skin cancer colorectal cancer
  • OV ovarian cancer
  • renal cancer or gallbladder cancer
  • the present invention is based, at least in part, on the development of dosages and dosing regimens for anti-latent TGF-beta 1 antibodies as described herein designed to provide significant anti-tumor activity.
  • acceptor human framework for the purposes herein is 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 comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some examples, the number of amino acid changes are 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.
  • the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments thereof.
  • antibody also includes any antigen binding molecule which comprises variable heavy chain and/or variable light chain structure(s) of immunoglobulin.
  • anti-latent TGF-beta 1 antibody and “an antibody that can bind to latent TGF-beta 1 ” refer to an antibody that is capable of binding latent TGF-beta 1 with sufficient binding activity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting latent TGF-beta 1 .
  • an antibody that can bind to latent TGF-beta 1 is an antibody that specifically binds to latent TGF-beta 1 .
  • the extent of binding activity of an anti-latent TGF-beta 1 antibody to an unrelated, non-latent TGF-beta 1 protein is less than about 10% of the binding activity of the antibody to latent TGF-beta 1 as measured, e.g., by a radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • an antibody that can bind to TGF-beta 1 has a dissociation constant (KD) 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 (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • KD dissociation constant
  • an anti-latent TGF-beta 1 antibody binds to an epitope of latent TGF-beta 1 that is conserved among latent TGF-beta 1 from different species.
  • the anti-latent TGF-beta 1 antibody is an anti-latent TGF-beta 1 antibody disclosed in WO 2021/039945, which is incorporated herein by reference in its entirety. In some examples, the anti-latent TGF-beta 1 antibody is SOF10.
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • 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.
  • an “antibody that binds to the same epitope” as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more.
  • An exemplary competition assay is provided in WO 2021/039945.
  • atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG 1 kappa immunoglobulin that binds PD-L1 .
  • Atezolizumab comprises a single amino acid substitution (asparagine to alanine) at position 297 on the heavy chain (N297A) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc receptors.
  • Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances (proposed INN)) List 112, Vol. 28, No. 4, 2014, p. 488.
  • binding activity refers to the strength of the sum total of noncovalent interactions between one or more binding sites of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • binding activity is not strictly limited to a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the binding activity is particularly called the intrinsic binding affinity (affinity).
  • affinity affinity
  • binding activity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD) or “binding amount of analyte per unit amount of ligand” (hereinbelow, may be referred to as “binding amount”).
  • KD dissociation constant
  • binding amount binding amount of analyte per unit amount of ligand
  • 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 in the following.
  • binding activity-matured refers to an antibody with one or more alterations (e.g., substitutions) in one or more hypervariable regions (HVRs), compared to a parent antigen-binding molecule or a parent antibody which does not carry such alterations, such alterations resulting in an improvement in the binding activity of the antigenbinding molecule or antibody for antigen.
  • HVRs hypervariable regions
  • cancer refers to a disease caused by an uncontrolled division of abnormal cells in a part of the body. Aspects of cancer include solid tumor cancers and non-solid tumor cancers. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • 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 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 carcinoma of the lung; cancer of the urinary tract; breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative); prostate cancer, such as castration-resistant prostate cancer (CRPC); cancer of the peritoneum; hepatocellular cancer; gastric or stomach cancer, including gastrointestinal cancer and gastrointestinal stromal cancer (GIST); pancreatic cancer (e.g., pancre
  • the cancer is a locally advanced, recurrent, or metastatic solid tumor (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, renal cancer, or gallbladder cancer).
  • the cancer may be locally advanced or metastatic. In some instances, the cancer is locally advanced. In other instances, the cancer is metastatic. In some instances, the cancer may be unresectable (e.g., unresectable locally advanced or metastatic cancer). In some instances, the cancer may be recurrent.
  • checkpoint inhibitor refers to a therapeutic agent that antagonizes an immune checkpoint protein, e.g., by blocking binding of an immune checkpoint protein to one or more of its binding partners.
  • exemplary checkpoint inhibitors include but are not limited to a PD-1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atezolizumab)) or a PD-1 binding antagonist (e.g., an anti-PD-1 antibody (e.g., nivolumab)), a CTLA-4 antagonist (e.g., an anti- CTLA-4 antibody (e.g., ipilimumab)), and a LAG-3 antagonist (e.g., an anti-LAG-3 antibody (e.g., relatlimab)).
  • a PD-1 axis binding antagonist e.g., a PD-L1 binding antagonist (e.g., an anti-PD-L
  • chemotherapeutic agent refers to a compound useful in the treatment of cancer, such as a locally advanced, recurrent, or metastatic solid tumor (e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, renal cancer, or gallbladder cancer).
  • a locally advanced, recurrent, or metastatic solid tumor e.g., NSCLC, gastric cancer, PDAC, UC, GIST, skin cancer, colorectal cancer, OV cancer, renal cancer, or gallbladder cancer.
  • chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech/OSI Pharm.); PD 183805 (Cl 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); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3- chloro-4-fluoro-phenyl)-N-
  • Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY1 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (let
  • Cytotoxic agent refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits proliferation, or otherwise hinders a cellular function).
  • Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , 1 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
  • radioactive isotopes e.g., At 211 , 1 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radio
  • Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism.
  • the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin).
  • the cytotoxic agent is an antagonist of EGFR, e.g., N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib).
  • the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and/or CRAF inhibitor.
  • the RAF inhibitor is vemurafenib.
  • the cytotoxic agent is a PI3K inhibitor.
  • Chemotherapeutic agents also include “platinum-based” chemotherapeutic agents, which comprise an organic compound which contains platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Platinum-based chemotherapeutic agents are sometimes called “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
  • additional chemotherapeutic agents e.g., an antimetabolite (e.g., gemcitabine).
  • an “effective amount” refers to the amount of a therapeutic agent (e.g., an anti-latent TGF-beta 1 antibody) or 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 result.
  • a therapeutic agent e.g., an anti-latent TGF-beta 1 antibody
  • therapeutic agents e.g., an anti-latent TGF-beta 1 antibody
  • additional therapeutic agents e.g., a checkpoint inhibitor (e.g., a PD-1 axis antagonist (e.g., an anti-PD-
  • the effective amount of a therapeutic agent or a combination of therapeutic agents is the amount of the agent or of the combination of agents that achieves a clinical endpoint of improved overall response rate (ORR), a complete response (CR), a pathological complete response (pCR), a 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).
  • ORR overall response rate
  • CR complete response
  • pCR pathological complete response
  • PR partial response
  • improved survival e.g., disease-free survival (DFS), progression-free survival (PFS) and/or overall survival (OS)
  • DOR improved duration of response
  • Improvement may be relative to a suitable reference treatment, for example, treatment that does not include the anti-latent TGF-beta 1 antibody and/or treatment that does not include the 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.
  • 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))
  • chemotherapeutic agents e.g., in terms of response rate (e.g., ORR, CR, and/or PR), survival (e.g., PFS and
  • partial response and “PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD prior to treatment.
  • ORR all response rate
  • objective response rate refers interchangeably to the sum of CR rate and PR rate.
  • ORR may be defined the proportion of patients with a CR or PR on two consecutive occasions > 4 weeks apart, as determined by the investigator according to RECIST v1 .1
  • progression-free survival and “PFS” refer to the length of time during and after treatment during which the cancer does not get worse.
  • PFS may include the amount of time subjects have experienced a CR or a PR, as well as the amount of time subjects have experienced stable disease.
  • PFS is defined as the time from the first anti-TGF-beta 1 antibody treatment day to the first occurrence of disease progression or death from any cause during a study (whichever occurs first), as determined by the investigator according to RECIST v1 .1 .
  • all survival and “OS” refer to the length of time from either the date of diagnosis or the start of treatment for a disease (e.g., cancer) that the subject is still alive.
  • the term “duration of response” and “DOR” refer to a length of time from documentation of a tumor response until disease progression or death from any cause, whichever occurs first. In some examples, DOR is defined as as the time from the first anti-TGF-beta 1 antibody treatment day to the first occurrence of disease progression or death from any cause during a study (whichever occurs first), as determined by the investigator according to RECIST v1 .1 .
  • cisplatin-containing chemotherapy means that the subject is not eligible for treatment with a cisplatin-based chemotherapy, either in the attending clinician’s judgment or according to standardized criteria for eligibility for platinum-based chemotherapy that are described herein or known in the art.
  • criteria set forth in Gaisky et al. Lancet Oncol. 12(3) :211 -4, 2011 may be used to determine whether a subject is eligible for cisplatin-based chemotherapy.
  • mUC metastatic UC
  • WHO World Health Association
  • ECG Eastern Cooperative Oncology Group
  • CHI Common Terminology Criteria for Adverse Events
  • CTCAE CTCAE v.4.0 Grade > 2 peripheral neuropathy
  • NYHA New York Heart Association
  • a subject is ineligible for cisplatin-based chemotherapy if they have one or more of the following: impaired renal function (e.g., glomerular filtration rate (GFR) >30 but ⁇ 60 mL/min); GFR may be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, 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 audiometric hearing loss of 25 decibels at two contiguous frequencies); peripheral neuropathy (e.g., NCI CTCAE v4.0 Grade > 2 peripheral neuropathy (i.e., sensory alteration or paresthesia, including tingling)); and/or ECOG performance status assessment (see Oken et al. Am. J. Clin. Oncol. 5:649-655
  • taxanes as used herein is an agent (e.g., a diterpene) which may bind to tubulin, promoting microtubule assembly and stabilization and/or prevent 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, milataxel, tesetaxel, and/or orataxel. Taxanes included herein also include taxoid 10-deacetylbaccatin III and/or derivatives thereof.
  • the taxane is an albumin-coated nanoparticle (e.g., nano-albumin bound (nab)-paclitaxel, i.e., ABRAXANE® and/or nab-docetaxel, ABI-008).
  • the taxane is nab-paclitaxel (ABRAXANE®).
  • the taxane is formulated in CREMAPHOR® (e.g., TAXOL®) and/or in TWEEN® such as polysorbate 80 (e.g., TAXOTERE®).
  • the taxane is liposome- encapsulated taxane.
  • the taxane is a prodrug form and/or conjugated form of taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel poliglumex, and/or linoleyl carbonate-paclitaxel).
  • the paclitaxel is formulated with substantially no surfactant (e.g., in the absence of CREMAPHOR® and/or TWEEN®, such as TOCOSOL® paclitaxel).
  • chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , lgG2, lgG3, lgG4, Ig At , and lgA2.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.
  • “in combination with” refers to administration of one treatment modality in addition to another treatment modality, for example, an anti-cancer therapy that includes administration of 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.
  • 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))
  • a checkpoint inhibitor e.g., a PD-1 axis antagonist (e.g., an anti-PD-L1 antibody (e
  • a drug that is administered “concurrently” with one or more other drugs is administered during the same treatment cycle, on the same day of treatment, as the one or more other drugs, and, optionally, at the same time as the one or more other drugs.
  • the concurrently administered drugs are each administered on day 1 of a 3 week cycle.
  • “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with 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; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions.
  • a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • the C-terminal lysine (Lys447) or glycine-lysine (residues 446-447) of the Fc region may or may not be present.
  • EU numbering system also called 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 .
  • “Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues.
  • the FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, 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.
  • full length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.
  • host cell refers to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells.
  • Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.
  • a “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • a “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.
  • the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences.
  • the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91 -3242, Bethesda MD (1991 ), vols. 1 -3.
  • the subgroup is subgroup kappa I as in Kabat et al., supra.
  • the subgroup is subgroup III as in Kabat et al., supra.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non- human HVRs and amino acid residues from human FRs.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
  • a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
  • a “humanized form” of an antibody, e.g., a non-human antibody refers to an antibody that has undergone humanization.
  • hypervariable region refers to each of the regions of an antibody variable domain which are hypervariable in sequence (“complementarity determining regions” or “CDRs”) and/or form structurally defined loops (“hypervariable loops”) and/or contain the antigencontacting residues (“antigen contacts”).
  • CDRs complementarity determining regions
  • hypervariable loops form structurally defined loops
  • antigen contacts antigen contacts
  • antibodies comprise six HVRs: three in the VH (H1 , H2, H3), and three in the VL (L1 , L2, L3).
  • Exemplary HVRs herein include:
  • HVR residues and other residues in the variable domain are numbered herein according to Kabat et al., supra.
  • an “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.
  • an “isolated” antibody is one which has been separated from a component of its natural environment.
  • an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC).
  • electrophoretic e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis
  • chromatographic e.g., ion exchange or reverse phase HPLC
  • isolated nucleic acid encoding an anti-latent TGF-beta 1 antibody or “nucleic acid encoding an anti-latent TGF-beta 1 antibody” refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.
  • the Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1 -107 of the light chain and residues 1 -113 of the heavy chain) (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 a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra).
  • the “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies composing the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
  • naked antibody refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel.
  • the naked antibody may be present in a pharmaceutical formulation.
  • “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures.
  • native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain.
  • VH variable heavy domain
  • VL variable region
  • the light chain of an antibody may be assigned to one of two types, called kappa (kappa) and lambda (lambda), based on the amino acid sequence of its constant domain.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
  • PD-1 axis binding antagonist refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and/or target cell killing).
  • a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.
  • the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist.
  • the PD-1 axis binding antagonist is a PD-L1 binding antagonist.
  • PD-L1 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1 .
  • a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners.
  • the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1 .
  • the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1 .
  • a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD- L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-L1 binding antagonist binds to PD-L1 .
  • a PD- L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody).
  • anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK- 106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636
  • the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab).
  • the PD-L1 binding antagonist is MDX-1105.
  • the PD-L1 binding antagonist is MEDI4736 (durvalumab).
  • the PD-L1 binding antagonist is MSB0010718C (avelumab).
  • the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 , which in some instances may be administered orally.
  • Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003.
  • the PD-L1 binding antagonist is atezolizumab.
  • PD-1 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction 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 death 1 ) is also referred to in the art as “programmed cell death 1 ,” “PDCD1 ,” “CD279,” and “SLEB2.”
  • An exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116.
  • the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2.
  • PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
  • a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T- cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-1 binding antagonist binds to PD-1 .
  • the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody).
  • anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI
  • a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MED1 -0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108.
  • a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab.
  • Other additional exemplary PD-1 binding antagonists include BION-004, CB201 , AUNP-012, ADG104, and LBL-006.
  • PD-L2 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 .
  • PD-L2 (programmed death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1 LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.”
  • An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51 .
  • a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners.
  • the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1 .
  • Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 .
  • a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-L2 binding antagonist binds to POUT
  • a PD-L2 binding antagonist is an immunoadhesin.
  • a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.
  • programmed death ligand 1 and “PD-L1” refer herein to native sequence human PD- L1 polypeptide.
  • Native sequence PD-L1 polypeptides are provided under Uniprot Accesion No. Q9NZQ7.
  • the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-1 (isoform 1 ).
  • the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-2 (isoform 2).
  • the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-3 (isoform 3).
  • PD-L1 is also referred to in the art as “programmed cell death 1 ligand 1 ,” “PDCD1 LG1 ,” “CD274,” “B7-H,” and “PDL1 .”
  • Percent (%) amino acid sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) software, or GENETYX (registered trademark) (Genetyx Co., Ltd.). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • subject refers to a human subject.
  • the subject may be an adult.
  • the subject may be a patient.
  • 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 that results from processing in the cell.
  • the term also encompasses naturally occurring variants of TGF-beta 1 , e.g., splice variants or allelic 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).
  • TGF-beta 1 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).
  • TGF-beta 1 encompasses both latent TGF-beta 1 and mature TGF-beta 1 .
  • latent TGF-beta 1 refers to any TGF-beta 1 which forms a latent TGF- beta 1 complex (“cell surface latent TGF-beta 1 ,” LLC or SLC (see below)) and/or which is incapable of binding to its receptors.
  • Transforming growth factor-beta 1 is a member of TGF-beta, which is a member of TGF-beta superfamily.
  • TGF-beta is synthesized as a precursor protein, which forms a homodimer that interacts with its latency-associated peptide (LAP) and a latent TGF-beta-binding protein (LTBP), forming a larger complex called the large latent complex (LLC).
  • LAP latency-associated peptide
  • LTBP latent TGF-beta-binding protein
  • LLC large latent complex
  • the amino acid sequence of an exemplary latent human TGF-beta 1 is amino acids 30-390 of SEQ ID NO: 53.
  • the amino acid sequence of and exemplary mouse latent TGF-beta 1 is amino acids 30-390 of SEQ ID NO: 55.
  • the amino acid sequence of an exemplary latent cynomolgus monkey TGF-beta 1 is amino acids 30-390 of SEQ ID NO: 57.
  • SLC Small Latent Complex
  • LTBP latent TGF-beta binding protein
  • LLC large latent complex
  • SLC may also be covalently linked to other additional proteins, such as glycoprotein A repetitions predominant (GARP) or leucine-rich repeatcontaining protein 33 (LRRC33).
  • GARP and LRRC have a transmembrane domain and associate with LAP on the cell surface (see, e.g., Wang et al., Mol Biol Cell. 2012 Mar;23(6):1129-39).
  • LLCs it is reported that LLCs associate covalently with the extracellular matrix (ECM) via the N-termini of the LTBPs (see, e.g., Saharinen et al., Cytokine Growth Factor Rev. 1999 Jun;10(2):99-117.).
  • latent TGF-beta 1 associated with the ECM on a cell surface is referred to as “cell surface latent TGF- beta 1
  • active TGF-beta 1 refers to any TGF-beta 1 homodimer which does not form a latent TGF-beta 1 complex (LLC or SLC) and which is capable of binding to its receptors.
  • LLC latent TGF-beta 1 complex
  • the TGF-beta 1 activation process involves the release of the LLC from the ECM, followed by further proteolysis of LAP to release active TGF-beta to its receptors.
  • 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 called “(latent) TGF- beta-cleaving proteases” or “(latent) TGF-beta 1 -cleaving proteases” in the context of the present invention.
  • thrombospondin 1 TSP-1
  • Neuropilin-1 Nrp1
  • ADAMSTS1 F-spondin activate latent TGF-beta.
  • integrins preferably integrin alpha V beta 8 and/or integrin alpha V beta 6
  • TGF-beta TGF-beta by binding to the RGD motif present in LAP and inducing the release of mature TGF-beta from its latent complex form.
  • treating comprises effective cancer treatment with an effective amount of a therapeutic agent (e.g., an anti-latent TGF-beta 1 antibody) or 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).
  • a therapeutic agent e.g., an anti-latent TGF-beta 1 antibody
  • therapeutic agents e.g., an anti-latent TGF-beta 1 antibody
  • additional therapeutic agents e.g., a checkpoint inhibitor (e.g., a PD-1 axis antagonist (e.g., an anti-PD-L1 antibody (e.g.,
  • Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy.
  • the treatment may be first-line treatment (e.g., the subject may be previously untreated or not have received prior systemic therapy), or second line or later (e.g., third line, fourth line, fifth line, or later) treatment.
  • Tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells
  • unresectable refers to a cancer for which surgical resection is not possible or cannot be safely performed.
  • variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • the variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs).
  • FRs conserved framework regions
  • HVRs hypervariable regions
  • antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991 ).
  • variable domain residue numbering as in Kabat or “amino acid position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain.
  • a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc., according to Kabat) after heavy chain FR residue 82.
  • the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.
  • compositions for use in treating cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • an anti-cancer therapy that includes an anti-latent TGF-beta 1 antibody.
  • a method of treating a subject having a cancer comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg.
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg.
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg.
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • the anti-latent TGF-beta 1 antibody is administered to the subject in a dosing regimen comprising one or more 21 -day dosing cycles.
  • the anti-latent TGF-beta 1 antibody may be administered to the subject on Day 1 of each 21 -day dosing cycle.
  • a method of treating a subject having a cancer comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg every three weeks (Q3W).
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg every three weeks (Q3W).
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg every three weeks (Q3W).
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • a method of treating a subject having a cancer comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg.
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg.
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg.
  • the anti-latent TGF-beta 1 antibody is administered to the subject in a dosing regimen comprising one or more 28-day dosing cycles.
  • the anti-latent TGF-beta 1 antibody may be administered to the subject on Days 1 and 15 of each 28-day dosing cycle.
  • the invention provides a method of treating a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the method comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg every two weeks (Q2W).
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg every two weeks (Q2W).
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • the invention provides the use of an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a cancer (e.g., a locally advanced, recurrent, or metastatic solid tumor), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg every two weeks (Q2W).
  • a cancer e.g., a locally advanced, recurrent, or metastatic solid tumor
  • the cancer is a locally advanced, recurrent, or metastatic solid tumor.
  • the cancer is NSCLC, gastric cancer, PDAC, or UC.
  • Any suitable anti-latent TGF-beta 1 antibody may be administered to the subject, including any anti-latent TGF-beta 1 antibody disclosed herein or in WO 2021/039945 or in Section III below.
  • 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 16, 17, and 18, respectively; (c) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 19, 20, and 21 , respectively, and HVR-L1 , HVR-L2, and HVR- L3 comprising the amino acid sequences of SEQ ID NO:
  • 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively.
  • the cancer is a a locally advanced, recurrent, or metastatic solid tumor.
  • a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15,
  • an anti-latent TGF-beta 1 for use in treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage of 1800 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-
  • the anti-latent TGF-beta 1 antibody is administered to the subject in a dosing regimen comprising one or more 21 -day dosing cycles.
  • the anti-latent TGF-beta 1 antibody may be administered to the subject on Day 1 of each 21 -day dosing cycle.
  • a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of S
  • an anti-latent TGF-beta 1 for use in treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 ,
  • a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14,
  • an anti-latent TGF-beta 1 for use in treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the following six HVRs: (
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and
  • the anti-latent TGF-beta 1 antibody is administered to the subject in a dosing regimen comprising one or more 28-day dosing cycles.
  • the anti-latent TGF-beta 1 antibody may be administered to the subject on Days 1 and 15 of each 28-day dosing cycle.
  • a method of treating a subject having a locally advanced, recurrent, or metastatic solid tumor comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of
  • an anti-latent TGF-beta 1 for use in treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and H
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of 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, renal cancer, or gallbladder cancer), the treatment comprising administering to the subject an anti-cancer therapy comprising an anti-latent TGF-beta 1 antibody at a dosage 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1
  • the anti-latent TGF-beta 1 antibody may be administered by any suitable route. In some examples, the anti-latent TGF-beta 1 antibody is administered to the subject intravenously. In some examples, the anti-latent TGF-beta 1 antibody is administered to the subject intravenously by infusion.
  • a tumor sample from the subject has been determined to have a detectable level of PD-L1 expression.
  • Any suitable approach to detect PD-L1 expression may be used, including any approach described herein (see, e.g., Section V below).
  • the subject is 18 years or older.
  • the subject may be an adult.
  • the anti-cancer therapy may represent any suitable line of treatment.
  • the anti-cancer therapy is a first-line therapy.
  • the anti-cancer therapy is a second-line therapy or a third-line therapy.
  • the anti-cancer therapy is a first-line therapy.
  • the patient may be previously untreated.
  • the subject has not been previously treated with a checkpoint inhibitor.
  • the solid tumor is metastatic. In other examples, the solid tumor is locally advanced. In yet other examples, the solid tumor is recurrent.
  • any suitable solid tumor may be treated.
  • the locally advanced, recurrent, or metastatic solid tumor is NSCLC, gastric cancer, PDAC, or UC.
  • the locally advanced, recurrent, or metastatic solid tumor is NSCLC.
  • the NSCLC may be histologically or cytolog ically confirmed metastatic nonsquamous NSCLC or metastatic squamous NSCLC.
  • the subject has had disease progression during or following treatment for metastatic or locally advanced, inoperable NSCLC that comprised a platinum- containing chemotherapy regimen and a PD-1 axis binding antagonist, given in combination as one line of therapy or as two separate lines of therapy, in either order, for a maximum of two prior lines of systemic therapy.
  • the subject has previously received a combination therapy comprising a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist.
  • the subject has previously received a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist as individual regimens.
  • the subject had disease progression or recurrence within 6 months of definitive therapy for locally advanced NSCLC.
  • a tumor sample from the subject has been determined to have a detectable level of PD-L1 expression.
  • the locally advanced, recurrent, or metastatic solid tumor is gastric cancer.
  • the subject has unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be adenocarcinoma.
  • the gastric cancer comprises esophagogastric junction cancer.
  • the gastric cancer is HER2-negative gastric cancer.
  • the subject is previously untreated for gastric cancer and/or the subject has not been previously treated with a checkpoint inhibitor.
  • the locally advanced, recurrent, or metastatic solid tumor is PDAC.
  • the subject has histologically or cytolog ically confirmed metastatic PDAC.
  • the subject is previously untreated for the PDAC and/or the subject has not been previously treated with a checkpoint inhibitor.
  • the locally advanced, recurrent, or metastatic solid tumor is UC.
  • the subject has histologically documented, locally advanced (T4b, any N; or any T, N2-N3) UC, or metastatic UC (M1 , Stage 4).
  • the subject is previously untreated for UC.
  • the subject is ineligible for cisplatin-containing chemotherapy.
  • the subject is ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) impaired renal function in terms of glomerular filtration rate (GFR) of > 30 mL/min but ⁇ 60 mL/min as assessed by direct measurement or by calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two contiguous frequencies as measured by audiometry; (iii) Grade 2 peripheral neuropathy; or (iv) Eastern Cooperative Oncology Group (ECOG) Performance Status of 2.
  • GFR glomerular filtration rate
  • the subject has previously received at least one platinum-containing chemotherapy regimen.
  • the subject had disease progression during or following treatment with at least one platinum-containing chemotherapy regimen.
  • the at least one platinum-containing chemotherapy regimen comprised (i) gemcitabine and cisplatin or carboplatin or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin.
  • the subject received prior adjuvant or neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.
  • the subject received one cycle of a platinum-containing chemotherapy regimen but discontinued because of a Grade 4 hematologic toxicity or a Grade 3-4 non-hematologic toxicity.
  • the subject received no more than two prior lines of treatment for the locally advanced or metastatic UC.
  • the subject has not received prior treatment with a T-cell costimulating therapy or a checkpoint inhibitor.
  • the anti-latent TGF-beta 1 antibody comprises: (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 to the amino acid sequence of SEQ ID NO: 7, (ii) a light chain variable domain (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 to the amino acid sequence of SEQ ID NO: 8, or (iii) a VH sequence as defined in (i) and a VL sequence as defined in (ii);
  • the anti-latent TGF-beta 1 antibody comprises: (a) a VH sequence of SEQ ID NO: 7 and a VL sequence of SEQ ID NO: 8; (b) a VH sequence of SEQ ID NO: 31 and a VL sequence of SEQ ID NO: 32; (c) a VH sequence of SEQ ID NO: 33 and a VL sequence of SEQ ID NO: 34; or (d) a VH sequence of SEQ ID NO: 35 and a VL sequence of SEQ ID NO: 36.
  • the anti-latent TGF-beta 1 antibody comprises a VH sequence of SEQ ID NO: 7 and a VL sequence of SEQ ID NO: 8.
  • the anti-latent TGF-beta 1 antibody is a chimeric antibody. In some examples, the anti-latent TGF-beta 1 antibody is a humanized antibody. In some examples, the anti-latent TGF-beta 1 antibody is a full-length antibody.
  • the anti-latent TGF-beta 1 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 38; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 and a light chain comprising the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising the amino acid sequence of SEQ ID NO: 42; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 44; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 47 and a light chain comprising the amino acid sequence of SEQ ID NO: 48; (g) a
  • the anti-latent TGF-beta 1 antibody comprises a modified IgG 1 Fc region having reduced effector function compared with a wild-type IgG 1 Fc region.
  • the modified IgG 1 Fc region comprises a constant heavy (CH) region comprising one or more of the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, and/or S440E (EU numbering).
  • the CH region comprises the amino acid sequence of SEQ ID NO: 9.
  • the modified IgG 1 Fc region comprises a constant light (CL) domain comprising the amino acid sequence of SEQ ID NO: 10.
  • the anti-latent TGF-beta 1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain sequence comprising the amino acid sequence of SEQ ID NO: 12.
  • the anti-latent TGF-beta 1 antibody is an antibody fragment that binds to latent TGF-beta 1 .
  • the anti-latent TGF-beta 1 antibody is administered to the subject as a monotherapy.
  • the anti-latent TGF-beta 1 antibody is administered to the subject in combination with one or more additional therapeutic agents. Any suitable additional therapeutic agents or combinations of additional therapeutic agents may be administered, including any described herein.
  • the one or more additional therapeutic agents comprises a checkpoint inhibitor.
  • the checkpoint inhibitor comprises a PD-1 axis binding antagonist or a CTLA4 antagonist.
  • the checkpoint inhibitor comprises a PD-1 axis binding antagonist, including any PD-1 axis binding antagonist disclosed herein (see, e.g., Section IV).
  • the PD-1 axis binding antagonist comprises a PD-L1 binding antagonist, a PD-1 binding antagonist, or a PD-L2 binding antagonist.
  • the PD-1 axis binding antagonist comprises a PD-L1 binding antagonist.
  • the PD-L1 binding antagonist comprises an anti-PD-L1 antibody. Any suitable anti-PD- L1 antibody may be used.
  • the anti-PD-L1 antibody comprises atezolizumab, durvalumab, avelumab, or MDX-1105.
  • the anti-PD-L1 antibody comprises atezolizumab.
  • the atezolizumab is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the atezolizumab is administered to the subject on Day 1 of each 21 -day dosing cycle.
  • the atezolizumab is administered to the subject at a dose of 1200 mg.
  • the one or more dosing cycles comprise 14-day dosing cycles or 28-day dosing cycles.
  • the one or more dosing cycles comprise 14-day dosing cycles, and the atezolizumab is administered to the subject at a dose of 840 mg. In some examples, the atezolizumab is administered to the subject on Day 1 of each 14-day dosing cycle. In some examples, the one or more dosing cycles comprise 28-day dosing cycles, and the atezolizumab is administered to the subject at a dose of 1680 mg. In some examples, the atezolizumab is administered to the subject on Day 1 of each 28-day dosing cycle. In some examples, the atezolizumab is administered to the subject intravenously. In some examples, the atezolizumab is administered to the subject intravenously by infusion.
  • Atezolizumab is administered to the subject intravenously at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks.
  • the PD-1 axis binding antagonist comprises a PD-1 binding antagonist.
  • the PD-1 binding antagonist comprises an anti-PD-1 antibody. Any suitable anti-PD-1 antibody may be used.
  • the anti-PD-1 antibody comprises nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, zimberelimab, balstilimab, genolimzumab, cetrelimab, or budigalimab.
  • the anti-PD-1 antibody comprises nivolumab.
  • the nivolumab is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the nivolumab is administered to the subject on Day 1 of each 21 -day dosing cycle.
  • the nivolumab is administered to the subject at a dose of 360 mg.
  • the nivolumab is administered to the subject intravenously.
  • the nivolumab is administered to the subject intravenously by infusion.
  • the one or more additional therapeutic agents is selected from a chemotherapeutic agent, an immunotherapy agent, a radiation therapy agent, an anti-angiogenic agent, and any combination thereof.
  • the one or more additional therapeutic agents includes an agonist directed against an activating co-stimulatory molecule.
  • an activating co-stimulatory molecule may include CD40, CD226, CD28, 0X40, GITR, CD137, CD27, HVEM, or CD127.
  • the one or more additional therapeutic agents includes an agonist antibody that binds to CD40, CD226, CD28, 0X40, GITR, CD137, CD27, HVEM, or CD127.
  • the one or more additional therapeutic agents includes an antagonist directed against an inhibitory co-stimulatory molecule.
  • an inhibitory co-stimulatory molecule may include CTLA-4 (also known as CD152), TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA/B, or arginase.
  • CTLA-4 also known as CD152
  • TIM-3 also known as CD152
  • BTLA also known as CD152
  • VISTA long-term intraosteal gammase
  • LAG-3 also known as CD152
  • B7-H3, B7-H4 IDO
  • TIGIT TIGIT
  • MICA/B arginase
  • the one or more additional therapeutic agents comprise one or more chemotherapeutic agents. Any suitable chemotherapeutic agents may be used, including any chemotherapeutic agents or combinations of chemotherapeutic agents disclosed herein (see, e.g., Section VI below).
  • the one or more chemotherapeutic agents comprise a platinumbased chemotherapeutic agent, an antimetabolite, a cytotoxic agent, a growth inhibitory agent, a taxane, a folate analog, or any combination thereof.
  • the platinum-based chemotherapeutic agent comprises oxaliplatin, cisplatin, or carboplatin. In some examples, the platinum-based chemotherapeutic agent comprises oxaliplatin. In some examples, the oxaliplatin is administered to the subject in a dosing regimen comprising one or more dosing cycles. In some examples, the one or more dosing cycles comprise 21 -day dosing cycles. In some examples, the oxaliplatin is administered to the subject on Day 1 of each 21 -day dosing cycle. In some examples, the oxaliplatin is administered to the subject at a dose of 130 mg/m 2 . In some examples, the oxaliplatin is administered to the subject intravenously.
  • the antimetabolite comprises capecitabine, gemcitabine, 5-fluorouracil, or tegafur. In some examples, the antimetabolite comprises capecitabine. In some examples, the capecitabine is administered to the subject in a dosing regimen comprising one or more dosing cycles. In some examples, the one or more dosing cycles comprise 21 -day dosing cycles. In some examples, the capecitabine is administered to the subject on Days 1 -14 of each 21 -day dosing cycle. In some examples, the capecitabine is administered to the subject at a dose of 1000 mg/m 2 twice daily. In some examples, the capecitabine is administered to the subject orally.
  • the antimetabolite comprises gemcitabine.
  • the gemcitabine is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 28-day dosing cycles.
  • the gemcitabine is administered to the subject on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the gemcitabine is administered to the subject at a dose of 1000 mg/m 2 twice daily.
  • the gemcitabine is administered to the subject intravenously.
  • the antimetabolite comprises tegafur.
  • the antimetabolite comprises S-1 (tegafur-gimeracil-oteracil potassium).
  • the S-1 is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the S-1 is administered to the subject on Days 1 -14 of each 21 -day dosing cycle.
  • the S-1 is administered to the subject at a dose of 40 mg/m 2 twice daily.
  • the S-1 is administered to the subject orally.
  • the taxane comprises nab-paclitaxel or paclitaxel.
  • the taxane comprises nab-paclitaxel.
  • the nab-paclitaxel is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 28-day dosing cycles.
  • the nab-paclitaxel is administered to the subject on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the nab-paclitaxel is administered to the subject at a dose of 125 mg/m 2 .
  • the nab-paclitaxel is administered to the subject intravenously.
  • the folate analog comprises leucovorin.
  • a method of treating a subject having a locally advanced, recurrent, or metastatic NSCLC comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic NSCLC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a locally advanced, recurrent, or metastatic NSCLC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-
  • the NSCLC is histologically or cytological ly confirmed metastatic nonsquamous NSCLC or metastatic squamous NSCLC.
  • the subject has had disease progression during or following treatment for metastatic or locally advanced, inoperable NSCLC that comprised a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist, given in combination as one line of therapy or as two separate lines of therapy, in either order, for a maximum of two prior lines of systemic therapy.
  • the subject has previously received a combination therapy comprising a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist. In some examples, the subject has previously received a platinum-containing chemotherapy regimen and a PD-1 axis binding antagonist as individual regimens.
  • the subject had disease progression or recurrence within 6 months of definitive therapy for locally advanced NSCLC.
  • a tumor sample from the subject has been determined to have a detectable level of PD-L1 expression.
  • a method of treating a subject having a locally advanced, recurrent, or metastatic gastric cancer comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic gastric cancer, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a locally advanced, recurrent, or metastatic gastric cancer, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti- latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-
  • the subject has unresectable locally advanced or metastatic gastric cancer that is histologically confirmed to be adenocarcinoma.
  • the gastric cancer comprises esophagogastric junction cancer.
  • the gastric cancer is HER2-negative gastric cancer.
  • the subject is previously untreated for gastric cancer and/or the subject has not been previously treated with a checkpoint inhibitor.
  • a method of treating a subject having a locally advanced, recurrent, or metastatic PDAC comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic PDAC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a locally advanced, recurrent, or metastatic PDAC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-
  • the subject has histologically or cytologically confirmed metastatic PDAC.
  • the subject is previously untreated for the PDAC and/or the subject has not been previously treated with a checkpoint inhibitor.
  • a method of treating a subject having a locally advanced, recurrent, or metastatic UC comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO:
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, recurrent, or metastatic UC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 compris
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a locally advanced, recurrent, or metastatic UC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H
  • the subject has histologically documented, locally advanced (T4b, any N; or any T, N2-N3) UC, or metastatic UC (M1 , Stage 4).
  • the subject is previously untreated for UC.
  • the subject is ineligible for cisplatin-containing chemotherapy.
  • the subject is ineligible for cisplatin-containing chemotherapy as defined by any one of the following criteria: (i) impaired renal function in terms of glomerular filtration rate (GFR) of > 30 mL/min but ⁇ 60 mL/min as assessed by direct measurement or by calculation from serum or plasma creatinine; (ii) hearing loss of 25 dB at two contiguous frequencies as measured by audiometry; (iii) Grade 2 peripheral neuropathy; or (iv) ECOG Performance Status of 2.
  • GFR glomerular filtration rate
  • the subject has previously received at least one platinum-containing chemotherapy regimen.
  • the subject had disease progression during or following treatment with at least one platinum-containing chemotherapy regimen.
  • the at least one platinum-containing chemotherapy regimen comprised (i) gemcitabine and cisplatin or carboplatin or (ii) methotrexate, vinblastine, doxorubicin, and cisplatin.
  • the subject received prior adjuvant or neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant or neoadjuvant regimen.
  • the subject received one cycle of a platinum-containing chemotherapy regimen but discontinued because of a Grade 4 hematologic toxicity or a Grade 3-4 non-hematologic toxicity.
  • the subject received no more than two prior regimens of treatment for the locally advanced or metastatic UC.
  • the subject has not received prior treatment with a T-cell co-stimulating therapy or a checkpoint inhibitor.
  • a method of treating a subject having a metastatic non- squamous NSCLC or a metastatic squamous NSCLC comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a metastatic non-squamous NSCLC or a metastatic squamous NSCLC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF- beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a metastatic non-squamous NSCLC or a metastatic squamous NSCLC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDY
  • a method of treating a subject having a locally advanced, unresectable, or metastatic HER2-negative gastric cancer comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced, unresectable, or metastatic HER2-negative gastric cancer, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti- latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (a) an HVR-H
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a locally advanced, unresectable, or metastatic HER2- negative gastric cancer, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (
  • a method of treating a subject having a metastatic PDAC comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti- latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR- H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of QASQSISTYLA (SEQ ID NO:
  • the invention provides an anti-latent TGF-beta 1 for use in treatment of a subject having a metastatic PDAC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a metastatic PDAC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 28-day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1200 mg intravenously on Days 1 and 15 of each 28-day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR
  • a method of treating a subject having a locally advanced or metastatic UC comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino acid sequence of QASQSISTYLA (S)
  • an anti-latent TGF-beta 1 for use in treatment of a subject having a locally advanced or metastatic UC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anticancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti-latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR- H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID NO:3); (d) an HVR-L1 comprising the amino
  • an anti-latent TGF-beta 1 in the manufacture of a medicament for treatment of a subject having a locally advanced or metastatic UC, the treatment comprising administering to the subject an anti-cancer therapy in a dosing regimen comprising one or more 21 -day dosing cycles, wherein the anti-cancer therapy comprises: (i) an anti-latent TGF-beta 1 antibody at a dosage of 1800 mg intravenously on Day 1 of each 21 -day dosing cycle, wherein the anti- latent TGF-beta 1 antibody comprises the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEAMN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of YIYTSGTTYRANWARG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of GTGIYDYYYWVMDL (SEQ ID N0:3); (d)
  • the subject may be administered the anti-latent TGF-beta 1 antibody until loss of clinical benefit or unacceptable toxicity.
  • each dosing cycle may have any suitable length, e.g., about 7 days, about 14 days, about 21 days, about 28 days, or longer. In some instances, each dosing cycle is about 21 days. In some instances, each dosing cycle is 21 days. In some instances, each dosing cycle is about 28 days. In some instances, each dosing cycle is 28 days.
  • the method comprises between 1 and 40 dosing 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 dosing cycles).
  • dosing 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 dosing cycles.
  • a subject is administered a total of 1 to 50 doses of a anti-latent TGF-beta 1 antibody, e.g., 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 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 1 to
  • the anti-latent TGF-beta 1 antibody and/or any additional therapeutic agent(s) may be administered in any suitable manner known in the art.
  • 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)
  • chemotherapeutic 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)
  • the anti-latent TGF-beta 1 antibody and/or any additional therapeutic agent(s) may be administered sequentially (on different days) or concurrently (on the same day or during the same treatment cycle).
  • the anti-latent TGF-beta 1 antibody is administered prior to the additional therapeutic agent. In other instances, the anti-latent TGF-beta 1 antibody is administered after the additional therapeutic agent. In some instances, the anti-latent TGF- beta 1 antibody and/or any additional therapeutic agent(s) may be administered on the same day. In some instances, the anti-latent TGF-beta 1 antibody may be administered prior to an additional therapeutic agent that is administered on the same day. For example, the anti-latent TGF-beta 1 antibody may be administered prior to chemotherapy on the same day.
  • the anti- latent TGF-beta 1 antibody may be administered prior to 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) on the same day.
  • 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))
  • the anti-latent TGF-beta 1 antibody may be administered after an additional therapeutic agent that is administered on the same day.
  • the anti-latent TGF-beta 1 antibody is administered at the same time as the additional therapeutic agent.
  • the PD anti-latent TGF-beta 1 antibody is in a separate composition as the additional therapeutic agent. In some instances, the anti-latent TGF-beta 1 antibody is in the same composition as the additional therapeutic agent. In some instances, the anti-latent TGF-beta 1 antibody is administered through a separate intravenous line from any other therapeutic agent administered to the subject on the same day.
  • the anti-latent TGF-beta 1 antibody and any additional therapeutic agent(s) may be administered by the same route of administration or by different routes of administration.
  • the anti- latent TGF-beta 1 antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • the additional therapeutic agent is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • the anti-latent TGF-beta 1 antibody is administered intravenously.
  • Also provided herein are methods for treating cancer in a subject comprising administering to the subject an anti-cancer 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) in combination with another anti-cancer agent or cancer therapy.
  • 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))
  • a PD-1 axis antagonist e.g., an anti-PD-L1 antibody (e.g., atezolizumab) or
  • an anti-latent TGF-beta 1 antibody may be administered in combination with an additional chemotherapy or chemotherapeutic agent (see definition above); a targeted therapy or targeted therapeutic agent; an immunotherapy or immunotherapeutic agent, for example, a monoclonal antibody; one or more cytotoxic agents (see definition above); or combinations thereof.
  • the treatment may further comprise an additional therapy.
  • Any suitable additional therapy known in the art or described herein may be used.
  • the additional therapy may be radiation therapy, surgery, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, gamma irradiation, or a combination of the foregoing.
  • the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence and/or severity of side effects of treatment, such as anti-nausea agents, a corticosteroid (e.g., prednisone or an equivalent, e.g., at a dose of 1 -2 mg/kg/day), hormone replacement medicine(s), and the like).
  • side-effect limiting agents e.g., agents intended to lessen the occurrence and/or severity of side effects of treatment, such as anti-nausea agents, a corticosteroid (e.g., prednisone or an equivalent, e.g., at a dose of 1 -2 mg/kg/day), hormone replacement medicine(s), and the like.
  • anti-latent TGF-beta 1 antibodies that can be used in the methods and compositions described herein. Any suitable anti-latent TGF-beta 1 antibody may be used, including any anti-latent TGF-beta 1 antibody disclosed in WO 2021/039945 or herein.
  • 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 comprising the amino acid sequences of SEQ ID NO: 1 , 2, and 3, respectively, and/or HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and/or HVR-L1 , HVR- L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 16, 17, and 18, respectively; (c) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 19, 20, and 21 , respectively, and/or HVR-L1 , HVR-
  • 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 comprising the amino acid sequences of SEQ ID NO: 1 , 2, and 3, respectively, and/or HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively.
  • 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively; (b) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 13, 14, and 15, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 16, 17, and 18, respectively; (c) HVR-H1 , HVR-H2, and HVR-H3 comprising the amino acid sequences of SEQ ID NO: 19, 20, and 21 , respectively, and HVR-L1 , HVR-L2, and HVR- L3 comprising the amino acid sequences of SEQ ID NO:
  • 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 NO: 1 , 2, and 3, respectively, and HVR-L1 , HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NO: 4, 5, and 6, respectively.
  • the anti-latent TGF-beta 1 antibody comprises: (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 to the amino acid sequence of SEQ ID NO: 7, (ii) a light chain variable domain (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 to the amino acid sequence of SEQ ID NO: 8, or (Hi) a VH sequence as defined in (i) and a VL sequence as defined in (ii); (b
  • any of the preceding anti-latent TGF-beta 1 antibodies above may include at least one, two, three, four, five, or six HVRs disclosed above.
  • a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-latent TGF-beta 1 antibody comprising that sequence retains the ability to bind to latent TGF-beta 1 .
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-latent TGF-beta 1 antibody comprising that sequence retains the ability to bind to latent TGF-beta 1 .
  • the anti-latent TGF-beta 1 antibody comprises: (a) a VH sequence of SEQ ID NO: 7 and a VL sequence of SEQ ID NO: 8; (b) a VH sequence of SEQ ID NO: 31 and a VL sequence of SEQ ID NO: 32; (c) a VH sequence of SEQ ID NO: 33 and a VL sequence of SEQ ID NO: 34; or (d) a VH sequence of SEQ ID NO: 35 and a VL sequence of SEQ ID NO: 36.
  • the anti-latent TGF-beta 1 antibody comprises a VH sequence of SEQ ID NO: 7 and a VL sequence of SEQ ID NO: 8.
  • the anti-latent TGF-beta 1 antibody is a chimeric antibody. In some examples, the anti-latent TGF-beta 1 antibody is a humanized antibody. In some examples, the anti-latent TGF-beta 1 antibody is a full-length antibody.
  • the anti-latent TGF-beta 1 antibody comprises: (a) a heavy chain comprising 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 to the amino acid sequence of SEQ ID NO: 37 and a light chain comprising 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 to the amino acid sequence of SEQ ID NO: 38; (b) a heavy chain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%,
  • the anti-latent TGF-beta 1 antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 38; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 and a light chain comprising the amino acid sequence of SEQ ID NO: 40; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 41 and a light chain comprising the amino acid sequence of SEQ ID NO: 42; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 44; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 47 and a light chain comprising the amino acid sequence of SEQ ID NO: 48; (g) a
  • the anti-latent TGF-beta 1 antibody comprises a modified IgG 1 Fc region having reduced effector function compared with a wild-type IgG 1 Fc region.
  • the modified IgG 1 Fc region comprises a constant heavy (CH) region comprising one or more of the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, and/or S440E (EU numbering).
  • the modified IgG 1 Fc region comprises a CH region comprising the following substitutions: K214R, L235R, G236R, M428L, N434A, Q438R, and S440E (EU numbering).
  • the CH region comprises 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 to the amino acid sequence of SEQ ID NO: 9.
  • the CH region comprises the amino acid sequence of SEQ ID NO: 9.
  • the modified IgG 1 Fc region comprises a constant light (CL) domain comprising the amino acid sequence of SEQ ID NO: 10 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 to the amino acid sequence of SEQ ID NO: 10.
  • CL constant light
  • the modified IgG 1 Fc region comprises a CL domain comprising the amino acid sequence of SEQ ID NO: 10.
  • the anti-latent TGF-beta 1 antibody comprises a heavy chain comprising 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 to the amino acid sequence of SEQ ID NO: 11 and a light chain sequence comprising 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 to the amino acid sequence of SEQ ID NO: 12.
  • the anti-latent TGF-beta 1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain sequence comprising the amino acid sequence of SEQ ID NO: 12.
  • the anti-latent TGF-beta 1 antibody is an antibody fragment that binds to latent TGF-beta 1 .
  • any of the anti-latent TGF-beta 1 antibodies disclosed herein may include one or more post- translational modifications.
  • Post-translational modifications include but are not limited to a modification of glutamine or glutamate in N-terminus of heavy chain or light chain to pyroglutamic acid by pyroglutamylation.
  • the anti-latent TGF-beta 1 antibody is an antibody that competes for binding to latent TGF-beta 1 and/or that binds to the same epitope as any of the anti-latent TGF-beta 1 antibodies disclosed herein.
  • an anti-latent TGF-beta 1 antibody as disclosed herein or according to any of the above examples may incorporate any of the features, singly or in combination, as described in Sections 1 -7 below:
  • an antibody provided herein has a dissociation constant (KD) 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 (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • KD dissociation constant
  • binding activity of an antibody is measured by a radiolabeled antigen binding assay (RIA) and represented by KD.
  • RIA radiolabeled antigen binding assay
  • an RIA is performed with the Fab version of an antibody of interest and its antigen.
  • solution binding activity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of ( 125 l)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)).
  • MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 microgram/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23 degrees Celsius (C)).
  • a non-adsorbent plate (Nunc #269620)
  • 100 pM or 26 pM ( 125 l)-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res.
  • the Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150 microliter/well of scintillant (MICROSCINT-20TM; Packard) is added, and the plates are counted on a TOPCOUNTTM gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.
  • ligand-capturing methods for example, using BIACORE® T200 or BIACORE® 4000 (GE Healthcare, Uppsala, Sweden), which rely upon surface plasmon resonance analysis methods as the measurement principle, are used.
  • BIACORE® Control Software is used for operation of devices.
  • amine-coupling kit (GE Healthcare, Uppsala, Sweden) is used according to the manufacturer's instructions to let a molecule for ligand capturing, for example, an anti-tag antibody, an anti-IgG antibody, protein A, etc. fixed onto a sensor chip (GE Healthcare, Uppsala, Sweden) coated with carboxymethyldextran.
  • the ligand-capturing molecule is diluted with a 10 mM sodium acetate solution at an appropriate pH and is injected at an appropriate flow rate and for an appropriate injection time. Binding activity measurements are measured using a 0.05% polysorbate 20 (Tween®-20)-containing buffer as a measurement buffer, at a flow rate of 10-30 microliter/minute, and at a measurement temperature of preferably at 25 degrees C or 37 degrees C.
  • a measurement buffer preferably at 25 degrees C or 37 degrees C.
  • an antigen and/or an Fc receptor captured by the ligand-capturing molecule as a ligand an antigen and/or an Fc receptor is injected to let a target amount thereof captured, and then a serial dilution of an antibody (analyte) prepared using the measurement buffer is injected.
  • the measurement results are analyzed using BIACORE® Evaluation Software.
  • Kinetics parameter calculation is carried out by fitting sensorgrams of association and dissociation at the same time using a 1 :1 binding model, and an association rate (k O n or k a ), a dissociation rate (k o tf or kd), and an equilibrium dissociation constant (KD) may be calculated.
  • association rate k O n or k a
  • a dissociation rate k o tf or kd
  • KD equilibrium dissociation constant
  • binding amount of analyte per unit ligand amount may be calculated by dividing a binding amount of analyte (resonance unit: RU) at a specific concentration by an amount of captured ligand.
  • an antibody provided herein is an antibody fragment.
  • Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below.
  • Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments and other fragments described below.
  • Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments and other fragments described below.
  • Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01 161 ; 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).
  • Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody.
  • a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1 ).
  • Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.
  • recombinant host cells e.g., E. coli or phage
  • the present invention also relates to antigen-binding molecules which bind to TGF-beta 1 , which include, but are not limited to, for example, minibodies (low molecular weight antibodies), and scaffold proteins.
  • any scaffold protein is acceptable as long as it is a peptide that has a stable three-dimensional structure and is capable of binding to at least an antigen.
  • Such peptides include, for example, fragments of antibody variable regions, fibronectin, protein A domain, LDL receptor A domain, 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.
  • anti-latent TGF-beta 1 antibody should be replaced with “anti-latent TGF-beta 1 antigen-binding molecule” in the context of the present specification.
  • an antibody provided herein is a chimeric antibody.
  • Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81 :6851 -6855 (1984)).
  • a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
  • a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
  • a chimeric antibody is a humanized antibody.
  • a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and binding activity of the parental non-human antibody.
  • a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences.
  • HVRs e.g., CDRs, (or portions thereof) are derived from a non-human antibody
  • FRs or portions thereof
  • a humanized antibody optionally will also comprise at least a portion of a human constant region.
  • some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or binding activity.
  • a non-human antibody e.g., the antibody from which the HVR residues are derived
  • Human framework regions that may 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 the consensus sequence of human antibodies of a particular subgroup of light 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 mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.
  • an antibody provided herein is a human antibody.
  • Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001 ) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).
  • Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge.
  • Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated.
  • Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., 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 generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci.
  • Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
  • Antibodies of the invention may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1 -37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001 ) and further described, e.g., in the McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991 ); Marks et al., J. Mol. Biol.
  • repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994).
  • Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments.
  • naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., EMBO J, 12: 725-734 (1993).
  • naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381 -388 (1992).
  • Patent publications describing human antibody phage libraries include, for example: US Patent No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
  • Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.
  • an antibody provided herein is a multispecific antibody, e.g., a bispecific antibody.
  • Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for TGF-beta 1 and the other is for any other antigen.
  • bispecific antibodies may bind to two different epitopes of TGF-beta 1 . Bispecific antibodies may also be used to localize cytotoxic agents to cells which express TGF-beta 1 . Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.
  • Multispecific antibodies include, but are not limited to, recombinant coexpression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10: 3655 (1991 )), and "knob-in-hole” engineering (see, e.g., U.S. Patent No. 5,731 ,168). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1 ); cross-linking two or more antibodies or fragments (see, e.g., US Patent No.
  • Engineered antibodies with three or more functional antigen binding sites, including “Octopus antibodies,” are also included herein (see, e.g., US 2006/0025576A1 ).
  • the antibody or fragment herein also includes a “Dual Acting Fab” or “DAF” comprising an antigen binding site that binds to TGF-beta 1 as well as another, different antigen (see, US 2008/0069820, for example). 7. Antibody Variants
  • amino acid sequence variants of the antibodies provided herein are contemplated.
  • Amino acid sequence variants of an antibody 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, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding. a) Substitution, Insertion, and Deletion Variants
  • antibody variants having one or more amino acid substitutions are provided.
  • Sites of interest for substitutional mutagenesis include the HVRs and FRs.
  • Conservative substitutions are shown in Table A under the heading of "preferred substitutions.” More substantial changes are provided in Table A under the heading of "exemplary substitutions,” and as further described below in reference to amino acid side chain classes.
  • Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.
  • Amino acids may be grouped according to common side-chain properties:
  • substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody).
  • a parent antibody e.g., a humanized or human antibody
  • the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased binding activity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody.
  • An exemplary substitutional variant is a binding activity matured antibody, which may be conveniently generated, e.g., using phage display-based binding activity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding activity).
  • Alterations may be made in HVRs, e.g., to improve antibody binding activity.
  • Such alterations may be made in HVR “hotspots,” i.e. , residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding activity.
  • Binding activity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al.
  • binding activity maturation diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis).
  • a secondary library is then created. The library is then screened to identify any antibody variants with the desired binding activity.
  • Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized.
  • HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.
  • substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
  • conservative alterations e.g., conservative substitutions as provided herein
  • Such alterations may, for example, be outside of antigen contacting residues in the HVRs.
  • each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.
  • a useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081 -1085.
  • a residue or group of target residues e.g., charged residues such as Arg, Asp, His, Lys, and Glu
  • a neutral or negatively charged amino acid e.g., alanine or polyalanine
  • a crystal structure of an antigenantibody complex may be analyzed to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • terminal insertions include an antibody with an N-terminal methionyl residue.
  • Other insertional variants of the antibody molecule include the fusion of an enzyme (e.g., for ADEPT) or a polypeptide which increases the plasma half-life of the antibody to the N- or C-terminus of the antibody. b) Glycosylation variants
  • an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated.
  • Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.
  • the carbohydrate attached thereto may be altered.
  • Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997).
  • the oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GIcNAc), galactose, and sialic acid, as well as a fucose attached to a GIcNAc in the “stem” of the biantennary oligosaccharide structure.
  • modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.
  • antibody variants having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
  • the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%.
  • the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example.
  • Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about +/- 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).
  • Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621 ; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053742;
  • Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys.
  • knockout cell lines such as alpha-1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003/085107).
  • Antibodies variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GIcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with 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, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant.
  • the Fc region variant may comprise a human Fc region sequence (e.g., a human lgG1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.
  • a human Fc variant may comprise a chimeric human Fc region sequence (e.g., a human IgG 1 /4 or human lgG2/4 Fc region), or a chimeric human Fc region sequence which further comprises an amino acid modification (e.g., a substitution) at one or more amino acid positions.
  • a chimeric human Fc region sequence e.g., a human IgG 1 /4 or human lgG2/4 Fc region
  • an amino acid modification e.g., a substitution
  • the invention contemplates an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious.
  • In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities.
  • Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks Fc gamma R binding (hence likely lacking ADCC activity), but retains FcRn binding ability.
  • NK cells express Fc gamma Rill only, whereas monocytes express Fc gamma Rl, Fc gamma RII and Fc gamma Rill.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991 ).
  • Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci.
  • non-radioactive assays methods may be employed (see, for example, ACT1 TM non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox® 96 non-radioactive cytotoxicity assay (Promega, Madison, Wl).
  • PBMC peripheral blood mononuclear cells
  • NK Natural Killer
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in a animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998).
  • C1 q binding assays may also be carried out to confirm that the antibody is unable to bind C1 q and hence lacks CDC activity. See, e.g., C1 q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
  • a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al., Blood 101 :1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, Blood 103:2738-2743 (2004)).
  • FcRn binding and in vivo clearance/half life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al., Int'l. Immunol. 18(12):1759-1769 (2006)).
  • Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056).
  • Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581 ).
  • Certain antibody variants with increased or decreased binding to FcRs are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol.
  • an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).
  • alterations are made in the Fc region that result in altered (i.e., either increased or decreased) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No. 6,194,551 , WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).
  • CDC Complement Dependent Cytotoxicity
  • Antibodies with increased half lives and increased binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which increase binding of the Fc region to FcRn.
  • Such Fc variants include those with substitutions at one or more of 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, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826).
  • cysteine engineered antibodies e.g., “thioMAbs”
  • one or more residues of an antibody are substituted with cysteine residues.
  • the substituted residues occur at accessible sites of the antibody.
  • reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linkerdrug moieties, to create an immunoconjugate, as described further herein.
  • any 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 engineered antibodies may be generated as described, e.g., in U.S. Patent No. 7,521 ,541. e) Antibody Derivatives
  • an antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available.
  • the moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers.
  • water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1 , 3-dioxolane, poly-1 ,3,6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., gly
  • Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water.
  • the polymer may be of any molecular weight, and may be branched or unbranched.
  • the number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.
  • conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided.
  • the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)).
  • the radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody-nonproteinaceous moiety are killed.
  • Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4,816,567.
  • isolated nucleic acid encoding an anti-latent TGF-beta 1 antibody described herein is provided.
  • Such nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody).
  • one or more vectors e.g., expression vectors
  • a host cell comprising such nucleic acid is provided.
  • a host cell comprises (e.g., has been transformed with): (1 ) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody.
  • the host cell is eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp2/0 cell).
  • a method of making an anti-latent TGF-beta 1 antibody comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).
  • nucleic acid encoding an antibody is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell.
  • nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).
  • Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.
  • antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
  • U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli.
  • the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.
  • eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).
  • Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.
  • Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIESTM technology for producing antibodies in transgenic plants).
  • Vertebrate cells may also be used as hosts.
  • mammalian cell lines that are adapted to grow in suspension may be useful.
  • Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod.
  • monkey kidney cells (CV1 ); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK); buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells.
  • Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci.
  • the expression of PD-L1 may be assessed in a subject treated according to any of the methods and compositions for use described herein or known in the art.
  • the methods and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the subject.
  • the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the subject has been determined prior to initiation of treatment or after initiation of treatment.
  • PD-L1 expression may be determined using any suitable approach.
  • 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 may be used, e.g., a formalin-fixed and paraffin- embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.
  • FFPE formalin-fixed and paraffin-
  • PD-L1 expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1 , as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1 , and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1 .
  • the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody).
  • Any suitable anti-PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28- 8 (Dako), E1 L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11 .
  • the anti-PD-L1 antibody is SP142.
  • the anti-PD-L1 antibody is SP263.
  • a tumor sample obtained from the subject has a detectable expression level of PD-L1 in less than 1% of the tumor cells in the tumor sample, in 1% or more of the tumor cells in the tumor sample, in from 1% to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in from 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.
  • a tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, from 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, from 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.
  • tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or in tumor cells according to the criteria for diagnostic assessment shown in Table B and/or Table C, respectively.
  • Table B Tumor-infiltrating immune cell (IC) IHC diagnostic criteria
  • Table C Tumor cell (TC) IHC diagnostic criteria
  • an anti-latent TGF-beta 1 antibody is administered in combination with a PD-1 axis binding antagonist.
  • PD-1 axis binding antagonists may include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used.
  • the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 . In yet other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1 . In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1 .
  • the PD-L1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.
  • the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 ).
  • the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA.
  • the PD-L1 binding antagonist is CA-170 (also known as AUPM-170).
  • the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3.
  • the small molecule is a compound described in WO 2015/033301 and/or WO 2015/033299.
  • the PD-L1 binding antagonist is an anti-PD-L1 antibody.
  • a variety of anti-PD- L1 antibodies are contemplated and described herein.
  • the isolated anti- PD-L1 antibody can bind to a human PD-L1 , for example a human PD-L1 as shown in UniProtKB/Swiss- Prot Accession No. Q9NZQ7-1 , or a variant thereof.
  • the anti-PD-L1 antibody is capable of inhibiting binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1 .
  • the anti-PD-L1 antibody is a monoclonal antibody.
  • the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.
  • the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody.
  • Exemplary anti-PD-L1 antibodies include atezolizumab, MDX- 1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.
  • anti-PD-L1 antibodies useful in the methods of this invention and methods of making them are described in International Patent Application Publication No. WO 2010/077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.
  • the anti-PD-L1 antibody is atezolizumab.
  • the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8).
  • Avelumab also known as MSB0010718C, is a human monoclonal lgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).
  • the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60- 7).
  • Durvalumab also known as MEDI4736, is an Fc-optimized human monoclonal IgG 1 kappa anti-PD- L1 antibody (Medlmmune, AstraZeneca) described in WO 2011/066389 and US 2013/034559.
  • 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 WO 2007/005874.
  • the anti-PD-L1 antibody is LY3300054 (Eli Lilly).
  • the anti-PD-L1 antibody is STI-A1014 (Sorrento).
  • STI-A1014 is a human anti- PD-L1 antibody.
  • the anti-PD-L1 antibody is KN035 (Suzhou Alphamab).
  • KN035 is singledomain antibody (dAB) generated from a camel phage display library.
  • the anti-PD-L1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety.
  • the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).
  • the anti-PD-L1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-L1 antibody described in US 20160108123, WO 2016/000619, WO 2012/145493, U.S. Pat. No. 9,205,148, WO 2013/181634, or WO 2016/061142.
  • the anti-PD-L1 antibody has reduced or minimal effector function.
  • the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation.
  • the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region.
  • the effector-less Fc mutation is an N297A substitution in the constant region.
  • the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O- linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue.
  • the tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain.
  • O-linked glycosylation refers to the attachment 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 an antibody is conveniently accomplished by altering the amino acid sequence such that one of the abovedescribed tripeptide sequences (for N-linked glycosylation sites) is removed.
  • the alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).
  • an anti-PD-L1 antibody may incorporate any of the features, singly or in combination, as described in Sections 1 -7 of Section lll(A) above.
  • the PD-1 axis binding antagonist is a PD-1 binding antagonist.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 .
  • the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2.
  • the PD-1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.
  • the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
  • the PD-1 binding antagonist is an Fc-fusion protein.
  • the PD-1 binding antagonist is AMP-224.
  • AMP-224 also known as B7-DCIg, is a PD- L2-Fc fusion soluble receptor described in WO 2010/027827 and WO 2011/066342.
  • the PD-1 binding antagonist is a peptide or small molecule compound.
  • the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317, and WO 2011 /161699.
  • the PD-1 binding antagonist is a small molecule that inhibits PD-1 .
  • the PD-1 binding antagonist is an anti-PD-1 antibody.
  • a variety of anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the instances herein, the PD-1 antibody can bind to a human PD-1 or a variant thereof.
  • the anti-PD-1 antibody is a monoclonal antibody. In some instances, 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 instances, the anti-PD-1 antibody is a humanized antibody. In other instances, the anti-PD-1 antibody is a human antibody.
  • anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI
  • 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 OPDI VO®, is an anti-PD-1 antibody described in WO 2006/121168.
  • the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853- 91 -4).
  • Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009/114335.
  • the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca).
  • MEDI-0680 is a humanized lgG4 anti-PD-1 antibody.
  • the anti-PD-1 antibody is PDR001 (CAS Registry No. 1859072-53-9; Novartis).
  • PDR001 is a humanized lgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.
  • the anti-PD-1 antibody is REGN2810 (Regeneron).
  • REGN2810 is a human anti-PD-1 antibody.
  • the anti-PD-1 antibody is BGB-108 (BeiGene).
  • the anti-PD-1 antibody is BGB-A317 (BeiGene).
  • the anti-PD-1 antibody is JS-001 (Shanghai Junshi).
  • JS-001 is a humanized anti-PD-1 antibody.
  • the anti-PD-1 antibody is STI-A1110 (Sorrento).
  • STI-A1110 is a human anti- PD-1 antibody.
  • the anti-PD-1 antibody is INCSHR-1210 (Incyte).
  • INCSHR-1210 is a human lgG4 anti-PD-1 antibody.
  • the anti-PD-1 antibody is PF-06801591 (Pfizer).
  • the anti-PD-1 antibody is TSR-042 (also known as ANB011 ; Tesaro/AnaptysBio).
  • the anti-PD-1 antibody is AM0001 (ARMO Biosciences).
  • 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 binding of PD-L1 to PD-1.
  • the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings).
  • ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits binding of PD-L1 to PD-1 .
  • the anti-PD-1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-1 antibody described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769 , WO2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 2012/145493, US 9,205,148, WO 2015/119930, WO 2015/119923, WO 2016/032927, WO 2014/179664, WO 2016/106160, and WO 2014/194302.
  • the six HVR sequences e.g., the three heavy chain HVRs and the three light chain HVRs
  • the heavy chain variable domain and light chain variable domain from an anti-PD-1 antibody described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769 , WO2016/0898
  • the anti-PD-1 antibody has reduced or minimal effector function.
  • the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation.
  • the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region.
  • the isolated anti-PD-1 antibody is aglycosylated.
  • an anti-PD-1 antibody may incorporate any of the features, singly or in combination, as described in Sections 1 -7 of Section lll(A) above.
  • the PD-1 axis binding antagonist is a PD-L2 binding antagonist.
  • the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partners.
  • the PD-L2 binding ligand partner is PD-1 .
  • the PD-L2 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.
  • the PD-L2 binding antagonist is an anti-PD-L2 antibody.
  • the anti-PD-L2 antibody can bind to a human PD-L2 or a variant thereof.
  • the anti-PD-L2 antibody is a monoclonal antibody.
  • 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.
  • the anti-PD-L2 antibody is a humanized antibody.
  • the anti-PD-L2 antibody is a human antibody.
  • the anti-PD-L2 antibody has reduced or minimal effector function.
  • the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation.
  • the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region.
  • the isolated anti-PD-L2 antibody is aglycosylated.
  • an anti-PD-L2 antibody may incorporate any of the features, singly or in combination, as described in Sections 1 -7 of Section lll(A) above.
  • compositions for use, kits, and articles of manufacture. Any of the methods, compositions for use, kits, or articles of manufacture described herein may include or involve any of the agents described herein.
  • any suitable chemotherapeutic agents may be used, including any chemotherapeutic agents or combinations of chemotherapeutic agents disclosed herein.
  • the one or more chemotherapeutic agents comprise a platinum-based chemotherapeutic agent, an antimetabolite, a cytotoxic agent, a growth inhibitory agent, a taxane, a folate analog, or any combination thereof.
  • the chemotherapeutic agent or combination of chemotherapeutic agents may be a standard of care (SOC) therapy for a cancer.
  • SOC standard of care
  • platinum-based chemotherapeutic agent Any suitable platinum-based chemotherapeutic agent may be used.
  • platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, and satraplatin.
  • the platinum-based chemotherapeutic agent comprises oxaliplatin, cisplatin, or carboplatin.
  • the platinum-based chemotherapeutic agent comprises oxaliplatin.
  • the oxaliplatin is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the oxaliplatin is administered to the subject on Day 1 of each 21 -day dosing cycle. In some examples, the oxaliplatin is administered to the subject at a dose of 130 mg/m 2 . In some examples, the oxaliplatin is administered to the subject intravenously.
  • the antimetabolite comprises capecitabine, gemcitabine, 5-fluorouracil, or tegafur. In some examples, the antimetabolite comprises capecitabine. In some examples, the capecitabine is administered to the subject in a dosing regimen comprising one or more dosing cycles. In some examples, the one or more dosing cycles comprise 21 -day dosing cycles. In some examples, the capecitabine is administered to the subject on Days 1 -14 of each 21 -day dosing cycle. In some examples, the capecitabine is administered to the subject at a dose of 1000 mg/m 2 twice daily. In some examples, the capecitabine is administered to the subject orally.
  • the antimetabolite comprises gemcitabine.
  • the gemcitabine is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 28-day dosing cycles.
  • the gemcitabine is administered to the subject on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the gemcitabine is administered to the subject at a dose of 1000 mg/m 2 twice daily.
  • the gemcitabine is administered to the subject intravenously.
  • the antimetabolite comprises tegafur.
  • the antimetabolite comprises S-1 (tegafur-gimeracil-oteracil potassium).
  • the S-1 is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 21 -day dosing cycles.
  • the S-1 is administered to the subject on Days 1 -14 of each 21 -day dosing cycle.
  • the S-1 is administered to the subject at a dose of 40 mg/m 2 twice daily.
  • the S-1 is administered to the subject orally.
  • taaxanes include, but are not limited to, paclitaxel (i.e., TAXOL®, CAS # 33069-62-4), docetaxel (i.e., TAXOTERE®, CAS # 114977-28-5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel.
  • the taxane comprises nab-paclitaxel or paclitaxel.
  • the taxane comprises nab-paclitaxel.
  • the nab-paclitaxel is administered to the subject in a dosing regimen comprising one or more dosing cycles.
  • the one or more dosing cycles comprise 28-day dosing cycles.
  • the nab-paclitaxel is administered to the subject on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the nab-paclitaxel is administered to the subject at a dose of 125 mg/m 2 .
  • the nab-paclitaxel is administered to the subject intravenously.
  • Any suitable folate analog may be used.
  • Exemplary, non-limiting folate analogs include leucovorin and levoleucovorin.
  • the folate analog comprises leucovorin.
  • compositions and formulations comprising an anti-latent TGF-beta 1 antibody and, optionally, a pharmaceutically acceptable carrier.
  • the disclosure also provides pharmaceutical compositions and formulations comprising 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, and optionally, a pharmaceutically acceptable carrier.
  • 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))
  • chemotherapeutic agents e.g., chemotherapeutic agents
  • compositions and formulations as described herein can be prepared by mixing the active ingredients (e.g., a PD-1 axis binding antagonist) having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (see, e.g., Flemington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), e.g., in the form of lyophilized formulations or aqueous solutions.
  • active ingredients e.g., a PD-1 axis binding antagonist
  • optional pharmaceutically acceptable carriers see, e.g., Flemington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)
  • An exemplary atezolizumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20, and sucrose, with a pH of 5.8.
  • atezolizumab may be provided in a 20 mL vial containing 1200 mg of atezolizumab that is 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.
  • Atezolizumab may be provided in a 14 mL vial containing 840 mg of atezolizumab that is 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.
  • an article of manufacture or a kit comprising an anti-latent TGF-beta 1 antibody.
  • the article of manufacture or kit further comprises package insert comprising instructions for using the anti-latent TGF-beta 1 antibody to treat or delay progression of cancer in a subject.
  • the article of manufacture or kit further comprises package insert comprising instructions for using an anti-latent TGF-beta 1 antibody in combination with 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) to treat or delay progression of cancer in a subject.
  • 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))
  • chemotherapeutic agents e.g., chemotherapeutic agents
  • any of the anti-latent TGF- beta 1 antibodies and additional therapeutic agents e.g., checkpoint inhibitors such as PD-1 axis binding antagonists and/or one or more chemotherapeutic agents
  • additional therapeutic agents e.g., checkpoint inhibitors such as PD-1 axis binding antagonists and/or one or more chemotherapeutic agents
  • the anti-latent TGF-beta 1 antibody and the one or more additional therapeutic agents are in the same container or separate containers.
  • 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))
  • chemotherapeutic agents are in the same container or separate containers.
  • Suitable containers include, for example, bottles, vials, bags and syringes.
  • the container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy).
  • the container holds the formulation and the label on, or associated with, the container may indicate directions for use.
  • the article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • the article of manufacture further includes one or more of another agent (e.g., an additional chemotherapeutic agent or anti- neoplastic agent).
  • Suitable containers for the one or more agents include, for example, bottles, vials, bags and syringes.
  • any of the articles of manufacture or kits may include instructions to administer an anti-latent TGF-beta 1 antibody and/or 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) to a subject in accordance with any of the methods described herein, e.g., any of the methods set forth in Section II above.
  • 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))
  • chemotherapeutic agents e.g., chemotherapeutic agents
  • EXAMPLE 1 A PHASE lb, OPEN-LABEL, MULTICENTER DOSE-EXPANSION STUDY EVALUATING THE SAFETY, PHARMACOKINETICS, AND ACTIVITY OF SOF10 IN COMBINATION WITH A CHECKPOINT INHIBITOR WITH OR WITHOUT STANDARD-OF-CARE CHEMOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS
  • a Phase lb, open-label, multicenter, dose-expansion study was designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary anti-tumor activity of the anti-latent TGF- beta 1 antibody SOF10 when administered in combination with a checkpoint inhibitor (CPI), e.g., an anti- PD-L1 antibody such as atezolizumab or an anti-PD-1 antibody such as nivolumab, with or without standard of care (SOC) chemotherapy in patients with locally advanced or metastatic solid tumors.
  • CPI checkpoint inhibitor
  • an anti- PD-L1 antibody such as atezolizumab
  • an anti-PD-1 antibody such as nivolumab
  • SOC standard of care
  • “study treatment” refers to the combination of all treatments assigned to patients as part of this study (e.g., SOF10 in combination with atezolizumab or nivolumab, with or without SOC chemotherapy).
  • This study evaluates the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary anti-tumor activity of SOF10 when administered in combination with a checkpoint inhibitor (i.e., atezolizumab or nivolumab) with or without standard-of-care chemotherapy in patients with non-small cell lung cancer, gastric cancer, and pancreatic ductal adenocarcinoma.
  • a checkpoint inhibitor i.e., atezolizumab or nivolumab
  • UC urothelial carcinoma
  • ADA anti-drug antibody
  • CA19-9 carbohydrate antigen 19-9
  • CPI checkpoint inhibitor
  • Definitions for the criteria used to determine objective tumor response for target lesions are as follows:
  • Partial response (PR) at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters
  • PD Progressive disease: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
  • the appearance of one or more new lesions is also considered progression.
  • Stable disease neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study.
  • CPI e.g., atezolizumab or nivolumab
  • the study includes a screening period of up to 28 days, a treatment period, a minimum follow-up period of 90 days after treatment, and survival follow-up.
  • Approximately 120 patients are to be enrolled in this study in three non-randomized indicationspecific cohorts, at approximately 30 global investigative sites.
  • the patient populations include patients with NSCLC (Cohort A), GC (Cohort B), and PDAC (Cohort C); a substudy for UC is described in Example 2.
  • Each cohort enrolls up to approximately 40 patients and consist of two stages: an initial safety run-in stage and an expansion stage.
  • the safety run-in stage enrolls a total of approximately 18 patients (e.g., 6 patients for each treatment regimen).
  • Patients in the safety run-in receive at least one cycle of study treatment, with both SOF10 and atezolizumab or nivolumab given concurrently starting from Cycle 1 .
  • Accrual in the expansion stage for a given cohort begins after the safety run-in stage for that safety run-in group has been fully enrolled.
  • Efficacy analyses is performed after approximately 15 patients have completed at least one tumor assessment in a given cohort.
  • Patient populations include patients with NSCLC (Cohort A), gastric cancer (GC) (Cohort B), and PDAC (Cohort C). Each cohort includes two stages: an initial safety run-in stage and an expansion stage. Patients in the safety run-in receive at least one cycle of study treatment, with both SOF10 and atezolizumab or nivolumab given concurrently starting from Cycle 1 . Efficacy analyses are performed based on a tumor assessment.
  • Patients in this study are initially assessed for eligibility during the screening period (lasting ⁇ 28 days). Following confirmation of eligibility, patients receive SOF10 in combination with a CPI (Cohort A); or SOF10 in combination with a CPI and SOC chemotherapy (Cohorts B and C) (e.g., see Table 4). Patients receive study treatment in 21 -day cycles (Cohorts A and B) or 28-day cycles (Cohort C). Treatment is continued as long as patients are experiencing clinical benefit in the opinion of the investigator (e.g., in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression).
  • the study includes a screening period of up to 28 days, a treatment period, a minimum follow-up period of 90 days after treatment, and survival follow-up. Treatment is continued as long as patients are experiencing clinical benefit in the opinion of the investigator. The total duration of study participation for each patient is expected to range from 1 day to more than 12 months.
  • Dosing for each cohort in the safety run-in stage are performed as described in Table 4. After 6 patients in a safety run-in group (e.g., Cohort A, Cohort B, or Cohort C) have completed at least one cycle of study treatment in the safety run-in stage, safety data are formally reviewed. Continued enrollment or recommended changes to the conduct of the study are determined based on the investigator’s (e.g., a clinician) review of the safety data.
  • a safety run-in group e.g., Cohort A, Cohort B, or Cohort C
  • Safely accessible lesions are defined as those lesions that would not place the patient at undue risk from the procedure per the investigator’s (e.g., a clinician) discretion (e.g., risk of hemorrhage due to proximity to major blood vessels, etc.).
  • Patients with archival tumor specimens may decline to undergo a pretreatment baseline biopsy and submit the archival specimen instead.
  • the on-treatment biopsy must still be performed, preferably from the same lesion or organ as the archival tumor specimen, if feasible.
  • Serial biopsy patients whose pretreatment biopsy is found to be non-evaluable may still receive study treatment. If the pretreatment biopsy is found to be non-evaluable prior to Cycle 2, Day 4, the patient may decline to undergo an on-treatment biopsy.
  • Such patients, as well as patients whose on-treatment biopsy is found to be non-evaluable or any patients with biopsies without sufficient viable tumor content, may be replaced for the purpose of serial biopsy assessment of evaluable patients in each cohort.
  • Patients who provide pretreatment biopsies should also submit available archival tumor specimens. If no archival tumor specimen is available, the pretreatment biopsy is sufficient to meet tissue eligibility requirements for the study.
  • Critical anatomical sites include the central nervous system (CNS), central airway, the great vessels, and other organs or tissues where compromised function secondary to tumor progression would be expected to result acutely in severe and/or irreversible disability or death.
  • CNS central nervous system
  • patients who have received at least one prior systemic treatment for metastatic disease may be considered for continued study treatment if they continue to meet the criteria above and have evidence of clinical benefit, as evidenced by at least one of the following:
  • Tumor shrinkage at least 30% decrease in diameter from baseline
  • Improvement in one or more symptoms or signs attributable to the underlying cancer e.g., decreased requirement for narcotics for pain, decreased dyspnea associated with pleural effusion, weight gain
  • improvements in one or more symptoms or signs attributable to the underlying cancer e.g., decreased requirement for narcotics for pain, decreased dyspnea associated with pleural effusion, weight gain
  • patients who are receiving their first systemic therapy for metastatic disease may be considered for continued study treatment at the investigator's discretion after discussion with the Medical Monitor, if they continue to meet the criteria above and have evidence of clinical benefit, as evidenced by tumor shrinkage (at least 30% decrease in diameter from baseline) of one or more evaluable lesions.
  • Investigator assessment of overall tumor response at all timepoints may be based only on RECIST v1.1.
  • ANC Absolute neutrophil count
  • AST Aspartate transaminase
  • ALT alanine transaminase
  • ALP alkaline phosphatase
  • Patients receiving therapeutic anticoagulation should be on a stable dose with INR in target range.
  • Measurable disease at least one target lesion
  • RECIST v1 .1 on computed tomography (CT) or magnetic resonance imaging (MRI) images within 28 days prior to enrollment.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
  • Enrollment is managed such that approximately half of the accrued patients have squamous NSCLC.
  • Patients with disease progression or recurrence within 6 months after completion of their definitive therapy for locally advanced disease are allowed to participate, provided their treatment for locally advanced inoperable NSCLC included a combination of at least a platinumbased chemotherapy (e.g., cisplatin or carboplatin) and a PD-L1/PD-1 CPI.
  • a platinumbased chemotherapy e.g., cisplatin or carboplatin
  • a PD-L1/PD-1 CPI Prior exposure to anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies is allowed if used in combination with a PD-L1/PD-1 CPI.
  • CTL-4 anti-cytotoxic T-lymphocyte-associated protein 4
  • Positive tumor PD-L1 status (e.g., > 1%), as determined by a local laboratory through use of a health authority-approved or CE-marked assay.
  • Patients in Cohort B must also meet the following criteria for study entry: o Unresectable locally advanced or metastatic GC (including esophagogastric junction cancer) that is histologically confirmed to be adenocarcinoma .
  • metastatic PDAC Patients in Cohort C must also meet the following criteria for study entry: o Histologically or cytologically confirmed metastatic PDAC.
  • the definitive diagnosis of metastatic PDAC may be made, e.g., by evaluating the histopathologic data within the context of clinical and/or radiographic data.
  • Herbal therapy intended for the treatment of cancer > 7 days before Day 1 of Cycle 1
  • Palliative radiotherapy for painful metastases or metastases in potentially sensitive locations > 2 weeks prior to Day 1 of Cycle 1 .
  • systemic immunostimulatory agents including, but not limited to, interferons (IFNs) and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment .
  • IFNs interferons
  • IL-2 interferons
  • TGF-p or TGF-p receptor inhibitor e.g., bintrafusp alpha, SRK-181 , NIS793, and the like.
  • Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:
  • Measurable disease per RECIST v1 .1 must be present outside the CNS.
  • Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
  • Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.
  • Any disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug may affect the interpretation of the results, or may render the patient at high risk from treatment complications, including, but not limited to:
  • liver disease including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse
  • Symptomatic lesions e.g., bone metastases or metastases causing nerve impingement
  • Symptomatic lesions e.g., bone metastases or metastases causing nerve impingement
  • patients should be recovered from the effects of radiation.
  • Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth should be considered for loco-regional therapy, if appropriate, prior to enrollment.
  • Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1 .5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN).
  • malignancy other than the disease under study within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
  • a negligible risk of metastasis or death e.g., 5-year OS rate > 90%
  • Adverse events from prior anti-cancer therapy (with the exception of immune-related adverse events attributed to cancer immunotherapy; see below) that have not resolved to Grade ⁇ 1 except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy.
  • autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
  • Rash must cover ⁇ 10% of body surface area.
  • Severe infection within 4 weeks prior to initiation of study treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
  • prophylactic antibiotics e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation
  • COPD chronic obstructive pulmonary disease
  • HbsAg Positive hepatitis B surface antigen
  • HbcAb positive total hepatitis B core antibody
  • HbcAb hepatitis B virus
  • Antiviral prophylaxis for patients at risk for HBV reactivation is permitted.
  • HCV hepatitis C virus
  • SARS-CoV-2 the virus that causes COVID-19
  • persistent symptoms of known prior SARS-CoV-2 infection the virus that causes COVID-19
  • known positive SARS-CoV-2 test within 4 weeks prior to screening.
  • a live, attenuated vaccine e.g., FLUMIST®
  • Administration of a live, attenuated vaccine within 4 weeks before first study treatment or anticipation that such a live, attenuated vaccine may be required during the study or within 5 months after the final dose of study treatment.
  • systemic immunosuppressive medication including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF) agents
  • systemic immunosuppressive medication including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF) agents
  • mineralocorticoids e.g., fludrocortisone
  • inhaled or low-dose corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
  • Patients with unknown EGFR and/or ALK status may undergo testing at a local laboratory at screening, with the exception of patients with squamous NSCLC.
  • Determination for positive is made on the basis of the reference at each site. If there is no reference, rough indication for positive is 3+ by IHC, or 2+ by IHC and positive by ISH.
  • T-cell co-stimulating or immune checkpoint blockade therapies including anti- CTLA-4, anti-PD-1 , and anti-PD-L1 therapeutic antibodies.
  • T-cell co-stimulating therapy or a CPI including anti-cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), anti-PD-1 , and anti-PD-L1 therapeutic antibodies.
  • CTL-4 anti-cytotoxic T-lymphocyte- associated antigen 4
  • anti-PD-1 anti-PD-L1 therapeutic antibodies.
  • the investigational medicinal products (IMPs) for this study are SOF10, atezolizumab, nivolumab, gemcitabine, nab-paclitaxel, capecitabine, oxaliplatin, and S-1.
  • SOC treatments (nivolumab, gemcitabine, nab-paclitaxel, capecitabine, oxaliplatin, and S-1 ) are supplied when required by local health authority regulations.
  • SOC treatments nivolumab, gemcitabine, nab-paclitaxel, capecitabine, oxaliplatin, and S-1 .
  • the investigational medicinal products (IMPs) for this study are SOF10, atezolizumab, nivolumab, gemcitabine, nab-paclitaxel, capecitabine, oxaliplatin, and S-1.
  • Patients receive SOF10 in combination with a checkpoint inhibitor (Cohort A); or SOF10 in combination with a checkpoint inhibitor and standard- of-care chemotherapy (Cohorts B and C) (e.g., see Table 4).
  • Patients receive study treatment in 21 -day cycles (Cohorts A and B) or 28-day cycles (Cohort C).
  • the treatment regimens are summarized in Table 4 below, with each treatment listed in order of administration.
  • BSA body surface area
  • nab-paclitaxel nanoparticle albumin-bound paclitaxel
  • PO by mouth
  • S-1 tegafur-gimeracil-oteracil potassium.
  • capecitabine or S-1 may be used at the investigator's discretion.
  • Capecitabine or S-1 may be administered prior to or after SOF10, nivolumab, and oxaliplatin infusions at the investigator's discretion.
  • c Capecitabine should be taken with water and within 30 minutes after a meal.
  • S-1 is administered twice a day at 40 mg/dose for body surface area (BSA) ⁇ 1 .25 m 2 , 50 mg/dose for BSA > 1 .25 m 2 and ⁇ 1 .5 m 2 , and 60 mg/dose for BSA > 1 .5 m 2 .
  • S-1 should be taken with water at least 60 minutes before or after a meal.
  • the SOF10 drug product is supplied as a sterile liquid in a single-use, 20-ml glass vial.
  • the vial contains approximately 10 mL (600 mg) of SOF10 solution.
  • SOF10 is administered by IV infusion at a fixed dose of 1800 mg on Day 1 of each 21 -day cycle in combination with atezolizumab or nivolumab and SOC chemotherapy.
  • SOF10 is administered by IV infusion at a fixed dose of 1200 mg on Day 1 and Day 15 of each 28-day cycle in combination with atezolizumab and SOC chemotherapy.
  • the dose level of SOF10 is based on the totality of data from the ongoing phase I study, and may be updated once additional data from the ongoing phase I study becomes available.
  • the initial dose of SOF10 is delivered over 60 ( ⁇ 10) minutes (although the infusion may be slowed or interrupted for patients who experience infusion-associated symptoms), followed by a 60- minute observation period prior to dosing with atezolizumab or nivolumab. If the 60-minute infusion is tolerated without infusion-associated adverse events (e.g., see Table 5), the second infusion may be delivered over 30 ( ⁇ 10) minutes, followed by a 30-minute observation period (e.g., see Table 6).
  • the atezolizumab drug product is supplied as a sterile liquid in a single-use, 15-ml or 20-mL glass vial.
  • the vial contains approximately 14 mL (840 mg) or 20 mL (1200 mg) of atezolizumab solution.
  • Atezolizumab is administered by IV infusion at a fixed dose of 840 mg on
  • Atezolizumab is administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each
  • Atezolizumab is administered after SOF10.
  • Atezolizumab infusions are administered per the instructions outlined in Table 7, including for patients who are administered atezolizumab alone (e.g., due to adverse events associated with SOF10). Administration of atezolizumab may be performed in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions.
  • IRR infusion-related reaction.
  • nivolumab is administered at a dose of 360 mg as an IV infusion over 30 ( ⁇ 10) minutes.
  • Nivolumab is administered after SOF10.
  • SOC chemotherapy oxaliplatin in combination with either capecitabine or S-1
  • SOF10 and nivolumab as part of the treatment regimens outlined in Table 4.
  • SOC chemotherapy may be administered per local prescribing information. Patients may receive either capecitabine or S-1 . S-1 may be administered only at sites that can produce drug supply for patients from local sources.
  • the same SOC regimen e.g., oxaliplatin and capecitabine or oxaliplatin and S-1 ) may be administered for the duration of the study treatment period.
  • Oxaliplatin 130 mg/m 2 is administered by IV infusion over approximately 2 hours on Day 1 of each 21 -day cycle after completion of the nivolumab infusion.
  • Capecitabine 1000 mg/m 2 or S-1 40 mg/m 2 (40 mg/dose for body surface area (BSA) ⁇ 1 .25 m 2 , 50 mg/dose for BSA between > 1 .25 m 2 and ⁇ 1 .5 m 2 , and 60 mg/dose for BSA > 1 .5 m 2 ) is administered orally twice a day for 14 days (Days 1 -14 of each cycle) followed by a 7-day rest period.
  • Capecitabine or S-1 may be administered prior to or after the SOF10, nivolumab, and oxaliplatin infusions. The first dose of capecitabine or S-1 should be administered on the morning of Day 1 and the last dose on the evening of Day 14.
  • the first dose of capecitabine may be administered on the evening of Day 1 an the last dose on the morning of Day 15.
  • Capecitabine is taken orally with water and within 30 minutes after a meal.
  • S-1 is taken orally with water at least 60 minutes before or after a meal.
  • Oxaliplatin, capecitabine, and S-1 may be administered according to local prescribing information in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions.
  • Oxaliplatin, capecitabine, and S-1 treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures). Patients may receive prophylactic supportive medications per institutional guidelines.
  • Corticosteroids may be used in the usual dosage and mode of administration in the site for patients in whom chemotherapy-induced nausea/vomiting is concerned.
  • nab-paclitaxel in combination with gemcitabine in combination with SOF10 and atezolizumab as part of the treatment regimens outlined in, e.g., Table 4.
  • Nab-paclitaxel and gemcitabine may be administered per local prescribing information.
  • patients receive nab-paclitaxel 125 mg/m 2 administered by IV infusion over 30 ( ⁇ 5) minutes, followed by gemcitabine 1000 mg/m 2 administered by IV infusion over 30 ( ⁇ 5) minutes.
  • gemcitabine 1000 mg/m 2 administered by IV infusion over 30 ( ⁇ 5) minutes On Days 1 and 15 of each cycle, nab-paclitaxel is administered after completion of the atezolizumab infusion.
  • Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment to the treatment discontinuation visit. All such medications should be reported to the investigator and recorded on the Concomitant Medication eCRF.
  • medication e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements
  • Vaccinations such as influenza, COVID-19
  • Mineralocorticoids e.g., fludrocortisone
  • Palliative radiotherapy is permitted if patients are otherwise deriving benefit. Study treatment may be continued or suspended during palliative radiotherapy and should be discussed with the investigator in consultation with the Medical Monitor.
  • Premedication with antihistamines, anti-pyretic medications, and/or analgesics may be administered for the second and subsequent SOF10 or atezolizumab infusions only.
  • Patients who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice.
  • Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and p2- adrenergic agonists).
  • Systemic corticosteroids, immunosuppressive medications, and TNF-a inhibitors may attenuate potential beneficial immunologic effects of treatment with SOF10 in combination with CPIs. Therefore, in situations in which systemic corticosteroids, immunosuppressive medications, or TNF-a inhibitors would be routinely administered, alternatives, including antihistamines, should be considered, except when systemically administered for orthostatic hypotension or adrenocortical insufficiency or chemotherapy- induced nausea/vomiting. If the alternatives are not feasible, systemic corticosteroids, immunosuppressive medications, and TNF-a inhibitors may be administered. Systemic corticosteroids or immunosuppressive medications are recommended, at the discretion of the investigator, for the treatment of specific adverse events when associated with SOF10 and/or CPI therapy.
  • cytochrome CYP isoenzymes CYP2C8 and CYP3A4.
  • Caution should be exercised when nab-paclitaxel is concomitantly administered with known CYP2C8 or CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) and inducers (e.g., rifampin and carbamazepine).
  • known CYP2C8 or CYP3A4 inhibitors e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin
  • inducers e.g., rifampin and carbamazepine
  • CYP2A6 is the major enzyme responsible for the conversion of tegafur to 5- FU
  • co-administration of a known CYP2A6 inhibitor e.g., letrozole, clotrimazole, tranylcypromine, pilocarpine, miconazole
  • S-1 should be avoided, as the effectiveness of S-1 could be decreased.
  • a known CYP2A6 inhibitor e.g., letrozole, clotrimazole, tranylcypromine, pilocarpine, miconazole
  • prophylactic or therapeutic anticoagulation therapies such as warfarin at a stable dose or low-molecular-weight heparin
  • prophylactic or therapeutic anticoagulation therapies such as warfarin at a stable dose or low-molecular-weight heparin
  • Vital signs may include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. Blood oxygen saturation may be measured at baseline and as clinically indicated by pulse oximetry. Vital signs for patients may be obtained according to Table 6 and Table 7.
  • tumor assessments are to continue according to schedule in patients who discontinue treatment for reasons other than disease progression or loss of clinical benefit.
  • Patients who continue treatment after radiographic disease progression may undergo tumor assessments every 6 weeks ( ⁇ 1 week) until loss of clinical benefit, as determined by the investigator (e.g., a clinician).
  • Tumor assessments may be continued every 6 weeks thereafter until two consecutive scans demonstrate stability or improvement with respect to the first scan that showed radiographic disease progression, at which point the scan frequency can revert to the initial schedule (e.g., see Table 8).
  • tumor assessments may be repeated at any time if progressive disease is suspected.
  • Screening assessments may include CT scans (with IV contrast, unless contraindicated, and oral contrast as appropriate per institutional standards) of the chest, abdomen, and pelvis.
  • CT scans of the abdomen and pelvis may be substituted by MRI scans.
  • a CT scan with contrast or MRI scan of the head must be performed at screening for patients with known or clinically suspected brain metastases or treated brain metastases.
  • an MRI scan of the brain is required to confirm or refute the diagnosis of CNS metastases.
  • Subsequent brain scans should be performed only if clinically indicated (e.g., if a patient becomes symptomatic). Bone scans and CT scans of the neck should also be performed if clinically indicated.
  • CT scan for tumor assessment is performed in a positron emission tomography-CT scanner, the CT acquisition must be consistent with the standards for a full-contrast diagnostic CT scan.
  • All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the schedules described above (e.g., see Table 8).
  • the same radiographic procedures used to assess disease sites at screening should be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans).
  • tumor assessments must be continued after disease progression per RECIST v1 .1 for patients who receive treatment beyond progression. This includes continued measurement of target lesions, evaluation of non-target lesions (including monitoring for further worsening of any non-target lesions that have shown unequivocal progression), and evaluation of any newly identified lesions (including measurements, if lesions are measurable) at all subsequent assessments.
  • Samples for the following laboratory tests may be sent to the study site's local laboratory for analysis:
  • Hematology WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells (if indicated))
  • Thyroid function testing thyroid-stimulating hormone, free T3 (or total T3 for sites where free T3 is not performed), and free T4
  • HIV serology HIV-1/2 antibody or HIV-1 and HIV-2 antibodies, unless not permitted per local regulations
  • HBV serology HBsAg, hepatitis B surface antibody (HBsAb), and total HBcAb for all patients; HBV DNA for patients with negative HBsAg and HBsAb tests and a positive total HBcAb test
  • HCV serology HCV antibody for all patients; HCV RNA for patients with a positive HCV antibody test
  • an HCV RNA test must also be performed to determine if the patient has an HCV infection.
  • Tuberculosis testing (only if patient is considered at increased risk for infection with Mycobacterium tuberculosis): IFN-y release assays or tuberculin skin test (according to local standard practice)
  • Carbohydrate antigen 19-9 (e.g., for GC and PDAC cohorts only)
  • Electrocardiograms ECGs
  • ECG recordings may be obtained at specified timepoints, as outlined in the schedule of activities. ECGs acquired on different days should be as closely time-matched as feasible. Three interpretable ECG recordings (e.g., without artifacts) may be obtained at each timepoint ( ⁇ 10 minutes). The average of the three readings may be used to determine ECG intervals (e.g., PR, QRS, QT). Single ECG recordings may be obtained at unscheduled timepoints as clinically indicated. ECG recordings may be performed after the patient has been resting in a supine or semi-supine position for at least 10 minutes, and the patient should remain in a supine or semi-supine position during recording.
  • ECG intervals e.g., PR, QRS, QT
  • ECGs must be performed within 5-10 minutes of each other. The same positioning should be maintained for each patient throughout the study. ECG recordings should be performed prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws) and should not be performed within 2.5 hours after any meal. Circumstances that may induce changes in heart rate, including environmental distractions (e.g., television, radio, conversation), should be avoided during the pre-ECG resting period and during ECG recording.
  • environmental distractions e.g., television, radio, conversation
  • Consenting patients may undergo an optional biopsy at any time at the investigator's discretion (if deemed clinically feasible by the investigator), such as at time of disease progression.
  • a biopsy of that residual mass is recommended to assess for viable tumor cells (vs. fibrotic or necrotic tissue). Samples collected via resection, core-needle biopsy (at least three cores preferred), or excisional, incisional, punch, or forceps biopsy are preferred.
  • Example 2 describes a substudy of the clinical trial described in Example 1 that is directed to treatment of urothelial carcinoma with anti-latent TGF-beta 1 antibodies as disclosed herein, e.g., SOF10, in combination with a checkpoint inhibitor (e.g., an anti-PD-L1 antibody such as atezolizumab).
  • a checkpoint inhibitor e.g., an anti-PD-L1 antibody such as atezolizumab.
  • the present example is a urothelial carcinoma (UC) substudy of the clinical study described in Example 1 that evaluates the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of SOF10 when administered in combination with atezolizumab in patients with urothelial carcinoma.
  • UC urothelial carcinoma
  • “study treatment” refers to the combination of all treatments assigned to patients as part of this study (e.g., SOF10 in combination with atezolizumab).
  • ADA anti-drug antibody
  • CR complete response
  • CTCAE v5.0 National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 5.0
  • DOR duration of response
  • ORR objective response rate
  • OS overall survival
  • PD pharmacodynamic
  • PFS progression-free survival
  • PK pharmacokinetic
  • PR partial response
  • RECIST v1 .1 Response Evaluation Criteria in Solid Tumors, Version 1 .1 .
  • This urothelial carcinoma substudy is designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary anti-tumor activity of SOF10 when administered in combination with atezolizumab in patients with locally advanced or metastatic UC.
  • the substudy includes a screening period of up to 28 days, a treatment period, a minimum followup period of 90 days after treatment, and survival follow-up.
  • the substudy includes two stages: an initial safety run-in stage and an expansion stage.
  • Patients in the safety run-in receive at least one cycle of study treatment, with both SOF10 and atezolizumab given concurrently starting from Cycle 1 .
  • Accrual in the expansion stage begins after the safety run-in stage has fully enrolled.
  • Patients in this substudy are initially assessed for eligibility during the screening period (lasting ⁇ 28 days). Following confirmation of eligibility, patients receive SOF10 in combination with atezolizumab. Patients receive study treatment in 21 -day cycles. Treatment is continued as long as patients are experiencing clinical benefit in the opinion of the investigator (e.g., in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression) after an integrated investigator assessment of radiographic data, tissue biopsy results (if available), and clinical status. Patients are permitted to continue study treatment after disease progression per Response Evaluation Criteria in Solid Tumors, Version 1 .1 (RECIST v1 .1 ) if they meet certain criteria, including, but not limited to, evidence of clinical benefit as assessed by the investigator.
  • Dosing of the first 2 patients in the safety run-in stage is separated by at least 24 hours. After 6 patients have received at least one cycle of study treatment in the safety run-in stage, safety data is formally reviewed by the investigator.
  • Accrual in the expansion stage begind after the safety run-in stage has been fully enrolled (e.g., 6 patients have received at least one cycle of study treatment). Approximately 34 additional patients are to be enrolled in the expansion stage for a total of approximately 40 patients enrolled in the substudy. Patients receive study treatment as described herein to obtain additional safety, tolerability, and pharmacokinetic (PK) data, as well as preliminary evidence of clinical activity.
  • PK pharmacokinetic
  • Patients may continue study treatment in the safety run-in or expansion stages of the study as described in Example 1 and, e.g., FIG. 2.
  • the total duration of study participation for each patient is expected to range from 1 day to more than 12 months.
  • Adequate hematologic and end-organ function defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
  • ANC > 1.0 x 10 9 /L (> 1000/ .L)without granulocyte colony-stimulating factor support.
  • INR and aPTT ⁇ 1 .5 x ULN For patients not receiving therapeutic anticoagulation: INR and aPTT ⁇ 1 .5 x ULN.
  • Patients receiving therapeutic anticoagulation should be on a stable dose with INR in target range.
  • Measurable disease (at least one target lesion) according to RECIST v1 .1 on CT or MRI images within 28 days prior to enrollment.
  • Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
  • T4b any N; or any T, N2-N3
  • metastatic UC M1 , Stage IV
  • transitional cell carcinoma or urothelial cell carcinoma of the urinary tract including renal pelvis, ureters, urinary bladder, and urethra
  • Enrollment can be managed to ensure that approximately up to half of the accrued patients are positive for PD-L1 expression (e.g., > 1%) as determined by a local laboratory through use of a health authority-approved or CE-marked assay.
  • Previously untreated patients must not be eligible for any cisplatin-containing chemotherapy.
  • Ineligible (“unfit”) for cisplatin-based chemotherapy is defined by any one of the following criteria:
  • GFR should be assessed by direct measurement (e.g., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine.
  • a hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies.
  • Grade 2 peripheral neuropathy e.g., sensory alteration or paresthesias including tingling.
  • Previously treated patients must have had disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin or carboplatin; methotrexate, vinblastine, doxorubicin, and cisplatin):
  • at least one platinum-containing regimen e.g., gemcitabine and cisplatin or carboplatin; methotrexate, vinblastine, doxorubicin, and cisplatin
  • a regimen is defined as patients receiving at least two cycles of a platinum- containing regimen.
  • Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen can be considered as second-line patients.
  • Patients may have received no more than two prior regimens of treatment (including the required platinum-based regimen) for their advanced or metastatic UC. Patients must have demonstrated disease progression during or following all prior regimen(s).
  • Adjuvant or neoadjuvant treatment with cancer immunotherapy for localized disease is permitted if discontinued at least 6 months prior to Day 1 of Cycle 1 .
  • Palliative radiotherapy for painful metastases or metastases in potentially sensitive locations e.g., epidural space
  • TGF-p or TGF-p receptor inhibitor e.g., bintrafusp alpha, SRK-181 , NIS793, and the like
  • Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:
  • Measurable disease per RECIST v1 .1 must be present outside the CNS.
  • the patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.
  • the patient has no ongoing requirement for corticosteroids as therapy for CNS disease, with corticosteroids discontinued for > 2 weeks prior to enrollment. Anticonvulsant therapy at a stable dose is permitted.
  • Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
  • Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.
  • Any disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug may affect the interpretation of the results, or may render the patient at high risk from treatment complications, including, but not limited to:
  • liver disease including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse.
  • Symptomatic lesions e.g., bone metastases or metastases causing nerve impingement
  • Symptomatic lesions e.g., bone metastases or metastases causing nerve impingement
  • patients should be recovered from the effects of radiation.
  • Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth should be considered for loco-regional therapy, if appropriate, prior to enrollment.
  • Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1 .5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN).
  • malignancy other than the disease under study within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
  • a negligible risk of metastasis or death e.g., 5-year OS rate > 90%
  • Adverse events from prior anti-cancer therapy (with the exception of immune-related adverse events attributed to cancer immunotherapy; see below) that have not resolved to Grade ⁇ 1 except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy.
  • autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
  • Rash must cover ⁇ 10% of body surface area.
  • Severe infection within 4 weeks prior to initiation of study treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
  • prophylactic antibiotics e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation
  • COPD chronic obstructive pulmonary disease
  • HbsAg Positive hepatitis B surface antigen
  • HbcAb positive total hepatitis B core antibody
  • HbcAb hepatitis B virus

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Abstract

L'invention concerne des procédés et des compositions pour le traitement du cancer (par exemple, une tumeur solide localement avancée, récurrente ou métastatique) chez un sujet, par exemple, par administration d'une thérapie anticancéreuse qui comprend un anticorps anti-TGF-bêta 1 latent au sujet. L'invention concerne également des compositions (par exemple, un anticorps anti-TGF-bêta 1 latent, des compositions pharmaceutiques de celui-ci, des kits de celui-ci, et des articles de fabrication de celui-ci) destinées à être utilisées dans le traitement du cancer chez un sujet.
PCT/US2024/028339 2023-05-10 2024-05-08 Méthodes et compositions pour le traitement du cancer Pending WO2024233646A1 (fr)

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