Dosing regimen of Anti-LAG3 antibody and combination therapy with Anti-pd-1 antibody for treating cancer

Abstract

To provide dosing regimens of an anti-LAG3 antibody useful for the treatment of cancer.SOLUTION: The present invention provides a pharmaceutical composition containing an anti-LAG3 antibody for treating cancer in a patient, where the anti-LAG3 antibody is administered at 700 mg or 800 mg via intravenous infusion on Day 1 once every three weeks, together with pembrolizumab administered at 200 mg via intravenous infusion on Day 1 once every three weeks, and where the anti-LAG3 antibody contains two heavy chains and two light chains, where the heavy chains include a specific amino acid sequence, and the light chains include a different specific amino acid sequence.SELECTED DRAWING: Figure 12

Description

[Technical field]

[0001] The present invention provides dosing regimens of anti-LAG3 antibodies useful for the treatment of cancer. In particular, the present invention relates to a therapeutic regimen that inhibits the programmed death 1 protein (PD-1 ) or antibodies against programmed death-ligand 1 (PD-L1) and lymphocyte activation gene 3 ( The present invention relates to a dosing regimen for combination therapy comprising administering an antibody to LAG3. The present invention also provides a method for treating a patient, the method comprising administering to the patient an anti-LAG3 antibody and an anti-PD-1 antibody. A method for treating cancer in a patient, comprising: and may be positive for LAG3 expression. [Background technology]

[0002] PD-1 is recognized as an important molecule in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T cells, B cells, and NKT cells and is involved in lymphocyte Upregulated by T / B cell receptor signaling on myeloid, monocyte, and myeloid cells will be (1).

[0003] There are two known ligands for PD-1: PD-L1 (B7-H1) and PD-L2. (B7-DC) is expressed in human cancers occurring in a variety of tissues, including the ovary. Large-scale sample centers for cancers including kidney, colorectal, pancreatic, and liver cancers and melanoma In patients with PD-L1 expression, PD-L1 expression was associated with poor prognosis and poor overall survival, regardless of subsequent treatment. It has been shown that the expression of P on tumor-infiltrating lymphocytes correlates with a decrease in the expression of β- D-1 expression characterizes dysfunctional T cells in breast cancer and melanoma (14-1 5) and was found to correlate with poor prognosis in kidney cancer (16). In addition, tumor cells expressing PD-L1 can interact with T cells expressing PD-1. attenuates T cell activation to evade immune surveillance, thereby enhancing immunity against tumors It has been proposed to contribute to the impaired response.

[0004] PD-1 and one or both of its ligands PD-L1 and PD-L2 Several monoclonal antibodies that block the interaction between Pembrolizumab has been shown to have high binding specificity to the programmed cell death 1 (PD-1) receptor. It is a potent humanized immunoglobulin G4 (IgG4) mAb with isomeric Programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD -L2). Based on preclinical in vitro data, pembrolizumab inhibits the interaction with Mab has high affinity for PD-1 and potent receptor blocking activity. Eytruda® (pembrolizumab) is a treatment for patients across several indications. There are indications for treatment.

[0005] Lymphocyte-Activation Gene 3 3, LAG3) is an inhibitory regulator that regulates the homeostasis, proliferation, and activation of effector T cells. It is an immunomodulatory receptor that plays a role in the suppressor activity of regulatory T cells (Tregs). LAG3 is involved in the regulation of activated CD8+ and CD4+ T cells, Tregs and On the Tr1 regulatory T cell population, natural killer cells and tolerogenic plasmacytoid cells were also identified. It is expressed on a subset of T-like cells and acts on both effector T cells and Tregs. Because of the proposed role of both, LAG3 may have an antitumor effect by simultaneously blocking both cell populations. It is one of several immune checkpoint molecules that have the potential to enhance tumor immunity.

[0006] LAG3 is structurally related to cluster of differentiation (CD) 4 and is involved in the expression of immunoglobulin (Ig) It is a member of the CD4 superfamily. Like CD4, its ligand is the major histocompatibility complex. Its interaction with ligands involves dimerization and schizophrenia. Following T cell activation, LAG3 mediates signaling that leads to changes in T cell activation. Most LAG3 molecules are found in intracellular stores and are expressed transiently on the surface of T cells. When activated, LAG3 can rapidly translocate to the plasma membrane. It is regulated by extracellular cleavage to generate a soluble form of LAG3 (sLAG3) , which can be detected in serum. Expression of LAG3 is tightly regulated and These antibodies represent a self-limiting mechanism to counteract the activity of unregulated T cells. The bodies are described in WO2016 / 028672.

[0007] Anti-LAG3 antibody as monotherapy or in combination with anti-PD-1 or anti-PD-L1 therapy The choice of dosage regimen for treatment depends on the subject's blood serum or tissue turnover rate, level of symptoms, immunogenicity of the substance, anti-drug antibody endpoints and the accessibility of the target cells, tissues or organs in the individual being treated, as well as the safety and The formation of anti-drug antibodies can potentially limit drug exposure at therapeutic doses. In addition, anti-LAG3 and / or anti- Anti-PD-1 / anti-PD-L1 treatment may stimulate immune responses and reduce cytokine release, which may affect safety. It can bring possibilities. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2016 / 028672 Summary of the Invention [Means for solving the problem]

[0009] The present invention relates to a method for treating a patient comprising administering 7 to 1200 mg of anti-LAG3 antibody Ab6 to a patient. In one embodiment, a method for treating cancer using 200 to 800 μg of ethanol is provided. g of anti-LAG3 antibody Ab6 are administered. In one embodiment, the method comprises administering anti-PD-1 or anti-PD-2 antibody Ab6. In one embodiment, the combination of an anti-LAG3 antibody and an anti-PD-L1 antibody may include co-administration with an anti-LAG3 antibody. and the anti-PD-1 antibody are combined. In another embodiment, the patient's tumor tissue section is In a further embodiment, the patient's tumor cells express PD-L1 positive. In one embodiment, the anti-PD-1 antibody is a PD-L1 or PD-L2 antibody. The present invention also provides a method for treating PD-L2-associated leukemia. Antibody Ab6 or Ab6 variant, and 200 mg of pembrolizumab or pembrolizumab A pharmaceutical composition comprising a lolizumab variant is provided. In one embodiment, the pharmaceutical composition The product contains 800 mg of anti-LAG3 antibody Ab6 or Ab6 variant, and 200 mg of Includes pembrolizumab or pembrolizumab variants.

[0010] The present invention also relates to a method for treating a patient comprising administering to the patient an anti-LAG3 antibody and an anti-PD-1 antibody. for treating non-MSI-H colorectal cancer, gastric cancer or head and neck squamous cell carcinoma in The method includes: determining whether a tumor tissue section from a patient is positive for PD-L1 expression and positive for LAG3 expression; The method may further include the steps of: [Brief description of the drawings]

[0011] [Figure 1] CT scan of a patient with non-MSI-H colorectal cancer before (left) and after (right) treatment with 21 mg of anti-LAG3 antibody Ab6 and pembrolizumab. The patient had received 5 lines of prior chemotherapy but no prior anti-PD-1 or anti-PD-L1 therapy. The patient had a partial response with a 45% reduction in tumor volume. There was also a reduction in lung lesions and lymph node burden, and the presacral mass was stable. Response is ongoing at 13.5 months. [Diagram 2] CT scan of a 60-year-old male with renal cell carcinoma and lung and bone metastases before (left) and after (right) treatment with 7 mg of the anti-LAG3 antibody Ab6 and pembrolizumab. The patient had received 3 lines of therapy, including prior anti-PD-1 therapy. The patient had a partial response with a 49% reduction in tumor volume at 9 weeks. Reductions in tumor volume were observed at all sites of visible disease, including the lungs and multiple lymph nodes. The response was sustained for 15 months before disease progression. [Diagram 3] Waterfall plot of subjects using best target lesion change from baseline based on investigator assessment by RECIST 1.1 FAS population in the colorectal cancer expansion cohort (Part B) using PD-L1 IHC combined positive score (CPS).

[0012] Each bar represents an individual subject. More than 30% reduction in tumor size from baseline (Y-axis) A small change is a response; a change between a 30% decrease and a 20% increase is stable disease; a change greater than a 20% increase is stable disease Changes are considered as disease progression. Tumor samples with CPS ≥ 1 or < 1 are shown. Tumor samples with fewer than 100 cannot be interpreted. [Figure 4] Waterfall plot of subjects using best target lesion change from baseline based on investigator assessment by RECIST 1.1 FAS population in the colorectal cancer expansion cohort (Part B) using the LAG3 IHC CPS-like % LAG3 positive cells scoring system.

[0013] Each bar represents an individual subject. More than 30% reduction in tumor size from baseline (Y-axis) a change between a 30% decrease and a 20% increase is considered stable disease; A change of more than 20% was considered to be disease progression. Tumor samples with CPS ≥ 1 or < 1 were Tumor samples with fewer than 100 tumor cells cannot be interpreted. [Diagram 5] Serum concentrations of Ab6 following intravenous administration of 7 mg to 700 mg in Part A of a Phase I study, Cycle 1. The arithmetic mean serum concentrations for each dose are plotted over nominal time. [Figure 6] Serum concentrations of total soluble LAG-3 following intravenous administration of 7 mg to 700 mg in Part A of the Phase I study, Cycle 1. Arithmetic mean values ​​of total soluble LAG-3 are plotted over nominal time. [Figure 7A] Figures 7A-B show that the Cmax of pembrolizumab at steady state of 400 mg Q6W ranges from 2 mg / kg and 200 mg Q3W to 10 mg / kg Q2W. 7A: Cmax of pembrolizumab at steady state of 2 mg / kg and 200 mg Q3W. [Figure 7B]Figures 7A-B show that the Cmax of pembrolizumab at steady state of 400 mg Q6W is in the range of 2 mg / kg and 200 mg Q3W to 10 mg / kg Q2W. 7B: Cmax of pembrolizumab at steady state of 400 mg Q6W and 10 mg / kg Q2W. [Figure 8] Figure 8 shows that steady-state pembrolizumab exposure (Cavg and Cmin) was similar at 400 mg Q6W versus 2 mg / kg Q3W and 200 mg Q3W. [Figure 9A] 9A-B show the pharmacokinetic profiles of pembrolizumab at steady state for the 400 mg Q6W dosing regimen compared to the Q3W, 200 mg flat dosing regimen (top) and the Q3W, 2 mg / kg body weight-based dosing regimen (bottom). 9A shows concentrations on a logarithmic scale. [Figure 9B] 9A-B show the pharmacokinetic profiles of pembrolizumab at steady state for the 400 mg Q6W dosing regimen compared to the Q3W, 200 mg flat dosing regimen (top) and the Q3W, 2 mg / kg body weight-based dosing regimen (bottom). 9B shows concentrations on a linear scale. [Figure 10] Serum concentrations of Ab6 following intravenous dosing of 7 mg to 700 mg in cycle 1 on a linear scale with additional patient sampling compared to Figure 5. Arithmetic mean values ​​of Ab6 serum concentrations are plotted over nominal time. [Figure 11] Serum concentrations of Ab6 following intravenous dosing of 7 mg to 700 mg in cycle 1 on a logarithmic scale with additional patient sampling compared to Figure 5. Arithmetic mean values ​​of Ab6 serum concentrations are plotted over nominal time. [Figure 12] Serum concentrations of total soluble LAG-3 following intravenous dosing of 7 mg to 700 mg in cycle 1 with additional patient sampling compared to Figure 6. Arithmetic mean values ​​of total soluble LAG-3 are plotted over nominal time. [Figure 13]Predicted Ab6 serum concentration-time profile in cycle 1 corresponding to the 800 mg dose overlaid with observed concentrations for the 700 mg dose. The solid markers represent the observed Ab6 serum concentrations at 700 mg from the Phase I study. The shaded areas represent the 2.5th and 97.5th percentiles of predicted concentrations for the 800 mg dose. Ab6 exposure from cycle 1 is expected to be representative of subsequent treatment cycles. [Figure 14] Predicted Ab6 exposure (AUC, Ctrof, Cmax) as a function of dose showing substantial overlap in exposure between the 700mg and 800mg doses. Line: median, box: 25th and 75th percentiles, whiskers: 5th and 95th percentiles. [Figure 15] Boxplot of Ab6 serum C trough on day 21 showing PK variability. [Figure 16] Waterfall plot of subjects using best target lesion change from baseline based on investigator assessment by RECIST 1.1 FAS population in the gastric cancer expansion cohort (Part B) using PD-L1 IHC combined positivity score (CPS).

[0014] Each bar represents an individual subject. More than 30% reduction in tumor size from baseline (Y-axis) a change between a 30% decrease and a 20% increase is considered stable disease; A change of more than 20% was considered to be disease progression. Tumor samples with CPS ≥1 or <1 were Tumor samples with fewer than 100 tumor cells cannot be interpreted. [Figure 17] Waterfall plot of subjects using the LAG3 IHC CPS-like % LAG3 positive cells scoring method and best target lesion change from baseline based on investigator assessment per RECIST 1.1 FAS population in the gastric cancer expansion cohort (Part B).

[0015] Each bar represents an individual subject. More than 30% reduction in tumor size from baseline (Y-axis) a change between a 30% decrease and a 20% increase is considered stable disease; A change of more than 20% was considered to be disease progression. Tumor samples with CPS ≥ 1 or < 1 were Tumor samples with fewer than 100 tumor cells cannot be interpreted. [Figure 18] Waterfall plot of subjects using best target lesion change from baseline based on investigator assessment by RECIST 1.1 FAS population in the HSNCC PD-L1 naive cancer expansion cohort (Part B) using the PD-L1 IHC TPS+MIDS scoring system.

[0016] Each bar represents an individual subject. More than 30% reduction in tumor size from baseline (Y-axis) a change between a 30% decrease and a 20% increase is considered stable disease; A change of more than 20% was considered to be disease progression. Tumor samples with CPS ≥ 1 or < 1 were Tumor samples with fewer than 100 tumor cells cannot be interpreted. [Figure 19] Waterfall plot of subjects using best target lesion change from baseline based on investigator assessment by RECIST 1.1 FAS population in the HSNCC PD-L1 naive cancer expansion cohort (Part B) using the LAG3 IHC %LAG3 positive cells scoring system.

[0017] Each bar represents an individual subject. More than 30% reduction in tumor size from baseline (Y-axis) a change between a 30% decrease and a 20% increase is considered stable disease; A change of more than 20% was considered to be disease progression. Tumor samples with CPS ≥ 1 or < 1 were Tumor samples with fewer than 100 tumor cells cannot be interpreted. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Abbreviations The following abbreviations are used throughout the detailed description and examples: BOR Best Overall Efficacy BID twice daily dosing CBR clinical usefulness rate CDR Complementarity Determining Region CHO Chinese hamster ovary CR Complete response DCR Disease control rate DFS disease-free survival DLT dose-limiting toxicity DOR Duration of response DSDR Sustained disease stability rate FFPE Formalin-fixed Paraffin-embedded FR Framework Area IgG Immunoglobulin G IHC immunohistochemistry or immunohistochemistry irRC Immune-Related Response Criteria IV Intravenous MTD maximum capacity NCBI National Center for Biotechnology Information NCI: National Cancer Institute ORR Objective Response Rate OS overall survival PD Progression PD-1 Program Death 1 PD-L1 Programmed Cell Death 1 Ligand 1 PD-L2 Programmed cell death 1 ligand 2 PFS Progression-free survival PR partial response Q2W: Once every two weeks Q3W: Once every 3 weeks QD once daily dosing RECIST Response Evaluation Criteria for Solid Tumors on Criteria in Solid Tumors SD Stable disease VH immunoglobulin heavy chain variable region VK immunoglobulin kappa light chain variable region I. Definition In order that the present invention may be more readily understood, certain technical and scientific terms are specifically defined below. As used herein, unless specifically defined elsewhere in this document, All other technical and scientific terms used herein are understood to be within the skill of those of ordinary skill in the art to which this invention pertains. It has a meaning that is universally understood.

[0019] As used in this specification, including the appended claims, the singular forms of words, e.g. "a," ​​"an," and "the" etc. are used unless the content clearly indicates otherwise. It also includes the references to their corresponding plural forms.

[0020] As used herein, an "Ab6 variant" refers to an Ab6 variant that has 3 amino acids at positions outside the light chain CDRs. 1, 2, or 1 conservative amino acid substitution and 6, 5, or 6-fold outside the heavy chain CDRs. Ab6 (see below) except that it has one, four, three, two or one conservative amino acid substitution. and WO2016028672, which are incorporated by reference in their entireties. Monoclonal antibodies comprising heavy and light chain sequences substantially identical to those in For example, the mutation site is in the FR region or the constant region, and the heavy chain There may be a deletion of a lysine residue at the C-terminus. In other words, Ab6 and Ab6 variants contain identical CDR sequences, but in their full-length light and heavy chain sequences, They differ from each other by having conservative amino acid substitutions at no more than three or six other positions. The b6 variant has the following properties: binding affinity to human LAG3 and Virtually identical to Ab6 in its ability to block binding to human MHC class II .

[0021] "Administering" means administering to an animal, human, experimental subject, cell, tissue, organ, or biological fluid. When applied, the foreign body is a substance that causes an infection in an animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell refers to the contact of a therapeutic agent, diagnostic agent, or composition with a therapeutic agent having a therapeutic effect on the cell. Contact includes contacting a liquid with a reagent, as well as contacting the liquid with a cell. A "subject" refers to any organism, preferably an animal, more preferably a mammal (e.g., a rat, mouse, dog, cat, rabbit) and most preferably human.

[0022] As used herein, the term "antibody" refers to an antibody that exhibits a desired biological or binding activity. It is therefore used in the broadest sense and specifically refers to any form of antibody that , but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies) ), polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies), humanized antibodies , fully human antibodies, chimeric antibodies and camelized single domain antibodies. , prior to modification of the antibody for its intended use, e.g., for use as a human therapeutic. These are antibodies obtained by exposing the immune system to an antigen prior to, for example, humanization of an antibody.

[0023] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer contains two identical polypeptides. It contains a peptide chain pair, each pair consisting of one "light" chain (approximately 25 kDa) and one "heavy" chain. The amino-terminal portion of each chain is primarily involved in antigen recognition. The heavy chain comprises a variable region of about 100 to 110 amino acid residues or more. The portion may define a constant region primarily responsible for effector function. Typically, Chains are classified as kappa and lambda light chains. Furthermore, human heavy chains are typically mu, They are classified as delta, gamma, alpha or epsilon, which represent the antibody isotype. IgM, IgD, IgG, IgA and IgE are defined. Within the light and heavy chains, the variable regions The heavy chain has a constant region and a constant region connected by a "J" region of about 12 or more amino acid residues. It also includes a "D" region of about 10 amino acid residues. Fundamental Immunology Ch.7 (Paul,W.,ed.,2nd ed. Rav See Press, NY (1989).

[0024] The variable regions of each light / heavy chain pair form the antibody binding site. An intact antibody has two binding sites. A bifunctional or bispecific antibody has two binding sites. Except for the , the two binding sites are generally identical.

[0025] Typically, both heavy and light chain variable domains contain relatively conserved framework regions. The three hypervariable regions, also called complementarity determining regions (CDRs), are located within the FR. The CDRs are usually aligned with the framework regions and enable binding to a specific epitope. Generally, from N-terminus to C-terminus, the variable domains of both the light and heavy chains are Each domain contains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to amino acids is generally Sequences of Proteins of Immunological Interest ,Kabat,et al.;N ational Institutes of Health,Bethesda,Md. .;5 th ed.;NIH Publ.No.91-3242(1991);Kaba t(1978) Adv.Prot.Chem. 32:1-75;Kabat,et al.,(1977) J.Biol.Chem. 252:6609-6616;Ch othia,et al.,(1987) J.Mol.Biol. 196:901- 917 or Chothia, et al., (1989) Nature 342:8 As defined in 78-883.

[0026] As used herein, unless otherwise indicated, the term "antibody fragment" or "antigen-binding The term "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., specific for the antigen bound by a full-length antibody. An antibody fragment that retains the ability to bind to a specific antibody, for example, one or more CDR regions. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies; single chain antibody molecules Examples include sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments. can be done.

[0027] An antibody that "specifically binds" to a particular target protein is one that specifically binds to that protein compared to other proteins. Antibodies that exhibit preferential binding to a target, but this specificity does not require absolute binding specificity. Antibodies do not detect unwanted results, e.g. their binding indicates the presence of a target protein in a sample. , without producing false positives, etc., a given antibody is "specific" for its intended target. The antibodies or binding fragments thereof useful in the present invention are believed to be At least 2 times stronger, preferably at least 10 times stronger, than the affinity of the antibody to the protein. More preferably, the antisense oligonucleotide is at least 20 times stronger, and most preferably, the antisense oligonucleotide is at least 100 times stronger. As used herein, a given For example, the amino acid sequence of a mature human PD-1 or human PD-L1 molecule. An antibody is an antibody that binds to a polypeptide containing the sequence but does not bind to a protein lacking that sequence. It is said to specifically bind to a polypeptide containing that sequence.

[0028] A "chimeric antibody" refers to an antibody in which some portion of the heavy and / or light chains are derived from a particular species (e.g., human). or a corresponding sequence in an antibody belonging to a particular antibody class or subclass. The sequence is identical or homologous to the sequence, but the remainder of the strand(s) is from another species (e.g., mouse). The antibody may be identical or similar to a corresponding sequence in an antibody of the same or a different antibody class or subclass. The term "antibody" refers to antibodies that are identical to or homologous to the antibody, so long as they exhibit the desired biological activity. It also refers to a fragment of an antibody.

[0029] As used herein, an agent, such as a PD-1 antagonist or a LAG3 antagonist, "Co-administration" as used herein means administering agents such that their therapeutic activities overlap, and It does not necessarily mean that the agents are administered simultaneously to a subject. The agents may be physically combined prior to administration. In certain embodiments, the agents are administered simultaneously or at approximately the same time. The anti-PD-1 antibody and the anti-PD-2 antibody are administered to the subject simultaneously. For example, the anti-PD-1 antibody and the anti-PD-2 antibody are administered to the subject simultaneously. When the anti-LAG3 formulation is in solution, it is placed in the same intravenous infusion bag or injection device. The pharmaceutical compositions may be mixed and administered to a patient at the same time.

[0030] As used herein, "co-formulated" or "combined" means "Co-formulation" or "Coformulation" Or "coformulated" means that the drugs are formulated and stored separately. are formulated together, rather than being mixed prior to administration or administered separately. and stored as a combination product in a single vial or container (e.g., an injection device). In one embodiment, the term "antibody" refers to at least two different antibodies or antigen-binding fragments thereof. In this case, the combination contains two different antibodies or antigen-binding fragments thereof.

[0031] Pharmacokinetic "steady state" is the state where some accumulation of drug concentration occurs over multiple doses. This is the period during which systemic drug exposure is considered constant following administration of each subsequent dose; In the specific case of mbrolizumab, steady state is achieved after approximately 16 weeks of dosing.

[0032] AUCss, Cavg,ss and Cmin,ss are the (b) A pharmacokinetic measure of the systemic exposure to a drug in humans following administration, typically AUCss and Cavg,ss are considered to be the drivers of drug efficacy. "Cmin,ss" represents the average exposure over a period of time, but differs in terms of units. , the minimum or nadir (trough) observed at the end of a dosing interval, just before the next dose is administered Represents drug concentration.

[0033] "Cmax,ss" is the maximum or highest (peak) drug concentration observed immediately after administration. In the specific case of pembrolizumab administered as an intravenous infusion, Peak concentrations occur shortly after the dose. Cmax,ss is typically considered a safety driver. It is a metric that can be used.

[0034] A "human antibody" refers to an antibody that contains only human immunoglobulin protein sequences. The antibody may be produced in a mouse, a mouse cell, or a hybridoma derived from a mouse cell. Similarly, a "mouse antibody" or a "rat antibody" may contain mouse glycosylation. These refer to antibodies that contain only mouse or rat immunoglobulin sequences, respectively.

[0035] A "humanized antibody" refers to a compound that is modified with sequences from a non-human (e.g., murine) antibody, as well as sequences from a human antibody. Such antibodies are the most widely used antibodies derived from non-human immunoglobulins. Generally, a humanized antibody contains at least one, and typically two, possible and comprising substantially all of the variable domains, wherein the high frequency domains correspond to those of non-human immunoglobulins. All or substantially all of the variable loops and all or substantially all of the FR regions are The humanized antibody also has an immunoglobulin constant region (Fc ), typically containing at least a portion of a human immunoglobulin. "hu" or "h" is used when it is necessary to distinguish a humanized antibody from the parent rodent antibody. The humanized form of a rodent antibody is generally identical to the parent rodent antibody. Contains the same CDR sequences but with improved stability of humanized antibodies for improved affinity Certain amino acid substitutions may be included to enhance the binding of amino acids to a target protein, or for other reasons.

[0036] Cancer patients treated with a therapeutic regimen, such as the combination therapy described herein. An "anti-tumor response" when referring to a patient is defined as at least one positive therapeutic effect, e.g., Reduction in cell number, tumor size, and rate of cancer cell invasion into peripheral organs. or a reduction in the rate of tumor growth or progression-free survival. The therapeutic effect can be measured in a variety of ways (W.A. Weber, J. Null. ed. 50:1S-10S (2009); see Eisenhauer et al. In some embodiments, the combination treatments described herein are Antitumor response to IRRC was assessed by RECIST 1.1 criteria, bi-dimensional irRC or uni-dimensional irRC. In some embodiments, the anti-tumor response is evaluated using SD, PR, CR, P It is either FS or DFS.

[0037] "Two-dimensional irRC" refers to Wolchok JD, et al. Guideline s for the evaluation of immune therapy a activity in solid tumors:immune-related r esponse criteria. Clin Cancer Res. 2009; 15(23):7412-7420. These criteria The method utilizes two-dimensional tumor measurements of target lesions, multiplied by the longest diameter and longest perpendicular diameter of each lesion. Calculating (cm 2) is obtained.

[0038] "Biotherapeutic agents" refer to agents that support tumor maintenance and / or growth or induce an anti-tumor immune response. Inhibits biological pathways that block ligand / receptor signaling The term biotherapeutic agents refers to biological molecules, such as antibodies or fusion proteins. These include, but are not limited to, VEGF, EGFR, Her2 / neu, and other growth factor receptors. Condition, CD20, CD40, CD-40L, CTLA-4, OX-40, 4-1BB and and antibodies against ICOS.

[0039] "CBR" or "clinical benefit rate" means CR+PR+sustained SD.

[0040] As used herein, "CDR (singular)" or "CDR (plural)" refers specifically to Immunoglobulins, defined using the Kabat numbering system, unless otherwise indicated It refers to the complementarity determining region(s) in the variable region.

[0041] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. These include, but are not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle blockers, and the like. Poison Plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase omerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor Modulators (SERMs), antiprogesterone agents, estrogen receptor downregulators estrogen receptor antagonists (ERDs), luteinizing hormone (LH) inhibitors Releasing hormone agonists, antiandrogens, aromatase EGFR inhibitors, VEGF inhibitors, and drugs related to abnormal cell proliferation or tumor growth The present invention also provides an antisense oligonucleotide that inhibits the expression of a gene that is involved in the treatment of the present invention. Chemotherapeutic agents useful in the methods include cytostatic and / or cytotoxic agents. Can be obtained.

[0042] “Chothia” is Al-Lazikani et al., JMB 273:9 By "numbering" is meant the antibody numbering system described in J. Immunol. 27-948 (1997).

[0043] "comprising" or variations such as "comprising" "comprise", "comprises" or "comprises" "sed of" etc., when the context requires otherwise, either by explicit language or necessary implication. Unless otherwise stated, the term "compound" is used throughout the specification and claims in an inclusive sense, i.e. It is understood that the presence of the stated features does not necessarily imply a function or utility of any of the embodiments of the present invention. This is used without excluding the presence or addition of further features which may enhance the quality.

[0044] "Conservatively modified variants" or "conservative substitutions" refer to variants that have the same or similar biological activity or without altering other desirable properties, such as antigen affinity and / or specificity. The amino acids in a protein have similar properties ( Other amines with different properties (e.g. charge, side chain size, hydrophobicity / hydrophilicity, backbone structure and rigidity, etc.) Those skilled in the art will generally recognize the substitution of a single amino acid in a non-essential region of a polypeptide. Recognize that amino acid substitutions do not substantially alter biological activity (see, e.g., Watson et al.(1987) Molecular Biology of the Ge ne,The Benjamin / Cummings Pub.Co.,p.224(4 In addition, the substitution of structurally or functionally similar amino acids Conservative substitutions are unlikely to destroy biological activity. Exemplary conservative substitutions are shown in Table 1 below. can be.

[0045] Table 1. Exemplary conservative amino acid substitutions [Table 1]

[0046] "consists essentially of" and Relations, e.g. "consist essentially of "consisting essentially of" or "consisting essentially of" As used throughout this specification and claims, "any of" and the like are intended to mean any The inclusion of any enumerated element or group of elements and the inclusion of elements similar or similar to the enumerated elements These methods and methods are not intended to limit the scope of the present invention, but rather to provide a method and / or a method for implementing the invention. This indicates that other elements that do not qualitatively change the sequence may be included. The PD-1 antagonists consisting essentially of the amino acid sequences listed above have the following binding properties: It may also include one or more amino acids that do not substantially affect the function of one or more amino acids. This includes substitution of amino acid residues.

[0047] "DCR" or "Disease Control Rate" means CR+PR+SD.

[0048] "Diagnostic anti-PD-L monoclonal antibodies" are antibodies that express PD-L on the surface of certain mammalian cells. Specifically binds to the mature form of the designated PD-L (PD-L1 or PDL2) Mature PD-L contains a pre-secretory leader sequence, also called leader peptide. The terms "PD-L" and "mature PD-L" are used interchangeably herein. and, unless otherwise indicated or readily apparent from the context, refer to the same molecule. Then it will be understood.

[0049] As used herein, a diagnostic anti-human PD-L1 mAb or anti-hPD-L 1 mAb refers to a monoclonal antibody that specifically binds to mature human PD-L1. The mature human PD-L1 molecule consists of amino acids 19 to 290 of the following sequence: MRIFAVFIFMTYWHLLNAFTTVTVPKDLYVVEYGSNMTIEC KFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSS YRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGG ADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGY PKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRIN TTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTH LVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSK KQSDTHLEET (sequence number 32).

[0050] Immunodetection of PD-L1 expression in formalin-fixed paraffin-embedded (FFPE) tumor tissue sections Diagnostic anti-human PD-L1 useful as a diagnostic mAb for immunohistochemical (IHC) detection Specific examples of mAbs include the 20C3 and 22C3 antibodies, which are described in WO2014 / IHC testing of PD-L1 expression in FFPE tissue sections is described in 100079. Another anti-human PD-L1 mAb (Chen, BJ) has been reported to be useful for et al., Clin Cancer Res 19:3462-3473(2013 )) is a publicly available rabbit anti-human antibody from Sino Biological, Inc. PD-L1 mAb (Beijing, People's Republic of China; Catalog No. 10084-R015 ). [Table 2]

[0051] As used herein, expression of "PD-L1" or "PD-L2" refers to expression of PD-L1 or PD-L2 on the cell surface. A specified PD-L protein or a specified PD-L mR in a cell or tissue PD-L protein expression is a diagnostic test for the presence of any detectable level of PD-L. PD-L antibodies can be used to detect PD-L in IHC assays on tumor tissue sections or by flow cytometry. Alternatively, expression of PD-L protein by tumor cells can be detected by immunohistochemistry. PET imaging can be used to target desired PD-L targets, e.g., PD-L1 or PD-L2. L2 is detected using a binding agent (e.g., an antibody fragment, an affibody, etc.) that specifically binds to L2. Techniques for detecting and measuring PD-L mRNA expression include RT-PCR and R, Real-time quantitative RT-PCR, RNAseq and Nanostring platform (J.Clin.Invest. 2017;127(8):2 930-2940).

[0052] A method for quantifying PD-L1 protein expression in IHC assays of tumor tissue sections. Several approaches have been described, see, for example, Thompson, RH, et al. l.,PNAS 101(49);17174-17179(2004);Thomps on,RHet al.,Cancer Res. 66:3381-3385(2 006);Gadiot, J., et al., Cancer 117:2192-22 01(2011);Taube,JM et al.,Sci Transl Me d 4,127ra37(2012); and Toplian,SL et al. ,New Eng.J Med. 366(26):2443-2454(2012) See U which describes the hematoxylin and eosin stain used by pathologists. Please refer to S20170285037.

[0053] One approach is to use a simple binary endpoint of positive or negative PD-L1 expression. A positive result is based on histological evidence of cell surface membrane staining. The tumor tissue sections were analyzed for PD-L1 expression, which is defined as the percentage of tumor cells expressing PD-L1. PD-L1 expression was counted as positive if expression was in at least 1% of all tumor cells will be done.

[0054] In another approach, PD-L1 expression in tumor tissue sections was compared with that in tumor cells, as well as It is quantified primarily in infiltrating immune cells, including lymphocytes. The percentage of immune cells was increased from <5%, 5 to 9%, and then in 10% increments up to 1%. PD-L1 expression in immune infiltrates was calculated as a corrected inflammation score. The percentage of membrane-stained cells is reported as a semiquantitative measurement called the AIS. The score was determined by multiplying the intensity of the infiltration by the number of lymphocytes, and was chosen as none (0), mild (score 1, lymphocytes only) or no (score 2, lymphocytes only). almost none), moderate (score 2, focal infiltration of the tumor with lymphohistiocytic aggregates) or Tumor tissue sections were graded as severe (score 3, diffuse infiltration) if the AIS was ≥ 5. If present, the immune infiltrate is counted as positive for PD-L1 expression.

[0055] PD-L1 mRNA expression levels are often measured using quantitative RT-PCR. The mRNA expression levels of one or more reference genes may be compared to those of the corresponding mRNA.

[0056] In some embodiments, by malignant cells and / or infiltrating immune cells within the tumor. PD-L1 expression levels (protein and / or mRNA) were evaluated using appropriate controls. Based on comparison with the expression levels (protein and / or mRNA) of D-L1, For example, a control PD-L1 protein or mRNA is determined to be “expressed” or “elevated.” The expression levels of A were measured in non-malignant cells of the same type or in sections from corresponding normal tissues. In some preferred embodiments, the level of PD in a tumor sample may be quantified. -L1 protein (and / or PD-L1 mRNA) was less than that in controls PD-L1 expression was elevated in tumor samples if it was at least 10%, 20%, or 30% higher It is decided that:

[0057] The "Tumor Proportion Score (TPS)" is a score based on the number of tumors expressing PD-L1 on the cell membrane at any intensity (weak, medium or Percentage of tumor cells expressing chromatin (intensity) Staining of the vesicle membrane is interpreted as PD-L1 positivity.

[0058] The "Mononuclear Inflammation Density Score (MIDS)" is a measure of the number of PD-L1 molecules infiltrating or adjacent to the tumor. Mononuclear inflammatory cells (MICs) expressing IL-1 (small lymphocytes, large lymphocytes, and IL-1) in the tumor nests and adjacent supporting stroma The ratio of the number of lymphocytes, monocytes, and macrophages to the total number of tumor cells. was scored on a scale of 0 to 4, where 0 = absent; 1 = present but not exceeding 100 tumor cells MIC of less than 1 per 100 tumor cells (<1%); 2 = at least 1 per 100 tumor cells MICs but less than 1 MIC per 10 tumor cells (1–9%); = at least 1 MIC per 10 tumor cells, but more MICs than tumor cells 4 = MIC at least as high as tumor cells (≥100%); ).

[0059] "Combined Positive Score (CPS)" refers to the number of PD-L1 positive cells in the tumor nest and adjacent supporting stroma. The number (numerator) of PD-L1-positive tumor cells and PD-L1-positive mononuclear inflammatory cells (MIC) in tumor cells of PD-L1 positive and negative tumor cells (denominator; i.e., number of PD-L1 positive and negative tumor cells) PD- of any intensity, i.e. weak (1+), moderate (2+) or strong (3+) L1 expression is considered positive.

[0060] "PD-L1 expression positive" means a tumor proportion score of at least 1% and a mononuclear inflammation density score of at least 1% or combined positive score; AIS ≥ 5; or malignancy within the tumor compared with appropriate controls Expression levels of PD-L1 by cells and / or infiltrating immune cells (protein and This refers to an increase in the level of GABAergic receptor agonist (GAA) and / or mRNA.

[0061] LAG3 protein expression was measured by immunohistochemistry of tumor tissue sections using a diagnostic anti-LAG3 antibody. The antibody may be detected in a C assay or by flow cytometry. In the present study, the diagnostic anti-LAG3 antibody is clone 17B4 from LSBio. The expression of LAG3 protein by tumor cells was confirmed by PET imaging. can be detected using a binding agent (e.g., an antibody fragment, an affibody, etc.) that specifically binds to Techniques for detecting and measuring LAG3 mRNA expression include RT-PCR, Real-time quantitative RT-PCR, RNAseq and Nanostring platforms (J.Clin.Invest. 2017;127(8):2930 -2940).

[0062] "% LAG3 positive cells" refers to LAG3 positive cells in the tumor area / total cells x 100 Linear, partial or complete immune cell membrane staining in IHC assays indicates LAG3 positivity. This is interpreted as:

[0063] "CPS-like % LAG3 positive cells" refers to the ratio of LAG3 positive cells in the tumor area to tumor cells x 100. Linear, partial or complete immune cell membrane staining in IHC assays is This is interpreted as AG3 positive.

[0064] "LAG3 expression positive" refers to % LAG3 positive cells or CPS-like % LAG3 positive cells is ≥ 1%.

[0065] "DSDR" or "sustained stable disease rate" means SD for ≥ 23 weeks.

[0066] As used herein, "framework region" or "FR" refers to a region other than the CDR regions. The term "variable region of an immunoglobulin" refers to a region of an immunoglobulin that is

[0067] As used herein, "Kabat" refers to the methodology used by Elvin A. Kabat (1991 ) Sequences of Proteins of Immunological Interest,5th Ed. Public Health Service, National Institutes of Health,Bethesda,M d.) The immunoglobulin alignment and numbering system developed by means.

[0068] The "anti-LAG3 antibody" is a marker expressed on immune cells (such as T cells, Treg or NK cells). The term "monoclonal antibody" refers to a monoclonal antibody that blocks the binding of LAG3 to MHC class II molecules. Human LAG3 contains the following amino acid sequence: MWEAQFLGLL FLQPLWVAPV KPLQPGAEVP VVWAQEG APA QLPCSPTIPL QDLSLLRRAG VTWQHQPDSG PPAAAPGHPL APGPHPAAPS SWGPRPR RYT VLSVGPGGLR SGRLPLQPRV QLDERGRQRG DFSLWLRPAR RADAGEYRAA VHLRDRA LSC RLRLRLGQAS MTASPGSLR ASDWVILNCS FSRPDRPASV HWFRNRGQGR VPVRESP HHH LAESFLFLPQ VSPMDSGPWG CILTYRDGFN VSIMYNLTVL GLEPPTPLTV YAGAGSR VGL PCRLPAGVGT RSFLTAKWTP PGGGPDLLVT GDNGDFTLRL EDVSQAQAGT YTCHIHL QEQ QLNATVTLAI ITVTPKSFGS PGSLGKLLCE VTPVSGQERF VWSSLDTPSQ RSFSGPW LEA QEAQLLSQPW QCQLYQGERL LGAAVYFTEL SSPGAQRSGR APGALPAGHL LLFLILG VLS LLLLVTGAFG FHLWRRQWRP RRFSALEQGI HPPQAQSKIE ELEQEPEPEP EPEPEPE PEP EPEQL (SEQ ID NO: 33); see also Uniprot Accession No. P18627.

[0069] "Microsatellite instability (MSI)" refers to the lack of DNA mismatch repair in tumors. This refers to a form of genomic instability associated with deletions. Boland et al., Cancer See Research 58, 5258-5257, 1998. In this embodiment, MSI analysis is performed using the five microarrays recommended by the National Cancer Institute (NCI). Rosatellite marker BAT25 (GenBank accession number 9834508) , BAT26 (GenBank accession number 9834505), D5S346 (G enBank accession number 181171), D2S123 (GenBank accession number Accession number 187953), D17S250 (GenBank accession number 17 7030). Additional markers, such as BAT40, BAT 34C4, TGF-β-RII and ACTC can be used. Commercially available kits for this purpose include, for example, the Promega MSI Multiplex PCR Assay Kit. Sei is one example.

[0070] "High frequency microsatellite instability" or "high microsatellite instability (MS Instability (IH) is defined as any instability in two or more of the five NCI markers or If ≥ 30-40% of all markers demonstrate instability (i.e., have insertion / deletion mutations), This refers to the combination.

[0071] "Low frequency microsatellite instability" or "low frequency microsatellite instability (MS "IL" refers to instability of one of the five NCI markers or all markers. <30–40% of the markers are unstable (i.e., have insertion / deletion mutations). cormorant.

[0072] As used herein, "non-MSI-H colorectal cancer" refers to cancer that is microsatellite stable or This refers to colorectal cancer with multiple sclerosis (MSS) and low-level MSI (MSI-L).

[0073] "Microsatellite stability (MSS)" refers to the absence of any of the five NCI markers. This refers to cases where the gene does not show any qualitative abnormality (i.e., does not have any insertion / deletion mutations).

[0074] "Mismatch repair proficient (pMMR) colorectal cancer" refers to CRC tumors detected by IHC. Normal levels of MMR proteins (MLH1, PMS2, MSH2 and MSH6) in the body Commercially available kits for MMR analysis include Ventana MMR IH C assay.

[0075] "Mismatch repair deficient (dMMR) colorectal cancer" refers to CRC tumor detection by IHC. The expression of one or more MMR proteins (MLH1, PMS2, MSH2 and MS This refers to low expression of H6).

[0076] As used herein, "monoclonal antibody" or "mAb" or "Mab" refers to refers to a population of substantially homogeneous antibodies, i.e., the amino acid sequence of the antibody molecules that make up the population. The sequences are identical except for potential naturally occurring mutations that may exist in small amounts. In contrast, conventional Polyclonal antibody preparations typically contain their variable domains, particularly their C The DR contains many different antibodies with different amino acid sequences, which are often The modifier "monoclonal" refers to a substantially homogeneous antibody. It refers to the properties of antibodies as they are obtained from a population of cells and indicate that they are anti- For example, the present disclosure is not intended to be construed as requiring somatic production. The monoclonal antibody that resulted was described by Kohler et al. (1975) in Nature. It can be produced by the hybridoma method first described by Re 256:495, and or may be produced by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" also include those isolated from phage antibody libraries, e.g. Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:58 1-597. Presta (2005) J. See also Allergy Clin. Immunol. 116:731.

[0077] A "non-responder patient" is a patient who is particularly susceptible to treatment with the combination therapy described herein. When referring to an atypical anti-tumor response, it is meant that the patient did not exhibit an anti-tumor response.

[0078] "ORR" or "objective response rate" refers in some embodiments to CR+PR. I, ORR (24週) is the irR in each patient in the cohort after 24 weeks of anticancer treatment. Refers to CR and PR measured using ECIST.

[0079] "Patient" or "Subject" means any person for whom treatment is desired or who is participating in a clinical trial or epidemiological study. Refers to any single subject who is being examined or used as a control, and includes human and mammalian patients. Domestic animals include, for example, cattle, horses, dogs and cats.

[0080] "PD-1 antagonist" refers to a drug that inhibits the expression of PD-L1 on cancer cells by immune cells (T cells). The present invention is directed to blocking the binding of PD-1 expressed on the surface of preferred Alternatively, PD-L2 expressed on cancer cells may bind to PD-1 expressed on immune cells. PD-1 and its ligands Alternative names or synonyms for PD-1 include PDCD1, PD1, CD279, and and SLEB2; for PD-L1, PDCD1L1, PDL1, B7H1, B7-4 , CD274 and B7-H; and for PD-L2, PDCD1L2, PDL2 , B7-DC, Btdc and CD273. In any of the methods of treatment, medicaments and uses, the PD-1 antagonist is a human PD- Blocks the binding of PD-L1 to human PD-1, and preferably human PD-L1 and PD-L2 The amino acid sequence of human PD-1 is Human PD-L1 and The amino acid sequences of PD-L2 and PD-L2 are available from NCBI Locus No. NP_054, respectively. 862 and NP_079515.

[0081] As used herein, a "pembrolizumab variant" refers to a variant that is a pembrolizumab variant that is a pembrolizumab variant outside of the light chain CDRs. and having three, two or one conservative amino acid substitutions at positions outside the heavy chain CDRs. 6, 5, 4, 3, 2, or 1 conservative amino acid substitution in each Monoclonal antibodies containing heavy and light chain sequences substantially identical to those in mbrolizumab For example, the mutation site is in the FR region or the constant region, and the heavy chain There may be a deletion of a lysine residue at the C-terminus. In other words, pembrolizumab and The lolizumab variants contain identical CDR sequences, but their full-length light chain and heavy chain sequences Conservative amino acid substitutions at no more than three or six other positions in the sequence, respectively. The pembrolizumab variants differ from each other in the following properties: binding affinity to PD-1; and their ability to block the binding of PD-L1 and PD-L2 to PD-1, respectively. It is substantially the same as pembrolizumab with respect to

[0082] As used herein, "RECIST 1.1 response criteria" refers to the set of criteria by which a response is measured. Eisenhau for target or non-target lesions, as appropriate based on the context er et al., EA et al., Eur. J Cancer 45:228 -247(2009).

[0083] A "responder patient" is a patient who has a specific response to treatment with the combination therapy described herein. When referring to an effective anti-tumor response, it is meant that the patient exhibited an anti-tumor response.

[0084] "Sustained response" refers to a response that persists after cessation of treatment with a therapeutic agent or combination therapy described herein. In some embodiments, sustained response refers to the persistence of a therapeutic effect after cessation of treatment. The duration of the treatment is at least equal to the duration of the treatment or at least 1.5 times longer than the duration of the treatment. , 2.0, 2.5 or 3 times longer.

[0085] "Tissue section" means a single portion or piece of a tissue sample, e.g., a normal tissue or tumor sample. A thin section of tissue cut from a specimen.

[0086] As used herein, "treating" or "treating" a cancer refers to the therapeutic The drug is administered to subjects with cancer or diagnosed with cancer and shows at least one positive therapeutic effect. The results include, for example, a reduction in the number of cancer cells, a reduction in tumor size, and a slower rate of cancer cell invasion into peripheral organs. or to reduce tumor metastasis or tumor growth rate, etc. Positive treatment outcomes in cancer can be measured in a variety of ways (WA See Weber, J. Null. Med. 50:1S-10S (2009) For example, regarding tumor growth inhibition, according to the NCI standard, T / C ≦ 42% is considered to be antitumor activity. T / C < 10% is considered a high level of antitumor activity, where T / C(%) = median treated tumor volume / median control tumor volume × 100. In some embodiments, the response to a combination therapy described herein is The ST 1.1 criteria or irRC (bidimensional or unidimensional) were used to evaluate the composition of the present invention. Treatment achieved by the combination was PR, CR, OR, PFS, DFS, and OS. PFS is defined as the time to progression of tumor. Also called a “treatment cessation,” this refers to the period during and after treatment during which cancer does not grow. This includes the time when a patient experienced a CR or PR, as well as the time when a patient experienced SD. FS refers to the period during and after treatment during which the patient is disease-free. It refers to an increase in life expectancy compared to an untreated or untreated individual or patient. In one embodiment, response to the combination of the present invention is assessed using RECIST 1.1 response criteria. The outcome is either PR, CR, PFS, DFS, OR or OS, which are evaluated according to the patient's condition. Treatment regimens for the combinations of the present invention that are effective for treating patients include, for example, The cancer treatment may be performed in a variety of ways, including taking into account the patient's condition, age, and weight, and the ability of the treatment to elicit an anti-cancer response in the subject. Any embodiment of any of the aspects of the invention may vary depending on various factors. Although the use of any of the methods described herein may not be effective in achieving a positive therapeutic effect in all subjects, it is contemplated that such methods may be used in combination with methods known in the art. Any statistical test that is supported by the 2 Test, Mann and Whitney U test, Kruskal-Wallis test (H test), J The results were determined by the Onckheere-Terpstra test and the Wilcoxon test. This will be the case for a specified statistically significant number of subjects.

[0087] The terms "treatment regimen," "dosing protocol," and "dosing regimen" refer to the compositions of the present invention. Used interchangeably to refer to the dose and timing of administration of each therapeutic agent in the combination. can be.

[0088] "Tumor" as applied to a subject diagnosed with or suspected of having cancer means any A malignant or potentially malignant neoplasm or tissue mass of any size, including primary and secondary tumors. Solid tumors include neoplasms. A solid tumor is an abnormal increase in tissue that does not usually contain cysts or areas of liquid. Different types of solid tumors are classified according to the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemia (blood tumors) Cancers generally do not form solid tumors (National Cancer Institute, tute,Dictionary of Cancer Terms). "Tumor burden" is the same as "tumor load." The tumor burden is also called the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells in the body that contain the tumor or the overall size of the tumor or tumors. Tumors (multiple tumors) may be isolated by various methods known in the art, including, for example, by a tumor or tumors isolated from a subject upon removal from the subject. The dimensions of the catheter can be measured, for example with calipers, or while in the body. Imaging techniques, such as ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) This can be determined, for example, by using a magnetic resonance imaging (MRI) scan.

[0089] The term "tumor size" refers to the overall size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be measured by various methods known in the art, e.g. Measure the dimensions of the tumor(s) upon removal from the subject, e.g., with calipers. and by imaging techniques, such as bone scans, ultrasound, and CT scans, while in the body Or it may be determined, such as by using an MRI scan.

[0090] "One-dimensional irRC" is a method developed by Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Dev eloping a Common Language for Tumor Resp onse to Immunotherapy:Immune-related Res ponse Criteria using Unidimensional meas Clin Cancer Res. 2013;19(14):3 These criteria are based on the longest duration of each lesion. Use the diameter (cm).

[0091] As used herein, a "variable region" or "V region" refers to a region that has sequence variation among different antibodies. Typically, this refers to the segment of an IgG chain that is at Kabat residue 1 in the light chain. 09 and 113 in the heavy chain.

[0092] PD-1 antagonist and anti-LAG3 antibody PD-1 antagonists useful in the treatment methods, medicaments and uses of the present invention include: Specific binding to PD-1 or PD-L1, preferably human PD-1 or human PD The present invention relates to a monoclonal antibody (mAb) or an antigen-binding fragment thereof that specifically binds to -L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may contain a human constant region. In some embodiments, the human constant region may be any of the following: IgG1, IgG2, Ig IgG3 and IgG4 constant regions, and in a preferred embodiment, human The constant region is an IgG1 or IgG4 constant region. The original binding fragments are Fab, Fab'-SH, F(ab')2, scFv and Fv fragments. The anti-PD-1 or anti-PD-L1 antibody is selected from the group consisting of: It may be produced using conventional cell culture and recovery / purification techniques.

[0093] Examples of mAbs that bind to human PD-1 and are useful in the treatment methods, medicaments and uses of the invention are US7488802, US7521051, US8008449, US835450 9, US8168757, WO2004 / 004771, WO2004 / 072286, It is described in WO2004 / 056875 and US2011 / 0271358. Specific anti-PD-1 antagonists useful in the treatment methods, medicaments and uses of the invention Examples of suitable anti-human PD-1 mAbs include: Pembrolizumab (also known as MK-3475), WHO Drug Infor mation, Vol. 27, No. 2, pages 161-162 (2013) A humanized antibody having the structure described and comprising the heavy and light chain amino acid sequences shown in Table 3. IgG4 mAb; Nivolumab (BMS-936558), WHO Drug Info rmation, Vol. 27, No. 1, pages 68-69 (2013) A human IgA having the structure described in Table 3 and comprising the heavy and light chain amino acid sequences shown in Table 3. G4 mAb; h4 mAb described in WO2008 / 156712, which is a humanized antibody 09A11, h409A16 and h409A17, and by MedImmune AMP-514 under development.

[0094] mAbs that bind to human PD-L1 and are useful in the methods of treatment, medicaments and uses of the invention Examples are WO2013 / 019906, WO2010 / 077634 A1 and US83 The methods of treatment, medicaments and uses of the present invention are described in US Pat. A specific anti-human PD-L1 mAb useful as an antagonist is MPDL328. 0A, BMS-936559, MEDI4736, MSB0010718C, and W The heavy chain variable regions of SEQ ID NO: 24 and SEQ ID NO: 21 of O2013 / 019906, respectively, and and a light chain variable region.

[0095] Other PD-1 antagonists useful in the treatment methods, medicaments and uses of the invention include specifically binds to PD-1 or PD-L1, preferably human PD-1 or human Immunoadhesins that specifically bind to PD-L1, e.g., The extracellular or PD-L1 or PD-L2 domains, such as Fc domains, 1-binding moiety. Examples of binding molecules are described in WO2010 / 027827 and WO2011 / 066342. As PD-1 antagonists in the treatment methods, medicaments and uses of the present invention, A useful specific fusion protein is the PD-L2-FC fusion protein, which is a human PD AMP-224 (also known as B7-DCIg), which binds to -1.

[0096] In some preferred embodiments of the methods, medicaments and uses of the present invention, PD-1 The antagonist comprises (a) light chain CDRs SEQ ID NOs: 1, 2 and 3, and (b) heavy chain CDRs SEQ ID NOs: 1, 2 and 3. DR A monoclonal antibody or an antigen-binding fragment thereof comprising SEQ ID NO: 6, 7, and 8. do.

[0097] In another preferred embodiment of the treatment methods, medicaments and uses of the present invention, a PD-1 antagonist The agonist specifically binds to human PD-1 and has (a) SEQ ID NO: 9 or a variant thereof. and (b) a light chain variable region comprising SEQ ID NO: 4 or a variant thereof. The heavy chain variable region sequence of the monoclonal antibody or its antigen-binding fragment is The ant has up to 17 conserved amino acids in the framework regions (i.e., outside the CDRs). is identical to a reference sequence except for having an amino acid substitution, preferably in the framework region Fewer than 10, 9, 8, 7, 6, or 5 conservative amino acids The light chain variable region sequence variants have substitutions in the framework regions (i.e., CDR is identical to a reference sequence except for up to five conservative amino acid substitutions (outside of Preferably, there are less than 4, 3 or 2 conserved amino acids in the framework regions. Has substitutions.

[0098] In another preferred embodiment of the treatment methods, medicaments and uses of the present invention, a PD-1 antagonist The agonist specifically binds to human PD-1 and has (a) a heavy chain comprising SEQ ID NO: 10 and (b) a monoclonal antibody comprising a light chain comprising sequence number 5.

[0099] In yet another preferred embodiment of the treatment methods, medicaments and uses of the present invention, the PD-1 antigen is The antagonist specifically binds to human PD-1 and (a) has a heavy chain comprising SEQ ID NO: 12 and and (b) a light chain comprising SEQ ID NO:11.

[0100] In all of the above treatment methods, agents and uses, the PD-1 antagonist inhibits PD-L 1 to PD-1, and preferably also inhibits the binding of PD-L2 to PD-1. In some embodiments of the above methods of treatment, medicaments and uses, a PD-1 antagonist The antibody specifically binds to PD-1 or PD-L1 and blocks the binding of PD-L1 to PD-1. In one embodiment, the antibody is a monoclonal antibody or an antigen-binding fragment thereof. The PD-1 antagonist is an anti-PD-1 antibody comprising a heavy chain and a light chain, The heavy and light chains comprise the amino acid sequences in SEQ ID NO:10 and SEQ ID NO:5, respectively.

[0101] Table 3 below lists exemplary anti-PD-1 antibodies for use in the treatment methods, agents and uses of the present invention. 5 provides a listing of the amino acid sequence of -1 mAb.

[0102] Table 3. Exemplary PD-1 Antibody Sequences [Table 3] TIFF2024156880000005.tif62158

[0103] The anti-LAG3 antibodies used in the claimed invention may be human antibodies, humanized antibodies, The antibody may be an antibody or a chimeric antibody and may include a human constant region. In the present invention, the human constant region consists of IgG1, IgG2, IgG3 and IgG4 constant regions. In a preferred embodiment, the human constant region is selected from the group consisting of IgG1 or IgG4 This is the constant region.

[0104] In one embodiment, the anti-LAG3 antibody is Ab6.

[0105] Ab6: A light chain immunoglobulin containing the following amino acid sequence: : DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWY LQKPGQPPQLLIYGASNLESGVPDRFSGSGSGTDFTLKIS RVEAEDVGVYYCQQSTEDPRTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO:22); and A heavy chain immunoglobulin comprising the following amino acid sequence: QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQA RGQRLEWIGDINPNDGGTIYAQKFQERVTITVDKSTSTAY MELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDG VEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL SLSLGK (SEQ ID NO:23); or A light chain immunoglobulin variable domain comprising the amino acid sequence: DIVMTQTPLSLSVTPGQPASISC KASQSLDYEGDSDMN WY LQKPGQPPQLLIY GASNLES GVPDRFSGSGSGTDFTLKIS RVEAEDVGVYYC QQSTEDPRT FGGGTKVEIK (SEQ ID NO:24 (underlined CDRs)); and A heavy chain immunoglobulin variable domain comprising the following amino acid sequence: QMQLVQSGPEVKKPGTSVKVSCKASGYTFT DYNVD WVRQA RGQRLEWIG DINPNDGGTIYAQKFQE RVTITVDKSTSTAY MELSSLRSEDTAVYYCAR NYRWFGAMDH WGQGTTVTVSS (SEQ ID NO:25 (underlined CDRs)); or Contains the following CDRs: CDR-L1: KASQSLDYEGDSDMN (SEQ ID NO: 26); CDR-L2: GASNLES (SEQ ID NO: 27); CDR-L3: QQSTEDPRT (SEQ ID NO: 28); CDR-H1: DYNVD (SEQ ID NO: 29); CDR-H2: DINPNDGGTIYAQKFQE (SEQ ID NO: 30); and CDR-H3: NYRWFGAMDH (SEQ ID NO: 31) In some preferred embodiments of the methods, medicaments and uses of the present invention, anti-LAG The three antibodies comprise (a) light chain CDRs SEQ ID NOs: 26, 27 and 28, and (b) heavy chain CDRs SEQ ID NOs: 26, 27 and 28. R includes SEQ ID NOs: 29, 30 and 31.

[0106] In another preferred embodiment of the treatment methods, medicaments and uses of the present invention, an anti-LAG3 antibody (a) a heavy chain variable region comprising SEQ ID NO: 25, or a variant thereof; and (b) SEQ ID NO: 24 or variants thereof. The amino acid sequence may contain up to 17 conservative amino acid substitutions in the framework regions (i.e., outside the CDRs). Preferably, the reference sequence has at least 10 amino acids in the framework regions. less than 9, less than 8, less than 7, less than 6, or less than 5 conservative amino acid substitutions Variants of the light chain variable region sequence may occur in the framework regions (i.e., outside the CDRs). ) is identical to the reference sequence except for up to five conservative amino acid substitutions in or fewer than four, three, or two conservative amino acid substitutions in the framework regions. Have.

[0107] In another preferred embodiment of the treatment methods, medicaments and uses of the present invention, an anti-LAG3 antibody The present invention comprises (a) a heavy chain comprising SEQ ID NO:23, and (b) a light chain comprising SEQ ID NO:22. In another preferred embodiment of the above-mentioned methods of treatment, medicaments and uses, the anti-LAG3 antibody is a) a heavy chain variable region comprising SEQ ID NO:25, and (b) a light chain variable region comprising SEQ ID NO:24. include.

[0108] In one embodiment, the anti-PD-1 or anti-LAG3 antibody or antigen-binding fragment is , a heavy chain constant region, e.g., a human constant region, e.g., a γ1, γ2, γ3 or γ4 human heavy chain In another embodiment, the anti-PD-1 or The anti-LAG3 antibody or antigen-binding fragment may further comprise a light chain constant region, e.g., a human light chain constant region. , such as lambda or kappa human light chain regions or variants thereof. As an alternative example, the human heavy chain constant region can be γ4 and the human light chain constant region can be γ5. In an alternative embodiment, the Fc region of the antibody can be Ser228Pr. o mutation (Schuurman, J et. al., Mol. Immunol. nol. 38:1-8,2001).

[0109] In some embodiments, different constant domains are provided with the CDRs Humanized V derived from L Area and V H For example, the antibody of the present invention (or If the specific application of the antibody (or fragment) requires alteration of effector function, human IgG1 Heavy chain constant domains other than those mentioned above may be used, or a hybrid IgG1 / IgG4 may be utilized. For example, a human IgG4 constant domain can be used. Use of anti-PD-1 or anti-LAG3 antibodies containing the same and antigen-binding fragments thereof In one embodiment, the IgG4 constant domain comprises 228 in the EU system. At position 241 in the KABAT system, the native human IgG4 The constant domain (Swiss-Prot accession number P01861.1) is different from where C, which may prevent proper intrachain disulfide bond formation, ys106 and Cys109 (positions Cys226 and Cys229 in the EU system, A potential link between the ABAT system (corresponding to Cys239 and Cys242 in the ABAT system) To prevent an inter-disulfide bond, native Ser108 is replaced with Pro. See Angal et al. (1993) Mol. Immunol. 30:105 I want to be.

[0110] Methods, Uses and Agents In one embodiment, the present invention provides a method for administering 7 to 1200 mg of an anti-LAG3 antibody via intravenous infusion. A method of treating cancer in a patient comprising administering to a patient an anti-LAG3 antibody ( a) the light chain CDRs of SEQ ID NOs: 26, 27 and 28 and (b) the light chain CDRs of SEQ ID NOs: 29, 30 and and 31 heavy chain CDRs. G3 antibody 7-1200mg administered intravenously in combination with anti-PD-1 or anti-PD-L1 antibody A method of treating cancer in a patient, comprising administering to a patient an anti-LAG3 antibody (a (b) the light chain CDRs of SEQ ID NOs: 26, 27 and 28 and (c) the light chain CDRs of SEQ ID NOs: 29, 30 and In one embodiment, the anti-PD-1 antibody comprises 31 heavy chain CDRs. The body blocks the binding of PD-1 to PD-L1 and PD-L2. In another embodiment, 7 to 800 mg of anti-LAG3 antibody is administered. In another embodiment, 0 to 800 mg of anti-LAG3 antibody is administered. In another embodiment, 700 mg of anti-LAG3 antibody is administered. In another embodiment, 800 mg of anti-LAG3 antibody is administered. In another embodiment, 200 to 800 mg of an anti-LAG3 antibody is administered. In another embodiment, 200 to 700 mg of anti-LAG3 antibody is administered. 700 mg of anti-LAG3 antibody is administered. In a further embodiment, 200 to 900 mg of anti-LAG3 antibody is administered. In a further embodiment, between 200 and 1000 mg of anti-LAG3 antibody is administered. of anti-LAG3 antibody is administered.

[0111] In a further embodiment, the present invention provides a method for administering 200 mg of penbuvir to an individual via intravenous infusion. Lorisumab or pembrolizumab variants and 200mg of anti-LAG3 Ab6 or a composition comprising an Ab6 variant. In another aspect, the present invention provides a method for administering to an individual via intravenous infusion: 200 mg pembrolizumab or pembrolizumab variant and 800 mg anti- administering to a patient a composition comprising the LAG3 antibody Ab6 or Ab6 variant. The present invention provides a method for treating cancer in a subject.

[0112] In one embodiment, the composition contains 200 mg of pembrolizumab or pembrolizumab. Ib variant and 200-800 mg of anti-LAG3 antibody Ab6 or Ab6 barrier In one embodiment, the composition comprises 200 mg of pembrolizumab or Pembrolizumab variant and 200-700 mg of anti-LAG3 antibody Ab6 or A In one embodiment, the composition comprises 200 mg of pembrolizumab. Mab or pembrolizumab variant and 100-800 mg of anti-LAG3 Ab In one embodiment, the composition comprises 200 mg of pegylated IgG1 or Ab6 variant. Pembrolizumab or pembrolizumab variant and 200–900 mg of anti-LAG 3 antibody Ab6 or Ab6 variants.

[0113] In one embodiment, the composition contains 200 mg of pembrolizumab or pembrolizumab. Ib variant and 200-600 mg of anti-LAG3 antibody Ab6 or Ab6 barrier In one embodiment, the composition comprises 200 mg of pembrolizumab or Pembrolizumab variant and 200-1000 mg of anti-LAG3 antibody Ab6 or Includes Ab6 variants.

[0114] In another embodiment, the present invention provides an anti-PD-1 or anti-PD- A medicament comprising an anti-LAG3 antibody for use in combination with an L1 antibody, The drug is administered via intravenous infusion at 7 to 1200 mg. In one embodiment, the present invention provides an anti-LAG3 antibody and an anti-PD-1 antibody for treating cancer. In one embodiment, the medicament comprises 200 mg of pembrolizumab. or pembrolizumab variant and 200 mg of anti-LAG3 antibody Ab6 or A In another embodiment, the agent comprises 200 mg of pembrolizumab or pembrolizumab variant and 800 mg of Ab6 or Ab6 variant In another embodiment, the agent comprises 400 mg of pembrolizumab or pembrolizumab. Includes zumab variant and 800mg of Ab6 or Ab6 variant.

[0115] In yet a further embodiment, the present invention provides a method for treating cancer in an individual comprising administering to said individual a Use of an anti-LAG3 antibody and an anti-PD-1 or anti-PD-L1 antibody in manufacturing In one embodiment, the agent is 200 mg of pembrolizumab or pembrolizumab. Contains mab variant and 200mg of anti-LAG3 antibody Ab6 or Ab6 variant In another embodiment, the agent is 200 mg of pembrolizumab or pembrolizumab vaccinia. In another embodiment, the composition comprises a medicament for the treatment of atopic dermatitis, the medicament for the treatment of atopic dermatitis, and 800 mg of Ab6 or Ab6 variant. Thus, the present invention relates to the use of an anti-LAG3 antibody in the manufacture of a medicament for treating cancer in an individual. The use, wherein 7 to 1200 mg of an anti-LAG3 antibody is administered intravenously In yet another embodiment, the method further comprises administering the above-mentioned compound to a subject in need of treatment with an anti-PD-1 antibody in a dose-dependent manner. The present invention relates to an anti-LAG3 antibody in the manufacture of a medicament for treating cancer in an individual. 200 mg of anti-LAG3 antibody is administered intravenously via intravenous infusion. In yet another embodiment, the method further comprises administering the above-mentioned compound to a subject in need of treatment with an anti-PD-1 antibody in a dose-dependent manner. The present invention relates to an anti-LAG3 antibody in the manufacture of a medicament for treating cancer in an individual. 2. Use of an antibody, comprising administering 800 mg of an anti-LAG3 antibody via intravenous infusion to a patient in need thereof, The method further provides the use of the present invention, wherein the anti-PD-1 antibody is co-administered with 200 mg of the administered anti-PD-1 antibody. In an embodiment, the present invention relates to the use of an anti-cancer agent in the manufacture of a medicament for treating cancer in an individual. Use of an LAG3 antibody, comprising administering 7 to 1200 mg of an anti-LAG3 antibody via intravenous infusion, co-administered with 400 mg of an anti-PD-1 antibody via intravenous infusion. In yet a further embodiment, the present invention provides a method for the treatment of cancer in an individual. Use of an anti-LAG3 antibody in the manufacture of a pharmaceutical composition, comprising: and co-administering 400 mg of an anti-PD-1 antibody via intravenous infusion via the same. In yet a further embodiment, the present invention provides a method for treating cancer in an individual. 200 mg of the anti-LAG3 antibody is administered intravenously via intravenous infusion, co-administered with 400 mg of anti-PD-1 antibody via intravenous infusion. Provide for use.

[0116] In one embodiment of the above methods, medicaments and uses, an anti-PD-1 antibody and and the anti-LAG3 antibody are combined. In one embodiment, 200 mg of pembryoly izumab or pembrolizumab variant and 200 mg of Ab6 or Ab6 barrier In one embodiment, a combination product containing the agent is used for intravenous infusion. , 200 mg of pembrolizumab or pembrolizumab variants and 300 mg of A combination product containing Ab6 or an Ab6 variant is used for intravenous infusion. In one embodiment, 200 mg of pembrolizumab or pembrolizumab valproate is administered. A combination product containing ant and 400 mg of Ab6 or Ab6 variant is administered intravenously. In another embodiment, 200 mg of pembrolizumab or Contains pembrolizumab variant and 500mg of Ab6 or Ab6 variant In another embodiment, the combined preparation is used for intravenous infusion. of pembrolizumab or pembrolizumab variant and 600 mg of Ab6 or A combination product containing the Ab6 variant is used for intravenous infusion. In patients with rheumatoid arthritis, 200 mg of pembrolizumab or pembrolizumab variants and 7 A combination product containing 0.00 mg of Ab6 or Ab6 variant is available for intravenous infusion. In a further embodiment, 200 mg of pembrolizumab or pembro A combination formulation containing limumab variant and 800 mg of Ab6 or Ab6 variant The product is used for intravenous infusion. In a further embodiment, a 200 mg pen Pembrolizumab or pembrolizumab variant and 900 mg of Ab6 or Ab6 A combination product containing the variant is used for intravenous infusion. In an embodiment, 200 mg of pembrolizumab or pembrolizumab variants and and a combined product containing 1,000 mg of Ab6 or Ab6 variant was administered intravenously. In yet a further embodiment, 200 mg of pembrolizumab is 1100 mg of Ab6 or pembrolizumab variant and 1100 mg of Ab6 or Ab6 variant A combination product containing the compound is used for intravenous infusion. In a randomized controlled trial, 200 mg of pembrolizumab or pembrolizumab variants and 12 A combination product containing 0.00 mg of Ab6 or Ab6 variant is available for intravenous infusion. Used.

[0117] The present invention also provides a pharmaceutical composition comprising 200 mg of pembrolizumab or a pembrolizumab variant, and 200 mg of Ab6 or Ab6 variant, and a pharma- ceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises 200 mg of penbuvir. Rolizumab or pembrolizumab variants and 300 mg of Ab6 or Ab6 In one embodiment, the pharmaceutical composition comprises a medicament for use in a pharmaceutical composition comprising ... The composition is 200 mg of pembrolizumab or pembrolizumab variant, and 40 0 mg of Ab6 or Ab6 variant, and a pharma- ceutically acceptable excipient. In an embodiment, the pharmaceutical composition comprises 200 mg of pembrolizumab or and 500 mg of Ab6 or Ab6 variant, and In a further embodiment, the pharmaceutical composition comprises 200 mg of pembromodiamine. pembrolizumab or pembrolizumab variants, and 600 mg of Ab6 or Ab6 variants In a further embodiment, the pharmaceutical composition comprises The composition is 200 mg of pembrolizumab or pembrolizumab variant, and 70 mg of 0 mg of Ab6 or Ab6 variant, and a pharma- ceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises 200 mg of pembrolizumab or pembrolizumab. Zumab variant, and 800 mg of Ab6 or Ab6 variant, and pharmacologic In a further embodiment, the pharmaceutical composition comprises a 200 mg penicillin tablet containing acceptable excipients. brolizumab or pembrolizumab variants, and 900 mg of Ab6 or Ab 6 variant, and a pharma- ceutically acceptable excipient. The pharmaceutical composition comprises 200 mg of pembrolizumab or a pembrolizumab variant. , and 1000 mg of Ab6 or Ab6 variant, and a pharma- ceutically acceptable additive. In yet a further embodiment, the pharmaceutical composition comprises 200 mg of pembryoly izumab or pembrolizumab variants and 1100 mg of Ab6 or Ab6 variants In yet a further embodiment, the composition comprises a medicament for use in treating or preventing atopic dermatitis, The pharmaceutical composition comprises 200 mg of pembrolizumab or a pembrolizumab variant, and 1200 mg of Ab6 or Ab6 variant, and a pharma- ceutically acceptable excipient. include.

[0118] In another embodiment of the above methods, medicaments and uses, anti-PD-1 or anti-P The D-L1 antibody and the anti-LAG3 antibody are co-administered. mg of pembrolizumab or pembrolizumab variant and 200 mg of Ab6 or or Ab6 variant is co-administered by intravenous infusion on day 1 of every 3 weeks. In patients with rheumatoid arthritis, 200 mg of pembrolizumab or pembrolizumab variants and 3 00 mg of Ab6 or Ab6 variant administered intravenously on day 1 of every 3 weeks In one embodiment, 200 mg of pembrolizumab or pembrolizumab Variant and 400 mg Ab6 or Ab6 variant administered intravenously on day 1 of every 3 weeks In another embodiment, 200 mg of pembrolizumab or Pembrolizumab variant and 500 mg Ab6 or Ab6 variant were administered at 3 weeks In another embodiment, 200 mg of pembrolizumab is co-administered by intravenous infusion on day 1 of each Rolizumab or pembrolizumab variant and 600 mg of Ab6 or Ab6 variant In a further embodiment, riant is co-administered by intravenous infusion on the first day of every three weeks. , 200 mg of pembrolizumab or pembrolizumab variants and 700 mg of Ab6 or an Ab6 variant will be co-administered by intravenous infusion on day 1 every 3 weeks. In one embodiment, 200 mg of pembrolizumab or pembrolizumab varian and 800 mg of Ab6 or Ab6 variant administered intravenously on day 1 of every 3 weeks In a further embodiment, 200 mg of pembrolizumab or pen Brolizumab variant and 900 mg Ab6 or Ab6 variant every 3 weeks In a further embodiment, 200 mg of pembrolizumab is co-administered by intravenous infusion on day 1. Rolizumab or pembrolizumab variant and 1000mg of Ab6 or Ab6 The variants are co-administered by intravenous infusion on day 1 of every 3 weeks. In these patients, 200 mg of pembrolizumab or pembrolizumab variants and 1 100 mg of Ab6 or Ab6 variant co-administered via intravenous infusion on day 1 every 3 weeks In yet a further embodiment, 200 mg of pembrolizumab or pen Brolizumab variant and 1200 mg Ab6 or Ab6 variant every 3 weeks Co-administered by intravenous infusion on day 1 with

[0119] In the above-mentioned methods, medicaments and uses, in one embodiment, 400 mg of pembrolizumab is administered. 200 mg of lorizumab or pembrolizumab variant on day 1 every 6 weeks 6 or Ab6 variant will be administered intravenously on day 1 of every 3 weeks. In the present study, 400 mg of pembrolizumab or pembrolizumab variants were administered for 6 weeks. 300 mg of Ab6 or Ab6 variant administered intravenously on day 1 of every 3 weeks In one embodiment, 400 mg of pembrolizumab or Pembrolizumab variants were administered at 400 mg Ab6 or Ab6 bacil- Page 1 of 6 weeks. In another embodiment, 40 5.0 mg pembrolizumab or pembrolizumab variant on day 1 of every 6 weeks 00 mg of Ab6 or Ab6 variant will be administered intravenously on day 1 of every 3 weeks In another embodiment, 400 mg of pembrolizumab or pembrolizumab valproate is administered. Ant on day 1 of every 6 weeks, 600 mg of Ab6 or Ab6 variant every 3 weeks On day 1, it is administered by intravenous infusion. In another embodiment, 400 mg of pembrolizumab is administered intravenously. Mab or pembrolizumab variants were administered at 700 mg Ab6 or pembrolizumab variants on day 1 of every 6 weeks. The Ab6 variant is administered by intravenous infusion on day 1 of every 3 weeks. 400 mg of pembrolizumab or pembrolizumab variants every 6 weeks 800 mg of Ab6 or Ab6 variant administered intravenously on day 1 of every 3 weeks In a further embodiment, 400 mg of pembrolizumab or pembrolizumab is administered by infusion. Ambrolizumab variant was administered at 900 mg Ab6 or Ab6 variant on day 1 every 6 weeks. In a further embodiment, the ant is administered by intravenous infusion on the first day of every three weeks. 00 mg of pembrolizumab or pembrolizumab variant on day 1 of every 6 weeks 1000mg Ab6 or Ab6 variant administered intravenously on day 1 of every 3 weeks In a further embodiment, 400 mg of pembrolizumab or pembrolizumab is administered. Mab variant 1200 mg Ab6 or Ab6 variant on day 1 every 6 weeks It will be administered by intravenous infusion on the first day of every three weeks.

[0120] In the above methods, medicaments and uses, in one embodiment, the cancer is colorectal The treatment is mFOLFOX7 (leucovorin (folinic acid) in the treatment of colorectal cancer. Calcium fluoride, fluorouracil, oxaliplatin) or FOLFIRI ( Administration of Icovorin (calcium folinate, fluorouracil, irinotecan hydrochloride) In one embodiment, the colorectal cancer may further comprise a non-microsatellite high Unstable (non-MSI-H) or mismatch repair proficient (pMMR) colorectal cancer .

[0121] In one embodiment, mFOLFOX7 is administered intravenously: oxaliplatin is administered at 65 or 85 mg / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 in , fluorouracil (5 FU) was 2000 or 2400 mg / m 2 And every two weeks In one embodiment, leucovorin is administered at 200 mg / m 2 No In one embodiment, the pen may be replaced with calcium bofolinate. Brolizumab or pembrolizumab variants, 200 mg daily on each 21-day cycle Ab6 or Ab6 variants are administered intravenously in each eye at a dose of 200 mg in each 21-day cycle. On day 1, mFOLFOX7 was administered intravenously: oxaliplatin was administered intravenously for 65 days. or 85 mg / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 in , fluorouracil (5 FU) was 2000 or 2400 mg / m 2 So, every two weeks In one embodiment, pembrolizumab or pen is administered on day 1 or day 8. Brolizumab variant was administered intravenously at 200 mg on day 1 of each 21-day cycle. b6 or Ab6 variants are administered intravenously at 700 mg on day 1 of each 21-day cycle. mFOLFOX7 is administered intravenously: oxaliplatin at 65 or 85 mg / m 2 in , leucovorin (calcium folinate) 400 mg / m 2 Fluorouracil (5 FU) is 2000 or 2400 mg / m 2 , administered on days 1 or 8 every 2 weeks In another embodiment, 200 mg of pembrolizumab or pembrolizumab and a pharmaceutical composition containing 200 mg of Ab6 or an Ab6 variant, mFOLFOX7 was administered intravenously on day 1 of the daily cycle. Latin is 65 or 85 mg / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 Fluorouracil (5 FU) was 2000 or 2400 mg / m 2 in, It is administered on day 1 or day 8 every two weeks. In another embodiment, a 200 mg pen is administered. Pembrolizumab or pembrolizumab variant and 800 mg of Ab6 or Ab6 A pharmaceutical composition containing the variant is administered intravenously on day 1 of each 21-day cycle, and mFOLF OX7 was administered intravenously: oxaliplatin at 65 or 85 mg / m 2 So, Roy Kobori Calcium folinate is 400 mg / m 2 And fluorouracil (5 FU) is 2 000 or 2400 mg / m 2 It is administered on either day 1 or day 8 every two weeks.

[0122] In one embodiment, pembrolizumab or a pembrolizumab variant is 40 0 mg intravenously on day 1 of every 6 weeks, and Ab6 or Ab6 variants at 200 mg g intravenously on day 1 of each 21-day cycle and mFOLFOX7 administered intravenously: Oxaliplatin 65 or 85 mg / m 2 Leucovorin (calcium folinate) ) is 400 mg / m 2 Fluorouracil (5 FU) is 2000 or 2400 mg. / m 2 and administered on day 1 or day 8 every two weeks. Brolizumab or pembrolizumab variants, 400 mg intravenously on day 1 every 6 weeks Ab6 or Ab6 variants are administered orally at 700 mg on day 1 of each 21-day cycle. mFOLFOX7 is given intravenously: oxaliplatin at 65 or 8 mg / kg / day. 5 mg / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 So, full-on Rouracil (5FU) is 2000 or 2400 mg / m 2 Then, on the first day of every two weeks is administered on day 8.

[0123] In another embodiment, FOLFIRI is administered intravenously; irinotecan is administered intravenously at 150 or 1 80 mg / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 So, full Orouracil (5FU) is 2000 or 2400 mg / m 2 , administered every two weeks In one embodiment, pembrolizumab or pembrolizumab valproate is administered Q2W. Ant was administered intravenously at 200 mg on day 1 of each 21-day cycle and was administered as Ab6 or Ab6 Valencia was administered intravenously at 200 mg on day 1 of each 21-day cycle and was administered intravenously at 200 mg on day 1 of each 21-day cycle. is given intravenously: irinotecan at 150 or 180 mg / m 2 So, Leucovorin ( Calcium linate) is 400mg / m 2 And fluorouracil (5 FU) is 2000 or 2400 mg / m 2 , administered on days 1 or 8 every 2 weeks. In each dose, pembrolizumab or pembrolizumab variant is administered in a 200 mg dose. Ab6 or Ab6 variants are administered intravenously at 700 mg on day 1 of each daily cycle. IV on day 1 of each 21-day cycle, FOLFIRI is given intravenously: Tecan is 150 or 180 mg / m 2 Leucovorin (calcium folinate) is 4 00mg / m 2 Fluorouracil (5 FU) was 2000 or 2400 mg / m 2 In another embodiment, pembrolizumab is administered at 100 mg / kg every 2 weeks on day 1 or day 8. Mab or pembrolizumab variants, 200 mg intravenously on day 1 of each 21-day cycle Ab6 or Ab6 variants are administered orally at 800 mg on day 1 of each 21-day cycle. Intravenous administration: FOLFIRI intravenously; Irinotecan 150 or 180 mg / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 So, Fluor Uracil (5 FU) was 2000 or 2400 mg / m 2 On the first day of every two weeks or On day 8, 200 mg of pembrolizumab or pentamoxifen is administered. Brolizumab variant and 200mg of Ab6 or a pharmaceutical composition containing Ab6 variant The composition will be administered intravenously on day 1 of each 21-day cycle, and FOLFIRI will be administered intravenously: Irinotecan is 150 or 180 mg / m 2 So, leucovorin (calcium folinate) 400mg / m 2 Fluorouracil (5 FU) is 2000 or 2400m g / m 2 In another embodiment, the dose is administered at 20 0 mg pembrolizumab or pembrolizumab variant and 800 mg Ab6 or a pharmaceutical composition containing the Ab6 variant is administered intravenously on day 1 of each 21-day cycle. FOLFIRI was administered intravenously; irinotecan was administered at 150 or 180 mg / m 2 in, Leucovorin (calcium folinate) 400 mg / m 2 Fluorouracil (5 FU) is 2000 or 2400 mg / m 2 Administered on days 1 or 8 every 2 weeks can be.

[0124] In one embodiment, pembrolizumab or a pembrolizumab variant is 40 0 mg intravenously on day 1 of every 6 weeks, and Ab6 or Ab6 variants at 200 mg g intravenously on day 1 of each 21-day cycle, and FOLFIRI was administered intravenously: Rinotecan is 150 or 180 mg / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 Fluorouracil (5 FU) is 2000 or 2400 mg / m 2 In one embodiment, the pembrolizumab is administered on day 1 or day 8 every two weeks. Lorisumab or pembrolizumab variants, 400 mg intravenously on day 1 of every 6 weeks Ab6 or Ab6 variants were administered intravenously at 700 mg on day 1 of each 21-day cycle. Intravenous administration of FOLFIRI and intravenous administration of irinotecan at 150 or 180 mg g / m 2 Leucovorin (calcium folinate) is 400 mg / m 2 So, Fluoro Rasil (5 FU) is 2000 or 2400 mg / m 2 On the 1st or 8th of every 2 weeks In another embodiment, pembrolizumab or pembrolizumab is administered on day 1. Rianto is administered intravenously at 400 mg on day 1 of every 6 weeks and is administered either as Ab6 or Ab6 Barrier. 800 mg of cefotidine was administered intravenously on day 1 of each 21-day cycle, and FOLFIRI was administered intravenously. Irinotecan is administered intravenously at 150 or 180 mg / m 2 So, Leucovorin (Holinar calcium) is 400 mg / m 2 Fluorouracil (5 FU) is 2000 or 2400mg / m 2 It is administered on either day 1 or day 8 every two weeks.

[0125] Cancers that can be treated with the antibodies, compositions and methods of the present invention include, but are not limited to, Cardiac: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myoma, rhabdomyoma , fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell) cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, Dermatoma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma) , leiomyosarcoma), pancreas (ductal carcinoma, insulinoma, glucagonoma, gastrinoma, lutinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma) (Karposi's sarcoma), leiomyoma, hemangioma, lipoma, neurofibroma, fibroma fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) colorectal; genitourinary tract: Kidneys (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous skin cancer, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, Teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma Osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma teochronfroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondroblastoma Chondromyxofibroma, osteoid osteoma and macrofibroma Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, Meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor [pineal somatic tumors], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), Spinal neurofibroma, meningioma, glioma, sarcoma; Gynecology: Uterus (endometrial cancer), Cervix ( Cervical cancer, preneoplastic cervical dysplasia), ovarian (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma , unclassified cancer], follicular granulosa cell tumor (granulosa thecal cell tumor) umor), Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, Botryoid rhabdomyosarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast; Hematology: blood (myeloid Leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome); leukemia, acute lymphoblastic leukemia, chronic lymphocytic Leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma , non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and ba Lymphoid hematopoiesis including Burkett's lymphoma Myeloid tumors; including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia hematopoietic tumors of myeloid lineage; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; astrocytic tumors; Tumors of the central and peripheral nervous system, including gliomas, neuroblastomas, gliomas, and schwannomas as well as melanoma, skin (non-melanoma) cancer, mesothelioma (cell), seminoma, teratocarcinoma , osteosarcoma, xeroderma pigmentosum, keratinocyte Includes keratoctanthoma, thyroid follicular carcinoma and Kaposi's sarcoma In one embodiment, the forgoing cancer is: In one embodiment, the patient is treated with anti-PD-1 or or are refractory to anti-PD-L1 therapy.

[0126] In one embodiment, the cancers that can be treated by the antibodies, compositions and methods of the invention are These include, but are not limited to, lung cancer, pancreatic cancer, colon cancer, colorectal cancer, bone marrow cancer, Myeloid leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, thyroid cancer, Myelodysplastic syndrome, bladder cancer, epidermal cancer, melanoma, breast cancer, prostate cancer, head and neck cancer, egg Neoplastic tumors, brain cancer, cancer of mesenchymal origin, sarcoma, tetracarcinoma, Neuroblastoma, kidney cancer, liver cancer, non-Hodgkin's lymphoma, multiple myeloma and anaplastic thyroid cancer Examples include:

[0127] In another embodiment, cancers that may be treated with the antibodies, compositions and methods of the invention include These include, but are not limited to, head and neck squamous cell carcinoma, gastric cancer, gastric and / or gastro- These include adenocarcinoma of the esophageal junction, renal cell carcinoma, fallopian tube carcinoma, endometrial carcinoma, and colorectal carcinoma. In one embodiment, colorectal cancer, gastric cancer, gastric and / or gastro-esophageal cancer is Adenocarcinoma of the endothelial junction (GEJ), or endometrial cancer, is a non-microsatellite-high ( In one embodiment, the tumor is MSI-H or mismatch repair-proficient (pMMR). In one embodiment, the cancer is gastric cancer, adenocarcinoma of the stomach and / or gastroesophageal junction. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is head and neck squamous cell carcinoma. The patient is refractory to anti-PD-1 or anti-PD-L1 treatment. Patients with cervical squamous cell carcinoma who had received prior anti-PD-1 or anti-PD-L1 therapy In one embodiment, the colorectal cancer is unresectable or metastatic (Stage I V). In one embodiment, the cancer is non-small cell lung cancer.

[0128] In another embodiment, cancers that may be treated with the antibodies, compositions and methods of the invention include Hematological malignancies, including but not limited to classical Hodgkin lymphoma (cHL), Diffuse large B-cell lymphoma (DLBCL), transformed DLBCL, gray zone lymphoma lymphoma, double-hit lymphoma, primary mediastinal B-cell lymphoma (PMBCL) or low-grade Intracranial non-Hodgkin's lymphoma (iNHL) (e.g., follicular lymphoma, marginal zone lymphoma, mucosal lymphoma) In one embodiment, the present invention includes lymphomas of the lymphoid tissue (IL-1, lymphoid tissue lymphoma, or small lymphocytic lymphoma). In this study, patients with Hodgkin lymphoma were refractory to anti-PD-1 or anti-PD-L1 treatment. do.

[0129] In further embodiments, cancers that may be treated by the antibodies, compositions and methods of the invention These include renal cell carcinoma, urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, melanoma, and gastric adenocarcinoma. and cancers selected from the group consisting of GEJ adenocarcinoma, non-small cell lung cancer, and bladder cancer. In further embodiments, the cancers that may be treated are renal cell carcinoma, gastric adenocarcinoma, GEJ adenocarcinoma, Non-small cell lung cancer, head and neck squamous cell carcinoma, fallopian tube cancer, endometrial cancer and colorectal cancer In one embodiment, the colorectal cancer is selected from the group consisting of non-microsatellite The mutations are either chromosome-high instability (non-MSI-H) or mismatch repair proficient (pMMR). In an embodiment, the forgoing cancer is advanced, unresectable or metastatic. In one embodiment, the non-small cell lung cancer is advanced or stage IV. In another embodiment, the melanoma is advanced or stage III. In embodiments, the patient is refractory to anti-PD-1 or anti-PD-L1 treatment.

[0130] In one embodiment, 200 mg of pembrolizumab or pembrolizumab valproate A combination product containing antagonism and 200 mg of Ab6 or Ab6 variant is used. In another embodiment, 200 mg of pembrolizumab or pembrolizumab vaccinia is administered. A combination product containing 600 mg of Ab6 or Ab6 variant and 100 mg of rifampicin is used. In one embodiment, 200 mg of pembrolizumab or pembrolizumab A combination product containing 700 mg of Ab6 or Ab6 variant and 700 mg of Ab variant is In another embodiment, 200 mg of pembrolizumab or pembrolizumab is used. A combination product containing mab variant and 800 mg of Ab6 or Ab6 variant In another embodiment, 200 mg of pembrolizumab or pembrolizumab is used. A combination formulation containing izumab variant and 1000mg of Ab6 or Ab6 variant The product is used.

[0131] In a further embodiment, the cancer is non-small cell lung cancer and the patient has tumor activated epithelial proliferation Mutations in the EGFR or B-Raf isoform of aggressive fibrosarcoma Absence of the mutation and expression of anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS 1) lacks the gene rearrangement. In a further embodiment, the cancer is non-small cell lung cancer, The tumor has squamous histology.

[0132] The combination therapy may also include one or more additional therapeutic agents. , e.g., chemotherapeutic agents, biotherapeutic agents, immunogenic agents (e.g., attenuated cancer cells, tumor antigens, , antigen-presenting cells, e.g., tumor-derived antigens or dendritic cells pulsed with nucleic acids, immune stimulators, Inhibitory cytokines (e.g., IL-2, IFNα2, GM-CSF), and immune stimulatory Transgenic mice are cultured using a recombinant human ovarian tumor suppressor, which is a gene encoding a cytokine, such as, but not limited to, GM-CSF. The specific dosage and dosage schedule of the additional therapeutic agent may be The schedule may further vary, and optimal doses, dosing schedules, and routes of administration may vary. This will be determined based on the specific therapeutic agent being used.

[0133] Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclosporine. alkylsulfonates, such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carboquone, Meturedopa and uredopa, etc.; Alto Retamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophospho Melamin and trimethylolomelamine Includes ethylenimines and methylamelamines acetogenins (especially bullatacin and bullatacinone); camptothecin (synthetic analogs topotecan; bryostatin; kallistatin; CC-1065 (including its dozelesin, carzelesin and biceresin synthetic analogs; Cryptofyci cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duophycins Calmycins (including synthetic analogs, KW-2189 and CBI-TMI); Eli Tuterobin; Pancratistatin; Sarcodictyin; Spongestatin; Nitrogen mustards, e.g. chlorambucil, chlornaphazine, colofosfamide lophosphamide), estramustine, ifosfamide, mechlorethamine, Mechlorethamine oxide hydrochloride, melphalan, nobuenbiquinone, phenesterin, prednisolone Donimustine, trofosfamide, uracil mustard, etc.; nitrosureas (nit rosurea), e.g. carmustine, chlorozotocin, fotemustine, lomustine , nimustine, ranimustine, etc.; antibiotics, such as enediyne antibiotics (e.g., ca calicheamicins, especially calicheamicin gamma 1I and calicheamicin phi I1; For example, see Agnew, Chem. Intl. Ed. Engl., 33:183-186 ( 1994); dynemycins, including dynemycin A; bisphosphonates esters, such as clodronate; esperamicin; as well as neocarzinostatin Enediyne antibiotic chromomophores and related chromoproteins omophore), aclacinomycins, actinomycins nomycin, autramycin, azaserine, bleomycin Cactinomycin, carabicin, caminomycin inomycin), carzinophilin, chromomycins, dactinomycin, daunomycin Rubicin, Detrubicin, 6-diazo-5-oxo-L-norleucine, Doxorubicin (Morpholino-doxorubicin, Cyanomorpholino-doxorubicin, 2-Pyrrolino -doxorubicin and deoxydoxorubicin), epirubicin, esorubicin cin, idarubicin, marcelomycin, mitomycins, such as mitomycin C Mycophenolic acid, nogalamycin, olivomycins, peplomycin, pothophy Potfiromycin, puromycin, queramycin lamycin, rodorubicin, streptonigrin, Treptozocin, tubercidin, ubenimex, zinostatin, zorubicin, etc.; antimetabolites Antibiotics, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs agonists, such as denopterin, methotrexate, pteropterin, trimetrexate, etc. Purine analogues, e.g. fludarabine, 6-mercaptopurine, thiamiprine, thiopurine, etc. guanine, etc.; pyrimidine analogues, e.g. ancitabine, azacitidine, 6-azauryl Zin, Carmofur, Cytarabine, Dideoxyuridine, Doxifluridine, Enocitabin androgens, such as calsterone, dromopropionate, etc.; Stanolone, epithiostanol, mepitiostane, testolactone, etc.; antiadrenal drugs, e.g. For example, aminoglutethimide, mitotane, trilostane, etc.; folic acid supplements (folic acid id replenisher, such as fluorinic acid Aceglatone; Aldophosphamide glycoside; Aminolevulinic acid; Eniluracil ;Amsacrine;Bestravsil;Bisantrene;Edatraxate (edatraxa te); defofamine; demecolcine; diazicon; erhol Elformithine; Elformitine acetate; Epothilone; Etoglucide ;Gallium nitrate;Hydroxyurea;Lentinan;Lonidamine;Maytansinoids, e.g. For example, maytansine and ansamitocins; mitoguazone; mitoxantrone; mopi Damor; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Rosoxant Podophyllinic acid; 2-ethylhydrazine procarbazine; razoxane; rhizoxin; schizofuran; spirogermanium; tenu Azonic acid;Triazicon;2,2',2''-Trichlorotriethylamine;Trichotecene Toxins (especially T-2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronate ol; mitolactol; pipobroman; gacytosine; arabino cyclophosphamide; thiotepa; taxoids, e.g., pak Litaxel and docetaxel; Chlorambucil; Gemcitabine; 6-thioguanine; Met methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitochondrial; Xantrone; Vincristine; Vinorelbine; Novantrone; Teniposide; Edatrex sate;daunomycin;aminopterin;xeloda;ibandronate;CPT-11 ;Topoisomerase inhibitor RFS2000;Difluoromethylornithine (DMFO); Retinoids, such as retinoic acid; capecitabine; and any of the above pharmaceutical Also, the present invention relates to a compound that is capable of controlling hormone action on tumors. or anti-hormonal agents that act to inhibit, such as tamoxifen and raloxifene , droloxifene, 4-hydroxytamoxifen, trioxyphene, ketoxifene These include LY117018, onapristone and toremifene (Fareston) Antiestrogens and selective estrogen receptor modulators (SERMs), etc.; Aromatase inhibitors block aromatase, an enzyme that controls estrogen production in the kidney. , e.g., 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exe Mestan, Formestane, Fadrozole, Vorozole, Letrozole and Anast lozole, etc.; and antiandrogens, such as flutamide, nilutamide, bicalutamide, and any of the above pharma- ceutical acceptable salts. Salts, acids or derivatives are also included.

[0134] Each therapeutic agent in the combination therapy of the invention may be administered alone or in combination in accordance with standard pharmaceutical practice. or a therapeutic agent and one or more pharma- ceutically acceptable carriers, vehicles, excipients, and diluents. The compound may be administered in a medicament (also referred to herein as a pharmaceutical composition) comprising:

[0135] Each therapeutic agent in the combination therapy of the invention may be administered simultaneously (i.e., in the same formulation) and simultaneously. (i.e., in separate drugs, one administered immediately followed by the other, in any order) and The combination agents may be administered sequentially in any order. Sequential administration is preferred when the therapeutic agents in the combination therapy are different. The dosage form is two-part (one part is a tablet or capsule and the other part is a sterile liquid) and / or different dosing schedules, e.g., when chemotherapy agents are administered Administered at least once daily, with biologics administered less frequently, e.g., once a week, once every two weeks It is particularly useful when administered once every three weeks or so.

[0136] In some embodiments, the anti-LAG3 antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody. In another embodiment, the anti-LAG3 antibody is administered prior to administration of the anti-PD- 1 antibody or anti-PD-L1 antibody. The G3 antibody is administered simultaneously with the anti-PD-1 antibody or anti-PD-L1 antibody.

[0137] In some embodiments, at least one of the therapeutic agents in the combination therapy is typically used when an agent is used as a monotherapy to treat the same cancer is administered using the same drug administration regimen (dose, frequency, and duration of treatment) as In other embodiments, at least one of the therapeutic agents in the combination therapy that the patient receives The total amount of any one agent is less than when the agent is used as monotherapy, e.g., at a dose that is The patient may require fewer treatments, less frequent dosing, and / or shorter duration of treatment.

[0138] Each small molecule therapeutic agent in the combination therapy of the present invention can be administered orally, intravenously, intramuscularly, or It can be administered parenterally, intraperitoneally, subcutaneously, rectally, topically and transdermally. The combination treatment of the present invention may be used before or after surgery to remove the tumor. It may be used before, during or after radiation therapy.

[0139] In some embodiments, the combination therapy of the invention is preceded by a biotherapeutic agent or It is administered to patients who have not been treated with chemotherapy, i.e., treatment-naive. In some cases, the combination therapy is a sustained therapy following prior treatment with a biotherapeutic or chemotherapy agent. It is administered to patients who have failed to achieve a response, i.e., treatment-experienced.

[0140] The combination therapy of the present invention is typically administered by palpation or by other methods well known in the art. It is detected by imaging techniques such as MRI, ultrasound or CAT scan. It is used to treat tumors large enough to

[0141] The combination treatment of the present invention preferably comprises one or more of PD-L1 and PD-L2. or both, preferably testing positive for PD-L1 expression. In some preferred embodiments, the PD-L1 Expression was assessed using a diagnostic anti-human PD-L1 antibody or its antigen-binding fragment in isolated PD-L1 tumor cells from patients. Detected in IHC assays on FFPE or frozen tissue sections of selected tumor samples Typically, a patient's physician will recommend treatment with an anti-PD-1 or anti-PD-L1 antibody and an anti-LAG3 antibody. Determine PD-L1 expression in tumor tissue samples removed from patients prior to the initiation of treatment with the antibody However, the physician may order diagnostic tests for the treatment at any time after the start of treatment, e.g., during the treatment cycle. Possibility to order initial or subsequent diagnostic tests on tumor tissue sections, e.g., after completion of In one embodiment, PD-L1 expression is PD-L1 I. In another embodiment, the HC 22C3 pharmDx assay is used. The patient has a mononuclear inflammation density score for PD-L1 expression of ≧2. In another embodiment, the patient has a mononuclear inflammation density score for PD-L1 expression of ≧3. In another embodiment, the patient has a mononuclear inflammation density score for PD-L1 expression of ≧4. In another embodiment, the patient has a tumor percentage score for PD-L1 expression of ≧1%. In one embodiment, the patient has a tumor percentage score for PD-L1 expression of ≥ 10%. In an embodiment, the patient has a tumor proportion score for PD-L1 expression of ≧20%. In another embodiment, the patient has a tumor proportion score for PD-L1 expression of ≧30%. In another embodiment, the patient has a tumor proportion score for PD-L1 expression of ≧50% In a further embodiment, the patient has a combined positive sequence for PD-L1 expression. In another embodiment, the mononuclear inflammation of the patient for PD-L1 expression is Density score ≥2 or tumor proportion score for PD-L1 expression ≥1% In a further embodiment, the patient has a combined positive score for PD-L1 expression. In a further embodiment, the patient's PD-L1 expression is between 1 and 20%. In a further embodiment, the patient's PD-L The combined positive score for one expression is ≧5%. In this study, the patient had a combined positive score for PD-L1 expression of ≥ 10%. In some embodiments, the patient has a combined positive score for PD-L1 expression of ≧15% In yet a further embodiment, the combination of PD-L1 expression in the patient is In another embodiment, the patient has non-small cell lung cancer and has a positive score of ≧20%. The tumor proportion score for PD-L1 expression is ≥ 50%.

[0142] In addition, the combination treatment of the present invention is useful in patients with cancer that tests positive for LAG3 expression. In some preferred embodiments, the LAG3 gene can be administered to a human patient. The present invention relates to a method for detecting the presence of LAG3 in a patient using a diagnostic anti-human LAG3 antibody or an antigen-binding fragment thereof. It is detected in IHC assays on FFPE or frozen tissue sections of tumor samples. Typically, a patient's physician will prescribe anti-PD-1 or anti-PD-L1 and anti-LAG3 antibodies. To determine LAG3 expression in tumor tissue samples removed from patients prior to the start of treatment with A diagnostic test may be ordered but not performed by the physician at any time after treatment has begun, e.g., at the completion of a treatment cycle. It is conceivable that initial or subsequent diagnostic tests may be ordered later, such as after the initial diagnosis. In one embodiment, the patient has CPS-like LAG3% positive cells ≧1%. In one embodiment, the patient has CPS-like LAG3% positive cells > 2%. In one embodiment, the patient has CPS-like LAG3% positive cells of ≧5%. In one embodiment, the patient has CPS-like LAG3% positive cells of ≧10%. In one embodiment, the patient has a LAG3 % positive cell count of ≧1%. % positive cells is ≧2%. In one embodiment, the patient's LAG3 % positive cells is ≧2%. ≧5%. In one embodiment, the patient's LAG3% positive cells are ≧10%. .

[0143] In one preferred embodiment of the invention, the anti-PD-1 antibody in the combination therapy is Nivolumab: 1mg / kg Q2W, 2mg / kg Q2W, 3mg / kg Q2 W, 5mg / kg Q2W, 10mg Q2W, 1mg / kg Q3W, 2mg / kg Q3W, 3mg / kg Q3W, 5mg / kg Q3W and 10mg / kg Q3W The compound is administered intravenously at a dose selected from the group consisting of:

[0144] In another preferred embodiment of the invention, the anti-PD-1 antibody in the combination therapy is Pembrolizumab or a pembrolizumab variant, liquid formulation, 1 mg / kg Q2W, 2mg / kg Q2W, 3mg / kg Q2W, 5mg / kg Q2W, 10m g / kg Q2W, 1mg / kg Q3W, 2mg / kg Q3W, 3mg / kg Q3 W, 5mg / kg Q3W, 10mg / kg Q3W and any one of these doses A dose selected from the group consisting of a rate-equivalent dose, i.e., 200 mg Q3W, etc. In some embodiments, pembrolizumab is administered at 10 mM histidine. 25mg / ml pembrolizumab in PBS pH 5.5, 7% (w / v) It is provided as a liquid formulation containing 0.02% (w / v) polysorbate 80. In other embodiments, pembrolizumab is administered at a concentration of about 125 to about 200 mg / mL of pembrolizumab. Lorisumab or an antigen-binding fragment thereof; about 10 mM Histidine buffer; about 10 mM L-methionine or a pharma- ceutically acceptable salt thereof; about 7% (w / v) sucrose; and and about 0.02% (w / v) polysorbate 80.

[0145] In some embodiments of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof The patient is administered once every 4 or 6 weeks for 12 or more weeks. Anti-PD-1 antibody or its antigen-binding fragment is administered once every 6 weeks for at least 16 weeks, followed by administration for 18 weeks. 20 weeks or more, 24 weeks or more, 28 weeks or more, 30 weeks or more, 32 weeks or more, 36 weeks or more, 40 weeks or more, 42 weeks or more, 44 weeks or more, 48 weeks or more, 52 weeks or more, 54 weeks or more, 56 weeks or more, 60 weeks or more, 64 weeks or more, 66 weeks or more, 68 weeks or more Above, 72 weeks or more, 76 weeks or more, 78 weeks or more, 80 weeks or more, 84 weeks or more, 88 weeks In another embodiment, the anti-PD-1 antibody is administered to the patient for 90 weeks or more. or an antigen-binding fragment thereof is administered at 400 mg every six weeks.

[0146] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered IV. Depending on the injection, the drug is administered over a period of between 25 to 40 minutes, or approximately 30 minutes.

[0147] In some embodiments, the patient is treated with at least 24 weeks, e.g., eight 3-week subcutaneous injections. In some embodiments, the patient is treated with a combination therapy of cyclosporine and cyclosporine. Treatment is continued until patients demonstrate evidence of PD or CR.

[0148] Pharmaceutically acceptable additives of the present disclosure include, for example, solvents, bulking agents, buffers, osmolality Modifiers and preservatives (see, e.g., Pramanick et al., Ph.D. (See Arma Times, 45:65-77, 2013.) In the form, the pharmaceutical composition may comprise one or more of a solvent, a bulking agent, a buffer, and an osmolality adjusting agent. may contain additives that function in multiple ways (e.g., sodium chloride in saline is The pharmaceutical compositions of the present disclosure may be administered parenterally. Suitable for.

[0149] In some embodiments, the pharmaceutical composition comprises an aqueous medium as a solvent. Examples of suitable solutions include sterile water, saline, phosphate buffered saline, and Ringer's solution. In some embodiments, the composition is isotonic.

[0150] The pharmaceutical composition may include a bulking agent. The bulking agent is used when the pharmaceutical composition is lyophilized prior to administration. In some embodiments, the bulking agent is lyophilized or sprayed. A protectant that helps stabilize and prevent degradation of the active agent during fog drying and / or storage. Suitable bulking agents are sugars (mono-, di- and polysaccharides), such as sucrose, lactose, , trehalose, mannitol, sorbital, glucose and raffinose. do.

[0151] The pharmaceutical composition may include a buffer. The buffer may be used during processing, storage, and optionally during reconstitution. The pH is controlled to inhibit the decomposition of the active agent. Suitable buffers include, e.g. For example, salts include acetate, citrate, phosphate or sulfate. Other suitable bases include Buffers include, for example, amino acids such as arginine, glycine, histidine and lysine. The buffer may further include hydrochloric acid or sodium hydroxide. In some embodiments, the buffer maintains the pH of the composition within the range of 4 to 9. In some embodiments, the pH is greater than 4, 5, 6, 7, or 8 (lower limit). In some embodiments, the pH is less than 9, 8, 7, 6, or 5 (upper limit). The pH is within the range of about 4 to 9, with the lower limit being lower than the upper limit.

[0152] The pharmaceutical composition may include an osmolality adjusting agent. Suitable osmolality adjusting agents include, for example, glucose. Examples of suitable sugars include glycerol, sodium chloride, glycerin and mannitol.

[0153] The pharmaceutical composition may include a preservative. Suitable preservatives include, for example, antioxidants and antimicrobials. In a preferred embodiment, the pharmaceutical composition is prepared under sterile conditions. They are in single-use containers and therefore do not need to contain preservatives.

[0154] In some embodiments, the drug comprises an anti-PD-1 antibody as a PD-1 antagonist. The agent may be provided as a liquid formulation or a lyophilized powder that is reconstituted with sterile water for injection prior to use. WO2012 / 135408 discloses a method for preparing a compound according to the present invention. Several liquid and lyophilized drug formulations containing pembrolizumab suitable for use in In some embodiments, the pembrolizumab-containing agent is about 100 ml in 4 ml of solution. The vials contain 25 g of pembrolizumab. mg of pembrolizumab, L-histidine (1.55 mg), polysorbate 8 It is formulated in 0 (0.2 mg), sucrose (70 mg) and water for injection USP. The solution requires dilution for IV infusion.

[0155] In some embodiments, the medicament comprising the anti-LAG3 antibody is provided as a liquid formulation. or by reconstituting the lyophilized powder with sterile water for injection prior to use. In one embodiment, the liquid formulation comprises about 25 mg / mL of anti-LAG3 antibody; mg / mL sucrose; approximately 0.2 mg / mL polysorbate 80; pH approximately 5.8 6.0 about 10 mM L-histidine buffer; about 70 mM L-arginine-H Cl; and optionally about 10 mM L-methionine.

[0156] The pharmaceutical preparations described herein are in a capsule containing a first container and a second container and a package insert. The first container may be provided as a medicament containing a PD-1 antagonist. The first container contains 7 to 1200 mg of a drug containing an anti-LAG3 antibody, and the second container contains 7 to 1200 mg of a drug containing an anti-LAG3 antibody, and The accompanying paperwork or label includes instructions for using the agent to treat a patient's cancer. and the second container may be of the same or different shape (e.g., vials, syringes, and bottles). can be of the same or different materials (e.g. plastic or The kit may further include other materials that may be useful in administering the drug, such as diluents. The kit may include diluents, filters, IV bags and lines, needles and syringes, etc. In some preferred embodiments, the PD-1 antagonist is an anti-PD-1 antibody. The explanation was that the drug tested positive for PD-L1 expression by IHC assay. The patent states that the drug is intended for use in the treatment of patients with certain types of cancer.

[0157] In other embodiments, the agent comprises an anti-LAG3 antibody or antigen-binding fragment and an anti-PD-1 antibody or or antigen-binding fragment thereof, at a total concentration of 10 to 1000 mM arginine or a pharma- ceutical acceptable and a buffer having a pH of about 5-8, and optionally 3-100 mM methyl In one embodiment, the combination contains about 10 to 120 mg / mL of anti-LAG3 antibody; approximately 10 to 120 mg / mL of anti-PD-1 antibody; approximately 30 to 12 0 mg / mL sucrose or trehalose; approximately 0.05 to 2 mg / mL polysol Buffer 80; approximately 3 to 30 mM L-histidine buffer with a pH of approximately 5.0 to 6.5 about 40 to 150 mM L-arginine or a pharma- ceutically acceptable salt thereof; and Optionally, about 5 to 70 mM L-methionine. Ab6 suitable for use in the invention, including Ab6 combined with pembrolizumab Liquid and lyophilized drug formulations are described.

[0158] These and other aspects of the present invention are also disclosed in the following exemplary embodiments, including those listed below: , as is apparent from the teachings contained herein.

[0159] Specific Exemplary Embodiments of the Invention 1. An anti-LAG3 antibody for use in treating cancer in a patient, comprising: (a) a polypeptide comprising (b) the light chain CDRs of SEQ ID NOs: 26, 27 and 28 and (c) SEQ ID NOs: 29, 30 and 31 and administered via intravenous infusion at 7 to 1200 mg. 3 antibodies.

[0160] 2. The method of claim 1, wherein the patient is administered 100 mg of anti-LAG3 antibody. LAG3 antibody.

[0161] 3. The method of claim 1, wherein the patient is administered 200 mg of anti-LAG3 antibody. LAG3 antibody.

[0162] 4. The method of claim 1, wherein the patient is administered 700 mg of anti-LAG3 antibody. LAG3 antibody.

[0163] 5. The method of claim 1, wherein the patient is administered 800 mg of anti-LAG3 antibody. LAG3 antibody.

[0164] 6. The method of claim 1, wherein the patient is administered the anti-LAG3 antibody on the first day of every three weeks. Anti-LAG3 antibody for use.

[0165] 7. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variant comprising SEQ ID NO: 25. 7. The method of any one of embodiments 1 to 6, wherein the light chain comprises a light chain variable region comprising SEQ ID NO: 24. Anti-LAG3 antibody for one or both uses.

[0166] 8. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 23 and the light chain 7. The anti-LAG3 antibody for use according to any one of embodiments 1 to 6, wherein the antibody comprises SEQ ID NO: 22. .

[0167] 9. Any one of embodiments 1 to 6, wherein the anti-LAG3 antibody is an Ab6 variant. Anti-LAG3 antibody for use.

[0168] 10. The anti-LAG3 antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody or an antibody thereof 10. The anti-LAG antibody for use according to any one of embodiments 1 to 9, co-administered with an original binding fragment 3 antibodies.

[0169] 11. The anti-LAG3 antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody or an antibody thereof. The anti-LAG3 antibody for use according to any one of the preceding embodiments, which is combined with an original binding fragment.

[0170] 12. An anti-PD-1 antibody or an antigen-binding fragment thereof, which specifically binds to human PD-1; The use of embodiment 10 or 11 for blocking the binding of human PD-L1 to human PD-1 Anti-LAG3 antibody for.

[0171] 13. The anti-PD-1 antibody or antigen-binding fragment thereof also binds to human PD-L2. 13. The anti-LAG3 antibody for use in embodiment 12, which blocks binding to .

[0172] 14. The anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: (a) the antibody represented by SEQ ID NOs: 1, 2, and 3. 14. The method of claim 13, comprising (a) the light chain CDRs and (b) the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8. Anti-LAG3 antibody for use.

[0173] 15. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:9. For use of embodiment 13, the light chain comprises a light chain variable region comprising SEQ ID NO: 4. of anti-LAG3 antibody.

[0174] 16. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 10 and the light chain comprises 14. The anti-LAG3 antibody for use according to embodiment 13, wherein the chain comprises SEQ ID NO:5.

[0175] 17. The anti-PD-1 antibody for use in embodiment 13, wherein the anti-PD-1 antibody is pembrolizumab. AG3 antibody.

[0176] 18. The use of embodiment 13, wherein the anti-PD-1 antibody is a pembrolizumab variant. Anti-LAG3 antibody for

[0177] 19. Anti-LAG3 for use in embodiment 10, wherein the anti-PD-1 antibody is nivolumab antibody.

[0178] 20. The anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab 11. The anti-LAG3 antibody for use according to embodiment 10.

[0179] 21. Anti-PD-1 antibody administered via intravenous infusion at 200 mg once every 3 weeks on day 1 The anti-LAG3 antibody for use according to any one of embodiments 14 to 18, wherein the antibody is administered

[0180] 22. Anti-PD-1 antibody administered via intravenous infusion at 400 mg on day 1 once every 6 weeks The anti-LAG3 antibody for use according to any one of embodiments 14 to 18, wherein the antibody is administered

[0181] 23. The anti-PD-1 antibody is a humanized anti-PD-1 antibody comprising a heavy chain and a light chain, The heavy chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NO: 6, 7 and 8, and the light chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NO: a light chain variable region comprising light chain CDRs 1, 2 and 3; and and a light chain comprising a heavy chain selected from SEQ ID NOs: 29, 30 and 40. and 31 heavy chain CDRs, and the light chain comprises the heavy chain variable region of SEQ ID NOs: 26, 27, and 28. 12. Anti-LAG antibody for use according to embodiment 10 or 11, comprising a light chain variable region comprising the light chain CDRs. 3 antibodies.

[0182] 24. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 9. and the light chain comprises a light chain variable region comprising SEQ ID NO:4; and the anti-LAG3 antibody comprises and a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises a sequence 12. The anti-LAG antibody for use in embodiment 10 or 11, comprising a light chain variable region comprising sequence number 24. 3 antibodies.

[0183] 25. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 10 and the light chain comprises and the anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain is For use of embodiment 10 or 11, wherein the antibody comprises SEQ ID NO: 23 and the light chain comprises SEQ ID NO: 22. of anti-LAG3 antibody.

[0184] 26. Anti-PD-1 antibody is administered via intravenous infusion at 200 mg once every 3 weeks on day 1. The anti-LAG3 antibody was administered via intravenous infusion at 200 mg once every 3 weeks on day 1. 26. The anti-LAG3 antibody for use according to any one of embodiments 23 to 25.

[0185] 27. Anti-PD-1 antibody is administered via intravenous infusion at 400 mg once every 6 weeks on day 1. The anti-LAG3 antibody was administered via intravenous infusion at 200 mg once every 3 weeks on day 1. 26. The anti-LAG3 antibody for use according to any one of embodiments 23 to 25.

[0186] 28. Anti-PD-1 antibody is administered via intravenous infusion at 200 mg once every 3 weeks on day 1. Anti-LAG3 antibody was administered intravenously on day 1 at 700 or 800 mg once every 3 weeks. 26. The anti-LAG3 antibody for use according to any one of embodiments 23 to 25, which is administered via infusion. body.

[0187] 29. Anti-PD-1 antibody is administered via intravenous infusion at 400 mg once every 6 weeks on day 1. Anti-LAG3 antibody was administered intravenously on day 1 at 700 or 800 mg once every 3 weeks. 26. The anti-LAG3 antibody for use according to any one of embodiments 23 to 25, which is administered via infusion. body.

[0188] 30. 200mg of anti-PD-1 antibody is combined with 200mg of anti-LAG3 antibody. The anti-LAG3 antibody for use according to any one of embodiments 23 to 25.

[0189] 31. 200mg of anti-PD-1 antibody is combined with 800mg of anti-LAG3 antibody. The anti-LAG3 antibody for use according to any one of embodiments 23 to 25.

[0190] 32. The cancer is head and neck squamous cell carcinoma, gastric cancer, or adenocarcinoma of the stomach and / or gastroesophageal junction , renal cell carcinoma, fallopian tube carcinoma, endometrial carcinoma, and non-microsatellite instability-high ( and colorectal cancer selected from the group consisting of non-MSI-H (non-MSI-H) or mismatch repair proficient (pMMR). 32. The anti-LAG3 antibody for use according to any one of embodiments 1 to 31, selected from the group consisting of

[0191] 33. The cancer is renal cell carcinoma, urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra, melanoma, 31. The method according to any one of the preceding claims, wherein the patient is a patient selected from the group consisting of gastric cancer, non-small cell lung cancer, and bladder cancer. The anti-LAG3 antibody for use in any one of the following:

[0192] 34. Cancer is classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL) or indolent non-Hodgkin's lymphoma (iNHL). 31. Anti-LAG3 antibody for use in any one of the following:

[0193] 35. The individual has not been previously treated with anti-PD-1 or anti-PD-L1 therapy, or or confirmed to be progressive on prior anti-PD-1 or anti-PD-L1 therapy 35. The anti-LAG3 antibody for use according to any one of embodiments 1 to 34,

[0194] 36. Any of embodiments 1 to 35, wherein the individual's tumor cells are PD-L1 positive. Anti-LAG3 antibody for one use.

[0195] 37. An embodiment in which the individual has a mononuclear inflammation density score for PD-L1 expression of ≧2%. 1 to 36. Use of the anti-LAG3 antibody according to any one of claims 1 to 36.

[0196] 38. The individual has a combined positive score for PD-L1 expression of ≥ 1%. 38. An anti-LAG3 antibody for use in any one of embodiments 1 to 37.

[0197] 39. The individual has a combined positive score for PD-L1 expression of ≥ 10%. The anti-LAG3 antibody for use in any one of forms 1 to 37.

[0198] 40. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay. The anti-LAG3 antibody for use in any one of embodiments 37 to 39, wherein the anti-LAG3 antibody is determined by the following:

[0199] 41. 200 mg of pembrolizumab or pembrolizumab variants and 20 1. A pharmaceutical composition comprising: composition.

[0200] 42. 200 mg of pembrolizumab or pembrolizumab variants and 80 1. A pharmaceutical composition comprising: composition.

[0201] 43. Use in combination with an anti-PD-1 antibody for the treatment of gastric cancer in a patient wherein the patient's tumor tissue section is positive for PD-L1 expression; The anti-LAG3 antibody.

[0202] 44. The use of embodiment 43, wherein the gastric cancer is adenocarcinoma of the stomach and / or gastroesophageal junction. Anti-LAG3 antibody for.

[0203] 45. In combination with anti-PD-1 antibodies for the treatment of head and neck squamous cell carcinoma in patients an anti-LAG3 antibody for use in treating a patient whose tumor tissue sections positively express PD-L1; The anti-LAG3 antibody,

[0204] 46. ​​Non-microsatellite instability-high (non-MSI-H) or mismatched gene in patients In combination with anti-PD-1 antibodies for the treatment of pMMR colorectal cancer an anti-LAG3 antibody for use in treating a patient in whom tumor tissue sections are positive for PD-L1 expression; and % LAG3 positive cells or CPS-like % LAG3 positive cells are ≥ 1%. Anti-LAG3 antibody.

[0205] 47. Patients must not have received prior treatment with anti-PD-1 or anti-PD-L1 antibodies. The anti-LAG3 antibody for use in embodiments 43 to 46.

[0206] 48. Combined positive score for PD-L1 expression (CP) of tumor tissue sections of patients The anti-LAG3 antibody for use in embodiments 43 to 47, wherein S) is ≧1%.

[0207] 49. The patient's tumor tissue sections have a combined positive score for PD-L1 expression of ≥ 5%.

[0208] 50. The patient's tumor tissue sections have a combined positive score for PD-L1 expression of ≥ 10%.

[0209] 51. The patient's tumor tissue sections have a combined positive score for PD-L1 expression of ≥ 20%.

[0210] 52. Patients have a tumor proportion score (TPS) of ≥ 1% or mononuclear tumor tissue sections. The anti-LA for use in embodiments 43 to 47, wherein the inflammation density score (MIDS) is ≧2%. G3 antibody.

[0211] 53. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay. The anti-LAG3 antibody for use in embodiments 43 to 52, which is measured according to the following:

[0212] 54. The method of any one of embodiments 43 to 53, wherein the percent LAG3 positive cells in the tumor tissue section is ≧1%. Anti-LAG3 antibody for use.

[0213] 55. The CPS-like % LAG3 positive cells in tumor tissue sections are ≧1% according to embodiment 43 to 53 use of anti-LAG3 antibodies.

[0214] 56. An anti-PD-1 antibody or an antigen-binding fragment thereof specifically binds to human PD-1 and inhibits human PD-1. For use of embodiments 43 to 55, blocking the binding of human PD-L1 to human PD-1. of anti-LAG3 antibody.

[0215] 57. The anti-PD-1 antibody or its antigen-binding fragment also binds to human PD-L2. 57. The anti-LAG3 antibody for use in embodiment 56, which blocks binding to .

[0216] 58. An anti-PD-1 antibody or antigen-binding fragment thereof, comprising: (a) a polypeptide selected from the group consisting of SEQ ID NOs: 1, 2, and 3; 58. The method of claim 57, comprising (a) the light chain CDRs and (b) the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8. Anti-LAG3 antibody for use.

[0217] 59. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variant comprising SEQ ID NO: 9. For use of embodiment 57, the light chain comprises a light chain variable region comprising SEQ ID NO: 4. of anti-LAG3 antibody.

[0218] 60. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 10 and the light chain comprises 58. The anti-LAG3 antibody for use in embodiment 57, wherein the chain comprises SEQ ID NO:5.

[0219] 61. The anti-PD-1 antibody for use in embodiment 57, wherein the anti-PD-1 antibody is pembrolizumab. AG3 antibody.

[0220] 62. The use of embodiment 57, wherein the anti-PD-1 antibody is a pembrolizumab variant. Anti-LAG3 antibody for

[0221] 63. Anti-LAG3 for use in embodiment 57, in which the anti-PD-1 antibody is nivolumab antibody.

[0222] 64. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 25. 64. The method of claim 43, wherein the light chain comprises a light chain variable region comprising SEQ ID NO: 24. Anti-LAG3 antibody for any one use.

[0223] 65. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 23 and the light chain comprises The anti-LAG3 antibody for use according to any one of the embodiments 43 to 63, wherein the chain comprises SEQ ID NO: 22. antibody.

[0224] 66. Any one of embodiments 43 to 63, in which the anti-LAG3 antibody is an Ab6 variant. Anti-LAG3 antibody for one use.

[0225] 67. An anti-LAG3 antibody is co-administered with an anti-PD-1 antibody or an antigen-binding fragment thereof. The anti-LAG3 antibody for use according to any one of embodiments 43 to 66.

[0226] 68. An anti-LAG3 antibody is combined with an anti-PD-1 antibody or an antigen-binding fragment thereof. The anti-LAG3 antibody for use according to any one of embodiments 43 to 66.

[0227] General method Standard methods in molecular biology are described by Sambrook, Fritsch and Ma niatis (1982&1989 2 nd Edition, 2001 3 rd Ed ition) Molecular Cloning,A Laboratory Ma nual,Cold Spring Harbor Laboratory Press ,Cold Spring Harbor,NY;Sambrook and Russ ell(2001) Molecular Cloning, 3 rd ed., Cold Spring Harbor Laboratory Press,Cold Spr. ing Harbor,NY;Wu(1993) Recombinant DNA,V ol.217, Academic Press, San Diego, CA) Standard methods are also described by Ausbel, et al. (2001) Curren t Protocols in Molecular Biology,Vols.1- 4. John Wiley and Sons, Inc. New York, NY This is the first paper in the series on cloning and DNA mutagenesis in bacterial cells (Vol. ), Cloning in mammalian cells and yeast (Vol. 2), Glycoconjugates and proteins We describe protein expression (Vol. 3) and bioinformatics (Vol. 4). There are.

[0228] Protein analysis including immunoprecipitation, chromatography, electrophoresis, centrifugation and crystallization The purification method was described (Coligan, et al. (2000) Curr ent Protocols in Protein Science,Vol.1,J ohn Wiley and Sons, Inc., New York). chemical analysis, chemical Chemical modifications, post-translational modifications and production of fusion proteins, protein glycosylation have been described. (See, for example, Coligan, et al. (2000) Current Proceedings otocols in Protein Science,Vol.2,John Wi ley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular B iology, Vol. 3, John Wiley and Sons, Inc., NY ,NY,pp.16.0.5-16.22.17;Sigma-Aldrich,Co. (2001) Products for Life Science Research h,St.Louis,MO;pp.45-89;Amersham Pharmaci a Biotech(2001) BioDirectory, Piscataway, NJ, pp. 384-391). Polyclonal and monoclonal antibodies Production, purification and fragmentation of clonal antibodies have been described (Coligan, et al. (2001) Current Protocols in Immunology,V ol.1, John Wiley and Sons, Inc., New York; arlow and Lane(1999) Using Antibodies,Co ld Spring Harbor Laboratory Press,Cold S Spring Harbor, NY; Harlow and Lane, NY. Standard techniques for the characterization of receptor interactions are available (e.g., Colig an,et al.(2001) Current Protocols in Imm See Unology, Vol. 4, John Wiley, Inc., New York. I want to be illuminated.

[0229] Monoclonal, polyclonal and humanized antibodies can be prepared. (See, for example, Sheperd and Dean (eds.) (2000) Monoc lonal Antibodies,Oxford Univ.Press,New Y ork, NY; Kontermann and Dubel(eds.) (2001) Antibody Engineering,Springer-Verlag,Ne w York;Harlow and Lane(1988) Antibodies A Laboratory Manual,Cold Spring Harbor L aboratory Press, Cold Spring Harbor, NY,pp. .139-243;Carpenter,et al.(2000) J.Immuno l. 165:6205;He,et al.(1998) J.Immunol. 1 60:1029;Tang et al. (1999) J.Biol.Chem. 2 74:27371-27378;Baca et al. (1997) J.Biol. Chem. 272:10678-10684;Chothia et al.(198 9) Nature 342:877-883;Foote and Winter(1 992) J.Mol.Biol. 224:487-499; U.S. Patent No. 6,329, (See issue 511).

[0230] An alternative approach to humanization is to use human antibody libraries or transfectants displayed on phage. The first step is to use a human antibody library in a transgenic mouse (Vaugh an et al. (1996) Nature Biotechnol. 14:30 9-314;Barbas(1995) Nature Medicine 1:837 -839;Mendez et al. (1997) Nature Genetics 15:146-156;Hoogenboom and Chames(2000) Immunol.Today 21:371-377;Barbas et al.(2 001) Phage Display:A Laboratory Manual,C old Spring Harbor Laboratory Press,Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins:A Laboratory Manual,Academic Press,San Di ego, CA; de Bruin et al. (1999) Nature Biot Echnol. 17:397-399).

[0231] Purification of the antigen is not necessary for antibody production. Immunizing an animal with cells bearing the desired antigen is the same as Spleen cells are then isolated from the immunized animal and fused with a myeloma cell line. Hybridomas can be produced by the method described in Meyaard et al. (1997) Immunity 7:283-290;Wright et al. (2000) Immunity 13:233-242; Preston et al. al.;Kaithamana et al.(1999) J.Immunol. 1 63:5157-5164).

[0232] Antibodies are used as a fusion protein with low molecular weight drug molecules, enzymes, liposomes, polyethylene glycol ( The antibodies can be conjugated to a PEG (polyoxyethylene terephthalate). The antibodies can be used as therapeutic agents, diagnostic agents, kits or They may be useful for other purposes, e.g. dyes, radioisotopes, enzymes, or metals, e.g. These include antibodies conjugated to gold colloids (see, for example, Le Doussal et al. (1991) J.Immunol. 146:169-175;Gibellini et al.(1998) J.Immunol. 160:3891-3898;Hs ing and Bishop (1999) J. Immunol. 162:2804 -2811;Everts et al.(2002) J.Immunol. 168 :883-889).

[0233] Flow cytometry methods, including fluorescence activated cell sorting (FACS), are available. (See, for example, Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice ice,John Wiley and Sons,Hoboken,NJ;Givan (2001) Flow Cytometry, 2 nd ed.;Wiley-Lis s, Hoboken, NJ; Shapiro (2003) Practical Flo w Cytometry,John Wiley and Sons,Hoboken, See, for example, U.S. Pat. No. 6,239,363, and U.S. Pat. No. 6,239,363, for use as diagnostic reagents. Fluorescent reagents suitable for modification of nucleic acids, polypeptides and antibodies, including probes, are available It is possible (Molecular Probes (2003) Catalogue, M Olecular Probes, Inc., Eugene, OR; Sigma-Ald rich(2003) Catalog, St. Louis, MO).

[0234] Standard methods for immune system histology have been described (e.g., Muller-Harme et al. link(ed.) (1986) Human Thymus:Histopatho logy and Pathology,Springer Verlag,New Y ork, NY; Hiatt, et al. (2000) Color Atlas of Histology,Lippincott,Williams,and Wilki ns, Phila, PA; Louis, et al. (2002) Basic His tology:Text and Atlas,McGraw-Hill,New Yo rk, NY).

[0235] Examples include antigenic fragments, leader sequences, protein folding, functional domains, Software packages and methods for determining glycosylation sites and sequence alignments and databases are available (e.g. GenBank, Vector NTI (Registered Trademark) Suite (Informax, Inc., Bethesda, MD); CG Wisconsin Package(Accelrys,Inc.,San D iego, CA); DeCypher (registered trademark) (TimeLogic Corp., Crystal Bay,Nevada);Menne,et al.(2000) B ioinformatics 16:741-742;Menne,et al.(20 00) Bioinformatics Applications Note 16: 741-742;Wren,et al.(2002) Comput.Methods Programs Biomed. 68:177-181;von Heijne( 1983) Eur.J.Biochem. 133:17-21;von Heijn e(1986) Nucleic Acids Res. 14:4683-4690. Please refer to. EXAMPLES

[0236] Example 1: Clinical Trial of Anti-LAG3 Antibody in Advanced Solid Tumors This is an anti-cancer drug in subjects with histologically or cytologically confirmed advanced solid tumors. Monotherapy with Ab6, an antibody against LAG3 (Part A, Arm 1) and with pembrolizumab A multicenter, open-label, dose-escalation study of Ab6 in combination with This will be followed by an evaluation of the efficacy of Ab6 as monotherapy and in combination with pembrolizumab. Both randomized and non-randomized trials of Ab6 in combination with pembrolizumab, with This is a dose confirmation study (Part B).

[0237] During Part A of the study, subjects were non-randomly assigned to one of two treatment arms. was assigned to one.

[0238] Arm 1: Ab6 escalating doses of 7, 21, 70, 210 or 700 mg for 3 consecutive days as monotherapy weekly (Q3W) by intravenous infusion (IV).

[0239] Arm 2: Pembrolizumab (200mg Q3W) IV in combination with Ab6 escalation Doses of 7, 21, 70, 210, or 700 mg IV every 3 weeks (Q3W).

[0240] Part B was a dose confirmation study of Ab6 in combination with pembrolizumab. A large cohort will evaluate the antitumor efficacy of Ab6 as monotherapy and in combination with pembrolizumab. Efficacy will be evaluated. Part B consists of five treatment arms.

[0241] Table 4. Investigational Treatment [Table 4] TIFF2024156880000007.tif234169TIFF2024156880000008.tif86169

[0242] The trial used an adaptive design based on pre-specified dose-limiting toxicity (DLT) criteria. For dose escalation (Part A, Arm 1 and Arm 2), a 3+3 dose escalation design was used. For dose confirmation (Part B), preliminary data from Part A, Arm 2 were used. Toxicity Probability Intervals (TPIs) were used to refine the estimate of the Phase 2 Recommended Dose (RPTD). In addition, Part B will utilize a 2-dose combination of A and pembrolizumab. To compare the safety and antitumor efficacy of b6.

[0243] In Part A, Arm 1 (Ab6 monotherapy), preliminary maximum tolerated dose (MTD) or Part A of the study was designed to determine the maximum effective dose (MAD) of 100 mg / kg / day. During the 3+3 dose escalation in both arms, initial cohorts of 3 subjects per dose level None of the 3 subjects experienced DLTs during the first 21-day cycle. If 1 of 3 subjects experienced a DLT, escalation to the next dose was performed. An additional 3 subjects were enrolled at this dose level. One DLT was observed among 6 subjects. Dose escalation continued if >1 of 3 subjects at a dose level or if more than 1 of 6 subjects experienced a DLT, dose escalation was discontinued and subjects were maintained at the previous dose. The test was carried out at the level.

[0244] Treatment in Part A, arm 2 (Ab6 in combination with pembrolizumab) was We started with a 3+3 design to identify a preliminary RPTD for Ab6. The starting dose must be at least one dose level higher than the dose being studied in Part A, Arm 1. A fixed dose of 200 mg pembrolizumab was administered in arm 2 of part A. Used.

[0245] The dose of Ab6 in combination with pembrolizumab should be at least 1x higher than the monotherapy dose. Dose levels were low and did not exceed the MTD or MAD in Part A, Arm 1. However, once the MTD or MAD has been established for Part A, Arm 1, Dose escalation of Ab6 in arm 2 of part A was continued in the final two doses of arm 2. All 3 subjects (or all 6 subjects) at the next highest dose level for dose-level enrollment Subjects were randomly assigned to receive one cycle of treatment and D LT evaluation has been completed.

[0246] In Part B, PD-1-naïve head and neck squamous cell carcinoma (HNSCC), MSI-H or pMMR colorectal cancer (CRC), PD-1-failed HNSCC Dose-finding and preliminary anti-PD-1 / PDL-1 treatment-naïve gastric cancer Part B will also evaluate tumor efficacy in patients with microsatellite inhibitors who have received ≤1 line of prior therapy. Pembrolizumab-resistant Staphylococcus aureus (MSS) in subjects with PD-1-treated naïve CRC Lorisumab and mFOLFOX7 (up to 20 subjects) or FOLFIRI (up to 2 Safety and immunological outcomes of Ab6 (at preliminary RP2D) administered in combination with Antitumor efficacy is assessed.

[0247] Cohort A was randomized to receive all available PD-1 / PD-L1 therapy-naïve patients. The study included subjects with non-MSI-H or pMMR CRC who had progressed on standard of care The antitumor efficacy of Ab6 was evaluated both as monotherapy (arm 1) and in combination with pembrolizumab. in combination (arms 2A and 2C) and as a fixed-dose drug (Ab6A, arm 5) Ab6 monotherapy (arm 1) will be administered at a dose of 800 mg to up to 20 subjects. In arm 2, up to 100 subjects will receive 200 mg of Ab6 plus pembrolizumab. Approximately 40 subjects were treated with a combination of 800 mg Ab6 + penicillin (Arm 2A), and In cohort A, 40 patients will be treated with a combination of brolizumab and brolizumab (arm 2C). The study included the safety of Ab6A, the 800mg Ab6 and pembrolizumab combination product, Enrolled to evaluate PK and preliminary efficacy (Arm 5).

[0248] Cohort B is comprised of patients who have not received prior PD-1 / PD-L1 therapy and have received prior ≤1 Patients with non-MSI-H or pMMR CRC who have progressed on first-line therapy were included. Cohort B will include pembrolizumab and mFOLFOX7 (maximum 20 subjects, Arm 3) or in combination with FOLFIRI (up to 20 subjects, Arm 4) The antitumor efficacy of administered Ab6 (800 mg) was tested.

[0249] Cohort C includes patients who have not received prior PD-1 / PD-L1 therapy and have received prior ≥1 Subjects were enrolled who had HNSCC that had progressed after first-line chemotherapy. Receive 200 mg of Ab6 in combination with limumab (arm 2A) to determine antitumor efficacy did.

[0250] Cohort D has HNSCC that progressed after prior anti-PD-1 / PD-L1 therapy Subjects were enrolled who received 200 mg of Ab6 in combination with pembrolizumab. (Arm 2A) and assessed antitumor efficacy.

[0251] Cohort E includes patients who have not received prior PD-1 / PD-L1 therapy and have received prior ≥1 Cohort E included subjects with gastric adenocarcinoma who had progressed to first-line chemotherapy. Two doses of Ab6 in combination with fixed dose pembrolizumab (200 mg [Arm 2A] and A randomized comparison of 0.1 mg [arm 1B] and 700 mg [arm 2B] was used. In addition, Antitumor activity observed in group 2 (≥ 40 subjects, regardless of dose) 8 patients with objective response), 20 additional subjects with gastric cancer were enrolled and Ab6( 800 mg) monotherapy (arm 1).

[0252] Inclusion Criteria 1. Part A - Histological or cellular disease for which no clinically effective treatment is available Patients with cytologically confirmed metastatic solid tumors.

[0253] Part B - Has one of the following histologically or cytologically confirmed tumor types: : Cohort A - C for Arm 1, Arm 2A, Arm 2C and Arm 5 RC: CRC of colon or rectum origin, locally advanced unresectable or metastatic (i.e., stage IV) and Patients who have progressed on all available standard therapies, including irinotecan, but not previously treated with anti-PD-1 / PD-L1 therapy.

[0254] b. Cohort B - CRC for Arm 3 and Arm 4: colon or rectum origin CRC of origin that is locally advanced, unresectable or metastatic (i.e., stage IV ) and have been treated with ≤1 line of systemic therapy, including prior anti-PD-1 / Subjects not previously treated with PD-L1 therapy are eligible to receive EGFR-targeted therapy. , patients must have undergone this procedure prior to being eligible for the study.

[0255] c. Cohort C and Cohort D - HNSCC deemed incurable by local treatment Patients had progressed after platinum-containing systemic therapy. Systemic therapy given as part of treatment is permitted. Eligible primary tumor locations are oropharyngeal The head, oral cavity, hypopharynx and larynx. The subjects were primary tumors of the nasopharynx (any histological type). The tumor location should not be in the PD-1-naïve HNSCC cohort (Cohort C). Enrolled subjects must not have been treated with prior anti-PD-1 / PD-L1 therapy.

[0256] The PD-1-failed HNSCC cohort (Cohort D) will include: or other approved checkpoint inhibitors as monotherapy, as defined in or FDA-approved anti-PD-1 / PD-2 in combination with other therapies according to their labeling. Patients must be refractory to L1 monoclonal antibody (mAb) (subjects must meet the following criteria) must be met): i. Have received at least two doses of anti-PD-1 / PD-L1 mAb.

[0257] ii. Anti-PD-1 / PD-L1 mAb followed by RECIST 1.1 The first evidence of PD is that in the absence of rapid clinical progression, PD is initially This is to be confirmed by a second evaluation not less than four weeks after the date of initial documentation.

[0258] iii. PD documented within 24 weeks of the last dose of anti-PD-1 / PD-L1 mAb Patients re-treated with anti-PD-1 / PD-L1 mAb and patients with anti-PD-1 / P Patients maintained on D-L1 mAb had the highest (anti-PD-1 / PD-L1 mAb) Patients will be allowed to participate in the study as long as they have documented PD within 24 weeks of the end of treatment. .

[0259] d. Cohort E - Adenocarcinoma of the stomach and / or gastroesophageal junction (GEJ) Patients considered inoperable and who have received at least one prior chemotherapy regimen or HER2 / n If you have received approved eu-targeted therapy (if HER2 / neu positive), In both cases, subjects were treated with prior anti-PD-1 / PD-L1 therapy. Patients must not have had prior chemotherapy or chemotherapy prior to refractory disease. Patients must have measurable disease by irRECIST 1.1 criteria.

[0260] In Part A of the study, Ab6 given in combination was well tolerated and manageable across all doses tested. Dose escalation was achieved up to 700 mg without any DLTs. The dose was then adjusted.

[0261] 18 subjects treated with Ab6 monotherapy and Efficacy data are available for subjects including 15 subjects treated with combination therapy. In Part A, subjects will receive 5 preselected doses between 7 mg and 700 mg. One of three Ab6 doses alone or a fixed dose of 200 mg pembrolizumab In subjects treated in arm 1 at all doses of monotherapy, OR R was 5.5%, and one subject with endometrial cancer (microsatellite stable) This subject experienced a partial response. This subject received a dose of 210 mg of Ab6. Stable disease was also observed in patients with leiomyosarcoma and appendiceal cancer. Ta.

[0262] The objective response rate (O The RR was 26%, with 4 of 15 subjects experiencing a partial response, 3 of which were full-blown. Follow-up CT scans were used to confirm radiographic findings. Two subjects had colorectal cancer (microsatellite Light was good), and 1 subject with renal cell carcinoma at 7 mg Ab6 (Figure 2), and 1 subject with 70 mg Ab In Part A, one subject was diagnosed with fallopian tube cancer (BRCA negative). Among the six colorectal cancer subjects treated in the GE arm, the ORR was 33%. Patients with adenocarcinoma of the synovial zone received 70 mg of Ab6 in combination with pembrolizumab, Patients experienced a 28% reduction in target lesion size compared to baseline. Another patient with pulmonary sarcoma experienced stable disease.

[0263] Response rates in Part B subjects have demonstrated encouraging activity in several cohorts. In the non-MSI-H / pMMR CRC cohort in Part B, 4 of 39 subjects experienced an objective response (ORR and DCR were 10.2% and 25.6%, respectively). In comparison, the activity of pembrolizumab monotherapy was significantly higher in non-MSI-H / pMMR CRC. In some cases, it is scarce or nonexistent (O'Neil BH et al. PLoS One .2 017;12(12), regorafenib and TA, approved agents in 3L CRC S-102 has a 2-month OS benefit and an ORR of approximately 1-2%. In this study, 6 of 46 subjects experienced an objective response (ORR and DCR were 13% and 39%, respectively. Three responses were with the 700 mg Ab6 dose and three responses were with the 200 mg Ab6 dose. This was the third dose of pembrolizumab monotherapy. This compares with an ORR of 11.2% in first-line gastric subjects (Fuchs, et al. l. Journal of Clinical Oncology 35, no.15 _suppl(May 20 2017)4003-4003). PD-1 naive H In the NSCC cohort, 6 of 23 subjects experienced an objective response (ORR and and DCR were 26.1% and 69.5%, respectively. Results from lorizumab monotherapy showed progression against at least two lines of prior therapy In PD-1 naïve HNSCC patients, an objective response rate of 18% was demonstrated (Baum et al. i J. et.al. Journal of Clinical Oncology 34 no.15 suppl_(May 20 2016) 6011-6011) .

[0264] Fifty-nine subjects with head and neck squamous cell carcinoma (HNSCC) were included in the Phase I study. In Phase B, 200mg Q3W Ab6 vs. 200mg Q3W pembrolizumab 39 subjects with PD-1-treated naïve HNSCC and 20 subjects with PD-1-failed HNSCC. PD-1-naive HNSCC The ORR in subjects with confirmed disease was 12.8% (5 of 39, 95% C I: 4.3, 27.4), and DCR was 53.8% (21 of 39, 95% CI: 3 7.2, 69.9). O in subjects with PD-1-treated naïve HNSCC The RR (unconfirmed) was 23.1% (9 of 39, 95% CI: 11.1, 39.3). ), and DCR was 56.4% (22 of 39, 95% CI: 39.6, 72.2). Confirmed ORR in subjects with PD-1-failed HNSCC was 0% (0 of 20), DCR was 20.0% (4 of 20, 95% CI: 5.7 ORR (confirmed) in subjects with PD-1-failed HNSCC The proportion of patients with no confirmed disease was 5% (1 of 20, 95% CI: 0.1, 24.9), and the DCR was 25 % (5 of 20, 95% CI: 8.7, 49.1).

[0265] In Part B, 78 subjects with gastric cancer were randomized to receive Ab6 and 200 mg Q3W penicillin. Treated in combination with brolizumab: 39 patients at the 200 mg Ab6 dose level, 7 39 patients at the Ab6 dose level of 100 mg. ORR at the 200 mg dose level (confirmed) The mean age was 7.7% (3 of 39, 95% CI: 1.6, 20.9), and the DCR was 23.1 % (9 of 39, 95% CI: 11.1, 39.3). The ORR at volume level (not confirmed) was 7.7% (3 of 39 patients, 95% CI: 1.6 , 20.9), and DCR was 25.6% (10 of 39, 95% CI: 13.0, 4 2.1). The confirmed ORR at the 700 mg dose level was 10.3% (39 4 of 39 patients (95% CI: 2.9, 24.2), and DCR was 33.3% (of 39 patients). The mean mean mean of O2 intake at the 700 mg dose level was 13, 95% CI: 19.1, 50.2. RR (unconfirmed) was 15.4% (6 of 39, 95% CI: 5.9, 30.5). The DCR was 35.9% (14 of 39, 95% CI: 21.2, 52.8). I did.

[0266] Example 2: Pharmacokinetic (PK) study of Ab6 During Part A of Ab6 (alone and in combination with pembrolizumab), 7 mg PK data from subjects treated with doses of 100 to 700 mg demonstrated that serum Ab6 exposure increased with dose The results showed that the PK analysis was performed at 1, 2, 8, and 1 day after administration of Ab6. Blood samples were collected from patients on days 5 and 21. The PK profile of Ab6 exposure was: Clearance of Ab6 via the target receptor was saturated at doses of 210 mg and 700 mg. This suggests that this is the case (Figure 6).

[0267] Soluble (sLAG3) is a cleavage product of membrane-bound LAG3 expressed on immune cells. Cleavage of LAG3 is required for optimal T cell function (Goldberg and Dr ake,LAG-3 in Cancer Immunotherapy;Dranof f G.(eds) Cancer Immunology and Immunoth. erapy(2010);Current Topics in Microbiolo gy and Immunology,vol 344. Springer,Berl sLAG is detectable in the serum of healthy patients and sLAG3 is more highly detectable in the serum of patients with cancer and chronic inflammatory diseases. In preclinical models, a dose-dependent increase in serum levels of Ab6 was observed after administration. Ab6 binds to both sLAG3 and membrane LAG3. sLAG3 is highly saturated. In this case, the saturation of membrane LAG3 is also expected to be high. Therefore, sLAG3 is a target was chosen as a pharmacodynamic marker of engagement.

[0268] During Part A of Ab6 (alone and in combination with pembrolizumab), 7 mg Target engagement pharmacodynamic profiles from subjects treated with doses of 100 to 700 mg Carr sLAG3 data also showed a dose-dependent increase in total soluble LAG-3 in serum. , and generally approached saturation at doses of 210 mg and 700 mg (Figure 6).

[0269] Compared to the half-life of the antibody predicted based on cynomolgus monkey PK parameters, A Surprisingly, b6 had a predicted clearance from cynomolgus monkeys (predicted CL ヒト =0. 168 L / day) or because of its approximately three times faster clearance than typical monoclonal antibodies. It has a short half-life (R yman, JT, & Meibohm, B. (2017). Pharmacok inetics of Monoclonal Antibodies. CPT:ph armacometrics & systems pharmacology,6(9 ), 576-588). Preliminary PK analysis of exposure from the above Phase I study showed that the target Clearance via specific receptors (reflecting target engagement of membrane LAG-3) (Geometric CV > 100%) トラフ The variability of Considering these findings, it is suggested that doses of ≥ 700 mg were more likely to maintain saturation. (Figures 10, 11 and 15).

[0270] Targets from subjects treated during Parts A and B of the Phase I study above Pharmacodynamic markers of engagement data demonstrated a dose-dependent increase in serum total sLAG-3. These results demonstrate an increase in the expression of sLAG-3 in the IL-16 / IL-2 expression level, reflecting target engagement of sLAG-3 (Figure 1 12) At the clinical dose of 700 mg of Ab6, [sLAG3] was elevated throughout the dosing interval. The effect of Ab6 was sustained throughout the dosing interval compared with the lower dose. This suggests that this will continue.

[0271] Furthermore, Ab6 PK exposure (C at day 21) was significantly decreased in 13% of patients at 200 mg. Trough: Below limit of quantitation BLQ), and PK exposure (C trough on day 21) was ) is a BLQ (see Table 6). BLQ is a set of BLQs from J Pharm Biomed Anal. 2019 Jul 15;171:204-211. The high variability of K combined with the rapid clearance of Ab6 resulted in a lower B In general, the C trough for the 700 mg dose is 200 m g dose (see FIG. 15).

[0272] Table 5. Ab6 serum C on day 21 トラフ and variability [Table 5]

[0273] Table 6. Ab6 serum C on day 21 トラフ Percent of BLQ [Table 6]

[0274] Preliminary efficacy data from the gastric cancer dose comparison cohort (Cohort E) in Part B The data also suggested a trend toward better efficacy at 700 mg Ab6 (the highest dose tested). Interim analysis of randomized dose comparison in cohort E (Ab6 200 mg vs. 70 mg) At the time of analysis, a fixed dose of 200 mg of pembrolizumab was administered per arm. In total, 39 subjects with gastric cancer (total of 78) were treated with Ab6. Follow-up time The mean time to treatment was 98 days. Although not statistically significant, these data were consistent with those of the 200 mg and The ORR was 5.3% (95% CI: 0.6, 1 7.7) vs. 8.3% (95% CI: 1.8, 22.5), mean target lesion size The change was 29.9 cm (95% CI: 10.2, 49.7) versus 6.4 cm (95% CI: The study demonstrated a trend toward improved disease control at higher doses (CI: 9.3, 22.1). In addition, in a randomized dose-comparison cohort in gastric cancer, No significant differences in safety were observed at the 200 mg dose.

[0275] Based on a preliminary population PK analysis, the predicted median serum exposure of Ab6 at 800 mg was: higher than 700 mg. However, the distribution of Ab6 serum concentrations at doses of 700 mg and 800 mg are similar and are expected to result in substantial overlap in exposure between these two doses. Based on Ab6 drug concentration, the doses ranged between 700 mg and 800 mg (Figures 13 and 14). Because of the expected overlap in exposure at the 700 mg and 800 mg doses, A similar safety profile is expected.

[0276] Example 3: Measurement of PD-L1 and LAG3 expression levels Samples from patients with non-MSI-H colorectal cancer, gastric cancer, and HNSCC in Part B were The specimens for analysis were formalin-fixed paraffin-embedded (FFPE) tissue sections. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 p Dako Autostain validated for harmDx assays er Link 48 platform (Dako AS480) and automated staining pro- Using tocols, US2017 / 0285037 (which is incorporated by reference in its entirety) ) LAG-3 IHC Assay (LSBio, clone 17B4) was developed using clone 17B4 from LSBio at 0.05ug / ml and manufactured The Dako Autostainer Link 48 platform was used according to the protocol of the author. Validated on form. Formalin fixed, paraffin embedded 4 microns Sections from 1000 samples were used for the assay. Antigen retrieval was performed using Envisi on a Dako PT link. on FLEX Target Retrieval Solution,High p H (Agilent K800221-2). Vision FLEX+, High pH (Link) (Agilent, K8002 The stained slides were then washed with hematoxylin (Agile nt, K8008) and coverslipped.

[0277] For the entire CRC cohort in Part B, both PD-L1 and LAG3 expression were IHC data were collected. Figure 3 shows the results for this set using the CPS scoring system. PD-L1+ tumors (CPS Of those with >=1%), 4 of 46 were responders (9%). The CPS was 1% and one responder had a CPS of 7%. Among those with S<1%, 1 of 35 was a responder (3%). Using the DS scoring system, 4 of 14 patients with PD-L1+ tumors were responsive. Among PD-L1- tumors with MIDS score <2, 11 0 were responders (0%). TPS alone, MIDS alone, or TPS+MIDS Preliminary analysis of PDL1 IHC using the method of The DS method alone showed enrichment of the responder population. Using the MIDS scoring system, 4 of 14 patients had PD-L1+ tumors. Among PD-L1- tumors with MIDS score <2, 1 0 out of 1 were responders (0%). When the mean score was 2, 4 of 14 PD-L1+ tumors were responders (28% Among PD-L1 tumors with MIDS score <2, 0 of 11 were responders. This indicates that PDL-1 expression in inflammatory cells was significantly increased by anti-LAG3 and anti- These results suggest that PD-1 may be an important factor in predicting response to antibody treatment.

[0278] FIG. 4 shows the results of LAG3 IHC in CRC tumors. The % PS-like LAG3 positive cells were used to score the CRC tumors in this set. As shown in Table 7, 75% of LAG3-positive CRC tumors are LAG3-positive. are PD-L1 positive, whereas 29% of PD-L1 positive CRC tumors are LAG3 positive In other words, most LAG3-expressing CRC tumors also express PD-L1, but Only a minority of D-L1-expressing tumors also express LAG3.

[0279] Table 7: PD-L1 and LAG3 expression scores for CRC tumors [Table 7]

[0280] Gastric cancer expansion cohort receiving 700mg Ab6 and 200mg pembrolizumab IHC data for PD-L1 and LAG3 were collected for CPS Using the scoring system, 65% of gastric tumors in this set were PD-L1 positive. Among PD-L1+ tumors (CPS>=1%), 7 of 22 patients were responders. Among PD-L1- tumors (CPS < 1%), there were no responders. PD-L1 IHC CPS had an AUROC (95% CI) of 0.90 (0.7 5, 1). Area under the receiver operating characteristic AUROC) is a binary classification A common summary statistic about how good a predictor is at a task. ROC curves are Plot the true positive rate (TPR) against the false positive rate (FPR) for different threshold settings. The ROC is a probability curve, and the AUC is a measure or measure of separability. A good model has an AUC close to 1.

[0281] FIG. 17 shows that 42% of gastric tumors in this set were scored using a CPS-like scoring system. Among LAG3+ tumors (CPS-like ≥ 1%), 14 patients Six were responders (43%). Among LAG3- tumors (CPS-like <1%), 19 One of the patients was a responder (5%). LAG3 IHC showed a significant improvement in AUROC (95% CI) was 0.79 (0.62, 0.96). 93% of LAG3-positive tumors were PD-L1 positive. 1 positive, and 65% of PD-L1 positive tumors were LAG3 positive (see Table 8 In other words, while almost all LAG3-positive tumors also express PD-L1, Only two-thirds of PD-L1-positive tumors also express LAG3.

[0282] Table 8: PD-L1 and LAG3 expression scores for gastric tumors [Table 8]

[0283] Table 9 shows the PD-L1 and LAG3 I among responders in this gastric cohort. Distribution of HC scores is shown. Six of seven responders expressed high levels of PD-L1. This suggests a higher cutoff for patient selection (CPS ≥ 10%). Similarly, for LAG3 IHC, the data suggest that a cutoff of CPS ≥ 1% is a strong predictor of response rates. This suggests that it will provide a

[0284] Table 9: PD-L1 and LAG3 expression for all responders in gastric tumors Score [Table 9]

[0285] Table 10 shows the PD-L1 IHC assay results at different CPS cut points in the gastric cohort. The clinical utility profile of the assay is shown, where PPV is the positive predictive value (PPV) of the selected Patient samples that were responders were called “positive” according to the CPS cut points is the negative predictive value (percentage of patients with CI according to the selected CPS cut point) and NPV is the negative predictive value (percentage of patients with CI according to the selected CPS cut point) (the percentage of patient samples that are non-responders, referred to as "positives" in Sensitivity is the % of responders who are positive according to the selected CPS cut point and the The discrepancy is expressed as the % of non-responders who are negative according to the selected CPS cut point. As the CPS cut point increases, the prevalence decreases but the PPV increases. Sensitivity was maintained at all cut points with CPS ≥ 1%, and specificity was The clinical utility profile in Table 10 also has a cutoff of CPS ≥ 10%. Supports: [Table 10]

[0286] PD-1-naïve patients receiving 200 mg Ab6 and 200 mg pembrolizumab We collected IHC data for PD-L1 and LAG3 in patients with BRCA HNSCC. Figure 1 8 was HNS in this set using the exploratory TPS+MIDS scoring system. This scoring system shows that 86% of CC tumors are PD-L1 positive. A tumor was considered positive if it had a TPS score >1 or a MIDS score >2. Among PD-L1+ tumors, 6 out of 30 were responders (20%). Of the L1- tumors, 2 of 5 were responders (40%) (Table 11).

[0287] Figure 19 shows that 49% (% LAG3 positive cells score) of tumors in the above HNSCC patients. Among the LAG3+ tumors, 17 Among LAG3- tumors, 4 of 14 were responders (29%). 100% of LAG3-positive tumors were PD-L1 positive and PD- 59% of L1 positive tumors are LAG3 positive (see Table 11). All LAG3-positive tumors also expressed PD-L1, whereas two-thirds of PD-L1-positive tumors Only one also expresses LAG3.

[0288] Table 11: PD-L1 and LAG3 Expression for PD-1 Naive HNSCC Tumors Score [Table 11]

[0289] Example 4: Clinical Trial of Anti-LAG3 Antibody in Advanced NSCLC This is in patients who have not received prior systemic treatment for progressive disease and have a defined oncogene FDA-approved targeted therapies (e.g., ER) as first-line (1L) treatment based on mutations Advanced NSCLC for which chemotherapy (e.g., rotinib, crizotinib, etc.) is not indicated (non-squamous NSCLC only) Pembrolizumab (MK-3475) 200 mg in study participants with CLC for the combination of Q3W IV infusion and Ab6 200mg Q3W IV infusion: This is a group-sequential, adaptive randomized, multicenter, open-label study.

[0290] Participants were eligible for inclusion in the study only if they met all of the following criteria: 1. Histologically or cytologically stage IV (American Joint Co The American Joint Committee on Cancer (AJCC) v.8 has confirmed the diagnosis of NSCLC. and study participants must not have received prior systemic treatment for progressive disease. .

[0291] 2. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c -ros oncogene 1 (ROS1) or aggressive fibrosarcoma B isoform (B-Ra f) It has been confirmed that directed therapy is not indicated as first-line treatment (tumor-activated EGF Absence of R- or B-Raf mutations and absence of ALK or ROS1 gene rearrangements If the participant's tumor was known to have predominantly squamous histology, Molecular testing for GFR mutations and ALK and ROS1 translocations is currently the diagnostic guideline. It is not required as it is not part of the guidelines.

[0292] 3. RECIST 1.1 assessed by local investigator / radiologist Lesions present in previously irradiated areas are A lesion is considered measurable if progression in the affected area has been documented.

[0293] Example 5: Clinical trial of anti-LAG3 antibodies in hematological cancers This is a PD-1 / L1 naïve, relapsed or refractory (R / R) classical Hodgkin lymphoma cohort 1), PD-1 / L1 refractory R / R cHL (cohort 2), R / R diffuse large B-cell lymphoma (DLBCL) (cohort 3), and R / R low Pembrolizumab (M K-3475) 200mg Q3W IV infusion and anti-LAG3 antibody Ab6 at doses of 100, 2 A non-randomized, multicenter study comparing 0.01 mg / kg or 700 mg / kg Q3W IV infusion with 0.01 mg / kg or 700 mg / kg Q3W IV infusion. This is a joint open-label study in which at least 10 participants in the R / R-iNHL group have follicular lymphoma. I have pancreatitis.

[0294] Patient selection criteria Participants were eligible for inclusion in the study only if they met all of the following criteria: 1. Correctly identify the lesion in two dimensions using diagnostic quality cross-sectional anatomical imaging (CT or MRI) No measurable disease, defined as at least one lesion that can be reliably measured The minimum measurement must be >15 mm for the major axis or >10 mm for the minor axis. Must be.

[0295] 2. At screening, biopsy was obtained from archived or newly obtained biopsy (within 3 months) A core biopsy or excision tumor biopsy can be provided for omarker analysis.

[0296] PD-1 / L1 naive R / R cHL (cohort 1) 1. Must have histologically confirmed classical Hodgkin lymphoma.

[0297] 2. Relapsed (defined as disease progression after most recent treatment) or refractory (defined as disease progression after most recent treatment) Patients with cHL (defined as failure to achieve CR or PR on a single dose of chemotherapy) and at least one of the following inclusion criteria: At least one of: a. Failure to achieve response or progression after autologous SCT. Participants relapsed after treatment with brentuximab vedotin after T or Those who responded unsuccessfully to dochin must have done so.

[0298] b. Failure to achieve CR or PR to salvage chemotherapy followed by autologous SCT Participants had relapsed after treatment with brentuximab vedotin or Patients must have had an unsuccessful response to brentuximab vedotin.

[0299] c. Participants who are ineligible for brentuximab vedotin or who are not receiving brentuximab vedotin due to toxicity Participants who discontinued brentituximab vedotin, and Participants who live in areas where brentuximab is not approved or available Those eligible for the study.

[0300] 3. Not previously treated with anti-PD-1 or anti-PD-L1 therapy.

[0301] PD-1 / L1 refractory R / R cHL (Cohort 2) 1. Must have histologically confirmed classical Hodgkin lymphoma.

[0302] 2. Relapsed (defined as disease progression after most recent treatment) or refractory (defined as disease progression after most recent treatment) Patients with cHL (defined as failure to achieve CR or PR on a single dose of chemotherapy) and who met one of the following inclusion criteria: Meet the following: a. Failed to achieve response or progressed after autologous SCT. Participants relapsed after treatment with brentuximab vedotin after T or Those who responded unsuccessfully to dochin must have done so.

[0303] b. Failure to achieve CR or PR to salvage chemotherapy followed by autologous SCT Participants had relapsed after treatment with brentuximab vedotin or Patients must have had an unsuccessful response to brentuximab vedotin.

[0304] c. Participants who are ineligible for brentuximab vedotin or who are not receiving brentuximab vedotin due to toxicity Participants who discontinued brentituximab vedotin, and Participants who live in areas where brentuximab is not approved or available Those eligible for the study.

[0305] 3. As monotherapy or in combination with other checkpoint inhibitors or other therapies Progression of PD-1 treatment A row is defined by satisfying all of the following criteria: a. At least one dose of an anti-PD-1 mAb approved for Hodgkin lymphoma Two doses were received and the drug was administered at the approved dose and schedule.

[0306] b. Post-PD-1 / L1, Lymphoma Disease Response Criteria Progression of disease as defined by the Chemotherapy Response Criteria was demonstrated (Che son et al. Revised Response Criteria for Malignant Lymphoma. J Clin Oncol. 2007; 25:579-586.).

[0307] c. Documented disease progression within 12 weeks of the last dose of anti-PD-1 / L1 mAb Ta.

[0308] 4. Undergoing pre-trial imaging.

[0309] R / R DLBCL (Cohort 3) 1. Histologically confirmed DLBCL. Transformed DLBCL, gray zone Lymphoma, double-hit lymphoma, and primary mediastinal B-cell lymphoma (PMBCL) were not recognized. can be done.

[0310] 2. Patients must have progressed after at least two prior lines of therapy, including progression after autologous SCT. must have refused SCT or be a candidate for autologous SCT (institution Participants who are ineligible for standard treatment or who justify discontinuing that treatment and are unable to receive the same treatment Withdrawal from standard therapy prior to disease progression due to unacceptable toxicity that precludes retreatment with Participants who have not completed the course of treatment are also eligible.

[0311] R / R-iNHL (Cohort 4) 1. FL, marginal zone lymphoma, mucosa-associated lymphoid tissue lymphoma or small lymphocytic lymphoma The patient has been histologically diagnosed with low-grade B-cell lymphoma, defined as "indolent B-cell lymphoma." Lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, chronic lymphocytic Leukemia (without small lymphocytic lymphoma) and T-cell lymphoma are not eligible. At least 10 participants must have FL.

[0312] 2. Participants have progressed after at least 2 lines of prior therapy, which may include autologous SCT. Participants who are ineligible for standard treatment or who have not yet progressed to standard treatment should be considered. Standard treatment was discontinued due to unacceptable toxicity that justified discontinuation of the standard treatment and precluded retreatment with the same agent. Participants who dropped out were also eligible.

[0313] Safety Implementation Phase At least 14 participants will be enrolled during the safety run-in phase (at least Participants received pembromodulin in combination with Ab6 (starting dose of 200 mg). Patients will receive lizumab (fixed dose of 200 mg) Q3W.

[0314] b. Modified Toxicity Probability Interval (mTPI) design [Ji, Y. and Wang, S -J. 2013], a phase 2 study of the combination of Ab6 with pembrolizumab The recommended dose (RP2D) will be established. Data from participants will be collected starting from cycle 1. The incidence of DLTs will continue to be monitored thereafter. Aggregate data will be evaluated at 6-month intervals. The safety, PK, and pharmacodynamic data available at each dose level are combined to determine the Lower and / or higher doses of b6 will be investigated.

[0315] c. If required by the mTPI design, the dose of Ab6 will be reduced to 100 mg. Up to 14 additional participants will be assessed at this dose level. Throughout, other lower doses of Ab6 may be explored.

[0316] d. Based on the totality of efficacy / PK and safety data from these safety run-in phase participants Based on this, higher Ab6 dose(s) up to 700 mg may be investigated. Additional participants may be included if necessary to achieve this.

[0317] e. 14 participants will be treated with any of the selected doses (which may include optional doses) After the safety implementation phase is completed, the pooled-adjacent biolator algorithm ( pool adjacent-violators algorithm)[Ji, Y and Wang, S.-J. 2013] to compare DLT rates with dose levels. The DLT rate between doses in each arm is estimated under the assumption of monotonicity between doses. The dose with the LT rate closest to 30% was treated as the preliminary RP2D.

[0318] f. For participants treated with the preliminary RPTD dose during the safety run-in phase, Efficacy and safety data will be combined with those from the corresponding efficacy expansion phase. For participants treated with doses other than Not merged with cohorts.

[0319] Efficacy expansion phase a. The efficacy expansion phase will enroll approximately 120 participants overall, with each of the four cohorts Each participant had approximately 30 participants (these sample sizes were In the efficacy expansion phase, the R / R-iNHL cohort ( At least 10 participants in Hort 4) must have FL.

[0320] b. In the efficacy expansion phase, 12 participants were enrolled (in a specific cohort) (Participants from the safety run-in phase were counted in the first phase) and the last participant to receive the first response assessment Upon completion or otherwise discontinuation of the study intervention, interim safety analyses and Interim efficacy analyses for efficacy and futility will be conducted for each cohort.

[0321] c. After the RP2D is established, cohorts 1 and 2 in the efficacy expansion phase will (see Safety Run-in Phase above). The first 12 After participants are enrolled in each cohort, efficacy evaluations are performed in that cohort. During this evaluation, enrollment into cohorts 1 and 2 will continue. ORR (≥6 of 12 participants; cohort 1 efficacy goal) was achieved in cohort 1 or an ORR of ≥8.3% (≥1 of 12 participants; cohort 2 If the efficacy goal is achieved for cohort 2, enrollment in each cohort will be The study will be expanded to approximately 30 participants if either cohort 1 or 2 achieves efficacy targets. If this occurs, cohorts 3 and 4 will be open to enrollment.

[0322] d. After the first 12 participants are enrolled in either cohort 3 or 4, Efficacy analyses will be conducted in each cohort. Enrollment will continue during these evaluations. Either cohort achieved an ORR of ≥ 16.7% (≥ 2 of 12 participants) If successful, enrollment in the cohort will be expanded to approximately 30 participants.

[0323] Example 6: Multiple tumor types as determined using modeling and simulation Pembrolizumab administered every 6 weeks (Q6W) Pembrolizumab is an anti-PD-1 inhibitor currently approved for use in multiple cancer indications. 1Checkpoint inhibitors, either 200 mg or 2 mg / kg Q3W It has been shown to be safe and effective when administered in doses of 10 mg / kg / day. The system offers the benefits of convenience and flexibility to both patients and prescribers. Pharmacokinetics (PK) and exposure (concentration) of pembrolizumab for both efficacy and safety Using a model-based approach, with robust characterization of response (ER) relationships This will enable support for alternative dosing regimens of pembrolizumab.

[0324] The Q6W dosing schedule for pembrolizumab was chosen to optimize exposure and achieve PK steady state. Combined with the approved Q3W (200 mg and 2 mg / kg) regimen, The efficacy and safety of the regimens were bridged based on ER knowledge. PK exposure was monitored across multiple tumor types to ensure steady state in all subjects. A well-established population PK model for pembrolizumab adequately described the PK (time-dependent Efficacy was simulated for up to 24 weeks of treatment using a 1:1 randomized controlled trial (with no clear resolution). The exposure metric AUCss or time-averaged concentration (Cavg,ss) and trough concentration The saturation intensity (Cmin,ss) was used to bridge and compare between regimens. The safety profile of pembrolizumab in the 10-mg / kg / day group was consistent with predicted steady-state peak concentrations. (Cmax,ss) is the maximum dose that has been clinically administered and well tolerated, 10 mg / kg Q This was bridged by ensuring that the peak concentration remained below 2W.

[0325] The PK of pembrolizumab following dosing at 400 mg Q6W was significantly higher than that of the approved 200 mg Q3 The PK profile was similar to that of the 2 mg / kg Q3W and 2 mg / kg Q3W dosing regimens. As expected (see Figure 8). Exposure metrics compared between regimens are summarized in Table 12. The pembrolizumab 400 mg Q6W dosing regimen was achieved with 200 mg Q3W. Similar predicted exposures (Cavg,ss or AUCss, geometric mean The 200 mg Q was selected based on the fact that the GM was approximately 1% higher (see FIG. 7). The Cmin,ss is predicted to be lower compared to those of 3W and 2mg / kg Q3W. The predicted Cmax for 400 mg Q6W was 1.27. ss has been shown to have acceptable safety across multiple tumor types / kg Q2W (GM is about 65% lower) (Fig. 7). Similar exposure profiles and established clinical trial doses Considering the uniform ER relationship for brolizumab, this is achieved with 400 mg Q6W. Clinical outcomes were similar to those of 200mg Q3W across tumor types It is expected.

[0326] Based on the modeling and simulation approach used herein, The pembrolizumab 400 mg Q6W dosing regimen was and 2 mg / kg dosing regimens are expected to result in similar PK exposures. Simulations were performed on the dosing interval of 400 mg Q6W in terms of pembrolizumab exposure. The average concentration (Cavg) (or area under the curve [AUC]) over the approved Similar to that of the Q3W dose, therefore bridging efficacy between dosing regimens. The trough concentration (Cmin) at 400 mg Q6W was mostly (> Concentrations were generally achieved at 2 mg / kg or 200 mg Q3W in 99% of patients. The peak concentration (Cmax) at 400 mg Q6W was within the range of 0.01–0.02 in the highest clinical trial. The Cmax was well below the test dose of 10 mg / kg Q2W, and The safety profile of W was similar to that of the established pembrolizumab Pembrolizumab exposure-response (ER) across indications The results demonstrated that OS predictions in melanoma and NSCLC were similar. Considering similar exposures, efficacy at 400 mg Q6W was greater than that at 200 mg or 2 mg / day. kg Q3W is expected to be similar in efficacy to that of 00 mg Q6W is expected to be effective across indications.

[0327] Table 12. Simulation-based Pembrolizumab for 400mg Q6W Dosing Regimen Summary of PK exposure metrics for lolizumab [Table 12]

[0328] Example 7: Pembrolizumab Q6 400 mg in participants with advanced melanoma A Phase 1 trial of pembrolizumab to determine the safety and tolerability of intravenous W infusion Damming Clinical Trials This study aimed to evaluate the pharmacokinetics (PK) of pembrolizumab when administered every 6 weeks (Q6W). K), designed to evaluate safety and tolerability. Participants in this cohort will receive 400 mg of pembrolizumab Q6W. PK, efficacy and safety data will be collected from the study. Male and female participants, both aged 18 and 18 years, will be enrolled in the study. No stratification based on things or characteristics is used.

[0329] Participants will receive 400 mg pembrolizumab Q6W IV infusion from cycles 1 to 18. PK, efficacy and safety data will be collected from these participants. The present study provides preliminary PK, efficacy, and safety data for pembrolizumab administered Q6W. Provide data on pembrolizumab based on a solid understanding of its clinical pharmacology and well-established Based on its ER profile, such a change in dosing schedule would be Pembrolizumab in all approved treatment settings (monotherapy and in combination with other agents) in Q3W are expected to produce similar efficacy and safety results in Therefore, the 400 mg Q6W regimen was evaluated based on modeling and simulation. Based on the analysis, a less frequent dosing regimen for pembrolizumab in clinical use would be: It has a similar benefit-risk profile to 200 mg Q3W.

[0330] Study design The study is a randomized, cross-sectional study of pembrolizumab in participants with advanced melanoma. This is a cross-over, multicenter, open-label safety study that complies with Good Clinical Practice Guidelines. This Phase 1 study will be conducted in accordance with GCP (Good Clinical Practices). The study will be conducted in participants with unresectable or metastatic melanoma. Treatment continues every 42 days for up to 18 cycles (approximately 2 years). Patients receiving the benefit and have not progressed or meet any of the criteria for withdrawal from the study In more detail, the study consists of: (1) the participant is A screening period lasting up to 28 days to ensure that patients are eligible for the study, and and (2) an intervention period of approximately 104 weeks of pembrolizumab treatment. Participants will receive Receive pembrolizumab via IV infusion over 30 minutes Q6W for 8 cycles; and (3) Participants were followed up for 30 days for AEs and 90 days for serious adverse events (SAEs) ( A follow-up period in which participants will be monitored for 30 days if they start a new anti-cancer treatment Participants with ongoing AEs at the time of treatment discontinuation were assessed for resolution, stabilization, or other explanation for the event. or until participants are lost to follow-up.

[0331] Participants who discontinued for reasons other than radiological disease progression were and until radiologically documented disease progression according to Until site confirmation according to iRECIST, or initiation of non-study cancer treatment. Patients were notified of their disease status until withdrawal of consent, loss to follow-up, or end of the study. Follow-up imaging will be performed after all procedures. All participants will remain in the study until death. Survival follow-up was continued until participants withdrew consent, were lost to follow-up, or the end of the study. Patients will be followed up by telephone for overall survival during the follow-up period. Participants may be enrolled in the pembrolizumab expansion trial when available.

[0332] All participants enrolled in this study have been diagnosed with advanced melanoma. The results provide insight into the PK characteristics of pembrolizumab when administered in a Q6W dosing regimen. Safety parameters commonly used to evaluate systemic anticancer treatments in clinical trials Targets include, but are not limited to, the occurrence of adverse events (AEs) / serious adverse events (SAEs). and safety, such as changes in vital signs and laboratory parameters. AEs are included as clinical endpoints in the National Cancer Institute's Cohort Study of Adverse Events. Common Terminology Criteria (National Cancer Institute Common Terminology Criteria) erminology Criteria for Adverse Events, [ Evaluated as specified by the National Comprehensive Testing and Coordination Agency (NCI CTCAE) Version 4.0 can be.

[0333] The objective of this study was to characterize the PK profile of pembrolizumab following administration Q6W as an IV infusion. The objective of this study is to characterize the PK data after all participants have completed cycle 5. The PK parameters include AUC, Cmax and Cmin. The formation of antibodies (ADAs) can potentially disrupt drug exposure at therapeutic doses and subsequently affect infusion relationships. Pembrolizumab at the start of each of cycles 1, 2, 4, and 5 may stimulate The anti-drug antibody response to ADA will be determined. It will be investigated whether this has any impact.

[0334] The primary endpoint of this study was blinded independent central review. R evaluated by independent central review (BICR) ORR based on ECIST 1.1 criteria will be used. Objective response rate is important, especially when the magnitude of the effect is large. If the treatment has an acceptable risk / benefit profile, As a measure of clinical benefit for late-stage trials demonstrating superiority of anti-cancer treatments The use of BICR and RECIST 1.1 to assess ORR is Generally considered acceptable by regulatory authorities. Images are generated using imaging CRO (iC The images will be submitted to the RO and reviewed by an independent central review agency blinded to treatment allocation. , minimizing bias in response assessment.

[0335] Overall survival (OS) was a secondary endpoint and was a novel endpoint in randomized clinical trials. It is recognized as the gold standard for demonstrating superiority of anti-cancer treatments. RECIST 1.1 is recommended by BICR when assessing images for efficacy assessment. The revised guidelines for evaluating immunotherapy are used by local authorities to determine eligibility and Modified RECIST 1.1 for immu iRECIST (i-based therapeutics) evaluation is based on RECIST The guidelines were developed and published by the Working Group and are supported by the U.S. Food and Drug Administration (USFDA). Food and Drug Administration and the European Medicines Agency The conference will be attended by industry and academia, with participation from the National Institute of Medical Sciences (NIMS) and the National Institute of Health (NHI). Contains input from leading experts in the surgical field. Qualitative assessment and response categories were progression by RECIST 1.1. The RECIST criteria are the same as RECIST 1.1 until the patient is clinically stable. If so, additional imaging may be performed to confirm radiographic progression. ST is used by investigators to assess tumor response and progression and to guide treatment decisions. These will also be used for exploratory efficacy analyses, when specified.

[0336] Selection Criteria Participants were eligible for inclusion in the study only if they met all of the following criteria: Participants had a histologically or cytologically confirmed diagnosis of advanced melanoma.

[0337] Participants had unresectable stage III or stage IV melanoma and were treated with chemotherapy in the United States. American Joint Committee on Cancer The patient is not amenable to local treatment according to the AJCC (American Joint Committee on Cancer) staging system.

[0338] Participants had not received any treatment for progressive or metastatic disease except for the following: BRAF V600 mutant melanomas are not treated with standard targeted therapies (e.g., BRAF / MEK Patients may have received chemotherapy or chemotherapy-induced pulmonary bypass (e.g., chemotherapy inhibitors, alone or in combination) and be eligible for this study.

[0339] Prior adjuvant or neoadjuvant melanoma treatment is randomized Treatment must be completed at least 4 weeks prior to initiation, and all relevant AEs must have returned to baseline, or or stabilized (toxic effects of most recent prior therapy have resolved to grade 1 or less (withdrawal If the patient has undergone major surgery or radiation therapy >30 Gy, If a patient has undergone surgery, they must have recovered from toxicity and / or complications from that intervention.

[0340] Female participants were required to be neither pregnant nor breastfeeding and to remain pregnant during the treatment period and for at least Agree to follow specific contraceptive guidelines for 120 days or provide informed consent If you have contributed at least one cent, you are eligible to participate.

[0341] Participants were from the Eastern Cooperative Oncology Group. eCOG performance status of 0 (complete are actively active and able to perform all of their pre-illness activities without limitation) or 1 (Limited physically strenuous activity but ambulatory, light or sedentary work, e.g. (e.g., light housework or office work can be performed) and Patients must have functional organs. Samples will be collected within 72 hours prior to the start of the study intervention.

[0342] Table 13. Pertinent Organ Function Laboratory Test Values [Table 13]

[0343] Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria: Participants must have had a positive urine pregnancy test within 72 hours prior to randomization or treatment assignment. Are women of childbearing potential (WOCBP); have a positive or confirmed negative urine test result; If not, a serum pregnancy test is required.

[0344] Participants had received prior systemic treatment for unresectable or metastatic melanoma. (except as stated in the selection criteria above).

[0345] Participants will receive chemotherapy with anti-PD-1, anti-PD-L1 or anti-PD-L2, or another stimulatory regimen or targeting co-inhibitory T cell receptors (e.g., OX-40 and CD137) Checkpoint inhibitors other than anti-CTLA-4 approved as adjuvants or in combination with other anti-CTLA-4 drugs Prior treatment with any other antibody or drug that specifically targets the IL-1 pathway .

[0346] Participants will receive prior radiation therapy within 2 weeks of starting study treatment. , recovered from all radiation-related toxicities, did not require corticosteroids, and had no radiation-induced You must not have pneumonia.

[0347] Participants received a live vaccine within 30 days prior to the first dose of study drug. Examples include, but are not limited to, measles, mumps, rubella, chickenpox / shingles ( Chickenpox), Yellow Fever, Rabies, Bacillus Calmette-Guerin (BCG) and Typhoid Vaccine Injectable seasonal influenza vaccines are generally killed bacteria vaccines. , is recognized; whereas, nasal influenza vaccines (e.g., FluMist® )) is a live attenuated vaccine and is not permitted.

[0348] Participants must be currently enrolled in an investigational drug trial or have been taking any study drug for at least 4 weeks prior to first dose of the study intervention. Participated in an investigational drug trial or used an investigational device during the study period.

[0349] Participants must have been diagnosed with an immunodeficiency or have a chronic condition within 7 days prior to receiving their first dose of study drug. Systemic steroid therapy (prednisone equivalent >10 mg / day) or other are receiving any form of immunosuppressive treatment.

[0350] Participants were required to have a history of any further malignancies that were ongoing or had required active treatment within the past 2 years. Known to have a tumor. Note: Skin lesions that have undergone potentially curative treatment. Basal cell carcinoma, squamous cell carcinoma of the skin or in situ carcinoma (e.g., breast carcinoma, in situ Participants with known cancer (cervical cancer) will not be excluded.

[0351] Participants were known to have active CNS metastases and / or carcinomatous meningitis. Participants who had prior treatment for brain metastases were re-imaging (Note: re-imaging is radiological examination for at least 4 weeks (must be performed during screening for the study) Patients with stable disease (i.e., no evidence of progression), clinically stable, and responding to study interventions Participation was contingent on the condition that participants had not required steroid treatment for at least 14 days prior to the first dose of the drug. It is possible.

[0352] Participants experienced severe adverse events to pembrolizumab and / or any of its excipients. If you have sensitivity (≥ grade 3).

[0353] Participants have ocular melanoma.

[0354] Participants had an active autoimmune disease that required systemic treatment within the past 2 years (all i.e. involving the use of disease-modifying drugs, corticosteroids or immunosuppressants). For example, physiological responses to thyroxine, insulin, or adrenal or pituitary insufficiency Interventional corticosteroid replacement therapy (IL-15) is not considered a form of systemic treatment and is permitted.

[0355] Participants were required to have a history of or current pneumonia requiring steroids (non-infectious). I am suffering.

[0356] Participant has an active infection requiring systemic treatment.

[0357] Participants have a known history of human immunodeficiency virus (HIV) infection.

[0358] Participants were required to have hepatitis B (defined as hepatitis B surface antigen (HBsAg) reactive) or Active hepatitis C virus infection (defined as detectable HCV RNA [qualitative]) The history is clear.

[0359] In the opinion of the investigator performing the procedure, this may confound the results of the study and There are circumstances that may prevent the participant from participating for the duration of the study or where participation is in the participant's best interest. Participants had no history or current evidence of any condition, treatment, or laboratory abnormality other than be.

[0360] Participants have no mental or substance abuse disorder that would prevent them from cooperating with the requirements of the study. It turns out he is ill.

[0361] Participants were not allowed to be pregnant or breastfeeding, or to participate in the study starting from the screening visit. To become pregnant or have a child within the planned study period up to 120 days after the last dose of the study intervention It is expected.

[0362] Discontinuation of study intervention and participant withdrawal Discontinuation of the study intervention does not represent withdrawal from the study. Certain data about the vent may be important to the study, so participants Data will be collected up to the participant's last scheduled follow-up, even if the intervention is discontinued. Therefore, study intervention must be discontinued prior to completion of the protocol-specified treatment period. All participants who discontinue will continue to participate in the study.

[0363] Participants may discontinue the study intervention at any time for any reason and without any inconvenience. If any of the above conditions are met, participants may be withdrawn from the study intervention at the discretion of the investigator. In the event of inappropriate intervention, violation of the study protocol, or administrative and / or other safety concerns The study intervention may be discontinued by the investigator for the above reasons.

[0364] A participant must discontinue the study intervention for any of the following reasons, but the participant The study must continue to monitor: The participant or the participant's legally authorized representative requests discontinuation of the study intervention.

[0365] Participant discontinued administration of the study intervention for more than 12 consecutive weeks or discontinued administration for 3 cumulative weeks Not taking medication.

[0366] The participant is not aware that, in the opinion of the investigator, continued administration of the study intervention would pose unnecessary risk to the participant. have a medical or personal condition that puts them at risk.

[0367] Participant had a confirmed positive serum pregnancy test.

[0368] Participant has radiologically confirmed disease progression.

[0369] Participants were not at risk of any progression or recurrence of any malignancy or of any active treatment There is the development of another malignant tumor that requires treatment.

[0370] · The participant had an adverse experience that was unacceptable.

[0371] The participant had a concurrent illness other than the other malignancies listed above that would prevent further administration of the treatment. There are.

[0372] The investigator decided to stop treatment.

[0373] Participant experienced a recurrence of recurrent grade 2 pneumonia.

[0374] Participants completed 35 treatments (approximately 2 years) with pembrolizumab.

[0375] If the participant or the participant's legally authorized representative withdraws consent to participate in the study, If a participant withdraws from the study, they will no longer receive any study treatment. and are not followed up at scheduled protocol visits.

[0376] Effectiveness / Evaluation Tumor evaluation includes all known or suspected sites of disease. Imaging is based on Thoracic, abdominal, and pelvic tumors at baseline and when progression or brain metastases are suspected This may include computed tomography (CT) or magnetic resonance imaging (MRI). Tumor imaging is strongly preferred, with CT scans of the chest, abdomen, and pelvis. When CT with iodine contrast is contraindicated or required by local practice, When the brain is attached, contrast-enhanced MRI can be used. For the brain, MRI is most preferred. It is a novel imaging modality.

[0377] Participants should be provided with the same imaging modality technology (ideally the same skills) throughout the study. Consistent use of imaging techniques is required to and optimizing the reproducibility of assessments of new tumor burden and the precision of assessments of response or progression. All scheduled images for all study participants will be Progression will be reviewed by the investigator. In addition, scheduled follow-up sessions will be conducted to determine progression. Images obtained at other times (including those obtained by other modalities) (as well as Obtained for other reasons but captured radiological progression based on investigator assessment Imaging) will also be on file at the testing facility.

[0378] Measurable disease based on RECIST 1.1 by BICR at screening Verification will be used to determine participant eligibility. Demonstrating at least one lesion suitable for selection as a target lesion according to ST 1.1 Verification by BICR of this is required prior to participant allocation.

[0379] Initial Tumor Imaging The first tumor imaging at screening will be performed within 28 days prior to the first dose. All imaging obtained after Day 1 of Cycle 1 treatment was included in the screening evaluation. The site study team will review the screening images and determine whether the participant has received RECI. Confirm measurable disease per ST 1.1. Document stability of existing metastases. When brain imaging is performed to document the brain function, MRI is used when possible. If MRI is medically contraindicated, CT with contrast is an acceptable alternative.

[0380] Tumor imaging under study The first on-study imaging evaluation was performed 12 weeks (84 days ± 7 days) from the date of first dose. Subsequent tumor imaging will be performed every 9 weeks (63 days ± 7 days) or as clinically indicated. More frequently if indicated. After 52 weeks (365 days ± 7 days), participants who continue treatment Imaging will be performed every 12 weeks (84 days ± 7 days).

[0381] Objective response is confirmed by repeat imaging evaluation. Tumor imaging for follow-up should be performed at least 4 weeks after the first signs of response. Participants were then asked to continue with their usual scheduled imaging sessions starting at the next scheduled imaging time. Participants who underwent additional imaging for confirmation were returned to their next scheduled tumor imaging session. If imaging is scheduled for 4 weeks or less, no imaging is required. Tumor imaging may be resumed.

[0382] Progressive disease (PD) in clinically stable participants according to modified iRECIST Progression is confirmed by the center 4-8 weeks after first radiological evidence of disease progression. Participants without documented disease progression may be screened for site-confirmed progression at the investigator's discretion. Participants who underwent confirmatory imaging may continue treatment until the next scheduled tumor imaging session. If imaging is performed within 4 weeks, no further imaging is required; if clinically stable, Tumor imaging may be resumed at the imaging time point determined by the institution. Participants who experience disease progression by iRECIST will discontinue study treatment.

[0383] End of treatment and follow-up tumor imaging For participants who discontinued study intervention, tumor imaging was performed at the time of treatment discontinuation (± 4 week window). If the previous imaging was performed within 4 weeks prior to the discontinuation date, treatment will be discontinued. Imaging at this time is not required. Patients who discontinued study intervention due to documented disease progression should be For participants with iRECIST, if the investigator chooses not to perform iRECIST, This will be the final tumor imaging required.

[0384] For participants who discontinued study intervention without documented disease progression, new anticancer Treatment initiation, disease progression, pregnancy, death, withdrawal of consent, or study termination, whichever occurred first. Until then, patients will be monitored every 12 weeks (± 7 days) using the same imaging schedule used during treatment. Every effort should be made to continue to monitor disease status with tumor imaging using You should pay attention.

[0385] RECIST 1.1 disease assessment RECIST 1.1 is the primary measure for assessing tumor response and the date of disease progression. and all protocol guidelines related to disease status (e.g., discontinuation of study intervention). RECIST 1.1 is used as the basis for a maximum of five total criteria, two per organ. Although the protocol refers to a single target lesion, it allows for more extensive tumor burden sampling. Up to 10 total target lesions, 5 per organ, if clinically justified is permitted.

[0386] iRECIST Disease Assessment iRECIST is based on RECIST 1.1 but takes into account the limitations of the fixed-response syndrome seen with immunotherapies. iRECIST is adapted to take into account the overall tumor response as determined by the investigator. These are used to assess tumor response and progression and to guide treatment decisions. Participants will be monitored until progression is confirmed by the investigator in collaboration with the local radiology department. This acceptance of continuing treatment despite early radiological PD is During the first few months after initiating immunotherapy, patients experienced a transient tumor relapse followed by a disease response. This takes into account the finding that some participants may experience

[0387] All participants who were deemed clinically unstable were evaluated at the first radiological site. Patients were discontinued from the study upon evidence of clinical PD and were followed for confirmation of PD by iRECIST. There is no need to undergo repeat tumor imaging for treatment if the investigator decides to continue treatment. If so, participants may continue to receive study intervention and will receive iRECI as assessed by the investigator. Tumor assessment should be repeated in 4-8 weeks to confirm PD by ST. Repeat imaging did not confirm PD per iRECIST as assessed by investigator If participants remain clinically stable, they will continue the study intervention and undergo regular imaging studies. If PD is confirmed, participants will discontinue the study intervention.

[0388] If a participant experienced radiological progression (iCPD), the study intervention was discontinued. If participants achieve a clinically meaningful benefit, they may continue the study intervention. In this case, if the study intervention is continued, tumor imaging should be continued. Imaging and treatment requirements after first radiological evidence of progression An overview is provided in Table 14.

[0389] Table 14. Imaging and Treatment After First Radiological Evidence of Disease Progression [Table 14] TIFF2024156880000019.tif73165

[0390] Safety assessment Safety assessments included collection of AEs and SAEs, vital signs and clinical laboratory assessments (pregnancy, Monitoring (including physical examinations), performing electrocardiograms (ECGs) and physical examinations, and Medication verification is included.

[0391] Adverse events The investigator or qualified designee will assess any AEs that may be new or worsening. Each subject will be evaluated for adverse events, or more frequently if clinically indicated. The value of the cancer may include, but is not limited to, the type, incidence, and severity of the cancer (as determined by the National Cancer Institute in the United States). According to the Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 The study will include any adverse events (graded by the investigator), timing, severity, and relationship to the study drug. Adverse events observed will be recorded, including baseline signs and symptoms.

[0392] Complete physical examination The investigator or qualified designee will conduct a complete physical examination during the screening period. Any clinically significant abnormal findings will be recorded in the medical history. After the first dose of the study intervention, Any new clinically significant abnormal findings will be recorded as an AE.

[0393] Directed physical examination For cycles that do not require a full physical examination, the investigator or a qualified subject The designee will conduct a clinically indicated physical examination prior to administration of the study intervention. Any abnormal findings that are clinically significant will be recorded as an AE.

[0394] Vital signs Vital signs were measured in semi-supine position after 5 min of rest and included temperature, systolic and diastolic These include blood pressure, respiratory rate, heart rate and weight. Height was measured only at screening. do.

[0395] electro-cardiogram A standard 12-lead ECG will be performed using local standard procedures. Screening Any clinically significant abnormal findings will be recorded in the medical history. Additional ECG(s) are performed. Clinically significant findings on follow-up ECGs The observation will be recorded as an AE.

[0396] Laboratory evaluation of clinical safety Testing detailed in Table 15 will be performed by local laboratories. Additional testing may be performed at any time during the study if determined necessary by the investigator.

[0397] Table 15. Safety Laboratory Assessments Required by the Protocol [Table 15] TIFF2024156880000021.tif47162

[0398] The duration and frequency of collecting information on AEs, SAEs, and other reportable safety events All AEs, SAEs, and and other reportable safety events occurred whether participants received placebo or other lead-in treatment. If the event caused the participant to be removed from the study, or if the event was not considered Washout or discontinuation of treatment, diet, or procedure, as specified by the protocol, If the outcome is the result of an intervention that was not performed, this must be reported by the investigator. All AEs from the time of admission / randomization through 30 days after cessation of study intervention were reported by the investigator. must be reported.

[0399] From the time of treatment assignment / randomization, 90 days after cessation of study intervention or if the participant develops a new anticancer agent If cancer treatment is started, the severity criteria will be met until 30 days after the end of the study intervention, whichever comes first. All AEs that meet the criteria above must be reported by the investigator. Any SAEs brought to the investigator's attention outside the scheduled time period were considered to be drug-related. If it is believed to be relevant, it will be reported immediately.

[0400] Statistical methods for efficacy analysis Objective Response Rate (ORR) - ORR was defined as confirmed CR or PR verified by BICR. Ratio of the number of participants who reported achieving the APaT target divided by the number of participants included in the APaT population Participants in the APaT analysis population without ORR assessment were classified as non-responders. 95% exact binomial CI (Clopper and Pearson, 1934 method) is calculated for the true ORR.

[0401] Progression-free survival (PFS) – Non-parametric Kap The Lan-Meier method was used. P 95% CIs for median FS and PFS point estimates will be calculated. Since the PD is evaluated automatically, the PD is different from the last evaluation in which the PD was not documented and This can occur at any time during the time interval between the evaluations recorded on the PD. The study was conducted in patients with PD objectively documented according to RECIST 1.1 by BICR. Death is always considered a PFS event. Participants who did not receive treatment were censored at their last disease assessment. For the analysis of PFS, If the event (or death) occurred immediately after two or more missed disease assessments, data were taken from the most recent visit prior to the missed visit. The data after new anticancer treatment are censored at the later disease evaluation. Participants are censored at the last disease assessment before starting treatment. If a participant meets multiple censoring criteria, If so, the earliest occurring censoring criterion is applied.

[0402] Overall Survival (OS) – Non-parametric Kaplan-Method was used to estimate OS distribution. The Meier method is used. Median OS at various follow-up times from the first day of study treatment and 95% CIs for OS point estimates will be calculated.

[0403] Duration of Response (DOR) - DOR was calculated using the nonparametric Kaplan-Meier Only the subset of participants who achieved CR or PR will be included in this study. Included in the analysis.

[0404] Analysis strategy for key efficacy endpoints Table 16 summarizes the primary analysis approach for the key efficacy endpoints.

[0405] Table 16. Analysis strategy for key efficacy endpoints [Table 16]

[0406] Statistical methods for safety analysis. Safety and tolerability were assessed using all relevant data, including adverse experiences and clinical laboratory parameters. AEs are assessed by clinical review of parameters. All AEs, drug-related AEs, serious AEs, Participants with AEs that were both drug-related and serious, as well as participants who discontinued due to AEs Broad AE categories consisting of percentages of patients with The results are summarized in Table 17.

[0407] Table 17. Analysis strategy for safety parameters [Table 17]

[0408] AEs may occur at any time following the use of the study intervention, whether or not they are considered related to the study intervention. Any adverse medical occurrence in a clinical trial participant associated with the use of the drug. An AE is any untoward and unintended symptom (laboratory finding) that is temporally associated with the use of a drug. AEs may be any abnormality in the body (including abnormalities in the nervous system), syndrome or disease (new or worsening). Includes: Any abnormal laboratory test results (blood, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiology scan, vital signs). Worsening from baseline or considered clinically significant in the medical and scientific judgment of the investigator. This includes those that:

[0409] Chronic or intermittent exacerbation of a pre-existing condition, including an increase in the frequency and / or intensity of the condition do.

[0410] may have been present before the start of the study but were detected or is a newly diagnosed condition.

[0411] Signs, symptoms or clinical sequelae of a suspected drug-drug interaction.

[0412] · Signs, symptoms, or clinical sequelae suggestive of overdose of the study intervention or concomitant medication.

[0413] Worsening signs and symptoms of malignancy during the study will be reported as an AE. Disease progression, as assessed by measurement of malignant lesions by other means, was determined based on whether the event required hospitalization or An AE is not reported unless it results in adverse events or death.

[0414] The following events do not meet the definition of an AE for the purposes of this study: Medical or surgical procedures (e.g., endoscopy, appendectomy): the cause leading up to the procedure The condition is AE.

[0415] A situation in which no adverse medical events occurred (socially and / or expediently hospitalized) (To enter).

[0416] Pre-existing disease(s) or condition(s) present or detected at the start of the study Expected day-to-day fluctuations in, but not worsening.

[0417] Surgery scheduled before informed consent to treat a pre-existing condition And it hasn't gotten worse.

[0418] If an event is not an AE according to the above definition, it is not an SAE even if it meets the seriousness criteria. An SAE is any untoward medical occurrence at any dose, including It is defined as: · Something that leads to death.

[0419] Life-threatening. The term "life-threatening" in the definition of "serious" means that at the time of the event This refers to an event in which participants were at risk of death if it had been more severe. It does not refer to an event that could have caused the

[0420] Requires the patient to be admitted to hospital or to have an existing hospital stay extended. Hospitalization of a patient was defined as a precautionary measure to continue observation, regardless of the length of time that the patient was hospitalized. Hospitalization for elective surgery to treat a pre-existing condition that has not worsened is not considered an SAE. No. Pre-existing conditions were diagnosed prior to use of MSD products and were documented in the participant's medical history. It is in a floor state.

[0421] · Resulting in a persistent or significant disability / incapacity. The term disability refers to It means a substantial disruption of the ability to carry out normal life functions for a period of time. Comparative medical disorders that may interfere with or hinder functioning but do not constitute a substantial disruption experiences of minor significance, e.g. uncomplicated headache, nausea, vomiting, diarrhea, influenza is not intended to include injuries such as bruising, accidental injuries (e.g., sprained ankles), etc. stomach.

[0422] No birth defects / birth defects in the offspring of participants who consumed this product, regardless of time to diagnosis There is a defect.

[0423] Other situations, such as those that are immediately life-threatening or result in death or hospitalization, Significant medical events that are not covered by the definition above but may endanger the participant may require medical or surgical intervention to prevent one of the other outcomes In determining whether an SAE report is appropriate for a particular important medical event, These events are usually considered to be serious. Examples include emergency treatment for invasive or malignant cancers and allergic bronchospasm. Intensive care in a ward or at home, blood disorders or convulsions not requiring hospitalization, or drug addiction or the occurrence of drug abuse.

[0424] Demographics and baseline characteristics Number and percentage of subjects screened and assigned; screening The main reasons for failure and for discontinuation will be tabulated. Demographic variables (e.g., age, sex), baseline characteristics, primary and secondary The subsequent diagnoses, and prior and concomitant treatments were presented using descriptive statistics or categorical tables. It can be summed up as follows.

[0425] Subgroup analysis To determine whether response rates were consistent across the various subgroups, each category of the following classification variables was Within categories, response rate estimates (with nominal 95% CI) for the primary endpoint ) is estimated.

[0426] Age category (<65 vs. ≥65) · Gender (female vs. male) · Race (white vs. non-white) Stage (III vs. IVM1a vs. IVM1b vs. IVM1c) Brain metastases (yes vs. no) ECOG status (0 vs. 1) PD-L1 status (positive vs. negative) BRAF wild type vs. BRAF mutant (no prior treatment) vs. BRAF mutant (prior treatment) can be) A forest plot was created, which was broken down into the subgroup categories listed above. We provide estimated point estimates and CIs for the treatment effect across 10 participants. Certain subgroups below this age are excluded from the analysis.

[0427] References 1. Sharpe, AH, Wherry, EJ, Ahmed R., and Freeman GJ The function of program med cell death 1 and its ligands in regu lating autoimmunity and infection. e Immunology (2007); 8:239-245. 2. Dong H et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential m echanism of immune evasion. Nat Med. 200 2 Aug;8(8):793-800. 3. Yang et al. PD-1 interaction contribution tes to the functional suppression of Tc ell responses to human uveal melanoma ce lls in vitro. Invest Ophthalmol Vis Sci. 2008 Jun;49(6 (2008): 49: 2518-2525. 4. Ghebeh et al. The B7-H1 (PD-L1) T lym phocyte-inhibitory molecule is expressed in breast cancer patients with infiltra ting ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia (2006) 8: 190-198. 5. Hamanishi J et al. Programmed cell de ath 1 ligand 1 and tumor-infiltrating CD 8+ T lymphocytes are prognostic factors of human ovarian cancer. Proceeding of t he National Academy of Sciences (2007): 104: 3360-3365. 6. Thompson RH et al. Significance of B7 -H1 overexpression in kidney cancer. Cli nical genitourin Cancer (2006): 5: 206-2 11. 7. Nomi, T. Sho, M., Akahori, T., et al. Clinical significance and therapeutic p otential of the programmed death- 1 liga nd / programmed death-1 pathway in human p ancreatic cancer. Clinical Cancer Resear ch (2007);13:2151-2157. 8. Ohigashi Y et al. Clinical significan ce of programmed death-1 ligand-1 and pr ogrammed death-1 ligand 2 expression in human esophageal cancer. Clin. Cancer Re search (2005): 11: 2947-2953. 9. Inman et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: association s with localized stage progression. Canc er (2007): 109: 1499-1505. 10. Shimauchi T et al. Augmented express ion of programmed death-1 in both neopla smatic and nonneoplastic CD4+ T-cells in adult T-cell Leukemia / Lymphoma. Int. J . Cancer (2007): 121:2585-2590. 11. Gao et al. Overexpression of PD-L1 s ignificantly associates with tumor aggre ssiveness and postoperative recurrence i n human hepatocellular carcinoma. Clinic al Cancer Research (2009) 15: 971-979. 12. Nakanishi J. Overexpression of B7-H1 (PD-L1) significantly associates with t umor grade and postoperative prognosis i n human urothelial cancers. Cancer Immun ol Immunother. (2007) 56: 1173- 1182. 13. Hino et al. Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma. Cancer ( 2010): 00: 1-9. 14. Ghebeh H. Foxp3+ tregs and B7-H1+ / PD -1+ T lymphocytes co-infiltrate the tumo r tissues of high-risk breast cancer pat ients: implication for immunotherapy. BM C Cancer. 2008 Feb 23;8:57. 15. Ahmadzadeh M et al. Tumor antigen-sp ecific CD8 T cells infiltrating the tumo r express high levels of PD-1 and are fu Blood (2009) 114: 1 537-1544. 16. Thompson RH et al. PD-1 is expressed by tumor infiltrating cells and is asso ciated with poor outcome for patients wi th renal carcinoma. Clinical Cancer Rese arch (2007) 15: 1757-1761. All references cited herein are to be interpreted as individual publications, database entries, and / or other references. (e.g., Genbank sequence or GeneID entry), patent application or patent to the same extent as if the permission was specifically and individually indicated to be incorporated by reference. Incorporated by reference. U.S. Provisional Application No. 62 / 755,756 is incorporated by reference in its entirety. This statement of incorporation by reference is hereby incorporated by reference in its entirety as set forth in 37 CF Pursuant to R. §1.57(b)(1), such citation is subject to the exclusive right of incorporation by reference. Each of the statements in 37 CFR §1.57(b) is true even if they are not immediately adjacent to the statement of use. Any individual publications, database entries, etc. that are clearly identified in accordance with (2) (e.g., Genbank sequence or GeneID entry), patent application or patent-related It is intended that the disclosure be linked to the present application. The inclusion of this statement, if any, shall not be construed as constituting any other provision of this general rule regarding incorporation by reference. The citation of a reference herein is not intended to in any way diminish the scope of the present invention to which the reference pertains. No admission of prior art is intended, and no reference is made to the contents or dates of these publications or documents. No admission is made that the invention is in accordance with the teachings of the present invention. To the extent that a definition is provided that contradicts the definitions provided herein, The definitions are used to interpret the claimed invention.

Claims

1. administering to the patient 7-1200 mg of an anti-LAG3 antibody via intravenous infusion; 1. A method for treating cancer in a patient, comprising administering to a patient an anti-LAG3 antibody selected from the group consisting of: (a) SEQ ID NO:2 (b) light chain CDRs of SEQ ID NOs: 6, 27 and 28 and (b) heavy chain CDRs of SEQ ID NOs: 29, 30 and 31. The method further comprises DR.

2. The method of claim 1, wherein the patient is administered 100 mg of the anti-LAG3 antibody.

3. The method of claim 1 , wherein the patient is administered 200 mg of the anti-LAG3 antibody.

4. The method of claim 1, wherein the patient is administered 700 mg of the anti-LAG3 antibody.

5. The method of claim 1, wherein the patient is administered 800 mg of the anti-LAG3 antibody.

6. 6. Any of claims 1 to 5, wherein the patient is administered the anti-LAG3 antibody on the first day of every three weeks. Method of one term.

7. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:

25.

7. The method of claim 1, wherein the light chain comprises a light chain variable region comprising SEQ ID NO:

24. Method of section.

8. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO:

24.

7. The method of claim 1, further comprising column number 22.

9. The method of any one of claims 1 to 6, wherein the anti-LAG3 antibody is an Ab6 variant.

10. The anti-LAG3 antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or an antigen binding agent thereof. The method of claim 1 , wherein the antibody is co-administered with a sexual fragment.

11. The anti-LAG3 antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or an antigen binding agent thereof. The method of any one of claims 1 to 9, wherein the compound is combined with a functional fragment.

12. The anti-PD-1 antibody or antigen-binding fragment thereof specifically binds to human PD-1 and inhibits human PD-1. The method of claim 10 or 11, which blocks binding of D-L1 to human PD-1.

13. The anti-PD-1 antibody or antigen-binding fragment thereof may also bind human PD-L2 to human PD-1. The method of claim 12, wherein the binding is blocked.

14. The anti-PD-1 antibody or antigen-binding fragment thereof comprises: (a) a light chain C of SEQ ID NOs: 1, 2, and 3; 14. The method of claim 13, comprising (a) a heavy chain CDR and (b) a heavy chain CDR of SEQ ID NOs: 6, 7 and 8.

15. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:

9. and wherein the light chain comprises a light chain variable region comprising SEQ ID NO:

4.

16. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 10 and the light chain comprises SEQ ID NO:

14. The method of claim 13, including column number 5.

17. The method of claim 13, wherein the anti-PD-1 antibody is pembrolizumab.

18. The method of claim 13, wherein the anti-PD-1 antibody is a pembrolizumab variant.

19. The method of claim 10, wherein the anti-PD-1 antibody is nivolumab.

20. The anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab. The method of claim 10.

21. The anti-PD-1 antibody is administered via intravenous infusion at 200 mg on day 1 once every 3 weeks. The method according to any one of claims 14 to 18,

22. The anti-PD-1 antibody will be administered via intravenous infusion at 400 mg on day 1 once every 6 weeks. The method according to any one of claims 14 to 18,

23. The anti-PD-1 antibody is a humanized anti-PD-1 antibody comprising a heavy chain and a light chain, wherein the heavy chain is The heavy chain variable region comprises the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8, and the light chain comprises the CDRs of SEQ ID NOs: 1, 2 and a light chain variable region comprising three light chain CDRs; and an anti-LAG3 antibody comprising a heavy chain and A humanized anti-LAG3 antibody comprising a light chain, wherein the heavy chain is a sequence selected from SEQ ID NOs: 29, 30 and 31. and a light chain variable region comprising the light chain CDRs of SEQ ID NOs: 26, 27 and 28.

12. The method of claim 10 or 11, comprising a light chain variable region comprising a DR.

24. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:

9. and the light chain comprises a light chain variable region comprising SEQ ID NO:4; and the anti-LAG3 antibody comprises a heavy chain and and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises SEQ ID NO: The method of claim 10 or 11, comprising a light chain variable region comprising:

25. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 10 and the light chain comprises SEQ ID NO: and the anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 23 and the light chain comprises SEQ ID NO:

22.

26. The anti-PD-1 antibody was administered via intravenous infusion at 200 mg on day 1 once every 3 weeks. The anti-LAG3 antibody was administered via intravenous infusion at 200 mg on day 1 once every 3 weeks. The method of any one of claims 23 to 25.

27. The anti-PD-1 antibody was administered via intravenous infusion at 400 mg on day 1 once every 6 weeks. The anti-LAG3 antibody was administered via intravenous infusion at 200 mg on day 1 once every 3 weeks. The method of any one of claims 23 to 25.

28. The anti-PD-1 antibody was administered via intravenous infusion at 200 mg on day 1 once every 3 weeks. Anti-LAG3 antibody was administered via intravenous infusion at 700 or 800 mg once every 3 weeks on day 1. The method of any one of claims 23 to 25, wherein the administration is by administration of

29. The anti-PD-1 antibody was administered via intravenous infusion at 400 mg on day 1 once every 6 weeks. Anti-LAG3 antibody was administered via intravenous infusion at 700 or 800 mg once every 3 weeks on day 1. The method of any one of claims 23 to 25, wherein the administration is by administration of

30. 200 mg of anti-PD-1 antibody is combined with 200 mg of anti-LAG3 antibody.

26. The method of any one of 23 to 25.

31. 200 mg of anti-PD-1 antibody is combined with 800 mg of anti-LAG3 antibody.

26. The method of any one of 23 to 25.

32. The cancer is head and neck squamous cell carcinoma, gastric cancer, adenocarcinoma of the stomach and / or gastroesophageal junction, renal cell carcinoma, alveolar cancer, fallopian tube cancer, endometrial cancer, and non-microsatellite instability (non-MS) I-H) or mismatch repair proficient (pMMR) colorectal cancer.

32. The method of any one of claims 1 to 31,

33. The cancer is renal cell carcinoma, urothelial carcinoma of the renal pelvis, ureter, bladder or urethra, melanoma, or gastric cancer.

32. Any of claims 1 to 31, wherein the cancer is selected from the group consisting of non-small cell lung cancer and bladder cancer. Or one method.

34. The cancer is classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DL-LCL), 32. Any of claims 1 to 31, which is a type of lymphoma that is a type of cancer ... Either one of the methods.

35. The patient has not been previously treated with anti-PD-1 or anti-PD-L1 therapy or have been confirmed to be progressive when treated with anti-PD-1 or anti-PD-L1 therapy 35. The method of any one of claims 1 to 34.

36. Any one of claims 1 to 35, wherein the patient's tumor tissue section is positive for PD-L1 expression. How to.

37. The patient's tumor tissue sections have a mononuclear inflammation density score of ≥ 2% for PD-L1 expression.

37. The method of any one of claims 1 to 36.

38. The patient's tumor tissue sections had a combined positive score for PD-L1 expression of ≥ 1%.

38. The method of any one of claims 1 to 37.

39. The patient's tumor tissue sections had a combined positive score for PD-L1 expression of ≥ 10%.

38. The method of any one of claims 1 to 37.

40. PD-L1 expression was detected by the PD-L1 IHC 22C3 pharmDx assay. The method of any one of claims 37 to 39, wherein the

41. 200 mg pembrolizumab or pembrolizumab variants, and 200 mg and a pharmaceutically acceptable excipient. .

42. 200 mg pembrolizumab or pembrolizumab variants, and 800 mg and a pharmaceutically acceptable excipient. .

43. The method comprises administering to the patient an anti-LAG3 antibody and an anti-PD-1 antibody. A method for treating gastric cancer, comprising: detecting PD-L1 expression in a tumor tissue section from a gastric tumor of a patient; The method, wherein the result is positive.

44. 44. The method of claim 43, wherein the gastric cancer is adenocarcinoma of the stomach and / or gastroesophageal junction.

45. A method for treating head and neck squamous cell carcinoma comprising administering to a patient an anti-LAG3 antibody and an anti-PD-1 antibody.

23. A method for treating a patient having a head and neck tumor, comprising: The method, wherein PD-L1 expression is positive.

46. A non-microsatelliterature method comprising administering to a patient an anti-LAG3 antibody and an anti-PD-1 antibody. Colorectal cancer with high chromosome instability (non-MSI-H) or mismatch repair proficient (pMMR) A method for treating a patient having a colorectal tumor, comprising: PD-L1 expression positive, % LAG3 positive cells or CPS-like % LAG3 positive cells is ≧1%.

47. The patient has not received prior treatment with an anti-PD-1 antibody or an anti-PD-L1 antibody. The method of any one of claims 43 to 46.

48. The combined positive score (CPS) for PD-L1 expression in tumor tissue sections of patients was 48. The method of any one of claims 43 to 47, wherein the .gamma.-to-.alpha. ratio is ≧1%.

49. The patient's tumor tissue sections had a combined positive score for PD-L1 expression of ≥ 5%. The method of any one of claims 43 to 47.

50. The patient's tumor tissue sections have a combined positive score for PD-L1 expression of ≥ 10%. The method of any one of claims 43 to 47, wherein

51. The patient's tumor tissue sections have a combined positive score for PD-L1 expression of ≥ 20%. The method of any one of claims 43 to 47, wherein

52. Patients were randomly assigned to receive a tumor tissue section with a tumor proportion score (TPS) of ≥ 1% or mononuclear inflammatory density.

48. The method of any one of claims 43 to 47, wherein the MIDS score is ≧2%.

53. PD-L1 expression was detected by the PD-L1 IHC 22C3 pharmDx assay. The method of any one of claims 43 to 52, wherein the

54. 54. The method according to claim 43, wherein the percentage of LAG3 positive cells in a tumor tissue section is ≧1%. Method of section.

55. Any of claims 43 to 53, wherein the CPS-like percentage of LAG3 positive cells in tumor tissue sections is ≧1%. Either one of the methods.

56. The anti-PD-1 antibody or its antigen-binding fragment specifically binds to human PD-1 and inhibits human PD 56. The method of any one of claims 43 to 55, which blocks binding of -L1 to human PD-1. .

57. The anti-PD-1 antibody or antigen-binding fragment thereof may also bind human PD-L2 to human PD-1. The method of claim 56, wherein the binding is blocked.

58. The anti-PD-1 antibody or antigen-binding fragment thereof comprises: (a) a light chain C of SEQ ID NOs: 1, 2, and 3; 58. The method of claim 57, comprising (a) a heavy chain CDR and (b) a heavy chain CDR of SEQ ID NOs: 6, 7 and 8.

59. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:

9. and wherein the light chain comprises a light chain variable region comprising SEQ ID NO:

4.

60. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 10 and the light chain comprises SEQ ID NO:

58. The method of claim 57, including column number 5.

61. 58. The method of claim 57, wherein the anti-PD-1 antibody is pembrolizumab.

62. 58. The method of claim 57, wherein the anti-PD-1 antibody is a pembrolizumab variant.

63. 58. The method of claim 57, wherein the anti-PD-1 antibody is nivolumab.

64. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:

25.

64. Any of claims 43 to 63, wherein the light chain comprises a light chain variable region comprising SEQ ID NO:

24. Method of one term.

65. The anti-LAG3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO:

24. The method of any one of claims 43 to 63, including column number 22.

66. 64. The method of any one of claims 43 to 63, wherein the anti-LAG3 antibody is an Ab6 variant. .

67. The invention relates to a method for treating a patient with an anti-LAG3 antibody, the method comprising administering the anti-LAG3 antibody or an antigen-binding fragment thereof to a patient in need thereof. 43-66. The method of any one of claims 43 to 66.

68. The anti-LAG3 antibody is combined with an anti-PD-1 antibody or an antigen-binding fragment thereof. 43-66. The method of any one of claims 43 to 66.

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