WO2021194481A1 - Dosage pour le traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1 - Google Patents

Dosage pour le traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1 Download PDF

Info

Publication number
WO2021194481A1
WO2021194481A1 PCT/US2020/024526 US2020024526W WO2021194481A1 WO 2021194481 A1 WO2021194481 A1 WO 2021194481A1 US 2020024526 W US2020024526 W US 2020024526W WO 2021194481 A1 WO2021194481 A1 WO 2021194481A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
cancer
administered
subject
weeks
Prior art date
Application number
PCT/US2020/024526
Other languages
English (en)
Inventor
Janet LAU
Diana Mendus
Raymond D. Meng
Heather Blythe STEVENS
Benjamin Wu
Xiaosong Zhang
Hila BARAK
Edward Namserk CHA
Hui Min Phyllis CHAN
Tien HOANG
Original Assignee
Genentech, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Genentech, Inc. filed Critical Genentech, Inc.
Priority to PCT/US2020/024526 priority Critical patent/WO2021194481A1/fr
Priority to CN202180022830.2A priority patent/CN115315256A/zh
Priority to PCT/US2021/015143 priority patent/WO2021154761A1/fr
Priority to EP21705841.1A priority patent/EP4096646A1/fr
Priority to KR1020227029306A priority patent/KR20220133243A/ko
Priority to JP2022545057A priority patent/JP2023511595A/ja
Priority to IL294800A priority patent/IL294800A/en
Priority to CA3165187A priority patent/CA3165187A1/fr
Priority to MX2022009170A priority patent/MX2022009170A/es
Priority to AU2021212662A priority patent/AU2021212662A1/en
Priority to TW110102913A priority patent/TW202142230A/zh
Publication of WO2021194481A1 publication Critical patent/WO2021194481A1/fr

Links

Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin

Definitions

  • the present invention relates to the treatment of cancer. More specifically, the invention concerns the treatment of patients having cancer by administering a combination of an anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-programmed death ligand-1 (PD-L1 ) antagonist antibody or an anti-programmed death-1 (PD-1 ) antagonist antibody).
  • TAGIT anti-T-cell immunoreceptor with Ig and ITIM domains
  • a PD-1 axis binding antagonist e.g., an anti-programmed death ligand-1 (PD-L1 ) antagonist antibody or an anti-programmed death-1 (PD-1 ) antagonist antibody.
  • Cancers are characterized by the uncontrolled growth of cell subpopulations. Cancers are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over eight million cancer deaths occurring each year. Cancer care thus represents a significant and ever-increasing societal burden.
  • the present invention includes methods of treating a subject having cancer by administering a combination of an anti-TIG IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)).
  • an anti-TIG IT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)
  • Methods of the invention include dosing regimens characterized by frequency of administration and, in some embodiments, combination with one or more chemotherapeutic agents. Compositions, uses, and kits involving such combinations and/or dosing regimens are also provided herein.
  • the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 700 mg to about 1000 mg (e.g., about 700 mg to about 800 mg, about 800 mg to about 900 mg, or about 900 mg to about 1000 mg, e.g., about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1000 mg, e.g., about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, or about 890) every four weeks and a PD-1 axis binding antagonist (e.g., atezolizumab) at a fixed dose of about 1400 mg
  • the anti-TIGIT antagonist antibody is administered at a fixed dose of about 800 mg to about 900 mg every four weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every four weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 1600 mg to 1800 mg every four weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 1680 mg every four weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every four weeks and the PD-1 axis binding antagonist is administered at a fixed dose of about 1680 mg every four weeks. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered intravenously.
  • the one or more dosing cycles are each 28-day dosing cycles.
  • the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered on Day 1 of each 28-day dosing cycle.
  • a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 300 mg to about 600 mg (e.g., about 350 mg to about 550 mg, about 400 mg to about 500 mg, or about 410 mg to about 450 mg, e.g., about 300 mg to about 320 mg, about 320 mg to about 340 mg, about 340 mg to about 360 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 400 mg to about 420 mg, about 420 mg to about 440 mg, about 440 mg to about 460 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 500 mg to about 520 mg, about 520 mg to about 540 mg, about 540 mg to about 560 mg, about 560 mg to about 580 mg, about 580 mg to about 600 mg
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • the anti-TIG IT antagonist antibody is administered at a fixed dose of about 400 mg to about 500 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 800 mg to 1000 mg every two weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks and the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered intravenously.
  • the one or more dosing cycles are each 28-day dosing cycles.
  • the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered on Day 1 and Day 15 of each 28-day dosing cycle.
  • the method does not comprise further administering to the subject one or more chemotherapeutic agents.
  • the method comprises further administering to the subject one or more chemotherapeutic agents.
  • the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent.
  • the first chemotherapeutic agent is a platinum agent (e.g., carboplatin or cisplatin) and/or the second chemotherapeutic agent is a non-platinum agent (e.g., an antimetabolite (e.g., pemetrexed), a topoisomerase II inhibitor (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331), or a taxane (e.g., paclitaxel or nab- paclitaxel)).
  • an antimetabolite e.g., pemetrexed
  • the platinum agent is carboplatin or cisplatin and the non-platinum agent is pemetrexed.
  • the cisplatin is administered at a dose of about 75 mg/m 2 .
  • the pemetrexed is administered at a dose of about 500 mg/m 2 .
  • the platinum agent is carboplatin or cisplatin and the non-platinum agent is paclitaxel.
  • the cisplatin is administered at a dose of about 75 mg/m 2 .
  • the paclitaxel is administered at a dose of about 175-200 mg/m 2 (e.g., about 175 mg/m 2 or about 200 mg/m 2 ).
  • the first chemotherapeutic agent is gemcitabine and the second chemotherapeutic agent is nab-paclitaxel.
  • the gemcitabine is administered at a dose of about 1000 mg/m 2 .
  • the nab-paclitaxel is administered at a dose of about 125 mg/m 2 .
  • the method comprises further administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents.
  • the one or more subsequent doses is equal to or lower than the preceding dose of the one or more chemotherapeutic agents (e.g., the one or more subsequent doses is about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the preceding dose).
  • the one or more chemotherapeutic agents are each administered once per week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.
  • the method comprises further administering to the subject gemcitabine at a cumulative dose of about 1000 mg/m 2 to about 6000 mg/m 2 (e.g., about 2000 mg/m 2 to about 5000 mg/m 2 , e.g., about 2500 mg/m 2 to about 3500 mg/m 2 ) over the course of each 28-day dosing cycle (e.g., at a cumulative dose of about 3000 mg/m 2 over the course of each 28-day dosing cycle).
  • the gemcitabine is administered three times over the course of each 28-day dosing cycle.
  • the gemcitabine is administered on Days 1 , 8, and 15 of each 28-day dosing cycle. In some embodiments, each dose of the gemcitabine is about 500 mg/m 2 to about 2000 mg/m 2 (e.g., about 1000 mg/m 2 ).
  • the method comprises further administering to the subject nab-paclitaxel at a cumulative dose of about 200 mg/m 2 to about 600 mg/m 2 (e.g., about 250 mg/m 2 to about 500 mg/m 2 , e.g., about 300 mg/m 2 to about 450 mg/m 2 ) over the course of each 28-day dosing cycle (e.g., at a cumulative dose of about 375 mg/m 2 over the course of each 28-day dosing cycle).
  • the nab-paclitaxel is administered three times over the course of each 28-day dosing cycle.
  • the nab-paclitaxel is administered on Days 1 , 8, and 15 of each 28- day dosing cycle. In some embodiments, each dose of the nab-paclitaxel is about 50 mg/m 2 to about 200 mg/m 2 (e.g., about 125 mg/m 2 ).
  • the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more 28-day dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 300 mg to about 600 mg (e.g., about 350 mg to about 550 mg, about 400 mg to about 500 mg, or about 410 mg to about 450 mg, e.g., about 300 mg to about 320 mg, about 320 mg to about 340 mg, about 340 mg to about 360 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 400 mg to about 420 mg, about 420 mg to about 440 mg, about 440 mg to about 460 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 500 mg to about 520 mg, about 520 mg to about 540 mg, about 540 mg to about 560 mg, about 560 mg to about 580 mg,
  • the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg on Days 1 and 15 of each 28-day dosing cycle.
  • the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg on Days 1 and 15 of each 28-day dosing cycle.
  • the gemcitabine is administered at a dose of about 1000 mg/m 2 on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the nab-paclitaxel is administered at a dose of about 125 mg/m 2 on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist
  • the nab-paclitaxel is administered after the anti-TIGIT antagonist antibody
  • the gemcitabine is administered after the nab- paclitaxel.
  • the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered intravenously.
  • the gemcitabine and the nab-paclitaxel are administered intravenously.
  • the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 30 mg to about 1200 mg every three weeks, a PD-1 axis binding antagonist (e.g., atezolizumab) at a fixed dose of about 80 and 1600 mg every three weeks, a platinum agent every three weeks, and a non-platinum agent every three weeks.
  • the platinum agent is carboplatin or cisplatin and/or the non-platinum agent is an antimetabolite or a taxane.
  • the platinum agent is carboplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed).
  • the platinum agent is cisplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed).
  • the cisplatin is administered at a dose of 75 mg/m 2 .
  • the antimetabolite is pemetrexed, and the pemetrexed is administered at a dose of about 500 mg/m 2 .
  • the dosing regimen comprises an induction phase comprising four to six initial 21- day dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum agent, and the antimetabolite are administered on Day 1 of each 21 -day dosing cycle of the induction phase.
  • the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist
  • the platinum agent is administered after the anti-TIGIT antagonist antibody
  • the antimetabolite is administered after the platinum agent.
  • the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg
  • the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg
  • the pemetrexed is administered at a dose of about 500 mg/m 2 , each on Day 1 of each 21 -day dosing cycle of the induction phase.
  • the dosing regimen comprises a maintenance phase following the induction phase, wherein the maintenance phase comprises one or more additional 21 -day dosing cycles, and wherein the anti-TIG IT antagonist antibody (e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., atezolizumab), and the antimetabolite (e.g., pemetrexed) are administered on Day 1 of each 21 -day dosing cycle of the maintenance phase.
  • the one or more additional 21 -day dosing cycles of the maintenance phase do not comprise administration of the platinum agent.
  • the platinum agent is carboplatin and the non-platinum agent is a taxane (e.g., paclitaxel).
  • the taxane e.g., paclitaxel
  • the carboplatin is administered at a dose of about 175-200 mg/m 2 (e.g., about 175 mg/m 2 or about 200 mg/m 2 ).
  • the dosing regimen comprises an induction phase comprising four to six initial 21 -day dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum agent, and the taxane are administered on Day 1 of each 21 -day cycle of the induction phase.
  • the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist
  • the platinum agent is administered after the anti-TIGIT antagonist antibody
  • the taxane is administered after the platinum agent.
  • the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, a PD-1 axis binding antagonist at a fixed dose of about 80 and 1600 mg every three weeks, gemcitabine, and nab-paclitaxel.
  • the anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 600 mg every three weeks.
  • the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg every three weeks.
  • the PD-1 axis binding antagonist is administered at a fixed dose of about 800 mg to about 1400 mg every three weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg every three weeks and the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg every three weeks.
  • a tumor sample (e.g., a solid tumor sample, e.g., a lung tumor) from the subject has been determined to have a PD-L1 -positive tumor cell fraction.
  • the tumor sample from the subject has been determined to have a PD- L1 -positive tumor cell fraction of greater than, or equal to, 30% (e.g., greater than, or equal to, 50%).
  • the PD-L1 -positive tumor cell fraction has been determined by an immunohistochemical (IHC) assay.
  • IHC immunohistochemical
  • the PD-L1 -positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody suitable for staining, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8. In some embodiments, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50%, as determined by positive staining with the anti-PD-L1 antibody SP263.
  • the PD-L1 -positive tumor cell fraction is calculated using the Ventana SP263 IHC assay. In some embodiments, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50%, as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the PD-L1 - positive tumor cell fraction is calculated using the pharmDx 22C3 IHC assay. In some embodiments, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 30% (e.g., greater than, or equal to, 50%), as determined by positive staining with the anti-PD-L1 antibody SP142. In some embodiments, the PD- L1 -positive tumor cell fraction is greater than, or equal to, 50%, as determined by positive staining with the anti-PD-L1 antibody 28-8.
  • a tumor sample from the subject has been determined to have a detectable nucleic acid expression level of PD-L1 , e.g., as determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.
  • the cancer is a lung cancer, e.g., a non-small cell lung cancer (NSCLC), e.g., a squamous NSCLC or a non-squamous NSCLC.
  • NSCLC non-small cell lung cancer
  • the NSCLC is a locally advanced unresectable NSCLC.
  • the NSCLC is a Stage NIB NSCLC.
  • the NSCLC is a recurrent or metastatic NSCLC (e.g., a Stage IV NSCLC).
  • the subject has not been previously treated for Stage IV NSCLC.
  • the subject does not have a sensitizing epidermal growth factor receptor (EGFR ) gene mutation or anaplastic lymphoma kinase ( ALK) gene rearrangement. In some embodiments, the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection and/or the subject is negative for EBV IgM or negative by EBV PCR (e.g., the subject is negative for EBV IgM and negative by EBV PCR).
  • EBV Epstein-Barr virus
  • the subject is positive for EBV IgG or positive for Epstein-Barr nuclear antigen (EBNA). In some embodiments, the subject is positive for EBV IgG and positive for EBNA. In other embodiments, the subject is negative for EBV IgG or negative for EBNA.
  • EBNA Epstein-Barr nuclear antigen
  • the anti-TIG IT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).
  • HVRs hypervariable regions
  • the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).
  • FRs light chain variable region framework regions
  • the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of Xi VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11 ), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of ITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).
  • Xi is E.
  • Xi is Q.
  • the anti-TIG IT antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) a VH domain as in (a) and a VL domain as in (b).
  • the anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.
  • the anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti- TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.
  • the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody. In some embodiments, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments, the anti-TIGIT antagonist antibody is tiragolumab.
  • the anti-TIGIT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.
  • the anti-TIGIT antagonist antibody is an IgG class antibody (e.g., an lgG1 subclass antibody).
  • the PD-1 axis binding antagonist is a PD- L1 binding antagonist or a PD-1 binding antagonist.
  • the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.
  • the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736. In some embodiments, the anti- PD-L1 antagonist antibody is atezolizumab.
  • the PD-1 binding antagonist is an anti-PD-1 antagonist antibody, e.g., nivolumab (MDX-1106), pembrolizumab (MK-3475), or AMP-224.
  • an anti-PD-1 antagonist antibody e.g., nivolumab (MDX-1106), pembrolizumab (MK-3475), or AMP-224.
  • the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21 ); an HVR- H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).
  • HVRs an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:
  • the anti- PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) a VH domain as in (a) and a VL domain as in (b).
  • the anti-PD-L1 antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 26; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27.
  • the PD-1 axis binding antagonist is a monoclonal antibody. In some embodiments, the PD-1 axis binding antagonist is a humanized antibody. In some embodiments, the PD-1 axis binding antagonist is a full-length antibody. In some embodiments, the PD-1 axis binding antagonist is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.
  • the PD-1 axis binding antagonist is an antibody fragment that binds PD-1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.
  • the PD-1 axis binding antagonist is an IgG class antibody (e.g., an IgG 1 subclass antibody).
  • the method comprises administering to the subject the PD-1 axis binding antagonist before the anti-TIGIT antagonist antibody.
  • the method comprises a first observation period following administration of the PD-1 axis binding antagonist and second observation period following administration of the anti-TIGIT antagonist antibody.
  • the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length.
  • the method comprises administering to the subject the anti-TIGIT antagonist antibody before the PD-1 axis binding antagonist. In some embodiments, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody and second observation period following administration of the PD-1 axis binding antagonist. In some embodiments, the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length.
  • the method comprises administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist simultaneously.
  • the method comprises administering to the subject the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist intravenously. In some embodiments, the method comprises administering to the subject the anti-TIGIT antagonist antibody by intravenous infusion over 60 ⁇ 10 minutes and/or administering to the subject the PD-1 axis binding antagonist by intravenous infusion over 60 ⁇ 15 minutes.
  • the method comprises administering to the subject the one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) intravenously (e.g., by intravenous infusion).
  • chemotherapeutic agents e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab
  • the cancer is a solid tumor. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is a lung cancer (e.g., a small cell lung cancer (SCLC), a non-small cell lung cancer (NSCLC)), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer, a gastric cancer (e.g., a gastroesophageal junction cancer), a bladder cancer (e.g., a urothelial bladder cancer), a colorectal cancer, or a breast cancer (e.g., HER2+ breast cancer
  • SCLC small cell lung cancer
  • the lung cancer is a non-small cell lung cancer.
  • the pancreatic cancer is a pancreatic duct adenocarcinoma (PDAC).
  • the PDAC is a metastatic PDAC.
  • the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 840 mg every four weeks and atezolizumab at a fixed dose of about 1680 mg every four weeks.
  • the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 420 mg every two weeks and atezolizumab at a fixed dose of about 840 mg every two weeks.
  • the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent.
  • the first chemotherapeutic agent is a platinum agent and the second chemotherapeutic agent is a non-platinum chemotherapeutic agent.
  • the platinum agent is carboplatin or cisplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed), a topoisomerase II inhibitor (e.g., etoposide), or a taxane (e.g., paclitaxel).
  • the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.
  • the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.
  • the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.
  • the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent, wherein the first chemotherapeutic agent is gemcitabine and the second chemotherapeutic agent is nab-paclitaxel.
  • the cancer is a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC).
  • the invention features a method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more 28- day dosing cycles of tiragolumab at a fixed dose of about 420 mg on Days 1 and 15 of each 28-day dosing cycle, atezolizumab at a fixed dose of about 840 mg on Days 1 and 15 of each 28-day dosing cycle, gemcitabine at a dose of about 1000 mg/m 2 on Days 1 , 8, and 15 of each 28-day dosing cycle, and nab-paclitaxel at a dose of about 125 mg/m 2 on Days 1 , 8, and 15 of each 28-day dosing cycle.
  • the cancer is a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC).
  • an effective amount of an anti-TIGIT antagonist antibody e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • an effective amount of an anti-TIGIT antagonist antibody is administered to a subject in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle).
  • an effective amount of an anti-TIGIT antagonist antibody e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • an effective amount of an anti-TIGIT antagonist antibody is administered to a subject in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle).
  • the treatment results in a complete response or a partial response. In some embodiments, the treatment results in an increase in progression-free survival of the subject as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • the subject is a human.
  • the invention features a kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist for treating a subject having a cancer according to any of the preceding methods.
  • the kit further comprises the PD-1 axis binding antagonist.
  • the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab.
  • the invention features a kit comprising a PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody for treating a subject having a cancer according to any of the preceding methods.
  • the kit further comprises the anti-TIGIT antagonist antibody.
  • the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab.
  • the invention provides an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in the method of any of the preceding aspects for treating a subject having a cancer.
  • an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the method of any one of the preceding aspects.
  • a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having a cancer in combination with an anti-TIGIT antagonist antibody, wherein the treatment is according to the method of any one of the preceding aspects.
  • the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are formulated separately.
  • the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are formulated together.
  • FIG. 1 is a flow chart showing the Phase lb chemotherapy expansion and Phase lb Q4W dosing expansion).
  • the present invention is based, at least in part, on the discovery that immunotherapies including an anti-TIGIT antibody (e.g., an anti-TIGIT antagonist antibody, such as tiragolumab) in combination with a PD-1 axis binding antagonist (e.g., an anti-programmed death ligand-1 (PD-L1 ) antibody (e.g., atezolizumab) or an anti-programmed death-1 (PD-1) antibody) can be useful in the treatment of cancer (e.g., a solid tumor or a locally advanced or metastatic cancer (e.g., lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSC
  • the invention features combinations of an anti-TIGIT antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., atezolizumab), and one or more chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))).
  • chemotherapeutic agent e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gem
  • the “amount,” “level,” or “expression level,” used herein interchangeably, of a biomarker is a detectable level in a biological sample.
  • “Expression” generally refers to the process by which information (e.g., gene-encoded and/or epigenetic) is converted into the structures present and operating in the cell. Therefore, as used herein, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and/or polypeptide modifications (e.g., posttranslational modification of a polypeptide).
  • Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and/or polypeptide modifications shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., by proteolysis.
  • “Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs). Expression levels can be measured by methods known to one skilled in the art and also disclosed herein.
  • the presence and/or expression level/amount of various biomarkers described herein in a sample can be analyzed by a number of methodologies, many of which are known in the art and understood by the skilled artisan, including, but not limited to, immunohistochemistry (“IHC”), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting (“FACS”), MassARRAY, proteomics, quantitative blood based assays (e.g., Serum ELISA), biochemical enzymatic activity assays, in situ hybridization, fluorescence in situ hybridization (FISH), Southern analysis, Northern analysis, whole genome sequencing, massively parallel DNA sequencing (e.g., next- generation sequencing), NANOSTRING®, polymerase chain reaction (PCR) including quantitative real time PCR (qRT-PCR) and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like, RNA-seq, microarray analysis,
  • Typical protocols for evaluating the status of genes and gene products are found, for example in Ausubel et al., eds., 1995, Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis). Multiplexed immunoassays such as those available from Rules Based Medicine or Meso Scale Discovery (“MSD”) may also be used.
  • MSD Meso Scale Discovery
  • TIGIT or “T -cell immunoreceptor with Ig and ITIM domains” as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM.
  • the term encompasses “full-length,” unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 30), as well as any form of TIGIT that results from processing in the cell (e.g., processed human TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO: 31).
  • the term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants.
  • the amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1 .
  • PD-L1 or “Programmed Cell Death Ligand 1 ” refers herein to any native PD-L1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • PD-L1 is also known in the art as CD274 molecule, CD274 antigen, B7 homolog 1 , PDCD1 Ligand 1 , PDCD1 LG1 , PDCD1 L1 , B7H1 , PDL1 , programmed death ligand 1 , B7-H1 , and B7-H.
  • the term also encompasses naturally occurring variants of PD-L1 , e.g., splice variants, or allelic variants.
  • the amino acid sequence of an exemplary human PD-L1 may be found under UniProt Accession Number Q9NZQ7 (SEQ ID NO: 32).
  • antagonist is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native polypeptide disclosed herein.
  • Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments (e.g., antigen- binding fragments), fragments or amino acid sequence variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc.
  • Methods for identifying antagonists of a polypeptide may comprise contacting a polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide.
  • 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 partner, 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, target cell killing).
  • a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist.
  • 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 , PD-L2.
  • 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 is an anti-PD-1 antibody.
  • a PD-1 binding antagonist is MDX- 1106 (nivolumab) described herein.
  • a PD-1 binding antagonist is pembrolizumab (formerly lambrolizumab (MK-3475)) described herein.
  • a PD-1 binding antagonist is AMP-224 described herein.
  • 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 , 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 , 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).
  • a PD-L1 binding antagonist is an anti-PD-L1 antibody.
  • an anti-PD-L1 antibody is atezolizumab described herein (e.g., MPDL3280A).
  • an anti-PD-L1 antibody is MDX-1105 described herein.
  • an anti- PD-L1 antibody is MEDI4736 described herein.
  • the term “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 .
  • 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 .
  • the 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).
  • a PD-L2 binding antagonist is an immunoadhesin.
  • anti-TIG IT antagonist antibody refers to an antibody or an antigen-binding fragment or variant thereof that is capable of binding TIGIT with sufficient affinity such that it substantially or completely inhibits the biological activity of TIGIT.
  • an anti-TIG IT antagonist antibody may block signaling through PVR, PVRL2, and/or PVRL3 so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation.
  • an anti-TIGIT antagonist antibody may block signaling through PVR without impacting PVR- CD226 interaction.
  • an anti- TIGIT antagonist antibody may antagonize one TIGIT activity without affecting another TIGIT activity.
  • an anti-TIGIT antagonist antibody for use in certain of the methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally affecting any of the other TIGIT interactions.
  • an anti-TIGIT antagonist antibody that binds to TIGIT has a dissociation constant (KD) of ⁇ 1 mM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 8 M or less, e.g.
  • an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that is conserved among TIGIT from different species or an epitope on TIGIT that allows for cross-species reactivity.
  • the anti-TIGIT antagonist antibody is tiragolumab.
  • administering is meant a method of giving a dosage of a compound (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), or a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an anti-TIGIT antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody),
  • the compounds and/or compositions utilized in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions.
  • the method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).
  • a “fixed” or “flat” dose of a therapeutic agent herein refers to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient.
  • the fixed or flat dose is therefore not provided as a mg/kg dose or a mg/m 2 dose, but rather as an absolute amount of the therapeutic agent (e.g., mg).
  • treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include delaying or decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
  • an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
  • conjunction with refers to administration of one treatment modality in addition to another treatment modality.
  • in conjunction with refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.
  • a “disorder” or “disease” is any condition that would benefit from treatment including, but not limited to, disorders that are associated with some degree of abnormal cell proliferation, e.g., cancer, e.g., lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)), kidney or renal cancer (e.g., renal cell carcinoma (RCC)), melanoma, head and neck cancer (e.g., head and neck squamous cell cancer
  • disfunctional also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., gamma interferon) and/or target cell killing.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • Cancers include locally advanced or metastatic cancers (e.g., locally advanced or metastatic tumors).
  • Particular examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • lung cancer such as small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung, or squamous cell cancer (e.g., epithelial squamous cell cancer); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)); head and neck cancer (e.g., head and neck squamous cell cancer (HNSCC)), ovarian cancer (OC), esophageal cancer; cancer of the peritoneum; hepatocellular cancer; gastric cancer
  • SCLC small cell lung cancer
  • NSCLC non-
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre
  • Tumor immunity refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.
  • Metastasis is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.
  • anti-cancer therapy refers to a therapy useful in treating cancer (e.g., lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)), kidney or renal cancer (e.g., renal cell carcinoma (RCC)), melanoma, head and neck cancer (e.g., head and neck squamous cell cancer (HNSCC)), ovarian cancer (OC), gastric cancer (GC) (e.g., gastroes, gastroe
  • anti-cancer therapeutic agents include, but are limited to, e.g., immunomodulatory agents (e.g., an immunomodulatory agent (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1 , PD-1 , CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®)), an anti-TIG IT antagonist antibody, or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM,
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
  • Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal
  • “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirol
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzi nostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, es
  • Chemotherapeutic agent also includes (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, LY117018, 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® (
  • Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RIT
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
  • Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.”
  • EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
  • Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No.
  • EMD 55900 Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)
  • EMD7200 a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding
  • human EGFR antibody HuMax-EGFR (GenMab)
  • fully human antibodies known as E1 .1 , E2.4, E2.5, E6.2, E6.4, E2.11 , E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol.
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001 , 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521 ,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391 ,874, 6,344,455, 5,760,041 , 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451 , W098/50038, W099/09016, and WO99/24037.
  • EGFR antagonists include OSI-774 (CP- 358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); 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)-N2-(1-methyl-methyl-methyl
  • Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; inhibitors of insulin receptor tyrosine kinases, including anaplastic lymphoma kinase (Aik) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP26113, crizotinib (XALKORI®), and ceritinib (ZYKADIA®); small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR- overexpressing cells; lapatini
  • Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective
  • Bi212, P32, Pb212 and radioactive isotopes of Lu miscellaneous investigational agents such as thioplatin, PS-341 , phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9- tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN
  • celecoxib or etoricoxib proteosome inhibitor
  • CCI-779 tipifarnib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone farnesyltransferase inhibitors
  • SCH 6636 farnesyltransferase inhibitors
  • pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects.
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumirac
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • Chemotherapeutic agents also include “platinum-based” chemotherapeutic agents, also referred to herein as “platinum 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, carboplatin, cisplatin, and oxaliplatin.
  • Chemotherapeutic agents also include “non-platinum agents,” which, as used herein, refer to chemotherapeutic agents that are not “platinum-based.”
  • exemplary non-platinum agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331), taxanes (e.g., paclitaxel (e.g., albumin-engineered paclitaxel, also referred to as nanoparticle- albumin-bound paclitaxel (nab-paclitaxel)), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel).
  • antimetabolites e
  • Taxanes as used herein is a diterpene which may bind to tubulin, promoting microtubule assembly and stabilization and/or prevent microtubule depolymerization.
  • Taxanes included herein include taxoid 10-deacetylbaccatin III and/or derivatives thereof.
  • Examplary 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.
  • the taxane is an albumin-coated nanoparticle (e.g., 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).
  • an “antimetabolite” as used herein is a chemotherapeutic agent that interferes with and inhibits (wholly or partially) an endogenous (normal) metabolic process within a cell (e.g., a cancer cell).
  • Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.
  • an “effective amount” of a compound for example, an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., anti-PD-L1 antibody), and/or a chemotherapeutic agent (e.g., a platinum agent, pemetrexed, a topoisomerase II inhibitor, paclitaxel (e.g., nab-paclitaxel), or gemcitabine) or a composition thereof (e.g., a pharmaceutical composition thereof, e.g., a pharmaceutical composition including an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), and/or a chemotherapeutic agent (e.g., a platinum agent, pemetrexed, a topoisomerase II inhibitor, paclitaxel (e.g., nab-paclitaxel), or gemcitabine)) is at least the minimum amount required to achieve the desired therapeutic result, such as a
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease (e.g., reduction or delay in cancer-related pain, symptomatic skeletal-related events (SSE), reduction in symptoms per the European Organization for Research and Treatment of Cancer Qual ity-of-Life Questionnaire (EORTC QLQ-C30, e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, or general level of physical emotional, cognitive, or social functioning), reduction in pain as measured by, e.g., the 10-point pain severity (measured at its worst) numerical rating scale (NRS), and/or reduction in symptoms associated with lung cancer per the health- related quality of life (HRQoL) questionnaire as assessed by symptoms in lung cancer (SILC) scale (e.g., time to deterioration (TTD) in cough dyspenea and chest pain), increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as
  • progression-free survival or radiographic progression-free survival rPFS
  • delay of unequivocal clinical progression e.g., cancer-related pain progression, symptomatic skeletal-related event, deterioration in Eastern Cooperative Group Oncology Group (ECOG) Performance Status (PS) (e.g., how the disease affects the daily living abilities of the patient), and/or initiation of next systemic anti-cancer therapy), and/or delaying time to lung-specific antigen progression), and/or prolonging survival.
  • ECOG Eastern Cooperative Group Oncology Group
  • PS Performance Status
  • an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder.
  • An effective amount can be administered in one or more administrations.
  • an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • Immunogenicity refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response. Examples of enhancing tumor immunogenicity include but are not limited to treatment with a TIGIT and/or PD-L1 antagonist (e.g., anti-TIG IT antagonist antibodies and/or anti-PD-L1 antibodies).
  • a TIGIT and/or PD-L1 antagonist e.g., anti-TIG IT antagonist antibodies and/or anti-PD-L1 antibodies.
  • “Individual response” or “response” can be assessed using any endpoint indicating a benefit to the subject, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., progression of cancer, e.g., e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RC
  • partial response refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD.
  • objective response rate refers to the sum of complete response (CR) rate and partial response (PR) rate.
  • DOR duration of objective response
  • DOR is defined as the time from the first occurrence of a documented objective response to disease progression, or death from any cause within 30 days of the last dose of a treatment, whichever occurs first.
  • sustained response refers to the sustained effect on reducing tumor growth after cessation of a treatment.
  • the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase.
  • the sustained response has a duration at least the same as the treatment duration, at least 1 .5x, 2. Ox, 2.5x, or 3. Ox length of the treatment duration.
  • an “effective response” of a subject or a subject’s “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a subject as risk for, or suffering from, a disease or disorder, such as cancer.
  • a disease or disorder such as cancer.
  • such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • a subject who “does not have an effective response” to treatment refers to a subject who does not have any one of extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • survival refers to the patient remaining alive, and includes overall survival as well as progression-free survival.
  • overall survival refers to the percentage of subjects in a group who are alive after a particular duration of time, e.g., 1 year or 5 years from the time of diagnosis or treatment.
  • progression-free survival refers to the length of time during and after treatment during which the disease being treated (e.g., cancer, e.g., lung cancer, e.g., SCLC, e.g., ES- SCLC) does not get worse.
  • Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • stable disease or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.
  • PD progressive disease
  • “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., cancer, e.g., lung cancer, e.g., SCLC, e.g., ES-SCLC).
  • This delay can be of varying lengths of time, depending on the history of the disease and/or subject being treated.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease.
  • CNS central nervous system
  • the term “reducing or inhibiting cancer relapse” means to reduce or inhibit tumor or cancer relapse, or tumor or cancer progression.
  • Reduce or inhibit is meant the ability to cause an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater.
  • Reduce or inhibit can refer to the symptoms of the disorder being treated (e.g., cancer, e.g., lung cancer, e.g., SCLC, e.g., ES-SCLC), the presence or size of metastases, or the size of the primary tumor.
  • extending survival is meant increasing overall or progression free survival in a treated patient relative to an untreated patient (e.g., relative to a patient not treated with the medicament), or relative to a patient who does not express a biomarker at the designated level, and/or relative to a patient treated with an approved anti-tumor agent.
  • An objective response refers to a measurable response, including complete response (CR) or partial response (PR).
  • Ventana SP263 IHC assay is conducted according to the Ventana PD-L1 (SP263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.
  • Ventana SP142 IHC assay is conducted according to the Ventana PD-L1 (SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.
  • the “pharmDx 22C3 IHC assay” is conducted according to the PD-L1 IHC 22C3 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.
  • Tumor-infiltrating immune cell refers to any immune cell present in a tumor or a sample thereof.
  • Tumor-infiltrating immune cells include, but are not limited to, intratumoral immune cells, peritumoral immune cells, other tumor stroma cells (e.g., fibroblasts), or any combination thereof.
  • Such tumor-infiltrating immune cells can be, for example, T lymphocytes (such as CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other bone marrow-lineage cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., interdigitating dendritic cells), histiocytes, and natural killer cells.
  • T lymphocytes such as CD8+ T lymphocytes and/or CD4+ T lymphocytes
  • B lymphocytes or other bone marrow-lineage cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., interdigitating dendritic cells), histiocytes, and natural killer cells.
  • granulocytes e.g., neutrophils,
  • biomarker refers to an indicator, e.g., predictive, diagnostic, and/or prognostic, which can be detected in a sample.
  • the biomarker may serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer, e.g., e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney
  • a biomarker is a gene.
  • Biomarkers include, but are not limited to, polypeptides, polynucleotides (e.g., DNA, and/or RNA), polynucleotide copy number alterations (e.g.,
  • the biomarker is PD- L1 .
  • antibody includes monoclonal antibodies (including full-length antibodies which have an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies), diabodies, and single-chain molecules, as well as antibody fragments, including antigen-binding fragments, such as Fab, F(ab’)2, and Fv.
  • immunoglobulin Ig is used interchangeably with “antibody” herein.
  • the basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains.
  • An IgM antibody consists of 5 of the basic heterotetramer units along with an additional polypeptide called a J chain, and contains 10 antigen binding sites, while IgA antibodies comprise from 2-5 of the basic 4-chain units which can polymerize to form polyvalent assemblages in combination with the J chain.
  • the 4-chain unit is generally about 150,000 Daltons.
  • Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype.
  • Each H and L chain also has regularly spaced intrachain disulfide bridges.
  • Each H chain has at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the a and g chains and four CH domains for m and e isotypes.
  • Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain at its other end. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (CH1 ). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen-binding site.
  • L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
  • immunoglobulins can be assigned to different classes or isotypes.
  • immunoglobulins There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, having heavy chains designated a, d, e, g, and m, respectively.
  • the g and a classes are further divided into subclasses on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: lgG1 , lgG2A, lgG2B, lgG3, lgG4, lgA1 and lgA2.
  • hypervariable region refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops.
  • antibodies comprise six HVRs; three in the VH (H1 , H2, H3), and three in the VL (L1 , L2, L3).
  • H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et at., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1 -25 (Lo, ed., Human Press, Totowa, NJ, 2003).
  • camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain. See, e.g., Hamers-Casterman etal., Nature 363:446-448 (1993); Sheriff etal., Nature Struct. Biol. 3:733-736 (1996).
  • HVR delineations are in use and are encompassed herein.
  • the Kabat Complementarity Determining Regions are based on sequence variability and are the most commonly used (Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)).
  • the AbM HVRs represent a compromise between the Kabat HVRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software.
  • the “contact” HVRs are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted below.
  • HVRs may comprise “extended HVRs” as follows: 24-36 or 24-34 (L1 ), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1 ), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH.
  • the variable domain residues are numbered according to Kabat etal., supra, for each of these definitions.
  • 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 etal., 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.
  • variable refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies.
  • the V domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen.
  • variability is not evenly distributed across the entire span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy chain variable domains.
  • HVRs hypervariable regions
  • the more highly conserved portions of variable domains are called the framework regions (FR).
  • the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure.
  • the HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs from the other chain, contribute to the formation of the antigen binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991 )).
  • the constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody- dependent cellular toxicity.
  • variable region refers to the amino-terminal domains of the heavy or light chain of the antibody.
  • variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites.
  • “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 interchangeably to refer to an antibody in its substantially intact form, as opposed to an antibody fragment.
  • whole antibodies include those with heavy and light chains including an Fc region.
  • the constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof.
  • the intact antibody may have one or more effector functions.
  • an “antibody fragment” comprises a portion of an intact antibody, preferably the antigen-binding and/or the variable region of the intact antibody.
  • antibody fragments include Fab, Fab’, F(ab’)2 and Fv fragments; diabodies; linear antibodies (see U.S. Patent 5,641 ,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produced two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily.
  • the Fab fragment consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1 ).
  • Each Fab fragment is monovalent with respect to antigen binding, i.e. , it has a single antigen-binding site.
  • Pepsin treatment of an antibody yields a single large F(ab’)2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of cross-linking antigen.
  • Fab’ fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region.
  • Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • the Fc fragment comprises the carboxy-terminal portions of both FI chains held together by disulfides.
  • the effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.
  • “Functional fragments” of the antibodies of the invention comprise a portion of an intact antibody, generally including the antigen binding or variable region of the intact antibody or the Fc region of an antibody which retains or has modified FcR binding capability.
  • antibody fragments include linear antibody, single-chain antibody molecules and multispecific antibodies formed from antibody fragments.
  • “Fv” is the minimum antibody fragment which contains a complete antigen-recognition and - binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • Single-chain Fv also abbreviated as “sFv” or “scFv” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain.
  • the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions.
  • the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl- terminus thereof.
  • the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody.
  • a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.
  • Suitable native-sequence Fc regions for use in the antibodies of the invention include human IgG 1 , lgG2 (lgG2A, lgG2B), lgG3 and lgG4.
  • numbering of amino acid residues in the Fc region or constant region is according to the 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 .
  • Fc receptor or “FcR” describes a receptor that binds to the Fc region of an antibody.
  • the preferred FcR is a native sequence human FcR.
  • a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors, FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
  • Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.
  • FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel etal., Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995).
  • Other FcRs including those to be identified in the future, are encompassed by the term “FcR” herein.
  • diabodies refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10) residues) between the VH and VL domains such that inter-chain but not intra-chain pairing of the V domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment having two antigen-binding sites.
  • Bispecific diabodies are heterodimers of two “crossover” sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains.
  • Diabodies are described in greater detail in, for example, EP 404,097; WO 93/11161 ; Hollinger etal., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993).
  • the monoclonal antibodies herein specifically include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • Chimeric antibodies of interest herein include PRIMATIZED ® antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with an antigen of interest.
  • humanized antibody is used a subset of “chimeric antibodies.”
  • the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, d, e, g, and m, respectively.
  • Binding affinity refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen, e.g., TIGIT or PD- L1). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.
  • a “human antibody” is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks etal., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.
  • Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSETM technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.
  • “Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR (hereinafter defined) of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and/or capacity.
  • donor antibody such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and/or capacity.
  • framework (“FR”) residues of the human immunoglobulin are replaced by corresponding non human residues.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc.
  • the number of these amino acid substitutions in the FR are typically no more than 6 in the H chain, and in the L chain, no more than 3.
  • the humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • an “isolated antibody” when used to describe the various antibodies disclosed herein, means an antibody that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.
  • 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).
  • the antibody will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated antibody includes antibodies in situ within recombinant cells, because at least one component of the polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts.
  • Monoclonal antibodies are highly specific, being directed against a single antigenic site.
  • polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody is directed against a single determinant on the antigen.
  • the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins.
  • 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, for example, the hybridoma method (e.g., Kohler and Milstein ., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14 (3): 253-260 (1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2 nd ed.
  • the term “binds,” “specifically binds to,” or is “specific for” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.
  • an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets.
  • the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, for example, by a radioimmunoassay (RIA).
  • an antibody that specifically binds to a target has a dissociation constant (KD) of ⁇ 1 mM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, or ⁇ 0.1 nM.
  • KD dissociation constant
  • an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species.
  • specific binding can include, but does not require exclusive binding.
  • the term as used herein can be exhibited, for example, by a molecule having a KD for the target of 10 _4 M or lower, alternatively 10 _5 M or lower, alternatively 10 -6 M or lower, alternatively 10 -7 M or lower, alternatively 10 -8 M or lower, alternatively 10 -9 M or lower, alternatively 10 _1 ° M or lower, alternatively 10 -11 M or lower, alternatively 10 -12 M or lower or a KD in the range of 10 -4 M to 10 -6 M or 10 -6 M to 10 -10 M or 10 -7 M to 10 -9 M.
  • affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value.
  • the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.
  • 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 or Megalign (DNASTAR) software. 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.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
  • 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 or “individual” is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. In some embodiments, the subject is a human. Patients are also subjects herein.
  • sample refers to a composition that is obtained or derived from a subject and/or individual of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics.
  • tumor sample refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized.
  • the sample is a tumor tissue sample (e.g., a lung cancer tumor tissue sample, e.g., an NSCLC tumor tissue sample, e.g., squamous or non-squamous NSCLC tumor tissue sample, e.g., locally advanced unresectable NSCLC tumor tissue sample (e.g., Stage NIB NSCLC tumor tissue sample), or recurrent or metastatic NSCLC tumor tissue sample (e.g., Stage IV NSCLC tumor tissue sample).
  • a lung cancer tumor tissue sample e.g., an NSCLC tumor tissue sample, e.g., squamous or non-squamous NSCLC tumor tissue sample, e.g., locally advanced unresectable NSCLC tumor tissue sample (e.g., Stage NIB NSCLC tumor tissue sample), or recurrent or metastatic NSCLC tumor tissue sample (e.g., Stage IV NSCLC tumor tissue sample).
  • NSCLC tumor tissue sample e.g., squamous
  • samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum, tears, perspiration, mucus, stool, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, cellular extracts, and combinations thereof.
  • tissue sample or “cell sample” is meant a collection of similar cells obtained from a tissue of a subject or individual.
  • the source of the tissue or cell sample may be solid tissue as from a fresh, frozen, and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject.
  • the tissue sample may also be primary or cultured cells or cell lines.
  • the tissue or cell sample is obtained from a diseased tissue/organ.
  • the tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.
  • a “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue,” as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject.
  • healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue e.g., cells or tissue adjacent to a tumor.
  • a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of a subject who is not the subject.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of an individual who is not the subject.
  • protein refers to any native protein 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 protein as well as any form of the protein that results from processing in the cell.
  • the term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.
  • Polynucleotide or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length, and include DNA and RNA.
  • the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase, or by a synthetic reaction.
  • polynucleotides as defined herein include, without limitation, single- and double-stranded DNA, DNA including single- and double-stranded regions, single- and double-stranded RNA, and RNA including single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single- stranded or, more typically, double-stranded or include single- and double-stranded regions.
  • polynucleotide refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules.
  • the regions may include all of one or more of the molecules, but more typically involve only a region of some of the molecules.
  • One of the molecules of a triple-helical region often is an oligonucleotide.
  • polynucleotide and nucleic acid specifically includes mRNA and cDNAs.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label.
  • modifications include, for example, “caps,” substitution of one or more of the naturally-occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, and the like) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, and the like), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, and the like), those with intercalators (e.g., acridine, psoralen, and the like), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, and the like), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids
  • any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid or semi-solid supports.
  • the 5’ and 3’ terminal OFI can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms.
  • Other hydroxyls may also be derivatized to standard protecting groups.
  • Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2’-0-methyl-, 2’-0-allyl-, 2’-fluoro-, or 2’-azido-ribose, carbocyclic sugar analogs, a-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and abasic nucleoside analogs such as methyl riboside.
  • One or more phosphodiester linkages may be replaced by alternative linking groups.
  • linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(0)S (“thioate”), P(S)S (“dithioate”), “(0)NR2 (“amidate”), P(0)R, P(0)OR’, CO or CH2 (“formacetal”), in which each R or R’ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.
  • Carriers as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
  • physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • proteins such as serum albumin,
  • phrases “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • cancer e.g., a solid tumor and/or a locally advanced or metastatic cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squa
  • a lung cancer e.
  • the present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) to a subject in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle).
  • an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • administering results in a complete response (CR) or a partial response (PR).
  • a complete response CR
  • PR partial response
  • administering results in an increase in progression-free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • the effective amount of the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • the effective amount of the anti-TIGIT antagonist antibody extends overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • the present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle).
  • an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • administration of the effective amount of the anti-TIGIT antagonist antibody results in a complete response or a partial response. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in progression-free survival of the subject compared to a reference. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends overall survival of the subject.
  • the present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) to a subject in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle).
  • an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • administering results in a complete response or a partial response.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • administering results in an increase in progression-free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • the anti- TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • administering extends overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • the present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle).
  • administration of the effective amount of the anti-TIGIT antagonist antibody results in a complete response or a partial response.
  • administration of the effective amount of the anti-TIGIT antagonist antibody results in an increase in progression-free survival of the subject compared to a reference.
  • administration of the effective amount of the anti-TIGIT antagonist antibody extends overall survival of the subject.
  • the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered without a chemotherapeutic agent (e.g., without any chemotherapeutic agent, e.g., the entire dosing regimen is devoid of administration of a chemotherapeutic agent to the subject).
  • the subject has not received chemotherapy within the month prior to the administration with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (e.g., within the two months prior, three months prior, four months prior, six months prior, one year prior, two years prior, three years prior, four years prior, five years prior, or ten years prior to the administration with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody).
  • the subject is chemotherapy naive.
  • the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered in conjunction with a chemotherapy.
  • a once-every-two-weeks (Q2W), once-every-three-weeks (Q3W), or once-every-four-weeks (Q4W) dosing regimen of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can be administered in conjunction with one or more chemotherapeutic agents.
  • the one or more chemotherapeutic agents can be administered at the same frequency as the frequency of administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (Q2W, Q3W, or Q4W) or at a different frequency.
  • the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every two weeks and the one or more chemotherapeutic agents is administered every two weeks, every three weeks, or every four weeks.
  • the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every three weeks and the one or more chemotherapeutic agents is administered every two weeks, every three weeks, or every four weeks.
  • the PD-1 axis binding antagonist and the anti-TIG IT antagonist antibody are administered every four weeks and the one or more chemotherapeutic agents is administered every two weeks, every three weeks, or every four weeks.
  • a chemotherapeutic agent is administered multiple times per week (e.g., 2,
  • the dose of a chemotherapeutic agent is reduced after one or more initial doses (e.g., after one, two, three, four, or more initial doses).
  • a subsequent dose of the chemotherapeutic agent e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel or nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))
  • a platinum agent e.g., carboplatin or cisplatin
  • non platinum agents e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel or nab-paclitaxel), and/or
  • an initial dose of nab-paclitaxel of 125 mg/m 2 can be reduced for a subsequent dose, e.g., to 100 mg/m 2 or 75 mg/m 2 ; an initial dose of paclitaxel of about 175 mg/m 2 can be reduced for a subsequent dose, e.g., to 150 mg/m 2 , 125 mg/m 2 , 100 mg/m 2 , or 75 mg/m 2 ; an initial dose of paclitaxel of about 200 mg/m 2 can be reduced for a subsequent dose, e.g., to 175 mg/m 2 , 150 mg/m 2 ,
  • an initial dose of gemcitabine of about 1000 mg/m 2 can be reduced for a subsequent dose, e.g., to 900 mg/m 2 , 800 mg/m 2 , 750 mg/m 2 , 700 mg/m 2 , 600 mg/m 2 , or 500 mg/m 2 ;
  • an initial dose of cisplatin of about 75 mg/m 2 can be reduced for a subsequent dose, e.g., to 70 mg/m 2 , 65 mg/m 2 , 60 mg/m 2 , 55 mg/m 2 , 50 mg/m 2 , or 45 mg/m 2 ;
  • the present invention includes methods and uses involving administration of an effective amount of an anti-TIG IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination to a subject in need thereof.
  • an anti-TIG IT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • the anti-TIGIT antagonist antibody e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab
  • the chemotherapy combination includes an effective amount of a first non-platinum agent and an effective amount of a second non-platinum agent.
  • the first non-platinum agent is an antimetabolite and the second non-platinum agent is a taxane.
  • the chemotherapy combination e.g., the antimetabolite and the taxane (e.g., gemcitabine and paclitaxel)
  • the chemotherapy combination is administered weekly, biweekly, or three times every four weeks (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle).
  • the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), gemcitabine, and paclitaxel to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle) and the chemotherapy combination (e.g., the antimetabolite and the taxane (e.g., gemcitabine and paclitaxel)) is administered every two weeks
  • administering results in a complete response or a partial response.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the antimetabolite e.g., gemcitabine
  • the taxane e.g., paclitaxel
  • administering results in an increase in progression-free survival of the subject.
  • the anti-TIGIT antagonist antibody e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the antimetabolite e.g., gemcitabine
  • the taxane e.g., paclitaxel
  • administering extends overall survival of the subject.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the antimetabolite e.g., gemcitabine
  • the taxane e.g., paclitaxel
  • the subject receiving the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the antimetabolite e.g., gemcitabine
  • the taxane e.g., paclitaxel
  • a pancreatic cancer e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC
  • the present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum agent and an effective amount of a non-platinum agent.
  • an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • a chemotherapy combination includes an effective amount of a platinum agent and an effective amount of a non-platinum agent.
  • the anti-TIGIT antagonist antibody e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab
  • the anti-TIGIT antagonist antibody are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21 -day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle).
  • the platinum agent is carboplatin or cisplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed).
  • the chemotherapy combination e.g., the platinum agent and the antimetabolite (e.g., pemetrexed)
  • the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a platinum agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21 -day dosing cycle) and the chemotherapy combination (e.g.,
  • maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles.
  • the one or more maintenance dosing cycles does not include the platinum agent.
  • administering results in a complete response or a partial response.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the antimetabolite e.g., pemetrexed
  • administering results in an increase in progression- free survival of the subject.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the antimetabolite e.g., pemetrexed
  • administering extends overall survival of the subject.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the antimetabolite e.g., pemetrexed
  • the subject receiving the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the antimetabolite e.g., pemetrexed
  • the cancer may be a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., SCLC
  • the present invention also includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum agent and an effective amount of a non-platinum agent, wherein the non-platinum agent is a taxane (e.g., paclitaxel or nab-paclitaxel).
  • an anti-TIGIT antagonist antibody e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • a chemotherapy combination includes an
  • the anti-TIGIT antagonist antibody e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab
  • the anti-TIGIT antagonist antibody are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21 -day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle).
  • the chemotherapy combination e.g., the platinum agent and the taxane (e.g., paclitaxel or nab-paclitaxel)
  • the chemotherapy combination are administered weekly, every two weeks, every four weeks, or three times every four weeks (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle).
  • the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a platinum agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21 -day dosing cycle)
  • the dosing continues for four-to-six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles).
  • maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles.
  • the one or more maintenance dosing cycles does not include the platinum agent.
  • administering results in a complete response or a partial response.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the taxane e.g., paclitaxel or nab-paclitaxel
  • administering results in an increase in progression-free survival of the subject.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the taxane e.g., paclitaxel or nab-paclitaxel
  • administering extends overall survival of the subject.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the taxane e.g., paclitaxel or nab- paclitaxel
  • the subject receiving the anti-TIGIT antagonist antibody e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the taxane e.g., paclitaxel or nab-paclitaxel
  • the cancer may be a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., SCLC
  • an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab
  • the chemotherapy combination includes an effective amount of a platinum agent and an effective amount of a non-platinum agent, wherein the non-platinum agent is a topoisomerase II inhibitor (e.g., etoposide).
  • the anti-TIGIT antagonist antibody e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab
  • the anti-TIGIT antagonist antibody are administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21 -day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle).
  • the chemotherapy combination e.g., the platinum agent and the topoisomerase II inhibitor (e.g., etoposide)
  • the topoisomerase II inhibitor e.g., etoposide
  • is administered more frequently than the platinum agent e.g., three times per week, e.g., on Days 1 , 2, and 3 of each dosing cycle).
  • the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a platinum agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each 21 -day dosing cycle) and the chemotherapy combination (e.g.,
  • the dosing continues for four-to- six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles).
  • maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles.
  • the one or more maintenance dosing cycles does not include the platinum agent or the topoisomerase II inhibitor (e.g., etoposide).
  • the effective amount of the anti-TIG IT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the topoisomerase II inhibitor e.g., etoposide
  • the effective amount of the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the topoisomerase II inhibitor e.g., etoposide
  • the effective amount of the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the topoisomerase II inhibitor e.g., etoposide
  • the subject receiving the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., anti- PD-L1 antagonist antibody, such as atezolizumab
  • the platinum agent e.g., carboplatin or cisplatin
  • the topoisomerase II inhibitor e.g., etoposide
  • the cancer may be a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., SCLC
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 600 mg, e.g., between about 400 mg to about 500 mg, e.g., between about 405 mg to about 450 mg, e.g., between about 410 mg to about 430 mg, e.g., about 420 mg) every two weeks (Q2W).
  • an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of about 420 mg every two weeks (e.g., 420 mg ⁇ 10 mg, e.g., 420 ⁇ 6 mg, e.g., 420 ⁇ 5 mg, e.g., 420 ⁇ 3 mg, e.g., 420 ⁇
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg ⁇ 10 mg, e.g., 600 ⁇ 6 mg, e.g., 600 ⁇ 5
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of between about 200 mg to about 2000 mg (e.g., between about 200 mg to about 1600 mg, e.g., between about 250 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1500 mg, e.g., between about 500 mg to about 1400 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every four weeks
  • the effective amount of anti-TIGIT antagonist antibody is a fixed dose of about 840 mg every four weeks (e.g., 840 mg ⁇ 10 mg, e.g., 840 ⁇ 6 mg, e.g., 840 ⁇ 5 mg, e.g., 840 ⁇ 3 mg, e.g., 840 ⁇ 1 mg, e.g., 840 ⁇ 0.5 mg, e.g.,
  • the fixed dose of the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a combination therapy e.g., a combination treatment with a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)
  • chemotherapeutic agents e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or a non-platinum agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel or nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))
  • chemotherapeutic agents e.g., a platinum agent (e.g., carboplatin or cis
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the anti-TIGIT antagonist antibody is administered subcutaneously. Dosing of PD-1 axis binding antagonists
  • the effective amount of the PD-1 axis binding antagonist is a fixed dose of between about 20 mg to about 1600 mg (e.g., between about 40 mg to about 1500 mg, e.g., between about 200 mg to about 1400 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1400 mg, e.g., between about 500 mg to about 1300 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every two weeks
  • the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 840 mg every two weeks (e.g., 840 mg ⁇ 10 mg, e.g., 840 ⁇ 6 mg, e.g., 840 ⁇ 5 mg, e.g., 840 ⁇ 3 mg, e.g., 840 ⁇ 1 mg, e.g., 840 ⁇ 0.5 mg, e.g., 840 mg every two weeks).
  • the effective amount of the PD-1 axis binding antagonist is a fixed dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150
  • the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 1200 mg every three weeks (e.g., 1200 mg ⁇ 10 mg, e.g., 1200 ⁇ 6 mg, e.g., 1200 ⁇ 5 mg, e.g., 1200 ⁇ 3 mg, e.g., 1200 ⁇ 1 mg, e.g., 1200 ⁇ 0.5 mg, e.g., 1200 mg every three weeks).
  • the effective amount of the PD-1 axis binding antagonist is a fixed dose of between about 500 mg to about 3000 mg (e.g., between about 500 mg to about 2800 mg, e.g., between about 600 mg to about 2700 mg, e.g., between about 650 mg to about 2600 mg, e.g., between about 700 mg to about 2500 mg, e.g., between about 1000 mg to about 2400 mg, e.g., between about 1100 mg to about 2300 mg, e.g., between about 1200 mg to about 2200 mg, e.g., between about 1300 mg to about 2100 mg, e.g., between about 1400 mg to about 2000 mg, e.g., between about 1500 mg to about 1900 mg, e.g., between about 1600 mg to about 1800 mg, e.g., between about 1620 mg to about 1700 mg,
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody (e.g.,
  • the effective amount of the PD-1 axis binding antagonist is a fixed dose of 1680 mg every four weeks (e.g., 1680 mg ⁇ 10 mg, e.g., 1680 ⁇ 6 mg, e.g., 1680 ⁇ 5 mg, e.g., 1680 ⁇ 3 mg, e.g., 1680 ⁇ 1 mg, e.g., 1680 ⁇ 0.5 mg, e.g., 1680 mg every four weeks).
  • the fixed dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab), with or without one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or a non-platinum agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide)))
  • chemotherapeutic agents e.g., a platinum agent (e.g.,
  • the PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)
  • the PD-1 axis binding antagonist is administered subcutaneously.
  • chemotherapeutic agents are known in the art and contemplated in the present invention.
  • one or more chemotherapeutic agents e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) are administered according to the doses recited herein.
  • a platinum agent e.g., carboplatin or cisplatin
  • non-platinum agents e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-
  • the effective amount of a platinum agent is a dose sufficient to achieve an AUC from 1 -50 mg/ml/min (e.g., 2-25 mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, e.g., 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/ml/m/min, 1 -50 mg/ml/min (e.g., 2
  • AUC can be calculated using the Calvert formula (Calvert et al., J. Clin. Oncol. 1989, 7:1748-56):
  • Total dose (mg) (target AUC) x (glomerular filtration rate [GFR] + 25)
  • the effective amount of the platinum agent is 200 mg-1500 mg (e.g., 300 mg-1200 mg, 400 mg-1100 mg, or 500 mg-1000 mg, e.g., 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-750 mg, 750 mg-800 mg, 800 mg-900 mg,
  • the effective amount of the platinum agent is about 500 mg-1000 mg (e.g., about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg).
  • the platinum agent e.g., carboplatin or cisplatin
  • the subject intravenously (e.g., over a 30-120-minute infusion).
  • carboplatin is administered intravenously over a 30-60-minute infusion.
  • cisplatin is administered intravenously over a 60-120-minute infusion.
  • the effective amount of a topoisomerase II inhibitor is from 10-1000 mg/m 2 (e.g., from 20-800 mg/m 2 , from 30-700 mg/m 2 , from 40-500 mg/m 2 , from 50-300 mg/m 2 , from 75-200 mg/m 2 , or from 80-150 mg/m 2 , e.g., about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 ,
  • 10-1000 mg/m 2 e.g., from
  • the topoisomerase II inhibitor e.g., etoposide
  • the topoisomerase II inhibitor is administered to the subject intravenously (e.g., over a 60-minute infusion).
  • a therapeutically effective amount of a taxane (e.g., nab-paclitaxel (ABRAXANE®) or paclitaxel) administered to a human will be in the range of about 25 to about 300 mg/m 2 (e.g., about 25 mg/m 2 , about 50 mg/m 2 , about 75 mg/m 2 , about 100 mg/m 2 , about 125 mg/m 2 , about 150 mg/m 2 , about 175 mg/m 2 , about 200 mg/m 2 , about 225 mg/m 2 , about 250 mg/m 2 , about 275 mg/m 2 , or about 300 mg/m 2 ) whether by one or more administrations.
  • a taxane e.g., nab-paclitaxel (ABRAXANE®) or paclitaxel
  • nab-paclitaxel ABRAXANE®
  • nab-paclitaxel ABRAXANE®
  • paclitaxel is administered at 200 mg/m 2 IV every 3 weeks.
  • the taxane e.g., nab-paclitaxel (ABRAXANE®) or paclitaxel
  • the taxane e.g., nab-paclitaxel (ABRAXANE®) or paclitaxel
  • the subject intravenously (e.g., over a 3-hour infusion).
  • the effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) administered as part of the methods described herein is from 10-10000 mg/m 2 (e.g., from 20-8000 mg/m 2 , from 30-5000 mg/m 2 , from 40-2500 mg/m 2 , from 50-2000 mg/m 2 , from 100-1500 mg/m 2 , or from 400-1200 mg/m 2 , e.g., about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2
  • the effective amount of pemetrexed administered as part of the methods described herein is from 10-1000 mg/m 2 (e.g., from 20-900 mg/m 2 , from 30-800 mg/m 2 , from 40-700 mg/m 2 , from 50-650 mg/m 2 , from 100-600 mg/m 2 , or from 200-550 mg/m 2 , e.g., about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg/m 2 , a
  • the pemetrexed is administered to the subject intravenously (e.g., over a 10-minute infusion).
  • the effective amount of gemcitabine administered as part of the methods described herein is from 10-10000 mg/m 2 (e.g., from 20-8000 mg/m 2 , from 30-5000 mg/m 2 , from 40-2500 mg/m 2 , from 50-2000 mg/m 2 , from 100-1500 mg/m 2 , or from 400-1200 mg/m 2 , e.g., about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg/m 2 ,
  • the gemcitabine is administered to the subject intravenously (e.g., over a 30-minute infusion).
  • the cancer may be solid tumor or a locally advanced or metastatic cancer.
  • the cancer is a lung cancer, such as NSCLC.
  • the cancer may be at an early or late stage.
  • the NSCLC is a squamous NSCLC.
  • the NSCLC is a non-squamous NSCLC.
  • the NSCLC is a locally advanced unresectable NSCLC.
  • the NSCLC is a Stage NIB NSCLC.
  • the NSCLC is a recurrent or metastatic NSCLC.
  • the NSCLC is a Stage IV NSCLC. In some instances, the subject has not been previously treated for Stage IV NSCLC.
  • the subject has no EGFR or ALK genomic tumor aberrations. In some instances, in any of the methods, uses, or compositions for use described herein, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or anaplastic lymphoma kinase ( ALK) gene rearrangement. In some instances, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 .
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • Methods for detecting the mutational status EGFR and ALK are well known in the art, and include, but are not limited to, sequencing DNA from clinical samples (e.g., tumor biopsies or blood samples (e.g., circulating tumor DNA in blood)) using a next-generation sequencing method, such as the targeted gene pulldown and sequencing method described in Frampton et al. ( Nature Biotechnology. 31 (11): 1023-1033, 2013), which is incorporated by reference herein in its entirety.
  • Such a next- generation sequencing method can be used with any of the methods disclosed herein to detect various mutations (e.g., insertions, deletions, base substitutions, focal gene amplifications, and/or homozygous gene deletions), while enabling the use of small samples (e.g., from small-core needle biopsies, fine- needle aspirations, and/or cell blocks) or fixed samples (e.g., formalin-fixed and paraffin-embedded (FFPE) samples).
  • Other methods for the detection of the mutational status of EGFR and ALK include fluorescence in situ hybridization (FISH) and immunohistochemical (IHC) methods. Exemplary methods for the detection of the mutational status of ALK are disclosed in U.S. Patent No: 9,651 ,555, which is herein incorporated by reference in its entirety.
  • the VENTANA® anti -ALK (D5F3) IHC assay is used to determine the mutational status of the ALK gene.
  • the mutation is a sensitizing EGFR mutation.
  • Sensitizing EGFR mutations are well known in the art and include those described in U.S. Publication No: US 2018/0235968 and in Juan et al. (Therapeutic Advances in Medical Oncology. 9(3): 201-216, 2017), which are incorporated by reference herein in their entireties.
  • the sensitizing EGFR mutation is a mutation in any one of exons 18-21 (e.g., a mutation in exon 18, exon 19, exon 20, and/or exon 21).
  • the sensitizing EGFR mutation is a deletion of exon 19 (dell 9).
  • sensitizing EGFR mutation is a L858R point mutation in exon 21 .
  • the sensitizing EGFR mutation is a G719X point mutation in exon 18, wherein “X” is most commonly C, A, or S.
  • the sensitizing EGFR mutation is a G719S point mutation in exon 18.
  • the sensitizing EGFR mutation is a G719A point mutation in exon 18.
  • the sensitizing EGFR mutation is a S720F point mutation in exon 18.
  • the sensitizing EGFR mutation is a L861 Q point mutation in exon 21 .
  • the sensitizing EGFR mutation is a L861 R point mutation in exon 21 . In other instances, the sensitizing EGFR mutation is a T790M point mutation. In some instances, the sensitizing EGFR mutation is an E709X point mutation, where “X” is most commonly K, A, or H. In some instances, the sensitizing EGFR mutation is a S768I point mutation.
  • the mutation is an ALK gene rearrangement.
  • ALK gene rearrangements are well known in the art and include those described in U.S. Patent No: 9,651 ,555 and in Du et al. ( Thoracic Cancer. 9: 423-430, 2018), which are incorporated herein by reference in their entireties.
  • the ALK gene rearrangement results in the creation of an oncogenic ALK tyrosine kinase that activates downstream signaling pathways resulting in increased cell proliferation and survival.
  • the A K- gene rearrangement is an A K " rearrangement with a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, BIRC6, RANBP2, ATIC, CLTC, TMP4, and MSN resulting in the formation of a fusion oncogene.
  • the ALK gene rearrangement is an EML4 rearrangement with ALK resulting in the formation of the fusion oncogene EML4-ALK.
  • the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.
  • Methods for detecting the subtype of NSCLC are well known in the art, and include, but are not limited to, methods of determination by histopathological criteria, or by molecular features (e.g., a subtype characterized by expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by said genes)).
  • the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample.
  • the tissue sample is a tumor sample.
  • the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection.
  • Indicators of active or chronic active EBV infections for use in the methods described herein can include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral particles detected in a sample from the subject (e.g., a blood or serum sample).
  • EBV IgM EBV IgG
  • Epstein-Barr nuclear antigen (EBNA) Epstein-Barr viral particles
  • EBNA Epstein-Barr nuclear antigen
  • Epstein-Barr viral particles in a sample from a subject are well known in the art, and include, but are not limited to, methods involving serological diagnosis (e.g., the detection of EBV DNA (e.g., by PCR analysis of a blood sample for the detection of EBV viral particles) or EBV antigens or anti-EBV antibodies (e.g., detection of EBNA, EBV IgM, or EBV IgG using heterophilic antibodies).
  • the sample is selected from the group consisting of a whole blood sample, a serum sample, and a plasma sample.
  • the subject is negative for EBV IgM and/or negative by EBV PCR.
  • the subject is negative for EBV IgM and/or negative by EBV PCR and is positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA).
  • EBNA Epstein-Barr nuclear antigen
  • the subject is negative for EBV IgG and/or negative for EBNA.
  • the subject has a PD-L1 selected tumor (e.g., a tumor PD-L1 expression with a minimum PD-L1 -positive tumor cell fraction or TPS > 30% (e.g., > 50%) as determined by an IHC with the SP263 or 22C3 antibody).
  • the PD-L1 selected tumor is a tumor that has been determined to have a PD-L1 -positive tumor cell fraction or PD-L1 TPS of greater than, or equal to, 30% (e.g., greater than, or equal to, 50%) by an immunohistochemical (IHC) assay.
  • IHC immunohistochemical
  • the IHC assay uses the anti- PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the tumor sample has been determined to have a TPS of greater than, or equal to, 50%.
  • the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50% (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using the pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 30%, as determined by positive staining with the anti-PD-L1 antibody SP142.
  • a tumor sample obtained from the individual has a detectable protein expression level of PD-L1 .
  • the detectable protein expression level of PD-L1 has been determined by an IHC assay.
  • the IHC assay uses anti-PD-L1 antibody SP142.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% of the tumor cells in the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% and less than 5% of the tumor cells in the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% and less than 5% of the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 5% and less than 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 10% of the tumor sample.
  • a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1 .
  • the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.
  • the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample.
  • the tissue sample is a tumor sample.
  • the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof.
  • a subject’s response to the therapy can be characterized by one or more measures.
  • the treatment results in a complete response or a partial response.
  • the treatment results in an increase in progression-free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIG IT antagonist antibody or as compared to treatment with the anti-TIG IT antagonist antibody without the PD-1 axis binding antagonist.
  • the treatment may result in an increase in progression- free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIG IT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • an anti-TIG IT antagonist antibody e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • one or more chemotherapeutic agents e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))
  • the treatment may result in an increase in progression-free survival of the subject, e.g., as compared to (i) treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) as
  • the treatment extends overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • the treatment may result in an increase in overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
  • an anti- TIGIT antagonist antibody e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • one or more chemotherapeutic agents e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))
  • the treatment may result in an increase in overall survival of the subject, e.g., as compared to (i) treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) as compared to treatment with
  • Progression-free survival of the subject can be measured according to RECIST v1 .1 criteria, as described in Eisenhauer et al., Eur. J. Cancer. 2009, 45:228-47.
  • PFS is measured as the period of time from the start of treatment to the first occurrence of disease progression as determined by RECIST v1 .1 criteria.
  • PFS is measured as the time from the start of treatment to the time of death.
  • a treatment described herein extends the PFS of the subject by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months,
  • the treatment extends the PFS of the subject by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months,
  • the treatment extends the PFS of the subject by at least about 2 months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0
  • overall survival is measured as the period of time from the start of treatment to death.
  • the treatment extends the OS of the subject by at least about 2 months (e.g., by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months,
  • the treatment extends the overall survival of the subject by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months,
  • the treatment extends the overall survival of the subject by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
  • 5.3 months e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0
  • Exemplary anti-TIG IT antagonist antibodies and PD-1 axis binding antagonists useful for treating a subject (e.g., a human) having cancer (e.g., a solid tumor or a locally advanced or metastatic cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g.,
  • cancer e.g., a solid tumor
  • the invention provides anti-TIG IT antagonist antibodies useful for treating cancer (e.g., a solid tumor or a locally advanced or metastatic cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma), a melanoma, a head and neck cancer (e.g., a head and neck squamous
  • the anti-TIGIT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8).
  • Tiragolumab (Genentech) is also known as MTIG7192A.
  • the anti-TIGIT antagonist antibody includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and/or (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g.,
  • anti-TIGIT antagonist antibodies may include (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).
  • the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of,
  • EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 17) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of,
  • QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 18); and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 19).
  • the anti-TIG IT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 17 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19.
  • the anti-TIG IT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 18 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19.
  • VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19.
  • the anti-TIGIT antagonist antibody includes a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence:
  • the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and/or an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 7-10.
  • FRs light
  • the antibody further comprises an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).
  • the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR- H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity)
  • the anti-TIGIT antagonist antibody may further include, for example, at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%,
  • the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14.
  • the anti-TIGIT antagonist antibody may further include at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of
  • QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%,
  • the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).
  • an anti-TIGIT antagonist antibody comprising a VH as in any of the instances provided above, and a VL as in any of the instances provided above, wherein one or both of the variable domain sequences include post-translational modifications.
  • any one of the anti-TIGIT antagonist antibodies described above is capable of binding to rabbit TIGIT, in addition to human TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some instances, any one of the anti-TIG IT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some instances, any one of the anti-TIG IT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not murine TIGIT.
  • the anti-TIGIT antagonist antibody binds human TIGIT with a KD of about 10 nM or lower and cyno TIGIT with a KD of about 10 nM or lower (e.g., binds human TIGIT with a KD of about 0.1 nM to about 1 nM and cyno TIGIT with a KD of about 0.5 nM to about 1 nM, e.g., binds human TIGIT with a KD of about 0.1 nM or lower and cyno TIGIT with a KD of about 0.5 nM or lower).
  • the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR).
  • PVR poliovirus receptor
  • the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or lower (e.g., 1 nM to about 10 nM).
  • the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with PVR, without impacting PVR-CD226 interaction.
  • the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or lower (e.g., 1 nM to about 50 nM, e.g., 1 nM to about 5 nM).
  • the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 with TIGIT.
  • the anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.
  • the methods or uses described herein may include using or administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with any of the anti-TIGIT antagonist antibodies described above.
  • the method may include administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with an anti-TIGIT antagonist antibody having the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-H1
  • an anti-TIGIT antagonist antibody may be a monoclonal antibody, comprising a chimeric, humanized, or human antibody.
  • the anti-TIGIT antagonist antibody is tiragolumab.
  • an anti-TIGIT antagonist antibody is an antibody fragment, for example, a Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment.
  • the antibody is a full-length antibody, e.g., an intact IgG antibody (e.g., an intact lgG1 antibody) or other antibody class or isotype as defined herein.
  • an anti-TIGIT antagonist antibody may incorporate any of the features, singly or in combination, as described in Section C below.
  • cancer e.g., a solid tumor or a locally advanced or metastatic cancer, (e.g., a lung cancer, e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non- squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer), an
  • PD-1 axis binding antagonists include PD-L1 binding antagonists (e.g., PD-L1 antagonist antibodies), PD-1 binding antagonists (e.g., PD-1 antagonist antibodies), and PD-2 binding antagonists (e.g., PD-L2 antagonist antibodies).
  • PD-L1 binding antagonists e.g., PD-L1 antagonist antibodies
  • PD-1 binding antagonists e.g., PD-1 antagonist antibodies
  • PD-2 binding antagonists e.g., PD-L2 antagonist antibodies
  • the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody that inhibits the binding of PD-L1 to its binding partners.
  • PD-L1 binding partners are PD-1 and/or B7-1 .
  • the anti-PD-L1 antagonist antibody is capable of inhibiting binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1.
  • the PD-1 axis binding antagonist is an anti-PD-L1 antibody.
  • the anti-PD-L1 antibody is atezolizumab (CAS Registry Number: 1422185-06- 5). Atezolizumab (Genentech) is also known as MPDL3280A.
  • the anti-PD-L1 antibody includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 sequence is GFTFSDSWIH (SEQ ID NO: 20); (b) an HVR-H2 sequence is AWISPYGGSTYYADSVKG (SEQ ID NO: 21); (c) an HVR-H3 sequence is RHWPGGFDY (SEQ ID NO: 22), (d) an HVR-L1 sequence is RASQDVSTAVA (SEQ ID NO: 23); (e) an HVR-L2 sequence is SASFLYS (SEQ ID NO: 24); and (f) an HVR-L3 sequence is QQYLYHPAT (SEQ ID NO: 25).
  • HVR-H1 sequence is GFTFSDSWIH (SEQ ID NO: 20); (b) an HVR-H2 sequence is AWISPYGGSTYYADSVKG (SEQ ID NO: 21); (c) an HVR-H3 sequence is RHWPGGFDY
  • the anti-PD-L1 antibody (e.g., atezolizumab) comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain variable (VH) region sequence comprises the amino acid sequence:
  • the light chain variable (VL) region sequence comprises the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 27).
  • the anti-PD-L1 antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRF TISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE P
  • the anti-PD-L1 antibody comprises (a) a VH domain comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of (SEQ ID NO: 26); (b) a VL domain comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of (SEQ ID NO: 27); or (c) a VH domain as in (a) and a VL domain as in (b).
  • a VH domain comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of (SEQ ID NO: 26)
  • a VL domain comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%
  • the anti-PD-L1 antagonist antibody is selected from YW243.55.S70, MDX- 1105, and MEDI4736 (durvalumab), and MSB0010718C (avelumab).
  • Antibody YW243.55. S70 is an anti- PD-L1 described in PCT Pub. No. WO 2010/077634.
  • MDX-1105 also known as BMS-936559, is an anti- PD-L1 antibody described in PCT Pub. No. WO 2007/005874.
  • MEDI4736 (durvalumab) is an anti-PD-L1 monoclonal antibody described in PCT Pub. No. WO 2011/066389 and U.S. Pub. No. 2013/034559.
  • anti-PD-L1 antibodies useful for the methods of this invention, and methods for making thereof are described in PCT Pub. Nos. WO 2010/077634, WO 2007/005874, and WO 2011/066389, and also in U.S. Pat. No. 8,217,149, and U.S. Pub. No. 2013/034559, which are incorporated herein by reference.
  • the anti-PD-L1 antagonist antibodies e.g., atezolizumab
  • useful in this invention including compositions containing such antibodies, may be used in combination with an anti-TIGIT antagonist antibody, a topoisomerase II inhibitor, and/or a platinum agent to treat lung cancer, e.g., SCLC, e.g., ES- SCLC.
  • the anti-PD-L1 antagonist antibody is a monoclonal antibody. In some instances, the anti-PD-L1 antagonist antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L1 antagonist antibody is a humanized antibody. In some instances, the anti-PD-L1 antagonist antibody is a human antibody. In some instances, the anti-PD-L1 antagonist antibody described herein binds to human PD-L1 .
  • the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody that inhibits the binding of PD-1 to its binding partner (e.g., PD-L1). In some instances, the anti-PD-1 antagonist antibody is capable of inhibiting binding between PD-L1 and PD-1 .
  • the PD-1 axis binding antagonist is an anti-PD-1 antibody.
  • the anti-PD-1 antibody is nivolumab (MDX-1106), pembrolizumab (formerly lambrolizumab (MK-3475)), or AMP-224.
  • a PD-1 axis binding antagonist is a PD-1 axis binding antagonist antibody according to any of the above instances may incorporate any of the features, singly or in combination, as described in Section C below.
  • an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) provided herein has a dissociation constant (KD) of ⁇ 1 mM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (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
  • KD is measured by a radiolabeled antigen binding assay (RIA).
  • RIA radiolabeled antigen binding assay
  • an RIA is performed with the Fab version of an antibody of interest and its antigen.
  • solution binding affinity 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 pg/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°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 mI/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.
  • KD is measured using a BIACORE ® surface plasmon resonance assay.
  • a BIACORE ® surface plasmon resonance assay For example, an assay using a BIACORE ® -2000 or a BIACORE ® -3000 (BIAcore, Inc.,
  • CM5 chips at -10 response units (RU).
  • CM5 carboxymethylated dextran biosensor chips
  • EDC N- ethyl-N’- (3-dimethylaminopropyl)-carbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg/ml (-0.2 pM) before injection at a flow rate of 5 pl/minute to achieve approximately 10 response units (RU) of coupled protein.
  • an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist 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. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., PluckthOn, in The Pharmacology of Monoclonal Antibodies, vol.
  • Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161 ; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).
  • 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
  • an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist 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 affinity 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.
  • 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 affinity.
  • 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 anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist 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.
  • 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. USA, 103:3557-3562 (2006).
  • Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas).
  • Human hybridoma technology Trioma technology
  • Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).
  • 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.
  • Anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist 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.
  • 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.
  • scFv single-chain Fv
  • Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
  • 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.
  • Anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibodies e.g., anti-PD-L1 antagonist antibodies
  • antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.
  • amino acid sequence variants of the anti-TIG IT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) of the invention are contemplated.
  • anti-TIG IT antagonist antibodies and PD-1 axis binding antagonist antibodies may be optimized based on desired structural and functional properties. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody.
  • 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, for example, antigen-binding.
  • anti-TIG IT antagonist antibody and/or PD-1 axis binding antagonist antibody e.g., anti-PD-L1 antagonist antibody
  • 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, for example, retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.
  • Amino acids may be grouped according to common side-chain properties:
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class.
  • 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 affinity, 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 an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity 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 affinity).
  • Alterations may be made in HVRs, e.g., to improve antibody affinity. 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 affinity.
  • Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al.
  • affinity 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 affinity.
  • 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 includes 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
  • Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions.
  • a crystal structure of an antigen- antibody complex 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 to the N- or C-terminus of the antibody to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody. II. Glycosylation variants
  • anti-TIG IT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) of the invention can be altered to increase or decrease the extent to which the antibody is glycosylated.
  • Addition or deletion of glycosylation sites to anti-TIG IT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) of the invention 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 (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.
  • modifications of the oligosaccharide in an antibody of the invention are made in order to create antibody variants with certain improved properties.
  • anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody 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.
  • 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).
  • the methods of the invention involve administering to the subject in the context of a fractionated, dose-escalation dosing regimen an anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab) and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) variant that comprises an aglycosylation site mutation.
  • the aglycosylation site mutation reduces effector function of the antibody.
  • the aglycosylation site mutation is a substitution mutation.
  • the antibody comprises a substitution mutation in the Fc region that reduces effector function.
  • the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering). In some instances, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G. In some instances, the substitution mutation is at amino acid residue N297. In a preferred instance, the substitution mutation is N297A.
  • Anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) variants are further provided with bisected oligosaccharides, for example, in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc.
  • 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 are introduced into the Fc region of an anti-TIGIT antagonist (e.g., an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab) antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) of the invention, thereby generating an Fc region variant (see e.g., US 2012/0251531 ).
  • an anti-TIGIT antagonist e.g., an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab
  • PD-1 axis binding antagonist antibody e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)
  • the Fc region variant may comprise a human Fc region sequence (e.g., a human IgG 1 , 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 region sequence e.g., a human IgG 1 , lgG2, lgG3 or lgG4 Fc region
  • an amino acid modification e.g., a substitution
  • the invention contemplates an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist 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.
  • an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody e.g., anti-PD-L1 antagonist 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 FcyR
  • NK cells express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII, and Fc(RIII.
  • 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. Flellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Flellstrom, I et al., Proc.
  • non-radioactive assays methods may be employed (see, for example, ACTITM non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CYTOTOX 96 ® non-radioactive cytotoxicity assay (Promega, Madison, Wl).
  • Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998).
  • C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
  • a CDC assay may be performed (see, for example, Gazzano-Santoro etal. J. Immunol.
  • 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 Nos. 6,737,056 and 8,219,149).
  • 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 and 8,219,149).
  • the proline at position 329 of a wild-type human Fc region in the antibody is substituted with glycine or arginine or an amino acid residue large enough to destroy the proline sandwich within the Fc/Fc.
  • gamma receptor interface that is formed between the proline 329 of the Fc and tryptophan residues Trp 87 and Trp 110 of FcgFtlll (Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)).
  • the antibody comprises at least one further amino acid substitution.
  • the further amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S
  • the at least one further amino acid substitution is L234A and L235A of the human lgG1 Fc region or S228P and L235E of the human lgG4 Fc region (see e.g., US 2012/0251531)
  • the at least one further amino acid substitution is L234A and L235A and P329G of the human lgG1 Fc region.
  • 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 improved or diminished) 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 improved 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 improve binding of the Fc region to FcFtn.
  • 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).
  • the anti-TIGIT antagonist antibody e.g., an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab
  • anti-PD-L1 antagonist antibody e.g., atezolizumab
  • the anti-TIGIT antagonist antibody comprises an Fc region comprising an N297G mutation (EU numbering).
  • the anti-TIGIT antagonist antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 domain, a first CH2 (CH2j) domain, a first CH3 (CH3j) domain, a second CH1 (CH1 2 ) domain, second CH2 (CH2 2 ) domain, and a second CH3 (CH3 2 ) domain.
  • the CH3j and CH3 2 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3j domain is positionable in the cavity or protuberance, respectively, in the CH3 2 domain.
  • the CH3j and CH3 2 domains meet at an interface between said protuberance and cavity.
  • the CH2j and CH2 2 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH2 2 domain.
  • the CH2j and CH2 2 domains meet at an interface between said protuberance and cavity.
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab
  • anti-PD-L1 antagonist antibody e.g., atezolizumab
  • cysteine engineered anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies e.g., anti-PD-L1 antagonist antibodies
  • thioMAbs e.g., anti-PD-L1 antagonist antibodies
  • 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 linker-drug moieties, to create an immunoconjugate, as described further herein.
  • any one or more of the following residues are 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, for example, in U.S. Patent No. 7,521 ,541 .
  • an anti-TIGIT antagonist antibody of the invention e.g., an anti-TIG IT antagonist antibody (e.g., tiragolumab) or a variant thereof) and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody of the invention (e.g., atezolizumab or a variant thereof)
  • PD-1 axis binding antagonist antibody e.g., anti-PD-L1 antagonist antibody of the invention (e.g., atezolizumab or a variant thereof)
  • the moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers.
  • Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), 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, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof.
  • 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 branche
  • 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.
  • Anti-TIGIT antagonist antibodies e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab
  • PD-1 axis binding antagonist antibodies e.g.,anti-PD-L1 antagonist antibodies (e.g., atezolizumab)
  • Anti-TIGIT antagonist antibodies may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567, which is incorporated herein by reference in its entirety.
  • 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.,
  • 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 invention also provides immunoconjugates comprising an anti-TIG IT antagonist (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and/or PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) of the invention conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.
  • an anti-TIG IT antagonist e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • PD-1 axis binding antagonist e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)
  • cytotoxic agents such as chemo
  • an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1 ); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos.
  • ADC antibody-drug conjugate
  • drugs including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1 ); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF
  • an immunoconjugate comprises an anti-TIG IT antagonist antibody as described herein (e.g., tiragolumab) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, en
  • an immunoconjugate comprises an anti-TIG IT antagonist antibody as described herein (e.g., tiragolumab) and/or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) as described herein (e.g., atezolizumab) conjugated to a radioactive atom to form a radioconjugate.
  • a radioactive isotopes are available for the production of radioconjugates. Examples include At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu.
  • the radioconjugate When used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131 , indium-111 , fluorine- 19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.
  • NMR nuclear magnetic resonance
  • Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N- maleimidomethyl) cyclohexane-1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCI), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as
  • a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987).
  • Carbon-14-labeled 1 -isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026.
  • the linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell.
  • an acid- labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker, or disulfide-containing linker (Chari et al. , Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) may be used.
  • the immunuoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL, U.S. A).
  • cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SM
  • Platinum agents include an organic compound which contains platinum as an integral part of the molecule.
  • platinum-based chemotherapeutic agents are coordination complexes of platinum agents include, but are not limited to, carboplatin, cisplatin, and oxaliplatin.
  • Platinum agents are widely used antitumor drugs that cause crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks. Platinum agents typically act on the adjacent N-7 position of guanine, forming a 1 , 2 intrastrand crosslink (Poklar et al. (1996). Proc. Natl. Acad. Sci. U.S.A. 93 (15): 7606-11 ; Rudd et al. (1995). Cancer Chemother. Pharmacol. 35 (4): 323-6). The resultant crosslinking inhibits DNA repair and/or DNA synthesis in cancer cells.
  • Carboplatin is an exemplary platinum coordination compound used in the methods described herein.
  • the chemical name for carboplatin is platinum, diammine[l, l-cyclobutanedicarboxylato(2-)- 0,0']-, (SP- 4-2), and carboplatin has the following structural formula:
  • Carboplatin is a crystalline powder with the molecular formula of C6H12N204Pt and a molecular weight of 371 .25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1 % solution is 5 to 7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide. Carboplatin produces predominantly interstrand DNA cross-links, and this effect is cell-cycle nonspecific.
  • Carboplatin is commercially available as PARAPLATIN®, BIOCARN, BLASTOCARB, BLASTOPLATIN, CARBOKEM, CARBOMAX, CARBOPA, CARBOPLAN, CARBOTEEN, CARBOTINAL, CYTOCARB, DUCARB, KARPLAT, KEMOCARB, NAPROPLAT, NEOPLATIN, NISCARBO, ONCOCARBIN, TEVACARB, WOMASTIN, and others.
  • Another exemplary platinum agent useful in the methods of the present invention is cisplatin, which has the following structure:
  • Non-platinum agents are another class of chemotherapeutic agents useful as part of the methods, uses, and compositions described herein.
  • exemplary non-platinum agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331), and taxanes (e.g., paclitaxel (e.g., nanoparticle-albumin bound (nab)-paclitaxel), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel).
  • antimetabolites e.g., pemetrexed and gemcitabine
  • topoisomerase II inhibitors e.g., e
  • Antimetabolites interfere with and inhibit (wholly or partially) an endogenous (normal) metabolic process within a cell (e.g., a cancer cell).
  • Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.
  • Gemcitabine is an exemplary antimetabolite used in the methods described herein and has the following structure:
  • pemetrexed can be administered as part of the methods of the present invention.
  • Pemetrexed has the following structure:
  • Inhibitors of topoisomerase II are also widely used antitumor drugs that stabilize topoisomerase IEDNA covalent complexes (i.e., cleavage complexes) following the formation of enzyme-mediated DNA breaks. The accumulation of such cleavage complexes induces cell death pathways.
  • Etoposide is an exemplary topoisomerase II inhibitor used in the methods described herein.
  • Etoposide is typically administered as the prodrug etoposide phosphate, the chemical name for which is: 4'-Demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene- -Dglucopyranoside], 4' (dihydrogen phosphate).
  • Etoposide phosphate has the following structure:
  • Etoposide phosphate a phosphate ester of etoposide
  • Etoposide phosphate is a semi-synthetic derivative of podophyllotoxin and is converted to etoposide by dephosphorylation.
  • Etoposide causes the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals, leading to cell cycle arrest (primarily at the G2 stage of the cell cycle) and cell death.
  • Etoposide is commercially available as ETOPOPHOS®, TOPOSARTM, VP-16, VEPESID®, ACTITOP, ASIDE, BIOPOSIDE, CTOP, CYTOP, EPOSED, ESIDE, ETHOPUL, ETOLON, ETONIS, ETOPLAST, ETOSID, ETOVEL, FYTOP, FYTOSID, LASTET, NZYTOP, ONCOSIDE, PLACID, POSID, RETOPSON, TEV ASIDE, TOPOK, TOPOSIDE, and others.
  • Taxanes are chemotherapeutic agents that may bind to tubulin, promoting microtubule assembly and stabilization and/or prevent microtubule depolymerization.
  • Taxanes included herein include taxoid 10-deacetylbaccatin III and/or derivatives thereof.
  • Examplary 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.
  • 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).
  • Paclitaxel is administered as part of the methods of the present invention.
  • Paclitaxel may have the following structure:
  • the methods include administration of nano-albumin bound (nab)-paclitaxel.
  • any of the aforementioned chemotherapeutic agents can be administered in various forms, such as salt forms, which are contemplated as part of the present invention.
  • any of the anti-TIG IT antagonist antibodies, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies), and chemotherapeutic agents e.g., platinum agents (e.g., carboplatin or cisplatin) and/or non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) described herein can be used in pharmaceutical compositions and formulations.
  • platinum agents e.g., carboplatin or cisplatin
  • non-platinum agents e.g., an antimetabolite (e.g., pemetrexed or gemcitabine)
  • a taxane e.g., paclitaxel, e.g
  • compositions and formulations of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody), and/or one or more chemotherapeutic agents can be prepared by mixing one, two, three, or all four agents having the desired degree of purity with one or more optional pharmaceutically acceptable carriers ( Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.
  • Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arg
  • Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX ® , Baxter International, Inc.).
  • sHASEGP soluble neutral-active hyaluronidase glycoproteins
  • rHuPH20 HYLENEX ® , Baxter International, Inc.
  • Certain exemplary sHASEGPs and methods of use, including rHuPH20 are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968.
  • a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
  • Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958.
  • Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and WO 2006/044908, the latter formulations including a histidine-acetate buffer.
  • the formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
  • an additional therapeutic agent e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an anti-hormonal agent, such as those recited herein above.
  • active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules.
  • the formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.
  • kits comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist, a platinum agent, and a topoisomerase II inhibitor for treating a subject having a lung cancer according to any of the methods described herein.
  • the kit further comprises the PD-1 axis binding antagonist.
  • a kit comprises tiragolumab for use in combination with atezolizumab, a platinum agent, and a topoisomerase II inhibitor for treating a subject having cancer according to a any of the methods described herein.
  • the kit further comprises atezolizumab.
  • Kits provided herein may include a PD-1 axis binding antagonist (e.g., atezolizumab) for use in combination with an anti-TIGIT antagonist antibody (e.g., tiragolumab), and/or one or more chemotherapeutic agents for treating a subject having a cancer (e.g., a solid tumor or a locally advanced or metastatic cancer, (e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non- squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage 11 IB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (P
  • the kit further comprises tiragolumab. Any of the PD-1 axis binding antagonist and/or chemotherapeutic agents known in the art or described herein may be included in the article of manufacture or kits. In some embodiments, the kit comprises tiragolumab and atezolizumab.
  • the kit comprises tiragolumab, atezolizumab, and one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))).
  • chemotherapeutic agents e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-
  • Example 1 A Phase la/lb, open-label, dose-escalation study of the safety and pharmacokinetics of tiragolumab as a single agent and in combination with atezolizumab administered with and without chemotherapy in patients with locally advanced or metastatic tumors
  • This study evaluates the safety, PK, pharmacodynamics, and preliminary anti-tumor activity of tiragolumab (MTIG7192A) when administered as a single agent (Phase la) or in combination with atezolizumab with and without chemotherapy (Phase lb) in patients with locally advanced or metastatic tumors.
  • Specific objectives and corresponding endpoints for the study are outlined in Table 1 .
  • This study is also designed to enable evaluation of the safety, tolerability, and PK of tiragolumab when administered with atezolizumab with and without chemotherapy in patients with locally advanced, recurrent, or metastatic incurable tumors for whom standard therapy does not exist, has proven to be ineffective or intolerable, or is considered inappropriate, or for whom a clinical trial of an investigational agent is a recognized standard of care, or for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option.
  • FIG. 1 is a flow chart showing the Phase lb chemotherapy expansion and Phase lb Q4W dosing expansion).
  • cohorts of approximately 3-6 patients each will be evaluated at escalating dose levels to determine the MTD or maximum administered dose (MAD) for tiragolumab as a single agent or in combination with atezolizumab.
  • MAD maximum administered dose
  • Phase lb chemotherapy expansion cohorts and the Phase lb Q4W dosing expansion cohort (FIG. 1), a safety run-in of 3 patients is completed. All relevant safety data from the safety run-in is thoroughly reviewed by an IMC and with the investigators before enrollment is continued.
  • tiragolumab and atezolizumab is combined with specific chemotherapy regimens in each of the three cohorts: carboplatin or cisplatin and pemetrexed in Cohort A, carboplatin and paclitaxel in Cohort B and carboplatin or cisplatin and etoposide in Cohort C (see FIG. 1).
  • treatment includes of an induction phase and a maintenance phase.
  • the induction phase the combination of tiragolumab and atezolizumab with chemotherapy is administered by IV infusion on a 21 -day cycle for 4 to 6 cycles for Cohorts A and B and for 4 cycles for Cohort C.
  • the number of cycles of induction treatment for Cohort A and B is at the discretion of the investigator.
  • Atezolizumab is administered prior to tiragolumab. When chemotherapy is given, it is administered after atezolizumab and tiragolumab.
  • Adverse events will be graded according to the NCI CTCAE, Version 4.0.
  • RECIST Solid Tumors
  • Patients undergo tumor assessments at screening and during the study, which are measured by standard Response Evaluation Criteria in Solid Tumors (RECIST) v1 .1 criteria. Patients may be permitted to continue study treatment even if standard RECIST v1 .1 criteria for progression of disease are met in the Phase la or Phase lb portions of the study, provided that they meet the criteria for continued treatment. Patients who discontinue the Phase la portion of the study may be permitted to cross over into the Phase lb portion of the study and receive treatment with tiragolumab in combination with atezolizumab, provided that they meet the criteria for crossover and consent to a biopsy of an accessible lesion.
  • RECIST Solid Tumors
  • This expansion stage includes defined cohorts of patients to better characterize the safety, tolerability, PK variability, pharmacodynamic activity, and preliminary anti-tumor activity of tiragolumab as a single agent (Phase la) or in combination with atezolizumab with or without chemotherapy (Phase lb) in specific cancer settings.
  • Enrollment in the expansion cohorts will be initiated at a selected dose level at or below the MAD or MTD of tiragolumab as a single agent (Phase la) or tiragolumab in combination with atezolizumab with or without chemotherapy (Phase lb), as determined by the Sponsor in consultation with the study investigators, based on an assessment of accumulating safety, tolerability, PK, pharmacodynamic, and anti-tumor activity data.
  • a planned expansion cohort of multiple tumor indications that are PD-L1 -selected and/or TIGIT-selected, including NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC including GEJ cancer, UBC, and CRC, including CRC that is MSS or MSI-Low.
  • NSCLC Cancer immunotherapy (CIT)-Naive (e.g., no prior treatment with anti-PD-L1/PD-1 ); NSCLC: CIT-Treated (e.g., including prior treatment with anti-PD-L1/PD-1 ); RCC; TNBC; Melanoma; HNSCC; OC; GC, including GEJ cancer; UBC; CRC, including CRC that is MSS or MSI-Low; Biopsy cohort of specific tumor indications, including melanoma, OC, RCC, and UBC.
  • CIT Cancer immunotherapy
  • NSCLC CIT-Treated (e.g., including prior treatment with anti-PD-L1/PD-1 )
  • RCC TNBC
  • Melanoma HNSCC
  • OC OC
  • GC including GEJ cancer
  • UBC CRC, including CRC that is MSS or MSI-Low
  • Biopsy cohort of specific tumor indications including melanoma, OC, RCC, and UBC.
  • Cohort A receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV, followed by the combination of cisplatin 75 mg/m 2 IV or carboplatin AUC of 6 mg/mL min IV and pemetrexed 500 mg/m 2 IV on Day 1 of an every 21 -day cycle. Four to six cycles of induction-phase treatment will be administered in the absence of disease progression or unacceptable toxicity.
  • Cohort B receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV, followed by the combination of carboplatin AUC of 6 mg/mL min IV and paclitaxel 200 mg/m 2 IV on Day 1 of an every 21 -day cycle.
  • Four to six cycles of induction phase treatment will be administered in the absence of disease progression or unacceptable toxicity.
  • Cohort C receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV followed by cisplatin 75 mg/m2 IV or carboplatin AUC of 5 mg/mL min IV on Day 1 of an every 21 -day cycle and then etoposide 100 mg/m 2 IV on Days 1 - 3 of an every 21 -day cycle.
  • Four cycles of induction phase treatment will be administered in the absence of disease progression or unacceptable toxicity.
  • Cohort A receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV, followed by pemetrexed 500 mg/m 2 IV on Day 1 of an every-21 -day cycle;
  • Cohort B receives atezolizumab 1200 mg IV and then tiragolumab 600 mg IV on Day 1 of an every-21 -day cycle;
  • Cohort C receives atezolizumab 1200 mg IV and then tiragolumab 600 mg IV on Day 1 of an every-21 -day cycle.
  • the objectives of the Phase lb Q4W dosing expansion cohort are to better characterize the safety, tolerability, PK, and preliminary efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity in patients treated with tiragolumab 840 mg IV in combination with atezolizumab 1680 mg IV with an every 4 week (28 day) dosing schedule.
  • the Phase lb Q4W cohort includes approximately 20-40 patients with tumors that can be PD-L1 - selected and/or TIG IT-selected based on prospective testing of tumor tissue during screening or rescreening.
  • a patient with insufficient or unavailable archival tissue may be eligible for enrollment in this cohort, if deemed so by the Medical Monitor based upon a discussion with the investigator.
  • Patients with a tumor type for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option may be enrolled in these expansion cohorts.
  • the NSCLC Cohort includes patients with histologically confirmed incurable, advanced NSCLC not previously treated with CIT (investigational or approved), including anti-PD-L1/PD-1 and/or anti-CTLA-4, for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD-L1/PD-1 agents) is approved as treatment for NSCLC by local regulatory authorities.
  • Patients whose tumors have a known sensitizing epidermal growth factor receptor (EGFR) mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with an EGFR tyrosine kinase inhibitor(s).
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • the NSCLC cohort (CIT-treated) includes patients with histologically confirmed incurable, advanced NSCLC previously treated with CIT (investigational or approved) including anti-PD-L1/PD-1 .
  • Patients whose tumors have a known sensitizing EGFR mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with EGFR tyrosine kinase inhibitor(s).
  • Patients whose tumors have a known ALK rearrangement must also have experienced disease progression (during or after treatment) or intolerance to treatment with an ALK tyrosine kinase inhibitor(s).
  • Patients whose tumors have a known ROS1 rearrangement must also have experienced disease progression (during or after treatment) or intolerance to treatment with an ROS1 tyrosine kinase inhibitor(s).
  • Patients whose tumors have a BRAFV600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib.
  • Patients must have experienced documented disease progression on CIT monotherapy and/or combination therapy (investigational or approved), which must have included a prior anti-PD- L1/PD-1 .
  • At least approximately 10 patients who experienced a documented best response of investigator- assessed confirmed PR or CR per RECIST v1 .1 at any time while receiving the prior anti-PD-L1/PD-1 as monotherapy or combination therapy may be enrolled. At least approximately 10 patients who experienced a documented best response of investigator-assessed SD per RECIST v1 .1 at any time while receiving the prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy may be enrolled. At least approximately 10 patients who experienced a documented best response of investigator-assessed progressive disease (PD) per RECIST v1 .1 at any time while receiving the prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy may be enrolled.
  • PD investigator-assessed progressive disease
  • the prior anti-PD- L1/PD-1 as monotherapy and/or as combination therapy must represent the most recent systemic anti cancer therapy administered prior to enrollment in this expansion cohort. Patients who discontinued the prior anti-PD-L1/PD-1 monotherapy and/or combination therapy primarily for toxicity or intolerability are not eligible for enrollment in this expansion cohort.
  • the TNBC cohort includes patients with histologically confirmed incurable, advanced estrogen receptor (ER)-negative, progesterone receptor-negative, and human EGFR 2 (HER2)-negative adenocarcinoma of the breast (triple-negative). Triple-negative status must be documented as defined by the American Society of Clinical Oncology College of American Pathologists (ASCO-CAP) guidelines:
  • the CRC cohort includes patients with histologically confirmed incurable, advanced adenocarcinoma of the colon or rectum. Patients with tumors of appendiceal origin are not eligible.
  • the GC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic or recurrent gastric or GEJ adenocarcinoma, not amenable to curative therapy.
  • Patients with Type 1 GEJ tumor defined by RQdiger Siewert et al. (2000) as adenocarcinoma of the distal esophagus with the tumor center located within 1 to 5 cm above the anatomic esophagogastric junction, are eligible for the study.
  • Patients with esophageal cancers (squamous cell carcinoma or adenocarcinoma) may be eligible following a discussion with the Medical Monitor.
  • HER2-positivity is defined as either IHC 3+ or IHC 2+/ISH+ (where ISH positivity is defined as a HER2:CEP17 ratio of > 2), as assessed by a local laboratory test on the primary tumor or on a metastatic lesion. Patients who have not had HER2 testing due to insufficient or unavailable tissue (e.g., archival and/or biopsy), and thus the HER2 status of the tumor is unknown, may still be eligible.
  • the HNSCC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharnyx, or larynx), not amenable to curative therapy. Patients with HNSCC of any other primary anatomic location in the head and neck, patients with HNSCC of unknown primary, or patients with tumors of non-squamous histologies are not eligible. Patients with HNSCC of the nasopharynx may be eligible. HPV status for the HNSCC must be known.
  • the UBC cohort includes patients with histologically confirmed incurable advanced transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra). Patients with mixed histologies are required to have a dominant transitional cell pattern.
  • the melanoma cohort includes patients with histologically confirmed incurable, advanced metastatic melanoma. Patients with melanoma for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD-L1/PD-1 agents and/or anti-CTLA-4 agents) is approved as treatment for melanoma by local regulatory authorities. Patients whose tumors have a known BRAFV600 mutation must also have experienced disease progression (during or after treatment) or intolerance with BRAF inhibitor (s) and/or MEK inhibitor(s). Enrollment will be managed so that no more than approximately 20% of patients in this cohort will be patients with ocular (uveal) melanoma.
  • the OC cohort includes patients with histologically confirmed incurable, advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. Borderline ovarian epithelial neoplasms (e.g., tumors of low malignant potential, atypical proliferative tumors) are excluded.
  • Borderline ovarian epithelial neoplasms e.g., tumors of low malignant potential, atypical proliferative tumors
  • the RCC cohort includes patients with histologically confirmed incurable, advanced RCC with component of clear cell histology and/or component of sarcomatoid histology. Patients with RCC for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD-L1/PD-1 agents) is approved as treatment for RCC by local regulatory authorities. Dosing and Administration
  • the dose of atezolizumab administered in combination with tiragolumab in the Phase lb portion of this study is 1200 mg IV every three weeks, except in the Phase lb Q4W dosing cohort where atezolizumab 1680 mg IV Q4W is administered. This dose is fixed and not dependent on body weight.
  • atezolizumab is administered after the tiragolumab infusion and subsequent observation period.
  • atezolizumab is administered before tiragolumab.
  • the initial dose of atezolizumab will be delivered over 60 ( ⁇ 10) minutes. If the first infusion is tolerated without infusion-associated adverse events, the second infusion may be delivered over 30 ( ⁇ 10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 ( ⁇ 10) minutes. For Cycle 1 , dosing of atezolizumab will be followed by a 90-minute observation period.
  • Atezolizumab All subsequent infusions of atezolizumab may be followed by a 30-minute observation period. Patients who have previously received atezolizumab on another clinical trial may receive the initial dose at the fastest rate that was previously tolerated.
  • Chemotherapy is administered after the atezolizumab and tiragolumab infusions and subsequent observation periods.
  • a chemotherapy cycle counts toward the prespecified number of induction chemotherapy cycles as long as at least one chemotherapy component has been administered at least once during a 21 -day cycle. Cycles in which no chemotherapy component is given do not count toward the total number of induction chemotherapy cycles.
  • Table 4 lists suggested infusion times for treatment administration for pemetrexed and carboplatin or cisplatin during the induction phase and for pemetrexed during the maintenance phase.
  • IV intravenous
  • PO orally
  • Table 4 lists the suggested premedication for induction treatment for patients in Cohort B.
  • Table 5 lists the suggested infusion times for treatment administration for paclitaxel and carboplatin during the induction phase.
  • Table 6 lists the suggested infusion times for treatment administration for carboplatin or cisplatin and etoposide during the induction phase.
  • IV intravenous
  • AUC area under time-concentration curve
  • IV intravenous
  • the U.S. FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert formula described in the carboplatin label, the maximum doses can be calculated as follows:
  • the maximum dose is based on a GFR estimate that is capped at 150 mL/min for patients with normal renal function. No higher estimated GFR values should be used.
  • IV intravenous
  • Premedication doses administered complies with the prescribing information. All patients eligible for pemetrexed therapy should avoid taking non-steroidal anti-inflammatory drugs with long elimination half-lives for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration.
  • IV intravenous
  • Asian race/ethnicity refers to a panethnic/racial group that includes diverse populations who either live or have ancestral origins in East Asia, Southeast Asia, or South Asia. The applicability of such term in a particular patient will be at the discretion of the treating investigator and should be based on the patient’s clinical characteristics and country of origin.
  • IV intravenous Example 2. A Phase lb/11, open-label, randomized study of atezolizumab and chemotherapy in combination with tiragolumab
  • This study evaluates the efficacy, safety, and pharmacokinetics of atezolizumab and chemotherapy (nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and gemcitabine) in combination with tiragolumab in patients who have received no prior systemic therapy for metastatic pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • Patients in Cohort 1 are randomly assigned to a control arm (chemotherapy) or an experimental arm consisting of atezolizumab and chemotherapy in combination with tiragolumab. Enrollment within the experimental arms will take place in two phases: a preliminary phase followed by an expansion phase. Approximately 20 patients are enrolled during the preliminary phase. Randomization issuspended to allow for a safety evaluation in a minimum of 6 patients. The safety evaluation is based on safety data from a minimum of 6 patients who have received at least one dose of treatment (i.e. , one dose of each agent for a given combination) and completed safety follow-up assessments during at least one full treatment cycle. If the combination is determined to be sufficiently safe, enrollment is resumed in that arm.
  • chemotherapy chemotherapy
  • an experimental arm consisting of atezolizumab and chemotherapy in combination with tiragolumab.
  • Enrollment within the experimental arms will take place in two phases: a preliminary phase followed by an expansion phase. Approximately 20 patients are enrolled during the preliminary phase. Randomization issuspended to
  • Patients are randomly assigned to treatment arms, and the randomization ratio will depend on the number of experimental arms that are open for enrollment (e.g., if an arm is added or enrollment in an arm is suspended pending analysis of results from the preliminary phase), with the stipulation that the likelihood of being allocated to the control arm is no more than 35%.
  • the end of this study is defined as the date when the last patient completes the last visit (LPLV), including survival follow-up visits conducted by telephone or in the clinic.
  • LPLV last visit
  • the total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 3-5 years.
  • a schedule of the activities is outlined in Table 12.
  • ADA anti-drug antibody
  • Atezo + Chemo + Tira atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus tiragolumab
  • CIT cancer immunotherapy
  • CT computed tomography
  • ECOG Eastern Cooperative Oncology Group
  • eCRF electronic Case Report Form
  • HBV hepatitis B virus
  • PK pharmacokinetic
  • RBR Research Biosample Repository
  • Atezolizumab vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 ( ⁇ 5) minutes during and 30 ( ⁇ 10) minutes after the infusion.
  • vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 30 ( ⁇ 10) minutes after the infusion.
  • vital signs should be measured within 60 minutes prior to the infusion and every 15 ( ⁇ 5) minutes during and 30 ( ⁇ 10) minutes after the infusion.
  • Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).
  • k Chemistry panel includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.
  • HBV DNA increases to ⁇ 500 lU/mL
  • consultation with the Medical Monitor is required prior to continuation of study treatment and consultation with a hepatologist or gastroenterologist with specialty in hepatitis B is recommended.
  • All women of childbearing potential have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months and 6 months after the last dose of study treatment. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
  • Autoantibody analysis includes anti-nuclear antibody, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody.
  • P Autoantibody analysis should be repeated for patients who develop signs or symptoms suggestive of autoimmune disease (e.g., lupus erythematosus). r Not applicable for a site that has not been granted approval for RBR sampling. Performed only for patients at participating sites who have provided written informed consent to participate. s Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the investigator, if deemed clinically feasible by the investigator. Biopsies should be performed within 40 days after determination of unacceptable toxicity or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner.
  • autoimmune disease e.g., lupus erythematosus
  • patients enrolled during the expansion phase will undergo tumor biopsy sample collection 4 weeks ( ⁇ 7 days) after treatment initiation (if deemed clinically feasible), unless on-treatment tissue samples have already been collected, and determined to be evaluable, from a minimum of 15 patients treated with the same CIT combination.
  • tumor assessments are to continue according to schedule in patients who discontinue treatment for reasons other than disease progression, even if they start new non-protocol-specified anti-cancer therapy.
  • All measurable and/or evaluable lesions identified at baseline should be re-assessed at each subsequent tumor evaluations according to the tumor assessment schedule described above (see footnote “t”).
  • 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).
  • any medication e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements
  • y Atezolizumab is administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle.
  • the initial dose of atezolizumab is delivered over 60 ( ⁇ 15) minutes.
  • Subsequent infusions are delivered over 30 ( ⁇ 10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 ( ⁇ 15) minutes if the patient experienced an infusion-associated adverse event with the previous infusion.
  • z Treatment continues until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
  • a Tiragolumab is administered by IV infusion at a fixed dose of 420 mg on Days 1 and 15 of each 28-day cycle.
  • the initial dose of tiragolumab is delivered over 60 ( ⁇ 10) minutes.
  • Subsequent infusions will be delivered over 30 ( ⁇ 10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 ( ⁇ 10) minutes if the patient experienced an infusion-associated adverse event with the previous infusion.
  • tiragolumab will be administered 60 minutes after completion of the atezolizumab infusion.
  • the interval between subsequent infusions is 30 minutes if the previous atezolizumab infusion was tolerated without an IRR or 60 minutes if the patient experienced an IRR with the previous atezolizumab infusion.
  • b b On Days 1 , 8, and 15, 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. On Day 1 of Cycle 1 , nab-paclitaxel will be administered 60 minutes after completion of the tiragolumab infusion to allow for observation after tiragolumab administration.
  • the interval between subsequent infusions will be 30 minutes if the previous tiragolumab infusion was tolerated without an IRR or 60 minutes if the patient experienced an IRR with the previous tiragolumab infusion.
  • c c After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) is collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless the patient withdraws consent or the Sponsor terminates the study). If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the investigator. If the patient withdraws from the study, the study staff may use a public information source (e.g., county records) to obtain information about survival status only. Assessments and Monitoring
  • NCI CTCAE v4.0 National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0
  • Response per modified RECIST v1 .1 for immune based therapeutics (iRECIST) will be determined programmatically by the Sponsor on the basis of investigator- assessed individual lesion data. If clinical activity is demonstrated in an experimental arm, the Sponsor may request that tumor assessment scans for that arm be submitted for evaluation by an independent review facility.
  • Baseline tumor tissue samples are collected from all patients, e.g., by means of a biopsy performed at study entry. If a biopsy is not deemed feasible by the investigator, archival tumor tissue may be submitted after Medical Monitor approval has been obtained, provided the tissue was obtained within 3 months prior to enrollment and the patient has not received any anti-cancer therapy since the time of the biopsy. If deemed clinically feasible by the investigator, tumor tissue will also be collected for patients who discontinue Stage 1 because of unacceptable toxicity, disease progression per RECIST v1 .1 , or loss of clinical benefit as determined by the investigator.
  • an on-treatment tumor tissue sample will be collected 4 weeks after initiation of Stage 1 treatment (if clinically feasible), unless on-treatment tissue samples have already been collected, and determined to be evaluable, from a minimum of 15 patients treated with the same CIT combination. These samples will be utilized for biomarker research (see rationale for biomarker assessments
  • PK pharmacokinetic
  • ADA anti-drug antibody
  • Atezo + Chemo + Tira atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus tiragolumab
  • nab-paclitaxel nanoparticle albumin-bound paclitaxel
  • PBMC peripheral blood mononuclear cell
  • PK pharmacokinetic.
  • the number of PK and ADA samples may be reduced or sample collection may cease altogether. Additionally, collected samples may not be analyzed if not warranted.
  • the number of biomarker samples may be reduced or sample collection may cease altogether. Laboratory, Biomarker, and Other Biological Samples
  • Exploratory biomarker research includes, but is not limited to, analysis of genes or gene signatures associated with tumor immunobiology, PD-L1 , cytokines associated with T-cell activation, T- cell receptor repertoire, carcinoembryonic antigen, or density, localization, and activation status of immune cells and their subsets, and may involve DNA or RNA extraction, analysis of somatic mutations, and use of NGS (including WES).
  • NGS including WES
  • Hematology WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells)
  • Chemistry panel serum or plasma: CPK, bicarbonate or carbon dioxide (if considered standard of care for the region), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST
  • Thyroid function testing thyroid-stimulating hormone, free triiodothyronine (T3) (or total T3 for sites where free T3 is not performed), and free thyroxine (also known as T4)
  • HAV serology HAV IgM
  • HBV serology HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb test is positive) HBV DNA
  • an HBV DNA test must also be performed to determine if the patient has an HBV infection.
  • HCV serology HCV antibody and (if HCV antibody test is positive) HCV RNA
  • an HCV RNA test must also be performed to determine if the patient has an active HCV infection.
  • HEV serology HEV IgM
  • a woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
  • Urinalysis pH, specific gravity, glucose, protein, ketones, and blood
  • Dipstick urinalysis is permitted. However, patients with > 2+ protein on dipstick urinalysis at screening must undergo a 24-hour urine collection for protein if a bevacizumab-containing arm is open for enrollment.
  • Samples for the following laboratory test will be sent to a central laboratory or to the study site's local laboratory for analysis:
  • Serum sample for analysis of autoantibodies anti-nuclear antibody, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody
  • Plasma or serum samples for PK analysis through use of validated assays • Plasma or serum samples for immunogenicity analysis through use of validated assays
  • Baseline tumor tissue samples from the primary lesion or a metastatic lesion will be collected from all patients, preferably by means of a biopsy performed at study entry. If a biopsy is not deemed feasible by the investigator, archival tumor tissue may be submitted after Medical Monitor approval has been obtained, provided the tissue was obtained from a biopsy performed within 3 months prior to enrollment and the patient has not received any anti-cancer therapy since the time of the biopsy.
  • a representative FFPE tumor specimen in a paraffin block (preferred) or at least 16 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study enrollment. If only 10-15 slides are available, the patient may still be eligible for the study, after Medical Monitor approval has been obtained.
  • Tumor tissue should be of good quality based on total and viable tumor content. Samples must contain a minimum of 50 viable tumor cells that preserve cellular context and tissue architecture regardless of needle gauge or retrieval method. Samples collected via resection, core-needle biopsy (at least three cores, 18-gauge needle or larger [16-gauge needle preferred], embedded in a single paraffin block), or excisional, incisional, punch, or forceps biopsy are acceptable. Fine- needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or smears), brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. Tumor tissue from bone metastases that have been decalcified is not acceptable. Remaining archival tumor tissue blocks will be returned to the site upon request or 18 months after final closure of the study database, whichever occurs first.
  • Samples will not be collected if on-treatment tissue samples have already been collected, and determined to be evaluable, from a minimum of 15 patients treated with the same CIT combination.
  • Biopsies should be performed within 40 days after determination of unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner. Samples collected via resection, core-needle biopsy (at least three cores preferred), or excisional, incisional, punch, or forceps biopsy are preferred. Atezolizumab dose and schedule
  • Atezolizumab is administered at a fixed dose of 840 mg every two weeks (Q2W) (840 mg on Days 1 and 15 of each 28-day cycle).
  • Tiragolumab is administered at a fixed dose of 420 mg Q2W (420 mg on Days 1 and 15 of each 28-day cycle).
  • the average concentration following the 420 mg Q2W dose is expected to be equivalent to that of 600 mg every three weeks (Q3W).
  • the fixed tiragolumab dose of 600 mg IV Q3W was selected on the basis of available pharmacokinetic (PK), efficacy, and safety data from Study G030103, in which patients received single-agent tiragolumab or tiragolumab plus atezolizumab.
  • Patients receive treatment as outlined until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic deterioration such as pain secondary to disease).
  • nab-paclitaxel 125 mg/m 2 IV infusion on Days 1 , 8, and 15 of each 28 day cycle, administered by IV infusion over 30 ( ⁇ 5) minutes, followed by gemcitabine 1000 mg/m 2 , administered by IV infusion over 30 ( ⁇ 10) minutes.
  • nab-paclitaxel will be administered 60 minutes after completion of the tiragolumab infusion. The interval between subsequent infusions is 30 minutes if the previous tiragolumab infusion was tolerated without an IRR or 60 minutes if the patient experienced an IRR with the previous tiragolumab infusion.
  • Table 14 Administration of First and Subsequent Atezolizumab Infusions
  • the dose of nab-paclitaxel may be reduced by 25 mg/m 2 (one dose level) up to two times and the dose of gemcitabine may be reduced by 200 mg/m 2 (one dose level) up to two times, as outlined in Table 16.
  • nab-paclitaxel and/or gemcitabine after two dose reductions, that drug (or both drugs, if applicable) is discontinued, but the patient may continue other study treatments at the investigator’s discretion. After dose reduction, the dose may be escalated during subsequent administrations at the investigator's discretion.
  • Concomitant therapy includes 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 study treatment from 10 days prior to initiation of study treatment to the treatment discontinuation visit.
  • medication e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements
  • CSFs Colony-stimulating factors
  • G-CSFs granulocyte colony-stimulating factors
  • ESAs erythropoiesis-stimulating agents
  • Megestrol acetate administered as an appetite stimulant after initiation of study treatment Mineralocorticoids (e.g., fludrocortisone)
  • Inhaled corticosteroids administered for chronic obstructive pulmonary disease or asthma Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency Hormonal therapy with gonadotropin-releasing hormone agonists or antagonists for prostate cancer Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic relief of pain) as outlined below:
  • Palliative radiotherapy is permitted, provided it does not interfere with the assessment of tumor target lesions (e.g., the lesion to be irradiated must not be the only site of measurable disease).
  • Treatment with nab-paclitaxel and gemcitabine should be withheld during palliative radiotherapy.
  • Treatment with atezolizumab and tiragolumab may be continued during palliative radiotherapy.
  • Radiotherapy to the brain (either stereotactic radiosurgery or whole-brain radiation therapy) provided that all of the following criteria are met:
  • the patient has no evidence of progression or hemorrhage after completion of CNS-directed therapy.
  • the patient has no ongoing requirement for corticosteroids as therapy for CNS disease.
  • Premedication with antihistamines, anti-pyretics, and/or analgesics may be administered for the second and subsequent atezolizumab and tiragolumab infusions only, at the discretion of the investigator.
  • investigators should manage a patient’s care with supportive therapies as clinically indicated, per local standard practice.
  • 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).
  • the definitive diagnosis of metastatic PDAC is made by evaluating the histopathologic data within the context of clinical and radiographic data. Patients with endocrine or acinar pancreatic carcinoma are not eligible for the study.
  • Baseline tumor tissue samples will be collected from all patients, preferably by means of a biopsy performed at study entry. If a biopsy is not deemed feasible by the investigator, archival tumor tissue may be submitted after Medical Monitor approval has been obtained, provided the tissue was obtained from a biopsy performed within 3 months prior to enrollment and the patient has not received any anti-cancer therapy since the time of the biopsy.
  • a formalin-fixed, paraffin-embedded tumor specimen in a paraffin block (preferred) or at least 16 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study enrollment. If only 10-15 slides are available, the patient may still be eligible for the study, after Medical Monitor approval has been obtained.
  • Measurable disease at least one target lesion
  • Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.
  • - ANC > 1.5 x 10 9 /L (1500/pL) without granulocyte colony-stimulating factor support within 14 days prior to screening laboratory test
  • Measures are taken to ensure the safety of patients participating in this study, including the use of stringent inclusion and exclusion criteria and close monitoring of patients during the study. Administration of study treatment will be performed in a monitored setting in which there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions. Adverse events will be reported as described.
  • Treatment-emergent adverse events occurring after initiation of treatment will be summarized. For each patient, the maximum reported severity of each adverse event will be used in the summaries by severity grade. All treatment-emergent adverse events, serious adverse events, adverse events leading to withdrawal of study treatment, Grade 3 adverse events, deaths, and causes of death will be listed and summarized by mapped term, appropriate thesaurus level, and NCI CTCAE severity grade. Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data will be displayed by time, with grades identified where appropriate. Additionally, a shift table of selected laboratory tests will be used to summarize the baseline and maximum post-baseline severity grade. Changes in vital signs and ECGs will be summarized.
  • Atezolizumab has been associated with risks such as the following: IRRs and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barre syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, and myositis.
  • Immune-mediated reactions may involve any organ system and may lead to hemophagocytic lymphohistiocytosis and macrophage activation syndrome (considered to be potential risks for atezolizumab).
  • nab-paclitaxel neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration.
  • myelosuppression primarily neutropenia, anemia, thrombocytopenia
  • cranial nerve palsies hypersensitivity reactions
  • pneumonitis myalgia, arthralgia
  • cardiotoxicity myocardial disorders, cardiac failure, angina, tachycardia, ventricular arrhythmia
  • cystoid macular edema Stevens-Johnson syndrome/toxic epidermal necrolysis, sepsis, infusion-site reactions/extravasation, hepatic toxicity (drug- induced liver injury), acute renal failure, hemolytic-uremic syndrome, and drug-induced lupus erythematous.
  • gemcitabine The most common adverse events observed with gemcitabine are nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased ALP, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema.
  • IRR is an identified risk for tiragolumab. While clinical evaluation of tiragolumab is limited and not all risks are known, as an antagonist of TIGIT, tiragolumab is anticipated to enhance T-cell and NK-cell proliferation, survival, and function. Therefore, tiragolumab may increase the risk of autoimmune inflammation (also described as immune-mediated adverse events). In addition, due to the intact Fc effector function of tiragolumab, lymphopenia via antibody-dependent cellular cytotoxicity (ADCC) is a theoretical risk.
  • ADCC antibody-dependent cellular cytotoxicity
  • IRRs associated with hypersensitivity reactions, target-mediated cytokine release, and/or emergent ADAs may occur.
  • Clinical signs and symptoms of such reactions may include rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.
  • IRRs have been reported in patients treated with tiragolumab alone or in combination atezolizumab. The majority of events were mild to moderate and manageable.
  • the initial dose of tiragolumab will be administered over 60 minutes followed by a 60-minute observation period. Subsequent infusions and observation times may be shortened if the preceding infusion was well tolerated. All infusions of tiragolumab will be administered in an appropriate medical setting.
  • Nonclinical models have suggested a role of TIGIT signaling interruption in autoimmunity.
  • TIGIT -/- a knockout model
  • EAE experimental autoimmune encephalitis
  • TIGIT -/- and wild-type B6 mice were immunized with suboptimal doses of myelin oligodendrocyte glycoprotein peptide to induce EAE.
  • myelin oligodendrocyte glycoprotein peptide to induce EAE.
  • the majority of the TIGIT -/- mice developed severe EAE (Joller et al. 2011 ).
  • autoimmune inflammatory conditions is a general risk and may therefore be considered a potential risk of tiragolumab.
  • immune-mediated adverse events have been described for virtually all organ systems and include, but are not limited to, colitis, hepatitis, pneumonitis, endocrinopathy, ocular toxicity, pancreatic toxicity, neurologic toxicity, myocarditis, nephritis, myositis, and rash.
  • adverse events are potential overlapping toxicities associated with combination use of atezolizumab, nab-paclitaxel, gemcitabine, and tiragolumab: immune-mediated toxicities, including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and others, gastrointestinal toxicities, hematologic toxicity, and dermatologic toxicities.
  • Atezolizumab and/or tiragolumab may be temporarily suspended in patients experiencing toxicity considered to be related to study treatment. If corticosteroids are initiated for treatment of the toxicity, they must be tapered over > 1 month to equivalent of ⁇ 10 mg/day oral prednisone or equivalent before drug can be resumed. If atezolizumab or tiragolumab is withheld for > 12 weeks, the patient will be discontinued from that drug. However, the drug may be withheld for > 12 weeks to allow for patients to taper off corticosteroids prior to resuming treatment. Atezolizumab or tiragolumab can be resumed after being withheld for > 12 weeks if the Medical Monitor agrees that the patient is likely to derive clinical benefit.
  • tiragolumab may cause adverse events similar to, but independent of, atezolizumab. Tiragolumab may also exacerbate the frequency or severity of atezolizumab-related adverse events or may have non-overlapping toxicities with atezolizumab. Because these scenarios may not be distinguishable from each other in the clinical setting, immune-mediated adverse events should generally be attributed to both agents, and dose interruptions or treatment discontinuation in response to immune-mediated adverse events should be applied to both tiragolumab and atezolizumab.
  • Nab-paclitaxel and/or gemcitabine treatment may be temporarily suspended in patients experiencing toxicity considered to be related to study treatment. If nab-paclitaxel or gemcitabine have been withheld for > 56 days because of toxicity, the patient should be discontinued from both chemotherapy agents. However, nab-paclitaxel or gemcitabine can be resumed after being withheld for > 56 days if the Medical Monitor agrees that the patient is likely to derive clinical benefit.
  • nab-paclitaxel and gemcitabine may be continued if the patient is likely to derive clinical benefit, as determined by the investigator. If nab-paclitaxel, gemcitabine, or tiragolumab is discontinued, the other drugs can be continued if the patient is likely to derive clinical benefit, as determined by the investigator.
  • efficacy analyses will be based on the efficacy-evaluable population, defined as all patients who receive at least one dose of each drug for their assigned treatment regimen
  • safety analyses will be based on the safety-evaluable population, defined as all patients who receive any amount of study treatment.
  • Table 17 shows estimated differences in ORR between an experimental arm and a control arm, along with 90% confidence intervals, with a sample size of 15 patients each in the preliminary phase, assuming asymptotic normality.
  • Table 17 Estimated Differences in Objective Response Rate between Experimental and Control Arms of 15 Patients Each (Preliminary Phase)
  • Table 18 shows estimated differences in ORR between an experimental arm and a control arm, along with 90% confidence intervals, with a sample size of 40 patients each in the preliminary and expansion phases combined, assuming asymptotic normality.
  • Table 18 Estimated Differences in Objective Response Rate between Experimental and Control Arms of 15 Patients Each (Preliminary Phase) Objectives and Endpoints
  • ADA anti-drug antibody
  • DOR duration of response
  • iRECIST modified RECIST v1 .1 for immune- based therapeutics
  • OS overall survival
  • PFS progression-free survival
  • PK pharmacokinetic
  • RECIST Response Evaluation Criteria in Solid Tumors.
  • ORR the proportion of patients with a complete or partial response
  • Clopper- Pearson method The difference in ORR between the experimental arms and the control arm is calculated, along with 90% confidence intervals.
  • Confidence intervals are estimated by asymptotic normality methods, depending on the sample size.
  • the secondary efficacy endpoints are PFS, OS, OS at specific timepoints (e.g., 6 months), duration of response (DOR), and disease control PFS, DOR, and disease control are determined by the investigator according to RECIST v1 .1 .
  • DOR is derived for efficacy-evaluable patients with a complete or partial response. For patients who do not have documented disease progression or death in a study stage, PFS and DOR will be censored at the day of the last tumor assessment. Patients who are still alive at the time of OS analysis will be censored at the last date they were known to be alive.
  • the Kaplan-Meier method is used to estimate the median for PFS, OS, and DOR, with 90% confidence intervals constructed through use of the Brookmeyer and Crowley method.
  • OS rate at specific timepoints will also be estimated using the Kaplan-Meier method, with 90% confidence intervals calculated on the basis of Greenwood’s estimate for the variance.
  • Disease control rate the proportion of patients with stable disease for > 12 weeks, a partial response, or a complete response, will be calculated for each treatment arm, with 90% confidence intervals estimated through use of Clopper-Pearson’s exact method.
  • the exploratory efficacy endpoints are objective response, PFS, DOR, and disease control as determined by the investigator according to iRECIST ; and change from baseline in CA19-9 at subsequent timepoints during both stages. DOR will be derived for efficacy-evaluable patients with a complete or partial response. CA19-9 change from baseline over time will be summarized. In addition, the proportion of patients with a maximum decrease from baseline in CA19-9 of > 50% or other thresholds may be calculated for each treatment arm, with 90% confidence intervals estimated through use of Clopper- Pearson’s exact method.
  • Sparse samples can be collected for potential PK analyses of atezolizumab (patients who receive at least one dose of atezolizumab) and specified drugs given in combination with atezolizumab (patients who receive at least one dose of the drug).
  • Serum or plasma concentrations of the various study drugs may be reported as individual values and summarized (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation) by treatment arm, and by cycle and day when appropriate and as data allow. Individual and median serum or plasma concentrations of the various study drugs may be plotted by treatment arm and cycle and day.
  • PK data for combination drugs may be compared with available historical data from internal and published previous studies.
  • Atezolizumab concentration data may be pooled with data from other studies using an established population PK model to derive PK parameters such as clearance, volume of distribution, and area under the curve.
  • Immunogenicity may be assessed for atezolizumab and other study treatments as appropriate (refer to arm-specific appendices for details).
  • the immunogenicity analyses will include all patients with at least one anti-drug antibody (ADA) assessment. Patients will be grouped according to treatment received or, if no treatment is received prior to study discontinuation, according to treatment assigned.
  • ADA anti-drug antibody
  • ADA-positive patients and ADA-negative patients at baseline baseline prevalence
  • post-baseline incidence the numbers and proportions of ADA-positive patients and ADA-negative patients at baseline (baseline prevalence) and after baseline (post-baseline incidence) will be summarized by treatment group.
  • patients are considered to be ADA positive if they are ADA negative or are missing data at baseline but develop an ADA response following study drug exposure (treatment-induced ADA response), or if they are ADA positive at baseline and the titer of one or more post-baseline samples is at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response).
  • Patients are considered to be ADA negative if they are ADA negative or are missing data at baseline and all post-baseline samples are negative, or if they are ADA positive at baseline but do not have any post-baseline samples with a titer that is at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected).
  • ADA positivity will be determined according to standard methods established for previous studies of these drugs.
  • the relationship between ADA status and safety, efficacy, PK, and biomarker endpoints may be analyzed and reported via descriptive statistics.

Abstract

L'invention concerne des procédés de dosage pour le traitement de cancers. En particulier, l'invention concerne des procédés, des compositions, des utilisations et des kits pour traiter des sujets atteints d'un cancer par administration d'un anticorps antagoniste de l'IT anti-TIG (par ex., un anticorps antagoniste de l'IT anti-TIG tel que décrit ici, par ex., le tiragolumab) et un antagoniste de liaison à l'axe PD-1 (par ex., un anticorps antagoniste anti-PD-L1 (par ex., l'atzolizumab)).
PCT/US2020/024526 2020-01-27 2020-03-24 Dosage pour le traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1 WO2021194481A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
PCT/US2020/024526 WO2021194481A1 (fr) 2020-03-24 2020-03-24 Dosage pour le traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1
CN202180022830.2A CN115315256A (zh) 2020-01-27 2021-01-26 用抗tigit拮抗剂抗体治疗癌症的方法
PCT/US2021/015143 WO2021154761A1 (fr) 2020-01-27 2021-01-26 Méthodes de traitement du cancer au moyen d'un anticorps antagoniste anti-tigit
EP21705841.1A EP4096646A1 (fr) 2020-01-27 2021-01-26 Méthodes de traitement du cancer au moyen d'un anticorps antagoniste anti-tigit
KR1020227029306A KR20220133243A (ko) 2020-01-27 2021-01-26 항 tigit 길항제 항체를 이용한 암의 치료 방법
JP2022545057A JP2023511595A (ja) 2020-01-27 2021-01-26 抗ｔｉｇｉｔアンタゴニスト抗体を用いたがんを処置するための方法
IL294800A IL294800A (en) 2020-01-27 2021-01-26 Methods of treating cancer with an antibody to an anti-ti antagonist
CA3165187A CA3165187A1 (fr) 2020-01-27 2021-01-26 Methodes de traitement du cancer au moyen d'un anticorps antagoniste anti-tigit
MX2022009170A MX2022009170A (es) 2020-01-27 2021-01-26 Procedimientos para el tratamiento del cancer con un anticuerpo antagonista anti-tigit.
AU2021212662A AU2021212662A1 (en) 2020-01-27 2021-01-26 Methods for treatment of cancer with an anti-TIGIT antagonist antibody
TW110102913A TW202142230A (zh) 2020-01-27 2021-01-26 用於以抗ｔｉｇｉｔ拮抗體抗體治療癌症之方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2020/024526 WO2021194481A1 (fr) 2020-03-24 2020-03-24 Dosage pour le traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1

Publications (1)

Publication Number Publication Date
WO2021194481A1 true WO2021194481A1 (fr) 2021-09-30

Family

ID=70296084

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/024526 WO2021194481A1 (fr) 2020-01-27 2020-03-24 Dosage pour le traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1

Country Status (1)

Country Link
WO (1) WO2021194481A1 (fr)

Citations (137)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4943533A (en) 1984-03-01 1990-07-24 The Regents Of The University Of California Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
WO1991010741A1 (fr) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation d'anticorps xenogeniques
WO1993001161A1 (fr) 1991-07-11 1993-01-21 Pfizer Limited Procede de preparation d'intermediaires de sertraline
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5212290A (en) 1989-09-08 1993-05-18 The Johns Hopkins University Antibodies specific for type II mutant EGTR
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
WO1993016185A2 (fr) 1992-02-06 1993-08-19 Creative Biomolecules, Inc. Proteine de liaison biosynthetique pour marqueur de cancer
WO1994011026A2 (fr) 1992-11-13 1994-05-26 Idec Pharmaceuticals Corporation Application therapeutique d'anticorps chimeriques et radio-marques contre l'antigene a differentiation restreinte des lymphocytes b humains pour le traitement du lymphome des cellules b
WO1994029351A2 (fr) 1993-06-16 1994-12-22 Celltech Limited Anticorps
EP0659439A2 (fr) 1993-12-24 1995-06-28 MERCK PATENT GmbH Immunoconjugués
US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5475001A (en) 1993-07-19 1995-12-12 Zeneca Limited Quinazoline derivatives
WO1996003397A1 (fr) 1994-07-21 1996-02-08 Akzo Nobel N.V. Formulations de peroxides cetoniques cycliques
US5500362A (en) 1987-01-08 1996-03-19 Xoma Corporation Chimeric antibody with specificity to human B cell surface antigen
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5545807A (en) 1988-10-12 1996-08-13 The Babraham Institute Production of antibodies from transgenic animals
EP0425235B1 (fr) 1989-10-25 1996-09-25 Immunogen Inc Agents cytotoxiques contenant des maytansinoides et leur application thérapeutique
WO1996030347A1 (fr) 1995-03-30 1996-10-03 Pfizer Inc. Derives de quinazoline
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1996033978A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
US5571894A (en) 1991-02-05 1996-11-05 Ciba-Geigy Corporation Recombinant antibodies specific for a growth factor receptor
WO1996040210A1 (fr) 1995-06-07 1996-12-19 Imclone Systems Incorporated Anticorps et fragments d'anticorps inhibant la croissance des tumeurs
US5587458A (en) 1991-10-07 1996-12-24 Aronex Pharmaceuticals, Inc. Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5624821A (en) 1987-03-18 1997-04-29 Scotgen Biopharmaceuticals Incorporated Antibodies with altered effector functions
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5635483A (en) 1992-12-03 1997-06-03 Arizona Board Of Regents Acting On Behalf Of Arizona State University Tumor inhibiting tetrapeptide bearing modified phenethyl amides
US5641870A (en) 1995-04-20 1997-06-24 Genentech, Inc. Low pH hydrophobic interaction chromatography for antibody purification
US5648237A (en) 1991-09-19 1997-07-15 Genentech, Inc. Expression of functional antibody fragments
US5654307A (en) 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO1997030087A1 (fr) 1996-02-16 1997-08-21 Glaxo Group Limited Preparation d'anticorps glycosyles
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1997038983A1 (fr) 1996-04-12 1997-10-23 Warner-Lambert Company Inhibiteurs irreversibles de tyrosine kinases
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
WO1998014451A1 (fr) 1996-10-02 1998-04-09 Novartis Ag Derive de pyrazole condense et procede pour sa preparation
US5739116A (en) 1994-06-03 1998-04-14 American Cyanamid Company Enediyne derivatives useful for the synthesis of conjugates of methyltrithio antitumor agents
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US5750373A (en) 1990-12-03 1998-05-12 Genentech, Inc. Enrichment method for variant proteins having altered binding properties, M13 phagemids, and growth hormone variants
US5760041A (en) 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
WO1998024893A2 (fr) 1996-12-03 1998-06-11 Abgenix, Inc. MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
US5770701A (en) 1987-10-30 1998-06-23 American Cyanamid Company Process for preparing targeted forms of methyltrithio antitumor agents
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5770710A (en) 1987-10-30 1998-06-23 American Cyanamid Company Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methlytrithio group
US5780588A (en) 1993-01-26 1998-07-14 Arizona Board Of Regents Elucidation and synthesis of selected pentapeptides
US5789199A (en) 1994-11-03 1998-08-04 Genentech, Inc. Process for bacterial production of polypeptides
US5804396A (en) 1994-10-12 1998-09-08 Sugen, Inc. Assay for agents active in proliferative disorders
WO1998043960A1 (fr) 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
WO1998050038A1 (fr) 1997-05-06 1998-11-12 American Cyanamid Company Utilisation de composes de la quinazoline dans le traitement de la maladie polykystique des reins
WO1998050433A2 (fr) 1997-05-05 1998-11-12 Abgenix, Inc. Anticorps monoclonaux humains contre le recepteur du facteur de croissance epidermique
US5840523A (en) 1995-03-01 1998-11-24 Genetech, Inc. Methods and compositions for secretion of heterologous polypeptides
WO1998058964A1 (fr) 1997-06-24 1998-12-30 Genentech, Inc. Procedes et compositions concernant des glycoproteines galactosylees
US5866572A (en) 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
WO1999006396A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs bicycliques irreversibles de tyrosine kinases
WO1999006378A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs irreversibles de tyrosines kinases
WO1999009016A1 (fr) 1997-08-01 1999-02-25 American Cyanamid Company Derives de quinazoline substitues et leur utilisation en tant qu'inhibiteurs de la tyrosine kinase
US5891996A (en) 1972-09-17 1999-04-06 Centro De Inmunologia Molecular Humanized and chimeric monoclonal antibodies that recognize epidermal growth factor receptor (EGF-R); diagnostic and therapeutic use
WO1999022764A1 (fr) 1997-10-31 1999-05-14 Genentech, Inc. Compositions renfermant des glycoformes de glycoproteine et methodes afferentes
WO1999024037A1 (fr) 1997-11-06 1999-05-20 American Cyanamid Company Traitement des polypes du colon par des inhibiteurs de la tyrosine kinase a base de derives de quinazoline
US5959177A (en) 1989-10-27 1999-09-28 The Scripps Research Institute Transgenic plants expressing assembled secretory antibodies
WO1999051642A1 (fr) 1998-04-02 1999-10-14 Genentech, Inc. Variants d'anticorps et fragments de ceux-ci
US6002008A (en) 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6040498A (en) 1998-08-11 2000-03-21 North Caroline State University Genetically engineered duckweed
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6084095A (en) 1994-01-25 2000-07-04 Warner-Lambert Company Substituted pyrido[3,2-d]pyrimidines capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO2000061739A1 (fr) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle
US6140332A (en) 1995-07-06 2000-10-31 Novartis Ag Pyrrolopyrimidines and processes for the preparation thereof
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
WO2001029246A1 (fr) 1999-10-19 2001-04-26 Kyowa Hakko Kogyo Co., Ltd. Procede de production d'un polypeptide
US6248516B1 (en) 1988-11-11 2001-06-19 Medical Research Council Single domain ligands, receptors comprising said ligands methods for their production, and use of said ligands and receptors
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
US6344455B1 (en) 1998-11-19 2002-02-05 Warner-Lambert Company N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, and irreversible inhibitor of tyrosine kinases
WO2002031140A1 (fr) 2000-10-06 2002-04-18 Kyowa Hakko Kogyo Co., Ltd. Cellules produisant des compositions d'anticorps
US6391874B1 (en) 1996-07-13 2002-05-21 Smithkline Beecham Corporation Fused heterocyclic compounds as protein tyrosine kinase inhibitors
US6420548B1 (en) 1999-10-04 2002-07-16 Medicago Inc. Method for regulating transcription of foreign genes
US20020164328A1 (en) 2000-10-06 2002-11-07 Toyohide Shinkawa Process for purifying antibody
WO2003011878A2 (fr) 2001-08-03 2003-02-13 Glycart Biotechnology Ag Variants de glycosylation d'anticorps presentant une cytotoxicite cellulaire accrue dependante des anticorps
US20030115614A1 (en) 2000-10-06 2003-06-19 Yutaka Kanda Antibody composition-producing cell
US6596726B1 (en) 1994-01-25 2003-07-22 Warner Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6602684B1 (en) 1998-04-20 2003-08-05 Glycart Biotechnology Ag Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
US20030157108A1 (en) 2001-10-25 2003-08-21 Genentech, Inc. Glycoprotein compositions
US6630579B2 (en) 1999-12-29 2003-10-07 Immunogen Inc. Cytotoxic agents comprising modified doxorubicins and daunorubicins and their therapeutic use
WO2003084570A1 (fr) 2002-04-09 2003-10-16 Kyowa Hakko Kogyo Co., Ltd. Medicament contenant une composition d'anticorps appropriee au patient souffrant de polymorphisme fc$g(g)riiia
WO2003085119A1 (fr) 2002-04-09 2003-10-16 Kyowa Hakko Kogyo Co., Ltd. Procede d'amelioration de l'activite d'une composition d'anticorps de liaison avec le recepteur fc$g(g) iiia
WO2003085107A1 (fr) 2002-04-09 2003-10-16 Kyowa Hakko Kogyo Co., Ltd. Cellules à génome modifié
US20040093621A1 (en) 2001-12-25 2004-05-13 Kyowa Hakko Kogyo Co., Ltd Antibody composition which specifically binds to CD20
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
US20040110282A1 (en) 2002-04-09 2004-06-10 Kyowa Hakko Kogyo Co., Ltd. Cells in which activity of the protein involved in transportation of GDP-fucose is reduced or lost
US20040109865A1 (en) 2002-04-09 2004-06-10 Kyowa Hakko Kogyo Co., Ltd. Antibody composition-containing medicament
US20040132140A1 (en) 2002-04-09 2004-07-08 Kyowa Hakko Kogyo Co., Ltd. Production process for antibody composition
WO2004056312A2 (fr) 2002-12-16 2004-07-08 Genentech, Inc. Variants d'immunoglobuline et utilisations
US20050014934A1 (en) 2002-10-15 2005-01-20 Hinton Paul R. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
US20050079574A1 (en) 2003-01-16 2005-04-14 Genentech, Inc. Synthetic antibody phage libraries
WO2005035778A1 (fr) 2003-10-09 2005-04-21 Kyowa Hakko Kogyo Co., Ltd. Procede permettant de produire une composition d'anticorps par inhibition par l'arn de la fonction de $g(a)1,6-fucosyltransferase
WO2005035586A1 (fr) 2003-10-08 2005-04-21 Kyowa Hakko Kogyo Co., Ltd. Composition proteique hybride
US20050119455A1 (en) 2002-06-03 2005-06-02 Genentech, Inc. Synthetic antibody phage libraries
US20050123546A1 (en) 2003-11-05 2005-06-09 Glycart Biotechnology Ag Antigen binding molecules with increased Fc receptor binding affinity and effector function
WO2005053742A1 (fr) 2003-12-04 2005-06-16 Kyowa Hakko Kogyo Co., Ltd. Medicament contenant une composition a base d'anticorps
WO2005100402A1 (fr) 2004-04-13 2005-10-27 F.Hoffmann-La Roche Ag Anticorps anti-p-selectine
US20050260186A1 (en) 2003-03-05 2005-11-24 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases
US20050266000A1 (en) 2004-04-09 2005-12-01 Genentech, Inc. Variable domain library and uses
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
WO2006029879A2 (fr) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anticorps anti-ox40l
WO2006044908A2 (fr) 2004-10-20 2006-04-27 Genentech, Inc. Formulations d'anticorps
US7041870B2 (en) 2000-11-30 2006-05-09 Medarex, Inc. Transgenic transchromosomal rodents for making human antibodies
US20060104968A1 (en) 2003-03-05 2006-05-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
US7125978B1 (en) 1999-10-04 2006-10-24 Medicago Inc. Promoter for regulating expression of foreign genes
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
US7189826B2 (en) 1997-11-24 2007-03-13 Institute For Human Genetics And Biochemistry Monoclonal human natural antibodies
US20070061900A1 (en) 2000-10-31 2007-03-15 Murphy Andrew J Methods of modifying eukaryotic cells
US20070117126A1 (en) 1999-12-15 2007-05-24 Genentech, Inc. Shotgun scanning
US20070160598A1 (en) 2005-11-07 2007-07-12 Dennis Mark S Binding polypeptides with diversified and consensus vh/vl hypervariable sequences
US20070237764A1 (en) 2005-12-02 2007-10-11 Genentech, Inc. Binding polypeptides with restricted diversity sequences
US20070292936A1 (en) 2006-05-09 2007-12-20 Genentech, Inc. Binding polypeptides with optimized scaffolds
US7371826B2 (en) 1999-01-15 2008-05-13 Genentech, Inc. Polypeptide variants with altered effector function
WO2008077546A1 (fr) 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Anticorps contre le récepteur du facteur de croissance i de type insuline et leurs utilisations
US20090002360A1 (en) 2007-05-25 2009-01-01 Innolux Display Corp. Liquid crystal display device and method for driving same
US7498298B2 (en) 2003-11-06 2009-03-03 Seattle Genetics, Inc. Monomethylvaline compounds capable of conjugation to ligands
US7521541B2 (en) 2004-09-23 2009-04-21 Genetech Inc. Cysteine engineered antibodies and conjugates
US7527791B2 (en) 2004-03-31 2009-05-05 Genentech, Inc. Humanized anti-TGF-beta antibodies
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
WO2011066389A1 (fr) 2009-11-24 2011-06-03 Medimmmune, Limited Agents de liaison ciblés dirigés contre b7-h1
US8219149B2 (en) 2005-06-29 2012-07-10 Nokia Corporation Mobile communication terminal
US20120251531A1 (en) 2011-03-29 2012-10-04 Genentech, Inc. ANTIBODY Fc VARIANTS
US9651555B2 (en) 2012-09-24 2017-05-16 Ventana Medical Systems, Inc. Method of identifying treatment responsive non-small cell lung cancer using anaplastic lymphoma kinase (ALK) as a marker
US20180235968A1 (en) 2004-06-04 2018-08-23 Genentech, Inc. Egfr mutations
WO2019165434A1 (fr) * 2018-02-26 2019-08-29 Genentech, Inc. Dosage pour traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1

Patent Citations (158)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5891996A (en) 1972-09-17 1999-04-06 Centro De Inmunologia Molecular Humanized and chimeric monoclonal antibodies that recognize epidermal growth factor receptor (EGF-R); diagnostic and therapeutic use
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4943533A (en) 1984-03-01 1990-07-24 The Regents Of The University Of California Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor
US6982321B2 (en) 1986-03-27 2006-01-03 Medical Research Council Altered antibodies
US5500362A (en) 1987-01-08 1996-03-19 Xoma Corporation Chimeric antibody with specificity to human B cell surface antigen
US5624821A (en) 1987-03-18 1997-04-29 Scotgen Biopharmaceuticals Incorporated Antibodies with altered effector functions
US5648260A (en) 1987-03-18 1997-07-15 Scotgen Biopharmaceuticals Incorporated DNA encoding antibodies with altered effector functions
US5770710A (en) 1987-10-30 1998-06-23 American Cyanamid Company Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methlytrithio group
US5770701A (en) 1987-10-30 1998-06-23 American Cyanamid Company Process for preparing targeted forms of methyltrithio antitumor agents
US5545807A (en) 1988-10-12 1996-08-13 The Babraham Institute Production of antibodies from transgenic animals
US6248516B1 (en) 1988-11-11 2001-06-19 Medical Research Council Single domain ligands, receptors comprising said ligands methods for their production, and use of said ligands and receptors
EP0404097A2 (fr) 1989-06-22 1990-12-27 BEHRINGWERKE Aktiengesellschaft Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application
US5212290A (en) 1989-09-08 1993-05-18 The Johns Hopkins University Antibodies specific for type II mutant EGTR
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US5416064A (en) 1989-10-25 1995-05-16 Immunogen, Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
EP0425235B1 (fr) 1989-10-25 1996-09-25 Immunogen Inc Agents cytotoxiques contenant des maytansinoides et leur application thérapeutique
US5959177A (en) 1989-10-27 1999-09-28 The Scripps Research Institute Transgenic plants expressing assembled secretory antibodies
US6417429B1 (en) 1989-10-27 2002-07-09 The Scripps Research Institute Transgenic plants expressing assembled secretory antibodies
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1991010741A1 (fr) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation d'anticorps xenogeniques
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5750373A (en) 1990-12-03 1998-05-12 Genentech, Inc. Enrichment method for variant proteins having altered binding properties, M13 phagemids, and growth hormone variants
US5571894A (en) 1991-02-05 1996-11-05 Ciba-Geigy Corporation Recombinant antibodies specific for a growth factor receptor
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
WO1993001161A1 (fr) 1991-07-11 1993-01-21 Pfizer Limited Procede de preparation d'intermediaires de sertraline
US5648237A (en) 1991-09-19 1997-07-15 Genentech, Inc. Expression of functional antibody fragments
US5587458A (en) 1991-10-07 1996-12-24 Aronex Pharmaceuticals, Inc. Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof
WO1993011161A1 (fr) 1991-11-25 1993-06-10 Enzon, Inc. Proteines multivalentes de fixation aux antigenes
US5616582A (en) 1992-01-20 1997-04-01 Zeneca Limited Quinazoline derivatives as anti-proliferative agents
US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
WO1993016185A2 (fr) 1992-02-06 1993-08-19 Creative Biomolecules, Inc. Proteine de liaison biosynthetique pour marqueur de cancer
WO1994011026A2 (fr) 1992-11-13 1994-05-26 Idec Pharmaceuticals Corporation Application therapeutique d'anticorps chimeriques et radio-marques contre l'antigene a differentiation restreinte des lymphocytes b humains pour le traitement du lymphome des cellules b
US5635483A (en) 1992-12-03 1997-06-03 Arizona Board Of Regents Acting On Behalf Of Arizona State University Tumor inhibiting tetrapeptide bearing modified phenethyl amides
US5780588A (en) 1993-01-26 1998-07-14 Arizona Board Of Regents Elucidation and synthesis of selected pentapeptides
WO1994029351A2 (fr) 1993-06-16 1994-12-22 Celltech Limited Anticorps
US5475001A (en) 1993-07-19 1995-12-12 Zeneca Limited Quinazoline derivatives
EP0659439A2 (fr) 1993-12-24 1995-06-28 MERCK PATENT GmbH Immunoconjugués
US6084095A (en) 1994-01-25 2000-07-04 Warner-Lambert Company Substituted pyrido[3,2-d]pyrimidines capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6521620B1 (en) 1994-01-25 2003-02-18 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6455534B2 (en) 1994-01-25 2002-09-24 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6596726B1 (en) 1994-01-25 2003-07-22 Warner Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6265410B1 (en) 1994-01-25 2001-07-24 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5654307A (en) 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US6713484B2 (en) 1994-01-25 2004-03-30 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5679683A (en) 1994-01-25 1997-10-21 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5877296A (en) 1994-06-03 1999-03-02 American Cyanamid Company Process for preparing conjugates of methyltrithio antitumor agents
US5739116A (en) 1994-06-03 1998-04-14 American Cyanamid Company Enediyne derivatives useful for the synthesis of conjugates of methyltrithio antitumor agents
US5767285A (en) 1994-06-03 1998-06-16 American Cyanamid Company Linkers useful for the synthesis of conjugates of methyltrithio antitumor agents
US5773001A (en) 1994-06-03 1998-06-30 American Cyanamid Company Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
WO1996003397A1 (fr) 1994-07-21 1996-02-08 Akzo Nobel N.V. Formulations de peroxides cetoniques cycliques
US5804396A (en) 1994-10-12 1998-09-08 Sugen, Inc. Assay for agents active in proliferative disorders
US5789199A (en) 1994-11-03 1998-08-04 Genentech, Inc. Process for bacterial production of polypeptides
US5840523A (en) 1995-03-01 1998-11-24 Genetech, Inc. Methods and compositions for secretion of heterologous polypeptides
WO1996030347A1 (fr) 1995-03-30 1996-10-03 Pfizer Inc. Derives de quinazoline
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US5641870A (en) 1995-04-20 1997-06-24 Genentech, Inc. Low pH hydrophobic interaction chromatography for antibody purification
US5770599A (en) 1995-04-27 1998-06-23 Zeneca Limited Quinazoline derivatives
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996033978A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
WO1996040210A1 (fr) 1995-06-07 1996-12-19 Imclone Systems Incorporated Anticorps et fragments d'anticorps inhibant la croissance des tumeurs
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US6140332A (en) 1995-07-06 2000-10-31 Novartis Ag Pyrrolopyrimidines and processes for the preparation thereof
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
US5760041A (en) 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
US6399602B1 (en) 1996-02-14 2002-06-04 Zeneca Limited Quinazoline derivatives
US5866572A (en) 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
WO1997030087A1 (fr) 1996-02-16 1997-08-21 Glaxo Group Limited Preparation d'anticorps glycosyles
WO1997038983A1 (fr) 1996-04-12 1997-10-23 Warner-Lambert Company Inhibiteurs irreversibles de tyrosine kinases
US6344459B1 (en) 1996-04-12 2002-02-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6602863B1 (en) 1996-04-12 2003-08-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US6391874B1 (en) 1996-07-13 2002-05-21 Smithkline Beecham Corporation Fused heterocyclic compounds as protein tyrosine kinase inhibitors
WO1998014451A1 (fr) 1996-10-02 1998-04-09 Novartis Ag Derive de pyrazole condense et procede pour sa preparation
WO1998024893A2 (fr) 1996-12-03 1998-06-11 Abgenix, Inc. MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
WO1998043960A1 (fr) 1997-04-03 1998-10-08 American Cyanamid Company 3-cyano quinolines substituees
US6002008A (en) 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
WO1998050433A2 (fr) 1997-05-05 1998-11-12 Abgenix, Inc. Anticorps monoclonaux humains contre le recepteur du facteur de croissance epidermique
WO1998050038A1 (fr) 1997-05-06 1998-11-12 American Cyanamid Company Utilisation de composes de la quinazoline dans le traitement de la maladie polykystique des reins
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
WO1998058964A1 (fr) 1997-06-24 1998-12-30 Genentech, Inc. Procedes et compositions concernant des glycoproteines galactosylees
WO1999006378A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs irreversibles de tyrosines kinases
WO1999006396A1 (fr) 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs bicycliques irreversibles de tyrosine kinases
WO1999009016A1 (fr) 1997-08-01 1999-02-25 American Cyanamid Company Derives de quinazoline substitues et leur utilisation en tant qu'inhibiteurs de la tyrosine kinase
WO1999022764A1 (fr) 1997-10-31 1999-05-14 Genentech, Inc. Compositions renfermant des glycoformes de glycoproteine et methodes afferentes
WO1999024037A1 (fr) 1997-11-06 1999-05-20 American Cyanamid Company Traitement des polypes du colon par des inhibiteurs de la tyrosine kinase a base de derives de quinazoline
US7189826B2 (en) 1997-11-24 2007-03-13 Institute For Human Genetics And Biochemistry Monoclonal human natural antibodies
US7087409B2 (en) 1997-12-05 2006-08-08 The Scripps Research Institute Humanization of murine antibody
WO1999051642A1 (fr) 1998-04-02 1999-10-14 Genentech, Inc. Variants d'anticorps et fragments de ceux-ci
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
US6602684B1 (en) 1998-04-20 2003-08-05 Glycart Biotechnology Ag Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
US6040498A (en) 1998-08-11 2000-03-21 North Caroline State University Genetically engineered duckweed
US6344455B1 (en) 1998-11-19 2002-02-05 Warner-Lambert Company N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, and irreversible inhibitor of tyrosine kinases
US7332581B2 (en) 1999-01-15 2008-02-19 Genentech, Inc. Polypeptide variants with altered effector function
US7371826B2 (en) 1999-01-15 2008-05-13 Genentech, Inc. Polypeptide variants with altered effector function
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
WO2000061739A1 (fr) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle
US6420548B1 (en) 1999-10-04 2002-07-16 Medicago Inc. Method for regulating transcription of foreign genes
US7125978B1 (en) 1999-10-04 2006-10-24 Medicago Inc. Promoter for regulating expression of foreign genes
WO2001029246A1 (fr) 1999-10-19 2001-04-26 Kyowa Hakko Kogyo Co., Ltd. Procede de production d'un polypeptide
US20070117126A1 (en) 1999-12-15 2007-05-24 Genentech, Inc. Shotgun scanning
US6630579B2 (en) 1999-12-29 2003-10-07 Immunogen Inc. Cytotoxic agents comprising modified doxorubicins and daunorubicins and their therapeutic use
US20030115614A1 (en) 2000-10-06 2003-06-19 Yutaka Kanda Antibody composition-producing cell
US20020164328A1 (en) 2000-10-06 2002-11-07 Toyohide Shinkawa Process for purifying antibody
WO2002031140A1 (fr) 2000-10-06 2002-04-18 Kyowa Hakko Kogyo Co., Ltd. Cellules produisant des compositions d'anticorps
US20070061900A1 (en) 2000-10-31 2007-03-15 Murphy Andrew J Methods of modifying eukaryotic cells
US7041870B2 (en) 2000-11-30 2006-05-09 Medarex, Inc. Transgenic transchromosomal rodents for making human antibodies
WO2003011878A2 (fr) 2001-08-03 2003-02-13 Glycart Biotechnology Ag Variants de glycosylation d'anticorps presentant une cytotoxicite cellulaire accrue dependante des anticorps
US20030157108A1 (en) 2001-10-25 2003-08-21 Genentech, Inc. Glycoprotein compositions
US20040093621A1 (en) 2001-12-25 2004-05-13 Kyowa Hakko Kogyo Co., Ltd Antibody composition which specifically binds to CD20
US20040110704A1 (en) 2002-04-09 2004-06-10 Kyowa Hakko Kogyo Co., Ltd. Cells of which genome is modified
WO2003085119A1 (fr) 2002-04-09 2003-10-16 Kyowa Hakko Kogyo Co., Ltd. Procede d'amelioration de l'activite d'une composition d'anticorps de liaison avec le recepteur fc$g(g) iiia
WO2003085107A1 (fr) 2002-04-09 2003-10-16 Kyowa Hakko Kogyo Co., Ltd. Cellules à génome modifié
WO2003084570A1 (fr) 2002-04-09 2003-10-16 Kyowa Hakko Kogyo Co., Ltd. Medicament contenant une composition d'anticorps appropriee au patient souffrant de polymorphisme fc$g(g)riiia
US20040132140A1 (en) 2002-04-09 2004-07-08 Kyowa Hakko Kogyo Co., Ltd. Production process for antibody composition
US20040109865A1 (en) 2002-04-09 2004-06-10 Kyowa Hakko Kogyo Co., Ltd. Antibody composition-containing medicament
US20040110282A1 (en) 2002-04-09 2004-06-10 Kyowa Hakko Kogyo Co., Ltd. Cells in which activity of the protein involved in transportation of GDP-fucose is reduced or lost
US20050119455A1 (en) 2002-06-03 2005-06-02 Genentech, Inc. Synthetic antibody phage libraries
US20050014934A1 (en) 2002-10-15 2005-01-20 Hinton Paul R. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
WO2004056312A2 (fr) 2002-12-16 2004-07-08 Genentech, Inc. Variants d'immunoglobuline et utilisations
US20050079574A1 (en) 2003-01-16 2005-04-14 Genentech, Inc. Synthetic antibody phage libraries
US20050260186A1 (en) 2003-03-05 2005-11-24 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases
US20060104968A1 (en) 2003-03-05 2006-05-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases
WO2005035586A1 (fr) 2003-10-08 2005-04-21 Kyowa Hakko Kogyo Co., Ltd. Composition proteique hybride
WO2005035778A1 (fr) 2003-10-09 2005-04-21 Kyowa Hakko Kogyo Co., Ltd. Procede permettant de produire une composition d'anticorps par inhibition par l'arn de la fonction de $g(a)1,6-fucosyltransferase
US20050123546A1 (en) 2003-11-05 2005-06-09 Glycart Biotechnology Ag Antigen binding molecules with increased Fc receptor binding affinity and effector function
US7498298B2 (en) 2003-11-06 2009-03-03 Seattle Genetics, Inc. Monomethylvaline compounds capable of conjugation to ligands
WO2005053742A1 (fr) 2003-12-04 2005-06-16 Kyowa Hakko Kogyo Co., Ltd. Medicament contenant une composition a base d'anticorps
US7527791B2 (en) 2004-03-31 2009-05-05 Genentech, Inc. Humanized anti-TGF-beta antibodies
US20050266000A1 (en) 2004-04-09 2005-12-01 Genentech, Inc. Variable domain library and uses
WO2005100402A1 (fr) 2004-04-13 2005-10-27 F.Hoffmann-La Roche Ag Anticorps anti-p-selectine
US20180235968A1 (en) 2004-06-04 2018-08-23 Genentech, Inc. Egfr mutations
WO2006029879A2 (fr) 2004-09-17 2006-03-23 F.Hoffmann-La Roche Ag Anticorps anti-ox40l
US7521541B2 (en) 2004-09-23 2009-04-21 Genetech Inc. Cysteine engineered antibodies and conjugates
WO2006044908A2 (fr) 2004-10-20 2006-04-27 Genentech, Inc. Formulations d'anticorps
US8219149B2 (en) 2005-06-29 2012-07-10 Nokia Corporation Mobile communication terminal
WO2007005874A2 (fr) 2005-07-01 2007-01-11 Medarex, Inc. Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1)
US20070160598A1 (en) 2005-11-07 2007-07-12 Dennis Mark S Binding polypeptides with diversified and consensus vh/vl hypervariable sequences
US20070237764A1 (en) 2005-12-02 2007-10-11 Genentech, Inc. Binding polypeptides with restricted diversity sequences
US20070292936A1 (en) 2006-05-09 2007-12-20 Genentech, Inc. Binding polypeptides with optimized scaffolds
WO2008077546A1 (fr) 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Anticorps contre le récepteur du facteur de croissance i de type insuline et leurs utilisations
US20090002360A1 (en) 2007-05-25 2009-01-01 Innolux Display Corp. Liquid crystal display device and method for driving same
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
WO2010077634A1 (fr) 2008-12-09 2010-07-08 Genentech, Inc. Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t
WO2011066389A1 (fr) 2009-11-24 2011-06-03 Medimmmune, Limited Agents de liaison ciblés dirigés contre b7-h1
US20130034559A1 (en) 2009-11-24 2013-02-07 Medlmmune Limited Targeted Binding Agents Against B7-H1
US20120251531A1 (en) 2011-03-29 2012-10-04 Genentech, Inc. ANTIBODY Fc VARIANTS
US9651555B2 (en) 2012-09-24 2017-05-16 Ventana Medical Systems, Inc. Method of identifying treatment responsive non-small cell lung cancer using anaplastic lymphoma kinase (ALK) as a marker
WO2019165434A1 (fr) * 2018-02-26 2019-08-29 Genentech, Inc. Dosage pour traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1

Non-Patent Citations (111)

* Cited by examiner, † Cited by third party
Title
"Methods in Enzymology", 1995, ACADEMIC PRESS, INC., article "PCR 2: A Practical Approach"
"Remington's Pharmaceutical Sciences", 1980
"UniProt", Database accession no. Q9NZQ7
ALICE L. HUNG ET AL: "TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM", ONCOIMMUNOLOGY, 24 May 2018 (2018-05-24), pages e1466769, XP055688548, DOI: 10.1080/2162402X.2018.1466769 *
ALMAGROFRANSSON, FRONT. BIOSCI., vol. 13, 2008, pages 1619 - 1633
ANGEW CHEM. INTL. ED. ENGL., vol. 33, 1994, pages 183 - 186
ANONYMOUS: "Safety and Pharmacokinetics (PK) of Escalating Doses of MTIG7192A as a Single Agent and in Combination With Atezolizumab With and Without Chemotherapy in Locally Advanced or Metastatic Tumors - Full Text View - ClinicalTrials.gov", 9 June 2016 (2016-06-09), XP055758364, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/study/NCT02794571> [retrieved on 20201209] *
BACA ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 10678 - 10684
BOERNER ET AL., J. IMMUNOL., vol. 147, no. 1, 1991, pages 86 - 95
BRUGGEMANN ET AL., YEAR IN IMMUNOL., vol. 7, 1993, pages 33
BRUGGEMANN, M. ET AL., J. EXP. MED., vol. 166, 1987, pages 1351 - 1361
C.A. JANEWAYP. TRAVERS, IMMUNOBIOLOGY, 1997
CALVERT ET AL., J. CLIN. ONCOL., vol. 7, 1989, pages 1748 - 56
CAPEL ET AL., IMMUNOMETHODS, vol. 113, 1994, pages 269 - 315
CARTER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 89, 1992, pages 4285
CARUSO: "Tiragolumab Impresses in Multiple Trials", CANCER DISCOVERY, vol. 10, no. 8, 23 June 2020 (2020-06-23), US, pages 1086.2 - 1087, XP055758449, ISSN: 2159-8274, DOI: 10.1158/2159-8290.CD-NB2020-063 *
CHARI ET AL., CANCER RES., vol. 52, 1992, pages 127 - 131
CHEN ET AL., J. MOL. BIOL., vol. 293, 1999, pages 865 - 881
CHOTHIALESK, J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
CHOWDHURY, METHODS MOL. BIOL., vol. 207, 2008, pages 179 - 196
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
CLYNES ET AL., PROC. NAT'L ACAD. SCI. USA, vol. 95, 1998, pages 652 - 656
CRAGG, M.S. ET AL., BLOOD, vol. 101, 2003, pages 1045 - 1052
CRAGG, M.S.M.J. GLENNIE, BLOOD, vol. 103, 2004, pages 2738 - 2743
CUNNINGHAMWELLS, SCIENCE, vol. 244, 1989, pages 1081 - 1085
DALL'ACQUA ET AL., METHODS, vol. 36, 2005, pages 61 - 68
DE HAAS ET AL., J. LAB. CLIN. MED., vol. 126, 1995, pages 330 - 41
DU ET AL., THORACIC CANCER., vol. 9, 2018, pages 423 - 430
DUBOWCHIK, BIOORG. & MED. CHEM. LETTERS, vol. 12, 2002, pages 1529 - 1532
EISENHAUER ET AL., EUR. J. CANCER., vol. 45, 2009, pages 228 - 47
FELLOUSE, PROC. NATL. ACAD. SCI. USA, vol. 101, no. 34, 2004, pages 12467 - 12472
FISHWILD ET AL., NATURE BIOTECHNOL., vol. 14, 1996, pages 826 - 851
FLATMAN, J. CHROMATOGR. B, vol. 848, 2007, pages 79 - 87
FRAMPTON ET AL., NATURE BIOTECHNOLOGY, vol. 31, no. 11, 2013, pages 1023 - 1033
GAZZANO-SANTORO ET AL., J. IMMUNOL. METHODS, vol. 202, 1996, pages 163
GERNGROSS, NAT. BIOTECH., vol. 22, 2004, pages 1409 - 1414
GRAHAM ET AL., J. GEN VIROL., vol. 36, 1977, pages 59
GRIFFITHS ET AL., EMBO J, vol. 12, 1993, pages 725 - 734
GUYER ET AL., J. IMMUNOL., vol. 117, 1976, pages 587
HAMERS-CASTERMAN ET AL., NATURE, vol. 362, 1993, pages 255 - 258
HAMMERLING ET AL.: "Monoclonal Antibodies and T-Cell Hybridomas", 1981, ELSEVIER, pages: 563 - 681
HARLOW ET AL.: "Antibodies: A Laboratory Manual", 1988, COLD SPRING HARBOR LABORATORY PRESS
HARRIS, BIOCHEM. SOC. TRANSACTIONS, vol. 23, 1995, pages 1035 - 1038
HELLSTROM, I ET AL., PROC. NAT'L ACAD. SCI. USA, vol. 82, 1985, pages 1499 - 1502
HELLSTROM, I. ET AL., PROC. NAT'L ACAD. SCI. USA, vol. 83, 1986, pages 7059 - 7063
HINMAN ET AL., CANCER RES., vol. 53, 1993, pages 3336 - 3342
HONGO ET AL., HYBRIDOMA, vol. 14, no. 3, 1995, pages 253 - 260
HOOGENBOOMWINTER, J. MOL. BIOL., vol. 222, 1991, pages 581
HOOGENBOOMWINTER, J. MOL. BIOL., vol. 227, 1992, pages 381 - 388
HUDSON ET AL., NAT. MED., vol. 248, 2003, pages 129 - 134
HURLEGROSS, CURR. OP. BIOTECH., vol. 5, 1994, pages 428 - 433
IDUSOGIE ET AL., J. IMMUNOL., vol. 164, 2000, pages 4178 - 4184
JAKOBOVITS ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 2551 - 6448
JEFFREY, BIOORGANIC & MED. CHEM. LETTERS, vol. 16, 2006, pages 358 - 362
JOHNS ET AL., J. BIOL. CHEM., vol. 279, no. 29, 2004, pages 30375 - 30384
JONES ET AL., NATURE, vol. 321, 1986, pages 522 - 525
JUAN ET AL., THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, vol. 9, no. 3, 2017, pages 201 - 216
KAM ET AL., PROC. NATL. ACAD. SCI. USA, vol. 102, 2005, pages 11600 - 11605
KANDA, Y. ET AL., BIOTECHNOL. BIOENG., vol. 94, no. 4, 2006, pages 680 - 688
KIM ET AL., J. IMMUNOL., vol. 24, 1994, pages 249
KING, J. MED. CHEM., vol. 45, 2002, pages 4336 - 4343
KLIMKA ET AL., BR. J. CANCER, vol. 83, 2000, pages 252 - 260
KOHLERMILSTEIN., NATURE, vol. 256, 1975, pages 495 - 97
KOZBOR, J. IMMUNOL., vol. 133, 1984, pages 3001
KRATZ, CURRENT MED. CHEM., vol. 13, 2006, pages 477 - 523
LEE ET AL., J. IMMUNOL. METHODS, vol. 284, no. 1 -2, 2004, pages 119 - 132
LI ET AL., NAT. BIOTECH., vol. 24, 2006, pages 210 - 215
LI ET AL., PROC. NATL. ACAD. SCI. USA, vol. 103, 2006, pages 3557 - 3562
LODE, CANCER RES., vol. 58, 1998, pages 2925 - 2928
LONBERG ET AL., NATURE, vol. 368, 1994, pages 812 - 813
LONBERG, CURR. OPIN. IMMUNOL., vol. 20, 2008, pages 450 - 459
LONBERG, NAT. BIOTECH., vol. 23, 2005, pages 1117 - 1125
LONBERGHUSZAR, INTERN. REV. IMMUNOL., vol. 13, 1995, pages 65 - 93
M. DAERON, ANNU. REV. IMMUNOL., vol. 15, 1997, pages 203 - 234
MARKS ET AL., BIO/TECHNOLOGY, vol. 10, 1992, pages 779 - 783
MATHER ET AL., ANNALS N.Y. ACAD. SCI., vol. 383, 1982, pages 44 - 68
MATHER, BIOL. REPROD., vol. 23, 1980, pages 243 - 251
MORRISON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6851 - 6855
NAGY, PROC. NATL. ACAD. SCI. USA, vol. 97, 2000, pages 829 - 834
NI, XIANDAI MIANYIXUE, vol. 26, no. 4, 2006, pages 265 - 268
OKAZAKI ET AL., J. MOL. BIOL., vol. 336, no. 5, 2004, pages 1239 - 1249
P. FINCH, ANTIBODIES, 1997
PADLAN, MOL. IMMUNOL., vol. 28, 1991, pages 489 - 498
PETKOVA, S.B. ET AL., INT'L. IMMUNOL., vol. 18, no. 12, 2006, pages 1759 - 1769
POKLAR ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 93, no. 15, 1996, pages 7606 - 11
PRESTA ET AL., CANCER RES., vol. 57, 1997, pages 4593 - 4599
PRESTA ET AL., J. IMMUNOL., vol. 151, 1993, pages 2623
PRESTA, CURR. OP. STRUCT. BIOL., vol. 2, 1992, pages 593 - 596
QUEEN ET AL., PROC. NAT'L ACAD. SCI. USA, vol. 86, 1989, pages 10029 - 10033
RAVETCHKINET, ANNU. REV. IMMUNOL., vol. 9, 1991, pages 457 - 492
RIECHMANN ET AL., NATURE, vol. 322, 1988, pages 738 - 329
RIPKA ET AL., ARCH. BIOCHEM. BIOPHYS., vol. 249, 1986, pages 533 - 545
ROSOK ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 22611 - 22618
RUDD ET AL., CANCER CHEMOTHER. PHARMACOL., vol. 35, no. 4, 1995, pages 323 - 6
SHERIFF ET AL., NATURE STRUCT. BIOL., vol. 3, 1996, pages 733 - 736
SHIELDS ET AL., J. BIOL. CHEM., vol. 178, no. 2, 2001, pages 6591 - 6604
SONDERMANN ET AL., NATURE, vol. 406, 20 July 2000 (2000-07-20), pages 267 - 273
STRAGLIOTTO ET AL., EUR. J. CANCER, vol. 32A, 1996, pages 636 - 640
TORGOV, BIOCONJ. CHEM., vol. 16, 2005, pages 717 - 721
URLAUB ET AL., PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216
VAN DIJKVAN DE WINKEL, CURR. OPIN. PHARMACOL., vol. 5, 2001, pages 368 - 74
VASWANIHAMILTON, ANN. ALLERGY, ASTHMA & IMMUNOL., vol. 1, 1998, pages 105 - 115
VITETTA ET AL., SCIENCE, vol. 238, 1987, pages 1098
VOLLMERSBRANDLEIN, HISTOLOGY AND HISTOPATHOLOGY, vol. 20, no. 3, 2005, pages 927 - 937
VOLLMERSBRANDLEIN, METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY, vol. 27, no. 3, 2005, pages 185 - 91
WINTER ET AL., ANN. REV. IMMUNOL., vol. 12, 1994, pages 433 - 455
WRIGHT ET AL., TIBTECH, vol. 15, 1997, pages 26 - 32
XU ET AL., IMMUNITY, vol. 13, 2000, pages 37 - 45
YAMANE-OHNUKI ET AL., BIOTECH. BIOENG., vol. 87, 2004, pages 614
YAZAKIWU: "Methods in Molecular Biology", vol. 248, 2003, HUMANA PRESS, pages: 255 - 268
ZAPATA ET AL., PROTEIN ENG., vol. 8, no. 10, 1995, pages 1057 - 1062

Similar Documents

Publication Publication Date Title
US20220073623A1 (en) Therapeutic and diagnostic methods for cancer
AU2017339517B2 (en) Therapeutic and diagnostic methods for cancer
AU2019225249A1 (en) Dosing for treatment with anti-tigit and anti-PD-L1 antagonist antibodies
CA3015528A1 (fr) Methodes therapeutiques et de diagnostic du cancer
US20220098318A1 (en) Dosing for treatment with anti-tigit and anti-cd20 or anti-cd38 antibodies
US20220016243A1 (en) Methods for treatment of cancer with an anti-tigit antagonist antibody
US20200030443A1 (en) Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
US20220324981A1 (en) Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
US20210395366A1 (en) Treatment with anti-tigit antibodies and pd-1 axis binding antagonists
WO2022050954A1 (fr) Dosage pour traitement avec anticorps antagonistes anti-tigit et anti-pd-l1
WO2021194481A1 (fr) Dosage pour le traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1
US20230114626A1 (en) Methods and compositions for treating triple-negative breast cancer
EP4143345A1 (fr) Procédés et compositions pour l&#39;immunothérapie du cancer du poumon non à petites cellules

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20720227

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20720227

Country of ref document: EP

Kind code of ref document: A1