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WO2025040080A1 - Treatment of esophageal cancer with anti-lag3, anti-pd-1 and chemotherapy - Google Patents

Treatment of esophageal cancer with anti-lag3, anti-pd-1 and chemotherapy Download PDF

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Publication number
WO2025040080A1
WO2025040080A1 PCT/CN2024/113312 CN2024113312W WO2025040080A1 WO 2025040080 A1 WO2025040080 A1 WO 2025040080A1 CN 2024113312 W CN2024113312 W CN 2024113312W WO 2025040080 A1 WO2025040080 A1 WO 2025040080A1
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seq
antibody
administered
cdr
weeks
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Ningning DING
Liyun Li
Jinhui Zhang
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BeiGene Switzerland GmbH
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BeiGene Switzerland GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—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
    • C07K16/2818—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 CD28 or CD152
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • esophageal cancer e.g., unresectable, locally advanced and/or metastatic esophageal squamous cell carcinoma
  • an anti-LAG3 antibody or an antigen-binding fragment thereof an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and one or more chemotherapeutic drugs.
  • Esophageal cancer is the eighth most common cancer in terms of incidence and the sixth most common cause of cancer-related death worldwide, with 604, 100 new cases and 544, 076 deaths observed in 2020 (WHO International Agency for Research on Cancer. Oesophagus. GLOBOCAN 2020a. https: //gco. iarc. fr/today/data/factsheets/cancers/6-Oesophagus-fact-sheet. pdf. ) .
  • Esophageal squamous cell carcinoma is the predominant histological subtype of EC worldwide, accounting for approximately 90%of EC cases (Abnet CC, et al. Gastroenterology. 2018; 154 (2) : 360-73) .
  • ESCC is more common in the elderly (aged ⁇ 60 years) and has mean male-to-female ratios of 3: 1 to 4: 1 (Lagergren J, et al. Oesophageal cancer. Lancet. 2017; 390 (10110) : 2383-96) .
  • the main risk factors for ESCC include tobacco and/or alcohol abuse, consumption of hot food/beverage and pickled vegetables, and poor nutritional status (Engel, et al. J Natl Cancer Inst. 2003; 95 (18) : 1404-13.; Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN. CA Cancer J Clin. 2021; 71 (3) : 209-49.; Tran GD, et al. Int J Cancer.
  • Advanced ESCC is a rapidly progressing and symptomatic disease with poor clinical outcomes.
  • the 5-year survival rate is only 6.1%for patients with distant metastases (SEER 17 2012-2018; [SEER 2023] ) .
  • One-third to half of patients experienced disease progression after definitive therapies, and more than 30%of patients are initially diagnosed at metastatic stages (Abraham P, et al. Adv Ther. 2020; 37 (7) : 3392 403; Crosby T, et al. Br J Cancer. 2017; 116 (6) : 709-16.; Shapiro J, et al. Lancet Oncol. 2015; 16 (9) : 1090-8. ) .
  • the disclosure provides a method of treating an esophageal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-LAG3 antibody or an antigen binding fragment thereof, and a therapeutically effective amount of one or more chemotherapeutic drugs,
  • the anti-PD-1 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 1, CDR-H2 comprising SEQ ID NO: 2, and CDR-H3 comprising SEQ ID NO: 3, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 4, CDR-L2 comprising SEQ ID NO: 5, and CDR-L3 comprising SEQ ID NO: 6, and
  • CDR complementarity determining region
  • the anti-LAG3 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 31, CDR-H2 comprising SEQ ID NO: 32, and CDR-H3 comprising SEQ ID NO: 33, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 34, CDR-L2 comprising SEQ ID NO: 35, and CDR-L3 comprising SEQ ID NO: 36.
  • CDR complementarity determining region
  • the esophageal cancer is esophageal squamous cell carcinoma.
  • the cancer is unresectable, recurrent, locally advanced, and/or metastatic. In some embodiments, the cancer is unresectable and locally advanced. In some embodiments, wherein the cancer is stage IV cancer.
  • the cancer is metastatic.
  • the subject has liver, lung, lymph node, bone and/or adrenal gland metastasis.
  • the subject has 1, 2, 3 or more metastatic sites. In some embodiments, the subject has more than 3 metastatic sites.
  • the subject is human.
  • the disclosure provides a method of treating of metastatic and/or unresectable locally advanced esophageal squamous cell carcinoma in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-LAG3 antibody or an antigen binding fragment thereof, and a therapeutically effective amount of one or more chemotherapeutic drugs,
  • the anti-LAG3 antibody is any antibody known in the art or described herein. In some embodiments, the anti-LAG3 is antibody is any antibody that specifically binds to LAG3.
  • the anti-LAG3 antibody is administered once every two weeks.
  • an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 is administered once every two weeks.
  • the anti-LAG3 antibody is administered on Day 1 of the cycle (e.g., Day 1 of 21 day or 3 week cycle) .
  • the anti-LAG3 antibody is administered once every three weeks (Q3W) for 3 months or at least 3 months.
  • an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered once every three weeks (Q3W) for 3 months or at least 3 months.
  • the anti-LAG3 antibody is administered once every three weeks (Q3W) for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months (or more) .
  • an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered once every three weeks (Q3W) for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months (or more) .
  • one or more amino acid residues can be replaced with one or more different amino acid residues such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC) .
  • CDC complement dependent cytotoxicity
  • the glycosylation of an antibody is modified.
  • an aglycosylated antibody can be made (i.e., the antibody lacks or has reduced glycosylation) .
  • Glycosylation can be altered to, for example, increase the affinity of the antibody for “antigen. ”
  • Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence.
  • one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site.
  • Such aglycosylation can increase the affinity of the antibody for antigen.
  • Such an approach is described in, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al.
  • an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures.
  • altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
  • carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies to thereby produce an antibody with altered glycosylation.
  • EP 1,176,195 by Hang et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation.
  • PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lecl3 cells, with reduced ability to attach fucose to Asn (297) -linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields et al., (2002) J. Biol. Chem. 277: 26733-26740) .
  • PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta (1, 4) -N acetylglucosaminyltransferase III (GnTIII) ) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al., Nat. Biotech. 17: 176-180, 1999) .
  • glycoprotein-modifying glycosyl transferases e.g., beta (1, 4) -N acetylglucosaminyltransferase III (GnTIII)
  • human antibody subclass IgG4 was shown in many previous reports to have only modest ADCC and almost no CDC effector function (Moore G L, et al., 2010 MAbs, 2: 181-189) .
  • natural IgG4 was found less stable in stress conditions such as in acidic buffer or under increasing temperature (Angal, S. 1993 Mol Immunol, 30: 105-108; Dall'A cqua, W. et al., 1998 Biochemistry, 37: 9266-9273; Aalberse et al., 2002 Immunol, 105: 9-19) .
  • Reduced ADCC can be achieved by operably linking the antibody to IgG4 engineered with combinations of alterations to have reduced or null Fc ⁇ R binding or C1q binding activities, thereby reducing or eliminating ADCC and CDC effector functions.
  • IgG4 Considering physicochemical properties of antibody as a biological drug, one of the less desirable, intrinsic properties of IgG4 is dynamic separation of its two heavy chains in solution to form half antibody, which lead to bi-specific antibodies generated in vivo via a process called “Fab arm exchange” (Van der Neut Kolfschoten M, et al., 2007 Science, 317: 1554-157) .
  • the mutation of serine to proline at position 228 appeared inhibitory to the IgG4 heavy chain separation (Angal, S.
  • Anti-PD1 antibodies and antigen-binding fragments thereof and anti-LAG3 antibodies and antigen-binding fragments thereof can be produced by any means known in the art, including but not limited to, recombinant expression, chemical synthesis, and enzymatic digestion of antibody tetramers, whereas full-length monoclonal antibodies can be obtained by, e.g., hybridoma or recombinant production.
  • Recombinant expression can be from any appropriate host cells known in the art, for example, mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc.
  • the disclosure further provides polynucleotides encoding the antibodies described herein, e.g., polynucleotides encoding heavy or light chain variable regions or segments comprising the complementarity determining regions as described herein.
  • the polynucleotide encoding the heavy chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%nucleic acid sequence identity with a polynucleotide encoding the amino acid sequences disclosed herein.
  • the polynucleotide encoding the light chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%nucleic acid sequence identity with a polynucleotide encoding the amino acid sequences described herein.
  • the polynucleotides of the present disclosure can encode the variable region sequence of an anti-PD1 antibody or anti-LAG3 antibody. They can also encode both a variable region and a constant region of the antibody. Some of the polynucleotide sequences encode a polypeptide that comprises variable regions of both the heavy chain and the light chain. Some other polynucleotides encode two polypeptide segments that respectively are substantially identical to the variable regions of the heavy chain and the light chain.
  • expression vectors and host cells for producing the anti-PD1 antibodies and antigen-binding fragments thereof or anti-LAG3 antibodies and antigen-binding fragments thereof.
  • the choice of expression vector depends on the intended host cells in which the vector is to be expressed.
  • the expression vectors contain a promoter and other regulatory sequences (e.g., enhancers) that are operably linked to the polynucleotides encoding the antibodies or antigen-binding fragments thereof.
  • an inducible promoter is employed to prevent expression of inserted sequences except under the control of inducing conditions.
  • Inducible promoters include, e.g., arabinose, lacZ, metallothionein promoter or a heat shock promoter.
  • Cultures of transformed organisms can be expanded under non-inducing conditions without biasing the population for coding sequences whose expression products are better tolerated by the host cells.
  • other regulatory elements can also be required or desired for efficient expression of an antibody or antigen-binding fragment. These elements typically include an ATG initiation codon and adjacent ribosome binding site or other sequences.
  • the efficiency of expression can be enhanced by the inclusion of enhancers appropriate to the cell system in use (see, e.g., Scharf et al., Results Probl. Cell Differ. 20: 125, 1994; and Bittner et al., Meth. Enzymol., 153: 516, 1987) .
  • the SV40 enhancer or CMV enhancer can be used to increase expression in mammalian host cells.
  • the host cells for harboring and expressing the antibody chains can be either prokaryotic or eukaryotic.
  • E. coli is one prokaryotic host useful for cloning and expressing the polynucleotides of the present disclosure.
  • Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis, and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species.
  • bacilli such as Bacillus subtilis
  • enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas species.
  • expression vectors which typically contain expression control sequences compatible with the host cell (e.g., an origin of replication) .
  • any number of a variety of well-known promoters will be present, such as the lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a promoter system from phage lambda.
  • the promoters typically control expression, optionally with an operator sequence, and have ribosome binding site sequences and the like, for initiating and completing transcription and translation.
  • Other microbes, such as yeast can also be employed to express anti-OX40 polypeptides. Insect cells in combination with baculovirus vectors can also be used.
  • mammalian host cells are used to express and produce the antibody polypeptides of the present disclosure.
  • they can be either a hybridoma cell line expressing endogenous immunoglobulin genes or a mammalian cell line harboring an exogenous expression vector.
  • These include any normal mortal or normal or abnormal immortal animal or human cell.
  • suitable host cell lines capable of secreting intact immunoglobulins have been developed, including the CHO cell lines, various COS cell lines, HEK 293 cells, myeloma cell lines, transformed B-cells and hybridomas.
  • Expression vectors for mammalian host cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89: 49-68, 1986) , and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences.
  • expression control sequences such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89: 49-68, 1986)
  • necessary processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences.
  • These expression vectors usually contain promoters derived from mammalian genes or from mammalian viruses.
  • Suitable promoters can be constitutive, cell type-specific, stage-specific, and/or modulatable or regulatable.
  • Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIII promoter, the constitutive MPSV promoter, the tetracycline-inducible CMV promoter (such as the human immediate-early CMV promoter) , the constitutive CMV promoter, and promoter-enhancer combinations known in the art.
  • a subject described herein is administered an anti-cancer agent.
  • anti-cancer agent refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents, including cellular therapies.
  • the anti-PD-1 antibodies and antigen-binding fragments of the present disclosure are used in combination with one or more anti-cancer agents.
  • a subject described herein is administered an anti-PD-1 antibody and further administered an anti-cancer agent described herein.
  • the anti-PD-1 antibodies of the present disclosure are used in combination with one or more chemotherapeutic agents or drugs (e.g., one, two or three chemotherapeutic agents or drugs) .
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure and one or more chemotherapeutic drugs (e.g., one, two or three chemotherapeutic drugs) .
  • Classes of chemotherapeutic agents that can be used include, but are not limited to: microtubule inhibitors, e.g., taxanes (paclitaxel, docetaxel) , and vinca alkaloids (vincristine, vinblastine, vinorelbine) ; antimetabolites (5-fluorouracil, capecitabine, gemcitabine) , and antifolates (methotrexate, pemetrexed) ; kinase inhibitors (crizotinib, erlotinib, sunitinib) ; topoisomerase inhibitors (deruxtecan, topotecan, irinotecan, anthracyclines, etoposide) ; cell-cycle independent drugs, e.g., platinum compounds and analogues (oxaliplatin) , triazenes, alkylating agents (cyclophosphamide) , spindle poison plant alkaloids (doxorubicin) ,
  • SOC Current standard of care treatments for certain cancers, in the early-line setting include chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan used in combination or sequentially, with option for monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (e.g., bevacizumab, ziv-aflibercept) or its receptors (e.g., ramucirumab) , and in patients with Ras wild type tumors, monoclonal antibodies targeting the epidermal growth factor (EGF) receptor (e.g., cetuximab, panitumumab) .
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • Treatment options for heavily pre-treated patients beyond the second-line setting are especially limited and associated toxicities can be severe.
  • the chemotherapeutic agent is selected from one or more of the following: paclitaxel or a paclitaxel agent; (e.g., ) , docetaxel; carboplatin; topotecan; deruxtecan; cisplatin; irinotecan, doxorubicin, lenalidomide, 5-azacytidine, ifosfamide, oxaliplatin, pemetrexed disodium, cyclophosphamide, etoposide, decitabine, fludarabine, vincristine, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, and pemetrexed disodium.
  • paclitaxel or a paclitaxel agent e.g., ) , docetaxel
  • carboplatin topotecan
  • deruxtecan cisplatin
  • irinotecan dox
  • the chemotherapeutic drug is a platinum chemotherapy.
  • the chemotherapeutic drug is cisplatin.
  • the chemotherapeutic drug is carboplatin. In some embodiments, it is in physician’s discretion whether to administer cisplatin or carboplatin.
  • the chemotherapeutic drug is 5-fluorouracil.
  • the chemotherapeutic drug is paclitaxel.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure, anti-LAG3 antibody of the present disclosure, cisplatin and 5-fuorouracil.
  • the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure, anti-LAG3 antibody of the present disclosure, cisplatin and paclitaxel.
  • the methods described herein comprise administration of 5-fluorouracil five times every cycle, wherein each cycle is three weeks, on Days 1-5 of each cycle, e.g., for at least 4 cycles.
  • the amounts of the antibodies disclosed herein and the one or chemotherapy drugs, as well as their relative timings of administration be determined by the individual needs of the patient to be treated, administration route, severity of disease or illness, dosing schedule, as well as evaluation and judgment of the designated doctor.
  • the anti-LAG3 antibody in cycle 2 and subsequent cycles (if tolerated) , is infused over 30 (+/-5) minutes, then anti-PD-1 antibody is infused over 30 (+/-5) minutes, followed by administration of cisplatin and/or 5-FU.
  • anti-PD-1 antibody such as an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO
  • cisplatin is administered IV at 60 to 80 mg/m 2 (and optionally infused over 6 to 8 hours) .
  • paclitaxel is administered IV at 175 mg/m 2 .
  • the anti-LAG3 antibody is infused over 60 (+/-5) minutes, then anti-PD-1 antibody is infused over 60 (+/-5) minutes, followed by administration of cisplatin and/or paclitaxel.
  • the anti-LAG3 antibody in cycle 2 and subsequent cycles (if tolerated) , is infused over 30 (+/-5) minutes, then anti-PD-1 antibody is infused over 30 (+/-5) minutes, followed by administration of cisplatin and/or paclitaxel.
  • the cancer is esophageal squamous cell carcinoma (ESCC) .
  • ESCC esophageal squamous cell carcinoma
  • the cancer is mid-stage esophageal cancer (e.g., ESCC) .
  • the cancer is late-stage esophageal cancer (e.g., ESCC) .
  • the cancer is locally advanced esophageal cancer (e.g., ESCC) .
  • the cancer is advanced stage esophageal cancer (e.g., ESCC) .
  • the esophageal cancer e.g., ESCC
  • the esophageal cancer is unresectable.
  • the esophageal cancer e.g., ESCC
  • metastatic is metastatic.
  • the esophageal cancer (e.g., ESCC) is stage IV cancer. In some embodiments, the esophageal cancer (e.g., ESCC) is stage IVa cancer. In some embodiments, the esophageal cancer (e.g., ESCC) is stage IVb cancer.
  • the esophageal cancer (e.g., ESCC) has not undergone prior treatment.
  • the esophageal cancer (e.g., ESCC) is unresectable locally advanced or metastatic and has not received any prior line therapy.
  • the esophageal cancer (e.g., ESCC) is metastatic and has not received prior chemotherapy (e.g., platinum-based) or immunotherapy.
  • the human patient has received at least one prior line chemotherapy (e.g., platinum-based systemic anticancer therapy) .
  • the human patient has received at least one prior line chemotherapy (e.g., platinum-based systemic anticancer therapy) for unresectable locally advanced and/or metastatic ESCC.
  • the esophageal cancer is chemotherapy-resistant. In some embodiments, the esophageal cancer has progressed after prior chemotherapy.
  • the esophageal cancer (e.g., ESCC) is characterized by one or more of liver, lung, lymph node, bone, or adrenal gland metastasis.
  • the cancer is characterized by liver metastasis.
  • the cancer is characterized by lung metastasis.
  • the cancer is characterized by lymph node metastasis.
  • the cancer is characterized by bone metastasis.
  • the cancer is characterized by adrenal gland metastasis.
  • the esophageal cancer (e.g., ESCC) is assessed for expression of immune-mediated biomarkers that are related to response or clinical benefit of the anti-PD-1 antibody, such as tislelizumab, e.g., using tumor biopsy.
  • the biomarker can be, without limitation, PD-L1, TMB, GEP and MSI.
  • Biomarkers expression can be assessed by multiplex immunohistochemistry assay (IHC) .
  • the cancer to be treated can be a cancer that has a detectable expression of PD-L1.
  • the cancer to be treated can be a cancer that has a detectable expression of TMB.
  • the cancer to be treated can be a cancer that has a detectable expression of GEP (such as immune-mediated GEP) .
  • the cancer to be treated can be a cancer that has a detectable expression of MSI.
  • the cells of the cancer comprise high level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the total tumor area. In some embodiments, the cells of the cancer comprise a low level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the total tumor area. In some embodiments, PD-L1 expression has TAP score of equal to or more than 10%. In some embodiments, PD-L1 expression has TAP score of less than 10%.
  • the cells of the cancer have intermediate or high tumor mutational burden, optionally wherein the tumor has more than 5 or between 5 and 20 mutations, more than 20 or between 20 and 50 mutations, or more than 50 mutations.
  • the patient is a mammal. In some embodiments, the mammal is human. In some embodiments, the patient is an adult. In some embodiments, the patient is 18 years of age or over 18 years of age. In some embodiments, the patient is over 40 years of age, over 45 years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age, over 70 years of age, over 75 years of age, or over 80 years of age. In some embodiments, the patient is 65 years or older. In some embodiments, the patient is 60 years or older.
  • the patient is male. In some embodiments, the patient is female.
  • the patient is a current smoker. In some embodiments, the patient is a former smoker. In some embodiments the patient has never smoked or was never a smoker.
  • the subject has (e.g., has been diagnosed with) esophageal cancer. In some embodiments, the subject has any of the cancers described herein. In some embodiments, the subject has mid-stage cancer. In some embodiments, the subject has late-stage cancer. In some embodiments, the subject has (e.g., has been diagnosed with) ESCC. In some embodiments, the subject has (e.g., has been diagnosed with) unresectable locally advanced ESCC. In some embodiments, the subject has (e.g., has been diagnosed) with stage IV ESCC. In some embodiments, the subject has (e.g., has been diagnosed) with stage IVb ESCC.
  • the subject has (e.g., has been diagnosed with) metastatic cancer.
  • the subject has one or more of liver, lung, lymph node, bone, and/or adrenal gland metastasis.
  • the subject has liver, lung or lymph node metastasis.
  • the subject has liver metastasis.
  • the subject has lung metastasis.
  • the subject has lymph node metastasis.
  • the subject has bone metastasis.
  • the subject has adrenal gland metastasis.
  • the subject has 1, 2, 3, or more metastatic sites.
  • the subject has 1 or more metastatic sites.
  • the subject has 2 or more metastatic sites.
  • the subject has 3 or more metastatic sites.
  • the subject does not have brain metastasis. In other embodiments, the subject has brain metastasis.
  • the subject has been diagnosed using histological markers. In some embodiments, the subject has been diagnosed using cytological markers. In some embodiments, the subject has been diagnosed using histological and cytological markers. In some embodiments, the subject has been diagnosed using a biopsy.
  • the subject has received prior chemotherapy treatment (e.g., for the cancer being treated) .
  • the subject has received prior immunotherapy treatment (e.g., for the cancer being treated) .
  • the disclosure relates to a method of treating esophageal cancer (such as ESCC) in a subject (e.g., a human) , the method comprising administering to the subject effective amounts of an anti-LAG3 antibody, an anti-PD-1 antibody and one or more chemotherapeutic drug.
  • the one or more chemotherapeutic drugs is cisplatin and 5-FU.
  • the one or more chemotherapeutic drugs is cisplatin and paclitaxel.
  • the disclosure relates to a method of treating esophageal cancer (such as ESCC) in a subject (e.g., a human) , the method comprising administering to the subject an effective amounts of an anti-LAG3 antibody, an anti-PD-1 antibody, cisplatin and 5-FU.
  • the disclosure relates to a method of treating esophageal cancer (such as ESCC) in a subject (e.g., a human) , the method comprising administering to the subject an effective amounts of an anti-LAG3 antibody, an anti-PD-1 antibody, cisplatin and paclitaxel.
  • the subject is treated in accordance with a treatment regimen (such as dosing, frequency and duration of the treatment) described herein.
  • the methods described herein are for treating locally advanced unresectable ESCC.
  • the methods described herein are for treating metastatic ESCC.
  • the response to treatment is measured by overall survival, progression-free or event-free survival, overall response or objective response rate, complete response, partial response, and/or duration of response. In some embodiments, the response to treatment is measured by tumor volume.
  • the antibodies and one or more chemotherapeutic drugs disclosed herein may be administered parenterally.
  • parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the anti-LAG3, anti-PD-1 antibody and chemotherapeutic drug (s) may be administered by different routes.
  • the antibodies are administered intravenously, and the one or more chemotherapeutic drugs are also administered intravenously.
  • esophageal cancer e.g., ESCC
  • a method of treating esophageal cancer comprising administering to the subject (i) a therapeutically effective amount of an anti-LAG3 antibody, wherein the LAG3 antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO: 37 and SEQ ID NO: 38, respectively; (ii) a therapeutically effective amount of an anti-PD-1 antibody, wherein the PD-1 antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO: 7 and SEQ ID NO: 8, respectively, and (iii) a therapeutically effective amount of one or more chemotherapeutic drugs.
  • an anti-LAG3 antibody wherein the LAG3 antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO: 37 and SEQ ID NO: 38, respectively
  • the ESCC is unresectable and locally advanced. In some embodiments, the ESCC is metastatic. In some embodiments, the one or more chemotherapeutic drugs are (i) cisplatin and 5-FU, or (ii) cisplatin and paclitaxel.
  • a subject is administered the described combination therapy in accordance with the dosage and regime of administration described in the examples provided herein.
  • Embodiments of the present disclosure also include the agents and combinations described herein (i) for use in, (ii) for use as a medicament or composition for, or (iii) for use in the preparation of a medicament for:
  • a. therapy e.g., of the human body
  • compositions including pharmaceutical formulations, comprising an anti-LAG3 antibody or an antigen-binding fragment thereof described herein
  • compositions, including pharmaceutical formulations, comprising an anti-PD-1 antibody or an antigen-binding fragment thereof described herein are also provided herein.
  • compositions of any antibody as described herein are prepared by mixing such antibody or antigen-binding fragment 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,
  • the surfactant is a polysorbate.
  • exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP) , for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 ( Baxter International, Inc. ) .
  • sHASEGP soluble neutral-active hyaluronidase glycoproteins
  • rHuPH20 Baxter International, Inc.
  • Certain exemplary sHASEGPs and methods of use, including rHuPH20 are described in US Patent Nos. US 7,871,607 and 2006/0104968.
  • a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
  • Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958.
  • Aqueous antibody formulations include those described in US Patent No. 6,171,586 and WO2006/044908, the latter formulations including a histidine-acetate buffer.
  • the formulations include a histidine-citric acid buffer.
  • Sustained-release preparations can 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, e.g., films, or microcapsules.
  • the formulations to be used for in vivo administration are generally sterile. Sterility can be readily accomplished, e.g., by filtration through sterile filtration membranes.
  • the pharmaceutical composition or formulation comprises a formulation buffer comprising histidine, acetate, citrate, succinate, phosphate, mixture of histidine and acetic acid, mixture of histidine and citric acid, salt or hydrate thereof, or any combination of them.
  • the formulation buffer comprises a histidine buffer that comprises histidine, histidine hydrochloride, L-histidine, L-histidine hydrochloride, L-histidine hydrochloride hydrate, L-histidine hydrochloride monohydrate, or a combination thereof.
  • the histidine buffer comprises L-histidine/L-histidine hydrochloride monohydrate buffer (His/His HCl) .
  • the histidine buffer comprises histidine/L-histidine hydrochloride monohydrate buffer and citric acid monohydrate.
  • concentration of the histidine buffer e.g., L-histidine/L-histidine hydrochloride monohydrate
  • the concentration of the histidine buffer is between about 5 mM to about 30 mM.
  • the concentration of the histidine buffer is between about 5 mM to about 10 mM, between about 5 mM to about 15 mM, between about 5 mM to about 20 mM, between about 10 mM to about 15 mM, between about 10 mM to about 20 mM, between about 10 mM to about 25 mM, between about 15 mM to about 20 mM, between about 15 mM to about 25 mM, between about 15 mM to about 30 mM, between about 20 mM to about 25 mM, or between about 25 mM to about 30 mM.
  • the histidine buffer e.g., L-histidine/L-histidine hydrochloride monohydrate
  • the concentration of the histidine buffer is about 5 mM or more, about 10 mM or more, about 15 mM or more, about 20 mM or more, about 25 mM or more, about 30 mM or more. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine/L-histidine hydrochloride monohydrate) is 10mM.
  • the concentration of the histidine is about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM.
  • the concentration of the L-histidine hydrochloride monohydrate is about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM.
  • the formulation comprises histidine at a concentration of about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM, and L-histidine hydrochloride monohydrate at a concentration of about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM.
  • the formulation buffer is a mixture of histidine, L-histidine hydrochloride monohydrate, citric acid monohydrate, and sodium citrate; wherein the formulation comprises histidine at a concentration of about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM, and L-histidine hydrochloride monohydrate at a concentration of about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM, wherein the citric acid monohydrate is at a concentration of about 1-5 mM, preferably 2 mM, and sodium citrate is present at a concentration of 15-30 mM, preferably about 23 mM.
  • the pharmaceutical composition or formulation comprises a stabilizer.
  • the stabilizer comprises trehalose, sucrose, sorbitol, mannitol, L-arginine hydrochloride, maltose, dextran, (2-hydroxypropyl) -b-cyclodextrin, sodium chloride, magnesium chloride, calcium chloride, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or a combination thereof.
  • the stabilizer comprises trehalose, sucrose, L-arginine hydrochloride, sodium chloride, or a combination thereof.
  • the stabilizer is trehalose.
  • the trehalose is a-trehalose dihydrate.
  • the concentration of the stabilizer is between about 50 mM to about 300 mM. In some embodiments, the concentration of the stabilizer is between about 50 mM to about 100 mM, between about 50 mM to about 150 mM, between about 50 mM to about 200 mM, between about 100 mM to about 150 mM, between about 100 mM to about 200 mM, between about 100 mM to about 250 mM, between about 150 mM to about 200 mM, between about 150 mM to about 250 mM, or between about 150 mM to about 300 mM.
  • the concentration of the stabilizer is about 50 mM or more, about 60 mM or more, about 70 mM or more, about 80 mM or more, about 90 mM or more, about 100 mM or more, about 110 mM or more, about 120 mM or more, about 130 mM or more, about 140 mM or more, about 150 mM or more, about 160 mM or more, about 170 mM or more, about 180 mM or more, about 190 mM or more, about 200 mM or more, about 210 mM or more, about 220 mM or more, about 230 mM or more, about 240 mM or more, about 250 mM or more, about 260 mM or more, about 270 mM or more, about 280 mM or more, about 290 mM or more, or about 300 mM or more. In some embodiments, the concentration of the stabilizer is about 190 mM.
  • the pharmaceutical composition or formulation comprises a non-ionic surfactant.
  • the non-ionic surfactant comprises polysorbate 80 (PS80) , polysorbate 20 (PS20) , poloxamer188 (P188) , or a combination thereof.
  • the non-ionic surfactant is PS20.
  • the concentration of the non-ionic surfactant is between about 0.01%to about 1%.
  • the concentration of the non-ionic surfactant is between about 0.01%to about 0.03%, between about 0.01%to about 0.06%, between about 0.01%to about 0.09%, between about 0.03%to about 0.06%, between about 0.03%to about 0.09%, between about 0.03%to about 0.2%, between about 0.06%to about 0.09%, between about 0.06%to about 0.2%, between about 0.06%to about 0.5%, between about 0.09%to about 0.2%, between about 0.09%to about 0.5%, between about 0.09%to about 0.8%, between about 0.2%to about 0.5%, between about 0.2%to about 0.8%, between about 0.2%to about 1%, between about 0.5%to about 0.8%, between about 0.5%to about 1%, or between about 0.8%to about 1%.
  • the concentration of the non-ionic surfactant is about 0.01%or more, is about 0.02%or more, is about 0.03%or more, is about 0.04%or more, is about 0.05%or more, is about 0.06%or more, is about 0.07%or more, is about 0.08%or more, is about 0.09%or more, is about 0.1%or more, is about 0.2%or more, is about 0.3%or more, is about 0.4%or more, is about 0.5%or more, is about 0.6%or more, is about 0.7%or more, is about 0.8%or more, is about 0.9%or more, or is about 1%or more. In some embodiments, the concentration of the non-ionic surfactant is 0.2%.
  • the pharmaceutical composition or formulation comprises between about 1 mg/ml to about 10 mg/ml of the multi-specific antibody or antigen-binding fragment as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises between about 1 mg/ml to about 2 mg/ml, between about 1 mg/ml to about 3 mg/ml, between about 1 mg/ml to about 4 mg/ml, between about 2 mg/ml to about 3 mg/ml, between about 2 mg/ml to about 4 mg/ml, between about 2 mg/ml to about 5 mg/ml, between about 3 mg/ml to about 4 mg/ml, between about 3 mg/ml to about 5 mg/ml, between about 3 mg/ml to about 6 mg/ml, between about 4 mg/ml to about 5 mg/ml, between about 4 mg/ml to about 6 mg/ml, between about 4 mg/ml to about 7 mg/ml, between about 5 mg/ml to about 6 mg/ml, between about 5 mg/m/ml,
  • the pharmaceutical composition or formulation comprises about 1 mg/ml or more, 2 mg/ml or more, 3 mg/ml or more, 4 mg/ml or more, 5 mg/ml or more, 6 mg/ml or more, 7 mg/ml or more, 8 mg/ml or more, 9 mg/ml or more, or 10 mg/ml or more of the multi-specific antibody or antigen-binding fragment as disclosed herein.
  • the pharmaceutical composition or formulation comprises 10 mg/ml of the antibody (e.g., PD-1 antibody or tislelizumab) as disclosed herein.
  • the pharmaceutical composition or formulation has a pH of between about 4.5 to about 7.5. In some embodiments, the pharmaceutical composition or formulation has a pH of between about 4.5 to about 5.0, between about 4.5 to about 5.5, between about 4.5 to about 6.0, between about 5.0 to about 5.5, between about 5.0 to about 6.0, between about 5.0 to about 6.5, between about 5.5 to about 6.0, between about 5.5 to about 6.5, between about 5.5 to about 7.0, between about 6.0 to about 6.5, between about 6.0 to about 7.0, between about 6.0 to about 7.5, between about 6.5 to about 7.0, between about 6.5 to about 7.5, or between about 7.0 to about 7.5.
  • the pharmaceutical composition or formulation has a pH of about 4.5 or more, about 5.0 or more, about 5.5 or more, about 6.0 or more, about 6.5 or more, about 7.0 or more, or about 7.5 or more. In some embodiments, the pharmaceutical composition or formulation has a pH of 6.5.
  • the antibody e.g. PD-1 antibody or tislelizumab
  • a pharmaceutical composition comprising a histidine buffer, a surfactant and a stabilizer.
  • the surfactant is a polysorbate.
  • the stabilizer is trehalose.
  • the PD-1 antibody e.g. tislelizumab
  • a pharmaceutical composition comprising citric acid monohydrate, histidine, L-histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, and trehalose.
  • pharmaceutically acceptable refers to a molecule or composition that, when administered to a recipient, is not deleterious to the recipient thereof, or that any deleterious effect is outweighed by a benefit to the recipient thereof.
  • materials which may serve as pharmaceutically acceptable carriers comprise: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’
  • a “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion) .
  • compositions disclosed herein can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusion solutions) , dispersions or suspensions, liposomes, and suppositories.
  • a suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusion solutions.
  • One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular) .
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • the antibody is administered by way of a syringe infusion system.
  • kits comprising ati-LAG3 and anti-PD-1 antibodies or antigen-binding fragments thereof, and instructions for use and/or administration.
  • a kit comprises at least one anti-LAG3 antibody or antigen-binding fragment thereof, at least one anti-PD-1 antibody or antigen-binding fragment thereof, at least one chemotherapeutic agent, and a pharmaceutically acceptable carrier, and instructions for use and/or administration.
  • kits for use in various methods disclosed herein can comprise a description of administering of one or more pharmaceutical compositions described herein to a subject to achieve an intended activity in a subject.
  • a kit may further comprise a description of selecting a human suitable for treatment based on identifying whether the human is in need of treatment.
  • Instructions generally include information as to dosage, dosing schedule, and route of administration for an intended treatment.
  • Containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • Instructions supplied in kits of the disclosure are typically written instructions on a label or package insert.
  • a label or package insert may indicate that one or more pharmaceutical compositions described herein are used for treating, delaying the onset, and/or alleviating a disease, disorder or condition in a subject.
  • kits provided herein are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Also contemplated are packages for use in combination with a specific device, such as an infusion device.
  • a kit may have a sterile access port (for example, a container may be an intravenous solution bag or a vial having a stopper pierce able by a hypodermic injection needle) .
  • a container may also have a sterile access port.
  • Kits can include additional components such as buffers and interpretive information.
  • a kit can comprise a container and a label or one or more package inserts on or associated with a container.
  • the disclosure provides articles of manufacture comprising contents of kits described above.
  • the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “comprising essentially of” can mean within one or more than one standard deviation per the practice in the art. “About” or “comprising essentially of” can mean a range of up to 10% (i.e., ⁇ 10%) .
  • “about” can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.001%greater or less than the stated value.
  • about 5 mg can include any amount between 4.5 mg and 5.5 mg.
  • the terms can mean up to an order of magnitude or up to 5-fold of a value.
  • anti-cancer agent refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.
  • administering when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, means contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administration and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human. Treating any disease or disorder refer in one aspect, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another aspect, “treat, ” “treating, ” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat, ” “treating, ” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat, ” “treating, ” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • subject in the context of the present disclosure is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein) .
  • affinity refers to the strength of interaction between antibody and antigen. Within the antigen, the variable region of the antibody “arm” interacts through non-covalent forces with the antigen at numerous sites; the more interactions, the stronger the affinity.
  • antibody refers to a polypeptide of the immunoglobulin family that can bind a corresponding antigen non-covalently, reversibly, and in a specific manner.
  • a naturally occurring IgG antibody is a tetramer comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs) , interspersed with regions that are more conserved, termed framework regions (FR) .
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • antibody includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and anti-idiotypic (anti-Id) antibodies.
  • the antibodies can be of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA and IgY) , or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) .
  • the term “monoclonal antibody” or “mAb” or “Mab” herein means a population of substantially homogeneous antibodies, i.e., the antibody molecules comprised in the population are identical in amino acid sequence except for possible naturally occurring mutations that can be present in minor amounts.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their complementarity determining regions (CDRs) , which are often specific for different epitopes.
  • CDRs complementarity determining regions
  • 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.
  • Monoclonal antibodies can be obtained by methods known to those skilled in the art. See, for example Kohler et al., Nature 1975 256: 495-497; U.S. Pat. No. 4,376,110; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY 1992; Harlow et al., ANTIBODIES: A LABORATORY MANUAL, Cold spring Harbor Laboratory 1988; and Colligan et al., CURRENT PROTOCOLS IN IMMUNOLOGY 1993.
  • the antibodies disclosed herein can be of any immunoglobulin class including IgG, IgM, IgD, IgE, IgA, and any subclass thereof such as IgG1, IgG2, IgG3, IgG4.
  • a hybridoma producing a monoclonal antibody can be cultivated in vitro or in vivo.
  • High titers of monoclonal antibodies can be obtained in in vivo production where cells from the individual hybridomas are injected intraperitoneally into mice, such as pristine-primed Balb/c mice to produce ascites fluid containing high concentrations of the desired antibodies.
  • Monoclonal antibodies of isotype IgM or IgG can be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light chain” (about 25 kDa) and one “heavy chain” (about 50-70 kDa) .
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy-terminal portion of the heavy chain can define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as ⁇ , ⁇ , ⁇ , ⁇ , or ⁇ , and define the antibody's isotypes as IgA, IgD, IgE, IgG, and IgM, respectively.
  • the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids.
  • variable regions of each light/heavy chain (VL/VH) pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, the same.
  • variable domains of both the heavy and light chains comprise three hypervariable regions, also called “complementarity determining regions (CDRs) , ” which are located between relatively conserved framework regions (FR) .
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chain variable domains comprise FR-1 (or FR1) , CDR-1 (or CDR1) , FR-2 (FR2) , CDR-2 (CDR2) , FR-3 (or FR3) , CDR-3 (CDR3) , and FR-4 (or FR4) .
  • the positions of the CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, and AbM (see, e.g., Johnson et al., Nucleic Acids Res., 29: 205-206 (2001) ; Chothia and Lesk, J. Mol. Biol., 196: 901-917 (1987) ; Chothia et al., Nature, 342: 877-883 (1989) ; Chothia et al., J. Mol. Biol., 227: 799-817 (1992) ; Al-Lazikani et al., J. Mol. Biol., 273: 927-748 (1997) ) .
  • antigen combining sites are also described in the following: Ruiz et al., Nucleic Acids Res., 28: 219-221 (2000) ; and Lefranc, M. P., Nucleic Acids Res., 29: 207-209 (2001) ; MacCallum et al., J. Mol. Biol., 262: 732-745 (1996) ; and Martin et al., Proc. Natl. Acad. Sci. USA, 86: 9268-9272 (1989) ; Martin et al., Methods Enzymol., 203: 121-153 (1991) ; and Rees et al., In Sternberg M. J. E. (ed.
  • the CDRs correspond to the amino acid residues that are part of a Kabat CDR, a Chothia CDR, or both.
  • the CDRs correspond to amino acid residues 26-35 (HC CDR1) , 50-65 (HC CDR2) , and 95- 102 (HC CDR3) in a VH, e.g., a mammalian VH, e.g., a human VH; and amino acid residues 24-34 (LC CDR1) , 50-56 (LC CDR2) , and 89-97 (LC CDR3) in a VL, e.g., a mammalian VL, e.g., a human VL.
  • hypervariable region means the amino acid residues of an antibody that are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from a “CDR” (i.e., VL-CDR1, VL-CDR2 and VL-CDR3 in the light chain variable region and VH-CDR1, VH-CDR2 and VH-CDR3 in the heavy chain variable domain) .
  • CDR i.e., VL-CDR1, VL-CDR2 and VL-CDR3 in the light chain variable region and VH-CDR1, VH-CDR2 and VH-CDR3 in the heavy chain variable domain
  • CDR CDR
  • sequences of Proteins of Immunological Interest 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.
  • CDR regions of an antibody by sequence see also Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917 (defining the CDR regions of an antibody by structure) .
  • an “antigen-binding fragment” means antigen-binding fragments of antibodies, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g., fragments that retain one or more CDR regions.
  • antigen-binding fragments include, but not limited to, Fab, Fab', F (ab') 2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., single chain Fv (ScFv) ; nanobodies and multispecific antibodies formed from antibody fragments.
  • An antibody “specifically binds” to a target protein, meaning the antibody exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity.
  • An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives.
  • Antibodies or antigen-binding fragments thereof, useful in the current disclosure will bind to the target protein with an affinity that is at least two fold greater, preferably at least 10-times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.
  • An antibody herein is said to bind specifically to a polypeptide comprising a given amino acid sequence, if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.
  • human antibody herein means an antibody that comprises human immunoglobulin protein sequences only.
  • mouse antibody or “rat antibody” mean an antibody that comprises only mouse or rat immunoglobulin protein sequences, respectively.
  • humanized antibody means forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin.
  • the 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 and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc) , typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the prefix “hum, ” “hu, ” “Hu, ” or “h” is added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies.
  • the humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions can be included to increase affinity, increase stability of the humanized antibody, remove a post-translational modification or for other reasons.
  • corresponding human germline sequence refers to the nucleic acid sequence encoding a human variable region amino acid sequence or subsequence that shares the highest determined amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other known variable region amino acid sequences encoded by human germline immunoglobulin variable region sequences.
  • the corresponding human germline sequence can also refer to the human variable region amino acid sequence or subsequence with the highest amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other evaluated variable region amino acid sequences.
  • the corresponding human germline sequence can be framework regions only, complementarity determining regions only, framework and complementary determining regions, a variable segment (as defined above) , or other combinations of sequences or subsequences that comprise a variable region. Sequence identity can be determined using the methods described herein, for example, aligning two sequences using BLAST, ALIGN, or another alignment algorithm known in the art.
  • the corresponding human germline nucleic acid or amino acid sequence can have at least about 90%, 91, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity with the reference variable region nucleic acid or amino acid sequence.
  • Equilibrium dissociation constant refers to the dissociation rate constant (kd, time -1 ) divided by the association rate constant (ka, time -1 , M -l ) . Equilibrium dissociation constants can be measured using any known method in the art.
  • the antibodies of the present disclosure generally will have an equilibrium dissociation constant of less than about 10 -7 or 10 -8 M, for example, less than about 10 -9 M or 10 -10 M, in some aspects, less than about 10 -11 M, 10 -12 M or 10 -13 M.
  • cancer or “tumor” herein has the broadest meaning as understood in the art and refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of the present disclosure, the cancer is not limited to certain type or location.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner. Such administration also encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids can be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • conservative substitution means substitution of the original amino acid by a new amino acid that does not substantially alter the chemical, physical and/or functional properties of the antibody or fragment. Specifically, common conservative substitutions of amino acids are well known in the art.
  • HSPs high scoring sequence pairs
  • the word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always ⁇ 0) . For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • W word length
  • E expectation
  • B B- 50
  • E expectation
  • the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90: 5873-5787, 1993) .
  • One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N) ) , which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
  • P(N) the smallest sum probability
  • a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.
  • the percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci. 4: 11-17, (1988) , which has been incorporated into the ALIGN program (version 2.0) , using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch, J. Mol. Biol. 48: 444-453, (1970) , algorithm which has been incorporated into the GAP program in the GCG software package using either a BLOSUM62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • nucleic acid is used herein interchangeably with the term “polynucleotide” and refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single-or double-stranded form.
  • the term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides.
  • Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs) .
  • compositions e.g., pharmaceutically acceptable compositions, which include an anti-PD1 antibody and/or anti-LAG3 antibody described herein, formulated together with at least one pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion) .
  • compositions disclosed herein can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusion solutions) , dispersions or suspensions, liposomes, and suppositories.
  • liquid solutions e.g., injectable and infusion solutions
  • dispersions or suspensions e.g., liposomes, and suppositories.
  • a suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusion solutions.
  • One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular) .
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • This example describes a Phase 2, Randomized, Active-Controlled, Open-Label Study of the Efficacy and Safety of an anti-LAG3 antibody (LBL-007) in Combination With an anti-PD1 antibody (Tislelizumab) Plus Chemotherapy as First-Line Treatment in Patients With Unresectable Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma.
  • ORR is defined as the proportion of patients whose best overall response (BOR) is complete response (CR) or partial response (PR) as assessed by the investigator per RECIST v1.1.
  • PFS Progression-free Survival
  • Duration of Response defined as the time from the first determination of an overall response until the first documentation of progression assessed by the investigator per RECIST v1.1 or death, whichever comes first.
  • DCR Disease Control Rate
  • OS Overall Survival
  • biomarkers include, but are not limited to, programmed cell death protein-ligand 1 (PD ⁇ L1) expression, (lymphocyte activation gene-3) LAG-3 expression, LAG-3 ligands expression, gene expression profile (GEP) , tumor mutational burden (TMB) /microsatellite instability (MSI) /DNA mutation analysis in tumor tissue, concentrations of cytokine/chemokine and soluble proteins in plasma or serum, and blood tumor mutational burden (bTMB) /circulating tumor DNA (ctDNA) /DNA. mutation profile in peripheral blood.
  • PD ⁇ L1 programmed cell death protein-ligand 1
  • MSI microsatellite instability
  • bTMB blood tumor mutational burden
  • ctDNA circulating tumor DNA
  • the study was designed as a randomized, active-controlled, open-label, Phase 2 study to compare the efficacy of treatment with LBL-007 in combination with tislelizumab plus chemotherapy versus tislelizumab plus chemotherapy when given as the first-line treatment in patients with unresectable, locally advanced or metastatic ESCC (i.e., Stage IV disease at the initial diagnosis of ESCC, or patients who have unresectable, recurrent, locally advanced or metastatic disease with at least a 6-month treatment-free interval, after previous curative intended treatment including surgery with/without neoadjuvant or adjuvant treatment, or definitive chemoradiation) .
  • Staging criteria for this study are defined by the American Joint Committee on Cancer (AJCC) , 8th Edition.
  • ⁇ LBL-007 is administered at a dose of 600 mg intravenously once every 3 weeks, on Day 1 of every 21-day cycle.
  • ⁇ Tislelizumab is administered at a dose of 200 mg intravenously once every 3 weeks, on Day 1 of every 21-day cycle.
  • ⁇ Tislelizumab is administered at a dose of 200 mg intravenously once every 3 weeks, on Day 1 of every 21-day cycle.
  • a 5-FU 750 to 800 mg/m 2 via intravenously continuous infusion over 24 hours daily on Day 1 to Day 5 once every 3 weeks is administered for patients who were selected to with 5-FU treatment.
  • Cisplatin therapy may be stopped after 6 cycles, per site or investigator preference or standard practice. If platinum treatment is stopped, 5-FU or paclitaxel may continue at the regular schedule.
  • the selection of chemotherapy regimen is determined by the investigator according to local standard practice or clinical practice before randomization.
  • the study treatments are to start within 2 days after randomization, and treatment is to continue until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met (whichever occurs first) .
  • Treatment with cisplatin may be stopped after 6 cycles, as per site or investigator preference or standard practice. If cisplatin treatment is stopped, the 5-FU or paclitaxel may continue at the regular schedule if appropriate; treatment with LBL-007 and tislelizumab will continue until a treatment discontinuation criterion is met.
  • LBL-007 600 mg is administered followed by tislelizumab 200 mg on Day 1 of each 21-day cycle (once every 3 weeks) .
  • All drugs are administered by intravenous infusion through an intravenous line containing a sterile, nonpyrogenic, low-protein-binding 0.2-or 0.22-micron in-line or add-on filter.
  • a volumetric pump is recommended to control the infusion speed and to avoid potential infusion reactions associated with too rapid administration. The pump may not be needed if the infusion speed is controlled through alternative means.
  • Cisplatin is administered on Day 1, then given once every 3 weeks at a dose of 60 to 80 mg/m 2 by intravenous infusion over 6 to 8 hours (or in doses consistent with treatment guidelines and standards) .
  • 5-FU is administered on Days 1 to 5, given once every 3 weeks at a dose of 750 to 800 mg/m 2 by continuous intravenous infusion over 24 hours. The actual infusion time of 5-FU should be recorded, and a total infusion time of 120 ⁇ 3 hours is acceptable.
  • the initial treatment of cisplatin in combination with 5-FU is administered within 2 business days of randomization. Alternate dose and dosing schedules are allowed according to treatment guidelines and standards.
  • the first doses of cisplatin and 5-FU are dependent upon the patient’s baseline body weight. Subsequent doses must be recalculated if the change of body weight (increase or decrease) from baseline ⁇ 10%. If the dose is recalculated because of a ⁇ 10%change in body weight from baseline, this body weight will then be used as the new baseline to calculate the platinum and 5-FU dose in subsequent cycles.
  • Premedication is recommended before infusion of cisplatin.
  • the premedication regimen should be administered as close to treatment as possible.
  • Premedication may consist of hydration with 1 to 2 liters of fluid infused 8 to 12 hours before dosing.
  • the use of diuretics for fluid maintenance is allowable.
  • Cisplatin is administered on Day 1, then given every 21 days at a dose of 60 to 80 mg/m2 by intravenous infusion over 6 to 8 hours (or in doses consistent with treatment guidelines and standards) .
  • Paclitaxel is administered on Day 1, then given once every 3 weeks at a dose of 175 mg/m2 by intravenous infusion over 3 hours.
  • the initial treatment of cisplatin in combination with paclitaxel is administered within 2 business days of randomization. Alternate dose and dosing schedules are allowed according to treatment guidelines and standards) .
  • the first doses of cisplatin and paclitaxel are dependent upon the patient’s baseline body weight. Subsequent doses should be recalculated if the change (increase or decrease) of body weight from baseline ⁇ 10%. If the dose is recalculated because of a ⁇ 10%change in body weight from baseline, this body weight will then be used as the new baseline to calculate the platinum and paclitaxel dose in subsequent cycles.
  • Premedication is recommended before infusion of cisplatin.
  • the premedication regimen should be administered as close to treatment as possible.
  • Premedication may consist of hydration with 1 to 2 liters of fluid infused 8 to 12 hours before dosing.
  • Premedication is recommended before infusion of paclitaxel.
  • the premedication regimen should be administered as close to treatment as possible.
  • Premedication may consist of an oral steroid (such as dexamethasone 8 to 20 mg or equivalent administered 6 to 12 hours orally or 30 to 60 minutes intravenously before paclitaxel) , an antihistamine (H1 antagonist such as diphenhydramine hydrochloride 50 mg intravenously or equivalent, or H2 antagonist such as cimetidine 300 mg intravenously or equivalent) , and an antiemetic (such as ondansetron 8 mg/kg intravenously or equivalent administered 30 to 120 minutes before paclitaxel) .
  • an oral steroid such as dexamethasone 8 to 20 mg or equivalent administered 6 to 12 hours orally or 30 to 60 minutes intravenously before paclitaxel
  • H1 antagonist such as diphenhydramine hydrochloride 50 mg intravenously or equivalent, or H2 antagonist such as cimetidine 300 mg intravenously or equivalent
  • both treatments are to be delayed (i.e., LBL-007 and tislelizumab must both be delayed and, if applicable, restarted at the same time) . Exceptions may be considered.
  • treatment may resume only after the adverse events have returned to baseline or ⁇ Grade 1 severity.
  • Treatment with tislelizumab or LBL-007 + tislelizumab should resume as soon as possible after the adverse events recover to baseline or Grade 1 (whichever is more severe) and ⁇ 12 weeks after the last dose of tislelizumab/LBL-007 + tislelizumab.
  • Treatment with immunotherapy will need to be resynchronized with chemotherapy at the subsequent cycles according to the chemotherapy dose administration date, but the time between 2 consecutive doses of tislelizumab/LBL-007 + tislelizumab should be at least 10 days (Section 5.5.2) .
  • Dose adjustments are allowed for chemotherapy based on nadir blood counts since the preceding chemotherapy administration. Dose level adjustments are relative to that of the preceding administration. A maximum of 2 dose reductions for each chemotherapeutic agent are permitted (Table 3) . Once the dose has been decreased, it should remain reduced for all subsequent administrations or further reduced if necessary.
  • chemotherapy administration may restart as soon as is feasible. All subsequent chemotherapy doses must be rescheduled according to the last chemotherapy dose administration date.
  • the treatment with immunotherapies is recommended to continue as scheduled during the delay of chemotherapy, and to be resynchronized with chemotherapy from subsequent cycles according to chemotherapy administration date.
  • chemotherapy administration can occur during an unscheduled visit and resynchronize with tislelizumab/LBL-007 + tislelizumab at subsequent cycle (s) , if possible.
  • Dosing intervals of subsequent cycles of tislelizumab/LBL-007 + tislelizumab may be shortened or extended as clinically feasible to allow for resynchronization, but the time between 2 consecutive doses of tislelizumab/LBL-007 +tislelizumab should be at least 10 days. If clinically appropriate, treatment components may be delayed up to a maximum of 7 days to allow synchronized administration of all agents and realigned dosing of treatment cycles according to the original schedule. Chemotherapy may be delayed up to 3 weeks to allow sufficient time for recovery. Upon recovery, chemotherapy is recommended to be administered according to the dosing schedule described herein.
  • a repeat course of cisplatin should not be given until the serum creatinine is ⁇ 1.5 mg/100 mL, and/or the blood urea nitrogen (BUN) is ⁇ 25 mg/100 mL.
  • a repeat course should not be given until circulating blood elements are at an acceptable level (platelets ⁇ 100 x 109 /L, white blood cell [WBC] ⁇ 4 x 109/L) .
  • Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.
  • BUN blood urea nitrogen
  • WBC white blood cell
  • G-CSF granulocyte colony stimulating factor
  • paclitaxel For any grade toxicity, paclitaxel must be discontinued if the platelet count does not recover by the next planned treatment cycle.
  • liver function test abnormalities do not recover by the next planned cycle, paclitaxel must be discontinued. All dose reductions for liver function abnormalities are permanent.
  • Patient Inclusion Criteria include:
  • Patient Exclusion Criteria include:
  • Prior systemic therapy for advanced or metastatic ESCC (Note: Patients with prior curative intended neoadjuvant/adjuvant therapy, or definitive chemoradiotherapy are eligible provided the treatment-free interval [TFI: duration from the end-date of last prior systemic therapy or radiotherapy to the date of the diagnosis of disease progression] ⁇ 6 months) (FIG. 2) .
  • FTI duration from the end-date of last prior systemic therapy or radiotherapy to the date of the diagnosis of disease progression] ⁇ 6 months
  • Inactive hepatitis B surface antigen carriers, treated and stable hepatitis B can be enrolled. Patients with detectable hepatitis B surface antigen or detectable HBV DNA should be managed at the discretion of the investigator. (16) 16. Patients with active hepatitis C. Note: Patients with a negative HCV antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV antibody. Patients receiving antivirals at screening should have been treated for > 2 weeks before randomization. (17) A known history of HIV infection.
  • the following medications are restricted: (1) Alcohol or other drugs abuse. (2) Use of potentially hepatotoxic drugs in patients with impaired hepatic function should be carefully monitored. (3) Radiation therapy is not allowed, except for palliative radiation therapy (wherein the therapy is permitted only for pain control of prophylaxis of bone fracture to sites of bone disease present at baseline if the following criteria are met: i) Repeated imaging shows no new sites of bone metastases; ii) The lesion being considered for palliative radiation is not a target lesion per RECIST v1.1; and, iii) The case is discussed with the medical monitor, and he/she agrees that the conditions required to receive palliative radiation are met.
  • palliative radiation or other focally ablative therapy for other nontarget sites of the disease is permitted if clinically indicated per the investigator’s discretion and after consultation with the medical monitor. Whenever possible, these patients should have a tumor assessment of the lesion (s) before receiving the radiation therapy to rule out disease progression. It is not required to withhold study treatments during palliative radiotherapy.
  • Immunosuppressive agents except to treat a treatment-related adverse event
  • Systemic corticosteroids > 10 mg daily (prednisone or equivalent) , except to treat or control an adverse event (per protocol) or for short-term use as prophylactic treatment.
  • CT computed tomography
  • PET positron-emission tomography
  • Other known or suspected sites of disease must be included in the imaging assessments (brain, etc) .
  • CT/MRI of the head is required at baseline. MRI may be used when it is the standard-of-care at a site, regardless of whether or not CT is contraindicated.
  • Treatment is permitted to continue after the initial assessment of progressive disease, provided that the criteria for treatment beyond disease progression are met.
  • LBL-007 and tislelizumab may elicit immune response.
  • Validated screening and confirmatory assays are employed to detect ADAs at multiple timepoints.
  • blood samples are collected for characterization of LBL-007 and tislelizumab PK.
  • Serum samples are assayed for LBL-007 and tislelizumab concentrations using validated immunoassays.
  • ⁇ ADA assays Serum samples are tested for the presence of ADAs to LBL-007 and tislelizumab using a validated immunoassay.
  • ⁇ PK assays Serum samples are assayed for LBL-007 and tislelizumab concentrations using a validated immunoassay.
  • Biomarker analyses are performed to explore pharmacodynamics, as well as the association of biomarkers with patient prognosis, response, and potential resistance to the treatment.
  • the planned biomarker analyses include but are not limited to PD-L1 expression, LAG-3 expression, LAG-3 ligands expression, cytokine/chemokine and soluble proteins, gene expression profile (GEP) , tumor mutational burden (TMB) /microsatellite instability (MSI) /DNA mutation, and blood tumor mutational burden (bTMB) /circulating tumor DNA (ctDNA) /DNA mutation.
  • PD-L1 is expressed in tumor cells and tumor-infiltrating immune cells, and its expression levels were shown to correlate with the clinical efficacy of anti-PD-1 treatment in ESCC patients.
  • TEP Tumor Area Positivity
  • PD-L1 expression status TAP score (TAP ⁇ 10%or TAP ⁇ 10%) is used to guide patient stratification.
  • the TAP score is defined as the total percentage of the tumor area (tumor and any desmoplastic stroma) covered by tumor cells with PD-L1 membrane staining at any intensity and tumor-associated immune cells with PD-L1 staining at any intensity, as visually estimated.
  • PD-L1 expression will be assessed centrally by the Ventana PD-L1 (SP263) assay, and its predictive role is analyzed.
  • LAG-3 and LAG-3 ligands expression, cytokine/chemokine and soluble proteins, GEP, TMB/MSI/DNA mutation, and bTMB/ctDNA/DNA mutation are assessed to investigate their predictive, prognostic, or pharmacodynamic roles including any association with response to study treatment and mechanism (s) of resistance.
  • PD-L1 expression (TAP ⁇ 10%or ⁇ 10%) is determined by Ventana PD-L1 (SP263) assay.
  • Biomarker analysis in tumor tissues includes but not limited to PD-L1 expression, LAG-3 expression, LAG-3 ligands expression, GEP, and TMB/MSI/DNA mutation analysis (e.g., for the association between these biomarkers and clinically relevant outcomes including response, resistance, and prognosis) .
  • Expected study enrollment is approximately 116 patients with a 2: 1 randomization ratio to receive either LBL-007 in combination with tislelizumab plus chemotherapy (Arm A) or tislelizumab plus chemotherapy (Arm B) .
  • the ORR for the current standard-of-care, anti-PD-1 plus chemotherapy is approximately 50%to 65% (Doki Y, et al. N Engl J Med. 2022; 386 (5) : 449-62.; Lu Z, et al. BMJ. 2022; 377: e068714.; Sun JM, et al. Lancet. 2021; 398 (10302) : 759-71) ; the ORR in the control arm is considered as 55%. Assuming an ORR difference of 20% (increase from 55%to 75%) , 116 patients provide 80%power to detect ORR difference at a 1-sided alpha level of 0.1.
  • Patients will be randomized using the IRT system by permuted block stratified randomization with stratification factors of PD-Ll expression level (TAP ⁇ 10%or TAP ⁇ 10%) .
  • the Intent-to-Treat (ITT) Analysis Set includes all randomized patients. Patients will be analyzed according to their randomized treatment arm. This will be the primary analysis set used for all efficacy analyses.
  • the Safety Analysis Set includes all patients who have received ⁇ 1 dose of any component of study treatment; this will be the analysis set used for the safety analyses.
  • the PK Analysis Set includes all patients who receive ⁇ 1 dose of investigational agents per the protocol and for whom any quantifiable postbaseline PK data are available.
  • the ADA Analysis Set includes all patients who received ⁇ 1 dose of investigational agents per the protocol and in whom both baseline ADA and ⁇ 1 postbaseline ADA results are available.
  • Efficacy endpoints are assessed by the investigator according to RECIST v1.1. The efficacy endpoints will be analyzed and summarized in order to evaluate the antitumor activities of LBL-007 in combination with tislelizumab plus chemotherapy in the first-line ESCC. These analyses are intended to be preliminary efficacy evidence.
  • ORR and DCR along with the 95%Clopper-Pearson CI will be summarized for each arm.
  • the difference in ORR and DCR between arms will be provided using the Cochran-Mantel-Haenszel (CMH) chi-square test. Waterfall plots of maximum tumor shrinkage per patient will be presented.
  • Time-to-event endpoints, PFS, DOR, and OS will be analyzed using the Kaplan-Meier method.
  • Hazard ratio and corresponding 2-sided 95%CI will be estimated using a stratified Cox proportional hazards model.
  • ORR is defined as the proportion of patients achieving confirmed BOR of CR or PR as assessed by the investigator per RECIST v1.1.
  • BOR is defined as the best response recorded from the first dose of study drug (post randomization) until data cutoff or the initiation of new anticancer treatment, whichever occurs earlier.
  • PFS is defined as the time from the date of randomization to the date of the first documentation of disease progression or death, whichever occurs first.
  • the HR and corresponding 2-sided 95%CI will be estimated using a stratified Cox proportional hazards model with stratification factors (PD-L1 status TAP ⁇ 10%or TAP ⁇ 10%) collected from the IRT system.
  • DOR is defined as the time from the first determination of a confirmed overall response until the first documentation of progression assessed by the investigator per RECIST v1.1 or death because of any cause, whichever comes first.
  • DCR is defined as the proportion of patients achieving confirmed BOR of CR, PR, and stable disease assessed by the investigator per RECIST v1.1. DCR will be analyzed similarly like ORR.

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Abstract

Described herein are methods of treating esophageal cancer (e.g., unresectable, locally advanced and/or metastatic ESCC esophageal squamous cell carcinoma) using an anti-LAG3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and one or more chemotherapeutic drugs. In some embodiments, the one or more chemotherapeutic drugs is cisplatin and 5-fluorouracil. In some embodiments, the one or more chemotherapeutic drugs is cisplatin and paclitaxel. In some embodiments, the treated subject is a human (e.g., a human who has not had a prior therapy for ESCC).

Description

TREATMENT OF ESOPHAGEAL CANCER WITH ANTI-LAG3, ANTI-PD-1 AND CHEMOTHERAPY
FIELD OF THE DISCLOSURE
Disclosed herein are methods of treating esophageal cancer (e.g., unresectable, locally advanced and/or metastatic esophageal squamous cell carcinoma) using an anti-LAG3 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, and one or more chemotherapeutic drugs.
BACKGROUND
Esophageal cancer (EC) is the eighth most common cancer in terms of incidence and the sixth most common cause of cancer-related death worldwide, with 604, 100 new cases and 544, 076 deaths observed in 2020 (WHO International Agency for Research on Cancer. Oesophagus. GLOBOCAN 2020a. https: //gco. iarc. fr/today/data/factsheets/cancers/6-Oesophagus-fact-sheet. pdf. ) . Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of EC worldwide, accounting for approximately 90%of EC cases (Abnet CC, et al. Gastroenterology. 2018; 154 (2) : 360-73) . ESCC is more common in the elderly (aged ≥ 60 years) and has mean male-to-female ratios of 3: 1 to 4: 1 (Lagergren J, et al. Oesophageal cancer. Lancet. 2017; 390 (10110) : 2383-96) . The main risk factors for ESCC include tobacco and/or alcohol abuse, consumption of hot food/beverage and pickled vegetables, and poor nutritional status (Engel, et al. J Natl Cancer Inst. 2003; 95 (18) : 1404-13.; Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN. CA Cancer J Clin. 2021; 71 (3) : 209-49.; Tran GD, et al. Int J Cancer. 2005; 113 (3) : 456 63. ) . Advanced ESCC is a rapidly progressing and symptomatic disease with poor clinical outcomes. The 5-year survival rate is only 6.1%for patients with distant metastases (SEER 17 2012-2018; [SEER 2023] ) . One-third to half of patients experienced disease progression after definitive therapies, and more than 30%of patients are initially diagnosed at metastatic stages (Abraham P, et al. Adv Ther. 2020; 37 (7) : 3392 403; Crosby T, et al. Br J Cancer. 2017; 116 (6) : 709-16.; Shapiro J, et al. Lancet Oncol. 2015; 16 (9) : 1090-8. ) .
There is a long-standing unmet need in the art to effectively treat ESCC. In particular, there is a need to increase life span, survival rate and response to treatment in patients with esophageal cancer, such as unresectable, locally advanced and/or metastatic ESCC. The present disclosure satisfies these needs.
SUMMARY OF THE DISCLOSURE
In some aspects, the disclosure provides a method of treating an esophageal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-LAG3 antibody or an antigen binding fragment thereof, and a therapeutically effective amount of one or more chemotherapeutic drugs,
wherein the anti-PD-1 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 1, CDR-H2 comprising SEQ ID NO: 2, and CDR-H3 comprising SEQ ID NO: 3, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 4, CDR-L2 comprising SEQ ID NO: 5, and CDR-L3 comprising SEQ ID NO: 6, and
wherein the anti-LAG3 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 31, CDR-H2 comprising SEQ ID NO: 32, and CDR-H3 comprising SEQ ID NO: 33, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 34, CDR-L2 comprising SEQ ID NO: 35, and CDR-L3 comprising SEQ ID NO: 36.
In some embodiments, the esophageal cancer is esophageal squamous cell carcinoma.
In some embodiments, the cancer is unresectable, recurrent, locally advanced, and/or metastatic. In some embodiments, the cancer is unresectable and locally advanced. In some embodiments, wherein the cancer is stage IV cancer.
In some embodiments, the cancer is metastatic. In some embodiments, the subject has liver, lung, lymph node, bone and/or adrenal gland metastasis. In some embodiments, the subject has 1, 2, 3 or more metastatic sites. In some embodiments, the subject has more than 3 metastatic sites.
In some embodiments, the subject is human.
In some aspects, the disclosure provides a method of treating of metastatic and/or unresectable locally advanced esophageal squamous cell carcinoma in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-LAG3 antibody or an antigen binding fragment thereof, and a therapeutically effective amount of one or more chemotherapeutic drugs,
wherein the anti-PD-1 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 1, CDR-H2 comprising SEQ ID NO: 2, and CDR-H3 comprising SEQ ID NO: 3, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 4, CDR-L2 comprising SEQ ID NO: 5, and CDR-L3 comprising SEQ ID NO: 6, and
wherein the anti-LAG3 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 31, CDR-H2 comprising SEQ ID NO: 32, and CDR-H3 comprising SEQ ID NO: 33, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 34, CDR-L2 comprising SEQ ID NO: 35, and CDR-L3 comprising SEQ ID NO: 36.
In some embodiments, the subject has not been previously treated for the esophageal cancer or the treatment is a first line treatment. In some embodiments, the subject has not being previously treated with chemotherapy and/or immunotherapy.
In some embodiments, the esophageal cancer is chemotherapy-resistant.
In some embodiments, the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 7, and/or the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 8.
In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising an amino acid sequence selected from SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 13. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 14.
In some embodiments, the anti-PD-1 antibody is administered intravenously in the amount of 200 mg. In some embodiments, the administering is once every three weeks. In some embodiments, the administration is by IV infusion. In some embodiments, the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to about 5 mg/kg, and in another aspect the anti-PD-1 antibody is administered at a dose 200 mg tislelizumab every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at about 100 mg, about 150 mg, about 200, mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or  about 800 mg. In some embodiments, the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, and optionally wherein the anti-PD-1 antibody is administered at about 150 mg every two weeks, about 300 mg every four weeks, or about 400 mg every six weeks.
In some embodiments, the heavy chain variable region of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 37, and/or the light chain variable region of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 38.
In some embodiments, the heavy chain of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 39, and/or the light chain of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 40.
In some embodiments, the anti-LAG3 antibody is administered intravenously in the amount of about 600 mg. In some embodiments, the administering is once (optionally on day 1) every three weeks. In some embodiments, the administration is by IV infusion.
In some embodiments, the one or more chemotherapeutic drug is a platinum chemotherapy drug. In some embodiments, the one or more chemotherapeutic drug is cisplatin, paclitaxel and/or 5-fluoruracil. In some embodiments, the one or more chemotherapeutic drug is cisplatin or carboplatin. In some embodiments, the one or more chemotherapeutic drug is cisplatin and 5-fluouracil. In some embodiments, the one or more chemotherapeutic drug is cisplatin and paclitaxel.
In some embodiments, the cisplatin is administered intravenously in the amount of about 40 to 80 mg/m2. In some embodiments, the cisplatin is administered intravenously in the amount of about 60 to 80 mg/m2. In some embodiments, the administering is once (optionally on day 1) every three weeks (Q3W) . In some embodiments, the administration is by IV infusion.
In some embodiments, the 5-fluorouracil (also called “5-FU” ) is administered intravenously in the amount of about 400 to 800 mg/m2. In some embodiments, the 5-fluorouracil is administered intravenously in the amount of about 600 to 800 mg/m2. In some embodiments, the 5-fluorouracil is administered intravenously in the amount of about 750 to 800 mg/m2. In some embodiments, the administering is five times (optionally days 1, 2, 3, 4, and 5) every three weeks (Q3W) . In some embodiments, the administration is by IV infusion.
In some embodiments, the paclitaxel is administered intravenously at in the amount of about 90 to 175 mg/m2. In some embodiments, the paclitaxel is administered intravenously at  in the amount of about 135 to 175 mg/m2. In some embodiments, the paclitaxel is administered intravenously at in the amount of about 175 mg/m2. In some embodiments, the administering is once (optionally on Day 1) every three weeks (Q3W) . In some embodiments, the administration is by IV infusion.
In some embodiments, the administering of any of the above-mentioned agents is for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 cycles of three weeks each. In some embodiments, the administering of any of the above-mentioned agents is for at least 3 cycles of three weeks each. In some embodiments, the administering of any of the above-mentioned agents is for at least 4 cycles of three weeks each. In some embodiments, the administering of any of the above-mentioned agents is for at least 6 cycles of three weeks each.
In some embodiments, the response to treatment is measured by overall survival, progression-free or event-free survival, overall response rate, complete response, partial response, duration of response, and/or disease control rate. In some embodiments, the response to treatment is measured by tumor volume, size of diameter.
In some embodiments, the subject has been diagnosed with the esophageal cancer (e.g., ESCC) using histological and/or cytological markers.
In some embodiments, the esophageal cancer has PD-L1 tumor area positivity (TAP) score of 10%or more. In some embodiments, the esophageal cancer has PD-L1 tumor area positivity (TAP) score of less than 10%.
Both the foregoing summary and the following brief description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the invention, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 Provides a schematic of the study design. Abbreviations: DCR = disease control rate; DOR = duration of response; ESCC = esophageal squamous cell carcinoma; ORR = overall response rate; OS = overall survival; PD-L1 = programmed cell death protein-ligand 1; PFS = progression-free survival; TAP = tumor area positivity.
FIG. 2 Provides a treatment flow chart for esophageal squamous cell carcinoma treatment. Abbreviations: ESCC = esophageal squamous cell carcinoma; NCCN -= National  Comprehensive Cancer Network; TFI = treatment-free interval; dCRT = definitive chemoradiotherapy. 1. TFI: treatment-free interval. Duration from the end date of last prior systemic therapy/radiotherapy to the date of disease progression/recurrence/metastasis. 2. Patients who have surgery with neoadjuvant/adjuvant systemic therapy, TFI was required to＞6 months. Patients undergo surgical resection directly without neoadjuvant or adjuvant systemic, TFI ≤ 6 months are also eligible for the study. 3. Patients who have dCRT, TFI is required to＞6 months. Patients with TFI ≤ 6 months with no systemic chemotherapy received in sequence or combination with definitive radiotherapy are also eligible. 4. Patients who had progression after receiving ≥ 2 curative therapies are also allowed into this study as long as TFI > 6 mo.
DETAILED DESCRIPTION
In some aspects, provided herein are methods of treatment or delay of progression of esophageal cancer (e.g. ESCC) in a subject (e.g., human) by administering an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., tislelizumab or an anti-PD-1 antibody having CDRs of the tislelizumab) , anti-LAG3 antibody or an antigen-binding fragment thereof (e.g., BGB-1953 or an anti-LAG3 antibody having CDRs of BGB-1953) , and, optionally, chemotherapy (cisplatin, 5-fuorouracil and/or paclitaxel) . In some embodiments, the chemotherapy is cisplatin and 5-fluorouracil. In some embodiments, the chemotherapy is cisplatin and paclitaxel.
In some embodiments, provided herein are methods of treatment or delay of progression of advanced (e.g., locally advanced) extensive stage (e.g., stage IV or stage IVb) , unresectable or metastatic (e.g., with liver, lung or lymph node metastasis, e.g., with 2, 3 or more metastatic sites) EC (e.g. ESCC) in a subject (e.g., human) by administering an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., tislelizumab or an anti-PD-1 antibody having CDRs of the tislelizumab) , anti-LAG3 antibody or an antigen-binding fragment thereof (e.g., BGB-1953 or an anti-LAG3 antibody having CDRs of BGB-1953) and, optionally, chemotherapy (cisplatin, 5-fuorouracil and/or paclitaxel) . In some embodiments, the chemotherapy is cisplatin and 5-fluorouracil. In some embodiments, the chemotherapy is cisplatin and paclitaxel.
In some embodiments, the therapy is a first line therapy, i.e., the subject has not been treated (e.g., with chemotherapy and/or immunotherapy) for the ESCC.
In some embodiments, the subject has progressed after prior chemotherapy or did not tolerate prior chemotherapy.
Antibodies
Anti-PD1 and anti-LAG3 antibodies are described herein.
In some embodiments, the antibodies and fragments described herein are isolated. In some embodiments, the antibodies and fragments described herein are purified. In some embodiments, the antibodies and fragments described herein are isolated and purified.
In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the anti-PD-1 antibody is a chimeric antibody.
In some embodiments, the present disclosure provides for an antibody or antigen-binding fragment thereof, wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv) , a Fab fragment, a Fab′fragment, or a F (ab′) 2 fragment.
In some embodiments, the antibody is an immunoglobulin comprising any VH and VL regions described herein. The immunoglobulin molecules that can be used are of any type (e.g., IgG, IgE, IgM, IgD, IgY, IgA) . The immunoglobulin molecules that can be used are of any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, IgA2) . The immunoglobulin molecules that can be used are of any subclass.
In some embodiments, the antibody is an IgG4 antibody. In some embodiments, provided herein is an antibody or antigen-binding fragment thereof, wherein the Fc domain is of an IgG4.
In some embodiments, the antibody is an IgG1 antibody. In some embodiments, provided herein is an antibody or antigen-binding fragment thereof, wherein the Fc domain is of an IgG1.
In some embodiments, the antibody is a monoclonal humanized IgG1 antibody.
In some embodiments, the antibody is a monoclonal humanized IgG4 antibody.
In some embodiments, the antibody is a monoclonal fully human IgG4 antibody.
Anti-PD1 antibodies
In some embodiments, the anti-PD-1 antibody is any antibody known in the art or described herein. In some embodiments, the anti-PD-1 antibody is any antibody that specifically binds to PD-1. In some embodiments, the anti-PD-1 antibody inhibits PD-1-mediated cellular signaling and activity in immune cells. In some embodiments, the anti-PD-1 antibody binds to amino acid residues requires for its ligand binding and/or inhibits ligand binding.
The present disclosure provides for anti-PD1 antibodies described, for example, in US Patent No. 8,735,553, WO2015/035606 or Table 1 below. U.S. Patent No. 8,735,553 and WO2015/035606 A1 are incorporated by reference herein in their entirety, and in particular in respect to description therein of anti-PD-1 antibodies. In some embodiments, anti-PD-1 antibodies comprise a heavy chain variable region (VH) comprising the complementarity determining regions (CDRs) : HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3; and a light chain variable region (VL) comprising: LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.
In another embodiment, the anti-PD1 antibody or antigen-binding fragment which specifically binds human PD1 and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 8. In yet another embodiment, the anti-PD1 antibody comprises an IgG4 constant domain comprising any of SEQ ID NO: 9-14. In another aspect, the IgG4 constant domain comprises SEQ ID NO: 13 or 14.
In some embodiments, the described anti-PD-1 antibodies and fragments comprise a light chain variable region having a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%or 99%identity to the amino acid sequence of SEQ ID NO: 8 and/or a heavy chain variable region having a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%or 99%identity to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the described anti-PD-1 antibodies and fragments comprise a light chain variable region having a sequence with at least 85%, 90%or 95%identity to the amino acid sequence of SEQ ID NO: 8 (with at least 90%, 95%, 97%, 99%or 100%identity in the CDR regions, e.g., the six CDRs) and/or a heavy chain variable region having a sequence with at least 85%, 90%or 95%identity to the amino acid sequence of SEQ ID NO: 7 (with at least 90%, 95%, 97%, 99%or 100%identity in the CDR regions, e.g., the six CDRs) .
In some embodiments, the antibody comprises an IgG4 Fc region having a serine to proline mutation at position 228 (EU numbering system) . In some embodiments, this mutation  is referred to as the S228P mutation. In some embodiments, the antibody comprises an IgG4 Fc region having a mutation at one or more of positions 233, 234, 235, 265, 309, and 409 (EU numbering system) . For example, in some embodiments, the antibody comprises an IgG4 region having a mutation at 228 and at least one other position, wherein the at least one other mutation results in reduced binding to one or more FcγR. In further embodiments, the antibody comprises an IgG4 region having a mutation at position 228 and at least two, at least 3, at least 4, at least 5, or at least 6 additional positions, wherein one or more of the additional mutations results in reduced binding to one or more FcγR. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 234 and 235. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 233, 235, and 235. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 234, 235, and 265. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 233, 234, 235, and 265. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 234, 235, 265, and 409. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 233, 234, 235, 265, and 409. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 234, 235, 265, 309, and 409. In some embodiments, the antibody comprises an IgG4 region having mutations at positions 233, 234, 235, 265, 309, and 409. The mutation at position 234 may be a phenylalanine to valine substitution or a phenylalanine to alanine substitution. The mutation at position 235 may be a leucine to alanine substitution. The mutation at position 233 may be a glutamic acid to proline substitution. The mutation at position 265 may be a aspartic acid to valine substitution or an aspartic acid to threonine substitution. The mutation at position 309 may be a leucine to valine substitution. The mutation at position 409 may be an arginine to a lysine, threonine, or methionine substitution.
In some embodiments, the anti-PD-1 antibody is an antibody which comprises a IgG4 heavy chain effector or constant domain comprising any of SEQ ID NOs: 9-14. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 9. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 10. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 11. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 12. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 13. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region  comprising SEQ ID NO: 15. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 16.
In some embodiments, the anti-PD1 antibody is a humanized IgG4 monoclonal antibody In some embodiments, the anti-PD-1 antibody is Tislelizumab. The sequence of Tislelizumab is known in the art.
In some embodiments, the present disclosure provides for monoclonal anti-PD1 antibodies and antigen-binding fragments thereof having the sequences provided in the Table below (such as humanized antibodies having such sequences) . In some embodiments, the anti-PD1 antibody or antigen-binding fragment thereof specifically binds human PD1 and comprises the six CDRs provided in the Table below. In some embodiments, the anti-PD1 antibody or antigen-binding fragment thereof specifically binds human PD1 and comprises a heavy chain variable region and a light chain variable region comprising the sequences provided in the Table below. In some embodiments, the anti-PD1 antibody comprises an IgG4 constant domain comprising any of the sequences provided below. In some embodiments, the IgG4 constant domain comprises one of the last two sequences provided in the Table 1 below.


In some embodiments, the anti-PD1 antibodies or antigen-binding fragments thereof include amino acids that have been mutated, yet have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%percent identity in the CDR regions with the CDR regions depicted in the sequences described herein, such as in the Table above. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the CDR regions when compared with the CDRs disclosed herein.
In some embodiments, the anti-PD1 antibodies include those where the amino acids or nucleic acids encoding the amino acids have been mutated; yet have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%percent identity to the sequences described herein (e.g., in the heavy and light chain variable regions and/or IgG constant regions) , such as in the Table above. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the heavy and light chain variable regions when compared with the heavy and light chain variable regions in the sequence disclosed herein, while retaining substantially the same therapeutic activity.
Anti-PD-1 Antibody Dosing and Administration
In some embodiments, the anti-PD-1 antibody (e.g., any of the antibodies described herein) is administered by any suitable means. In some embodiments, the anti-PD-1 antibody is administered parenterally. In some embodiments, the anti-PD-1 antibody is administered intravenously (IV) . In some embodiments, the anti-PD-1 antibody is administered by IV infusion. In some embodiments, the anti-PD-1 antibody is infused over 60 minutes or more. In some embodiments, the anti-PD-1 antibody is infused over 30 minutes or more. In some embodiments, the anti-PD-1 antibody is administered subcutaneously. In some embodiments, the anti-PD-1 antibody is administered intramuscularly. In some embodiments, the anti-PD-1 antibody is administered peritoneally.
In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered parenterally. In some embodiments, Tislelizumab is administered by IV infusion. In some  embodiments, the IV infusion is over 60 minutes or more. In some embodiments, the IV infusion is over 30 minutes or more.
In some embodiments, the anti-PD-1 antibody (e.g., any of the antibodies described herein) is administered at a fixed dose. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered at a fixed dose.
In some embodiments, the anti-PD-1 antibody is administered at a dose of 200 mg or about 200 mg. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered at a dose of 200 mg or about 200 mg. In some embodiments, Tislelizumab is administered at a dose of 200 mg.
In some embodiments, the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to about 200 mg/kg (and any value in between) . In some embodiments, the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to about 5 mg/kg (e.g., 2 mg/kg to 5 mg/kg) . In some embodiments, the anti-PD-1 antibody is administered at a dose of 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg (or any value in between these values) . In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered at a dose from about 2 mg/kg to about 5 mg/kg (e.g., 2 mg/kg to 5 mg/kg) . In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered at a dose at a dose of 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg (or any value in between these values) . In some embodiments, Tislelizumab is administered at a dose of 2 mg/kg to 5 mg/kg.
In some embodiments, the anti-PD-1 antibody is administered at a dosage of about 2 mg/kg Q3W to about 200 mg/kg once every three weeks (Q3W) . In some embodiments, the anti-PD-1 antibody is administered at a dosage of about 2mg/kg Q3W, 5mg/kg Q3W or 200 mg flat Q3W.
In some embodiments, the anti-PD-1 antibody is administered intravenously in the amount of 200 mg. In some embodiments, the administering is once every three weeks. In some embodiments, the administration is by IV infusion. In some embodiments, the anti-PD-1 antibody is administered at a dose from about 2 mg/kg to about 5 mg/kg, preferably the anti-PD-1 antibody is administered at a dose 200 mg tislelizumab every 3 weeks. In some  embodiments, the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg. In some embodiments, the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks.
In some embodiments, the anti-PD-1 antibody is administered once every three weeks. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered once every three weeks.
In some embodiments, the anti-PD-1 antibody is administered once every two weeks. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered once every two weeks.
In some embodiments, the anti-PD-1 antibody is administered once every three weeks for 4 cycles or at least 4 cycles. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered once every three weeks for 4 cycles or at least 4 cycles.
In some embodiments, the anti-PD-1 antibody is administered in one treatment cycle. In some embodiments, the anti-PD-1 antibody is administered in two treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in three treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in four treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in five treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in six treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in seven treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in eight treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in nine treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in ten treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in eleven treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in twelve treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in thirteen treatment cycles. In some embodiments, the anti-PD-1 antibody is administered in fourteen treatment cycles. In some  embodiments, the anti-PD-1 antibody is administered in fifteen treatment cycles. In some embodiments, a treatment cycle is three weeks.
In some embodiments, the anti-PD-1 antibody is administered on Day 1 of the cycle (e.g., Day 1 of 21 day or 3 week cycle) .
In some embodiments, the anti-PD-1 antibody is IV infused over 60 minutes or more. In some embodiments, the anti-PD-1 antibody is IV infused over 60 minutes or more in cycle 1, and IV infused over 30 minutes or about 30 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle) . In some embodiments, the anti-PD-1 antibody is IV infused over 60 minutes or more in cycle 1, and IV infused over less than 60 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle) . In some embodiments, the infusion time for the anti-PD-1 antibody is reduced from 60 minutes to 30 minutes if, and only if, the 60 minute infusion time is well tolerated by the treated subject.
In some embodiments, the anti-PD-1 antibody is administered once every three weeks (Q3W) for 3 months or at least 3 months. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered once every three weeks (Q3W) for 3 months or at least 3 months. In some embodiments, the anti-PD-1 antibody is administered once every three weeks (Q3W) for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months (or more) . In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered once every three weeks (Q3W) for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months (or more) .
In some embodiments, the anti-PD-1 antibody is administered intravenously at a fixed dose of 200 mg. In some embodiments, the anti-PD-1 antibody is administered intravenously at a fixed dose of 200 mg once every three weeks. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered intravenously at a fixed dose of 200 mg. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered intravenously at a fixed dose of 200 mg once every three weeks. In some embodiments, the IV administration is by IV infusion.
In some embodiments, the anti-PD-1 antibody is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg) . In some embodiments, the anti-PD-1  antibody is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg) once every three weeks. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg) . In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg) every three weeks. In some embodiments, the IV administration is by IV infusion.
In some embodiments, the dosage and treatment regimens described herein are for administration to human subjects.
Anti-LAG3 antibodies
In some embodiments, the anti-LAG3 antibody is any antibody known in the art or described herein. In some embodiments, the anti-LAG3 is antibody is any antibody that specifically binds to LAG3.
The present disclosure provides for anti-LAG3 antibodies described, for example, in US Patent No. 10,844,121, WO2019/011306 or Table 3 below. US Patent No. 10,844,121 and WO2019/011306 are incorporated by reference herein in their entirety, and in particular in respect to description therein of anti-LAG3 antibodies.
In some embodiments, provided herein are anti-LAG3 antibody comprising an antibody antigen binding domain which specifically binds human LAG3, and comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) : HCDR1 of SEQ ID NO: 31, HCDR2 of SEQ ID NO: 32, and HCDR3 of SEQ ID NO: 33; and a light chain variable region (VL) comprising: LCDR1 of SEQ ID NO: 34, LCDR2 of SEQ ID NO: 35, and LCDR3 of SEQ ID NO: 36.
In some embodiments, the anti-LAG3 antibody comprises an antibody antigen binding domain which specifically binds human LAG3, and comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 37 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 38. In another embodiment, the anti-LAG3 antibody or antigen binding fragment thereof comprises a variant heavy chain constant region of human IgG4.
In some embodiments, the described anti-LAG3 antibodies and fragments comprise a light chain variable region having a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%or  99%identity to the amino acid sequence of SEQ ID NO: 38 and/or a heavy chain variable region having a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%or 99%identity to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the described anti-LAG3 antibodies and fragments comprise a light chain variable region having a sequence with at least 85%, 90%or 95%identity to the amino acid sequence of SEQ ID NO: 38 (with at least 90%, 95%, 97%, 99%or 100%identity in the CDR regions, e.g., the six CDRs) and/or a heavy chain variable region having a sequence with at least 85%, 90%or 95%identity to the amino acid sequence of SEQ ID NO: 37 (with at least 90%, 95%, 97%, 99%or 100%identity in the CDR regions, e.g., the six CDRs) .
In some embodiments, the anti-LAG3 antibody comprises a heavy chain having at least 95%, 96%, 97%, 98%, 99%or 100%sequence identity with the amino acid sequence of SEQ ID NO: 39. In some embodiments, the anti-LAG3 antibody comprises a light chain having at least 95%, 96%, 97%, 98%, 99%or 100%sequence identity with the amino acid sequence of SEQ ID NO: 40. In some embodiments, the anti-LAG3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 39, and a light chain comprising the amino acid sequence of SEQ ID NO: 40.
In some embodiments, the anti-LAG3 antibody is a fully human IgG4 monoclonal antibody. In some embodiments, the anti-LAG3 antibody is BGA-1953 or LBL-007.
In some embodiments, the present disclosure provides for monoclonal anti-LAG3 antibodies and antigen-binding fragments thereof having the sequences provided in the Table below (such as fully human antibodies having such sequences) . In some embodiments, the anti-LAG3 antibody or antigen-binding fragment thereof specifically binds human LAG-3 and comprises the six CDRs provided in the Table below. In some embodiments, the anti-LAG3 antibody or antigen-binding fragment thereof specifically binds human LAG-3 and comprises a heavy chain variable region and a light chain variable region comprising the sequences provided in the Table below. In some embodiments, the anti-LAG3 antibody specifically binds human LAG-3 and comprises a heavy chain and a light chain comprising the sequences provided in the Table below. In some embodiments, the anti-LAG3 antibody comprises an IgG4 constant domain comprising any of the sequences provided below.

In some embodiments, the anti-LAG3 antibodies or antigen-binding fragments thereof include amino acids that have been mutated, yet have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%percent identity in the CDR regions with the CDR regions depicted in the sequences described herein, such as in the Table above. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the CDR regions when compared with the CDRs disclosed herein.
In some embodiments, the anti-LAG3 antibodies include those where the amino acids or nucleic acids encoding the amino acids have been mutated; yet have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%percent identity to the sequences described herein (e.g., in the heavy and light chain variable regions and/or IgG constant regions) , such as in the Table above. In some aspects, it includes mutant amino acid sequences wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the heavy and light chain variable regions when compared with the heavy and light chain variable regions in the sequence disclosed herein, while retaining substantially the same therapeutic activity.
Anti-LAG3 Antibody Dosing and Administration
In some embodiments, the anti-LAG3 antibody (e.g., any of the antibodies described herein) is administered by any suitable means. In some embodiments, the anti-LAG3 antibody is administered parenterally. In some embodiments, the anti-LAG3 antibody is administered intravenously (IV) . In some embodiments, the anti-LAG3 antibody is administered by IV infusion. In some embodiments, the anti-LAG3 antibody is infused over 60 minutes or more. In some embodiments, the anti-LAG3 antibody is infused over 30 minutes or more. In some embodiments, the anti-LAG3 antibody is administered subcutaneously. In some embodiments, the anti-LAG3 antibody is administered intramuscularly. In some embodiments, the anti-LAG3 antibody is administered peritoneally.
In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered parenterally. In some embodiments, BGA-1953 is administered by IV infusion. In some embodiments, the IV infusion is over 60 minutes or more. In some embodiments, the IV infusion is over 30 minutes or more.
In some embodiments, the anti-LAG3 antibody (e.g., any of the antibodies described herein) is administered at a fixed dose. In some embodiments, an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered at a fixed dose.
In some embodiments, the anti-LAG3 antibody is administered at a dose of 600 mg or about 600 mg. In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered at a dose of 600 mg or about 600 mg. In some embodiments, BGA-1953 is administered at a dose of 600 mg.
In some embodiments, the anti-LAG3 antibody is administered once every three weeks. In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered once every three weeks.
In some embodiments, the anti-LAG3 antibody is administered once every two weeks. In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered once every two weeks.
In some embodiments, the anti-LAG3 antibody is administered once every three weeks for 4 cycles or at least 4 cycles. In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered once every three weeks for 4 cycles or at least 4 cycles.
In some embodiments, the anti-LAG3 antibody is administered in one treatment cycle. In some embodiments, the anti-LAG3 antibody is administered in two treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in three treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in four treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in five treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in six treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in seven treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in eight treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in nine treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in ten treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in eleven treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in twelve treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in thirteen treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in fourteen treatment cycles. In some embodiments, the anti-LAG3 antibody is administered in fifteen treatment cycles. In some embodiments, a treatment cycle is three weeks.
In some embodiments, the anti-LAG3 antibody is administered on Day 1 of the cycle (e.g., Day 1 of 21 day or 3 week cycle) .
In some embodiments, the anti-LAG3 antibody is IV infused over 60 minutes or more. In some embodiments, the anti-LAG3 antibody is IV infused over 60 minutes or more in cycle  1, and IV infused over 30 minutes or about 30 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle) . In some embodiments, the anti-LAG3 antibody is IV infused over 60 minutes or more in cycle 1, and IV infused over less than 60 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle) . In some embodiments, the infusion time for the anti-LAG3 antibody is reduced from 60 minutes to 30 minutes if, and only if, the 60 minute infusion time is well tolerated by the treated subject.
In some embodiments, the anti-LAG3 antibody is administered once every three weeks (Q3W) for 3 months or at least 3 months. In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered once every three weeks (Q3W) for 3 months or at least 3 months. In some embodiments, the anti-LAG3 antibody is administered once every three weeks (Q3W) for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months (or more) . In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered once every three weeks (Q3W) for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months (or more) .
In some embodiments, the anti-LAG3 antibody is administered intravenously at a fixed dose of 600 mg. In some embodiments, the anti-LAG3 antibody is administered intravenously at a fixed dose of 600 mg once every three weeks. In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered intravenously at a fixed dose of 600 mg.In some embodiments, an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) is administered intravenously at a fixed dose of 600 mg once every three weeks. In some embodiments, the IV administration is by IV infusion.
In some embodiments, the dosage and treatment regimens described herein are for administration to human subjects.
Further Alteration of the Framework of Fc Region
In yet other aspects, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector functions of the antibody. For example, one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for  example, an Fc receptor or the C1 component of complement. This approach is described in, e.g., U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
In another aspect, one or more amino acid residues can be replaced with one or more different amino acid residues such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC) . This approach is described in, e.g., U.S. Pat. No. 6,194,551 by Idusogie et al.
In yet another aspect, one or more amino acid residues are altered to thereby alter the ability of the antibody to fix complement. This approach is described in, e.g., the PCT Publication WO 94/29351 by Bodmer et al. In a specific aspect, one or more amino acids of an antibody or antigen-binding fragment thereof of the present disclosure are replaced by one or more allotypic amino acid residues, for the IgG1 subclass and the kappa isotype. Allotypic amino acid residues also include, but are not limited to, the constant region of the heavy chain of the IgG1, IgG2, and IgG3 subclasses as well as the constant region of the light chain of the kappa isotype as described by Jefferis et al., MAbs. 1: 332-338 (2009) .
In another aspect, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fcγ receptor by modifying one or more amino acids. This approach is described in, e.g., the PCT Publication WO 00/42072 by Presta. Moreover, the binding sites on human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn have been mapped and variants with improved binding have been described (see Shields et al., J. Biol. Chem. 276: 6591-6604, 2001) .
In still another aspect, the glycosylation of an antibody is modified. For example, an aglycosylated antibody can be made (i.e., the antibody lacks or has reduced glycosylation) . Glycosylation can be altered to, for example, increase the affinity of the antibody for “antigen. ” Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation can increase the affinity of the antibody for antigen. Such an approach is described in, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co et al.
Additionally, or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation  patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies to thereby produce an antibody with altered glycosylation. For example, EP 1,176,195 by Hang et al., describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lecl3 cells, with reduced ability to attach fucose to Asn (297) -linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields et al., (2002) J. Biol. Chem. 277: 26733-26740) . PCT Publication WO 99/54342 by Umana et al., describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta (1, 4) -N acetylglucosaminyltransferase III (GnTIII) ) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al., Nat. Biotech. 17: 176-180, 1999) .
In another aspect, if a reduction of ADCC is desired, human antibody subclass IgG4 was shown in many previous reports to have only modest ADCC and almost no CDC effector function (Moore G L, et al., 2010 MAbs, 2: 181-189) . On the other hand, natural IgG4 was found less stable in stress conditions such as in acidic buffer or under increasing temperature (Angal, S. 1993 Mol Immunol, 30: 105-108; Dall'A cqua, W. et al., 1998 Biochemistry, 37: 9266-9273; Aalberse et al., 2002 Immunol, 105: 9-19) . Reduced ADCC can be achieved by operably linking the antibody to IgG4 engineered with combinations of alterations to have reduced or null FcγR binding or C1q binding activities, thereby reducing or eliminating ADCC and CDC effector functions. Considering physicochemical properties of antibody as a biological drug, one of the less desirable, intrinsic properties of IgG4 is dynamic separation of its two heavy chains in solution to form half antibody, which lead to bi-specific antibodies generated in vivo via a process called “Fab arm exchange” (Van der Neut Kolfschoten M, et al., 2007 Science, 317: 1554-157) . The mutation of serine to proline at position 228 (EU numbering system) appeared inhibitory to the IgG4 heavy chain separation (Angal, S. 1993 Mol Immunol, 30:105-108; Aalberse et al., 2002 Immunol, 105: 9-19) . Some of the amino acid residues in the hinge and γFc region were reported to have impact on antibody interaction with Fcγ receptors (Chappel S M, et al., 1991 Proc. Natl. Acad. Sci. USA, 88: 9036-9040; Mukherjee, J. et al., 1995 FASEB J, 9: 115-119; Armour, K. L. et al., 1999 Eur J Immunol, 29: 2613-2624; Clynes, R.A. et al., 2000 Nature Medicine, 6: 443-446; Arnold J. N., 2007 Annu Rev immunol, 25: 21- 50) . Furthermore, some rarely occurring IgG4 isoforms in human population can also elicit different physicochemical properties (Brusco, A. et al., 1998 Eur J Immunogenet, 25: 349-55; Aalberse et al., 2002 Immunol, 105: 9-19) . To generate antibodies with low ADCC, CDC and instability, it is possible to modify the hinge and Fc region of human IgG4 and introduce a number of alterations. These modified IgG4 Fc molecules can be found in SEQ ID NOs: 83-88, U.S. Patent No. 8,735,553 to Li et al.
Antibody Production
Anti-PD1 antibodies and antigen-binding fragments thereof and anti-LAG3 antibodies and antigen-binding fragments thereof can be produced by any means known in the art, including but not limited to, recombinant expression, chemical synthesis, and enzymatic digestion of antibody tetramers, whereas full-length monoclonal antibodies can be obtained by, e.g., hybridoma or recombinant production. Recombinant expression can be from any appropriate host cells known in the art, for example, mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc.
The disclosure further provides polynucleotides encoding the antibodies described herein, e.g., polynucleotides encoding heavy or light chain variable regions or segments comprising the complementarity determining regions as described herein. In some aspects, the polynucleotide encoding the heavy chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%nucleic acid sequence identity with a polynucleotide encoding the amino acid sequences disclosed herein. In some aspects, the polynucleotide encoding the light chain variable regions has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%nucleic acid sequence identity with a polynucleotide encoding the amino acid sequences described herein.
The polynucleotides of the present disclosure can encode the variable region sequence of an anti-PD1 antibody or anti-LAG3 antibody. They can also encode both a variable region and a constant region of the antibody. Some of the polynucleotide sequences encode a polypeptide that comprises variable regions of both the heavy chain and the light chain. Some other polynucleotides encode two polypeptide segments that respectively are substantially identical to the variable regions of the heavy chain and the light chain.
Also provided in the present disclosure are expression vectors and host cells for producing the anti-PD1 antibodies and antigen-binding fragments thereof or anti-LAG3 antibodies and antigen-binding fragments thereof. The choice of expression vector depends on the intended host cells in which the vector is to be expressed. Typically, the expression vectors  contain a promoter and other regulatory sequences (e.g., enhancers) that are operably linked to the polynucleotides encoding the antibodies or antigen-binding fragments thereof. In some aspects, an inducible promoter is employed to prevent expression of inserted sequences except under the control of inducing conditions. Inducible promoters include, e.g., arabinose, lacZ, metallothionein promoter or a heat shock promoter. Cultures of transformed organisms can be expanded under non-inducing conditions without biasing the population for coding sequences whose expression products are better tolerated by the host cells. In addition to promoters, other regulatory elements can also be required or desired for efficient expression of an antibody or antigen-binding fragment. These elements typically include an ATG initiation codon and adjacent ribosome binding site or other sequences. In addition, the efficiency of expression can be enhanced by the inclusion of enhancers appropriate to the cell system in use (see, e.g., Scharf et al., Results Probl. Cell Differ. 20: 125, 1994; and Bittner et al., Meth. Enzymol., 153: 516, 1987) . For example, the SV40 enhancer or CMV enhancer can be used to increase expression in mammalian host cells.
The host cells for harboring and expressing the antibody chains can be either prokaryotic or eukaryotic. E. coli is one prokaryotic host useful for cloning and expressing the polynucleotides of the present disclosure. Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis, and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species. In these prokaryotic hosts, one can also make expression vectors, which typically contain expression control sequences compatible with the host cell (e.g., an origin of replication) . In addition, any number of a variety of well-known promoters will be present, such as the lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a promoter system from phage lambda. The promoters typically control expression, optionally with an operator sequence, and have ribosome binding site sequences and the like, for initiating and completing transcription and translation. Other microbes, such as yeast, can also be employed to express anti-OX40 polypeptides. Insect cells in combination with baculovirus vectors can also be used.
In other aspects, mammalian host cells are used to express and produce the antibody polypeptides of the present disclosure. For example, they can be either a hybridoma cell line expressing endogenous immunoglobulin genes or a mammalian cell line harboring an exogenous expression vector. These include any normal mortal or normal or abnormal immortal animal or human cell. For example, a number of suitable host cell lines capable of secreting intact immunoglobulins have been developed, including the CHO cell lines, various  COS cell lines, HEK 293 cells, myeloma cell lines, transformed B-cells and hybridomas. The use of mammalian tissue cell culture to express polypeptides is discussed generally in, e.g., Winnacker, From Genes to Clones, VCH Publishers, NY, N. Y., 1987. Expression vectors for mammalian host cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89: 49-68, 1986) , and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences. These expression vectors usually contain promoters derived from mammalian genes or from mammalian viruses. Suitable promoters can be constitutive, cell type-specific, stage-specific, and/or modulatable or regulatable. Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIII promoter, the constitutive MPSV promoter, the tetracycline-inducible CMV promoter (such as the human immediate-early CMV promoter) , the constitutive CMV promoter, and promoter-enhancer combinations known in the art.
Anti-Cancer Agents/Chemotherapeutic Drugs
In some embodiments, a subject described herein is administered an anti-cancer agent. The term “anti-cancer agent” as used herein refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents, including cellular therapies.
In some embodiments, the anti-PD-1 antibodies and antigen-binding fragments of the present disclosure are used in combination with one or more anti-cancer agents. In some embodiments, a subject described herein is administered an anti-PD-1 antibody and further administered an anti-cancer agent described herein.
In some embodiments, the anti-PD-1 antibodies of the present disclosure are used in combination with one or more chemotherapeutic agents or drugs (e.g., one, two or three chemotherapeutic agents or drugs) . In some embodiments, the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure and one or more chemotherapeutic drugs (e.g., one, two or three chemotherapeutic drugs) .
Classes of chemotherapeutic agents that can be used include, but are not limited to: microtubule inhibitors, e.g., taxanes (paclitaxel, docetaxel) , and vinca alkaloids (vincristine, vinblastine, vinorelbine) ; antimetabolites (5-fluorouracil, capecitabine, gemcitabine) , and  antifolates (methotrexate, pemetrexed) ; kinase inhibitors (crizotinib, erlotinib, sunitinib) ; topoisomerase inhibitors (deruxtecan, topotecan, irinotecan, anthracyclines, etoposide) ; cell-cycle independent drugs, e.g., platinum compounds and analogues (oxaliplatin) , triazenes, alkylating agents (cyclophosphamide) , spindle poison plant alkaloids (doxorubicin) , cytotoxic/antitumor antibiotics (bleomycin, mithramycin, mitomycin) , photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs) , anti-progesterones, estrogen receptor down-regulators (ERDs) , estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and anti-sense oligonucleotides that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth. Current standard of care (SOC) treatments for certain cancers, in the early-line setting include chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan used in combination or sequentially, with option for monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (e.g., bevacizumab, ziv-aflibercept) or its receptors (e.g., ramucirumab) , and in patients with Ras wild type tumors, monoclonal antibodies targeting the epidermal growth factor (EGF) receptor (e.g., cetuximab, panitumumab) . Treatment options for heavily pre-treated patients beyond the second-line setting are especially limited and associated toxicities can be severe.
In some embodiments, the chemotherapeutic agent is selected from one or more of the following: paclitaxel or a paclitaxel agent; (e.g., ) , docetaxel; carboplatin; topotecan; deruxtecan; cisplatin; irinotecan, doxorubicin, lenalidomide, 5-azacytidine, ifosfamide, oxaliplatin, pemetrexed disodium, cyclophosphamide, etoposide, decitabine, fludarabine, vincristine, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, and pemetrexed disodium.
In some embodiments, the chemotherapeutic drug is a platinum chemotherapy.
In some embodiments, the chemotherapeutic drug is cisplatin.
In some embodiments, the chemotherapeutic drug is carboplatin. In some embodiments, it is in physician’s discretion whether to administer cisplatin or carboplatin.
In some embodiments, the chemotherapeutic drug is 5-fluorouracil.
In some embodiments, the chemotherapeutic drug is paclitaxel.
In some embodiments, the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure, anti-LAG3 antibody of the present disclosure, cisplatin and 5-fuorouracil.
In some embodiments, the treatment methods described herein comprise administration to a subject (e.g., a human) of an anti-PD-1 antibody of the present disclosure, anti-LAG3 antibody of the present disclosure, cisplatin and paclitaxel.
The dosing of the chemotherapy drugs can be any dosing known in the art (e.g., any dose and administration regimen known in the art to be effective) or any dosing described herein.
Cisplatin
In some embodiments, a patient described herein is administered Cisplatin in combination with an anti-PD-1 and anti-LAG3 antibodies described herein. In some embodiments, a patient is administered Cisplatin in combination with Tislelizumab and BGA-1953. In some embodiments, a patient is administered Cisplatin in combination with an anti-PD-1 and anti-LAG3 antibodies described herein and 5-fluorouracil. In some embodiments, a patient is administered Cisplatin in combination with an anti-PD-1 and anti-LAG3 antibodies described herein and paclitaxel.
In some embodiments, Cisplatin is administered parenterally. In some embodiments, Cisplatin is administered at a dose of about 20 mg/m2 to about 100 mg/m2. In some embodiments, Cisplatin is administered at about 20 mg/m2, 25 mg/m2, 30 mg/m2, 35 mg/m2, 40 mg/m2, 45 mg/m2, 50 mg/m2, 55 mg/m2, 60 mg/m2, 65 mg/m2, 70 mg/m2, 75 mg/m2, 80 mg/m2, 85 mg/m2, 90 mg/m2, 95 mg/m2, or 100 mg/m2 (or any value in between of these values) . In some embodiments, Cisplatin is administered at about 40 to 80 mg/m2. In some embodiments, Cisplatin is administered at about 60 to 80 mg/m2.
In some embodiments, Cisplatin is administered intravenously. In some embodiments, Cisplatin is administered as an intravenous infusion over at least 2 hours. In some embodiments, Cisplatin is administered as an intravenous infusion over 6 to 8 hours. In some embodiments, Cisplatin is administered once every week. In some embodiments, Cisplatin is administered once every 3 weeks. In some embodiments, Cisplatin is administered on Day 1 once every 3 weeks. In some embodiments, Cisplatin is administered on Day 2 once every 3 weeks. In some embodiments, Cisplatin is administered on Days 1-3 every 3 weeks. In some embodiments, Cisplatin is administered on Days 1-5 every 3 weeks.
In some embodiments, Cisplatin is administered for 1 cycle. In some embodiments, Cisplatin is administered for 2 cycles. In some embodiments, Cisplatin is administered for 3  cycles. In some embodiments, Cisplatin is administered for 4 cycles. In some embodiments, a cycle is 3 weeks.
In some embodiments, Cisplatin is administered for 4 three-week cycles or more.
In some embodiments, Cisplatin is administered on Day 1 of each cycle. In some embodiments, Cisplatin is administered on Day 2 of each cycle. In some embodiments, Cisplatin is administered on Day 3 of each cycle. In some embodiments, Cisplatin is administered on Day 4 of each cycle. In some embodiments, Cisplatin is administered on Day 5 of each cycle.
In some embodiments, the methods described herein comprise administration of Cisplatin once every cycle, wherein each cycle is three weeks, on Day 1 of each cycle for, e.g., 4 cycles.
In some embodiments, the methods described herein comprise intravenous administration of from 40 to 80 mg/m2 Cisplatin on Day 1 of each 21 days cycle (and optionally wherein Cisplatin is infused over 2 hours or more) , and optionally the administration is for 4 cycles or more.
In some embodiments, the methods described herein comprise intravenous administration of from 60 to 80 mg/m2 Cisplatin on Day 1 of each 21 days cycle (and optionally wherein Cisplatin is infused over 2 hours or more) , and optionally the administration is for 4 cycles or more.
5-fluorouracil
In some embodiments, a patient described herein is administered 5-fluorouracil in combination with an anti-PD-1 and anti-LAG3 antibodies described herein. In some embodiments, a patient is administered 5-fluorouracil in combination with Tislelizumab and BGA-1953. In some embodiments, a patient is administered 5-fluorouracil in combination with an anti-PD-1 and anti-LAG3 antibodies described herein and cisplatin.
In some embodiments, 5-fluorouracil is administered parenterally. In some embodiments, 5-fluorouracil is administered at about 300 mg/m2, 350 mg/m2, 400 mg/m2, 450 mg/m2, 500 mg/m2, 550 mg/m2, 600 mg/m2, 650 mg/m2, 700 mg/m2, 750 mg/m2, 800 mg/m2, 850 mg/m2, 900 mg/m2, 950 mg/m2, 1000 mg/m2 (or any value in between of these values) . In some embodiments, 5-fluorouracil is administered at a dose of about 400 mg/m2 to about 800 mg/m2. In some embodiments, 5-fluorouracil is administered at about 600 to 800 mg/m2. In some embodiments, 5-fluorouracil is administered at about 750 to 800 mg/m2.
In some embodiments, 5-fluorouracil is administered intravenously. In some embodiments, 5-fluorouracil is administered as an intravenous infusion over at least 24 hours. In some embodiments, 5-fluorouracil is administered as an intravenous infusion over 24 hours. In some embodiments, 5-fluorouracil is administered five times every 3 weeks. In some embodiments, 5-fluorouracil is administered on Days 1-5 every 3 weeks.
In some embodiments, 5-fluorouracil is administered for 1 cycle. In some embodiments, 5-fluorouracil is administered for 2 cycles. In some embodiments, 5-fluorouracil is administered for 3 cycles. In some embodiments, 5-fluorouracil is administered for 4 cycles. In some embodiments, a cycle is 3 weeks.
In some embodiments, 5-fluorouracil is administered for 4 three-week cycles or more.
In some embodiments, 5-fluorouracil is administered on Day 1 of each cycle. In some embodiments, 5-fluorouracil is administered on Day 2 of each cycle. In some embodiments, 5-fluorouracil is administered on Day 3 of each cycle. In some embodiments, 5-fluorouracil is administered on Day 4 of each cycle. In some embodiments, 5-fluorouracil is administered on Day 5 of each cycle.
In some embodiments, the methods described herein comprise administration of 5-fluorouracil five times every cycle, wherein each cycle is three weeks, on Days 1-5 of each cycle, e.g., for at least 4 cycles.
In some embodiments, the methods described herein comprise intravenous administration of from 400 to 800 mg/m2 5-fluorouracil on Days 1-5 of each 21 days cycle (and optionally wherein 5-fluorouracil is infused over 24 hours or more) , and optionally the administration is for 4 cycles or more.
In some embodiments, the methods described herein comprise intravenous administration of from 600 to 800 mg/m2 5-fluorouracil on Days 1-5 of each 21 days cycle (and optionally wherein 5-fluorouracil is infused over 24 hours or more) , and optionally the administration is for 4 cycles or more.
In some embodiments, the methods described herein comprise intravenous administration of from 750 to 800 mg/m2 5-fluorouracil on Days 1-5 of each 21 days cycle (and optionally wherein 5-fluorouracil is infused over 24 hours or more) , and optionally the administration is for 4 cycles or more.
Paclitaxel
In some embodiments, a patient described herein is administered paclitaxel in combination with an anti-PD-1 and anti-LAG3 antibodies described herein. In some embodiments, a patient is administered paclitaxel in combination with Tislelizumab and BGA-1953. In some embodiments, a patient is administered paclitaxel in combination with an anti-PD-1 and anti-LAG3 antibodies described herein and cisplatin.
In some embodiments, paclitaxel is administered parenterally. In some embodiments, paclitaxel is administered at a dose of about 90 mg/m2 to about 175 mg/m2. In some embodiments, paclitaxel is administered at about 80 mg/m2, 85 mg/m2, 90 mg/m2, 95 mg/m2, 100 mg/m2, 105 mg/m2, 110 mg/m2, 115 mg/m2, 120 mg/m2, 125 mg/m2, 130 mg/m2, 135 mg/m2, 140 mg/m2, 145 mg/m2, 150 mg/m2, 155 mg/m2, 160 mg/m2, 165 mg/m2, 170 mg/m2, 175 mg/m2, 180 mg/m2, 185 mg/m2, or 190 mg/m2 (or any value in between of these values) . In some embodiments, paclitaxel is administered at about 135 to 175 mg/m2. In some embodiments, paclitaxel is administered at about 175 mg/m2.
In some embodiments, paclitaxel is administered intravenously. In some embodiments, paclitaxel is administered as an intravenous infusion over at least 2 hours. In some embodiments, paclitaxel is administered once every week. In some embodiments, paclitaxel is administered once every 3 weeks. In some embodiments, paclitaxel is administered on Day 1 once every 3 weeks.
In some embodiments, paclitaxel is administered for 1 cycle. In some embodiments, paclitaxel is administered for 2 cycles. In some embodiments, paclitaxel is administered for 3 cycles. In some embodiments, paclitaxel is administered for 4 cycles. In some embodiments, a cycle is 3 weeks.
In some embodiments, paclitaxel is administered for 4 three-week cycles or more.
In some embodiments, paclitaxel is administered on Day 1 of each cycle. In some embodiments, paclitaxel is administered on Day 2 of each cycle. In some embodiments, paclitaxel is administered on Day 3 of each cycle. In some embodiments, paclitaxel is administered on Day 4 of each cycle. In some embodiments, paclitaxel is administered on Day 5 of each cycle.
In some embodiments, the methods described herein comprise administration of paclitaxel once every cycle, wherein each cycle is three weeks, on Day 1 of each cycle for, e.g., 4 cycles.
In some embodiments, the methods described herein comprise intravenous administration of from 90 to 175 mg/m2 paclitaxel on Day 1 of each 21 days cycle (and optionally wherein paclitaxel is infused over 2 hours or more) , and optionally the administration is for 4 cycles or more.
In some embodiments, the methods described herein comprise intravenous administration of from 135 to 175 mg/m2 paclitaxel on Day 1 of each 21 days cycle (and optionally wherein Cisplatin is infused over 2 hours or more) , and optionally the administration is for 4 cycles or more.
In some embodiments, the methods described herein comprise intravenous administration of from 175 mg/m2 paclitaxel on Day 1 of each 21 days cycle (and optionally wherein Cisplatin is infused over 2 hours or more) , and optionally the administration is for 4 cycles or more.
Combination Therapies
The combination therapy may be administered as a simultaneous, or separate or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes co-administration, using separate formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or each of) active agents simultaneously exert their biological activities.
In some embodiments, the combination therapies provided herein provide a synergistic and/or statistically improved effect relative to either therapy when used as a single agent.
Suitable dosages for any of the above co-administered agents are those presently used and may be lowered due to the combined action (synergy) , such as to increase the therapeutic index or mitigate toxicity or other side-effects or consequences.
In some embodiments, the therapies described herein may be further combined with any other therapy. In some embodiments, the therapies described herein may be further combined with any therapy except any one or more therapies listed in the exclusion criteria described in the example section of this application.
In some embodiments, the combination therapy is any combination therapy described herein, including without limitation the combination therapies, dosing, duration and regimens described in the example section of this application. In some embodiments, the combination  therapy described herein can be combined with additional therapies consistent with the exclusion criteria described in the example section of this application (i.e., wherein the therapies listed in the exclusion criteria are excluded or not selected for the combination) . In some embodiments, the combination therapy described herein can be combined with additional therapies consistent with the inclusion criteria described in the example section of this application.
In some embodiments, the amounts of the antibodies disclosed herein and the one or chemotherapy drugs, as well as their relative timings of administration, be determined by the individual needs of the patient to be treated, administration route, severity of disease or illness, dosing schedule, as well as evaluation and judgment of the designated doctor.
In some embodiments, the anti-LAG3 antibody is administered before (e.g., 30 minutes or more before) administration of anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is administered before (e.g., 30 minutes or more before) administration of one or more chemotherapy drugs. In some embodiments, the anti-LAG3 antibody is administered before the anti-PD-1 antibody, and the anti-PD-1 antibody is administered before one or more chemotherapy drugs. In some embodiments, anti-Lag3 antibody, anti-PD-1 antibody and one or more chemotherapy drugs are each not to be administered concurrently, such as administered by separate infusions.
In some embodiments, the dosing, frequency and/or duration of administration of the anti-PD-1 antibody, anti-LAG3 antibody, and one or more chemotherapeutic agents is as described herein.
In some embodiments, the anti-LAG3 antibody, anti-PD-1 antibody and the one or more chemotherapeutic drugs described herein are administered on the same day.
In some embodiments, anti-LAG3 antibody (such as an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) ) is administered intravenously at a dose of 600 mg on Day 1 of each 21 cycle; anti-PD-1 antibody (such as an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) ) is administered intravenously at a dose of 200 mg on Day 1 of each 21 cycle; cisplatin is administered intravenously on Day 1 of each 21 day cycle; and 5-fluorouracil is administered intravenously on Days 1 to 5 of each 21 day cycle. In some of these embodiments, cisplatin is administered IV at 60 to 80 mg/m2 (and optionally infused over 6 to 8 hours) . In some of these embodiments, 5-fluorouracil is administered IV at 750-800 mg/m2 (and optionally  infused over 24 hours) . In some of these embodiments, in cycle 1, the anti-LAG3 antibody is infused over 60 (+/-5) minutes, then anti-PD-1 antibody is infused over 60 (+/-5) minutes, followed by administration of cisplatin and/or 5-FU. In some of these embodiments, in cycle 2 and subsequent cycles (if tolerated) , the anti-LAG3 antibody is infused over 30 (+/-5) minutes, then anti-PD-1 antibody is infused over 30 (+/-5) minutes, followed by administration of cisplatin and/or 5-FU.
In some embodiments, anti-LAG3 antibody (such as an anti-LAG3 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 37, and/or the Vl of SEQ ID NO: 38 (e.g., BGA-1953) ) is administered intravenously at a dose of 600 mg on Day 1 of each 21 cycle; anti-PD-1 antibody (such as an anti-PD-1 antibody comprising the CDRs described herein, the Vh of SEQ ID NO: 7, and/or the Vl of SEQ ID NO: 8 (e.g., Tislelizumab) ) is administered intravenously at a dose of 200 mg on Day 1 of each 21 cycle; cisplatin is administered intravenously on Day 1 of each 21 day cycle; and paclitaxel is administered intravenously on Days 1 to 5 of each 21 day cycle. In some of these embodiments, cisplatin is administered IV at 60 to 80 mg/m2 (and optionally infused over 6 to 8 hours) . In some of these embodiments, paclitaxel is administered IV at 175 mg/m2. In some of these embodiments, in cycle 1, the anti-LAG3 antibody is infused over 60 (+/-5) minutes, then anti-PD-1 antibody is infused over 60 (+/-5) minutes, followed by administration of cisplatin and/or paclitaxel. In some of these embodiments, in cycle 2 and subsequent cycles (if tolerated) , the anti-LAG3 antibody is infused over 30 (+/-5) minutes, then anti-PD-1 antibody is infused over 30 (+/-5) minutes, followed by administration of cisplatin and/or paclitaxel.
Cancers Treated As Provided Herein
Treatment regimens for esophageal cancer are disclosed herein. In some embodiments, the cancer is esophageal squamous cell carcinoma (ESCC) .
In some embodiments, the cancer is mid-stage esophageal cancer (e.g., ESCC) . In some embodiments, the cancer is late-stage esophageal cancer (e.g., ESCC) . In some embodiments, the cancer is locally advanced esophageal cancer (e.g., ESCC) . In some embodiments, the cancer is advanced stage esophageal cancer (e.g., ESCC) . In some embodiments, the esophageal cancer (e.g., ESCC) is unresectable. In some embodiments, the esophageal cancer (e.g., ESCC) is metastatic.
In some embodiments, the esophageal cancer (e.g., ESCC) is stage IV cancer. In some embodiments, the esophageal cancer (e.g., ESCC) is stage IVa cancer. In some embodiments, the esophageal cancer (e.g., ESCC) is stage IVb cancer.
In some embodiments, the esophageal cancer (e.g., ESCC) has not undergone prior treatment. In some embodiments, the esophageal cancer (e.g., ESCC) is unresectable locally advanced or metastatic and has not received any prior line therapy. In some embodiments, the esophageal cancer (e.g., ESCC) is metastatic and has not received prior chemotherapy (e.g., platinum-based) or immunotherapy.
In some embodiments, the human patient has received at least one prior line chemotherapy (e.g., platinum-based systemic anticancer therapy) . In some embodiments, the human patient has received at least one prior line chemotherapy (e.g., platinum-based systemic anticancer therapy) for unresectable locally advanced and/or metastatic ESCC.
In some embodiments, the esophageal cancer is chemotherapy-resistant. In some embodiments, the esophageal cancer has progressed after prior chemotherapy.
In some embodiments, the esophageal cancer (e.g., ESCC) is characterized by one or more of liver, lung, lymph node, bone, or adrenal gland metastasis. In some embodiments, the cancer is characterized by liver metastasis. In some embodiments, the cancer is characterized by lung metastasis. In some embodiments, the cancer is characterized by lymph node metastasis. In some embodiments, the cancer is characterized by bone metastasis. In some embodiments, the cancer is characterized by adrenal gland metastasis.
In some embodiments, the esophageal cancer (e.g., ESCC) is assessed for expression of immune-mediated biomarkers that are related to response or clinical benefit of the anti-PD-1 antibody, such as tislelizumab, e.g., using tumor biopsy. The biomarker can be, without limitation, PD-L1, TMB, GEP and MSI. Biomarkers expression can be assessed by multiplex immunohistochemistry assay (IHC) . The cancer to be treated can be a cancer that has a detectable expression of PD-L1. The cancer to be treated can be a cancer that has a detectable expression of TMB. The cancer to be treated can be a cancer that has a detectable expression of GEP (such as immune-mediated GEP) . The cancer to be treated can be a cancer that has a detectable expression of MSI.
In some embodiments, the cells of the cancer comprise high level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the total tumor area. In some embodiments, the cells of the cancer comprise a low level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the areas occupied by PD-L1 positive tumor and immune cells, divided by the  total tumor area. In some embodiments, PD-L1 expression has TAP score of equal to or more than 10%. In some embodiments, PD-L1 expression has TAP score of less than 10%.
In some embodiments, the cells of the cancer have intermediate or high tumor mutational burden, optionally wherein the tumor has more than 5 or between 5 and 20 mutations, more than 20 or between 20 and 50 mutations, or more than 50 mutations.
Patient Populations
In some embodiments, the patient is a mammal. In some embodiments, the mammal is human. In some embodiments, the patient is an adult. In some embodiments, the patient is 18 years of age or over 18 years of age. In some embodiments, the patient is over 40 years of age, over 45 years of age, over 50 years of age, over 55 years of age, over 60 years of age, over 65 years of age, over 70 years of age, over 75 years of age, or over 80 years of age. In some embodiments, the patient is 65 years or older. In some embodiments, the patient is 60 years or older.
In some embodiments, the patient is male. In some embodiments, the patient is female.
In some embodiments, the patient is a current smoker. In some embodiments, the patient is a former smoker. In some embodiments the patient has never smoked or was never a smoker.
In some embodiments, the subject has (e.g., has been diagnosed with) esophageal cancer. In some embodiments, the subject has any of the cancers described herein. In some embodiments, the subject has mid-stage cancer. In some embodiments, the subject has late-stage cancer. In some embodiments, the subject has (e.g., has been diagnosed with) ESCC. In some embodiments, the subject has (e.g., has been diagnosed with) unresectable locally advanced ESCC. In some embodiments, the subject has (e.g., has been diagnosed) with stage IV ESCC. In some embodiments, the subject has (e.g., has been diagnosed) with stage IVb ESCC.
In some embodiments, the subject has (e.g., has been diagnosed with) metastatic cancer. In some embodiments, the subject has one or more of liver, lung, lymph node, bone, and/or adrenal gland metastasis. In some embodiments, the subject has liver, lung or lymph node metastasis. In some embodiments, the subject has liver metastasis. In some embodiments, the subject has lung metastasis. In some embodiments, the subject has lymph node metastasis. In some embodiments, the subject has bone metastasis. In some embodiments,  the subject has adrenal gland metastasis. In some embodiments, the subject has 1, 2, 3, or more metastatic sites. In some embodiments, the subject has 1 or more metastatic sites. In some embodiments, the subject has 2 or more metastatic sites. In some embodiments, the subject has 3 or more metastatic sites. In some embodiments, the subject does not have brain metastasis. In other embodiments, the subject has brain metastasis.
In some embodiments, the subject has been diagnosed using histological markers. In some embodiments, the subject has been diagnosed using cytological markers. In some embodiments, the subject has been diagnosed using histological and cytological markers. In some embodiments, the subject has been diagnosed using a biopsy.
In some embodiments, the subject has not previously been treated with an immunotherapy. In some embodiments, the subject has not previously been treated with a chemotherapy (e.g., platinum-based chemotherapy) . In some embodiments, the subject has not previously been treated with any immune checkpoint inhibitor. In some embodiments, the subject has not previously been treated with an immunotherapy or a chemotherapy. In some embodiments, the subject has not previously been treated with an immunotherapy and/or a chemotherapy for the cancer being treated in accordance with the methods described herein.
In some embodiments, the subject has received prior chemotherapy treatment (e.g., for the cancer being treated) . In some embodiments, the subject has received prior immunotherapy treatment (e.g., for the cancer being treated) .
Uses and Methods of Treatment Provided Herein
In some embodiments, the disclosure relates to a method of treating esophageal cancer (such as ESCC) in a subject (e.g., a human) , the method comprising administering to the subject effective amounts of an anti-LAG3 antibody, an anti-PD-1 antibody and one or more chemotherapeutic drug. In some embodiments, the one or more chemotherapeutic drugs is cisplatin and 5-FU. In some embodiments, the one or more chemotherapeutic drugs is cisplatin and paclitaxel.
In some embodiment, the disclosure relates to a method of treating esophageal cancer (such as ESCC) in a subject (e.g., a human) , the method comprising administering to the subject an effective amounts of an anti-LAG3 antibody, an anti-PD-1 antibody, cisplatin and 5-FU. In some embodiment, the disclosure relates to a method of treating esophageal cancer (such as ESCC) in a subject (e.g., a human) , the method comprising administering to the subject an effective amounts of an anti-LAG3 antibody, an anti-PD-1 antibody, cisplatin and  paclitaxel. In some embodiments, the subject is treated in accordance with a treatment regimen (such as dosing, frequency and duration of the treatment) described herein.
In some embodiments, the methods described herein are for treating locally advanced unresectable ESCC.
In some embodiments, the methods described herein are for treating metastatic ESCC.
In some embodiments, the response to treatment is measured by overall survival, progression-free or event-free survival, overall response or objective response rate, complete response, partial response, and/or duration of response. In some embodiments, the response to treatment is measured by tumor volume.
The antibodies and one or more chemotherapeutic drugs disclosed herein may be administered parenterally. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. In some embodiments, the anti-LAG3, anti-PD-1 antibody and chemotherapeutic drug (s) may be administered by different routes. In some embodiments, the antibodies are administered intravenously, and the one or more chemotherapeutic drugs are also administered intravenously.
In some embodiments, described herein is a method of treating esophageal cancer (e.g., ESCC) in a subject in need thereof, comprising administering to the subject (i) a therapeutically effective amount of an anti-LAG3 antibody, wherein the LAG3 antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO: 37 and SEQ ID NO: 38, respectively; (ii) a therapeutically effective amount of an anti-PD-1 antibody, wherein the PD-1 antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO: 7 and SEQ ID NO: 8, respectively, and (iii) a therapeutically effective amount of one or more chemotherapeutic drugs. In some embodiments, the ESCC is unresectable and locally advanced. In some embodiments, the ESCC is metastatic. In some embodiments, the one or more chemotherapeutic drugs are (i) cisplatin and 5-FU, or (ii) cisplatin and paclitaxel.
In some embodiments, a subject is administered the described combination therapy in accordance with the dosage and regime of administration described in the examples provided herein.
Embodiments of the present disclosure also include the agents and combinations described herein (i) for use in, (ii) for use as a medicament or composition for, or (iii) for use in the preparation of a medicament for:
a. therapy (e.g., of the human body) ;
b. medicine;
c. induction of or augmenting an anti-tumor immune response;
d. decreasing the number of one or more tumor markers in a patient;
e. halting or delaying the growth of the cancer described herein;
f. halting or delaying the progression of the cancer described herein;
g. halting or delaying the progression of the cancer described herein;
h. stabilization of the cancer;
i. inhibiting the growth or survival of the cancer cells;
j. eliminating or reducing the size of one or more cancerous lesions;
k. reduction of the progression, onset or severity of the cancer described herein;
l. reducing the severity or duration of the clinical symptoms of the cancer described herein;
m. prolonging the survival of a patient relative to the expected survival in a similar untreated patient;
n. inducing complete or partial remission of the cancer described herein; or
o. treatment of the cancer described herein.
In some embodiments, the patient is responsive to treatment by one, two, three or more criteria described herein and/or known in the art. In some embodiments, the responsiveness criteria are any criterial described herein, including but not limited to those described in the example section of this application.
Pharmaceutical Composition
Provided herein are compositions, including pharmaceutical formulations, comprising an anti-LAG3 antibody or an antigen-binding fragment thereof described herein Provided herein are compositions, including pharmaceutical formulations, comprising an anti-PD-1 antibody or an antigen-binding fragment thereof described herein. Also provided herein are  compositions, including pharmaceutical formulations, comprising one or more chemotherapeutic drugs described herein.
Pharmaceutical formulations of any antibody as described herein are prepared by mixing such antibody or antigen-binding fragment 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, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes) ; and/or non-ionic surfactants such as polyethylene glycol (PEG) . In some embodiments, the surfactant is a polysorbate. Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP) , for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (Baxter International, Inc. ) . Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Nos. US 7,871,607 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171,586 and WO2006/044908, the latter formulations including a histidine-acetate buffer. In some embodiments, the formulations include a histidine-citric acid buffer. Sustained-release preparations can 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, e.g., films, or microcapsules. The formulations to be  used for in vivo administration are generally sterile. Sterility can be readily accomplished, e.g., by filtration through sterile filtration membranes.
In some embodiments, the pharmaceutical composition or formulation comprises a formulation buffer comprising histidine, acetate, citrate, succinate, phosphate, mixture of histidine and acetic acid, mixture of histidine and citric acid, salt or hydrate thereof, or any combination of them. In some embodiments, the formulation buffer comprises a histidine buffer that comprises histidine, histidine hydrochloride, L-histidine, L-histidine hydrochloride, L-histidine hydrochloride hydrate, L-histidine hydrochloride monohydrate, or a combination thereof. In some embodiments, the histidine buffer comprises L-histidine/L-histidine hydrochloride monohydrate buffer (His/His HCl) . In some embodiments, the histidine buffer comprises histidine/L-histidine hydrochloride monohydrate buffer and citric acid monohydrate. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine/L-histidine hydrochloride monohydrate) is between about 5 mM to about 30 mM. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine/L-histidine hydrochloride monohydrate) is between about 5 mM to about 10 mM, between about 5 mM to about 15 mM, between about 5 mM to about 20 mM, between about 10 mM to about 15 mM, between about 10 mM to about 20 mM, between about 10 mM to about 25 mM, between about 15 mM to about 20 mM, between about 15 mM to about 25 mM, between about 15 mM to about 30 mM, between about 20 mM to about 25 mM, or between about 25 mM to about 30 mM. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine/L-histidine hydrochloride monohydrate) is about 5 mM or more, about 10 mM or more, about 15 mM or more, about 20 mM or more, about 25 mM or more, about 30 mM or more. In some embodiments, the concentration of the histidine buffer (e.g., L-histidine/L-histidine hydrochloride monohydrate) is 10mM.
In some embodiments, the concentration of the histidine is about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM. In some embodiments, the concentration of the L-histidine hydrochloride monohydrate is about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM. In some embodiments, the formulation comprises histidine at a concentration of about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM, and L-histidine hydrochloride monohydrate at a concentration of about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM. In some embodiments, the formulation buffer is a mixture of histidine, L-histidine hydrochloride monohydrate, citric  acid monohydrate, and sodium citrate; wherein the formulation comprises histidine at a concentration of about 5-15 mM, in a preferred embodiment the concentration of histidine is about 11 mM, and L-histidine hydrochloride monohydrate at a concentration of about 1-5 mM, in a preferred embodiment the concentration of L-histidine hydrochloride monohydrate is about 4 mM, wherein the citric acid monohydrate is at a concentration of about 1-5 mM, preferably 2 mM, and sodium citrate is present at a concentration of 15-30 mM, preferably about 23 mM.
In some embodiments, the pharmaceutical composition or formulation comprises a stabilizer. In some embodiments, the stabilizer comprises trehalose, sucrose, sorbitol, mannitol, L-arginine hydrochloride, maltose, dextran, (2-hydroxypropyl) -b-cyclodextrin, sodium chloride, magnesium chloride, calcium chloride, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or a combination thereof. In some embodiments, the stabilizer comprises trehalose, sucrose, L-arginine hydrochloride, sodium chloride, or a combination thereof. In some embodiments, the stabilizer is trehalose. In some embodiments the trehalose is a-trehalose dihydrate.
In some embodiments, the concentration of the stabilizer is between about 50 mM to about 300 mM. In some embodiments, the concentration of the stabilizer is between about 50 mM to about 100 mM, between about 50 mM to about 150 mM, between about 50 mM to about 200 mM, between about 100 mM to about 150 mM, between about 100 mM to about 200 mM, between about 100 mM to about 250 mM, between about 150 mM to about 200 mM, between about 150 mM to about 250 mM, or between about 150 mM to about 300 mM. In some embodiments, the concentration of the stabilizer is about 50 mM or more, about 60 mM or more, about 70 mM or more, about 80 mM or more, about 90 mM or more, about 100 mM or more, about 110 mM or more, about 120 mM or more, about 130 mM or more, about 140 mM or more, about 150 mM or more, about 160 mM or more, about 170 mM or more, about 180 mM or more, about 190 mM or more, about 200 mM or more, about 210 mM or more, about 220 mM or more, about 230 mM or more, about 240 mM or more, about 250 mM or more, about 260 mM or more, about 270 mM or more, about 280 mM or more, about 290 mM or more, or about 300 mM or more. In some embodiments, the concentration of the stabilizer is about 190 mM.
In some embodiments, the pharmaceutical composition or formulation comprises a non-ionic surfactant. In some embodiments, the non-ionic surfactant comprises polysorbate 80 (PS80) , polysorbate 20 (PS20) , poloxamer188 (P188) , or a combination thereof. In some  embodiments, the non-ionic surfactant is PS20. In some embodiment, the concentration of the non-ionic surfactant is between about 0.01%to about 1%. In some embodiments, the concentration of the non-ionic surfactant is between about 0.01%to about 0.03%, between about 0.01%to about 0.06%, between about 0.01%to about 0.09%, between about 0.03%to about 0.06%, between about 0.03%to about 0.09%, between about 0.03%to about 0.2%, between about 0.06%to about 0.09%, between about 0.06%to about 0.2%, between about 0.06%to about 0.5%, between about 0.09%to about 0.2%, between about 0.09%to about 0.5%, between about 0.09%to about 0.8%, between about 0.2%to about 0.5%, between about 0.2%to about 0.8%, between about 0.2%to about 1%, between about 0.5%to about 0.8%, between about 0.5%to about 1%, or between about 0.8%to about 1%. In some embodiments, the concentration of the non-ionic surfactant is about 0.01%or more, is about 0.02%or more, is about 0.03%or more, is about 0.04%or more, is about 0.05%or more, is about 0.06%or more, is about 0.07%or more, is about 0.08%or more, is about 0.09%or more, is about 0.1%or more, is about 0.2%or more, is about 0.3%or more, is about 0.4%or more, is about 0.5%or more, is about 0.6%or more, is about 0.7%or more, is about 0.8%or more, is about 0.9%or more, or is about 1%or more. In some embodiments, the concentration of the non-ionic surfactant is 0.2%.
In some embodiments, the pharmaceutical composition or formulation comprises between about 1 mg/ml to about 10 mg/ml of the multi-specific antibody or antigen-binding fragment as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises between about 1 mg/ml to about 2 mg/ml, between about 1 mg/ml to about 3 mg/ml, between about 1 mg/ml to about 4 mg/ml, between about 2 mg/ml to about 3 mg/ml, between about 2 mg/ml to about 4 mg/ml, between about 2 mg/ml to about 5 mg/ml, between about 3 mg/ml to about 4 mg/ml, between about 3 mg/ml to about 5 mg/ml, between about 3 mg/ml to about 6 mg/ml, between about 4 mg/ml to about 5 mg/ml, between about 4 mg/ml to about 6 mg/ml, between about 4 mg/ml to about 7 mg/ml, between about 5 mg/ml to about 6 mg/ml, between about 5 mg/ml to about 7 mg/ml, between about 5 mg/ml to about 8 mg/ml, between about 6 mg/ml to about 7 mg/ml, between about 6 mg/ml to about 8 mg/ml, between about 6 mg/ml to about 9 mg/ml, between about 7 mg/ml to about 8 mg/ml, between about 7 mg/ml to about 9 mg/ml, between about 7 mg/ml to about 10 mg/ml, between about 8 mg/ml to about 9 mg/ml, between about 8 mg/ml to about 10 mg/ml, or between about 9 mg/ml to about 10 mg/ml of the multi-specific antibody or antigen-binding fragment as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises about 1 mg/ml or more, 2 mg/ml or more, 3 mg/ml or more, 4 mg/ml or more, 5 mg/ml or  more, 6 mg/ml or more, 7 mg/ml or more, 8 mg/ml or more, 9 mg/ml or more, or 10 mg/ml or more of the multi-specific antibody or antigen-binding fragment as disclosed herein. In some embodiments, the pharmaceutical composition or formulation comprises 10 mg/ml of the antibody (e.g., PD-1 antibody or tislelizumab) as disclosed herein.
In some embodiments, the pharmaceutical composition or formulation has a pH of between about 4.5 to about 7.5. In some embodiments, the pharmaceutical composition or formulation has a pH of between about 4.5 to about 5.0, between about 4.5 to about 5.5, between about 4.5 to about 6.0, between about 5.0 to about 5.5, between about 5.0 to about 6.0, between about 5.0 to about 6.5, between about 5.5 to about 6.0, between about 5.5 to about 6.5, between about 5.5 to about 7.0, between about 6.0 to about 6.5, between about 6.0 to about 7.0, between about 6.0 to about 7.5, between about 6.5 to about 7.0, between about 6.5 to about 7.5, or between about 7.0 to about 7.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 or more, about 5.0 or more, about 5.5 or more, about 6.0 or more, about 6.5 or more, about 7.0 or more, or about 7.5 or more. In some embodiments, the pharmaceutical composition or formulation has a pH of 6.5.
In some embodiments, the antibody (e.g. PD-1 antibody or tislelizumab) is formulated in a pharmaceutical composition comprising a histidine buffer, a surfactant and a stabilizer. In some embodiments, the surfactant is a polysorbate. In some embodiments, the stabilizer is trehalose. In a particular embodiment, the PD-1 antibody (e.g. tislelizumab) is formulated in a pharmaceutical composition comprising citric acid monohydrate, histidine, L-histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, and trehalose.
The term “pharmaceutical composition” refers to preparations with pharmaceutically acceptable excipients which are in such form as to permit the active ingredients to be effective, and which contains no additional components which are toxic to the subjects to which the composition would be administered. In some embodiments, a pharmaceutical composition may be formulated for administration in solid or liquid form, comprising, without limitation, a form adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) , tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream,  or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces. In some aspects, the present disclosure provides compositions, e.g., pharmaceutically acceptable compositions, which include an anti-PD-1 antibody described herein, formulated together with at least one pharmaceutically acceptable excipient.
The term “pharmaceutically acceptable” refers to a molecule or composition that, when administered to a recipient, is not deleterious to the recipient thereof, or that any deleterious effect is outweighed by a benefit to the recipient thereof.
Some examples of materials which may serve as pharmaceutically acceptable carriers comprise: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.
A “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion) .
The compositions disclosed herein can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusion solutions) , dispersions or suspensions, liposomes, and suppositories. A suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusion solutions. One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular) . In some embodiments, the antibody is administered by intravenous infusion or injection. In some embodiments, the antibody is administered by intramuscular or subcutaneous injection. In some embodiments, the antibody is administered by way of a syringe infusion system.
Kits
The present disclosure, among other things, provides kits comprising ati-LAG3 and anti-PD-1 antibodies or antigen-binding fragments thereof, and instructions for use and/or administration. In some embodiments, a kit comprises at least one anti-LAG3 antibody or antigen-binding fragment thereof, at least one anti-PD-1 antibody or antigen-binding fragment thereof, at least one chemotherapeutic agent, and a pharmaceutically acceptable carrier, and instructions for use and/or administration.
Also provided are kits for use in various methods disclosed herein. Instructions can comprise a description of administering of one or more pharmaceutical compositions described herein to a subject to achieve an intended activity in a subject. A kit may further comprise a description of selecting a human suitable for treatment based on identifying whether the human is in need of treatment.
Instructions generally include information as to dosage, dosing schedule, and route of administration for an intended treatment. Containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in kits of the disclosure are typically written instructions on a label or package insert. A label or package insert may indicate that one or more pharmaceutical compositions described herein are used for treating, delaying the onset, and/or alleviating a disease, disorder or condition in a subject.
In some embodiments, kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Also contemplated are packages for use in combination with a specific device, such as an infusion device. A kit may have a sterile access port (for example, a container may be an intravenous solution bag or a vial having a stopper pierce able by a hypodermic injection needle) . A container may also have a sterile access port.
Kits can include additional components such as buffers and interpretive information. A kit can comprise a container and a label or one or more package inserts on or associated with a container. In some embodiment, the disclosure provides articles of manufacture comprising contents of kits described above.
Definitions
Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art.
As used herein, including the appended claims, the singular forms of words such as “a, ” “an, ” and “the, ” include their corresponding plural references unless the context clearly dictates otherwise.
The term “or” is used to mean, and is used interchangeably with, the term “and/or” unless the context clearly dictates otherwise.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise” , and variations such as “comprises” and “comprising” , will be understood to imply the inclusion of a stated amino acid sequence, DNA sequence, step or group thereof, but not the exclusion of any other amino acid sequence, DNA sequence, step. When used herein the term “comprising” can be substituted with the term “containing” , “including” or sometimes “having” .
Unless specifically stated or evident from context, as used herein, the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “comprising essentially of” can mean within one or more than one standard deviation per the practice in the art. “About” or “comprising essentially of” can mean a range of up to 10% (i.e., ±10%) . Thus, “about” can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.001%greater or less than the stated value. For example, about 5 mg can include any amount between 4.5 mg and 5.5 mg. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the instant disclosure, unless otherwise stated, the meaning of “about” or “comprising essentially of” should be assumed to be within an acceptable error range for that particular value or composition.
Numeric ranges are inclusive of the numbers defining the range.
The term “anti-cancer agent” as used herein refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.
The terms “administration, ” “administering, ” “treating, ” and “treatment” herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid,  means contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. The term “administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human. Treating any disease or disorder refer in one aspect, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another aspect, “treat, ” “treating, ” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another aspect, “treat, ” “treating, ” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both. In yet another aspect, “treat, ” “treating, ” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
The term “subject” in the context of the present disclosure is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein) .
The term “affinity” as used herein refers to the strength of interaction between antibody and antigen. Within the antigen, the variable region of the antibody “arm” interacts through non-covalent forces with the antigen at numerous sites; the more interactions, the stronger the affinity.
The term “antibody” as used herein refers to a polypeptide of the immunoglobulin family that can bind a corresponding antigen non-covalently, reversibly, and in a specific manner. For example, a naturally occurring IgG antibody is a tetramer comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs) , interspersed with  regions that are more conserved, termed framework regions (FR) . Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
The term “antibody” includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and anti-idiotypic (anti-Id) antibodies. The antibodies can be of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA and IgY) , or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) .
The term “monoclonal antibody” or “mAb” or “Mab” herein means a population of substantially homogeneous antibodies, i.e., the antibody molecules comprised in the population are identical in amino acid sequence except for possible naturally occurring mutations that can be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their complementarity determining regions (CDRs) , which are often specific for different epitopes. 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. Monoclonal antibodies (mAbs) can be obtained by methods known to those skilled in the art. See, for example Kohler et al., Nature 1975 256: 495-497; U.S. Pat. No. 4,376,110; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY 1992; Harlow et al., ANTIBODIES: A LABORATORY MANUAL, Cold spring Harbor Laboratory 1988; and Colligan et al., CURRENT PROTOCOLS IN IMMUNOLOGY 1993. The antibodies disclosed herein can be of any immunoglobulin class including IgG, IgM, IgD, IgE, IgA, and any subclass thereof such as IgG1, IgG2, IgG3, IgG4. A hybridoma producing a monoclonal antibody can be cultivated in vitro or in vivo. High titers of monoclonal antibodies can be obtained in in vivo production where cells from the individual hybridomas are injected intraperitoneally into mice, such as pristine-primed Balb/c mice to produce ascites fluid containing high concentrations of the desired antibodies. Monoclonal antibodies of isotype IgM or IgG can be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
In general, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light chain” (about 25 kDa) and one “heavy chain” (about 50-70 kDa) . The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain can define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy chains are typically classified as α, δ, ε, γ, or μ, and define the antibody's isotypes as IgA, IgD, IgE, IgG, and IgM, respectively. Within light and heavy chains, the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids.
The variable regions of each light/heavy chain (VL/VH) pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are, in general, the same.
Typically, the variable domains of both the heavy and light chains comprise three hypervariable regions, also called “complementarity determining regions (CDRs) , ” which are located between relatively conserved framework regions (FR) . The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C-terminal, both light and heavy chain variable domains comprise FR-1 (or FR1) , CDR-1 (or CDR1) , FR-2 (FR2) , CDR-2 (CDR2) , FR-3 (or FR3) , CDR-3 (CDR3) , and FR-4 (or FR4) . The positions of the CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, and AbM (see, e.g., Johnson et al., Nucleic Acids Res., 29: 205-206 (2001) ; Chothia and Lesk, J. Mol. Biol., 196: 901-917 (1987) ; Chothia et al., Nature, 342: 877-883 (1989) ; Chothia et al., J. Mol. Biol., 227: 799-817 (1992) ; Al-Lazikani et al., J. Mol. Biol., 273: 927-748 (1997) ) . Definitions of antigen combining sites are also described in the following: Ruiz et al., Nucleic Acids Res., 28: 219-221 (2000) ; and Lefranc, M. P., Nucleic Acids Res., 29: 207-209 (2001) ; MacCallum et al., J. Mol. Biol., 262: 732-745 (1996) ; and Martin et al., Proc. Natl. Acad. Sci. USA, 86: 9268-9272 (1989) ; Martin et al., Methods Enzymol., 203: 121-153 (1991) ; and Rees et al., In Sternberg M. J. E. (ed. ) , Protein Structure Prediction, Oxford University Press, Oxford, 141-172 (1996) . In a combined Kabat and Chothia numbering scheme, in some embodiments, the CDRs correspond to the amino acid residues that are part of a Kabat CDR, a Chothia CDR, or both. For example, the CDRs correspond to amino acid residues 26-35 (HC CDR1) , 50-65 (HC CDR2) , and 95- 102 (HC CDR3) in a VH, e.g., a mammalian VH, e.g., a human VH; and amino acid residues 24-34 (LC CDR1) , 50-56 (LC CDR2) , and 89-97 (LC CDR3) in a VL, e.g., a mammalian VL, e.g., a human VL.
The term “hypervariable region” means the amino acid residues of an antibody that are responsible for antigen-binding. The hypervariable region comprises amino acid residues from a “CDR” (i.e., VL-CDR1, VL-CDR2 and VL-CDR3 in the light chain variable region and VH-CDR1, VH-CDR2 and VH-CDR3 in the heavy chain variable domain) . See, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (defining the CDR regions of an antibody by sequence) ; see also Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917 (defining the CDR regions of an antibody by structure) . The term “framework” or “FR” residues means those variable domain residues other than the hypervariable region residues defined herein as CDR residues.
Unless otherwise indicated, an “antigen-binding fragment” means antigen-binding fragments of antibodies, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g., fragments that retain one or more CDR regions. Examples of antigen-binding fragments include, but not limited to, Fab, Fab', F (ab') 2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., single chain Fv (ScFv) ; nanobodies and multispecific antibodies formed from antibody fragments.
An antibody “specifically binds” to a target protein, meaning the antibody exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies or antigen-binding fragments thereof, useful in the current disclosure will bind to the target protein with an affinity that is at least two fold greater, preferably at least 10-times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins. An antibody herein is said to bind specifically to a polypeptide comprising a given amino acid sequence, if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.
The term “human antibody” herein means an antibody that comprises human immunoglobulin protein sequences only. Similarly, “mouse antibody” or “rat antibody” mean an antibody that comprises only mouse or rat immunoglobulin protein sequences, respectively.
The term “humanized antibody” means forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the 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 and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc) , typically that of a human immunoglobulin. The prefix “hum, ” “hu, ” “Hu, ” or “h” is added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions can be included to increase affinity, increase stability of the humanized antibody, remove a post-translational modification or for other reasons.
The term “corresponding human germline sequence” refers to the nucleic acid sequence encoding a human variable region amino acid sequence or subsequence that shares the highest determined amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other known variable region amino acid sequences encoded by human germline immunoglobulin variable region sequences. The corresponding human germline sequence can also refer to the human variable region amino acid sequence or subsequence with the highest amino acid sequence identity with a reference variable region amino acid sequence or subsequence in comparison to all other evaluated variable region amino acid sequences. The corresponding human germline sequence can be framework regions only, complementarity determining regions only, framework and complementary determining regions, a variable segment (as defined above) , or other combinations of sequences or subsequences that comprise a variable region. Sequence identity can be determined using the methods described herein, for example, aligning two sequences using BLAST, ALIGN, or another alignment algorithm known in the art. The corresponding human germline nucleic acid or amino acid sequence can have at least about 90%, 91, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity with the reference variable region nucleic acid or amino acid sequence.
The term “equilibrium dissociation constant (KD, M) ” refers to the dissociation rate constant (kd, time-1) divided by the association rate constant (ka, time-1, M-l) . Equilibrium  dissociation constants can be measured using any known method in the art. The antibodies of the present disclosure generally will have an equilibrium dissociation constant of less than about 10-7 or 10-8 M, for example, less than about 10-9 M or 10-10 M, in some aspects, less than about 10-11 M, 10-12 M or 10-13 M.
The terms “cancer” or “tumor” herein has the broadest meaning as understood in the art and refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of the present disclosure, the cancer is not limited to certain type or location.
The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner. Such administration also encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids can be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
In the context of the present disclosure, when reference is made to an amino acid sequence, the term “conservative substitution” means substitution of the original amino acid by a new amino acid that does not substantially alter the chemical, physical and/or functional properties of the antibody or fragment. Specifically, common conservative substitutions of amino acids are well known in the art.
Examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST algorithms, which are described in Altschul et al., Nuc. Acids Res. 25: 3389-3402, 1977; and Altschul et al., J. Mol. Biol. 215: 403-410, 1990, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold. These initial neighborhood word hits act as values for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each  sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0) . For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLAST program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.
The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90: 5873-5787, 1993) . One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N) ) , which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.
The percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci. 4: 11-17, (1988) , which has been incorporated into the ALIGN program (version 2.0) , using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch, J. Mol. Biol. 48: 444-453, (1970) , algorithm which has been incorporated into the GAP program in the GCG software package using either a BLOSUM62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
The term “nucleic acid” is used herein interchangeably with the term “polynucleotide” and refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single-or double-stranded form. The term encompasses nucleic acids containing known nucleotide  analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs) .
The term “operably linked” in the context of nucleic acids refers to a functional relationship between two or more polynucleotide (e.g., DNA) segments. Typically, it refers to the functional relationship of a transcriptional regulatory sequence to a transcribed sequence. For example, a promoter or enhancer sequence is operably linked to a coding sequence if it stimulates or modulates the transcription of the coding sequence in an appropriate host cell or other expression system. Generally, promoter transcriptional regulatory sequences that are operably linked to a transcribed sequence are physically contiguous to the transcribed sequence, i.e., they are cis-acting. However, some transcriptional regulatory sequences, such as enhancers, need not be physically contiguous or located in close proximity to the coding sequences whose transcription they enhance.
In some aspects, the present disclosure provides compositions, e.g., pharmaceutically acceptable compositions, which include an anti-PD1 antibody and/or anti-LAG3 antibody described herein, formulated together with at least one pharmaceutically acceptable excipient. As used herein, the term “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion) .
The compositions disclosed herein can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusion solutions) , dispersions or suspensions, liposomes, and suppositories. A suitable form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusion solutions. One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular) . In some embodiments, the antibody is administered by intravenous infusion or injection. In certain embodiments, the antibody is administered by intramuscular or subcutaneous injection.
The term “therapeutically effective amount” as herein used, refers to the amount of an antibody that, when administered to a subject for treating a disease, or at least one of the  clinical symptoms of a disease or disorder, is sufficient to effect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary with the antibody, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In the case of combination therapy, the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
EXAMPLES
Example 1: Clinical Study of Efficacy and Safety of an anti-LAG3 antibody (LBL-007) in Combination with an anti-PD1 antibody (Tislelizumab) Plus Chemotherapy as First-Line Treatment in Patients With Unresectable Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma
This example describes a Phase 2, Randomized, Active-Controlled, Open-Label Study of the Efficacy and Safety of an anti-LAG3 antibody (LBL-007) in Combination With an anti-PD1 antibody (Tislelizumab) Plus Chemotherapy as First-Line Treatment in Patients With Unresectable Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma.
Primary Objectives and Endpoints
i. Objectives
Evaluation of the efficacy of LBL-007 in combination with tislelizumab plus chemotherapy versus tislelizumab plus chemotherapy as measured by overall response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1, when given as the first-line treatment in patients with unresectable, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) .
ii. Endpoints
ORR is defined as the proportion of patients whose best overall response (BOR) is complete response (CR) or partial response (PR) as assessed by the investigator per RECIST v1.1.
Secondary Objectives and Endpoints
i. Objectives
(1) Evaluation of the efficacy of LBL-007 in combination with tislelizumab plus chemotherapy compared to tislelizumab plus chemotherapy as the first-line treatment in unresectable, locally advanced or metastatic ESCC as measured by progression-free survival  (PFS) , duration of response (DOR) , and disease control rate (DCR) assessed by the investigator per RECIST v1.1
(2) Evaluation of the safety of LBL-007 in combination with tislelizumab plus chemotherapy as the first-line treatment in patients with unresectable, locally advanced or metastatic ESCC.
ii. Endpoints
(1) Progression-free Survival (PFS) -defined as the time from the date of randomization to the date of first documentation of disease progression assessed by the investigator per RECIST v1.1 or death, whichever occurs first.
(2) Duration of Response (DOR) -defined as the time from the first determination of an overall response until the first documentation of progression assessed by the investigator per RECIST v1.1 or death, whichever comes first.
(3) Disease Control Rate (DCR) -defined as the proportion of patients whose BOR is CR, PR, and stable disease as assessed by the investigator per RECIST v1.1.
(4) The incidence and severity of adverse events (AEs) according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.
Other Study Objectives and Endpoints
i. Objectives
(1) Comparing the overall survival (OS) of LBL-007 in combination with tislelizumab plus chemotherapy versus tislelizumab plus chemotherapy.
(2) Assessing predictive, prognostic, and pharmacodynamic biomarkers, including any association with response to study treatment and mechanism (s) of resistance.
ii. Endpoints
(1) Overall Survival (OS) -defined as the time from the date of randomization until the date of death due to any cause.
(2) Evaluation of biomarkers from patient derived tumor tissue (s) and blood (or blood derivative) samples obtained before, during, and/or after treatment. Candidate biomarkers include, but are not limited to, programmed cell death protein-ligand 1 (PD‐L1) expression, (lymphocyte activation gene-3) LAG-3 expression, LAG-3 ligands expression, gene expression profile (GEP) , tumor mutational burden (TMB) /microsatellite instability (MSI) /DNA mutation analysis in tumor tissue, concentrations of cytokine/chemokine and  soluble proteins in plasma or serum, and blood tumor mutational burden (bTMB) /circulating tumor DNA (ctDNA) /DNA. mutation profile in peripheral blood.
(3) Serum concentrations of tislelizumab and LBL-007 at specified timepoints.
(4) Immunogenic responses to LBL-007 and tislelizumab, evaluated through the detection of antidrug antibodies (ADAs) .
Study Design
The study was designed as a randomized, active-controlled, open-label, Phase 2 study to compare the efficacy of treatment with LBL-007 in combination with tislelizumab plus chemotherapy versus tislelizumab plus chemotherapy when given as the first-line treatment in patients with unresectable, locally advanced or metastatic ESCC (i.e., Stage IV disease at the initial diagnosis of ESCC, or patients who have unresectable, recurrent, locally advanced or metastatic disease with at least a 6-month treatment-free interval, after previous curative intended treatment including surgery with/without neoadjuvant or adjuvant treatment, or definitive chemoradiation) . Staging criteria for this study are defined by the American Joint Committee on Cancer (AJCC) , 8th Edition.
Treatment Period
After completing all screening activities, approximately 116 patients are randomized with a 2: 1 ratio to receive either LBL-007 in combination with tislelizumab plus chemotherapy or tislelizumab plus chemotherapy. Patient randomization is stratified by baseline PD-L1 expression status TAP score (TAP ≥ 10%or TAP < 10%) by the Ventana PD-L1 (SP263) assay. Patients to begin treatment with one of the following regimens after randomization (Depicted in FIG. 1 and outlined in Table 1 and Table 2) :
Arm A: LBL-007 + tislelizumab + chemotherapy doublet
·LBL-007 is administered at a dose of 600 mg intravenously once every 3 weeks, on Day 1 of every 21-day cycle.
·Tislelizumab is administered at a dose of 200 mg intravenously once every 3 weeks, on Day 1 of every 21-day cycle.
·The chemotherapy is: cisplatin + 5-FU OR cisplatin + paclitaxel:
Cisplatin + 5-FU
Cisplatin 60 to 80 mg/m2 intravenously on Day 1 of every 21-day cycle, once every 3 weeks + 5-FU 750 to 800 mg/m2 intravenously continuous infusion over 24 hours daily on Days 1 to 5, once every 3 weeks
OR
Cisplatin + paclitaxel
Cisplatin 60 to 80 mg/m2 intravenously on Day 1 of every 21-day cycle, once every 3 weeks + Paclitaxel 175 mg/m2 intravenously on Day 1 of every 21-day cycle, once every 3 weeks
Arm B: tislelizumab + chemotherapy doublet
·Tislelizumab is administered at a dose of 200 mg intravenously once every 3 weeks, on Day 1 of every 21-day cycle.
·The chemotherapy is: cisplatin + 5-FU OR cisplatin + paclitaxel:
Cisplatin + 5-FU
Cisplatin 60 to 80 mg/m2 intravenously on Day 1 of every 21-day cycle, once every 3 weeks + 5-FU 750 to 800 mg/m2 intravenously continuous infusion over 24 hours daily on Days 1 to 5, once every 3 weeks
OR
Cisplatin + paclitaxel
Cisplatin 60 to 80 mg/m2 intravenously on Day 1 of every 21-day cycle, once every 3 weeks + Paclitaxel 175 mg/m2 intravenously on Day 1 of every 21-day cycle, once every 3 weeks

a 5-FU 750 to 800 mg/m2 via intravenously continuous infusion over 24 hours daily on Day 1 to Day 5 once every 3 weeks is administered for patients who were selected to with 5-FU treatment.
b Cisplatin therapy may be stopped after 6 cycles, per site or investigator preference or standard practice. If platinum treatment is stopped, 5-FU or paclitaxel may continue at the regular schedule.
The selection of chemotherapy regimen is determined by the investigator according to local standard practice or clinical practice before randomization. The study treatments are to start within 2 days after randomization, and treatment is to continue until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met (whichever occurs first) . Treatment with cisplatin may be stopped after 6 cycles, as per site or investigator preference or standard practice. If cisplatin treatment is stopped, the 5-FU or paclitaxel may continue at the regular schedule if appropriate; treatment with LBL-007 and tislelizumab will continue until a treatment discontinuation criterion is met.
In both arms, treatment beyond the initial RECIST v1.1 defined disease progression is permitted provided that the patient has investigator-assessed clinical benefit and is tolerating the drug. The following criteria must be met to treat patients after initial evidence of radiological disease progression:
·Absence of clinical symptoms and signs of disease progression (including clinically significant worsening of laboratory values) .
·Stable ECOG Performance Status ≤ 1
·Absence of a rapid progression of disease or of a progressive tumor at critical anatomical sites (e.g., spinal cord compression) that requires urgent alternative medical intervention.
Safety is assessed throughout the study by monitoring adverse events/serious adverse events (toxicity grades assigned per NCI-CTCAE v5.0) and laboratory results. Vital signs, physical examinations, ECOG Performance Status change, electrocardiogram (ECG) results, and other examinations are also used for safety assessment.
To determine the PK properties of LBL-007 and tislelizumab and the host immunogenic response to LBL-007 and tislelizumab, blood samples are collected.
Dosage Administration
i. LBL-007 and Tislelizumab Treatment
In Arm A, LBL-007 600 mg is administered followed by tislelizumab 200 mg on Day 1 of each 21-day cycle (once every 3 weeks) .
In Arm B, only tislelizumab 200 mg is administered on Day 1 of each 21-day cycle (once every 3 weeks) .
All drugs are prepared and administered as separate infusions and are not concurrently administered with any other drug. Specific instructions for product preparation and administration are provided in the Pharmacy Manual.
All drugs are administered by intravenous infusion through an intravenous line containing a sterile, nonpyrogenic, low-protein-binding 0.2-or 0.22-micron in-line or add-on filter. Use of a volumetric pump is recommended to control the infusion speed and to avoid potential infusion reactions associated with too rapid administration. The pump may not be needed if the infusion speed is controlled through alternative means.
ii. Chemotherapy Option-1: Cisplatin in Combination with 5-Fluorouracil
Cisplatin is administered on Day 1, then given once every 3 weeks at a dose of 60 to 80 mg/m2 by intravenous infusion over 6 to 8 hours (or in doses consistent with treatment guidelines and standards) . 5-FU is administered on Days 1 to 5, given once every 3 weeks at a dose of 750 to 800 mg/m2 by continuous intravenous infusion over 24 hours. The actual infusion time of 5-FU should be recorded, and a total infusion time of 120 ± 3 hours is acceptable. The initial treatment of cisplatin in combination with 5-FU is administered within 2 business days of randomization. Alternate dose and dosing schedules are allowed according to treatment guidelines and standards.
The first doses of cisplatin and 5-FU are dependent upon the patient’s baseline body weight. Subsequent doses must be recalculated if the change of body weight (increase or decrease) from baseline ≥ 10%. If the dose is recalculated because of a ≥ 10%change in body weight from baseline, this body weight will then be used as the new baseline to calculate the platinum and 5-FU dose in subsequent cycles.
Premedication is recommended before infusion of cisplatin. The premedication regimen should be administered as close to treatment as possible. Premedication may consist of hydration with 1 to 2 liters of fluid infused 8 to 12 hours before dosing. The use of diuretics for fluid maintenance is allowable.
There is a 3-day window for all treatments in subsequent cycles. If dosing is delayed, the subsequent dosing visit should be scheduled as clinically appropriate.
Patients are monitored continuously for adverse events. Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of therapy.
iii. Chemotherapy Option-2: Cisplatin in Combination with Paclitaxel
Cisplatin is administered on Day 1, then given every 21 days at a dose of 60 to 80 mg/m2 by intravenous infusion over 6 to 8 hours (or in doses consistent with treatment guidelines and standards) .
Paclitaxel is administered on Day 1, then given once every 3 weeks at a dose of 175 mg/m2 by intravenous infusion over 3 hours. The initial treatment of cisplatin in combination with paclitaxel is administered within 2 business days of randomization. Alternate dose and dosing schedules are allowed according to treatment guidelines and standards) .
The first doses of cisplatin and paclitaxel are dependent upon the patient’s baseline body weight. Subsequent doses should be recalculated if the change (increase or decrease) of body weight from baseline ≥ 10%. If the dose is recalculated because of a ≥ 10%change in body weight from baseline, this body weight will then be used as the new baseline to calculate the platinum and paclitaxel dose in subsequent cycles.
Premedication is recommended before infusion of cisplatin. The premedication regimen should be administered as close to treatment as possible. Premedication may consist of hydration with 1 to 2 liters of fluid infused 8 to 12 hours before dosing.
Premedication is recommended before infusion of paclitaxel. The premedication regimen should be administered as close to treatment as possible. Premedication may consist of an oral steroid (such as dexamethasone 8 to 20 mg or equivalent administered 6 to 12 hours orally or 30 to 60 minutes intravenously before paclitaxel) , an antihistamine (H1 antagonist such as diphenhydramine hydrochloride 50 mg intravenously or equivalent, or H2 antagonist such as cimetidine 300 mg intravenously or equivalent) , and an antiemetic (such as ondansetron 8 mg/kg intravenously or equivalent administered 30 to 120 minutes before paclitaxel) .
There is a 3-day window for all treatments in subsequent cycles. If dosing is delayed, the subsequent dosing visit should be scheduled as clinically appropriate.
Patients will be monitored continuously for adverse events. Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of therapy.
Dose Interruption or Delay for LBL-007 and Tislelizumab
If a dose delay is required, both treatments are to be delayed (i.e., LBL-007 and tislelizumab must both be delayed and, if applicable, restarted at the same time) . Exceptions may be considered.
If treatment is delayed because of treatment-emergent adverse events, treatment may resume only after the adverse events have returned to baseline or ≤ Grade 1 severity.
Treatment with tislelizumab or LBL-007 + tislelizumab should resume as soon as possible after the adverse events recover to baseline or Grade 1 (whichever is more severe) and ≤ 12 weeks after the last dose of tislelizumab/LBL-007 + tislelizumab. Treatment with immunotherapy will need to be resynchronized with chemotherapy at the subsequent cycles according to the chemotherapy dose administration date, but the time between 2 consecutive doses of tislelizumab/LBL-007 + tislelizumab should be at least 10 days (Section 5.5.2) .
Reduction of the LBL-007 dose may be allowed.
Dose Modification for Chemotherapy
Dose modifications for chemotherapy should be performed per applicable local prescribing information and per local practice according to the investigator’s clinical judgment.
Dose adjustments are allowed for chemotherapy based on nadir blood counts since the preceding chemotherapy administration. Dose level adjustments are relative to that of the preceding administration. A maximum of 2 dose reductions for each chemotherapeutic agent are permitted (Table 3) . Once the dose has been decreased, it should remain reduced for all subsequent administrations or further reduced if necessary.
If chemotherapy-related toxicities warrant a dosing delay, chemotherapy administration may restart as soon as is feasible. All subsequent chemotherapy doses must be rescheduled according to the last chemotherapy dose administration date. The treatment with immunotherapies is recommended to continue as scheduled during the delay of chemotherapy, and to be resynchronized with chemotherapy from subsequent cycles according to chemotherapy administration date. For example, chemotherapy administration can occur during an unscheduled visit and resynchronize with tislelizumab/LBL-007 + tislelizumab at subsequent cycle (s) , if possible. Dosing intervals of subsequent cycles of tislelizumab/LBL-007 + tislelizumab may be shortened or extended as clinically feasible to allow for resynchronization, but the time between 2 consecutive doses of tislelizumab/LBL-007 +tislelizumab should be at least 10 days. If clinically appropriate, treatment components may be delayed up to a maximum of 7 days to allow synchronized administration of all agents and  realigned dosing of treatment cycles according to the original schedule. Chemotherapy may be delayed up to 3 weeks to allow sufficient time for recovery. Upon recovery, chemotherapy is recommended to be administered according to the dosing schedule described herein.
If chemotherapy-related toxicities warrant a dosing delay, toxicities related to chemotherapies must be resolved to baseline or ≤ Grade 1 before administering the next dose of chemotherapy, with the exception of alopecia, Grade 2 fatigue, and certain other adverse events.
Dose Modification for Cisplatin
A repeat course of cisplatin should not be given until the serum creatinine is < 1.5 mg/100 mL, and/or the blood urea nitrogen (BUN) is < 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100 x 109 /L, white blood cell [WBC] ≥ 4 x 109/L) . Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.
Abbreviations: BUN, blood urea nitrogen; WBC, white blood cell.
Dose Modifications for 5-Fluorouracil
5-FU dose modification scheme as described below is recommended for the management of adverse events.

Dose Modifications for Paclitaxel
i. Paclitaxel Dose Modifications for Decreased Neutrophils
If a patient experiences febrile neutropenia or ≥ Grade 2 infection at any time, granulocyte colony stimulating factor (G-CSF) should be added initially and in advance of any dose reduction for the next cycle of paclitaxel. In the event of a second episode of febrile neutropenia or ≥ Grade 2 infection, paclitaxel should be dose reduced to the next lower level. For a third episode of febrile neutropenia or ≥ Grade 2 infection, paclitaxel should be discontinued. Any dose reductions for neutropenic fever are permanent.
ii. Paclitaxel Dose Modifications for Decreased Platelet Counts
Abbreviation: LLN, lower limit of normal
For any grade toxicity, paclitaxel must be discontinued if the platelet count does not recover by the next planned treatment cycle.
iii. Paclitaxel Dose Modifications for Neuropathy
All dose reductions for neuropathy are permanent.
iv. Paclitaxel Dose Modifications for Hepatic Impairment
Abbreviation: ULN = upper limit of normal.
If the liver function test abnormalities do not recover by the next planned cycle, paclitaxel must be discontinued. All dose reductions for liver function abnormalities are permanent.
STUDY POPULATION
Patient Inclusion Criteria include:
(1) Able to provide written informed consent. (2) Age ≥ 18 years on the day of the informed consent. (3) Pathologically (histologically) confirmed diagnosis of esophageal squamous cell carcinoma (ESCC) . (4) Metastatic ESCC or unresectable, locally advanced ESCC. (5) At least 1 measurable lesion as defined per RECIST v1.1. Note: A lesion in an area subjected to prior locoregional therapy, including previous radiotherapy, is not considered measurable unless there has been demonstrated progression in the lesion since such therapy as defined by RECIST v1.1. (6) ECOG Performance Status ≤ 1. (7) Adequate organ function as indicated by the following laboratory values during screening and within ≤ 7 days before randomization: (a) Patients must not have required blood transfusion or growth factor support ≤ 14 days before sample collection for the following: Absolute neutrophil count ≥ 1.5 x 109/L; Platelet count ≥ 100 x 109/L; Hemoglobin ≥ 90 g/L, (b) Estimated glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. (c) Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (total bilirubin must be < 3 x ULN for patients with Gilbert syndrome) . (d) AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver metastases)
Patient Exclusion Criteria include:
(1) Prior systemic therapy for advanced or metastatic ESCC (Note: Patients with prior curative intended neoadjuvant/adjuvant therapy, or definitive chemoradiotherapy are eligible provided the treatment-free interval [TFI: duration from the end-date of last prior systemic therapy or radiotherapy to the date of the diagnosis of disease progression] ≥ 6 months) (FIG. 2) . (2) Locally advanced ESCC that is either resectable or potentially curable with definitive chemoradiation therapy per local investigator. (3) Palliative radiation treatment for ESCC within 4 weeks of study treatment initiation. (4) Patients with evidence of fistula (either esophageal/bronchial or esophageal/aorta) . (5) Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention (clinically significant recurrence requiring an additional intervention within 2 weeks of intervention) . (6) Evidence of complete esophageal obstruction not amenable to treatment. (7) Received prior therapies targeting PD-1, PD-L1, PD-L2, LAG-3, or other immune-oncological drugs. (8) Ineligible for treatment with either protocol-specified chemotherapy regimen. (9) Active leptomeningeal disease or uncontrolled brain metastasis. Patients with a history of treated and, at the time of screening, stable central nervous system (CNS) metastases are eligible, provided they meet all the following: (Brain imaging at screening shows no evidence of interim progression and no  evidence of new brain metastases; patient is clinically stable for ≥ 2 weeks; no ongoing requirement for corticosteroids as therapy for CNS disease; off steroids 7 days before randomization; anticonvulsants at a stable dose are allowed; no stereotactic radiation or whole-brain radiation within 14 days before randomization) . (10) Active autoimmune diseases or history of autoimmune diseases that may relapse. Note: Patients with the following diseases are not excluded and may proceed to further screening: (a) Controlled type 1 diabetes. (b) Hypothyroidism (provided that it is managed with hormone replacement therapy only) . (c) Celiac disease controlled by diet alone. (d) Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) . (e) Any other disease that is not expected to recur in the absence of external triggering factors. (11) Any active malignancy ≤ 5 years before randomization except for the specific cancer under investigation in this study and any localized cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast) . (12) Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before randomization. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: (a) Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) . (b) Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption. (c) Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a nonautoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen. (13) With history of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including pulmonary fibrosis, or acute lung diseases, etc. (14) With infections (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal or antiviral therapy within 14 days before randomization. (Note: antiviral therapy is permitted for patients with chronic hepatitis B virus [HBV] or hepatitis C virus [HCV] infection) . (15) Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA ≥ 500 IU/mL (or ≥ 2500 copies/mL) at screening. Note: Inactive hepatitis B surface antigen carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Patients with detectable hepatitis B surface antigen or detectable HBV DNA should be managed at the discretion of the investigator. (16) 16. Patients with active hepatitis C. Note: Patients with a negative HCV antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV  antibody. Patients receiving antivirals at screening should have been treated for > 2 weeks before randomization. (17) A known history of HIV infection. (18) Any major surgical procedure requiring general anesthesia ≤ 28 days before randomization. Patients must have recovered adequately from the toxicity and/or complications from the intervention before randomization. (19) Prior allogeneic stem cell transplantation or organ transplantation. (20) Any of the following cardiovascular risk factors: (a) Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before randomization. (b) Pulmonary embolism ≤ 28 days before randomization. (c) Any history of acute myocardial infarction ≤ 6 months before randomization. (d) Any history of heart failure meeting New York Heart Association Classification III or IV ≤ 6 months before randomization. (e) Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before randomization. (f) Any history of cerebrovascular accident ≤ 6 months before randomization. (g) Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before randomization. (h) Any episode of syncope or seizure ≤ 28 days before randomization. (21) A history of severe hypersensitivity reactions to other monoclonal antibodies. (22) Was administered a live vaccine ≤ 28 days before randomization. Note: Vaccines for COVID-19 are allowed except for any live vaccine that may be developed. Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed. (23) Concurrent participation in another therapeutic clinical study. (24) Pregnant or breastfeeding woman. (25) Has received any chemotherapy, immunotherapy (e.g., interleukin, interferon, thymosin, etc. ) or any investigational therapies within 14 days or 5 half-lives (whichever is shorter) of the first study drug administration. (26) Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that are unfavorable for the administration of study drug, will affect the explanation of drug toxicity or adverse events, or will result in insufficient or impaired compliance with study conduct. (27) Patients with toxicities (as a result of prior anticancer treatment) which have not recovered to baseline or stabilized, except for adverse events not considered a likely safety risk (e.g., alopecia and specific laboratory abnormalities) .
Concomitant Medications/Procedures
i. Prohibited Concomitant Medications/Procedures
The following medications/therapies are prohibited during screening and through the EOT Visit: (1) Any other concurrent anticancer treatment (i.e., chemotherapy other than those used in this study, hormonal therapy, or immunotherapy) that are standard or investigational agents. (2) Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) within 28 days or 5 half-lives (whichever is longer) of randomization and during the study. (3) Herbal remedies with immune-stimulating properties or that are known to potentially interfere with the liver or other major organ functions. (4) Live vaccines administered ≤ 28 days before randomization through the 60 days after the last dose of LBL-007 or tislelizumab, whichever is later.
ii. Restricted Concomitant Medications/Procedures
The following medications are restricted: (1) Alcohol or other drugs abuse. (2) Use of potentially hepatotoxic drugs in patients with impaired hepatic function should be carefully monitored. (3) Radiation therapy is not allowed, except for palliative radiation therapy (wherein the therapy is permitted only for pain control of prophylaxis of bone fracture to sites of bone disease present at baseline if the following criteria are met: i) Repeated imaging shows no new sites of bone metastases; ii) The lesion being considered for palliative radiation is not a target lesion per RECIST v1.1; and, iii) The case is discussed with the medical monitor, and he/she agrees that the conditions required to receive palliative radiation are met. Additionally, palliative radiation or other focally ablative therapy for other nontarget sites of the disease is permitted if clinically indicated per the investigator’s discretion and after consultation with the medical monitor. Whenever possible, these patients should have a tumor assessment of the lesion (s) before receiving the radiation therapy to rule out disease progression. It is not required to withhold study treatments during palliative radiotherapy. ) (4) Herbal remedies for the treatment of cancer or Chinese patent medicines with approval from the China National Medical Products Administration (NMPA) for use as anticancer treatment (regardless of the type of cancer) used ≤ 14 days before the first dose of study treatment (s) or during the study treatment. (5) Immunosuppressive agents (except to treat a treatment-related adverse event) . (6) Systemic corticosteroids > 10 mg daily (prednisone or equivalent) , except to treat or control an adverse event (per protocol) or for short-term use as prophylactic treatment.
Tumor and Response Evaluations
During the study, tumor response is evaluated every 6 weeks (± 7 days) for the first 48 weeks then every 9 weeks (± 7 days) after 48 weeks in accordance with RECIST v1.1. Screening assessments and each subsequent assessment must include computed tomography (CT) scans (with oral/intravenous contrast, unless contraindicated) of the neck, chest, and abdomen. If a contraindication exists, other modalities can be allowed after consultation with the medical monitor (e.g., magnetic resonance imaging [MRI] or CT without contrast) ; a bone scan or positron-emission tomography (PET) is required if clinically indicated. Other known or suspected sites of disease must be included in the imaging assessments (brain, etc) . For patients who are suspected to have CNS metastases, CT/MRI of the head is required at baseline. MRI may be used when it is the standard-of-care at a site, regardless of whether or not CT is contraindicated.
All measurable and evaluable lesions are assessed and documented at the Screening Visit and reassessed at each subsequent tumor evaluation. Response is assessed using RECIST v1.1 (Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer. 2009; 45 (2) : 228-47) .
After first documentation of response (CR or PR) , confirmation of tumor response should occur at the next scheduled assessment timepoint.
Treatment is permitted to continue after the initial assessment of progressive disease, provided that the criteria for treatment beyond disease progression are met.
Pharmacokinetic and Antidrug Antibody Assessments
LBL-007 and tislelizumab may elicit immune response. Validated screening and confirmatory assays are employed to detect ADAs at multiple timepoints. In addition, blood samples are collected for characterization of LBL-007 and tislelizumab PK. Serum samples are assayed for LBL-007 and tislelizumab concentrations using validated immunoassays.
·ADA assays: Serum samples are tested for the presence of ADAs to LBL-007 and tislelizumab using a validated immunoassay.
·PK assays: Serum samples are assayed for LBL-007 and tislelizumab concentrations using a validated immunoassay.
Tumor Tissue and Biomarker Assessment
Biomarker analyses are performed to explore pharmacodynamics, as well as the association of biomarkers with patient prognosis, response, and potential resistance to the treatment. The planned biomarker analyses include but are not limited to PD-L1 expression, LAG-3 expression, LAG-3 ligands expression, cytokine/chemokine and soluble proteins, gene expression profile (GEP) , tumor mutational burden (TMB) /microsatellite instability (MSI) /DNA mutation, and blood tumor mutational burden (bTMB) /circulating tumor DNA (ctDNA) /DNA mutation.
PD-L1 is expressed in tumor cells and tumor-infiltrating immune cells, and its expression levels were shown to correlate with the clinical efficacy of anti-PD-1 treatment in ESCC patients. In 1L ESCC subgroup analysis from the BGB-A317-306 study, ESCC patients with tumors exhibiting PD-L1 Tumor Area Positivity (TAP) score ≥ 10%derived significant benefit from treatment with tislelizumab in combination with chemotherapy, compared with placebo + chemotherapy regimen (median OS 16.6 months versus 10.0 months, HR = 0.62) , suggesting PD-L1 could be a predictive biomarker of response for the first-line ESCC.
In this study, PD-L1 expression status TAP score (TAP ≥ 10%or TAP < 10%) is used to guide patient stratification. The TAP score is defined as the total percentage of the tumor area (tumor and any desmoplastic stroma) covered by tumor cells with PD-L1 membrane staining at any intensity and tumor-associated immune cells with PD-L1 staining at any intensity, as visually estimated. PD-L1 expression will be assessed centrally by the Ventana PD-L1 (SP263) assay, and its predictive role is analyzed.
Additionally, LAG-3 and LAG-3 ligands expression, cytokine/chemokine and soluble proteins, GEP, TMB/MSI/DNA mutation, and bTMB/ctDNA/DNA mutation are assessed to investigate their predictive, prognostic, or pharmacodynamic roles including any association with response to study treatment and mechanism (s) of resistance.
During the screening period, PD-L1 expression (TAP ≥ 10%or < 10%) is determined by Ventana PD-L1 (SP263) assay.
Biomarker analysis in tumor tissues includes but not limited to PD-L1 expression, LAG-3 expression, LAG-3 ligands expression, GEP, and TMB/MSI/DNA mutation analysis (e.g., for the association between these biomarkers and clinically relevant outcomes including response, resistance, and prognosis) .
Statistical Analysis
Sample Size Justification
Expected study enrollment is approximately 116 patients with a 2: 1 randomization ratio to receive either LBL-007 in combination with tislelizumab plus chemotherapy (Arm A) or tislelizumab plus chemotherapy (Arm B) . Based on historical information, the ORR for the current standard-of-care, anti-PD-1 plus chemotherapy, is approximately 50%to 65% (Doki Y, et al. N Engl J Med. 2022; 386 (5) : 449-62.; Lu Z, et al. BMJ. 2022; 377: e068714.; Sun JM, et al. Lancet. 2021; 398 (10302) : 759-71) ; the ORR in the control arm is considered as 55%. Assuming an ORR difference of 20% (increase from 55%to 75%) , 116 patients provide 80%power to detect ORR difference at a 1-sided alpha level of 0.1.
Randomization Methods
Patients will be randomized using the IRT system by permuted block stratified randomization with stratification factors of PD-Ll expression level (TAP ≥ 10%or TAP <10%) .
Analysis Sets
The Intent-to-Treat (ITT) Analysis Set includes all randomized patients. Patients will be analyzed according to their randomized treatment arm. This will be the primary analysis set used for all efficacy analyses. The Safety Analysis Set includes all patients who have received ≥ 1 dose of any component of study treatment; this will be the analysis set used for the safety analyses. The PK Analysis Set includes all patients who receive ≥ 1 dose of investigational agents per the protocol and for whom any quantifiable postbaseline PK data are available. The ADA Analysis Set includes all patients who received ≥ 1 dose of investigational agents per the protocol and in whom both baseline ADA and ≥ 1 postbaseline ADA results are available.
Efficacy Analyses
Efficacy endpoints are assessed by the investigator according to RECIST v1.1. The efficacy endpoints will be analyzed and summarized in order to evaluate the antitumor activities of LBL-007 in combination with tislelizumab plus chemotherapy in the first-line ESCC. These analyses are intended to be preliminary efficacy evidence.
ORR and DCR along with the 95%Clopper-Pearson CI will be summarized for each arm. The difference in ORR and DCR between arms will be provided using the Cochran-Mantel-Haenszel (CMH) chi-square test. Waterfall plots of maximum tumor shrinkage per patient will be presented. Time-to-event endpoints, PFS, DOR, and OS will be analyzed using  the Kaplan-Meier method. Hazard ratio and corresponding 2-sided 95%CI will be estimated using a stratified Cox proportional hazards model.
ORR is defined as the proportion of patients achieving confirmed BOR of CR or PR as assessed by the investigator per RECIST v1.1. BOR is defined as the best response recorded from the first dose of study drug (post randomization) until data cutoff or the initiation of new anticancer treatment, whichever occurs earlier.
PFS is defined as the time from the date of randomization to the date of the first documentation of disease progression or death, whichever occurs first. The HR and corresponding 2-sided 95%CI will be estimated using a stratified Cox proportional hazards model with stratification factors (PD-L1 status TAP ≥ 10%or TAP < 10%) collected from the IRT system.
DOR is defined as the time from the first determination of a confirmed overall response until the first documentation of progression assessed by the investigator per RECIST v1.1 or death because of any cause, whichever comes first.
DCR is defined as the proportion of patients achieving confirmed BOR of CR, PR, and stable disease assessed by the investigator per RECIST v1.1. DCR will be analyzed similarly like ORR.
***
While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.
The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising, ” “including, ” “containing, ” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do  not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified.
The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.
As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to, ” “at least, ” “greater than, ” “less than, ” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.
All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.
Other embodiments are set forth in the following claims.
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Claims (38)

  1. A method of treating an esophageal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-LAG3 antibody or an antigen binding fragment thereof, and a therapeutically effective amount of one or more chemotherapeutic drugs,
    wherein the anti-PD-1 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 1, CDR-H2 comprising SEQ ID NO: 2, and CDR-H3 comprising SEQ ID NO: 3, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 4, CDR-L2 comprising SEQ ID NO: 5, and CDR-L3 comprising SEQ ID NO: 6, and
    wherein the anti-LAG3 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 31, CDR-H2 comprising SEQ ID NO: 32, and CDR-H3 comprising SEQ ID NO: 33, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 34, CDR-L2 comprising SEQ ID NO: 35, and CDR-L3 comprising SEQ ID NO: 36.
  2. The method of claim 1, wherein the esophageal cancer is esophageal squamous cell carcinoma.
  3. The method of claim 1 or 2, wherein the cancer is unresectable, recurrent, locally advanced, and/or metastatic.
  4. The method of claim 3, wherein the cancer is unresectable and locally advanced.
  5. The method of any one of claims 1-4, wherein the cancer is stage IV cancer.
  6. The method of any one of claims 1-5, wherein the cancer is metastatic.
  7. The method of any one of claims 1-6, wherein the subject has liver, lung, lymph node, bone and/or adrenal gland metastasis.
  8. The method of any one of claims 1-7, wherein the subject has 1, 2, 3 or more metastatic sites, optionally wherein the subject has more than 3 metastatic sites.
  9. The method of any one of claims 1-8, wherein the subject is human.
  10. A method of treating of metastatic and/or unresectable locally advanced esophageal squamous cell carcinoma in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-LAG3 antibody or an antigen binding fragment thereof, and a therapeutically effective amount of one or more chemotherapeutic drugs,
    wherein the anti-PD-1 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 1, CDR-H2 comprising SEQ ID NO: 2, and CDR-H3 comprising SEQ ID NO: 3, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 4, CDR-L2 comprising SEQ ID NO: 5, and CDR-L3 comprising SEQ ID NO: 6, and
    wherein the anti-LAG3 antibody comprises (i) a heavy chain variable region comprising complementarity determining region (CDR) -H1 comprising SEQ ID NO: 31, CDR-H2 comprising SEQ ID NO: 32, and CDR-H3 comprising SEQ ID NO: 33, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO: 34, CDR-L2 comprising SEQ ID NO: 35, and CDR-L3 comprising SEQ ID NO: 36.
  11. The method of any one of claims 1-10, wherein the subject has not been previously treated for the esophageal cancer or the treatment is a first line treatment, optionally wherein the subject has not being previously treated with chemotherapy and/or immunotherapy.
  12. The method of any one of claims 1-10, wherein the esophageal cancer is chemotherapy-resistant.
  13. The method of any one of claims 1-12, wherein the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 8.
  14. The method of any one of claims 1-13, wherein the anti-PD-1 antibody comprises an IgG constant region comprising an amino acid sequence selected from SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14.
  15. The method of any one of claims 1-14, wherein the heavy chain variable region of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 37, and the light chain variable region of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 38.
  16. The method of any one of claims 1-15, wherein the heavy chain of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 39, and the light chain of the anti-LAG3 antibody comprises the amino acid sequence of SEQ ID NO: 40.
  17. The method of any one of claims 1-16, wherein the anti-LAG3 antibody is administered intravenously in the amount of about 600 mg, optionally wherein the administering is once (optionally on day 1) every three weeks, optionally wherein the administration is by IV infusion.
  18. The method of any one of claims 1-17, wherein the one or more chemotherapeutic drug is a platinum chemotherapy drug.
  19. The method of any one of claims 1-17, wherein the one or more chemotherapeutic drug is cisplatin, paclitaxel and/or 5-fluoruracil.
  20. The method of any one of claims 1-17, wherein the one or more chemotherapeutic drug is cisplatin or carboplatin.
  21. The method of claim 20 or 21, wherein the one or more chemotherapeutic drug is cisplatin and 5-fluouracil.
  22. The method of claim 20 or 21, wherein the one or more chemotherapeutic drug is cisplatin and paclitaxel.
  23. The method of any one of claims 20-23, wherein the cisplatin is administered intravenously in the amount of about 40 to 80 mg/m2, or about 60 to 80 mg/m2, optionally wherein the administering is once (optionally on day 1) every three weeks (Q3W) , optionally wherein the administration is by IV infusion.
  24. The method of claim 20, 22 or 24, wherein the 5-fluorouracil is administered intravenously in the amount of about 400 to 800 mg/m2, or about 750 to 800 mg/m2, optionally wherein the administering is five times (optionally days 1, 2, 3, 4, and 5) every three weeks (Q3W) , optionally wherein the administration is by IV infusion.
  25. The method of claim 20, 23 or 24, wherein the paclitaxel is administered intravenously at in the amount of about 90 to 175 mg/m2, or about 175 mg/m2, optionally wherein the administering is once (optionally on Day 1) every three weeks (Q3W) , optionally wherein the administration is by IV infusion.
  26. The method of any one of claims 1-26, wherein the administering is for at least 4 cycles of three weeks each.
  27. The method of any one of claims 1-27, wherein the response to treatment is measured by overall survival, progression-free or event-free survival, overall response rate, complete response, partial response, duration of response, and/or disease control rate.
  28. The method of any one of claims 1-28, wherein the response to treatment is measured by tumor volume, size of diameter.
  29. The method of any one of claims 1-29, wherein the subject has been diagnosed with the esophageal cancer using histological and/or cytological markers.
  30. The method of any one of claims 1-29, wherein the esophageal cancer has PD-L1 tumor area positivity (TAP) score of 10%or more.
  31. The method of any one of claims 1-29, wherein the esophageal cancer has PD-L1 tumor area positivity (TAP) score of less than 10%.
  32. The method of any one of claims 1-31, wherein the anti-PD-1 antibody is administered at a dose from about 50 to 800 mg, optionally wherein the anti-PD-1 antibody is administered at 100 mg, 150 mg, 200, mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg.
  33. The method of claim 32, wherein the PD-1 antibody is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, preferably wherein the anti-PD-1 antibody is administered at 150 mg every two weeks, 300 mg every four weeks, or 400 mg every six weeks.
  34. The method of any one of claims 1-31, wherein the anti-PD-1 antibody is administered intravenously in the amount of about 200 mg, optionally wherein the administering is once every three weeks, optionally wherein the administration is by IV infusion.
  35. The method of any one of claims 1-34, wherein the anti-PD-1 antibody is formulated in a pharmaceutical composition comprising a histidine buffer, a surfactant and at least one stabilizer.
  36. The method of claim 35, wherein the surfactant is a polysorbate.
  37. The method of claims 35 or 36, wherein the stabilizer is trehalose.
  38. The method of any one of claims 1-37, wherein the anti-PD-1 antibody is formulated in a pharmaceutical composition comprising citric acid monohydrate, histidine, L-histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, and trehalose.
PCT/CN2024/113312 2023-08-21 2024-08-20 Treatment of esophageal cancer with anti-lag3, anti-pd-1 and chemotherapy Pending WO2025040080A1 (en)

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CN110382545A (en) * 2017-01-09 2019-10-25 泰萨罗公司 With the method for anti-PD-1 antibodies for treating cancer
US20190225687A1 (en) * 2017-02-22 2019-07-25 I-Mab Anti-lag-3 antibodies and uses thereof
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