Dosing regimen of Anti-tigit antibody for treatment of cancer

Abstract

To provide dosing regimens of an anti-TIGIT antibody useful for the treatment of cancer, in particular, dosing regimens in a combination therapy which comprises administering an anti-TIGIT antibody and an antibody of a Programmed Death 1 protein (PD-1) or Programmed Death Ligand 1 (PD-L1).SOLUTION: A method for treating cancer in a patient comprises administering, to a patient, 2.1 mg to 700 mg of an anti-TIGIT antibody comprising a heavy chain and a light chain, where the light chain comprises light chain CDRs of specific sequences and the heavy chain comprises heavy chain CDRs of specific sequences.SELECTED DRAWING: Figure 2A

Description

[Technical Field]

[0001] Related Applications This application is a continuation of U.S. Provisional Patent Application No. 62 / 755,805, filed November 5, 2018. No. 6,239,999, filed on Oct. 1, 2003, which is hereby incorporated by reference in its entirety. do.

[0002] FIELD OF THE INVENTION The present invention provides dosing regimens for anti-TIGIT antibodies useful for the treatment of cancer. In particular, the present invention relates to a therapeutic regimen for the treatment of cancer with programmed death 1 protein (PD-1). 1) or antibodies against programmed death-ligand 1 (PD-L1) and anti-TIGIT (I T cell immunoreceptor with g and ITIM domains receptor with Ig and ITIM domains) antibody and a dosing regimen in a combination therapy comprising: [Background technology]

[0003] PD-1 is recognized as an important molecule in immune regulation and the maintenance of peripheral tolerance. PD-1 is expressed at moderate levels on naive T cells, B cells, and NKT cells, and is expressed in lymphocytes. Upregulated by T / B cell receptor signaling on leukocytes, monocytes, and myeloid cells (1)

[0004] 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 ovarian cancer. Large-scale sample centers for cancer, kidney cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma In these patients, PD-L1 expression was associated with poor prognosis and poor overall survival, regardless of subsequent treatment. It has been shown that P on tumor-infiltrating lymphocytes correlates with a decrease in P D-1 expression characterizes dysfunctional T cells in breast cancer and melanoma (14-1 5) and was found to be correlated with poor prognosis in kidney cancer (16). In addition, tumor cells expressing PD-L1 interact with T cells expressing PD-1. attenuating T cell activation to evade immune surveillance, thereby enhancing immunity against tumors It has been proposed to contribute to impaired response.

[0005] PD-1 and one or both of its ligands, PD-L1 and PD-L2 Several monoclonal antibodies that inhibit the interaction between Pembrolizumab has high binding specificity to the programmed cell death 1 (PD1) receptor. It is a potent humanized immunoglobulin G4 (IgG4) mAb with Programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD- L2). Based on preclinical in vitro data, pembrolizumab Ke has high affinity for PD-1 and potent receptor blocking activity. Ytruda® (pembrolizumab) is helping patients across several indications Treatment is indicated.

[0006] TIGIT (T cell immunoreceptor with Ig and ITIM domains) is primarily involved in the activation of TIGIT is an immunoregulatory receptor expressed on activated T cells and NK cells. Also known as VSIG9; VSTM3; and WUCAM. Its structure is The outer immunoglobulin domain, the type I transmembrane region and the two ITIM motifs are shown. The GIT encodes a positive immunoregulatory receptor (CD226) and a negative immunoregulatory receptor (NIR) on T cells. (TIGIT) and its ligands (CD155 and CD112) expressed on APCs It forms part of a costimulatory network consisting of: The presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic terminal domains Similar to PD-1 and CTLA-4, the ITIM domain in the cytoplasmic domain of TIGIT is involved. The domains are tyrosine phosphatases, such as SHP-1 and SHP-2. and subsequent immunoreceptor tyrosine-based activity on T cell receptor (TCR) subunits It is predicted to recruit dephosphorylation of tyrosine residues within the ITAM (Integrated Transitional Amino Acid Motif) Therefore, receptor-ligand CD155 and CD112 (on tumor cells or TAMs) Ligation of TIGIT by S (expressed by TCR) inhibits TCR signaling and T cell activation. This may contribute to tumorigenesis, which is essential for initiating effective antitumor immunity. IGIT-specific antagonist antibodies inhibit CD155- and CD112-induced T cell proliferation. Anti-TIGIT antibodies can inhibit response suppression and enhance anti-tumor immunity. 16 / 028656 and WO2017 / 030823.

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

[0008] [Patent Document 1] WO2016 / 028656 [Patent Document 2] WO2017 / 030823 Summary of the Invention [Means for solving the problem]

[0009] The present invention provides a method for producing a TIGIT antibody 31C6 or a 31C6 barrier antibody containing 2.1 mg to 700 mg of the anti-TIG ... The present invention provides a method for treating cancer in a patient, comprising administering a compound to the patient. In embodiments, the method includes co-administration with an anti-PD-1 or anti-PD-L1 antibody. In one embodiment, the anti-TIGIT antibody and the anti-PD-1 antibody are combined. In a further embodiment, the individual's tumor cells are positive for PD-L1 expression. In this embodiment, the anti-PD-1 antibody inhibits the binding of PD-1 to PD-L1 and PD-L2. The present invention also provides a method for treating TIGIT disease by administering 2.1 mg to 700 mg of the anti-TIGIT antibody 31C. 6 or 31C6 variant, and 200 mg of pembrolizumab or pembrolizumab Pharmaceutical compositions comprising the mab variants are provided.

[0010] In one embodiment of the invention, a patient is administered 2.1 mg to 700 mg of an anti-TI drug containing heavy and light chains. A method for treating cancer in a patient comprising administering a GIT antibody, The light chain comprises the CDRs of SEQ ID NOs: 26, 27 and 28, and the heavy chain comprises the CDRs of SEQ ID NOs: 29, 30 and 31. and 31 heavy chain CDRs.

[0011] In various embodiments of the method, the anti-TIGIT antibody is administered via intravenous infusion. .

[0012] In various embodiments of the method, the patient receives between about 2.1 mg and about 700 mg of anti-TIGI In various embodiments of the method, the patient is administered about 2.1 mg of anti-TIG antibody. In various embodiments of the method, the patient is administered about 7 mg of anti-TIGI antibody. In various embodiments of the method, the patient is administered about 21 mg of anti-TIGI antibody. In various embodiments of the method, the patient is administered about 70 mg of anti-TIGI antibody. In various embodiments of the method, the patient is administered about 200 mg of anti-TIG antibody. In various embodiments of the method, the patient is administered about 210 mg of an anti-TI antibody. In various embodiments of the method, the patient is administered about 700 mg of anti-T GIT antibody. The patient is given IGIT antibodies.

[0013] In various embodiments of the method, the patient is administered 2.1 mg of an anti-TIGIT antibody. In various embodiments of the method, the patient is administered 7 mg of an anti-TIGIT antibody. In various embodiments of the method, the patient is administered 21 mg of an anti-TIGIT antibody. In various embodiments, the patient is administered 70 mg of an anti-TIGIT antibody. In various embodiments, the patient is administered 200 mg of an anti-TIGIT antibody. In various embodiments, the patient is administered 210 mg of an anti-TIGIT antibody. In various embodiments, the patient is administered 700 mg of an anti-TIGIT antibody.

[0014] In various embodiments of the method, the patient receives an anti-TIGIT antibody on day 1, then is administered once every three weeks. For example, the duration of treatment may be several weeks or months.

[0015] In various embodiments of the method, the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain The chain comprises a heavy chain variable region comprising SEQ ID NO: 25. In various embodiments of the method, the anti-TIG The IT antibody comprises a heavy chain and a light chain, wherein the light chain comprises a light chain variable region comprising SEQ ID NO: 24. In various embodiments of the method, the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain The heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25, and the light chain comprises a light chain variable region comprising SEQ ID NO:24. include.

[0016] In various embodiments of the method, the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain The heavy chain comprises SEQ ID NO: 23. In various embodiments of the method, the anti-TIGIT antibody comprises a heavy chain and and a light chain, wherein the light chain comprises SEQ ID NO: 22. In various embodiments of the method, the anti-TIGI The T 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 Includes.

[0017] In various embodiments of the method, the anti-TIGIT antibody is the 31C6 variant.

[0018] In various embodiments of the method, the 31C6 variant comprises a heavy chain and a light chain, The heavy chain has 80%, 85%, 90%, 95% or 99% sequence identity to SEQ ID NO:25 In various embodiments of the method, the 31C6 variant comprises a heavy chain variable region comprising: and a light chain, wherein the light chain is 80%, 85%, 90%, 95% or In various embodiments of the method, the 31C comprises a light chain variable region that comprises 99% sequence identity. 6 variants include heavy and light chains, where the heavy chain is 80%, 85% relative to SEQ ID NO: 25 %, 90%, 95% or 99% sequence identity, and the light chain variable region comprises SEQ ID NO: Light chains containing 80%, 85%, 90%, 95%, or 99% sequence identity to No. 24 are acceptable. Includes variable regions.

[0019] In various embodiments of the method, the 31C6 variant comprises a heavy chain and a light chain, The heavy chain has 80%, 85%, 90%, 95% or 99% sequence identity to SEQ ID NO:23 In various embodiments of the method, the 31C6 variant comprises a heavy chain and a light chain, The light chain has 80%, 85%, 90%, 95% or 99% sequence identity to SEQ ID NO: 22 In various embodiments of the method, the 31C6 variant comprises a heavy chain and a light chain, wherein the heavy chain has a sequence 80%, 85%, 90%, 95% or 99% of SEQ ID NO: 23 and the light chain has 80%, 85%, 90%, 95% or 99% identity to SEQ ID NO: 22. % sequence identity.

[0020] In various embodiments of the method, the anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD -L1 antibody or antigen-binding fragment thereof.

[0021] In various embodiments of the method, the anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD It is formulated in combination with the -L1 antibody or an antigen-binding fragment thereof.

[0022] In various embodiments of the method, the anti-PD-1 antibody or antigen-binding fragment thereof is human PD-1. It specifically binds to human PD-L1 and blocks the binding of human PD-1 to human PD-L1.

[0023] In various embodiments of the method, the anti-PD-1 antibody or antigen-binding fragment thereof also It blocks the binding of human PD-L2 to human PD-1.

[0024] In various embodiments of the method, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (a) (b) light chain CDRs of SEQ ID NOs: 1, 2 and 3 and (b) heavy chain CDRs of SEQ ID NOs: 6, 7 and 8 In various embodiments of the method, the anti-PD-1 antibody comprises (a) SEQ ID NO: 1, 2, and and 3 and (b) the heavy chain CDRs of SEQ ID NOs: 6, 7, and 8. It is a variant.

[0025] In various embodiments of the method, 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.

[0026] In various embodiments of the method, the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain The main chain comprises SEQ ID NO: 10 and the light chain comprises SEQ ID NO: 5. For example, the anti-PD-1 antibody may be In various embodiments of the method, the anti-PD-1 antibody is pembrolizumab. In various embodiments of the method, the anti-PD-1 antibody is nivolumab. In various embodiments of the method, the anti-PD-L1 antibody is atezolizumab, durval Mab or avelumab.

[0027] In various embodiments of the method, the anti-PD-1 antibody is administered at 200 mg on day 1, followed by 200 mg on day 2. and once every three weeks thereafter via intravenous infusion. The anti-PD-1 antibody is administered intravenously at 400 mg on day 1, then once every 6 weeks thereafter. It is administered via the inlet.

[0028] In various embodiments of the method, the anti-PD-1 antibody is a humanized anti-PD-1 antibody comprising a heavy chain and a light chain. -1 antibody, wherein the heavy chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs: 6, 7, and 8. and the light chain comprises a light chain variable region comprising the light chain CDRs of SEQ ID NOs: 1, 2, and 3; and the anti-TIGIT antibody is a humanized anti-TIGIT 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 NOs: 29, 30 and 31, and the light chain comprises a It contains a light chain variable region comprising the light chain CDRs of columns 26, 27 and 28.

[0029] In various embodiments of the method, 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-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain comprising SEQ ID NO: 25. The light chain comprises a light chain variable region comprising SEQ ID NO:24.

[0030] In various embodiments of the method, the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain the heavy chain comprises SEQ ID NO: 10 and the light chain comprises SEQ ID NO: 5; and the anti-TIGIT antibody and a light chain, wherein the heavy chain comprises SEQ ID NO: 23 and the light chain comprises a light chain variable region comprising SEQ ID NO: 22. Includes the area.

[0031] In various embodiments of the method, the anti-PD-1 antibody is administered at 200 mg on day 1, followed by 200 mg on day 2. The anti-TIGIT antibody was administered via intravenous infusion at 200 mg once every three weeks. It is administered via intravenous infusion on day 1, and then once every three weeks thereafter.

[0032] In various embodiments of the method, the anti-PD-1 antibody is administered at 400 mg on day 1, followed by 400 mg on day 2. The anti-TIGIT antibody was administered via intravenous infusion at 200 mg for 3 weeks. It is administered via intravenous infusion on day 1, once weekly.

[0033] In various embodiments of the method, the anti-PD-1 antibody is administered at 200 mg on day 1, followed by 200 mg on day 2. The anti-TIGIT antibody was administered via intravenous infusion at 700 mg once every three weeks. It is administered via intravenous infusion on day 1, and then once every three weeks thereafter.

[0034] In various embodiments of the method, the anti-PD-1 antibody is administered at 400 mg on day 1, followed by 400 mg on day 2. The anti-TIGIT antibody was administered via intravenous infusion at 700 mg for 3 weeks. It is administered via intravenous infusion on day 1, once weekly.

[0035] In various embodiments of the method, 200 mg of anti-PD-1 antibody is administered in a dose of 2.1 mg to 70 mg of the antibody. For example, 200 mg of anti-PD-1 antibody is combined with 200 mg of anti-TIGIT antibody. It is combined with 00mg of anti-TIGIT antibody.

[0036] In various embodiments of the method, 200 mg of an anti-PD-1 antibody is administered to a subject in need thereof, as described in the Examples. In various embodiments of the method, 200 mg of an anti-TIGIT antibody is combined with The PD-1 antibody is combined with 7 mg of the anti-TIGIT antibody. In this case, 200 mg of anti-PD-1 antibody is combined with 21 mg of anti-TIGIT antibody. In various embodiments of the method, 200 mg of anti-PD-1 antibody is In various embodiments of the method, 200 mg of the anti-PD-1 antibody is combined with In various embodiments of the method, 200 mg of the anti-TIGIT antibody is combined with 210 mg of the anti-TIGIT antibody. mg of anti-PD-1 antibody is combined with 200 mg of anti-TIGIT antibody. In an embodiment, 200 mg of anti-PD-1 antibody is combined with 700 mg of anti-TIGIT antibody. It is formulated into a drug.

[0037] In various embodiments of the method, the cancer is a cancer that ... In various embodiments of the method, the cancer is selected from the cancers disclosed in C, colorectal cancer, cervical cancer, gastric cancer, breast cancer, ovarian cancer, epithelial cancer, fallopian tube cancer or primary and peritoneal cancer. For example, the cancer is NSCLC. In various embodiments, the subject or patient has cancer and has at least one breast cancer genetic disorder. In various embodiments, the cancer or sample from the subject expresses a gene (e.g., BRCA). The test requires the presence of some level of at least one breast cancer gene (BRCA) or at least These cells are found to express at least one breast cancer gene (BRCA). In the method, at least one BRCA gene is BRCA1 or BRCA2. In some embodiments, the cancer is BRCA-negative. In one embodiment, the cancer is a BRCA-positive cancer. It is sex.

[0038] In various embodiments, the method comprises (i) carboplatin and pemetrexed (5- substituted pyrrolo[2,3-d]pyrimidine) or (ii) carboplatin and paclitaxel further comprising administering a combination of cells.

[0039] In various embodiments of the method, the individual has previously received anti-PD-1 or anti-PD-L1 therapy. Not previously treated with anti-PD-1 or anti-PD-L1 therapy It has been confirmed to be progressive.

[0040] One embodiment of the invention is a 200 mg dose of pembrolizumab or pembrolizumab varian. anti-TIGIT 31C6 antibody or antigen-binding fragment or 31C6 variant, and and a pharmaceutically acceptable excipient. The pharmaceutical composition comprises about 2.1 mg to about 700 mg of 31C6 antibody or antigen-binding fragment or In various embodiments, the 31C6 antibody is administered in an amount of 2.1 mg to 700mg of anti-TIGIT antibody 31C6 antibody or antigen-binding fragment or 31C6 barrier Includes ent.

[0041] In various embodiments, the pharmaceutical composition comprises 2.1 mg of an anti-TIGIT antibody. In one embodiment, the pharmaceutical composition contains 7 mg of anti-TIGIT 31C6 antibody or antigen binding agent. In various embodiments, the pharmaceutical composition comprises a synthetic fragment or a 31C6 variant. 1 mg of anti-TIGIT 31C6 antibody or antigen-binding fragment or 31C6 variant In various embodiments, the pharmaceutical composition comprises 70 mg of anti-TIGIT 31C6 antibody. or an antigen-binding fragment or a 31C6 variant. The composition comprises 200 mg of anti-TIGIT 31C6 antibody or antigen-binding fragment or 31C In various embodiments of the method, the pharmaceutical composition comprises 210 mg of anti-T The method includes administering to a subject an IGIT 31C6 antibody or antigen-binding fragment or 31C6 variant. In various embodiments, the pharmaceutical composition comprises 700 mg of anti-TIGIT 31C6 antibody or comprises an antigen-binding fragment or 31C6 variant.

[0042] One embodiment of the invention is a 200 mg dose of pembrolizumab or pembrolizumab varian. 200 mg of 31C6 antibody or 31C6 variant, and pharmaceutically acceptable additives A pharmaceutical composition comprising an additive is provided.

[0043] In various embodiments of the method, the 31C6 antibody comprises a heavy chain and a light chain, wherein the heavy chain is In various embodiments, the 31C6 antibody comprises a heavy chain variable region comprising SEQ ID NO: 25. and a light chain, wherein the light chain comprises a light chain variable region comprising SEQ ID NO: 24. wherein the 31C6 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable fragment comprising SEQ ID NO: 25. The light chain comprises a light chain variable region comprising SEQ ID NO:24.

[0044] In various embodiments, the 31C6 antibody comprises a heavy chain and a light chain, wherein the heavy chain is In various embodiments, the 31C6 antibody comprises a heavy chain and a light chain, wherein the light chain is In various embodiments, the anti-TIGIT 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.

[0045] In various embodiments, the 31C6 antibody is a 31C6 variant.

[0046] In various embodiments, the 31C6 variant comprises a heavy chain and a light chain, wherein the heavy chain is Contains 80%, 85%, 90%, 95% or 99% sequence identity to SEQ ID NO: 25 In various embodiments, the 31C6 variant comprises a heavy chain and a light chain variable region. wherein the light chain comprises 80%, 85%, 90%, 95% or 99% of SEQ ID NO:24. In various embodiments, the 31C6 variant comprises a light chain variable region comprising sequence identity to comprises a heavy chain and a light chain, wherein the heavy chain is 80%, 85%, 90%, The heavy chain variable region contains 95% or 99% sequence identity to SEQ ID NO: 24. and a light chain variable region that contains 80%, 85%, 90%, 95%, or 99% sequence identity with the .

[0047] In various embodiments, the 31C6 variant comprises a heavy chain and a light chain, wherein the heavy chain is Contains 80%, 85%, 90%, 95% or 99% sequence identity to SEQ ID NO: 23 In various embodiments, the 31C6 variant comprises a heavy chain and a light chain, wherein the light chain is Contains 80%, 85%, 90%, 95% or 99% sequence identity to No. 22. In one embodiment, the 31C6 variant comprises a heavy chain and a light chain, wherein the heavy chain is 80%, 85%, 90%, 95% or 99% sequence identity to No. 23, and contains 80%, 85%, 90%, 95% or 99% sequence identity to SEQ ID NO:22 nothing.

[0048] In various embodiments, the anti-TIGIT antibody is pembrolizumab or pembrolizumab. Formulated to be co-administered with a mab variant.

[0049] In various embodiments, the anti-TIGIT antibody is pembrolizumab or pembrolizumab. It will be combined with Mab Variant.

[0050] In various embodiments, pembrolizumab or a pembrolizumab variant thereof (a) the light chain CDRs of SEQ ID NOs: 1, 2 and 3 and (b) the light chain CDRs of SEQ ID NOs: 6, 7 and 8 In various embodiments, the anti-PD-1 antibody comprises the heavy chain CDRs of: (a) SEQ ID NOs: 1, 2 and 3 and (b) the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8. There are 6 variants.

[0051] In various embodiments, pembrolizumab or a pembrolizumab variant 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 SEQ ID NO: The light chain variable region contains 4.

[0052] In various embodiments, pembrolizumab or a pembrolizumab variant 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: 5. For example, In various embodiments, the anti-PD-1 antibody is pembrolizumab. In various embodiments, the anti-PD-1 antibody is a pembrolizumab variant. , and nivolumab.

[0053] In various embodiments, pembrolizumab or a pembrolizumab variant is administered intravenously. It is formulated for intravenous infusion.

[0054] In various embodiments, pembrolizumab or a pembrolizumab variant comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs: 6, 7, and 8. and the light chain comprises a light chain variable region comprising the light chain CDRs of SEQ ID NOs: 1, 2, and 3; and 31C6 antibody is a humanized anti-TIGIT antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs: 29, 30 and 31, and a light chain variable region comprising the heavy chain CDRs of SEQ ID NOs: 29, 30 and 31. The light chain variable region comprises light chain CDRs 26, 27 and 28.

[0055] In various embodiments, pembrolizumab or a pembrolizumab variant 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 SEQ ID NO: 4; and the 31C6 antibody comprises a heavy chain and a light chain, wherein the heavy chain The heavy chain comprises a heavy chain variable region comprising SEQ ID NO: 25, and the light chain comprises a light chain variable region comprising SEQ ID NO: 24. include.

[0056] In various embodiments, pembrolizumab or a pembrolizumab variant 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: 5; and The anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 23 and the light chain comprises The light chain variable region comprises SEQ ID NO: 22. One embodiment of the present invention comprises 200 mg of Pembrolizumab. izumab or pembrolizumab variants, 2.1 to 700 mg of 31C6 antibody or A pharmaceutical composition is provided that includes a 31C6 variant and a pharmaceutically acceptable excipient.

[0057] One embodiment of the invention is a 400 mg dose of pembrolizumab or pembrolizumab varian. 2.1 to 700 mg of 31C6 antibody or 31C6 variant, and a pharmaceutically acceptable carrier. The present invention provides a pharmaceutical composition comprising an acceptable excipient.

[0058] In various embodiments, the pharmaceutical composition comprises 2.1 mg of 31C6 antibody or 31C6 antibody. In various embodiments, the pharmaceutical composition comprises 7 mg of 31C6 antibody or In various embodiments, the pharmaceutical composition comprises 21 mg of 31C6 variant. In various embodiments, the pharmaceutical composition comprises a 70 antibody or a 31C6 variant. In various embodiments, the pharmaceutical composition comprises 1 mg of the 31C6 antibody or 31C6 variant. The composition contains 200 mg of 31C6 antibody or 31C6 variant. In the present invention, the pharmaceutical composition contains 210 mg of the 31C6 antibody or 31C6 variant. In various embodiments, the pharmaceutical composition contains 700 mg of 31C6 antibody or 31C6 barrier. Includes ent.

[0059] In various embodiments of the pharmaceutical composition, the 31C6 antibody or 31C6 variant comprises a heavy chain and a light chain, wherein the light chain comprises the light chain CDRs of SEQ ID NOs: 26, 27 and 28, and a heavy chain. The chains comprise the heavy chain CDRs of SEQ ID NOs: 29, 30 and 31.

[0060] In various embodiments of the pharmaceutical composition, the 31C6 antibody comprises a heavy chain and a light chain, The heavy chain comprises a heavy chain variable region comprising SEQ ID NO: 25, and the light chain comprises a light chain variable region comprising SEQ ID NO: 24. Includes.

[0061] In various embodiments of the pharmaceutical composition, the 31C6 antibody comprises a heavy chain and a light chain, The heavy chain comprises a light chain variable region comprising SEQ ID NO:23 and the light chain comprises a light chain variable region comprising SEQ ID NO:22.

[0062] Certain aspects of the present invention include a method for treating cancer comprising any of the pharmaceutical compositions described herein. In various embodiments, the composition includes a kit for placing the composition in a patient's body. It also includes books. [Brief explanation of the drawings]

[0063] [Figure 1] Plot generated from pooled pharmacokinetic data of 31C6 anti-TIGIT antibody from both the monotherapy and combination therapy arms. Arithmetic mean concentrations were plotted using nominal sampling times. [Figure 2A] Each shows a waterfall plot of subjects using the best percentage change from baseline in target lesions based on investigator assessment per RECIST v1.1 (assessed in patients with measurable disease at baseline and an evaluable post-baseline imaging assessment of ≥1 (n=25 for 31C6 monotherapy, n=41 for 31C6 combination with pembrolizumab)). Each bar represents an individual subject. Data for the combination treatment include 32 patients originally assigned to the combination and 9 patients who crossed over from monotherapy. For 31C6 monotherapy, 25% showed any decrease, and 4% showed a decrease of ≥-30%. For the 31C6 and pembrolizumab combination treatment, 32% showed any decrease, and 24% showed a decrease of ≥-30%. [Figure 2B]Each shows a waterfall plot of subjects using the best percentage change from baseline in target lesions based on investigator assessment per RECIST v1.1 (assessed in patients with measurable disease at baseline and an evaluable post-baseline imaging assessment of ≥1 (n=25 for 31C6 monotherapy, n=41 for 31C6 combination with pembrolizumab)). Each bar represents an individual subject. Data for the combination treatment include 32 patients originally assigned to the combination and 9 patients who crossed over from monotherapy. For 31C6 monotherapy, 25% showed any decrease, and 4% showed a decrease of ≥-30%. For the 31C6 and pembrolizumab combination treatment, 32% showed any decrease, and 24% showed a decrease of ≥-30%. [Figure 3A] Subject plots are shown, each showing treatment duration and response based on investigator assessment per RECIST v1.1. Line length represents time to last dose of study treatment. Time to best response and subsequent PD or death, whichever occurred first, is shown for each patient. Only patients with ≥1 post-baseline imaging assessment are included. * denotes patients who crossed over from monotherapy to combination therapy. The combination therapy includes 32 patients originally assigned to the combination and 9 patients who crossed over from 31C6 monotherapy. [Figure 3B] Subject plots are shown, each showing treatment duration and response based on investigator assessment per RECIST v1.1. Line length represents time to last dose of study treatment. Time to best response and subsequent PD or death, whichever occurred first, is shown for each patient. Only patients with ≥1 post-baseline imaging assessment are included. * denotes patients who crossed over from monotherapy to combination therapy. The combination therapy includes 32 patients originally assigned to the combination and 9 patients who crossed over from 31C6 monotherapy. [Figure 4]1 shows plots of PD-1 naive NSCLC patients showing treatment duration and response based on investigator assessment per RECIST v1.1. [Figure 5A] 5A and 5B show plots of patients with PD-1 refractory NSCLC showing treatment duration and response based on investigator assessment according to RECIST v1.1. Patients received either 200 mg of 31C6 antibody monotherapy (FIG. 5A) or combination therapy of 200 mg of 31C6 antibody and 200 mg of pembrolizumab (FIG. 5B), as described in Example 2. [Figure 5B] 5A and 5B show plots of patients with PD-1 refractory NSCLC showing treatment duration and response based on investigator assessment according to RECIST v1.1. Patients received either 200 mg of 31C6 antibody monotherapy (FIG. 5A) or combination therapy of 200 mg of 31C6 antibody and 200 mg of pembrolizumab (FIG. 5B), as described in Example 2. [Figure 6] 1 shows plots of refractory ovarian patients showing treatment duration and response based on investigator assessment according to RECIST v1.1. The data summarizes the results for the treatments described in Part A (31C6 monotherapy) and Part B (31C6 in combination with pembrolizumab) of Example 1. [Figure 7] 1 shows plots of PD-1 naive breast cancer patients showing treatment duration and response based on investigator assessment according to RECIST v1.1. Patients were treated with 200 mg of 31C6 and pembrolizumab (200 mg) combination therapy, as described in Example 2. [Figure 8] 1 shows plots of PD-1 naive CRC breast cancer patients showing treatment duration and response based on investigator assessment according to RECIST v1.1. Patients were treated with 200 mg of 31C6 and pembrolizumab (200 mg) combination therapy, as described in Example 2. [Figure 9A]9A and 9B show plots of cervical patients showing treatment duration and response based on investigator assessment according to RECIST v1.1. Patients received either 200 mg (FIG. 9A) or 700 mg (FIG. 9B) of the 31C6 antibody and 200 mg of pembrolizumab combination treatment, as described in Example 2. [Figure 9B] 9A and 9B show plots of cervical patients showing treatment duration and response based on investigator assessment according to RECIST v1.1. Patients received either 200 mg (FIG. 9A) or 700 mg (FIG. 9B) of the 31C6 antibody and 200 mg of pembrolizumab combination treatment, as described in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0064] Abbreviations The following abbreviations are used throughout the detailed description and examples: ADA anti-drug antibodies AE Adverse Event ALT alanine aminotransferase ANC absolute neutrophil count aPTT Activated partial thromboplastin time All subjects treated with ASaT ASCO American Society of Clinical Oncology Clinical Oncology AST aspartate aminotransferase Area under the AUC curve BCG Bacillus Calmette-Guerin β-hCG β-human chorionic gonadotropin BOR Best Overall Effect BID twice daily dosing CBR clinical usefulness rate CDR Complementarity Determining Region CHO Chinese hamster ovary Cmax maximum concentration Cmin minimum concentration CNS central nervous system CR complete response CRF Case Report Form CSF colony-stimulating factors CSR Clinical Trial Report CT Computed Tomography CTCAE Common Terminology Criteria for Adverse Events CTLA-4 Cytotoxic T lymphocyte-associated antigen 4 D. De-escalation to the next lower dose DCR disease control rate DFS disease-free survival DILI (Drug-Induced Liver Injury) DLT dose-limiting toxicity DNA deoxyribonucleic acid DOR duration of response DSDR Sustained stable disease rate DU Unacceptable Toxic Dose ECG electrocardiogram ECI Notable adverse event(s) ECOG Eastern Cooperative Oncology Group rative Oncology Group) eCRF Electronic Case Report Form EMA European Medicines Agency FAS Maximum Analysis Set ELISA Enzyme-linked immunoassay FBR Future biomedical research research) FFPE formalin-fixed paraffin-embedded FR Framework Area FSH follicle-stimulating hormone G3 CTCAE (Category 3 of Adverse Events) GCP Good Clinical Practice ce) GFR glomerular filtration rate GGT gamma-glutamyltransferase HBsAg Hepatitis B surface antigen HCV Hepatitis C virus HIV human immunodeficiency virus HRT Hormone Replacement Therapy IB Study Drug Brochure ICF Informed Consent Form ICH International Conference on Harmonization iCPD iRECIST-confirmed disease progression IEC Independent Ethics Committee Ig immunoglobulin IgG immunoglobulin G IHC immunohistochemistry or immunohistochemistry IL Interleukin IM intramuscular INR International Normalized Ratio IO immuno-oncology agents irAE immune-related adverse events IRB Institutional Review Board iRECIST: Modified RECIST 1.1 for the evaluation of immunological therapies irRC Immune-Related Response Criteria iSD iRECIST stable disease iUPD iRECIST-unconfirmed disease progression IV (intravenous) IVRS Interactive Voice Response System IWRS Integrated Web Response System LDH lactate dehydrogenase LFT Liver function test mAb Monoclonal antibody MASCC Multinational Association for Supportive Care in Cancer l Association of Supportive Care in Canc. er) MRI Magnetic Resonance Imaging mRNA messenger ribonucleic acid MSD Merck Sharp & Dohme & Dohme Corp., Merck & Co. o., Inc.) MSI microsatellite instability MTD maximum capacity mTPI modified toxicity probability interval NCBI National Center for Biotechnology Information NCI: National Cancer Institute NK Natural Killer NOAEL No Adverse Effect Level NSAIDs (nonsteroidal anti-inflammatory drugs) NSCLC non-small cell lung cancer ORR Objective Response Rate OS overall survival OTC drugs PBMC peripheral blood mononuclear cells PD Progressive disease 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 PK Pharmacokinetics(s) PNA pneumonia PP protocol compliant PR partial response PT Prothrombin Time PTT Partial Thromboplastin Time Q2W: Once every two weeks Q3W: Once every 3 weeks QD once daily dosing RECIST Response Evaluation Criteria in Solid Tumors ation Criteria in Solid Tumors) RECIST 1.1 Response Evaluation Criteria in Solid Tumors Version 1.1 RNA ribonucleic acid RP2D Phase 2 recommended dose SAE serious adverse event SAP Statistical Analysis Plan SD stable disease SGOT serum glutamic oxaloacetic transaminase SGPT serum glutamic pyruvic transaminase SNP Single nucleotide polymorphism SoA Activity Schedule sSAP Supplemental Statistical Analysis Plan TCR T cell receptor TIGIT: A T cell immunoreceptor containing Ig and ITIM domains TNBC triple-negative breast cancer TNF tumor necrosis factor TSH thyroid-stimulating hormone ULN (Upper limit of normal) VH immunoglobulin heavy chain variable region VK immunoglobulin kappa light chain variable region WOCBP Women of childbearing potential 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 meaning of the present invention and are understood to be within the meaning of the present invention. It has a meaning that is generally understood.

[0065] As used in this specification, including the appended claims, the singular forms of words, e.g. "a," ​​"an," and "the," etc., unless the context clearly indicates otherwise. It encompasses the reference of their corresponding plural forms.

[0066] As used herein, a "31C6 variant" refers to a variant containing a nucleotide sequence at a position outside the light chain CDR. having three, two, or one conservative amino acid substitutions and six outside the heavy chain CDRs; 31C6( and in WO2016 / 028656, which is incorporated herein by reference. a monoclonal antibody comprising heavy and light chain sequences substantially identical to those in It refers to a clonal antibody, for example, where the mutation position is in the FR region or constant region. , the heavy chain C-terminal lysine residue may be deleted. In other words, 31C6 and 31C6 The variants contain identical CDR sequences but differ in their full-length light and heavy chain sequences. have conservative amino acid substitutions at no more than three or six other positions, respectively, and are therefore The 31C6 variant has the following properties: binding affinity to human TIGIT and The ability of human TIGIT to block binding to human CD155 and human CD112 and is essentially the same as 31C6.

[0067] "Administered" means that the When applied, the foreign substance is introduced into the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells refers to the contact of a drug, therapeutic agent, diagnostic agent, or composition with a target substance. Contact also includes contacting a fluid with a reagent when the fluid is in contact with a cell. A "subject" is any organism, preferably an animal, more preferably a mammal (e.g., a rat, mouse, dog, cat, rabbit) and most preferably human.

[0068] 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: , but are not limited to, monoclonal antibodies (including full-length monoclonal antibodies) 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 antibodies are obtained by exposing the immune system to an antigen prior to, for example, humanizing an antibody.

[0069] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer contains two identical polypeptides. It contains pairs of polypeptide chains, 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 contains 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. 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, each representing an antibody isotype. IgM, IgD, IgG, IgA, and IgE are defined. Within the light and heavy chains, the variable regions The heavy chain and constant region are 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 En Press, NY (1989).

[0070] 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 also has two binding sites. The two binding sites are generally identical, except for

[0071] 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 FRs. The CDRs are usually aligned with framework regions and enable binding to a specific epitope. Generally, from N- to C-terminus, the variable domains of both the light and heavy chains comprise: 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 78-883.

[0072] As used herein, unless otherwise indicated, the term "antibody fragment" or "antigen-binding "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., a fragment 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 formed from antibody fragments; and multispecific antibodies. can be done.

[0073] 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 signal the presence of a target protein in a sample, e.g., resulting in unwanted consequences. , without generating false positives, etc., is considered "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 for the protein; More preferably at least 20 times stronger, and most preferably at least 100 times stronger. As used herein, a given The amino acid sequence of, for example, the amino acid sequence of a mature human PD-1 or human PD-L1 molecule An antibody is characterized as a nucleotide sequence that binds to a polypeptide containing the nucleotide sequence but does not bind to a protein lacking that sequence. It is said to specifically bind to a polypeptide containing that sequence.

[0074] As used herein, "carboplatin" refers to a compound having a broad spectrum of anti-cancer activity. This refers to second generation platinum compounds. See US Pat. Nos. 888 and 6,770,653. Carboplatin is a It contains a platinum atom coordinated with a monia group and a cyclobutane-dicarboxyl residue. The agent is activated intracellularly and binds to nucleophilic groups, such as GC-rich sites in DNA. By forming reactive platinum complexes, intrastrand and interstrand DNA crosslinks as well as DNA-tagged crosslinks can be achieved. These carboplatin-induced cross-links to DNA and proteins The effects result in apoptosis and cell growth inhibition. It has similar tumoricidal activity to suplatin, but is more stable and less toxic. The analogs may also be administered for the treatment of cancer. Please refer to issue no.

[0075] A "chimeric antibody" is an antibody in which some portion of the heavy and / or light chains are derived from a particular species (e.g., human). or corresponding sequences in antibodies belonging to a particular antibody class or subclass. The sequence is identical or homologous to the sequence, but the remainder of the sequence(s) is derived from another species (e.g., mouse). The antibody may be identical or non-identical to a corresponding sequence in the antibody or in an antibody belonging to another antibody class or subclass. The term "antibody" refers to antibodies that are homologous to or identical to the antibody, as long as they exhibit the desired biological activity. It also refers to a fragment of an antibody.

[0076] The agents herein, such as PD-1 antagonists or TIGIT antagonists, "Co-administration" as used herein means administering agents such that their therapeutic activity overlaps; It does not necessarily mean that the agents are administered simultaneously to the subject. In some embodiments, the agents may be administered simultaneously or in combination. For example, an anti-PD-1 antibody and a PD-1 antibody contained in separate vials are administered to a subject at approximately the same time. and the anti-TIGIT antibody formulation, when in solution, may be administered in the same intravenous infusion bag or injection device. They can be mixed together and administered to the patient at the same time.

[0077] As used herein, "co-formulated" or "combined" "Co-formulation" or "coformulation" Or "coformulated" means that the drugs are formulated and stored separately. and then 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.

[0078] Pharmacokinetic "steady state" is the state where some accumulation of drug concentration is maximized by multiple doses. the period during which systemic drug exposure is considered constant after administration of each subsequent dose; In the specific case of mbrolizumab, steady state is achieved after approximately 16 weeks of dosing.

[0079] AUCss, Cavg,ss and Cmin,ss are the values ​​of the drug (e.g., pembrolizumab) (b) A pharmacokinetic measure of the systemic exposure to a drug in humans after administration, typically AUCss and Cavg,ss are considered to be 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 the dosing interval, just before the next dose is administered Represents drug concentration.

[0080] "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, Cmax,ss is typically considered a safety driver. It is a metric that can be used.

[0081] 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 a mouse carbohydrate chain. These refer to antibodies that contain only mouse or rat immunoglobulin sequences, respectively.

[0082] A "humanized antibody" refers to a compound that is derived from a non-human (e.g., murine) antibody, as well as a compound derived from a human antibody. Such antibodies are the most widely used antibodies derived from non-human immunoglobulins. Generally, humanized antibodies contain at least one, and typically two, possible sequences. containing 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 Humanized antibodies also contain immunoglobulin constant regions (Fc ), typically may contain at least a portion of a human immunoglobulin. "hu" or "h" is used when necessary to distinguish a humanized antibody from its parent rodent antibody. The humanized form of a rodent antibody is generally identical to the parent rodent antibody. Improved stability of humanized antibodies containing the same CDR sequences but with improved affinity Certain amino acid substitutions may be included to enhance the overall activity of the protein, or for other reasons.

[0083] Cancer patients treated with a therapeutic regimen, such as the combination therapy described herein. "Anti-tumor response" when referring to a patient is defined as at least one positive therapeutic effect, e.g., cancer Reduction in cell count, tumor size, and rate of cancer cell invasion into peripheral organs, as well as tumor metastasis or a reduction in tumor growth rate or progression-free survival. Therapeutic efficacy can be measured in a variety of ways (W.A. Weber, J. Null, M. ed. 50:1S-10S(2009); see Eisenhauer et al. In some embodiments, the combination therapy described herein Antitumor response to IRRC was assessed by RECIST 1.1 criteria, 2D IRRC, or 1D IRRC. In some embodiments, the anti-tumor response is evaluated using SD, PR, CR, P It is either FS or DFS.

[0084] "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 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 by

[0085] "Biotherapeutic agents" refer to agents that support tumor maintenance and / or growth or induce an anti-tumor immune response. Inhibits biological pathways by blocking ligand / receptor signaling Biotherapeutic agents are classified as: including, but 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.

[0086] "CBR" or "clinical benefit rate" means CR+PR+sustained SD.

[0087] 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.

[0088] 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), antiprogesterones, estrogen receptor downregulators estrogen receptor antagonist (ERD), luteinizing hormone (leutinizing hormone Releasing hormone (RNH) agonist, antiandrogen, aromatase enzyme inhibitors, EGFR inhibitors, VEGF inhibitors, and drugs related to abnormal cell proliferation or tumor growth The present invention also provides antisense oligonucleotides that inhibit the expression of genes involved in the treatment of cancer. Chemotherapeutic agents useful in the methods include cytostatic and / or cytotoxic agents. It can be obtained.

[0089] “Chothia” is Al-Lazikani et al., JMB 273:9 27-948 (1997) refers to the antibody numbering system described in

[0090] "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 not intended to identify the presence of a stated feature but to provide any function or utility of any of the embodiments of the present invention. This does not preclude the presence or addition of further features that may enhance the quality.

[0091] "Conservatively modified variants" or "conservative substitutions" refer to those that do not alter the biological activity or without altering other desirable properties, such as antigen affinity and / or specificity. The amino acids in proteins have similar properties ( Other amino acids with different properties (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone structure and rigidity) Those skilled in the art will generally understand the substitution of a single amino acid in a non-essential region of a polypeptide. It is recognized 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 (See the 1999 IEEE International Conference on Amino Acid Synthesis and Biological Chemistry (ICH 2001) Ed.). 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.

[0092] Table 1. Exemplary conservative amino acid substitutions [Table 1]

[0093] "consists essentially of" and tion, e.g., "consist essentially of" "consisting essentially of" or "consisting essentially of" "y of") and the like, as used throughout this specification and claims, The inclusion of any enumerated element or group of elements and the inclusion of elements similar or identical to the enumerated elements The specific drug dosage regimen, method, or composition may differ. Indicates that the invention may include other elements that do not materially change the basic or novel characteristics of the product. Non-limiting examples include PD-1 antigens consisting essentially of the amino acid sequences listed. The antagonist may also contain one or more amino acids that do not substantially affect the properties of the binding compound. This may involve the substitution of one or more amino acid residues.

[0094] "DCR" or "Disease Control Rate" means CR+PR+SD.

[0095] "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.

[0096] 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 LVILGAILLCLGVALTFIFR LRKGRMMDVKKCGIQDTNS KKQSDTHLEET (SEQ ID NO: 32).

[0097] Immunoassay 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 mAb include the 20C3 antibody and the 22C3 antibody, which are described in WO2014 / 100079. Table 2 below provides the properties of antibody 22C3. FFPE Another anti-human antibody reported to be useful for IHC detection of PD-L1 expression in tissue sections PD-L1 mAb (Chen, BJ et al., Clin Cancer R es 19:3462-3473(2013)) is Sino Biological, It is a publicly available rabbit anti-human PD-L1 mAb from Inc. (People's Republic of China). , Beijing; Catalog No. 10084-R015).

[0098] Table 2. Characteristics of monoclonal antibody MEB037.22C3 (22C3) [Table 2]

[0099] As used herein, the expression of "PD-L1" or "PD-L2" refers to the expression of PD-L1 or PD-L2 on the cell surface. A specified PD-L protein or a specified PD-L mRNA in a cell or tissue PD-L protein expression is a diagnostic test for PD-L. PD-L antibodies can be used to detect PD-L in IHC assays on tumor tissue sections or by flow cytometry. This can be detected by chemometry.

[0100] Alternatively, PD-L protein expression by tumor cells was correlated with PET imaging. thereby specifically binding to a desired PD-L target, e.g., PD-L1 or PD-L2. PD-L mRNA can be detected using binding agents (e.g., antibody fragments, affibodies, etc.). Techniques for detecting and measuring NA expression include RT-PCR, real-time quantitative PCR, RT-PCR, RNAseq, and Nanostring platforms (J.Clin.Invest. 2017;127(8):2930-2940).

[0101] 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) 15 hematoxylin-eosin stains used by pathologists are described. See US20170285037.

[0102] 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, defined as the percentage of tumor cells expressing PD-L1. PD-L1 expression was counted as positive if expression was present in at least 1% of all tumor cells will be done.

[0103] In another approach, PD-L1 expression in tumor tissue sections was compared with that in tumor cells, as well as It is quantified in infiltrating immune cells, primarily 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. It is reported as a semiquantitative measurement called (AIS), which is the percentage of membrane-stained cells. The score was determined by multiplying the infiltrate intensity by the number of lymphocytes, with a score of 0 being absent, 1 being mild (score 1, lymphocytes only) and 1 being severe (score 2). almost none), moderate (score 2, focal infiltration of the tumor by lymphohistiocytic aggregates) or Tumor tissue sections are graded as severe (score 3, diffuse infiltration) if the AIS is ≥ 5. If present, the patient is counted as PD-L1 positive due to immune infiltrate.

[0104] PD-L1 mRNA expression levels are often measured using quantitative RT-PCR. The mRNA expression levels of one or more reference genes can be compared to those of the corresponding genes.

[0105] In some embodiments, by malignant cells and / or infiltrating immune cells within the tumor. PD-L1 expression levels (protein and / or mRNA) were assessed by P<0.05 using appropriate controls. "Excess" 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 can be quantified. PD-L1 protein (and / or PD-L1 mRNA) was lower than that in controls PD-L1 expression in tumor samples was elevated if at least 10%, 20%, or 30% higher It is decided that:

[0106] 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 The percentage of tumor cells expressing chromatin (or chromatin intensity) is Staining of the vacuolar membrane is interpreted as PD-L1 positivity.

[0107] 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 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%); ).

[0108] "Combined Positive Score (CPS)" refers to the number of PD-L1 positive cells in the tumor nest and adjacent supporting stroma. The number (molecule) of PD-L1-positive tumor cells and PD-L1-positive mononuclear inflammatory cells (MIC) was of the total number of tumor cells (denominator; i.e., the number of PD-L1-positive and PD-L1-negative tumor cells) PD- of any intensity, i.e., weak (1+), moderate (2+), or strong (3+) L1 expression is considered positive.

[0109] "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 an appropriate control PD-L1 expression levels (protein and This refers to an increase in the expression of ATP and / or mRNA.

[0110] "DSDR" or "sustained stable disease rate" means SD for ≥ 23 weeks.

[0111] As used herein, "framework region" or "FR" refers to a region excluding the CDR regions. The term "immunoglobulin variable region" refers to an immunoglobulin variable region.

[0112] As used herein, "Kabat" refers to the work of 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.

[0113] "Anti-TIGIT antibody" means a monoclonal antibody that specifically binds to human TIGIT. Human TIGIT contains the following amino acid sequence: MRWCLLLIWA QGLRQAPLAS GMMTGTIETT GNISAEK GGS IILQCHLSST TAQVTQVNWE QQDQLLAICN ADL GWHISPS FKDRVAPGPG LGLTLQSLTV NDTGEYFCIY HTYPDGTYTGRIFLEVLESS VAEHGARFQI PLLGAMA ATL VVICTAVIVV VALTRKKKAL RIHSVEGDLRRKSA GQEEWS PSAPSPPGSC VQAEAAPAGL CGEQRGEDCA ELHDYFNVLS YRSLGNCSFF TETG (SEQ ID NO: 33); Genba Amino acid residues 25 to 244 of nk accession number NP_776160.2 (SEQ ID NO: See also SEQ ID NO: 33 (amino acid residues 1-24 of SEQ ID NO: 33 correspond to the leader peptide). do).

[0114] "Microsatellite instability (MSI)" refers to DNA mismatch repair in tumors. Refers to a form of genomic instability associated with defects. 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). satellite 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, e.g., BAT40, BAT 34C4, TGF-β-RII, and ACTC can be used for MSI analysis. Commercially available kits for this purpose include, for example, the Promega MSI Multiplex PCR Assay. Sei is one example.

[0115] "High frequency microsatellite instability" or "High microsatellite instability (MS IH) is defined as 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), It means combination.

[0116] "Low frequency microsatellite instability" or "low frequency microsatellite instability (MS "IL" refers to instability in one of the five NCI markers or in all markers. <30-40% of the target genes are unstable (i.e., have insertion / deletion mutations). cormorant.

[0117] As used herein, "non-MSI-H colorectal cancer" refers to a cancer that is microsatellite stable. This refers to both MSI-rich (MSS) and MSI-low (MSI-L) colorectal cancer.

[0118] "Microsatellite stability (MSS)" means that all five NCI markers are stable. This refers to cases where the mutation does not show any qualitative characteristics (i.e., does not have any insertion / deletion mutations).

[0119] "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 Ten commercially available kits for MMR analysis include Ventana MMR I HC assay.

[0120] "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 MSH3) in the body This refers to low expression of H6).

[0121] As used herein, "monoclonal antibody" or "mAb" or "Mab" refers to a refers to a population of antibodies that are substantially homogeneous, 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 be present in small amounts. Conventional (polyclonal) antibody preparations typically contain only a small amount of the variable domains, especially the These CDRs contain many different antibodies with different amino acid sequences. The modifier "monoclonal" refers to the 20 It refers to the properties of an antibody as being obtained from a qualitatively homogeneous antibody population and does not have any specific For example, the present disclosure does not construe the production of antibodies by the method described above. The monoclonal antibodies used in this study were those described by Kohler et al. 5) Produced by the hybridoma method first described by Nature 256:495 It can be synthesized by conventional methods or produced by recombinant DNA techniques (see, e.g., U.S. Pat. No. 4,816,626). (See, e.g., 567.) "Monoclonal antibodies" also include those derived from phage antibody libraries. For example, Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. 005) See also J. Allergy Clin. Immunol. 116:731 I want to be.

[0122] A "non-responder patient" is a patient who has a specific resistance to treatment with the combination therapy described herein. When referring to a substantial anti-tumor response, it is meant that the patient did not exhibit an anti-tumor response.

[0123] "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.

[0124] "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 studied or used as a control, and includes human and mammalian patients. Livestock include, for example, cattle, horses, dogs and cats.

[0125] "PD-1 antagonist" refers to a drug that inhibits the action of PD-L1 expressed on cancer cells against immune cells (T cells). PD-1 expressed on the surface of preferred PD-1 receptors (e.g., cytoplasmic reticulocytes, B cells, or NKT cells) is blocked from binding to PD-1. 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 PDCD1L2, PDL2 for PD-L2 , 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 human PD-L1 to human PD-1, and preferably human PD-L1 and PD-L2 The amino acid sequence of human PD-1 is similar to that of NCB Human PD-L1 and The amino acid sequences of PD-L2 and PD-L3 are available in NCBI Locus No. NP_054, respectively. 862 and NP_079515.

[0126] As used herein, a "pembrolizumab variant" refers to a variant of a pembrolizumab having a CDR outside of the light chain. 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 substitutions in each Monoclonal antibodies containing heavy and light chain sequences substantially identical to those in mbrolizumab For example, the mutation position is in the FR region or constant region, and the heavy chain There may be a deletion of a C-terminal lysine residue. 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. Pembrolizumab variants differ from each other because they have the following properties: binding affinity to PD-1; and the ability to block the binding of PD-L1 and PD-L2 to PD-1, respectively. It is substantially the same as pembrolizumab in terms of

[0127] As used herein, the term "pemetrexed" refers to a 5-substituted pyrrolo[2,3- d]pyrimidine. Specifically, this term is used to describe non-small cell lung cancer and Multi-targeted drug that shows anti-cancer effects against various cancers, including leukemia and malignant pleural mesothelioma Pemetrexed is an antimetabolite that inhibits the activity of metabolites involved in folic acid metabolism. This has led to anti-cancer effects against various cancers, such as non-small cell lung cancer and malignant pleural mesothelioma. Pemetrexed analogs and variants may also be used. See number WO2014084651A1.

[0128] As used herein, "RECIST 1.1 response criteria" refers to the 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)

[0129] 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 means that the patient exhibited an anti-tumor response.

[0130] "Sustained response" refers to a sustained response after cessation of treatment with a therapeutic 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.

[0131] Taxol is used to treat many types of cancer, including ovarian, breast, and lung cancer. Taxol is a useful cancer chemotherapy agent that can be used in the treatment of cancer. It is a natural product derived from the bark of the Pacific yew tree (Xus brevafolio). Taxol inhibits microtubule polymerization during mitosis, leading to subsequent cell death. Xol has a broad spectrum of tumoricidal activity against cancers such as breast, ovarian, and lung. (McGuire et al., 1996, N. Eng. J. Med. . 334:1-6; and Johnson et al., 1996, J. Clin. Ocol. 14:2054-2060). Taxol is effective in treating these malignant tumors. Although it is often effective, it is usually not curative because taxol resistance eventually develops. Cellular resistance to taxol is due to, for example, increased expression of P-glycoprotein and Mutations in the β-chain and β-chain genes alter the structure of tubulin or the tubulin structure within polymerized microtubules. This may involve mechanisms such as changes in the ratio of benzophenone isomers (Wahl et al., 1999). 6, Nature Medicine 2:72-79;Horwitz et al. ,1993,Natl.Cancer Inst. 15:55-61;Haber e t al.,1995,J.Biol.Chem. 270:31269-31275; and Giannakakou et al., 1997, J. Biol. Chem. 272:17118-17125). Some tumors undergo tachypnea through unknown mechanisms. Gain sole resistance.

[0132] "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.

[0133] As used herein, "treating" or "treating" cancer refers to the therapeutic use of the present invention. The drug is administered to subjects with or diagnosed with cancer, and the drug has at least one positive therapeutic effect. The results include 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 reduction in tumor metastasis or tumor growth rate, etc. Positive treatment effects 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 the combination therapy described herein is ST 1.1 criteria or irRC (bidimensional or unidimensional), and Treatment achieved by the combination is either PR, CR, OR, PFS, DFS, or OS. PFS is defined as the time to tumor progression. Also called "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 remains disease-free. It refers to an increase in life expectancy compared to an untreated or untreated individual or patient. In some embodiments, 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 assessed by the patient. Treatment regimens for the combinations of the present invention that are effective for treating patients include, for example, The patient's condition, age, and weight, as well as the ability of the treatment to elicit an anti-cancer response in the subject, may also be taken into consideration. The embodiments of any of the aspects of the present invention may vary depending on various factors. Although the use of any of the methods known in the art may not be effective in achieving a positive therapeutic effect in every subject, Any statistical test known to the public, e.g., Student's t-test, chi 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 is the case for a specified statistically significant number of subjects.

[0134] 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 a combination. can be.

[0135] "Tumor" as applied to a subject diagnosed with or suspected of having cancer means any refers to 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 growth of tissue that usually does not contain cysts or fluid areas. A solid tumor is a growth or mass. Different types of solid tumors are distinguished by the types 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." Also called the total amount of tumor material distributed throughout the body, tumor burden refers to the amount of tumor material that is distributed throughout the body, including the lymph nodes and bone marrow. The total number of cancer cells in the body or the overall size of the tumor(s) involved. By various methods known in the art, tumors (or tumors) can be isolated from a subject, for example, by removing the tumor(s). The dimensions of the implant (for example, using calipers) can be measured 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.

[0136] The term "tumor size" refers to the total 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 can be determined, such as by using an MRI scan.

[0137] "One-dimensional irRC" refers to 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).

[0138] As used herein, a "variable region" or "V region" refers to a region whose sequence varies among different antibodies. This refers to the segment of an IgG chain where Kabat residues 109 and 110 in the light chain are It spans 113 in the heavy chain.

[0139] PD-1 antagonist and anti-TIGIT 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 Monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to L1 are also included. mAbs can be human, humanized, or chimeric antibodies, and contain human constant regions. In some embodiments, the human constant region may be selected from the group consisting of 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 include 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.

[0140] 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 antibodies useful as PD-1 antagonists in the treatment methods, medicaments and uses of the present invention Suitable anti-human PD-1 mAbs include: Pembrolizumab (also known as MK-3475), WHO Drug Information mation, Vol. 27, No. 2, pages 161-162 (2013) Humanized IgG1 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) Human Ig having the structure described in Table 1 and comprising the heavy and light chain amino acid sequences shown in Table 3. G4 mAb; h4 mAb, a humanized antibody, as described in WO2008 / 156712 09A11, h409A16 and h409A17, and by MedImmune AMP-514 under development.

[0141] mAbs that bind to human PD-L1 and are useful in the methods of treatment, medicaments and uses of the invention Examples are PCT Publication Nos. WO2013 / 019906 and WO2010 / 077634 A1, as well as U.S. Patent No. 8,383,796. Specific anti-human PD-L1 compounds useful as PD-1 antagonists in therapeutic agents and uses - Patents.com mAbs include MPDL3280A, BMS-936559, MEDI4736, and MS B0010718C, and SEQ ID NO: 24 and SEQ ID NO: 25 of WO2013 / 019906, respectively. and an antibody comprising the heavy chain variable region and light chain variable region of SEQ ID NO: 21.

[0142] Other PD-1 antagonists useful in the treatment methods, medicaments and uses of the present 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 constant domain of immunoglobulin molecules PD-L1 or PD-L2 extracellular or PD-L1 fused to a region, e.g., an Fc region. PD-1 binding moieties. Examples of binding molecules are described in WO2010 / 027827 and WO2011 / 066342. As a PD-1 antagonist 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) binds to -1.

[0143] In some preferred embodiments of the treatment 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 NOs: 6, 7 and 8. do.

[0144] 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 (a) SEQ ID NO: 9 or a variant thereof and (b) a heavy chain variable region comprising SEQ ID NO: 4 or a variant thereof. The heavy chain variable region sequence is a monoclonal antibody or an antigen-binding fragment thereof. The ant may contain up to 17 conserved amino acids in the framework regions (i.e., outside the CDRs). Identical to the reference sequence except for having amino acid substitutions, preferably in the framework regions fewer than 10, fewer than 9, fewer than 8, fewer than 7, fewer than 6, or fewer than 5 conservative amino acids Variants of the light chain variable region sequence have substitutions in the framework regions (i.e., CDR is identical to the reference sequence except for up to five conservative amino acid substitutions (outside of Preferably, there are fewer than four, fewer than three, or fewer than two conserved amino acids in the framework regions. Has substitution.

[0145] 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 comprises (a) a heavy chain comprising SEQ ID NO: 10 and (b) A monoclonal antibody comprising a light chain comprising SEQ ID NO:5.

[0146] In yet another preferred embodiment of the treatment methods, medicaments and uses of the present invention, The antagonist specifically binds to human PD-1 and comprises (a) a heavy chain comprising SEQ ID NO: 12 and and (b) a light chain comprising SEQ ID NO: 11.

[0147] In all of the above treatment methods, agents and uses, the PD-1 antagonist inhibits PD-L inhibits the binding of PD-L1 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.

[0148] Table 3 below lists exemplary anti-PD antibodies for use in the treatment methods, medicaments and uses of the present invention. 1 provides a listing of the amino acid sequences of the -1 mAb.

[0149] Table 3. Exemplary PD-1 Antibody Sequences [Table 3] TIFF2025004212000005.tif236166

[0150] The anti-TIGIT antibody used in the claimed invention is a human antibody, In some embodiments, the antibody may be a humanized or chimeric antibody and may include a human constant region. In this case, the human constant region comprises IgG1, IgG2, IgG3, and IgG4 constant regions. In a preferred embodiment, the human constant region is selected from the group consisting of IgG1 or IgG 4 constant region.

[0151] In one embodiment, the anti-TIGIT antibody is 31C6. Therefore, the anti-TIGIT antibody is a 31C6 variant. The 31C6 antibody has two heavy chains and and two light chains, wherein each heavy chain is an amino acid sequence of SEQ ID NO: 23. Each light chain comprises the amino acid sequence of SEQ ID NO:22.

[0152] 31C6: A light chain immunoglobulin containing the following amino acid sequence: :DIQMTQSPSSLS ASVGDRVTITCRASEHIYSYLSWYQQKPGKVPKLLIYNAK TLAEGVPS RFSGSGSGTDFTLTISSLQPEDVATYYCQHH FGSPLTFGQGTRLEIKRTVAAPSVFIFPPSD EQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO: 22); and A heavy chain immunoglobulin comprising the following amino acid sequence: :EV QLVQSGAEVKKPGSSVKVSCKASGYTFSSYVMHWVRQAPG QGLEWIGYIDPYNDGA YAQKFQGRVTLTSDKSTSTAYME LSSLRSEDTAVYYCARGGPYGWYFDVWGQGTTV TVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDEL TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO: 23); or A light chain immunoglobulin containing the following amino acid sequence: Brin variable domain :DIQMTQSPSSLSASVGDRVTITC RASEHIY SYLS WYQQKPGKVPKLLIY NAKTLAE GVPSRFSGSGSGTD FTLTISSLQPEDVATYYC QHHFGSPLT FGQGTRLEIK(array Number 24 (underlined is CDR); and A heavy chain immunoglobulin comprising the following amino acid sequence: :E VQLVQSGAEVKKPGSSVKVSCKASGYTFS SYVMH WVRQAP GQGLEWIG YIDPYNDGAYAQKFQG RVTLTSDKSTSTAYME LSSLRSEDTAVYYCAR GGPYGWYFDV WGQGTTVTVSS(array No. 25 (underlined CDRs); or containing the following CDRs: CDR-L1: RASEHIYSYLS (SEQ ID NO: 26); CDR-L2: NAKTLAE (SEQ ID NO: 27); CDR-L3: QHHFGSPLT (SEQ ID NO: 28); CDR-H1: SYVMH (SEQ ID NO: 29); CDR-H2: YIDPYNDGAKYAQKFQG (SEQ ID NO: 30); and CDR-H3: GGPYGWYFDV (SEQ ID NO: 31) In some preferred embodiments of the treatment methods, medicaments and uses of the present invention, anti-TIG The IT antibody comprises (a) the light chain CDRs of SEQ ID NOs: 26, 30, 27, and 28 and (b) the light chain CDRs of SEQ ID NOs: 26, 30, 27, and 28. Contains heavy chain CDRs of sequences 29, 30 and 31.

[0153] In another preferred embodiment of the treatment methods, medicaments and uses of the present invention, an anti-TIGIT antibody The subject is a human subject comprising (a) a heavy chain variable region comprising SEQ ID NO: 25 or a variant thereof, and (b) a human subject comprising the sequence The heavy chain variable region sequence includes a light chain variable region containing SEQ ID NO: 24 or a variant thereof. The nucleotide sequence may contain up to 17 conserved amino acids in the framework regions (i.e., outside the CDRs). Identical to the reference sequence except for substitutions, preferably 10 or more in the framework regions fewer than 1, 9, 8, 7, 6, or 5 conservative amino acid substitutions Variants of the light chain variable region sequence may occur in the framework regions (i.e., outside the CDRs). A sequence identical to the reference sequence except for up to five conservative amino acid substitutions (at the bases of the sequence) is preferred. or fewer than four, fewer than three, or fewer than two conservative amino acid substitutions in the framework regions An example of such a variant is described in International Patent Publication No. WO2016 / 028656. (See, for example, SEQ ID NO: 12 of International Patent Publication No. WO2016 / 028656) 4-133 and 149-150).

[0154] In another preferred embodiment of the treatment methods, medicaments and uses of the present invention, an anti-TIGIT antibody The antibody 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 treatment methods, medicaments and uses of the invention, the anti-TIGIT antibody (a) a heavy chain variable region comprising SEQ ID NO: 25, and (b) a light chain variable region comprising SEQ ID NO: 24. Includes the area.

[0155] In one embodiment, an anti-PD-1 or anti-TIGIT antibody or antigen-binding fragment is a heavy chain constant region, e.g., a human constant region, e.g., γ1, γ2, γ3, or γ4 human heavy chain constant region. In another embodiment, the anti-PD-1 antibody also comprises an antibody fragment containing an antibody fragment containing a PD-1 chain constant region or a variant thereof. Alternatively, the anti-TIGIT antibody or antigen-binding fragment may contain a light chain constant region, e.g., a human light chain constant region. regions, such as lambda or kappa human light chain regions or variants thereof. As a non-limiting example, the human heavy chain constant region can be γ1 and the human light chain constant region can be In another embodiment, the human heavy chain constant region is γ4. and the human light chain constant region can be kappa. The Fc region of is γ4 with a Ser228Pro mutation (Schuurman, J et.al., Mol. Immunol. 38:1-8, 2001).

[0156] In some embodiments, different constant domains are used to encode the CDRs provided herein. 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 altered effector function, Heavy chain constant domains other than IgG1 / IgG4 may be used, or hybrid IgG1 / IgG4 may be utilized. For example, a human IgG4 constant domain can be used. Use of anti-PD-1 or anti-TIGIT antibodies containing the same or similar domains and their antigen-binding fragments In one embodiment, the IgG4 constant domain is 22 in the EU system. At position 8, a position corresponding to position 241 in the KABAT system is found to be native human IgG 4 constant domain (Swiss-Prot accession number P01861.1) wherein the amino acid sequence is a sequence that may prevent proper intrachain disulfide bond formation. Cys106 and Cys109 (positions Cys226 and Cys229 in the EU system, potential between the two sites (corresponding to positions Cys239 and Cys242 in the KABAT system) Native Ser108 is replaced with Pro to prevent interchain disulfide bonding See Angal et al. (1993) Mol. Immunol. 30:105. I want to be illuminated.

[0157] Methods, Uses and Agents In one embodiment, the present invention provides a method for administering 2.1 mg to 700 mg of an anti-TIGIT antibody. 1. A method of treating cancer in a patient, comprising: (a) administering to a subject an anti-TIGIT antibody; (b) the light chain CDRs of SEQ ID NOs: 26, 27 and 28 and (c) SEQ ID NOs: 29, 30 and 31 In one embodiment, the anti-TIGIT antibody comprises the heavy chain CDRs of: In another embodiment, the present invention provides an anti-TIGIT antibody 2.1 mg to 700 mg co-administered with an anti-PD-1 or anti-PD-L1 antibody A method for treating cancer in a patient, comprising administering to the patient an anti-TIGIT antibody selected from (a) SEQ ID NOs: 26, 27, and and 28 and (b) the heavy chain CDRs of SEQ ID NOs: 29, 30, and 31. In one embodiment, the anti-PD-1 antibody is a PD-1 antibody. In one embodiment, 2.1 mg or In various embodiments, 2.1 mg to 700 mg of anti-TIGIT antibody is administered. 7 mg, 21 mg, 70 mg, 200 mg, 210 mg, or 700 mg of anti-TIGIT In another embodiment, 200 to 700 mg of an anti-TIGIT antibody is administered. In another embodiment, 200 to 700 mg of an anti-TIGIT antibody is administered. In another embodiment, 200 mg or 210 mg of anti-TIGIT antibody is administered. In one embodiment, the anti-TIGIT antibody is administered via intravenous infusion. In this study, the anti-PD-1 antibody or anti-PD-L1 antibody is administered via intravenous infusion. In a further embodiment, an anti-TIGIT antibody and an anti-PD-1 antibody or anti-PD-L1 All antibodies are administered via intravenous infusion.

[0158] In a further embodiment, the present invention provides a method for administering 200 mg of penbuprofen to an individual via intravenous infusion. Lorisumab or pembrolizumab variant and 200 mg of anti-TIGIT antibody 31 and administering a composition comprising C6 or a 31C6 variant to a patient to treat cancer. In another aspect, the present invention provides a method for treating an individual with steroid hormone receptor agonist (SHR) via intravenous infusion. The body receives 200 mg of pembrolizumab or pembrolizumab variant and 210 mg and administering a composition comprising 1 g of the anti-TIGIT antibody 31C6 or 31C6 variant. In one embodiment, the present invention provides a method for treating cancer in a patient, the method comprising administering to the patient a composition comprising: The composition consists of 200 mg of pembrolizumab or pembrolizumab variant and 200 mg of Contains ~700mg of anti-TIGIT antibody 31C6 or a 31C6 variant. In the form, the composition contains 200 mg of pembrolizumab or pembrolizumab barrier. and 700 mg of anti-TIGIT antibody 31C6 or a 31C6 variant.

[0159] In another embodiment, the present invention provides an anti-PD-1 or anti-PD- A drug comprising an anti-TIGIT antibody for use in combination with an L1 antibody, In one embodiment, the T antibody is administered at 2.1 mg to 700 mg. In another embodiment, the anti-TIGIT antibody is administered via intravenous infusion. The present invention relates to a drug comprising an anti-TIGIT antibody and an anti-PD-1 antibody for treating cancer. In one embodiment, the medicament comprises 200 mg of pembrolizumab or pembrolizumab. Ambrolizumab variant and 200 mg of anti-TIGIT antibody 31C6 or 31C6 In another embodiment, the medicament comprises 200 mg of pembrolizumab or received pembrolizumab variant and 700 mg of 31C6 or 31C6 variant. include.

[0160] In yet a further embodiment, the present invention provides a method for treating cancer in an individual. Use of an anti-TIGIT antibody and an anti-PD-1 or anti-PD-L1 antibody in the manufacture of a pharmaceutical composition comprising: In one embodiment, the agent is 200 mg of pembrolizumab or pembrolizumab. Izumab Variant and 200 mg of anti-TIGIT antibody 31C6 or 31C6 Variant In another embodiment, the medicament comprises 200 mg of pembrolizumab or pembrolizumab. Contains izumab variant and 700 mg of 31C6 or 31C6 variant. In a further embodiment, the present invention provides a method for the manufacture of a medicament for treating cancer in an individual. 2.1 mg of anti-TIGIT antibody is used in a method for treating PD-1 In one embodiment, the anti-TIGIT inhibitor is co-administered with 00 mg of the anti-TIGIT inhibitor. Each of the antibody and the anti-PD-1 antibody is administered via intravenous infusion.

[0161] In one embodiment of the above methods, medicaments and uses, an anti-PD-1 antibody and and the anti-TIGIT antibody are combined. lizumab or pembrolizumab variant and 200 mg of antibody 31C6 or 31 A combined product containing the C6 variant is used for intravenous infusion. In this setting, 200 mg of pembrolizumab or pembrolizumab variants and 3 A combination product containing 00 mg of antibody 31C6 or a 31C6 variant is administered intravenously. In one embodiment, 200 mg of pembrolizumab or pembrolizumab is administered. mbrolizumab variant and 400 mg of antibody 31C6 or 31C6 variant In another embodiment, the combined product containing the compound is used for intravenous infusion. mg of pembrolizumab or pembrolizumab variant and 500 mg of antibody 31 Combination products containing the C6 or 31C6 variants are used for intravenous infusion. In another embodiment, 200 mg of pembrolizumab or pembrolizumab barrier A combination product containing 600 mg of antibody 31C6 or a 31C6 variant is In another embodiment, 200 mg of pembrolizumab is administered intravenously. pembrolizumab or pembrolizumab variant and 700 mg of antibody 31C6 or 31C6 variant A combination product containing cyclosporin is used for intravenous infusion.

[0162] The present invention also provides a pharmaceutical composition comprising 200 mg of pembrolizumab or a pembrolizumab variant, 2 00 mg of antibody 31C6 or a 31C6 variant, and one or more pharmaceutically acceptable salts of In one embodiment, the pharmaceutical composition comprises two additives. 00 mg pembrolizumab or pembrolizumab variant, 300 mg antibody 31 C6 or 31C6 variants, and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition contains 200 mg of pembrolizumab or pembrolizumab. lorizumab variant, 400 mg of antibody 31C6 or 31C6 variant, and 1 or more than one pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprises: 200 mg pembrolizumab or pembrolizumab variant, 500 mg antibody 3 1C6 or 31C6 variant, and one or more pharmaceutically acceptable excipients. In a further embodiment, the pharmaceutical composition contains 200 mg of pembrolizumab or pembrolizumab. mbrolizumab variant, 600 mg of antibody 31C6 or 31C6 variant, and and one or more pharmaceutically acceptable excipients. The composition is 200 mg pembrolizumab or pembrolizumab variant, 700 mg antibody 31C6 or a 31C6 variant thereof, and one or more pharmaceutically acceptable additives. Contains additives.

[0163] In another embodiment of the above methods, medicaments and uses, anti-PD-1 or anti-P The D-L1 antibody and the anti-TIGIT antibody are co-administered. 0 mg pembrolizumab or pembrolizumab variant and 200 mg antibody 3 1C6 or 31C6 variants administered intravenously on day 1, then every 3 weeks thereafter In one embodiment, 200 mg of pembrolizumab or Pembrolizumab variant and 300 mg of antibody 31C6 or 31C6 variant are co-administered via intravenous infusion on day 1 and then once every three weeks thereafter. In one embodiment, 200 mg of pembrolizumab or pembrolizumab variant and 400 mg of antibody 31C6 or a 31C6 variant on day 1, then are co-administered via intravenous infusion once every three weeks. g of pembrolizumab or pembrolizumab variant and 500 mg of 31C6 or or the 31C6 variant via intravenous infusion on day 1, then once every 3 weeks thereafter. In another embodiment, 200 mg of pembrolizumab or pembrolizumab are co-administered. lorizumab variant and 600 mg of antibody 31C6 or 31C6 variant The drugs are co-administered via intravenous infusion on day 1 of the study, and then once every three weeks thereafter. In some embodiments, 200 mg of pembrolizumab or a pembrolizumab variant and and 700 mg of antibody 31C6 or 31C6 variant on day 1, then 3 The drugs are co-administered via intravenous infusion once weekly.

[0164] In one embodiment of the above methods, medicaments and uses, 400 mg of pembroke steroids are administered. Lorisumab or pembrolizumab variant on day 1, then every 6 weeks thereafter and 200 mg of antibody 31C6 or 31C6 variant on day 1, then Each is administered via intravenous infusion once weekly. In one embodiment, 400 mg Pembrolizumab or pembrolizumab variant on day 1, then every 6 weeks thereafter and 300 mg of antibody 31C6 or 31C6 variant on day 1, then and once every three weeks thereafter, each administered via intravenous infusion. 400 mg of pembrolizumab or pembrolizumab variants on day 1, then and then once every 6 weeks, and 400 mg of antibody 31C6 or 31C6 variant is administered via intravenous infusion on day 1, and then once every three weeks thereafter. In an embodiment, 400 mg of pembrolizumab or pembrolizumab variant is on day 1, then once every 6 weeks thereafter, and 500 mg of antibody 31C6 or 31 The C6 variant was administered via intravenous infusion on day 1 and then once every 3 weeks thereafter. In another embodiment, 400 mg of pembrolizumab or pembrolizumab is administered. buvariant on day 1, then once every 6 weeks thereafter, and 600 mg of antibody 31 C6 or 31C6 variants intravenously on day 1, then once every 3 weeks thereafter In another embodiment, 400 mg of pembrolizumab or Pembrolizumab variant on day 1, then once every 6 weeks thereafter, and mg of antibody 31C6 or 31C6 variant on day 1, then every 3 weeks thereafter Each dose is administered via intravenous infusion.

[0165] Cancers that can be treated with the antibodies, compositions and methods of the present invention include, but are not limited to: Heart: 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, rucinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Karposi's sarcoma) (Karposi's sarcoma), leiomyoma, hemangioma, lipoma, neurofibroma, adenoma 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 (os teochronfroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromatosis 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 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 (embryonic rhabdomyosarcoma), fallopian tube (carcinoma), breast; hematology: blood (bone marrow Leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative Diseases, 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 Lymphoid hematopoiesis, including Burkett's lymphoma organ tumors; including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia hematopoietic tumors of the myeloid lineage; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; astrocytic tumors; Tumors of the central and peripheral nervous system, including cystomas, neuroblastomas, gliomas, and schwannomas as well as melanoma, skin (non-melanoma) cancer, mesothelioma (cell), seminoma, and teratocarcinoma , osteosarcoma, xeroderma pigmentosum, keratoconjunctivitis Includes keratoctanthoma, thyroid follicular carcinoma, and Kaposi's sarcoma In one embodiment, the forgoing cancer is: In one embodiment, the patient has advanced, unresectable, or metastatic disease. or refractory to anti-PD-L1 therapy.

[0166] In one embodiment, the cancers that can be treated by the antibodies, compositions and methods of the invention are: Cancers 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 cancer, 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:

[0167] 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- Adenocarcinoma of the esophageal junction, renal cell carcinoma, fallopian tube cancer, endometrial cancer, cervical cancer, and colon In one embodiment, colorectal cancer, gastric cancer, gastric and / or rectal cancer are included. or adenocarcinoma of the gastroesophageal junction (GEJ), or endometrial cancer, High instability (non-MSI-H) or mismatch repair proficient (pMMR). In this study, patients with head and neck squamous cell carcinoma received anti-PD-1 or anti-PD-L1 treatment. In one embodiment, the colorectal cancer is unresectable or metastatic (stage A). Page IV).

[0168] 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's 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 High-grade non-Hodgkin's lymphoma (iNHL) (e.g., follicular lymphoma, marginal zone lymphoma, mucosal lymphoma) In one embodiment, the present invention provides a method for treating lymphoma, including treatment with 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. .

[0169] In further embodiments, cancers that can 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 one embodiment, the forgoing cancer is advanced, unresectable or or metastatic.

[0170] In one embodiment, the non-small cell lung cancer is advanced or stage IV. In one embodiment, the melanoma is advanced or stage III. In this case, the patient is refractory to anti-PD-1 or anti-PD-L1 treatment.

[0171] In one embodiment, pembrolizumab or a pembrolizumab variant and Combination products containing 31C6 or 31C6 variants are used. In this setting, 200 mg of pembrolizumab or pembrolizumab variants and 2 A combination product containing 0.00 mg of 31C6 or a 31C6 variant is used. In an embodiment, 200 mg of pembrolizumab or pembrolizumab variant and and a combination product containing 700 mg of 31C6 or a 31C6 variant. .

[0172] In a further embodiment, the cancer is non-small cell lung cancer and the patient has tumor activated epithelial proliferation Mutations in the epidermal growth factor receptor (EGFR) or the B isoform (B-Raf) of aggressive fibrosarcoma lacking the mutation and expressing anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS In a further embodiment, the cancer is non-small cell lung cancer, and the cancer lacks the gene rearrangement of 1). The tumor has squamous histology.

[0173] The combination therapy may also include one or more additional therapeutic agents. , for example, chemotherapeutic agents, biotherapeutic agents, immunogenic agents (e.g., attenuated cancer cells, tumor antigens, , antigen-presenting cells, e.g., tumor-derived antigens or nucleic acid-pulsed dendritic cells, and immune stimulators. cytokines (e.g., IL-2, IFNα2, GM-CSF), and immunostimulatory Transfecting genes encoding cytokines, such as, but not limited to, GM-CSF. The specific dosage and dosage schedule of the additional therapeutic agent may be The schedule can be further varied, and the optimal dose, dosing schedule and route of administration may vary. This will be determined based on the specific therapeutic agent being used.

[0174] Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclosphamide. alkylsulfonates, such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carboquone, Meturedopa and uredopa, etc.; Alto Letamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophospho Melamide and trimethylolomelamine Includes ethylenimines and methylamelamines acetogenins (especially bullatacin and bullatacinone); camptothecin (synthetic analogs) including the drug topotecan; bryostatin; kallistatin; CC-1065 (its including synthetic analogs of dozelesin, carzelesin, and biceresin; Cryptofycine phycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duophycins Carmycins (including synthetic analogs, KW-2189 and CBI-TMI); Eli uterobin; pancratistatin; sarcodictyin; spongiostatin; nitrogen mustards, e.g., chlorambucil, chlornaphazine, colofosfamide lophosphamide), estramustine, ifosfamide, mechlorethamine, Mechlorethamine oxide hydrochloride, melphalan, nobuenbiquin, fenesterine, 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., kale calicheamicins, especially calicheamicin gamma 1I and calicheamicin phi 1I, See, for example, 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 chemocycin, 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, potofibrate, Potfiromycin, puromycin, queramicin lamycin, rodorubicin, streptonigrin, Treptozocin, tubercidin, ubenimex, zinostatin, zorubicin, etc.; antimetabolites Antibiotics, such as methotrexate and 5-fluorouracil (5-FU); folic acid agonists, such as denopterin, methotrexate, pteropterin, trimetrexate, etc. Purine analogues, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thiopurine guanine, etc.; pyrimidine analogues, e.g., ancitabine, azacitidine, 6-azauryl gin, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine androgens, such as calcitonin, dromycin, propionate, 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; erfor Elformithine; Elliptinium 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; Sizofuran; Spirogermanium; Tenu Azonic acid;Triazicone;2,2',2''-Trichlorotriethylamine;Trichotecene toxins (especially T-2 toxin, verracurin A, roridin A and Anguidine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitrite ol; mitolactol; pipobroman; gacytosine; arabino Cid ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., Pak rituximab and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; methotrexate; platinum analogs, such as cisplatin and carboplatin platin, etc.; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone 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 and its salts, acids or derivatives which are acceptable for the treatment of tumors. or antihormonal agents that act to inhibit the growth of the hormone, such as tamoxifen and raloxifene , droloxifene, 4-hydroxytamoxifen, trioxifen, keoxifen LY117018, onapristone, and toremifene (Fareston) Antiestrogens and selective estrogen receptor modulators (SERMs), etc.; Aromatase inhibitors inhibit aromatase, an enzyme that controls estrogen production in the kidney. , such as 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exe Mestan, Formestane, Fadrozole, Vorozole, Letrozole and Anast and antiandrogens, such as flutamide, nilutamide, bicalutamide, etc. leuprolide, goserelin, and the like; and any of the above pharmaceutically acceptable Salts, acids or derivatives are also included.

[0175] Each therapeutic agent in the combination therapy of the present invention may be administered alone or in combination in accordance with standard pharmaceutical practice. or a therapeutic agent and one or more pharmaceutically acceptable carriers, vehicles, excipients, and diluents The compound may be administered in a medicament (also referred to herein as a pharmaceutical composition) comprising:

[0176] Each therapeutic agent in the combination therapy of the present invention may be administered simultaneously (i.e., in the same formulation) and simultaneously. (i.e., in separate drugs, one administered immediately after the other, in any order) and The therapeutic agents in the combination therapy may be administered sequentially in any order. The dosage form is two separate units (one unit is a tablet or capsule and the other unit is a sterile liquid) and / or administered on different dosing schedules, e.g., when chemotherapy agents are 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.

[0177] In some embodiments, the anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD-L antibody. 1 antibody, while in other embodiments, the anti-TIGIT antibody is administered prior to administration of the anti-P In another embodiment, the anti-PD-L1 antibody is administered after administration of the anti-PD-1 antibody or anti-PD-L1 antibody. The TIGIT antibody is administered at the same time as the anti-PD-15 antibody or anti-PD-L1 antibody.

[0178] In some embodiments, at least one of the therapeutic agents in the combination therapy is typically used when the agent is used as a monotherapy to treat the same cancer The same drug dosage regimen (dose, frequency, and administration) as In another embodiment, the patient receives a combination The total amount of at least one of the therapeutic agents in a treatment is less than the recommended dose, e.g., lower doses and less frequent dosing, and / or The duration of treatment is shorter.

[0179] 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 by intraperitoneal, subcutaneous, rectal, topical and transdermal routes of administration. The combination treatment of the present invention may be used before or after surgery to remove the tumor. and may be used before, during or after radiation therapy.

[0180] In some embodiments, the combination therapy of the present invention is administered in combination with a prior biotherapeutic or It is administered to patients who have not been treated with chemotherapy, i.e., who are treatment-naive. In some cases, the combination therapy may be a prolonged or sustained therapy after prior treatment with a biotherapeutic or chemotherapy agent. It is administered to patients who have failed to achieve a response, i.e., treatment-experienced.

[0181] 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. The combination therapy of the present invention is used to treat tumors large enough to cause PD- Test positive for either or both PD-L1 and PD-L2, preferably P It can be administered to human patients with cancers that test positive for D-L1 expression. In some preferred embodiments, PD-L1 expression is measured using a diagnostic anti-human PD-L1 antibody or or its antigen-binding fragments to FFPE or frozen tissue samples removed from patients. It is detected in an IHC assay on tissue sections. Typically, the patient's physician will recommend anti-PD- 1 antibody or anti-PD-L1 antibody and anti-TIGIT antibody treatment in patients The patient will order a diagnostic test to determine PD-L1 expression in the tumor tissue sample obtained, but the physician The nurse may request an initial or subsequent treatment at any time after treatment has begun, for example, after completing a treatment cycle. It is also envisioned that diagnostic tests may be ordered. In one embodiment, the PD PD-L1 expression was measured by PD-L1 IHC 22C3 pharmDx assay. In another embodiment, the patient has a mononuclear inflammation density score for PD-L1 expression of ≧ 2. In another embodiment, the patient's mononuclear inflammation density score for PD-L1 expression is In another embodiment, the patient's PD-L1 expression is assessed by a mononuclear inflammatory density scale. In another embodiment, the patient's tumor percentage score for PD-L1 expression is ≧4. In another embodiment, the tumor percentage for PD-L1 expression in the patient is ≧1%. In another embodiment, the patient's PD-L1 expression is The tumor proportion score is ≧20%. In another embodiment, the patient's PD-L1 expression is In a further embodiment, the patient has a PD-L1 expression score of ≥ 30%. In a further embodiment, the combined positive score for the present is ≧1%. The combined positive score for PD-L1 expression is between 1 and 20%. In some embodiments, the patient has a combined positive score for PD-L1 expression of ≧2%. In a further embodiment, the patient's combined positive score for PD-L1 expression is In a still further embodiment, the patient is screened for PD-L1 expression. In a further embodiment, the patient has PD-L1 expression and the combined positive score is ≧10%. The combined positive score for the present is ≧15%. and patients have a combined positive score for PD-L1 expression ≥ 20%.

[0182] In one preferred embodiment of the invention, the anti-PD-1 antibody in the combination therapy is Nivolumab: 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / 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:

[0183] In another preferred embodiment of the invention, the anti-PD-1 antibody in the combination therapy is Pembrolizumab or a pembrolizumab variant, liquid, 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 10mg / kg Q3W, 5mg / kg Q3W, 10mg / kg Q3W, and any one of these doses Relative dose equivalents, i.e., doses selected from the group consisting of, for example, 200 mg Q3W In some embodiments, pembrolizumab is administered in 10 mM histidine. 25mg / ml pembrolizumab, 7% (w / v) in ethanol buffer pH 5.5 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. lolizumab or its antigen-binding fragment; about 10 mM histidine buffer; about 10 mM L-methionine or a pharmaceutically acceptable salt thereof; about 7% (w / v) sucrose; and and about 0.02% (w / v) polysorbate 80.

[0184] In some embodiments of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof In other embodiments, 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, and 20+ weeks, 24+ weeks, 28+ weeks, 30+ weeks, 32+ weeks, 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 90 weeks or more. or an antigen-binding fragment thereof is administered at 400 mg every six weeks.

[0185] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion. The dose is administered over a period of between 25 and 40 minutes, or approximately 30 minutes, depending on the dose.

[0186] In some embodiments, patients receive at least 24 weeks of treatment, 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 the patient shows evidence of PD or CR.

[0187] Pharmaceutically acceptable additives of the present disclosure include, for example, solvents, bulking agents, buffering agents, osmotic agents, 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.

[0188] 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.

[0189] 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 spray drying and / or storage. Suitable bulking agents are sugars (mono-, di- and polysaccharides), such as sucrose, lactose, , trehalose, mannitol, sorbital, glucose and raffinose. do.

[0190] The pharmaceutical composition may comprise a buffering agent. The buffering agent is used to prevent the release of the pharmaceutical composition during processing, storage, and, optionally, during reconstitution. The pH is controlled to prevent decomposition of the active agent. Suitable buffers include, for example, For example, salts include acetate, citrate, phosphate or sulfate. Buffers include, for example, amino acids such as arginine, glycine, histidine, and lysine, etc. The buffering agent 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 in the range of about 4 to 9, with the lower limit being lower than the upper limit.

[0191] The pharmaceutical composition may include a tonicity adjusting agent. Suitable tonicity adjusting agents include, for example, glucose. Examples of suitable sugars include glycerol, sodium chloride, glycerin, and mannitol.

[0192] The pharmaceutical composition may contain a preservative. Suitable preservatives include, for example, antioxidants and antimicrobial agents. On the other hand, in a preferred embodiment, the pharmaceutical composition is prepared under sterile conditions. It is in a single-use container and therefore does not need to contain a preservative.

[0193] 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 as a lyophilized powder that is reconstituted with sterile water for injection prior to use. WO2012 / 135408 discloses the use of the present invention. Several liquid and lyophilized drug formulations containing pembrolizumab suitable for In some embodiments, the pembrolizumab-containing formulation is about 100 ml in 4 ml of solution. It is provided in glass vials containing 25 g of pembrolizumab. Each 1 mL solution contains 25 mg of pembrolizumab, L-histidine (1.55 mg), polysorbate 8 Formulated in 0 (0.2 mg), sucrose (70 mg) and water for injection USP. The solution requires dilution for IV infusion.

[0194] In some embodiments, the medicament comprising the anti-TIGIT antibody is provided as a liquid formulation. or prepared by reconstituting the lyophilized powder with sterile water for injection before use. In one embodiment, the liquid formulation contains about 10 to 100 mg / mL of an anti-TIGIT antibody. antibody; approximately 7% (w / v) sucrose; approximately 0.02% (w / v) polysorbate 80; about 10 mM L-histidine buffer at a pH of about 5.8 to 6.0; and about 10 mM It contains approximately 15 mM L-methionine.

[0195] The pharmaceutical preparations described herein are packaged in a capsule containing a first container and a second container and a package insert. The first container may contain at least one agent comprising a PD-1 antagonist. The second container contains 2.1 to 700 mg of a drug containing an anti-TIGIT antibody. The package insert or label includes instructions for using the agent to treat cancer in a patient. The container and the second container may be of the same or different shapes (e.g., vials, syringes, and bottles) and / or made 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 These may include, for example, diluents, filters, IV bags and lines, needles and syringes, etc. In some preferred embodiments of the present invention, the PD-1 antagonist is an anti-PD-1 antibody. The explanation is that the drug tested positive for PD-L1 expression by IHC assay. The patent states that the drug is intended for use in treating patients with cancers that cause

[0196] These and other aspects of the present invention are also encompassed by the following exemplary specific embodiments: , as is apparent from the teachings contained herein.

[0197] Specific Exemplary Embodiments of the Invention 1. Patients will receive 2.1 mg to 700 mg of anti-TIGIT antibody containing heavy and light chains. 1. A method for treating cancer in a patient, comprising administering to said patient a nucleic acid sequence comprising a light chain of SEQ ID NO: 26. , 27 and 28, and the heavy chain comprises the heavy chain CDRs of SEQ ID NOs: 29, 30 and 31. R.

[0198] 2. The method of embodiment 1, wherein the anti-TIGIT antibody is administered via intravenous infusion.

[0199] 3. The method of embodiment 1, wherein the patient is administered 2.1 mg of the anti-TIGIT antibody.

[0200] 4. The method of embodiment 1, wherein the patient is administered 7 mg of the anti-TIGIT antibody.

[0201] 5. The method of embodiment 1, wherein the patient is administered 21 mg of the anti-TIGIT antibody.

[0202] 6. The method of embodiment 1, wherein the patient is administered 70 mg of the anti-TIGIT antibody.

[0203] 7. The method of embodiment 1, wherein the patient is administered 200 mg of the anti-TIGIT antibody.

[0204] 8. The method of embodiment 1, wherein the patient is administered 210 mg of the anti-TIGIT antibody.

[0205] 9. The method of embodiment 1, wherein the patient is administered 700 mg of the anti-TIGIT antibody.

[0206] 10. Patients receive anti-TIGIT antibodies on day 1 and then once every 3 weeks thereafter. 10. The method of any one of embodiments 1 to 9,

[0207] 11. 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: 24. 11. The method of any one of embodiments 1 to 10, comprising a variable region.

[0208] 12. The anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 23; 12. The method of any one of embodiments 1 to 11, wherein the light chain comprises SEQ ID NO: 22.

[0209] 13. Any of embodiments 1 to 10, wherein the anti-TIGIT antibody is a 31C6 variant. A single method.

[0210] 14. The anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or 14. The method of any one of embodiments 1 to 13, wherein the antibody is co-administered with an antigen-binding fragment.

[0211] 15. The anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or 14. The method of any one of embodiments 1 to 13, wherein the antibody is combined with an antigen-binding fragment.

[0212] 16. An anti-PD-1 antibody or an antigen-binding fragment thereof that specifically binds to human PD-1; 16. The method of embodiment 14 or 15, wherein the method blocks the binding of human PD-L1 to human PD-1. .

[0213] 17. The anti-PD-1 antibody or its antigen-binding fragment also binds to human PD-L2. 17. The method of embodiment 16, wherein binding to 1 is blocked.

[0214] 18. The anti-PD-1 antibody or antigen-binding fragment thereof is (a) a PD-1 antibody selected from the group consisting of SEQ ID NOs: 1, 2, and 3. 18. The method of claim 17, comprising (a) a light chain CDR and (b) a heavy chain CDR of SEQ ID NOs: 6, 7 and 8. method.

[0215] 19. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 9. 19. The method of embodiment 18, wherein the light chain comprises a light chain variable region comprising SEQ ID NO:4.

[0216] 20. 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: 11. 19. The method of embodiment 18, wherein the strand comprises SEQ ID NO:5.

[0217] 21. The method of embodiment 17, wherein the anti-PD-1 antibody is pembrolizumab.

[0218] 22. The method of embodiment 17, wherein the anti-PD-1 antibody is a pembrolizumab variant.

[0219] 23. The method of embodiment 14, wherein the anti-PD-1 antibody is nivolumab.

[0220] 24. The anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab , The method of embodiment 14.

[0221] 25. Anti-PD-1 antibody is administered intravenously at 200 mg on day 1, then once every 3 weeks thereafter. The method of any one of embodiments 18-24, wherein the administration is via intravenous infusion.

[0222] 26. Anti-PD-1 antibody is administered intravenously at 400 mg on day 1, then once every 6 weeks thereafter. The method of any one of embodiments 18-24, wherein the administration is via intravenous infusion.

[0223] 27. 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 NOs: 6, 7 and 8, and the light chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8. a light chain variable region comprising light chain CDRs 1, 2, and 3; and a humanized anti-TIGIT antibody comprising a heavy chain and a light chain, wherein the heavy chain is a sequence of SEQ ID NO: 29, 30, and 31 heavy chain CDRs, and the light chain comprises SEQ ID NOs: 26, 27 and 28. 16. The method of embodiment 14 or 15, comprising a light chain variable region comprising eight light chain CDRs.

[0224] 28. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 9. the light chain comprises a light chain variable region comprising SEQ ID NO: 4; and an anti-TIGIT antibody comprises 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 16. The method of embodiment 14 or 15, comprising a light chain variable region comprising SEQ ID NO:24.

[0225] 29. 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: 11. the chain comprises SEQ ID NO: 5; and the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain 14 or 15, wherein the antibody comprises SEQ ID NO: 23 and the light chain comprises a light chain variable region comprising SEQ ID NO: 22. Or 15 ways.

[0226] 30. Anti-PD-1 antibody 200 mg intravenously on day 1, then once every 3 weeks thereafter Anti-TIGIT antibody is administered via intravenous infusion at 200 mg on day 1, then at 3 mg thereafter. 30. Any one of embodiments 27-29, administered via intravenous infusion once weekly. Law.

[0227] 31. Anti-PD-1 antibody 400 mg intravenously on day 1, then once every 6 weeks thereafter The anti-TIGIT antibody is administered via intravenous infusion at 200 mg once every 3 weeks on day 1. The method of any one of embodiments 27-29, wherein the administration is via intravenous infusion.

[0228] 32. 200mg of anti-PD-1 antibody will be combined with 200mg of anti-TIGIT antibody. 29. The method of any one of embodiments 27 to 29.

[0229] 33. Cancer: NSCLC, colorectal cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer, upper 33. Any of embodiments 1 to 32, wherein the cancer is selected from the group consisting of skin cancer, fallopian tube cancer, or primary peritoneal cancer. Attribution Clinical Trial 34. The method of embodiment 33, wherein the cancer is NSCLC.

[0230] 35. (i) carboplatin and pemetrexed, or (ii) carboplatin and and paclitaxel.

[0231] 36. The individual has not been treated with prior anti-PD-1 or anti-PD-L1 therapy, or or confirmed to be progressive on prior anti-PD-1 or anti-PD-L1 therapy 36. The method of any one of embodiments 1 to 35, wherein

[0232] 37. 200 mg pembrolizumab or pembrolizumab variant, 200 mg and a pharmaceutically acceptable excipient. Finished product.

[0233] 38. Heavy and light chains in the manufacture of a medicament for treating cancer in a subject / patient. 26, 27 and 28. the light chain CDRs and the heavy chain CDRs of SEQ ID NOs: 29, 30 and 31. .

[0234] 39. The anti-TIGIT antibody is formulated for intravenous infusion and / or The use of embodiment 38, wherein the administration is by injection.

[0235] 40. Embodiment 38 or 39, in which the patient is administered 2.1 mg of an anti-TIGIT antibody. Use of.

[0236] 41. The method of embodiment 38 or 39, wherein the patient is administered 7 mg of an anti-TIGIT antibody. For.

[0237] 42. The method of embodiment 38 or 39, wherein the patient is administered 21 mg of an anti-TIGIT antibody. use.

[0238] 43. The method of embodiment 38 or 39, wherein the patient is administered 70 mg of an anti-TIGIT antibody. use.

[0239] 44. Embodiment 38 or 39, in which the patient is administered 200 mg of an anti-TIGIT antibody. Use of.

[0240] 45. Embodiment 38 or 39, in which the patient is administered 210 mg of an anti-TIGIT antibody. Use of.

[0241] 46. ​​Embodiment 38 or 39, in which the patient is administered 700 mg of an anti-TIGIT antibody. Use of.

[0242] 47. Patients are receiving anti-TIGIT antibodies on day 1 and then once every 3 weeks thereafter. The use of any one of embodiments 38 to 46.

[0243] 48. 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: 24. 11. The use of any one of embodiments 1 to 10, comprising a variable region.

[0244] 49. The anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 23; The use of any one of embodiments 38 to 48, wherein the light chain comprises SEQ ID NO: 22.

[0245] 50. Any of embodiments 38 to 47, wherein the anti-TIGIT antibody is a 31C6 variant. Use of one of the terms.

[0246] 51. The anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or The use of any one of embodiments 38 to 50, wherein the use is co-administered with an antigen-binding fragment.

[0247] 52. The anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or The use of any one of embodiments 38 to 50, wherein the use is combined with an antigen-binding fragment.

[0248] 53. An anti-PD-1 antibody or an antigen-binding fragment thereof that specifically binds to human PD-1; The use of embodiment 51 or 52, which blocks the binding of human PD-L1 to human PD-1. .

[0249] 54. The anti-PD-1 antibody or its antigen-binding fragment also binds to human PD-L2. 54. The use of embodiment 53, wherein the compound blocks binding to 1.

[0250] 55. The anti-PD-1 antibody or antigen-binding fragment thereof is (a) a PD-1 antibody or antigen-binding fragment thereof selected from the group consisting of SEQ ID NOs: 1, 2, and 3. 55. The method of claim 54, comprising (a) a light chain CDR and (b) a heavy chain CDR of SEQ ID NOs: 6, 7, and 8. use.

[0251] 56. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 9. 56. The use of embodiment 55, wherein the light chain comprises a light chain variable region comprising SEQ ID NO:4.

[0252] 57. 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: 11. 57. The use of embodiment 56, wherein the strand comprises SEQ ID NO:5.

[0253] 58. Any of embodiments 51 to 54, wherein the anti-PD-1 antibody is pembrolizumab. Use of.

[0254] 59. Embodiments 51 to 54, in which the anti-PD-1 antibody is a pembrolizumab variant. Use of either.

[0255] 60. The use of embodiment 51 or 52, wherein the anti-PD-1 antibody is nivolumab.

[0256] 61. The anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab , The method of embodiment 14.

[0257] 62. Anti-PD-1 antibody is administered intravenously at 200 mg on day 1, then once every 3 weeks thereafter. The use of any one of embodiments 55 to 58, wherein the use is administered via intravenous injection.

[0258] 63. Anti-PD-1 antibody is administered intravenously at 400 mg on day 1, then once every 6 weeks thereafter. The use of any one of embodiments 55 to 58, wherein the use is administered via intravenous injection.

[0259] 64. 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 NOs: 6, 7 and 8, and the light chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8. a light chain variable region comprising light chain CDRs 1, 2, and 3; and a humanized anti-TIGIT antibody comprising a heavy chain and a light chain, wherein the heavy chain is a sequence of SEQ ID NO: 29, 30, and 31 heavy chain CDRs, and the light chain comprises SEQ ID NOs: 26, 27 and 28. 53. The use of embodiment 51 or 52, comprising a light chain variable region comprising eight light chain CDRs.

[0260] 65. The anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 9. the light chain comprises a light chain variable region comprising SEQ ID NO: 4; and an anti-TIGIT antibody comprises 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 53. The use of embodiment 51 or 52, comprising a light chain variable region comprising SEQ ID NO: 24.

[0261] 66. 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: 11. the chain comprises SEQ ID NO: 5; and the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain 51 or 52, wherein the antibody comprises SEQ ID NO: 23 and the light chain comprises a light chain variable region comprising SEQ ID NO: 22. Use of or 52.

[0262] 67. Anti-PD-1 antibody 200 mg intravenously on day 1, then once every 3 weeks thereafter Anti-TIGIT antibody is administered via intravenous infusion at 200 mg on day 1, then at 3 mg thereafter. 67. The method of any one of embodiments 64 to 66, wherein the compound is administered via intravenous infusion once weekly. use.

[0263] 68. Anti-PD-1 antibody 400 mg intravenously on day 1, then once every 6 weeks thereafter The anti-TIGIT antibody is administered via intravenous infusion at 200 mg once every 3 weeks on day 1. The use of any one of embodiments 64 to 66, wherein the use is administered via intravenous infusion.

[0264] 69. 200mg of anti-PD-1 antibody is combined with 200mg of anti-TIGIT antibody. , the use of any one of embodiments 64 to 66.

[0265] 70. Cancer is NSCLC, colorectal cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer, epithelial cancer, fallopian tube cancer, or primary peritoneal cancer, from embodiment 38. Use any one of 69.

[0266] 71. The use of embodiment 70, wherein the cancer is NSCLC.

[0267] 72. (i) Carboplatin and pemetrexed, or (ii) Carboplatin and Any of embodiments 38 to 71, further comprising the use of a combination of paclitaxel and Use of.

[0268] 73. 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 The use of any one of embodiments 38 to 72, wherein

[0269] 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) and Curren t Protocols in Molecular Biology,Vols.1- 4, John Wiley and Sons, Inc. New York, NY This is a paper by the author, entitled "Cloning and DNA Mutagenesis in Bacterial Cells" (Vol. 1 ), Cloning in mammalian cells and yeast (Vol. 2), Glycoconjugates and proteins Protein expression (Vol. 3) and bioinformatics (Vol. 4) are described. There are.

[0270] Protein analysis including immunoprecipitation, chromatography, electrophoresis, centrifugation and crystallization The purification method has been 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 are described. (See, for example, Coligan, et al. (2000) Current Pro 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 The production, purification, and fragmentation of clonal antibodies has 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 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).

[0271] 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).

[0272] 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 transgenic mice (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).

[0273] Purification of the antigen is not necessary for antibody production. Immunizing an animal with cells bearing the target antigen is Spleen cells are then isolated from the immunized animal and fused with a myeloma cell line. Hybridomas can be produced by cleaving the nucleoside analogues (see, for example, 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).

[0274] Antibodies are used in a wide variety of applications, including small drug molecules, enzymes, liposomes, and polyethylene glycol ( The antibodies can be used in therapeutics, diagnostics, kits or Other useful purposes include dyes, radioisotopes, enzymes, or metals, e.g. These include antibodies conjugated to colloidal gold (see, e.g., 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).

[0275] 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, Nucleic Acid Primers and Fluorescent reagents suitable for modifying nucleic acids, including probes, polypeptides, and antibodies are available. It is possible (Molecular Probes (2003) Catalogue, M Olecular Probes, Inc., Eugene, OR; Sigma-Ald rich(2003) Catalog, St. Louis, MO).

[0276] 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).

[0277] 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); G CG Wisconsin Package(Accelrys,Inc.,San D DeCypher® (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. See the reference. [Example]

[0278] Example 1: Clinical Trial of Anti-TIGIT Antibodies in Advanced Solid Tumors The study included monotherapy with the anti-TIGIT antibody 31C6 (Part A, Arm 1) and and pembrolizumab in combination with 31C6 (Part A, Arm 2) Part B of the study was a dose-escalation study. Use to estimate the recommended Phase 2 dose of the 31C6 antibody when used in combination with This is a dose-finding phase. The antitumor activity of the 31C6 antibody when used in combination with pembrolizumab was Part B was determined using a non-randomized study design. Two doses of the 31C6 antibody, which is a marker for PD-1 activation, were administered to patients with naive cancer. The study was conducted using a 1:1 randomized trial design in participants.

[0279] During Part A of the study, subjects were assigned to one of two treatment arms: Arm 1 : 31C6 escalating doses of 2.1 mg, 7 mg, 21 mg, 70 mg as monotherapy, 210 mg and 700 mg every 3 weeks (Q3W) by intravenous infusion (IV).

[0280] Arm 2 : In combination with pembrolizumab (200 mg Q3W) IV, 31C6 gradually Increased doses of 2.1 mg, 7 mg, 21 mg, 70 mg, 210 mg, and 700 mg every 3 weeks and (Q3W) IV.

[0281] Part A will include patients with measurable disease per RECIST and ECOG PS 0-1. The study included adults with metastatic solid tumors for which there was no clinically effective treatment; Treatment with LA-4, PD-1, or PD-L1 inhibitors was not discontinued due to AEs. Dose escalation was permitted if the target dose was reached according to a modified toxicity probability interval design. The limiting toxicity rate was approximately 30%. Pembrolizumab was administered at 200 mg Q3W. The TIGIT 31C6 antibody was administered at doses ranging from 2.1 mg to 700 mg. The treatment with pembrolizumab was continued for 35 cycles or until progression, intolerable toxicity, or The study was continued until investigator or patient decision. Dose escalation and confirmation were performed in 14 patients at either dose level. The primary endpoint was the efficacy and safety of pembromodiluvinib as monotherapy and in combination with cefotaxime. The safety and tolerability of the anti-TIGIT antibody 31C6 in combination with tafamidis was high, which is The purpose of this study is to establish the recommended phase 2 dose (RP2D) for each study. The study included the use of anti-TIGIT antibodies3 as monotherapy and in combination with pembrolizumab. PK of 1C6, PK of pembrolizumab given with the anti-TIGIT antibody 31C6, etc. and anti-TIGIT antibodies as monotherapy and in combination with pembrolizumab31 ORR for C6 (RECIST v1.1, investigator review).

[0282] Part B is a dose confirmation study of 31C6 in combination with pembrolizumab. A large cohort will evaluate the efficacy and safety of 31C6 as monotherapy and in combination with pembrolizumab in anti-tumor Cancer efficacy was evaluated. Enrollment in the expansion part of the study was open to subjects with the following cancers: there were: - NSCLC refractory to PD-1 / PD-L1 inhibitor treatment, - PD-1 / PD-L1 inhibitor-naive NSCLC, - Colorectal cancer - Breast cancer - Ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer.

[0283] Baseline characteristics for Part A of the study are shown in the following table: Baseline Characteristics: Table 4 (Data Data cut-off date: August 16, 2018).

[0284] Table 4. Baseline characteristics (data cutoff date: August 16, 2018) [Table 4]

[0285] Table 5. Baseline characteristics (data cutoff date: August 16, 2018) [Table 5]

[0286] result: In this first-in-human trial , given as monotherapy and in combination with pembrolizumab (200 mg) 1C6 Anti-TIGIT antibody was well tolerated and manageable across all doses tested. There was satisfactory safety: dose-finding was completed without DLTs and there were no treatment-related deaths. Figure 1 depicts PK data from both the monotherapy and combination arms. Regarding monotherapy, the patient status was as follows: 2 patients on treatment, 32 patients discontinued treatment ( 27 patients had disease progression, 2 had physician decision, and 3 had withdrawal. Thirteen patients had pembrolizumab The patients crossed over to combination therapy with Breast Cancer Therapy.

[0287] The combination of anti-TIGIT 31C6 and pembrolizumab was pre-specified Dose escalation for each dose level was completed. No DLTs were observed. The patient status during treatment was as follows: 7 patients were on treatment, 27 patients discontinued treatment (25 patients had progressive disease), and Adverse events are summarized below: Table 6: Summary of adverse events [Table 6]

[0288] Table 7: Treatment-related adverse events: [Table 7]

[0289] Additionally, across multiple tumor types, particularly in heavily pretreated populations, Promising antitumor activity of the combination therapy was observed. An ORR of 31C6 and DCR of 35% were observed with the combination of 31C6 and pembrolizumab. For the combination therapy, an ORR of 19% and DCR of 47% were observed. Responses were observed in patients who crossed over to the combination treatment. Figure 2A and Figure 2 In B, the best percentage change from baseline in target lesions (RECIST v1.1 Figures 3A and 3B show the treatment duration and response time. The figure below shows the results of the RECIST v1.1 study (reviewed by the investigator). A summary of RECIST v1.1 (investigator review) is shown below: Table 8: Antitumor activity [Table 8]

[0290] Partial response observed in 75-year-old female patient with BRCA wild-type ovarian cancer The patient had received four lines of prior chemotherapy, none of which included anti-PD-1 or anti-PD-L No prior therapy had been administered. The patient received 31C6 anti-TIGIT antibody 2.1 mg Patients were treated with 2.1 mg of rituximab monotherapy with documented PD per RECIST and subsequently 31C6 Cross-reactivity to anti-TIGIT antibody + 200mg pembrolizumab combination therapy A partial response was observed 9 weeks after crossover. was reduced by 85% and all lesions (mesenteric deposits, lymph nodes (para-aortic, iliac, cervical)) The size of the tumors decreased. The response was ongoing at 13 months. Treatment was discontinued due to a rash. .

[0291] Example 2: Part B of the Phase I trial The design of Part B of the Phase I study described in Example 1 above is as follows: be: Table 9: Design of Part B of the Phase 1 Study [Table 9]

[0292] Additionally, the following combinations are ongoing: 31C6 + pembrolizumab + carboplatin in squamous PD1-naive NSCLC and paclitaxel (Taxol) 31C6 + pembrolizumab + carboplatin in non-squamous PD1-naive NSCLC Chin 31C6 + pembrolizumab + carboplatin in squamous PD1-naive NSCLC acetaminophen and taxol result: Safety Overview As of September 2019, the side effect profile of 31C6 and pembrolizumab was Side effect rates were observed to be comparable to those of 31C6 monotherapy treatment. Adrenal function was similar between 31C6 and pembrolizumab combination treatments. Insufficiency and infusion reactions are more common than pembrolizumab-induced reflex sympathetic dystrophy (RSD). See summary in Table 10.

[0293] Table 10. Summary of Adrenal Insufficiency and Infusion Reactions [Table 10]

[0294] For example, patients receiving a dose of 200 mg may show linear clearance. This was observed, consistent with previous findings in the Part A data (200 mg:CL = 0.49 L / day and t1 / 2 = 9.9 days; 700 mg: CL = 0.48 L / day and t1 / 2=9.4 days). PK variability was also analyzed and showed consistent results (C V=46%).

[0295] Effectiveness Antitumor activity was assessed in different patient populations tested in Part B. PD-1-naive NSCLC The results were analyzed in the group of patients.

[0296] Responses were observed in naive NSCLC patients and are shown in Figure 4 and Table 11 (R ECIST v1.1, investigator review). ORR data were based on all PD-L1 Patients with L1 levels were included, and despite being more advanced in treatment lines, The combination of 1C6 and pembrolizumab was shown to be higher than the control. Patients enrolled in KN-010 who had received multiple prior lines of therapy and had a TPS of ≥ 1% In NSCLC patients treated with EGFR, the ORR was 18%.

[0297] Table 11. Investigator-Based RECIST 1.1 in PD-1-Naive NSCLC Best overall effect [Table 11]

[0298] KN-010: 100% of pts had TPS ≥ 1, 29% of pts had 3L+ Pembro+31C6: 52% of pts have TPS ≥ 1, 60% of targets are 3L+ In addition, 31C6 antibody (200 mg) monotherapy or 31C6 (200 mg) and PD-1 refractory patients treated with any of the pembrolizumab (200m) combination therapies Investigator-Performed Best Response by RECIST 1.1 in Subjects with NSCLC Data were obtained showing that monotherapy activity was unselected. See Table 12. Significant ORR results were also observed in D1-refractory NSCLC. The responses were well-known, including complete response. The ORR results for were similar to those for combination therapy.

[0299] Table 12. PD-1 treated with 31C6 alone or in combination with pembrolizumab Investigator-performed RECIST 1.1 optimal response rate in subjects with refractory NSCLC Good overall effect [Table 12]

[0300] 83% of PD-1 refractory NSCLC patients in 31C6 were 3L+ 31C6 (200 mg) alone or in combination with pembrolizumab (200 mg) Duration of response data in subjects with PD-1 refractory NSCLC treated with , Table 13, and Figures 5A and 5B.

[0301] Table 13. PD-1 refractory NS treated with 31C6 (200 mg) + pembrolizumab Duration of response in subjects with CLC [Table 13]

[0302] ovarian cancer Efficacy data for the ovarian cancer patient population (Parts A and B) are summarized in Figure 6 and and Table 14. PD1-naive ovarian cancer (resistant to platinum-based therapy) In the PD-L1 positive tumor group, an ORR of 19% (n=27) was observed. Further enhancement was observed in tumors (CPS1, ORR 40%). The time was 3.5±2.3 months, and the median DOR was 4.1-11.2+ months.

[0303] Table 14. Investigator-reported best overall response rate according to RECIST 1.1 for patients with ovarian cancer Combined effect [Table 14]

[0304] Pembro+31C6: (74% of subjects 3L+); 3 confirmed responders 3L +, all responders were BRCA negative.

[0305] In a cohort of patients with platinum-resistant ovarian cancer in Part B (n=20), After two objective responses were observed in ovarian cancer patients (out of seven), preliminary efficacy data were obtained. Combination treatment of 31C6 antibody and pembrolizumab (Parts A and B) In subjects with ovarian cancer treated with EGFR-1, the ORR was 19% (5 / 27), with a DOR of 1.5% (0.7%). The mean age ranged from 4.2 to 11.4+ months. Of the 27 ovarian patients, P was PD-L1 data were available. PD-L1 data from ovarian patients treated with the 31C6 antibody In CPS1-positive (CPS1) tumors, the ORR was 40% (2 / 5) compared with pembrolizumab In patients with PD-L1+ ovarian cancer treated with lolizumab monotherapy, the rate was 14%. Of note, all ovarian responders in this study were BR CA was negative and therefore not limited to any specific treatment or mechanism. Based on efficacy and tolerability, monotherapy with the 31C6 antibody and 31C6 Antibody-pembrolizumab combination therapy may be an effective treatment option for this population with high unmet need. This could make it a very attractive treatment option that does not require chemotherapy.

[0306] Breast cancer In this study, there were no first-line patients, so 2L+, PD-1 / L- All patients who had undergone steroid therapy were eligible for inclusion. These patients had the following characteristics: One DLT (febrile neutropenia) was identified, leaving 7 of 10 patients remaining on the study The characteristics of patients who discontinued were as follows: 1 patient had clinical PD, 2 patients had AE [PNA (unrelated), G3 LFT elevation (io) (i.e., 31C6 antibody and penicillin-resistant strains)] In this study, 10 study subjects Patients underwent scanning, and all underwent only one scan (SD 7, PR 2, P Data from this breast cancer study are shown in Figure 7 and Table 15.

[0307] Table 15. PD-1 naive patients treated with 31C6 (200 mg) and pembrolizumab Breast Patient Data [Table 15]

[0308] Ancillary data for CRC breast patients are provided in Figure 8 and Table 16.

[0309] Table 16. PD-1 naive patients treated with 31C6 (200 mg) and pembrolizumab CRC breast cancer patient data [Table 16]

[0310] Cervical cancer At the time of data cutoff, 7 and 7 patients were treated with the 200 mg and 700 mg doses, respectively. Eight patients remain on the study. Data are shown in Figures 9A and 9B and Table 17. At this early stage, the 200 mg and 700 mg 31C6 combinations with pembrolizumab There are no significant differences in efficacy and safety between the combination treatment arms.

[0311] Table 17. For 200 mg or 700 mg of 31C6 antibody and pembrolizumab Data from randomized cervical cancer patients [Table 17]

[0312] In conclusion, it was observed that monotherapy with antibody 31C6 was well tolerated. Side effects are tolerable, and the 31C6 antibody in combination with pembrolizumab The observed side effect profile was consistent with that observed with pembrolizumab monotherapy. In terms of dose and PK data, the half-life of the 31C6 antibody was approximately 10 days. Normal PK variability was observed, with the observed incidence of ADA being 10-20%. Although many of the doses showed favorable results, the preliminary RP2D of 200 mg remains The data demonstrate that exposure to antibody treatment was maintained throughout the dosing interval. Initial data show that a randomized dose comparison of 200 mg and 700 mg The study demonstrates comparable safety and efficacy to the 31C6 antibody. Among the favorable efficacy data: 31C6 antibody as monotherapy and both 31C6 antibody and pembrolizumab Combined therapy in patients with NSCLC (PD-1 naive and PD-1 refractory) and Significant signals of clinical efficacy were observed for treating patients with ovarian cancer. Importantly, treatment with the 31C6 antibody (both as monotherapy and as part of a combination therapy) There was evidence that each of these compounds had antitumor activity in each cancer type tested. For example, antitumor activity of the monotherapy was observed in patients with PD-1-refractory NSCLC. Data include CR in patients treated with the 31C6 monotherapy chain and a CR in the heavy chain. The survey included 113 cases.

[0313] References 1. Sharpe, AH, Wherry, EJ, Ahmed R., and Freeman GJ The function of progra mmed cell death 1 and its ligands in reg ulating autoimmunity and infection. Natu re Immunology (2007);8:239-245. 2. Dong H et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 20 02 Aug;8(8):793-800. 3. Yang et al. PD-1 interaction contrib utes to the functional suppression of T- cell responses to human melanoma cells i n vitro. Invest Ophthalmol Vis Sci. 2008 Jun;49(6 (2008): 49: 2518-2525. 4. Ghebeh et al. The B7-H1 (PD-L1) T ly mphocyte-inhibitory molecule is expresse d in breast cancer patients with infiltr ating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia (2006) 8: 190-198. 5. Hamanishi J et al. Programmed cell d eath 1 ligand 1 and tumor-infiltrating C D8+ T lymphocytes are prognostic factors of human ovarian cancer. Proceeding of the National Academy of Sciences (2007): 104: 3360-3365. 6. Thompson RH et al. Significance of B 7-H1 overexpression in kidney cancer. Cl inical genitourin Cancer (2006): 5: 206- 211. 7. Nomi, T. Sho, M., Akahori, T., et al . Clinical significance and therapeutic potential of the programmed death- 1 lig and / programmed death-1 pathway in human pancreatic cancer. Clinical Cancer Resea rch (2007);13:2151-2157. 8. Ohigashi Y et al. Clinical significa nce of programmed death-1 ligand-1 and p rogrammed death-1 ligand 2 expression i n human esophageal cancer. Clin. Cancer Research (2005): 11: 2947-2953. 9. Inman et al. PD-L1 (B7-H1) expressio n by urothelial carcinoma of the bladder and BCG- induced granulomata: associati ons with localized stage progression. Ca ncer (2007): 109: 1499- 1505. 10. Shimauchi T et al. Augmented expres sion of programmed death-1 in both neopl asmatic and nonneoplastic CD4+ T-cells i n adult T-cell Leukemia / Lymphoma. Int. J. Cancer (2007): 121:2585-2590. 11. Gao et al. Overexpression of PD-L1 significantly associates with tumor aggr essiveness and postoperative recurrence in human hepatocellular carcinoma. Clini cal Cancer Research (2009) 15: 971-979. 12. Nakanishi J. Overexpression of B7-H 1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immu nol Immunother. (2007) 56:1173- 1182. 13. Hino et al. Tumor cell expression o f programmed cell death-1 is a prognosti c factor for malignant melanoma. Cancer (2010): 00: 1-9. 14. Ghebeh H. Foxp3+ tregs and B7-H1+ / P D-1+ T lymphocytes co-infiltrate the tum or tissues of high-risk breast cancer pa tients: implication for immunotherapy. B MC Cancer. 2008 Feb 23;8:57. 15. Ahmadzadeh M et al. Tumor antigen-s pecific CD8 T cells infiltrating the tum or express high levels of PD-1 and are f unctionally impaired. Blood (2009) 114: 1537-1544. 16. Thompson RH et al. PD-1 is expressed d by tumor infiltrating cells and is ass associated with poor outcome for patients w ith renal carcinoma. Clinical Cancer Res earch (2007) 15: 1757-1761. All references cited herein are to each individual publication, database entry, (e.g., Genbank sequence or GeneID entry), patent application or patent to the same extent as if the permission were specifically and individually indicated to be incorporated by reference. This statement of incorporation by reference is hereby incorporated by reference in its entirety by the applicant. Pursuant to 7 CFR §1.57(b)(1), such citations are incorporated by reference. Each of them is subject to 37 CFR §1, even if it is not directly adjacent to a dedicated statement about Any individual publication, database, or other publication specifically identified pursuant to § .57(b)(2) entries (e.g., Genbank sequences or GeneID entries), patent applications, or The invention is intended to be related to the invention or patents. The inclusion of a specific statement about the incorporation by reference, if any, The citation of references herein is hereby incorporated by reference. No admission is intended that the references are pertinent prior art, and the contents of these publications or documents No admissions are made as to the content or date of the claims. To the extent that any reference provides a definition that contradicts the definitions provided herein, The definitions provided in are to be used to interpret the claimed invention.

Claims

1. The patient is administered 2.1 mg to 700 mg of an anti-TIGIT antibody comprising a heavy chain and a light chain. A method for treating cancer in a patient, comprising administering to said patient a light chain sequence identical to SEQ ID NO: 26, 7 and 28, and the heavy chain comprises the heavy chain CDRs of SEQ ID NOs: 29, 30 and 31. The method comprising:

2. The method of claim 1 , wherein the anti-TIGIT antibody is administered via intravenous infusion.

3. The method of claim 1 , wherein the patient is administered 2.1 mg of the anti-TIGIT antibody.

4. The method of claim 1, wherein the patient is administered 7 mg of the anti-TIGIT antibody.

5. The method of claim 1 , wherein the patient is administered 21 mg of the anti-TIGIT antibody.

6. The method of claim 1, wherein the patient is administered 70 mg of the anti-TIGIT antibody.

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

8. The method of claim 1, wherein the patient is administered 210 mg of the anti-TIGIT antibody.

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

10. The patient is administered an anti-TIGIT antibody on day 1 and then once every three weeks thereafter.

10. The method of any one of claims 1 to 9.

11. The anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable domain comprising SEQ ID NO:

25.

11. Any one of claims 1 to 10, wherein the light chain comprises a light chain variable region comprising SEQ ID NO:

24. Or one method.

12. The anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises 12. The method of any one of claims 1 to 11, comprising SEQ ID NO:

22.

13. The method of any one of claims 1 to 10, wherein the anti-TIGIT antibody is a 31C6 variant. method.

14. The anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or an antigen-binding The method of claim 1 , wherein the compound is co-administered with a synthetic fragment.

15. The anti-TIGIT antibody is an anti-PD-1 antibody or an anti-PD-L1 antibody, or an antigen-binding The method of claim 1 , wherein the compound is combined with a synthetic fragment.

16. 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 14 or 15, which blocks binding of D-L1 to human PD-1.

17. The anti-PD-1 antibody or antigen-binding fragment thereof may also bind human PD-L2 to human PD-1. The method of claim 16, wherein the binding is blocked.

18. The anti-PD-1 antibody or antigen-binding fragment thereof comprises: (a) a light chain C of SEQ ID NOs: 1, 2, and 3; 20. The method of claim 17, comprising (a) a heavy chain CDR and (b) a heavy chain CDR of SEQ ID NOs: 6, 7 and 8.

19. 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.

20. 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.

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

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

23. The method of claim 14, wherein the anti-PD-1 antibody is nivolumab.

24. The anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab. Item 15. The method of item 14.

25. Anti-PD-1 antibody will be administered intravenously at 200 mg on day 1, then once every 3 weeks thereafter. The method of any one of claims 18 to 24, wherein the administration is via infusion.

26. Anti-PD-1 antibody will be administered intravenously at 400 mg on day 1 and then once every 6 weeks thereafter. The method of any one of claims 18 to 24, wherein the administration is via infusion.

27. 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 heavy chain CDRs of SEQ ID NOs: 1, 2 and a light chain variable region comprising three light chain CDRs; and an anti-TIGIT antibody comprising a heavy chain and a humanized anti-TIGIT antibody comprising a heavy chain and a light chain, wherein the heavy chain is a sequence selected from SEQ ID NOs: 29, 30 and 31; The heavy chain variable region comprises 31 heavy chain CDRs, and the light chain comprises the light chains represented by SEQ ID NOs: 26, 27 and 28.

16. The method of claim 14 or 15, comprising a light chain variable region comprising the light chain CDRs.

28. 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-TIGIT antibody comprises 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 SEQ ID NO: The method of claim 14 or 15, comprising a light chain variable region comprising SEQ ID NO:

24.

29. 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-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the sequence 23, and the light chain comprises a light chain variable region comprising SEQ ID NO:

22. How to.

30. Anti-PD-1 antibody, 200 mg, intravenously on day 1, then once every 3 weeks thereafter and anti-TIGIT antibody at 200 mg on day 1, then every 3 weeks thereafter.

30. The method of any one of claims 27 to 29, wherein the compound is administered via intravenous infusion once per day.

31. Anti-PD-1 antibody, 400 mg, intravenously on day 1, then once every 6 weeks thereafter The anti-TIGIT antibody was administered intravenously at 200 mg on day 1 once every 3 weeks.

30. The method of any one of claims 27 to 29, wherein the administration is via infusion.

32. Anti-PD-1 antibody, 200 mg, intravenously on day 1, then once every 3 weeks thereafter and anti-TIGIT antibody at 700 mg on day 1, then every 3 weeks thereafter.

30. The method of any one of claims 27 to 29, wherein the compound is administered via intravenous infusion once per day.

33. Anti-PD-1 antibody, 400 mg, intravenously on day 1, then once every 6 weeks thereafter The anti-TIGIT antibody was administered intravenously on day 1 at 700 mg once every 3 weeks.

30. The method of any one of claims 27 to 29, wherein the administration is via infusion.

34. 200 mg of anti-PD-1 antibody is combined with 200 mg of anti-TIGIT antibody.

30. The method of any one of items 27 to 29.

35. 200 mg of anti-PD-1 antibody is combined with 700 mg of anti-TIGIT antibody.

30. The method of any one of items 27 to 29.

36. Cancers include NSCLC, cervical cancer, colorectal cancer, gastric cancer, breast cancer, ovarian cancer, and epithelial cancer.

36. The method according to claim 1, wherein the cancer is selected from the group consisting of primary peritoneal cancer, fallopian tube cancer, or primary peritoneal cancer. Either one of the methods.

37. 37. The method of claim 36, wherein the cancer is NSCLC.

38. carboplatin and pemetrexed, or (ii) carboplatin and paclitaxel 38. The method of any of claims 1 to 37, further comprising administering a combination of cisplatin and ketamine.

39. The individual 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 39. The method of any one of claims 1 to 38.

40. 200 mg of pembrolizumab or pembrolizumab variant, 200 mg of 31 Pharmaceutical composition comprising a 31C6 antibody or a 31C6 variant and a pharma- ceutically acceptable excipient - Patent application thing.

41. 200 mg pembrolizumab or pembrolizumab variant, 2.1 to 700 mg of 31C6 antibody or 31C6 variant, and a pharma- ceutically acceptable excipient. , pharmaceutical compositions.

42. 400 mg pembrolizumab or pembrolizumab variant, 2.1 to 700 mg of 31C6 antibody or 31C6 variant, and a pharma- ceutically acceptable excipient. , pharmaceutical compositions.

43. 2.1 mg of 31C6 antibody or 31C6 variant of claim 41 or 42. Pharmaceutical compositions.

44. 43. The medicament of claim 41 or 42, comprising 7 mg of the 31C6 antibody or 31C6 variant. composition.

45. 21 mg of 31C6 antibody or 31C6 variant. Pharmaceutical composition.

46. 43. The pharmaceutical composition of claim 41 or 42, comprising 70 mg of 31C6 antibody or 31C6 variant. Pharmaceutical composition.

47. 43. The method of claim 41 or 42, comprising administering to said patient 200 mg of the 31C6 antibody or 31C6 variant. Pharmaceutical compositions.

48. 43. The method of claim 41 or 42, comprising administering to said patient 210 mg of the 31C6 antibody or 31C6 variant. Pharmaceutical compositions.

49. 43. The method of claim 41 or 42, comprising administering to said patient 700 mg of the 31C6 antibody or 31C6 variant. Pharmaceutical compositions.

50. The 31C6 antibody or 31C6 variant comprises a heavy chain and a light chain, wherein the light chain is The light chain comprises CDRs of SEQ ID NOs: 26, 27 and 28, and the heavy chain comprises CDRs of SEQ ID NOs: 29, 30 and 31.

50. The pharmaceutical composition of any of claims 40 to 49, comprising the CDRs of each of the three chains.

51. The 31C6 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:

25.

50. The method of claim 40, wherein the light chain comprises a light chain variable region comprising SEQ ID NO:

24. Pharmaceutical compositions.

52. The 31C6 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises the sequence 50. The pharmaceutical composition of any one of claims 40 to 49, comprising a light chain variable region comprising number 22.

53. A method for treating cancer comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 40 to 52 and instructions for use. Treatment kit.

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