Combinations of antibodies or their antigen-binding fragments and compositions for treating cancer

Abstract

The present invention relates to a combination of antibodies or antigen-binding fragments for use in the treatment of cancer in human subjects requiring such treatment, wherein the combination comprises at least one first antibody or antigen-binding fragment, at least one second antibody or antigen-binding fragment, and at least one third antibody or antigen-binding fragment, each of which antibodies independently and specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, Annexin A2, GSTO1, Annexin A5, MX1, RTN4, FASN, and PDIA4. The present invention further relates to a pharmaceutical composition for use in the treatment of cancer in human subjects requiring such treatment, comprising this combination of antibodies or antigen-binding fragments and a pharmaceutically acceptable carrier.

Description

[Technical Field]

[0001] This invention relates to the field of cancer treatment. In particular, this invention relates to combinations of antibodies against specific antigens and their implementation in cancer treatment. [Background technology]

[0002] Cancer is the second leading cause of death worldwide, accounting for an estimated 9.6 million deaths in 2018. Globally, approximately one in six deaths is attributed to cancer. Limited access to or inadequate treatments are common in this field. Therefore, there is a widespread recognition of the need to develop new and improved therapies for treating cancer.

[0003] Immunotherapy has become a true hope in the treatment of a great many cancers, especially those that are not currently effectively cured by conventional therapies. This treatment mainly consists of administering monoclonal antibodies against tumor cells or against checkpoint activators or checkpoint inhibitors of the immune response to cancer.

[0004] Antibodies against tumors (passive immunotherapy) - Caused by complement-dependent cell-dependent cytotoxicity (CDC), killer cell-dependent cytotoxicity (ADCC), or phagocytic cell-dependent cytotoxicity (ADCP), - Due to the induction of an adaptive immune response It can act through two complementary means. Opsonization of targets and local generation of complement molecules (C3a, C5a) (Strainic et al., Immunity, March 2008, 28(3):425~35) have been demonstrated to activate T lymphocyte co-stimulation and increase their survival. Therefore, passive administration of antitumor antibodies can release factors from complement in the first step, which in the second step promotes the T cell response.

[0005] However, 40% to 85% of patients are resistant to treatment based on the use of monoclonal antibodies. Evasion mechanisms include immune selection mechanisms, i.e., the ability of tumor cells to lose antigens recognized by the immune system, and immune subversion mechanisms (induction of specific immune tolerance). The emergence of tumor variants with low immunogenicity can be particularly detrimental to treatment based on the use of monoclonal antibodies (specific to the intrinsic epitope).

[0006] Therefore, treatments based on the use of a combination of antibodies targeting different antigens on tumor cells may minimize evasion mechanisms.

[0007] However, despite the potential efficacy of antibody combinations observed by Richet more than 100 years ago, antibody combinations, such as polyclonal antibodies derived from animals, have been rarely used in tumor treatment, particularly due to the high risk of toxicity in patients. This toxicity is mainly related to the expression of Neu5GC and alpha-1,3-galactose carbohydrates on animal immunoglobulins, which in humans trigger potent anti-Neu5GC and anti-alpha-1,3-galactose immune responses associated with allergies, serum sickness, and immune complex formation. Monoclonal antibody combinations have been considered to mimic polyclonal humoral immune responses for the purpose of treating cancer. However, the clinical efficacy of these as monotherapies does not guarantee their safety and clinical efficacy in combination (Berlin et al., Investigational News Drugs (2022) 40:586~595). The difficulties with such combinations lie primarily in the fact that the PK differs depending on the antibody (which makes toxicity control more difficult), and in the stability and manufacturing of the product depending on the isotype (see, for example, Larbouret et al., Cancers (Basel). September 15, 2021, 13(18):4620). [Prior art documents] [Patent Documents]

[0008]

Patent Document 1

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Non-licensed literature

[0009] [Non-licensed document 1] Strainicら、Immunity, March 2008, 28(3):425~35 [Non-licensed document 2] Berlinら、Investigational News Drugs (2022) 40:586~595 [Non-licensed document 3] Larbouretら、Cancers (Basel). September 15, 2021, 13(18):4620

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0010] Therefore, in this field, there is still a need for novel anti-cancer drugs, especially new drugs that are effective against a wide variety of cancers.

[0011] Furthermore, in this technological field, there is still a need for novel anticancer drugs that can kill a wide variety of cancers by binding to tumor cells, activating complement, and then activating apoptosis mechanisms.

[0012] Furthermore, in this field, there remains a need for effective and improved treatments for cancer that have reduced or no side effects.

[0013] Furthermore, there is still a need for new therapeutic drugs for cancers that have developed into circulating tumor cells (CTCs).

[0014] In fact, tumor metastasis is a series of sequential steps initiated by the infiltration of individual cells called circulating tumor cells (CTCs) into the bloodstream. The procedure of counting CTCs arising from a primary tumor is known to be a reliable method in cancer staging and treatment monitoring. The number of CTCs correlates well with various clinical time points, such as progression-free survival (PFS) and overall survival (OS).

[0015] The present invention aims to solve the above-mentioned needs. [Means for solving the problem]

[0016] The present invention relates in particular to the following items.

[0017] Item 1: A combination of an antibody or its antigen-binding fragment for use in the treatment of cancer in human subjects where such use is required, - At least one first antibody, or its antigen-binding fragment, - At least one second antibody, or its antigen-binding fragment, and - At least one third antibody, or its antigen-binding fragment Includes, Each of these antibodies independently and specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, Annexin A2, GSTO1, Annexin A5, MX1, RTN4, FASN, and PDIA4. The first, second, and third antibodies, or their antigen-binding fragments, each bind to a different antigen selected from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4. A combination of antibodies or their antigen-binding fragments for use.

[0018] As shown in the examples, the inventors have actually determined and demonstrated, in some interesting and unexpected ways, the ability of various combinations of antibodies against specific antigens, particularly various combinations of polyclonal antibodies from non-human mammals, to potently and specifically target various cancers that do not originate from the same tissue without apparent toxicity.

[0019] These findings clearly challenge the well-established preconception that combinations of three or more antibodies cannot be used in cancer treatment in patients being treated, given their expected high toxic effects as described above.

[0020] Even more interestingly, this provides clinicians with novel, active drugs that can be used against a wide range of cancers.

[0021] Item 2: The combination includes at least one fourth antibody or its antigen-binding fragment that specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, Annexin A2, GSTO1, Annexin A5, MX1, RTN4, FASN, and PDIA4. The antigen is, in particular, different from the three antigens to which the first, second, and third antibodies or their antigen-binding fragments bind. The combinations for use as described in item 1.

[0022] Item 3: A combination for use as described in Item 1 or 2, wherein the antigen-binding fragments of the antibodies present in the combination are independently Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, or diabody.

[0023] Item 4: Cancer includes myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma A selection is made from the group consisting of cancers with circulating tumor cells (CTCs), including: DLBCL; gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma and osteosarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; esophageal cancer; bladder cancer; pleural mesothelioma; kidney cancer; and cancers with circulating tumor cells (CTCs). More specifically, selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; and esophageal cancer. A combination for use as described in any one of items 1 through 3.

[0024] Item 5: - The first antibody or its antigen-binding fragment specifically binds to the antigen GSTO1, - The second antibody or its antigen-binding fragment specifically binds to the antigen annexin A5, - The third antibody or its antigen-binding fragment specifically binds to antigen MX1, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen RTN4, - Cancer is selected from the group consisting of melanoma; myeloma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; breast cancer; prostate cancer; colorectal cancer, especially colon cancer; and lung cancer, especially non-small cell lung cancer. More specifically, the group is selected from melanoma; prostate cancer; myeloma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; and lung cancer, especially non-small cell lung cancer. In particular, selected from the group consisting of melanoma; prostate cancer; myeloma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; and lung cancer, especially non-small cell lung cancer, and More specifically, selected from the group consisting of melanoma; myeloma, and liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer. A combination for use as described in any one of items 1 through 4.

[0025] Item 6: - The first antibody or its antigen-binding fragment specifically binds to the antigen annexin A2, - The second antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, - The third antibody or its antigen-binding fragment specifically binds to the antigen CKAP4, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen PDIA4, - Cancer is selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; gastric cancer; head and neck cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers. More specifically, selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially T-cell lymphoma or B-cell lymphoma, especially T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; gastric cancer; head and neck cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers. A combination for use as described in any one of items 1 through 4.

[0026] Item 7: Cancer is selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; and epidermal carcinoma. More specifically, the group is selected from myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; pancreatic cancer; and lymphoma, especially T-cell lymphoma. More specifically, the group is selected from myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; pancreatic cancer; and lymphoma, especially T-cell lymphoma. More specifically, selected from the group consisting of myeloma; melanoma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; and colorectal cancer, especially colon cancer, and In particular, selected from the group consisting of myeloma; melanoma; and liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer, The combinations for use described in item 6.

[0027] Item 8: - The first antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, - The second antibody or its antigen-binding fragment specifically binds to the antigen annexin A5, - The third antibody or its antigen-binding fragment specifically binds to the antigen RTN4, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen FASN, The combination further comprises a fifth antibody or its antigen-binding fragment that specifically binds to the antigen PDIA4, - Cancer is selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; gastric cancer; head and neck cancer; anal cancer; esophageal cancer; and prostate cancer. In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; gastric cancer; head and neck cancer; anal cancer; and esophageal cancer, In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; and prostate cancer, In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; and colorectal cancer, especially colon cancer, Furthermore, more specifically, liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer. A combination for use as described in any one of items 1 through 4.

[0028] Item 9: A combination of antibodies for use as described in any one of items 1 to 8, wherein at least one of the combination of antibodies for use lacks at least one antigenic determinant selected from (i) N-glycolylneuraminic acid (Neu5Gc) and (ii) α-1,3-galactose, and in particular lacks two antigenic determinants, N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose.

[0029] Item 10: A pharmaceutical composition for use in the treatment of cancer in a human subject requiring such use, comprising a combination of an antibody or an antigen-binding fragment thereof as described in any one of items 1 to 3 and 5 to 9, and a pharmaceutically acceptable carrier.

[0030] Item 11: Cancer includes myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma Selected from the group consisting of patoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; esophageal cancer; bladder cancer; pleural mesothelioma; kidney cancer; and cancers with circulating tumor cells (CTCs), Furthermore, selected from the group consisting particularly of myeloma; melanoma; breast cancer, particularly triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, particularly colon cancer; lung cancer, particularly non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, particularly B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, particularly Ewing's sarcoma or soft tissue sarcoma; leukemia, particularly leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; and esophageal cancer. A pharmaceutical composition for use as described in item 10.

[0031] Item 12: A pharmaceutical composition for use according to Item 10 or 11, further comprising at least one additional anticancer drug different from the antibody combination described in any one of Items 1 to 3 and 5 to 9.

[0032] Item 13: At least one additional anticancer drug is selected from the group consisting of monoclonal antibodies, in particular anti-CD137 monoclonal antibody, anti-CTLA4 monoclonal antibody, anti-TIM-3 monoclonal antibody, anti-B7-H3 monoclonal antibody, anti-CD134 monoclonal antibody, anti-CD154 monoclonal antibody, anti-LAG-3 monoclonal antibody, anti-CD227 monoclonal antibody, anti-BTNA3 monoclonal antibody, anti-CD39 monoclonal antibody, anti-CD73 monoclonal antibody, anti-CD115 monoclonal antibody A polyclonal antibody composition for use as specified in item 12, selected from the group consisting of anti-CD47 monoclonal antibody, anti-SIRP alpha monoclonal antibody, anti-SIRP gamma monoclonal antibody, anti-CD28 monoclonal antibody, anti-NCR monoclonal antibody, anti-NKp46 monoclonal antibody, anti-NKp30 monoclonal antibody, anti-NKp44 monoclonal antibody, anti-NKG2D monoclonal antibody, anti-PD1 monoclonal antibody, anti-PDL1 monoclonal antibody, and anti-DNAM-1 monoclonal antibody. [Brief explanation of the drawing]

[0033] [Figure 1] This figure shows FACS (BD FACSCanto®, BD Biosciences, US) cross-reactivity assays of XON5 pAb, XON7 pAb, or XON9 pAb in 100,000 cells from different human tumor cell lines. XON5 is a combination of anti-GSTO1 polyclonal antibody, anti-annexin 5 polyclonal antibody, anti-MX1 polyclonal antibody, and anti-RTN4 polyclonal antibody obtained from pigs. XON7 is a combination of anti-annexin A2 polyclonal antibody, anti-SLC3A2 polyclonal antibody, anti-CKAP4 polyclonal antibody, and anti-PDIA4 polyclonal antibody obtained from pigs. XON9 is a combination of anti-SLC3A2 polyclonal antibody, anti-annexin 5 polyclonal antibody, anti-RTN4 polyclonal antibody, anti-FASN polyclonal antibody, and anti-PDIA4 polyclonal antibody obtained from pigs. FITC anti-porcine IgG was used as the secondary antibody. The human cell lines used in the study were HepG2 (human hepatocellular carcinoma), KMS-12-BM (human myeloma), and SK-MEL-30 (human melanoma). Horizontal coordinate: Different human tumor cell lines. From left to right: HepG2, KMS-12-BM, and SK-MEL-30. Vertical coordinate: Median FITC fluorescence intensity. [Figure 2A] This figure shows the cross-CDC activity of XON5, XON7, and XON9 as defined above against different human cancer cell lines. Different antibody combinations according to the present invention XON5( [ka] ), XON7( [ka] ), and XON9( [ka] The percentage of specific cytotoxic activity of ). Figure 2A / XON5 against HCT-116 cell line [ka] ), XON7( [ka] ), and XON9( [ka] ). [Figure 2B] Figure 2B / XON5 against Capan-1 cell line [ka] ), XON7( [ka] ), and XON9( [ka] ). [Figure 2C] Figure 2C / XON5 against A549 cell line [ka] ), XON7( [ka] ), and XON9( [ka] ). [Figure 2D] Figure 2D / XON5 against SK-MEL-30 cell line [ka] ), XON7( [ka] ), and XON9( [ka] ). [Figure 2E] Figure 2E / XON5 against Hep-G2 cell line [ka] ), XON7( [ka] ), and XON9( [ka] ). [Figure 2F] Figure 2F / XON5 against LNPaC cell line [ka] ) and XON7( [ka] ). [Figure 2G] Figure 2G / XON5 against MDA-MB-231 cell line [ka] ) and XON7( [ka] ). [Figure 2H] Figure 2H / KMS-12-BM cell line vs. XON5( [ka] ), XON7( [ka] ), and XON9( [ka] ). In each of Figures 2A to 2H: Vertical coordinate: % of specific cell damage, Horizontal coordinate: concentration of the antibody combination under test (μg / mL). [Figure 3A] This figure shows the cross-apoptotic activity of XON5, XON7, and XON9 as defined above against different human cancer cell lines. Different antibody combinations according to the present invention: XON5( [ka] ), XON7( [ka] ), XON9( [ka] The percentage of apoptotic cells (SK MEL-30 (Figure 3A) or HepG2 (Figure 3B)) after treatment with ), and control IgG (CT IgG) (◆). Figure 3A / XON5( against SK MEL-30 cell line) [ka] ), XON7( [ka] ), XON9( [ka] ), and control IgG(◆). [Figure 3B] Figure 3B / XON5( against HepG2 cell line) [ka] ), XON7( [ka] ), XON9( [ka] ), and control IgG(◆). In Figures 3A and 3B, respectively: Vertical coordinate: % of apoptotic cells, Horizontal coordinate: concentration of the antibody being tested (μg / mL). [Figure 4A] This figure shows the cross-reactivity between anti-cancer pAbs and normal human PBMCs. The percentage of apoptotic cells was determined by FACS using different concentrations of the test anti-cancer pAb exposed to normal human PBMCs (black squares). Human tumor cell lines of the corresponding pAb were used as a positive control. [ka] ). The polyclonal antibodies tested are as follows: Figure 4A / XON9. [Figure 4B] Figure 4B / XON5. [Figure 4C] Figure 4C / XON7. In each of Figures 4A to 4C: Vertical coordinate: % of apoptotic cells, Horizontal coordinate: concentration of the antibody (pAb) combination under test (μg / mL). [Figure 5] This figure shows the in vivo efficacy of XON5 or XON7 as defined above against human lung cancer (A549 cell lineage). Figure 5 shows the efficacy of XON5 from 0 to 30 days after vaccination. [ka] The median volume of human lung tumors in a mouse model (A549 cell line) after treatment with ), after treatment with XON7 (black square), or without treatment (black triangle). Statistical analysis was performed using the ANOVA posthoc test, Newman-Keuls. Vertical coordinate: Median tumor volume (mm) 3 ) Horizontal coordinate: Number of days after vaccination with the antibody combination of test (XON5 or XON7). [Figure 6]This figure shows the in vivo efficacy of XON5 or XON7 as defined above against human breast cancer (MDA-MB-231 cell lineage). Figure 6 shows the efficacy of XON5 from 0 to 20 days after vaccination. [ka] The volume of a human breast cancer model (MDA-MB231 cell line) after treatment with XON7 (black square) or non-immune IgG (black triangle) as a control. Vertical coordinate: Tumor volume (mm) 3 ) Horizontal coordinate: Number of days after vaccination with the antibody combination being tested. [Figure 7] This figure shows the in vivo efficacy of XON5 or XON7 against human prostate cancer (LNPAC cell lineage). Figure 7 shows the results from 0 to 28 days after vaccination, after treatment with XON5 (black square), after treatment with XON7 (black triangle), or without treatment w / o (CTRL- [ka] This shows the median volume of human prostate tumors in a mouse model (LNPAC cell line). Statistical analysis was performed using one-way ANOVA. ***p<0.001 Vertical coordinate: Median tumor volume (mm) 3 ). Horizontal coordinate: Number of days after vaccination with the polyclonal antibody being tested. [Figure 8] This figure shows the in vivo efficacy of XON7 as defined above against human colon adenocarcinoma (HCT-116 cell lineage). Figure 8 shows the results from 0 to 38 days after vaccination, and after treatment with XON7 (black triangles), or without treatment w / o (CTRL- [ka] ) This shows the median volume of human colon adenocarcinoma in a mouse model (HCT-116 cell line). Vertical coordinate: Median tumor volume (mm) 3 ) Horizontal coordinate: Number of days after vaccination with the antibody combination being tested. [Figure 9] Figure 9 shows the in vivo efficacy of XON7 against human T-cell lymphoma (T1301 cell lineage). Figure 9 shows the results from 0 to 28 days after vaccination, and after treatment with XON7 (black triangles), or without treatment (CTRL- [ka] This shows the median volume of human T-cell lymphoma in a mouse model (T1301 cell line). T-test - **p<0.01, *p<0.05 Vertical coordinate: Median tumor volume (mm) 3 ) Horizontal coordinate: Number of days after vaccination with the polyclonal antibody being tested. [Figure 10] This figure shows in vitro binding assays of various monoclonal or polyclonal antibodies and antibody combinations against human melanoma cell lineage (SK-MEL-30) using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark). Alexa Fluor 488 protein A was used as the secondary antibody. The various antibodies or antibody combinations performed are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., antibody groups targeting different epitopes of CKAP4), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7. Vertical axis: Mean fluorescence intensity. [Figure 11]This figure shows in vitro binding assays of various monoclonal or polyclonal antibodies and antibody combinations against human pancreatic adenocarcinoma cell lineage (CAPAN-1) using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark). Alexa Fluor 488 protein A was used as the secondary antibody. The various antibodies or antibody combinations performed are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., antibody groups targeting different epitopes of CKAP4), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7. Vertical axis: Mean fluorescence intensity. [Figure 12] This figure shows in vitro binding assays of various monoclonal or polyclonal antibodies and antibody combinations against human myeloma cell lineage (KMS-12-BM) using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark). Alexa Fluor 488 protein A was used as the secondary antibody. The various antibodies or antibody combinations performed are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., antibodies targeting different epitopes of annexin A2), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7. Vertical axis: Mean fluorescence intensity. [Figure 13]This figure shows in vitro binding assays of various monoclonal or polyclonal antibodies and antibody combinations against human hepatocellular carcinoma cell lineage (HEP-G2) using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark). Alexa Fluor 488 protein A was used as the secondary antibody. The various antibodies or antibody combinations performed are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., antibody groups targeting different epitopes of CKAP4), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7. Vertical axis: Mean fluorescence intensity. [Figure 14]This figure shows in vitro binding assays of various monoclonal or polyclonal antibodies and antibody combinations against human myeloma cell lineage (KMS-12-BM) using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark). Alexa Fluor 488 protein A was used as the secondary antibody. The various antibodies or antibody combinations tested are as follows (from left to right on the horizontal axis): - Anti-GSTO1 polyclonal antibodies (i.e., antibody groups targeting different epitopes of GSTO1), - Anti-annexin A5 polyclonal antibodies (i.e., antibody groups targeting different epitopes of annexin A5), - Anti-MX1 polyclonal antibodies (i.e., antibody groups targeting different epitopes of MX1), - Anti-RNT4 polyclonal antibodies (i.e., antibody groups targeting different epitopes of RNT4), - Combinations of anti-GSTO1 polyclonal antibody, anti-annexin A5 polyclonal antibody, anti-MX1 polyclonal antibody, and anti-RTN4 polyclonal antibody ("Combo A"), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody ("Combo"), and - XON5. Vertical axis: Mean fluorescence intensity. [Figure 15]This figure shows in vitro binding assays of various monoclonal or polyclonal antibodies and antibody combinations against human hepatocellular carcinoma cell lineage (HEP-G2) using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark). Alexa Fluor 488 protein A was used as the secondary antibody. The various antibodies or antibody combinations tested are as follows (from left to right on the horizontal axis): - Anti-SLC3A2 monoclonal antibody, - Anti-annexin A5 polyclonal antibody (i.e., antibody group targeting different epitopes of annexin A5), - Anti-FASN polyclonal antibody (i.e., antibody group targeting different epitopes of FASN), - Anti-RNT4 polyclonal antibody (i.e., antibody group targeting different epitopes of RNT4), - Combination of anti-SLC3A2 monoclonal antibody, anti-annexin A5 polyclonal antibody, anti-FASN polyclonal antibody, and anti-RTN4 polyclonal antibody ("Combo C"), - Combination of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody ("Combo"), and - XON9. Vertical axis: Mean fluorescence intensity. [Figure 16] This figure shows the in vitro complement-dependent cell-mediated cytotoxicity (CDC) activity of various monoclonal or polyclonal antibodies and antibody combinations against human colon adenocarcinoma cell lineage (HCT-116). The various antibodies or antibody combinations tested are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., antibody groups targeting different epitopes of CKAP4), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7 in the presence of rabbit complement (final dilution 1 / 3). Vertical axis: % of specific cytotoxicity. [Figure 17]This figure shows the in vitro complement-dependent cell-mediated cytotoxicity (CDC) activity of various monoclonal or polyclonal antibodies and antibody combinations against human hepatocellular carcinoma (HEP-G2) cells. The various antibodies or antibody combinations tested are as follows (from left to right on the horizontal axis): - anti-annexin A2 monoclonal antibody, - anti-SLC3A2 monoclonal antibody, - anti-CKAP4 polyclonal antibody (i.e., antibody groups targeting different epitopes of CKAP4), - combination of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7 in the presence of rabbit complement (final dilution 1 / 3). Vertical axis: % of specific cytotoxicity. [Figure 18] This figure shows the in vitro complement-dependent cytotoxicity (CDC) activity of various monoclonal or polyclonal antibodies and antibody combinations against human myeloma cell lineage (KMS-12-BM). The various antibodies or antibody combinations tested are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., antibody groups targeting different epitopes of CKAP4), - Combination of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7 in the presence of rabbit complement (final dilution 1 / 3). - Negative control. Vertical axis: % of specific cytotoxicity. One-way Anova posthoc Newman Keuls **p<0.05 [Figure 19A]This figure shows the in vitro apoptotic activity of various monoclonal or polyclonal antibodies and antibody combinations against human myeloma cell lineage (KMS-12-BM) (Figure 19A) or human melanoma cell lineage (SK-MEL-30) (Figure 19B). The various antibodies or antibody combinations tested are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., a group of antibodies targeting different epitopes of CKAP4), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7 in the presence of rabbit complement (final dilution 1 / 3). - Negative control. Vertical axis: % of apoptotic cells. [Figure 19B] This figure shows the in vitro apoptotic activity of various monoclonal or polyclonal antibodies and antibody combinations against human myeloma cell lineage (KMS-12-BM) (Figure 19A) or human melanoma cell lineage (SK-MEL-30) (Figure 19B). The various antibodies or antibody combinations tested are as follows (from left to right on the horizontal axis): - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., a group of antibodies targeting different epitopes of CKAP4), - Combinations of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody, and - XON7 in the presence of rabbit complement (final dilution 1 / 3). - Negative control. Vertical axis: % of apoptotic cells. [Figure 20]This figure shows the median volume of multiple myeloma in a mouse model (KMS-12-BM) from 0 to 28 days after inoculation (intraperitoneal injection) and after treatment with various monoclonal or polyclonal antibodies and antibody combinations against the human myeloma cell line (KMS-12-BM). The various antibodies or antibody combinations used are as follows (from left to right on the horizontal axis): - Negative control: no treatment, - Anti-annexin A2 monoclonal antibody, - Anti-SLC3A2 monoclonal antibody, - Anti-CKAP4 polyclonal antibody (i.e., antibody groups targeting different epitopes of CKAP4), - Combination of anti-annexin A2 antibody, anti-SLC3A2 antibody, and anti-CKAP4 antibody, and - XON7. Vertical axis: Tumor volume in mm³. [Figure 21] This figure shows the cross-CDC activity of XON5 as defined above against different human melanoma cell lines (MeWo and A375). Vertical axis: % of cytotoxicity, horizontal axis: concentration of XON5 (μg / mL). [Figure 22] This figure shows the cross-apoptotic activity of XON5 as defined above against different human melanoma cell lines (MeWo and A375). Vertical axis: % of apoptotic cells, Horizontal axis: concentration of the antibody (XON5) under test (μg / mL). [Figure 23] This figure shows the cross-cytotoxic activity of XON7, as defined above, against three different primary tumors (colon cancer) in human patients: CXF 1103, CXF 243, and CXF 280. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 24] This figure shows the cross-cytotoxic activity of XON7, as defined above, against three different primary tumors (gastric cancer) in human patients: CXF 3067, CXF 251, and CXF 1172. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 25]This figure shows the cross-cytotoxic activity of XON7 as defined above against three different primary tumors and four different human cancer cell lines (head and neck cancers): HNXF 1853, HNXF 1859, CAL-27, SW579, SNU-1076, and FaDu (all head and neck cancers). Vertical coordinate: % of cytotoxicity, horizontal coordinate: concentration of XON7 (μg / mL). [Figure 26] This figure shows the cross-cytotoxic activity of XON7 as defined above against four different human cancer cell lines and one primary tumor from a human patient, namely (multiple myeloma): MM.1R, MM.1S, RPMI 8226, and U-266, as well as primary tumor 1023 (all myeloma). Vertical coordinate: % of cytotoxicity, horizontal coordinate: concentration of XON7 (μg / mL). [Figure 27] This figure shows the cross-cytotoxic activity of XON7, as defined above, against five different human cancer cell lines (leukemia): MOLT-4, RCH-ACV, PL-21, MEC-1, and MEG-01. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 28] This figure shows the cross-cytotoxic activity of XON7 as defined above against different human cancer cell lines (liver cancer): 575, JHH-6, SNU-449, and TFK-1. Vertical coordinate: % of cytotoxicity, horizontal coordinate: concentration of XON7 (μg / mL). [Figure 29] This figure shows the cross-cytotoxic activity of XON7 as defined above against seven different primary tumors (non-small cell lung cancer) in human patients: LXFA 1647, LXFA 289, LXFA 526, LXFA 586, LXFA 629, LXFA 677, and LXFA 737. Vertical coordinate: % of cytotoxicity, horizontal coordinate: concentration of XON7 (μg / mL). [Figure 30] This figure shows the cross-cytotoxic activity of XON7, as defined above, against the lymphoma DLBCL (diffuse large B-cell lymphoma). One human cancer cell line: OCI-LY7. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 31]This figure shows the cross-cytotoxic activity of XON7, as defined above, against two different primary tumors (bladder cancer) in human patients: BXF 1036 and BXF 1218. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 32] This figure shows the cross-cytotoxic activity of XON7 as defined above against two different primary tumors and five human cancer cell lines (breast cancer) from human patients: MAXFTN 401 and MX1, as well as BT20, CAL-51, HCC-1937, MCF 10A, and MDA-MB-468, respectively. Vertical coordinate: % of cytotoxicity, horizontal coordinate: concentration of XON7 (μg / mL). [Figure 33] This figure shows the cross-cytotoxic activity of XON7 as defined above against six different primary tumors (melanomas) in human patients: MEXF 1341, MEXF 1792, MEXF 2090, MEXF 276, MEXF 462, and MEXF 622. Vertical axis: % of cytotoxicity, Horizontal axis: concentration of XON7 (μg / mL). [Figure 34] This figure shows the cross-cytotoxic activity of XON7 as defined above against two different primary tumors and three human cancer cell lines (ovarian cancer) from human patients: OVXF 1023 and OVXF 899, as well as EFO-27, OVCAR-3, and SF-OV-3, respectively. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 35] This figure shows the cross-cytotoxic activity of the above-defined XON7 against four different primary tumors (pancreatic cancer) in human patients: PAXF 1657, PAXF 1997, PAXF 546, and PAXF, as well as the cell line PANC-1. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 36] This figure shows the cross-cytotoxic activity of XON7 as defined above against six different human tumor cell lines (prostate cancer): 22Rv1, BPH1, DU-145, PC-3, PC-3M, and VCap. Vertical coordinate: % of cytotoxicity, horizontal coordinate: concentration of XON7 (μg / mL). [Figure 37]This figure shows the cross-cytotoxic activity of XON7, as defined above, against three different primary tumors (pleural mesothelioma) in human patients: PXF 1118, PXF 1752, and PXF 698. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 38] This figure shows the cross-cytotoxic activity of the above-defined XON7 against five different primary tumors (renal cancer) in human patients: RXF 1183, RXF 2282, RXF 393, RXF 486, and RXF 786-O. Vertical coordinate: % of cytotoxicity, Horizontal coordinate: concentration of XON7 (μg / mL). [Figure 39] This figure shows the cross-cytotoxic activity of XON7 as defined above against two primary tumors from human patients and seven human cancer cell lines (sarcomas): SXF0 678, SXFS 1301, A-673, RD-ES, Saos-2, HT-1080, RH-30, SL-LMS-1, and TE671, respectively. Vertical coordinate: % of cytotoxicity, horizontal coordinate: concentration of XON7 (μg / mL). [Figure 40] This figure shows the differences in bioluminescence in SRG rats (n=10) to monitor the spread of cancer metastasis after intravenous injection of triple-negative cancer tumor cells (MDA-MB-231-Luc - which stably expresses firefly luciferase) and after injection of luciferin, followed by treatment with XON7 and a medium. Vertical coordinate: Bioluminescence (cpm / cm2), Horizontal coordinate: Days after inoculation (days). [Figure 41] This figure shows the cross-CDC activity and specificity of XON9 as defined above against two different hepatocellular carcinoma cell lines (Hep3B and HUH-7) and against non-tumor healthy human primary hepatocytes (hepatocyte I). Vertical axis: specific lysis (%), Horizontal axis: XON9 concentration (log). [Figure 42] This figure shows XON9-induced apoptosis in HUH-7, Hep3B, HCT116, and A549 cancer cell lines. Cells were exposed to increased doses of XON9 for 20 hours ± 4 hours. Apoptosis was then examined by annexin V and PI staining. Vertical axis: specific lysis (%), horizontal axis: XON9 concentration (log). [Figure 43] This figure shows the activation of caspases 8 and 9 by XON9 in different tumor cell lines (Hep G2, Hep 3B, HUH-7, HCT116, A549, or AsPC-1) treated with 250 μg / mL of XON9. The activity of caspase 8 (C8) or 9 (C9) was determined 20 hours ± 4 hours later using a fluorescent probe specific to caspase 8 or 9. (Paired t-test, *: p<0.05, **: p<0.01, ***: p<0.001, N=1). Vertical axis: Percentage of caspase 8 activity (8+) or caspase 9 activity (9+) (%) determined by intracellular green fluorescence level. Horizontal axis: Left: Control (CT), Right: XON9. [Modes for carrying out the invention]

[0034] 1.Definition Several definitions are given below. These definitions include grammatical equivalents.

[0035] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings generally understood by those skilled in the art. For example, *Concise Dictionary of Biomedicine and Molecular Biology*, Juo, Pei-Show, 2nd edition, 2002, CRC Press; *The Dictionary of Cell and Molecular Biology*, 3rd edition, 1999, Academic Press; and *Oxford Dictionary of Biochemistry and Molecular Biology*, Revised, 2000, Oxford University Press may provide those skilled in the art with the general meanings of many of the terms used in this disclosure. In cases of conflict, including definitions, this specification shall prevail. Typical methods and materials are described below, but similar or equivalent methods and materials may also be used in the practice or testing of the present invention. Units, prefixes, and symbols are given in their forms recognized by the International System of Units (SI). The headings described herein are not intended to limit the various aspects of this disclosure.

[0036] All publications and other references mentioned herein are incorporated in their entirety by reference.

[0037] It should be noted that the terms "a" or "an" entity refer to one or more such entities. For example, "an antibody" is understood to refer to one or more antibodies. Therefore, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein.

[0038] Throughout this specification and the embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” are intended to include the integer or set of integers mentioned, but not to exclude any other integer or set of integers. The words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” are intended to include the elements (such as the steps of a composition or method) mentioned, but not to exclude any other elements. The term “consists of” is intended to include the elements mentioned, but not to exclude any additional elements. The term “essentially consists of” is intended to include the elements mentioned, and, where applicable, other elements that do not materially affect the essential features of this disclosure. It is understood that any different embodiments of this disclosure that use the term "includes" or its equivalent will encompass embodiments in which this term is replaced by "includes only," "consists of," or "essentially consists of."

[0039] Whenever an aspect is described herein with the word “including,” it is understood that other similar aspects are also provided, which are described using the terms “consisting of” and / or “essentially consisting of.”

[0040] Furthermore, where used herein, “and / or” is interpreted as a specific disclosure of each of two particular features or components, with or without the other. Thus, where the term “and / or” is used herein in expressions such as “A and / or B,” it includes “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, where the term “and / or” is used in expressions such as “A, B, and / or C,” it includes each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0041] "Pharmacologically" or "pharmaceutically acceptable" refers to molecular entities and compositions that, when appropriately administered to mammals, particularly humans, do not cause adverse allergic or other adverse reactions. A pharmacopoeciably acceptable carrier or excipient refers to any type of non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid.

[0042] As used herein, “pharmaceutically acceptable carrier” includes any and all physiologically compatible solvents, dispersions, coatings, antimicrobial and antifungal agents, and similar substances. Examples of suitable carriers, diluents, and / or excipients include water, amino acids, physiological saline, phosphate-buffered saline, phosphate buffer, acetate buffer, citrate buffer, succinate buffer; amino acids and derivatives such as histidine, arginine, glycine, proline, and glycylglycine; inorganic salts such as NaCl and calcium chloride; sugars or polyalcohols such as dextrose, glycerol, ethanol, sucrose, trehalose, and mannitol; surfactants such as polysorbate 80, polysorbate 20, and polyoxamer 188; and one or more of these, as well as combinations thereof. In many cases, it is preferable to include isotonic agents such as sugars, polyalcohols, or sodium chloride in the composition, and the formulation may also contain antioxidants such as tryptamine and stabilizers such as Tween 20. The requirements for appropriate excipients and pharmaceutical formulations are described in "Remington: The Science & Practice of Pharmacy," a reference book in this field.

[0043] As used herein, the term “antibody” has the same meaning and is used interchangeably. As used herein, “antibody” refers to isolated or recombinant immunoglobulin molecules, and the immunologically active portion of an immunoglobulin molecule, i.e., a molecule having an antigen-binding site that immunospecifically binds to an antigen, such as the proteins SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, or PDIA4. Therefore, the term “antibody” encompasses not only the entire antibody molecule, but also antibody fragments, as well as variants (including derivatives) of antibodies and antibody fragments. In natural antibodies, two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond. Two types of light chains exist: lambda(1) and kappa(k). Five major heavy chain classes (or isotypes) determine the functional activity of antibody molecules: IgM, IgD, IgG, IgA, and IgE. Each chain has a different sequence domain. The light chain contains two domains: a variable domain (VL) and a constant domain (CL). The heavy chain contains four domains: one variable domain (VH) and three constant domains (CH1, CH2, and CH3, collectively called CH). Both the light chain variable region (VL) and the heavy chain variable region (VH) determine the binding recognition and specificity to the antigen. The light chain constant region domain (CL) and the heavy chain constant region domain (CH) confer important biological properties such as antibody chain binding, secretion, transplacental mobility, complement binding, and binding to the Fc receptor (FcR). The Fv fragment is the N-terminal portion of the Fab fragment of immunoglobulin and consists of one light chain and one heavy chain variable region. Antibody specificity depends on the structural complementarity between the antibody binding site and the antigenic determinant. The antibody binding site is mainly composed of residues in the hypervariable region or complementarity-determining region (CDR). Sometimes, residues in the non-hypervariable region or framework region (FR) can be involved in the antibody binding site, or can affect the entire domain structure and, consequently, the binding site. The complementarity-determining region, or CDR, refers to a series of amino acid sequences that both define the binding affinity and specificity of the native immunoglobulin binding site's innate Fv region.The light and heavy chains of immunoglobulins each contain three CDRs, called CDR1-L, CDR2-L, CDR3-L, and CDR1-H, CDR2-H, and CDR3-H, respectively. The antigen-binding site therefore typically contains six CDRs, including the CDR sets of the heavy chain V region and the light chain V region. The framework region (FR) refers to the amino acid sequence sandwiched between the CDRs.

[0044] The term "antibody" includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, camel antibodies, and chimeric antibodies. Antibodies can be of any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2).

[0045] In the context of this disclosure, the term “antibody” specifically includes antibodies that conjugate the SLC3A2 protein (also referred to as anti-SLC3A2 antibodies), and / or antibodies that conjugate the CKAP4 protein (also referred to as anti-CKAP4 antibodies), and / or antibodies that conjugate the annexin A2 protein (also referred to as anti-annexin A2 antibodies), and / or antibodies that conjugate the GSTO1 protein (also referred to as anti-GSTO1 antibodies), and / or antibodies that conjugate the annexin A5 protein (also referred to as anti-annexin A5 antibodies), and / or antibodies that conjugate the MX1 protein (also referred to as anti-MX1 antibodies), and / or antibodies that conjugate the RTN4 protein (also referred to as anti-RTN4 antibodies), and / or antibodies that conjugate the FASN protein (also referred to as anti-FASN antibodies), and / or antibodies that conjugate the PDIA4 protein (also referred to as anti-PDIA4 antibodies).

[0046] All references to the terms “antibody” or “antigen-binding fragment” used herein are intended to refer to the antibody or antigen-binding fragment described herein.

[0047] A (conventional) antibody "fragment" includes a portion of an intact antibody, particularly the antigen-binding region or variable region of the intact antibody. Examples of antibody fragments include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, diabodies, bispecific antibodies, and multispecific antibodies formed from antibody fragments. Conventional antibody fragments can also be heavy chain antibodies or single-domain antibodies such as VHH.

[0048] The term "Fab" refers to an antibody fragment with a molecular weight of approximately 50,000 and antigen-binding activity, in which nearly half of the N-terminal side of the heavy chain and the entire light chain are bound together via disulfide bonds. This is typically obtained by treating IgG with the protease papain between the fragments.

[0049] The term "F(ab')2" refers to an antibody fragment with a molecular weight of approximately 100,000 and antigen-binding activity that is slightly larger than two identical Fab fragments, linked via a disulfide bond in the hinge region. This is typically obtained between fragments by treating IgG with the protease pepsin.

[0050] The term "Fab'" refers to an antibody fragment with a molecular weight of approximately 50,000 and antigen-binding activity, obtained by cleaving the disulfide bond in the hinge region of F(ab')2.

[0051] A single-stranded Fv ("scFv") polypeptide is a covalently linked VH::VL heterodimer typically expressed from a gene fusion containing a gene encoding VH and a gene encoding VL, linked by a peptide coding linker. The human scFv fragments of this disclosure include CDRs with appropriate conformation, particularly by using recombination techniques. Divalent and multivalent antibody fragments can be formed spontaneously by the linking of monovalent scFv or can be produced by linking multiple monovalent scFv with a peptide linker, such as divalent sc(Fv)2. "dsFv" is a VH::VL heterodimer stabilized by a disulfide bond. "(dsFv)2" refers to two dsFv linked by a peptide linker.

[0052] The term "bispecific antibody" or "BsAb" refers to an antibody in which the antigen-binding sites of two antibodies are combined within a single molecule. Therefore, a BsAb can bind two different antigens simultaneously. Genetic engineering has been increasingly used to design, modify, and produce antibodies or antibody derivatives with desired combinations of binding properties and effector functions, as described, for example, in EP2050764A1.

[0053] The term "multispecific antibody" refers to an antibody in which the antigen-binding sites of two or more antibodies are combined within a single molecule.

[0054] The term "diabody" refers to a small antibody fragment having two antigen-binding sites, containing a heavy chain variable domain (VH) bound to a light chain variable domain (VL) within the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between two domains on the same chain, the domains pair with complementary domains on another chain, resulting in two antigen-binding sites.

[0055] Antibodies of compositions according to the present invention can be prepared, alone or in combination, by any technique known in the art, for example, any chemical, biological, genetic, or enzymatic technique, without limitation. Antibodies of the present invention may include polyclonal antibodies. Methods for preparing polyclonal antibodies are known to those skilled in the art (Harlow et al., Antibodies: a Laboratory Manual, Cold Spring Harbor Laboratory Press, 2nd edition (1988)).

[0056] The terms “monoclonal antibody” or “mAb,” as used herein, refer to an antibody molecule consisting of a single amino acid sequence, which is against a single specific antigen and should not be interpreted as requiring the production of the antibody by any particular method. Monoclonal antibodies may be produced by a single clone of a B cell or hybridoma, but may also be recombinant, i.e., produced by protein manipulation.

[0057] As used herein, "polyclonal antibody" means a mixture of antibodies that recognize different epitopes of a given antigen, or even different epitopes of different antigens expressed by a given cell or group of cells. Polyclonal antibodies include polyclonal antibodies contained in the body fluids, particularly serum or plasma, of non-human mammals, especially pigs, or polyclonal antibodies derived from such body fluids.

[0058] The term "humanized antibody" refers to an antibody that is entirely or partially of non-human origin and has been modified to evade or minimize the immune response in humans, particularly by substituting certain amino acids within the framework regions of the VH and VL domains. The constant domains of humanized antibodies are, in most cases, the human CH and CL domains.

[0059] The term "recombinant" refers to antibodies or their antigen-binding fragments, nucleic acid sequences, expression vectors, or, when applied to host cells, products of various combinations of in vitro cloning, restriction, ligation, and other genetic manipulation procedures.

[0060] In the context of the present invention, the term “antibody” means a porcine antibody, and more specifically, a porcine antibody that lacks at least one antigenic determinant selected from (i) N-glycolylneuraminic acid (Neu5Gc) and (ii) α-1,3-galactose, in particular lacks two antigenic determinants, N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose, and more preferably contains at least one sugar moiety different from the antigenic determinants (i) N-glycolylneuraminic acid (Neu5Gc) and / or (ii) α-1,3-galactose.

[0061] As used in this disclosure, the term “antigen” refers to a molecule or part of a molecule that can be conjugated to one or more antibodies. An antigen may have one or more epitopes. For example, in the context of this disclosure, an antigen is selected from the group consisting of proteins SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4.

[0062] The term "affinity," as used herein, refers to the strength of binding of an antibody to an epitope presented on an antigen. Antibody affinity is denoted by the dissociation constant KD, defined as [Ab] × [Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody, and [Ag] is the molar concentration of the unbound antigen. The affinity constant Ka is defined as 1 / Kd. Methods for determining the affinity of Ab can be found, for example, in Harlow et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988; Coligan et al., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993); or Muller, Methods Enzymol, 1983, 92:589-601, which are incorporated herein by reference in their entirety. A well-known and preferred standard method in the art for determining the affinity of an mAb is the measurement of surface plasmon resonance using an instrument from Biacore (Laure et al., Curr Protoc Protein Sci. September 2006, Chapter 19, Unit 19.13). For multimeric antigens such as viral capsids, where both antigen-binding sites of the antibody can bind simultaneously, the Ka and KD values ​​determined by such standard methods are measures of functional affinity, or affinity for interaction. For example, an antibody with a functional binding affinity (KD) of 10, preferably measured by surface plasmon resonance, is considered to have a functional binding affinity (KD) of 10. -8 mol / l(M) or less, preferably 10 -9 M to 10 -12 It is thought that the antigen binds when it is M.

[0063] As used herein, "IgG" means a polypeptide belonging to an antibody class substantially encoded by a recognized immunoglobulin gamma gene. In humans, IgG includes subclasses or isotypes IgG1, IgG2, IgG3, and IgG4. In mice, IgG includes IgG1, IgG2a, IgG2b, and IgG3. In pigs, immunoglobulins include class or isotype antibodies IgM, IgD, IgG, IgE, and IgA, with IgG isotypes including 11 subclasses (Butler et al., Developmental and Comparative Immunology 30 (2006) 199-221; Butler et al., Developmental and Comparative Immunology 33 (2009) 321-333). Full-length IgG consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain, each light chain containing immunoglobulin domains VL and CL, and each heavy chain containing immunoglobulin domains VH, Cγ1 (also called CH1), Cγ2 (also called CH2), and Cγ3 (also called CH3).

[0064] When applied herein to porcine antibodies, “antigenic determinant” (or “epitope”) means a structural component of an antigenic molecule, including antigenic proteins and antigenic carbohydrates, which is responsible for the specific interaction of the antigenic molecule with an antibody molecule caused by the same or related antigen. More broadly, when applied herein to porcine antibodies, the term “antigenic determinant” is also used collectively herein to refer to antigenic molecules containing multiple epitopes, which include a structural motif that requires the presence of a sugar moiety but corresponds to only a portion of an epitope readily recognizable by an antibody molecule caused by the same or related antigen. For example, the antigenic molecule N-glycolylneuraminic acid (Neu5Gc) may be described herein as an “antigenic determinant,” but the antigenic molecule may exhibit two or more epitopes recognizable by antibodies caused by Neu5Gc or molecules containing Neu5Gc.

[0065] As used herein, "conventional polyclonal antibody" means a polyclonal antibody that does not lack the antigenic determinants N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose, particularly porcine or rabbit polyclonal antibodies. In this regard, products marketed under the names Thymoglobulin, Grafaron, Atogum, or p-ALG® (registered trademark) can be specifically cited.

[0066] The term "cancer" is used herein in its conventional sense and refers to cells or groups of cells exhibiting uncontrolled growth and invasion into adjacent tissues, and in certain embodiments, circulating tumor cells (CTCs).

[0067] The term "circulating tumor cells" (CTCs) is defined as tumor cells that circulate in the peripheral bloodstream of cancer patients and are tumor cells that invade blood vessels from primary or metastatic tumors.

[0068] Metastatic liver cancer is a secondary cancer that spreads from the liver to another organ, such as the colon (colon cancer) or pancreas (pancreatic cancer). These cancers arise from metastatic cells originating from primary liver cancer.

[0069] Examples of cancers considered more specifically in this specification are described below. Cancers, in this specification, include in particular myeloma; melanoma; breast cancer, in particular triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, in particular colon cancer; lung cancer, in particular non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, in particular hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, in particular B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma. (DLBCL); may refer to cancers selected from the group consisting of gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; esophageal cancer; bladder cancer; pleural mesothelioma; kidney cancer; and cancers that have circulating tumor cells (CTCs).

[0070] Cancer, more specifically as used herein, may refer to cancers selected from the group consisting of myeloma; melanoma; breast cancer; prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma; gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; cancer of the central nervous system; gastrointestinal stromal cancer; epidermal cancer; and esophageal cancer.

[0071] The “therapeutic effective dose” of antibody combinations used in accordance with the present invention means a sufficient amount of antibodies to obtain the desired effect as described herein, particularly for treating human subjects with cancer. However, it is understood that the total amount of antibody combinations used daily in accordance with the present invention is to be determined by the attending physician within the bounds of medically accurate judgment. The specific therapeutic effective dose level for any particular patient depends on various factors, including the nature of the cancer being treated; the activity of the specific antibody used; the specific composition used; the patient’s age, weight, overall health, sex, and diet; the timing, route of administration, and elimination rate of the specific antibody used; the duration of treatment; drugs used in combination with or concurrently with the specific antibody used; and similar factors well known in the medical field. For example, it is a well known technique in the art to start administration of a compound at a dose lower than the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0072] The terms “treatment” or “therapy” refer to the administration of an active substance for the purpose of curing, healing, alleviating, relieving, altering, correcting, improving, or acting upon a condition (i.e., cancer) or the symptoms of cancer, or for the purpose of preventing or delaying the onset of symptoms, complications, or biochemical signs of a disease, or for the purpose of preventing or inhibiting further development of cancer in any other way.

[0073] The terms “wild-type” or “WT” are used herein in contrast to genetically modified animals. For example, “wild-type pig” means a pig that does not lack at least one gene selected from the group including (i) a gene encoding functional cytidine-5'-monophosphate N-acetylneuraminate hydrolase (CMAH) and (ii) a gene encoding functional α-(1,3)-galactosyltransferase.

[0074] Suitable methods for obtaining polyclonal antibodies that may be present in antibody combinations carried out according to the present invention include, in particular, fractionation and precipitation methods with ethanol, ammonium sulfate, rivanol, polyethylene glycol, or caprylic acid, and methods by passing through an ion-exchange column, other methods which may involve a protein A or G affinity column. The obtained antibodies can then be subjected to conventional treatments for intravenous administration, such as enzymatic cleavage with plasmin, papain, or pepsin. In this regard, the protocol carried out in Example 3 of EP0335804, which performs ion-exchange chromatography on DEAE cellulose, can be further specifically referenced.

[0075] Such antibodies can be produced, for example, by immunization of non-human animals, particularly non-human mammals, according to methods well known to those skilled in the art. Non-human mammals may be selected from the group consisting of rodents such as mice, rats, guinea pigs, and hamsters; lagomorphs such as rabbits; ferrets; felines such as cats; canids such as dogs; goats; sheep; bovines such as cows; pigs such as pigs and boars; camelids; horses; and non-human primates. More specifically, non-human mammals may be pigs. Therefore, "pig-derived anti-cancer pAb" means, for example, a polyclonal antibody obtained by immunization of pigs with a combination of proteins of interest, or with cells that naturally express the target protein on their surface, or cells that have been genetically modified to express the target protein, for which polyclonal antibodies against the target protein are desired. See Reynard et al., PLoS One. 2016, 11(6): e0156775; Schieferdecker et al., Oncotarget. October 11, 2016, 7(41): 67061~67070, and Zhang et al., 2014 (DOI: 10.1038 / srep04984).

[0076] The terms “polypeptide” and “protein” are used herein without distinction to refer to sequences of amino acid residues. These terms apply to amino acid sequences in which one or more amino acid residues are artificial chemical mimics of corresponding natural amino acids, as well as to natural and non-natural amino acid sequences.

[0077] 2. Antibody combinations carried out according to the present invention As described above, the present invention relates to the implementation of a combination of antibodies or antigen-binding fragments thereof for use in the treatment of cancer in human subjects where such use is required.

[0078] Such combinations are - At least one first antibody or its antigen-binding fragment, - At least one second antibody or its antigen-binding fragment, and - At least one third antibody or its antigen-binding fragment Includes, Each of these antibodies independently and specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4.

[0079] The first, second, and third antibodies or their antigen-binding fragments each bind to a different antigen selected from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4. Therefore, in the context of the present invention, it is understood that at least three antigens selected from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4 are subjected to antibody binding of the antibody combination carried out according to the present invention.

[0080] Each antibody present in the combination for use according to the present invention may, independently of other antibodies, be a monoclonal antibody, a polyclonal antibody, or its antigen-binding fragment. As defined above, the antigen-binding fragment may be independently selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, or diabody.

[0081] The antibody combination for use according to the present invention may include antibodies that target four or more different proteins from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4. The antibodies present in the antibody combinations for use according to the present invention can therefore target at least three proteins from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4, or four proteins, or at least four proteins, or five proteins, or at least five proteins, or six proteins, or at least six proteins, or seven proteins, or at least seven proteins, or eight proteins, or at least eight proteins, or nine proteins.

[0082] In particular, the antibody combination for use according to the present invention comprises three, four, or five antibodies, more specifically four or five, selected from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4, that target proteins.

[0083] Some or all of the antibodies in the antibody combination for use according to the present invention may lack at least one antigenic determinant selected from (i) N-glycolylneuraminic acid (Neu5Gc) and (ii) α-1,3-galactose. Some or all of the antibodies for use according to the present invention may, in particular, lack two antigenic determinants, N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose.

[0084] Methods that enable the identification or characterization of such antibodies are within the scope of the general knowledge of those skilled in the art. Methods that can be used by those skilled in the art to identify or characterize antibodies according to the present invention include, for example, enzyme-linked immunosorbent assays (ELISA) in which anti-Neu5Gc antibodies and anti-Gal antibodies are used as detection molecules.

[0085] The antibodies in the antibody combination implemented according to the present invention may be immunoglobulin G antibodies.

[0086] The structure and genetics of swine IgG are described, for example, in the literature (Butler et al., 2009 - DOI: 10.1007 / s00251-009-0356-0). Eleven isotypes, called IgG1a, IgG1b, IgG2a, IgG2b, IgG3, IgG4a, IgG4b, IgG5a, IgG5b, IgG6a, and IgG6b, have been proposed based on the analysis of the genomic IgH locus sequence. According to available knowledge regarding the relative amounts of porcine IgG subclasses and the affinity of the Fc domain to protein A (Butler et al., 2009 - DOI:10.1007 / s00251-009-0356-0), during conventional purification, the relative composition of IgG isotypes in porcine DKO polyAb is estimated to be >80% porcine IgG1a / b, 11% IgG2a / b, 5.5% IgG3, 3% IgG4a / b, with the remainder being other isotypes (IgG5-6). After purification using protein A chromatography, IgM or IgA isotypes are undetectable in porcine DKO IgG polyclonal antibody preparations.

[0087] The protein SLC3A2 belongs to the SLC (solute carrier) carrier protein family, which consists of genes forming a superfamily of 65 members. These are primarily involved in molecular / drug delivery and are frequently referenced research resources in drug resistance studies. Subdivisions of the SLC family are made according to the type of molecular delivery they are involved in, and these families include the SLC1 family, SLC2 family, ... SLC65 family. In addition, all families have submembers. For example, the SLC3 family has two members, such as SLC3a1 and SLC3a2. In their functional mechanisms, these usually act together with members of the SLC7 family, so in most studies, they are usually analyzed together. On the other hand, SLC3a2 dimerizes with SLC7a5 for it to function and is involved in amino acid delivery together. CD98 is a transmembrane protein found on the cell surface. Therefore, it can be easily targeted with drugs.

[0088] For the amino acid sequence of SLC3A2, please refer to GenBank:KAI2560544.1.

[0089] Antibodies capable of specifically targeting SLC3A2 (anti-SLC3A2 antibodies) are well known in the art. Examples include the monoclonal antibody sc-390154 (marketed by Santa Cruz Biotechnology), MA5-29573 (marketed by ThermoFischer Scientific), or the polyclonal antibody 15193-1-AP (marketed by Proteintech Group Inc). Application WO20172114458 also describes several antibodies against SLC3A2, which is incorporated by reference.

[0090] The protein CKAP4 (cytoskeleton-associated protein 4) is a Dickkopf1 (DKK1) receptor. DKK1 is a secreted protein that antagonizes oncogenic Wnt signaling by binding to the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), and it may also control its own signaling to promote cancer cell growth.

[0091] For the amino acid sequence of CKAP4, refer to NCBI reference sequence: NP_006816.2.

[0092] Antibodies that can specifically target CKAP4 (anti-CKAP4 antibodies) are well-known in the art. For example, polyclonal antibody 16686-1-AP (sold by Proteintech Group Inc), monoclonal antibody MOB-3287z (sold by Creative Biolabs), or monoclonal antibody sc-393544 (sold by Santa Cruz Biotechnology) can be mentioned. Application WO2019065747 also describes several antibodies against CKAP4, and this application is incorporated by reference.

[0093] The protein annexin A2 is a multifunctional calcium 2+ (Ca 2+ ) and phospholipid-binding protein.

[0094] For the amino acid sequence of annexin A2, refer to GenBank: AAH23990.1.

[0095] Antibodies capable of specifically targeting annexin A2 (anti-annexin A2 antibodies) are well known in the art. Examples include the monoclonal antibody 671001 (marketed by BioLegend), the monoclonal antibody bsm-54021R (marketed by BIOSS Antibodies), or the polyclonal antibody PA527566 (marketed by Invitrogen). Application WO2018 / 021972 also describes several antibodies against annexin A2, which is incorporated by reference.

[0096] The protein GSTO1 (glutathione-S-transferase Ω-1) belongs to the glutathione-S-transferase (GST) multi-gene family of phase II detoxification enzymes, which are activated in response to chemotherapy drugs in some cancers.

[0097] For the amino acid sequence of GSTO1, please refer to GenBank AAF7336.1.

[0098] Antibodies that can specifically target GSTO1 (anti-GSTO1 antibodies) are well known in the art. Examples include the polyclonal antibody PA583382 (marketed by Invitrogen) or the monoclonal antibody ABIN5596941 (marketed by Antibodies Online).

[0099] The protein annexin A5 is a member of the annexin family, a polyprotein family consisting of over 160 proteins that share the characteristic of binding to negatively charged phospholipid surfaces in a Ca2+-dependent manner. Annexin A5 specifically binds to phosphatidylserine, one of the "eat me" signals on the surface of apoptotic cells.

[0100] For the amino acid sequence of annexin A5, please refer to GenBank KAI2535760.

[0101] Antibodies that can specifically target annexin A5 (anti-annexin A5 antibodies) are well known in the art. Examples include the polyclonal antibody 157251131 (marketed by Fischer Scientific), the polyclonal antibody A304-788A (marketed by Bethyl Laboratories), or the monoclonal antibody abx100729 (marketed by Abbexa Ltd).

[0102] The protein MX1 (myxovirus resistance 1) is a GTPase that plays a crucial role in the defense of mammalian cells against influenza A and other viruses. The Mx1 protein can restrict many viruses regardless of the expression of other interferon-induced genes. Therefore, the Mx gene is considered a vital part of the antiviral innate immune response.

[0103] For the amino acid sequence of MX1, please refer to UNIPROT P20591.

[0104] Antibodies that can specifically target MX1 (anti-MX1 antibodies) are well known in the art. Examples include the monoclonal antibody LS-C784193 (marketed by LifeSpan BioSciences), the polyclonal antibody PA522101 (marketed by Invitrogen), or the monoclonal antibody ABIN6284316 (marketed by Antibodies Online).

[0105] RTN4 (reticulon-4), a protein commonly known as a neurite extension inhibitor (Nogo), is a surface protein expressed in neurons. It interacts with brain-specific angiogenesis inhibitor (BAI) adhesion-GPCRs (G protein-binding receptors) located in either neurons or glial cells via a glycan-mediated interface. This interaction regulates dendritic branching, axonal extension, and synapse formation in cultured human neurons.

[0106] For the amino acid sequence of RTN4, please refer to UNIPROT Q9NQC3.

[0107] Antibodies that can specifically target RTN4 (anti-RTN4 antibodies) are well known in the art. Examples include the polyclonal antibody LS-C753464 (marketed by LifeSpan BioSciences), the monoclonal antibody ab250023 (marketed by Abcam), or the polyclonal antibody ABIN3176379 (marketed by Antibodies Online).

[0108] The protein FASN (fatty acid synthase) is a multi-enzyme protein that functions as an important regulator in lipid metabolism, particularly fatty acid synthesis.

[0109] For the amino acid sequence of FASN, please refer to UNIPROT A0A0U1RQF0.

[0110] Antibodies that can specifically target FASN (anti-FASN antibodies) are well known in the art. Examples include the monoclonal antibody 15973814 (marketed by Fischer Scientific), the polyclonal antibody LS-B3636 (marketed by LifeSpan BioSciences), or the polyclonal antibody GTX109833 (marketed by GeneTex).

[0111] Protein PDIA4 (member A4 of the protein disulfide isomerase family) is a redox-dependent protein that possesses both chaperone and oxidoreductase activity. It is naturally found in the endoplasmic reticulum (ER) and is involved in protein folding.

[0112] For the amino acid sequence of PDIA4, please refer to UNIPROT P13667.

[0113] Antibodies that can specifically target PDIA4 (anti-PDIA4 antibodies) are well known in the art. Examples include the polyclonal antibody LS-B3756 (marketed by LifeSpan BioSciences), the monoclonal antibody CF503887 (marketed by LifeSpan BioSciences), or the polyclonal antibody A305-266A (marketed by Bethyl Laboratories).

[0114] A combination of antibodies for use according to the present invention may include at least one fourth antibody or its antigen-binding fragment that specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4. The antigen targeted by the at least fourth antibody may differ in particular from the three antigens to which the first, second, and third antibodies or their antigen-binding fragments bind.

[0115] Therefore, the combination of antibodies or their antigen-binding fragments for use in accordance with the present invention is - At least one first antibody or its antigen-binding fragment, - At least one second antibody or its antigen-binding fragment, - At least one third antibody or its antigen-binding fragment, and - At least one fourth antibody or its antigen-binding fragment May include, Each of these antibodies independently and specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, Annexin A2, GSTO1, Annexin A5, MX1, RTN4, FASN, and PDIA4. Each of the first, second, third, and fourth antibodies binds to a different antigen than the one to which the other antibodies bind.

[0116] In a particular embodiment, the combination of antibodies for use according to the present invention is as follows: - The first antibody or its antigen-binding fragment specifically binds to the antigen GSTO1, - The second antibody or its antigen-binding fragment specifically binds to the antigen annexin A5, - The third antibody or its antigen-binding fragment specifically binds to antigen MX1, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen RTN4.

[0117] The antibody combinations for use according to the present invention are: - A first monoclonal antibody or polyclonal antibody that specifically binds to the antigen GSTO1, or an antigen-binding fragment thereof, in particular, a first monoclonal antibody or polyclonal antibody that specifically binds to the antigen GSTO1, - A second monoclonal antibody or polyclonal antibody that specifically binds to the antigen annexin A5, or its antigen-binding fragment, a second monoclonal antibody or polyclonal antibody that specifically binds to the antigen annexin A5, - A third monoclonal antibody or polyclonal antibody that specifically binds to antigen MX1, or an antigen-binding fragment thereof, in particular a third monoclonal antibody or polyclonal antibody that specifically binds to antigen MX1, and - A fourth monoclonal antibody or polyclonal antibody that specifically binds to the antigen RTN4, or its antigen-binding fragment, in particular a fourth monoclonal antibody or polyclonal antibody that specifically binds to the antigen RTN4. It can be composed of

[0118] An example of such a combination is described in the examples herein under the name XON5.

[0119] In a particular embodiment, the combination of antibodies for use according to the present invention is as follows: - The first antibody or its antigen-binding fragment specifically binds to the antigen annexin A2, - The second antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, - The third antibody or its antigen-binding fragment specifically binds to the antigen CKAP4, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen PDIA4.

[0120] The antibody combinations for use according to the present invention are: - A first monoclonal antibody or polyclonal antibody that specifically binds to the antigen annexin A2, or an antigen-binding fragment thereof, in particular, a first monoclonal antibody or polyclonal antibody that specifically binds to the antigen annexin A2, - A second monoclonal antibody or polyclonal antibody that specifically binds to the antigen SLC3A2, or its antigen-binding fragment, a second monoclonal antibody or polyclonal antibody that specifically binds to the antigen SLC3A2, - A third monoclonal antibody or polyclonal antibody that specifically binds to the antigen CKAP4, or an antigen-binding fragment thereof, in particular a third monoclonal antibody or polyclonal antibody that specifically binds to the antigen CKAP4, and - A fourth monoclonal antibody or polyclonal antibody that specifically binds to the antigen PDIA4, or its antigen-binding fragment, in particular a fourth monoclonal antibody or polyclonal antibody that specifically binds to the antigen PDIA4. It can be composed of

[0121] An example of such a combination is described in the examples herein under the name XON7.

[0122] In a particular embodiment, the combination of antibodies for use according to the present invention is as follows: - The first antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, - The second antibody or its antigen-binding fragment specifically binds to the antigen annexin A5, - A third antibody or its antigen-binding fragment specifically binds to the antigen RTN4, - The fourth antibody or its antigen-binding fragment specifically binds to the antigen FASN, and - The fifth antibody or antigen-binding fragment thereof specifically binds to the antigen PDIA4.

[0123] The combination of antibodies for use according to the present invention is - The first monoclonal antibody or polyclonal antibody or antigen-binding fragment thereof that specifically binds to the antigen SLC3A2, - The second monoclonal antibody or polyclonal antibody or antigen-binding fragment thereof that specifically binds to the antigen annexin A5, - The third monoclonal antibody or polyclonal antibody or antigen-binding fragment thereof that specifically binds to the antigen RTN4, particularly, the third monoclonal antibody or polyclonal antibody that specifically binds to the antigen RTN4, - The fourth monoclonal antibody or polyclonal antibody or antigen-binding fragment thereof that specifically binds to the antigen FASN, particularly, the fourth monoclonal antibody or polyclonal antibody that specifically binds to the antigen FASN, and - The fifth antibody or antigen-binding fragment thereof that specifically binds to the antigen PDIA4, particularly, the fifth antibody that specifically binds to the antigen PDIA4 and may be composed of.

[0124] An example of such a combination is described in the examples herein under the name XON9.

[0125] As shown above, in all of these embodiments, the combination of antibodies may independently of other antibodies lack at least one antigen determinant selected from (i) N-glycolylneuraminic acid (Neu5Gc) and (ii) α-1,3-galactose, and more specifically, may lack the two antigen determinants N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose.

[0126] In certain embodiments, in all of the above embodiments, the combined antibody lacks at least one antigenic determinant selected from (i) N-glycolylneuraminic acid (Neu5Gc) and (ii) α-1,3-galactose, and more specifically lacks the two antigenic determinants N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose.

[0127] The combined antibody for use according to the invention can be of any origin, for example derived from non-human mammals or synthesis. Such non-human mammals can be selected from the group consisting of rodents such as mice, rats, guinea pigs, and hamsters; lagomorphs such as rabbits; ferrets; felids such as cats; canids such as dogs; goats; sheep; bovines such as cows; suids such as pigs and boars; camelids; horses; and non-human primates.

[0128] The combined antibody for use according to the invention is preferably derived from pigs that lack at least one gene selected from the group consisting of (i) the gene encoding functional cytidine-5'-monophosphate N-acetylneuraminic acid hydrolase (CMAH) and (ii) the gene encoding functional α-(1,3)-galactosyltransferase, and more specifically lacks both (i) the gene encoding functional cytidine-5'-monophosphate N-acetylneuraminic acid hydrolase (CMAH) and (ii) the gene encoding functional α-(1,3)-galactosyltransferase.

[0129] The invention also relates to a pharmaceutical composition for use in the treatment of cancer in a human subject in need thereof, comprising a combination of the antibody or antigen-binding fragment thereof as defined above and a pharmaceutically acceptable carrier.

[0130] The composition for use according to the invention can be in liquid form.

[0131] The composition for use according to the invention can be in solid form including a lyophilized form.

[0132] The compositions used in accordance with the present invention can be formulated according to standard methods, such as those described in Remington: The Science and Practice of Pharmacy (Lippincott Williams and Wilkins, 21st edition, 2005).

[0133] A composition for use according to the present invention may further comprise at least one additional anticancer drug different from the antibody of the antibody combination.

[0134] The term “combination of antibodies” is also used herein to refer to “a combination of antibodies or their antigen-binding fragments.”

[0135] Additional anticancer drugs may be selected from a group consisting of monoclonal antibodies, particularly anti-CD137 monoclonal antibody, anti-CTLA4 monoclonal antibody, anti-TIM-3 monoclonal antibody, anti-B7-H3 monoclonal antibody, anti-CD134 monoclonal antibody, anti-CD154 monoclonal antibody, anti-LAG-3 monoclonal antibody, anti-CD227 monoclonal antibody, anti-BTNA3 monoclonal antibody, anti-CD39 monoclonal antibody, anti-CD73 monoclonal antibody, and anti-CD11 The antibody may be selected from the group consisting of 5 monoclonal antibodies, anti-CD47 monoclonal antibodies, anti-SIRP alpha monoclonal antibodies, anti-SIRP gamma monoclonal antibodies, anti-CD28 monoclonal antibodies, anti-NCR monoclonal antibodies, anti-NKp46 monoclonal antibodies, anti-NKp30 monoclonal antibodies, anti-NKp44 monoclonal antibodies, anti-NKG2D monoclonal antibodies, anti-PD1 monoclonal antibodies, anti-PDL1 monoclonal antibodies, and anti-DNAM-1 monoclonal antibodies.

[0136] The dosage may be 0.001 to 100 mg per kg of body weight, or more, within the range of combinations for use according to the present invention as defined herein (mg / kg), or exceeding such amounts, for example, 0.1, 1.0, 10, or 50 mg per kg of body weight, with 1 to 20 mg / kg being preferred. The dosage and frequency of administration can be adapted as detailed above.

[0137] Furthermore, any injection of any combination or composition for use according to the present invention may be followed by any standard procedure to prevent and / or avoid anaphylactic reactions.

[0138] Furthermore, the injection of combinations or compositions carried out according to the present invention can be performed via a large peripheral access or, if possible, via a central venous catheter.

[0139] As is well known in the art, proteolysis, systemic and local delivery, and adjustments may be necessary depending on age, weight, overall health, sex, diet, administration time, possible allergies, drug interactions, and severity of condition, which can be readily determined by those skilled in the art through standard experiments.

[0140] The combinations or compositions for use of the present invention may be administered in a variety of ways, but are not limited to oral administration, subcutaneous administration, intravenous administration, parenteral administration, intranasal administration, intrarespiratory administration (e.g., spray or endotracheal spray), intracortical administration, intraocular administration, rectal administration, vaginal administration, transdermal administration, topical administration (e.g., gel), intraperitoneal administration, intramuscular administration, intrapulmonary administration, or intrathecal administration.

[0141] The administration of the combination or composition of the present invention can be carried out according to Besredka's method.

[0142] The combinations or compositions according to the present invention may be in a form particularly suitable for administration via an intravenous route.

[0143] 3. Implementation of antibody or antigen-binding fragment combinations or compositions in accordance with the present invention. A combination of antibodies or antigen-binding fragments thereof, or a composition containing them, carried out in accordance with the present invention, is used in a therapeutically effective amount.

[0144] As previously stated, the antibody combination or composition is intended for use in the treatment of cancer in human subjects.

[0145] Cancers include, in particular, myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma. (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; esophageal cancer; bladder cancer; pleural mesothelioma; kidney cancer; and cancers with circulating tumor cells (CTCs) may be selected from this group. More specifically, the group may be selected from myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer, epidermal cancer, and esophageal cancer.

[0146] In certain embodiments, the combination for use according to the present invention is as follows: - The first antibody or antigen-binding fragment thereof specifically binds to antigen GSTO1, particularly where the first antibody specifically binds to antigen GSTO1, - The second antibody or antigen-binding fragment thereof specifically binds to antigen annexin A5, particularly where the second antibody specifically binds to antigen annexin A5, - The third antibody or antigen-binding fragment thereof specifically binds to antigen MX1, particularly where the third antibody specifically binds to antigen MX1, and - The fourth antibody or antigen-binding fragment thereof specifically binds to antigen RTN4, particularly where the fourth antibody specifically binds to antigen RTN4, The cancer is selected from the group consisting of melanoma; myeloma; liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; breast cancer; prostate cancer; pancreatic cancer; colorectal cancer, particularly colon cancer; and lung cancer, particularly non-small cell lung cancer, and more specifically is selected from the group consisting of melanoma; prostate cancer; myeloma; liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, particularly colon cancer and lung cancer, particularly non-small cell lung cancer, and particularly is selected from the group consisting of melanoma; prostate cancer; pancreatic cancer; myeloma; liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; and lung cancer, particularly non-small cell lung cancer, and more specifically is selected from the group consisting of melanoma; myeloma and liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer.

[0147] In certain embodiments, the combination for use according to the present invention is as follows: - The first antibody or antigen-binding fragment thereof specifically binds to antigen annexin A2, particularly where the first antibody specifically binds to antigen annexin A2, - The second antibody or antigen-binding fragment thereof specifically binds to antigen SLC3A2, particularly where the second antibody specifically binds to antigen SLC3A2, - The third antibody or antigen-binding fragment thereof specifically binds to antigen CKAP4, particularly where the third antibody specifically binds to antigen CKAP4, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen PDIA4, and in particular, the fourth antibody specifically binds to the antigen PDIA4. Cancer is selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer, epidermal carcinoma; gastric cancer; head and neck cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers. More specifically, cancers are selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; pancreatic cancer; lymphoma, especially T-cell lymphoma or B-cell lymphoma, especially T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; gastric cancer; head and neck cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers.

[0148] In a particular embodiment, the combination for use according to the present invention is as follows: - The first antibody or its antigen-binding fragment specifically binds to the antigen annexin A2, and in particular, the first antibody specifically binds to the antigen annexin A2. - The second antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, and in particular, the second antibody specifically binds to the antigen SLC3A2. - The third antibody or its antigen-binding fragment specifically binds to the antigen CKAP4, and in particular, the third antibody specifically binds to the antigen CKAP4, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen PDIA4, and in particular, the fourth antibody specifically binds to the antigen PDIA4. Cancer is selected from the group consisting of myeloma; melanoma; breast cancer; prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; and epidermal carcinoma. More specifically, the group is selected from myeloma; melanoma; breast cancer; prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; pancreatic cancer; and lymphoma, especially T-cell lymphoma. More specifically, the group is selected from myeloma; melanoma; breast cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; pancreatic cancer; and lymphoma, especially T-cell lymphoma. More specifically, the group is selected from myeloma; melanoma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer and colorectal cancer, especially colon cancer, and also, In particular, the group consisting of myeloma; melanoma; and liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer, is selected.

[0149] In a particular embodiment, the combination for use according to the present invention is as follows: - The first antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, and in particular, the first antibody specifically binds to the antigen SLC3A2. - The second antibody or its antigen-binding fragment specifically binds to the antigen annexin A5, and in particular, the second antibody specifically binds to the antigen annexin A5. - The third antibody or its antigen-binding fragment specifically binds to the antigen RTN4, and in particular, the third antibody specifically binds to the antigen RTN4. - The fourth antibody or its antigen-binding fragment specifically binds to the antigen FASN, and in particular, the fourth antibody specifically binds to the antigen FASN, and - The fifth antibody or its antigen-binding fragment specifically binds to the antigen PDIA4, and in particular, the fifth antibody specifically binds to the antigen PDIA4. Cancer is selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; gastric cancer; head and neck cancer; anal cancer; esophageal cancer; and prostate cancer. In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; gastric cancer; head and neck cancer; anal cancer; and esophageal cancer, In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; and prostate cancer, In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; and colorectal cancer, especially colon cancer, More specifically, liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer.

[0150] This disclosure is further illustrated by the following embodiments, but is not limited to them. [Examples]

[0151] (Example 1) In vitro efficacy of antibody combinations according to the present invention against various human cancer cell lines Immunization of animals Protocols for obtaining specific CMAH and GAL double knockout non-human transgenic mammals are described in Lutz AL et al. (Xenotransplantation, 2013;20(1):27~35) or Conchon S. et al. (Xenotransplantation; special issue International Xenotransplantation Association IXA 2013, 2013, Vol. 20, No. 5).

[0152] The porcine antibody combinations XON5, XON7, and XON9 are obtained by immunizing GGTA1 / CMAH knockout pigs with cells that genetically express the following on their surface: - XON5 uses: GSTO1, Annexin 5, MX1, and RTN4. XON5 is therefore a combination of anti-GSTO1 antibody, anti-annexin 5 antibody, anti-MX1 antibody, and anti-RTN4 antibody obtained from the double knockout pigs defined above. - In XON7: SLC3A2, CKAP4, Annexin A2, and PDIA4. XON7 is therefore a combination comprising anti-annexin A2 antibody, anti-SLC3A2 antibody, anti-CKAP4 antibody, and anti-PDIA4 antibody obtained from the double knockout pigs defined above, and - In XON9: SLC3A2, Annexin 5, RTN4, FASN, and PDIA4. XON9 is therefore a combination of anti-SLC3A2 antibody, anti-annexin 5 antibody, anti-RTN4 antibody, anti-FASN antibody, and anti-PDIA4 antibody obtained from the double knockout pigs defined above.

[0153] The immunization process is carried out as described by Lutz AL et al. (Xenotransplantation, 2013;20(1):27~35) and Conchon S. et al. (Xenotransplantation; special issue International Xenotransplantation Association IXA 2013, 2013, Vol. 20, No. 5).

[0154] Cross-binding activity by FACS 100,000 cells were seeded in a conical 96-well plate and incubated with serial dilutions of the corresponding purified IgG (maximum concentration 400 ug / mL) at 4°C for 30 minutes. Subsequently, they were incubated with FITC-Prot A (1:250) at 4°C for 30 minutes and analyzed using a flow cytometer (BD FACSCanto®; BD Biosciences, US).

[0155] Cancer cell lines under test The following three different human tumor cell lines were tested: - Hep-G2 (hepatocellular carcinoma), - KMS-12-BM: (Myeloma), and - SK-MEL-30 (melanoma).

[0156] Apoptosis assay in human PBMCs To evaluate their apoptosis-inducing ability, all anti-cancer pAbs were compared using apoptosis assays.

[0157] Human PBMCs or human cancer cell lines were treated with increased doses (10, 30, 100, 300, and 900 μg / ml) of XON5, XON7, or XON9. Non-immune IgG was used as a negative control. After 3 hours of incubation (37°C, 5% CO2), apoptosis was monitored by flow cytometry with annexin V and DAPI staining. The percentage of cells classified as Q3 (annexin V+ / DAPI-, early apoptosis) and Q2 (annexin V+ / DAPI+, late apoptosis) were then added together to determine the percentage of apoptosis (n=3). (Figures 3 and 4).

[0158] Consideration Figure 1 shows the cross-binding studies for XON5, XON7, and XON9. XON5 strongly targets the SK-MEL-30 cell lineage and weakly targets the Hep-G2 and KMS-12-BM cell lines. XON7 recognizes a different antigen than XON5 and strongly targets the KMS-12-BM and SK-MEL-30 cell lines.

[0159] Interestingly, XON9 shares two antigens recognized by XON7, two antigens recognized by XON5, and one antigen specific to XON9, allowing it to specifically and robustly recognize hepatocellular carcinoma cells.

[0160] Next, the cross-CDC activity of XON5, XON7, and XON9 was tested in several human tumor cell lines. The results are shown in Figure 2.

[0161] XON5, XON7, and XON9 were all able to induce CDC in different cancer cell lines (Figures 2A to 2H).

[0162] XON5 was able to potently lyse melanoma, non-small cell lung cancer, prostate cancer, hepatocellular carcinoma, and breast cancer cell lines (with specific cytotoxicity between 60% and 100% at 800 μg / mL), as well as, to a lesser extent, adenocarcinoma cell lines of the colon and pancreas (with specific cytotoxicity of 25% and 45% at 800 μg / mL). XON7 was able to potently lyse myeloma, prostate cancer, breast cancer, and hepatocellular carcinoma cell lines (with specific cytotoxicity between 80% and 100% at 800 μg / mL), as well as, to a lesser extent, adenocarcinoma of the colon and pancreas, non-small cell lung cancer, and melanoma cell lines (with specific cytotoxicity of 20% and 45% at 800 μg / mL). XON9 was able to potently lyse hepatocellular carcinoma cell lines (80% apoptotic cells at a concentration of 200 μg / mL), and, to a lesser extent, colon adenocarcinoma, pancreatic adenocarcinoma, non-small cell lung cancer, and melanoma cell lines.

[0163] To determine whether this mechanism can be activated by anti-cancer pAbs in different human cell lines, we tested apoptosis.

[0164] The results shown in Figure 3 demonstrate that XON5, XON7, and XON9 can induce apoptosis in melanoma and hepatocellular carcinoma cell lines. XON5 exhibits the highest apoptotic activity against melanoma cells (80% apoptotic cells at a concentration of 300 μg / mL). XON9 exhibits the highest apoptotic activity against hepatocellular carcinoma cells compared to apoptosis induced by non-immune IgG (CT IgG) (80% apoptotic cells at a concentration of 200 μg / mL).

[0165] To test the safety of XON5, XON7, and XON9, apoptosis was tested in normal human PBMCs.

[0166] Figure 4 shows the results demonstrating that these antibody combinations prevent apoptosis in normal PBMCs.

[0167] (Example 2) In vivo therapeutic efficacy of XON5 or XON7 in human cancer models Mouse models of human lung cancer / breast cancer 3×10E 6 Individual tumor cells (A549, i.e., NSCLC cell lineage) were injected subcutaneously into the left flank of an 8-week-old female NMRI-Nude according to the procedure described below.

[0168] 3 × 10 in NaCl (total 100 μL) 6 Individual tumor cells were subcutaneously injected into the left flank of mice. The injection site was defined as the tumor being 50-150 mm in size. 3 Tumor growth was continuously monitored until it reached a certain size. Mice were divided into test groups and then injected with the target compound according to the administration schedule (35 mg / kg twice a week). Tumors were measured twice a week using calipers. 3 The study was terminated when the tumor reached a certain point, or when necrosis was observed (more than 50% of the surface).

[0169] 3×10E 6 Individual tumor cells MDA-MB-231 were injected into the mammary glands of 8-week-old female NMRI-Nudes according to the procedure described below.

[0170] 3 × 10 in NaCl (total 50 μL) 6 Individual tumor cells were injected into the mammary glands of mice. The injection site was defined as the tumor being 50-150 mm in size. 3 Tumor growth was continuously monitored until it reached a certain size. Mice were divided into test groups and then injected with the target compound according to the administration schedule (35 mg / kg twice a week). Tumors were measured twice a week using calipers. 3 The study was terminated when the tumor reached a certain point, or when necrosis was observed (more than 50% of the surface).

[0171] Consideration: The potential therapeutic efficacy of antibody combinations XON5 and XON7 was tested in different xenograft-based human cancer models in mice.

[0172] Figure 5 shows the in vivo median tumor volume after mice were inoculated with the A549 cell line and treated weekly with XON5 or XON7 for three weeks, or without treatment. Both combinations of the anti-cancer antibodies tested significantly reduced tumor volume compared to untreated animals, demonstrating the therapeutic efficacy of XON5 and XON7 against human lung cancer.

[0173] Human breast cancer tumor volume was tracked for 3 weeks after cell inoculation and treatment with XON5 or XON7. The results are shown in Figure 6, and these results indicate that both antibody combinations may demonstrate therapeutic activity against human breast cancer.

[0174] Tissue cross-reactivity assays were performed using XON5, XON7, or XON9 on normal and cancerous tissues derived from human patients (see Table 1). These TMAs (Charles River Discovery Research Services Germany) consisted of 10 cancerous tissues collected along with their normal counterparts (brain, muscle, liver, kidney, breast, pancreas, colon, lung, skin, and uterus).

[0175] After quenching endogenous peroxidase with 3% H2O2, tissue microarrays were incubated with 5 ug / μL of each antibody combination. Goat anti-porcine HRP was used as the secondary antibody, followed by staining with ImmPACT® VIP HRP substrate, resulting in a deep purple reaction product.

[0176] The results showed no cross-reactivity of XON5 and XON7 with normal, non-cancerous tissues, while cross-reactivity was observed with most of the corresponding cancerous tissues. This indicates the specificity of the polyclonal antibodies considered in this application to tumor tissues, and suggests negative off-target effects and therefore good safety.

[0177] [Table 1]

[0178] A mouse model of prostate cancer 2.5×10E 5 Individual tumor cells (LNCaP cell lineage) were injected subcutaneously into the left flank of 7-week-old female NMRI-Nude mice according to the procedure described below.

[0179] On day 0, 2.5 × 10⁻¹⁰E in NaCl (total 100 μL) 5 Numerous tumor cells were subcutaneously injected into the left flank of mice. The mice were divided into test groups, and the target compound was then intraperitoneally injected according to the administration schedule for a total of 28 days, starting from day D0 (35 mg / kg twice a week). Tumors were measured twice a week using calipers. Tumor size was 1000 mm 3 The study was terminated when the tumor reached a certain point, or when necrosis was observed (more than 50% of the surface).

[0180] The different groups were as follows: control group (no treatment - n=10), XON7-treated group ("XON7" group - n=10), and XON5-treated group ("XON5" group - n=10).

[0181] Consideration: Figure 7 shows the median tumor volume after the above-described mouse inoculation, as well as the in vivo results of the effects of XON7 and XON5 on the prostate cancer cell lineage. The control group mice showed a gradual increase in tumor size from day 0, with a median tumor size of 200 mm from day 20. 3 It reached 400mm by the end of the protocol (day 28). 3 The mice in the treatment groups (XON5 and XON7) showed significantly slower tumor growth (unified Anova-***p<0.001), reaching 100 mm at the end of the protocol (day 28). 3 It remained below that level. The antibody combination according to the present invention therefore significantly reduces the growth of prostate tumors.

[0182] A mouse model of colon adenocarcinoma 2.5×10E5 Human colon adenocarcinoma cells (HCT-116 cell line) were injected subcutaneously into the left flank of 7-week-old female NMRI-Nude mice according to the procedure described below.

[0183] On day 0, 2.5 × 10⁻¹⁰E in NaCl (total 100 μL) 5 Numerous tumor cells were subcutaneously injected into the left flank of mice. The mice were divided into test groups, and the target compound was then intraperitoneally injected according to the administration schedule for a total of 28 days, starting from day D0 (35 mg / kg twice a week). Tumors were measured twice a week using calipers. Tumor size was 3000 mm. 3 The experiment was terminated when the tumor reached a certain point, or when necrosis was observed (more than 50% of the surface). Surviving mice were observed from day 28, but no treatment was performed until the end of the protocol on day 38.

[0184] The different groups were as follows: the control group (no treatment - n=10) and the XON7 treatment group ("XON7" group - n=10).

[0185] Consideration: Figure 8 shows the median tumor volume after mouse inoculation as described above, and the in vivo results of the effect of XON7 on the colon adenocarcinoma cell lineage. The control group mice showed a rapid increase in tumor size from day 18, with a median tumor size of 1000 mm at the end of the protocol (day 38). 3 The treated group (XON7) mice showed slower tumor growth, reaching approximately 500 mm at the end of the protocol (day 38). 3 It remained at that stage. The antibody combination according to the present invention therefore significantly reduces the proliferation of colon adenocarcinoma.

[0186] A mouse model of T-cell lymphoma 2.5×10E 5 One T-cell lymphoma cell was subcutaneously injected into the left flank of 7-week-old female NMRI-Nude mice according to the procedure described below.

[0187] On day 0, 2.5 × 10⁻¹⁰E in NaCl (total 100 μL) 5 Numerous tumor cells were subcutaneously injected into the left flank of mice. The mice were divided into test groups, and the target compound was then intraperitoneally injected according to the administration schedule for a total of 28 days, starting from day D0 (35 mg / kg twice a week). Tumors were measured twice a week using calipers. Tumor size was 3000 mm. 3 The study was terminated when the tumor reached a certain point, or when necrosis was observed (more than 50% of the surface).

[0188] The different groups were as follows: the control group (no treatment - n=10) and the XON7 treatment group ("XON7" group - n=10).

[0189] Consideration: Figure 9 shows the median tumor volume after the above-described mouse inoculation and the in vivo results of the effect of XON7 on T-cell lymphoma. The control group mice showed a gradual increase in tumor size from day 0, and the median tumor size was 100 mm from day 20. 3 It reached 180mm by the end of the protocol (day 28). 3 The treated group (XON7) mice showed significantly slower tumor growth (T-test - **p<0.01, *p<0.05), reaching 100 mm at the end of the protocol (day 28). 3 It remained below that level. The antibody combination obtained by immunization with XON7 according to the present invention therefore significantly reduces the proliferation of T-cell lymphoma.

[0190] (Example 3) Relative efficacy in vitro of various monoclonal antibodies, polyclonal antibodies, and combinations thereof against various human cancer cell lines, as well as XON5, XON7, and XON9. Antibodies and combinations of antibodies The antibodies and antibody combinations used in these examples are as follows: - Synthetically prepared anti-SLC3A2 monoclonal antibody based on the instructions of WO2017214458, - Synthetically prepared anti-annexin A2 monoclonal antibody based on the instructions of WO2018 / 021972, - Anti-CKAP4 polyclonal antibodies (i.e., a group of antibodies targeting different epitopes of CKAP4) synthetically obtained by rabbit immunization using the peptide described in WO2019065747, - Anti-GSTO1 polyclonal antibody (16310345, marketed by Fischer Scientific), - Anti-annexin A5 polyclonal antibody (product code 15725131, sold by Fischer Scientific), - Anti-MX1 polyclonal antibody (product code 13229538, sold by Fischer Scientific), - Anti-RTN4 polyclonal antibody (ABIN3176379, sold by Antibodies-online), - Anti-FASN polyclonal antibody (15973814, marketed by Fischer Scientific), - A combination of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody ("combo") - A combination of anti-GSTO1 polyclonal antibody, anti-annexin A5 polyclonal antibody, anti-MX1 polyclonal antibody, and anti-RTN4 polyclonal antibody ("Combo A") - A combination of anti-SLC3A2 monoclonal antibody, anti-annexin A5 polyclonal antibody, anti-FASN polyclonal antibody, and anti-RTN4 polyclonal antibody ("Combo C") and - XON5, XON7, or XON9.

[0191] Cancer cell lines under test The following four different human tumor cell lines were tested: - SK-MEL-30 (melanoma) (Figures 10 and 14), - Capan1 (pancreatic adenocarcinoma cell lineage) (Figure 11) - KMS-12-BM: (Myeloma) (Figure 12), and - Hep-G2 (hepatocellular carcinoma) (Figures 13 and 15).

[0192] Cross-binding activity by FACS 300,000 cells were seeded in a conical 96-well plate and incubated with dilutions of the corresponding monoclonal antibody, polyclonal antibody, or antibody combination XON5, XON7, or XON9 according to the present invention at 4°C for 30 minutes. After washing, the conjugated anti-protein A secondary antibody Alexa Fluor 488 was added to each condition and incubated at 4°C for 30 minutes. The average fluorescence intensity was then analyzed using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark).

[0193] Consideration Comparative binding studies of each single-target antibody as defined above, and specific combinations of these antibodies known as "combos," as defined above, with XON5, XON9, or XON7 are shown in Figures 10 to 15, depending on the cancer cell line, antibody combination, and the "XON" being tested (i.e., XON5, XON7, or XON9).

[0194] In all of these figures, the combinations of single-target antibodies according to the present invention as detailed above ("combos" and "XONs") recognize the target cancer cell lineage more strongly than could have been predicted considering the binding results obtained with monotherapy. In fact, those skilled in the art would have expected that the single-target effects of each component of the combination would be added together, or that the overall effect would be reduced due to steric hindrance of the antibodies.

[0195] Interestingly, the "Combo C" combination, while sharing one antibody with the "Combo" combinations, exhibits stronger recognition of the Hep-G2 cell line, thus demonstrating that recognition is not related to the stronger recognition of a single antibody, but rather to all antibody combinations. The combinations are, in fact, different products from the antibodies alone.

[0196] Apoptosis assay To evaluate their apoptosis-inducing ability, all of these antibodies and antibody combinations were compared using apoptosis assays.

[0197] Human cancer cell lines KMS-12-BM (Figure 19A) and SK-MEL-30 (Figure 19B) were treated with the doses indicated above of the monoclonal antibody, polyclonal antibody, or antibody combination according to the present invention (i.e., the "combo" or combination XON7 as defined above). After incubation at 37°C for 3 hours, Annexin V-CF488A conjugate and Hoechst 33342 (final concentration: 10 μg / mL) were added, and the cells were incubated at 37°C for 15 minutes. After washing, the cell pellet was resuspended in 100 μL of Annexin V binding buffer with 10 μg / mL of PI added. Apoptotic cells were analyzed using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark).

[0198] Consideration While the monoclonal or polyclonal antibodies tested individually did not show signs of apoptosis in cancer cells, "Combo" and XON7 exhibited apoptotic activity against the two cancer cell lines. More specifically, "Combo" showed apoptotic activity in approximately 10% of KMS-12-BM cell lines, while XON7 showed a percentage exceeding 60%. Similar apoptotic activity was observed between "Combo" and XON7 in the SK-MEL-30 cell line.

[0199] (Example 4) In vitro and in vivo therapeutic efficacy of XON7 in human cancer models Antibodies and combinations of antibodies The antibodies and antibody combinations tested in these examples are the same as those in Example 3, i.e., - Synthetically prepared anti-annexin A2 monoclonal antibody based on the instructions of WO2018 / 021972, - Synthetically prepared anti-SLCA32 monoclonal antibody based on the instructions of WO2017214458, - Anti-CKAP4 polyclonal antibodies (i.e., a group of antibodies targeting different epitopes of CKAP4) synthetically obtained by rabbit immunization using the peptide described in WO2019065747, - A combination of anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody ("combo"), and - XON7 as defined above in Example 1, in the presence of rabbit complement (final dilution 1 / 3).

[0200] Three different human tumor cell lines were tested in vitro: - HCT-116 (colon adenocarcinoma) (Figure 16), - Hep-G2 (hepatocellular carcinoma) (Figure 17), and - KMS-12-BM: (Myeloma) (Figure 18).

[0201] The cell line KMS-12-BM (myeloma) was also tested in vivo.

[0202] In vitro complement-dependent cell injury (CDC) assay To evaluate their cytotoxic capacity, all of these antibodies and antibody combinations were compared using apoptosis assays.

[0203] Human cancer cell lines HCT-116 (Figure 16), Hep-G2 (Figure 17), and KMS-12-BM (Figure 18) were treated with the doses indicated above of the monoclonal antibodies, polyclonal antibodies, or antibody combinations according to the present invention (i.e., the "combo" or combination XON7 as defined above). After incubation at 37°C for 30 minutes, AO / DAPI was added, and cell viability was analyzed using a NucleoCounter® NC-3000® Advanced Image Cytometer (Chemometec, Denmark).

[0204] Consideration In the three cancer cell lines, only the anti-SLC3A2 monoclonal antibody showed significant specific cytotoxicity (approximately 45%, 30%, and 35%, respectively), while the anti-CKAP4 polyclonal antibody showed specific cytotoxicity of approximately 8% and 0%, slightly above 0%, respectively. No cytotoxicity was observed with the anti-annexin A2 monoclonal antibody.

[0205] Conversely, the percentage of specific cytotoxicity with the antibody combination according to the present invention ("combo" and XON7) is significantly and unexpectedly high.

[0206] More specifically, in the colon adenocarcinoma cell lineage, this percentage is similar for both "Combo" and XON7, with the percentage being close to 70% for "Combo" and approximately 80% for XON7. Similarly, in the hepatocellular carcinoma cell lineage, this percentage is close to 50% for "Combo" and approximately 70% for XON7. Finally, in the myeloma cell lineage, this percentage is also close to 50% for "Combo" and approximately 70% for XON7.

[0207] In vivo myeloma model On day 0, 3 × 10 in NaCl (total 100 μL) 6Nine KMS-12-BM tumor cells were subcutaneously injected into the left flank of mice. Treatment began at the onset of tumor growth and was administered twice a week for a total of 28 days. Treatment consisted of intraperitoneal injections of anti-annexin A2 monoclonal antibody (n=10), anti-SLC3A2 monoclonal antibody (n=10), anti-CKAP4 polyclonal antibody (n=10), a "combo" (i.e., a combination containing anti-annexin A2 antibody + anti-SLC3A2 antibody + anti-CKAP4 antibody as active substances) (n=10), and XON7 (n=10). The "negative control" group received no treatment (n=10).

[0208] Consideration Mice treated with monotherapy using anti-annexin A2 monoclonal antibody, anti-SLC3A2 monoclonal antibody, and anti-CKAP4 polyclonal antibody induced reductions in tumor growth of 75%, 71%, and 43%, respectively. Conversely, combinations of the three antibodies ("combos") almost completely eliminated tumor growth (82% and 85%, respectively), similar to treatment with XON7 (see Figure 20).

[0209] (Example 5) Cancer cross-response of XON5, XON7, and XON9 in PDX tumor tissue microarrays Oncotest® PDX tumor TMA slides were obtained from Charles River Discovery Research Services Germany. Shortly after deparaffinization, antigen retrieval with citrate buffer, and quenching with peroxidase, the slides were incubated overnight at 4°C with 5 μg / mL XON5, XON7, and XON9. Anti-porcine IgG-HRP was used as the secondary antibody and incubated at room temperature for 2 hours. Subsequently, development / staining was performed using ImmPACT® VIP peroxidase substrate (LSBio).

[0210] The different results obtained are shown in the table below.

[0211] [Table 2]

[0212] [Table 3]

[0213] [Table 4]

[0214] The table includes all patient tumors analyzed by TMA. It summarizes the number of biopsies recognized by each antibody combination and the average percentage of marked tissue regions. All antibody combinations (XONs) show cross-reactivity with several cancers, with certain cancers being specifically recognized by each XON or shared by several XONs.

[0215] (Example 6) In vitro efficacy of XON5 according to the present invention for other melanomas The following protocol, similar to that detailed in Example 1, was carried out using the previously defined combination of porcine antibodies, XON5, which includes the anti-GSTO1 antibody, anti-annexin 5 antibody, anti-MX1 antibody, and anti-RTN4 antibody obtained from the double knockout pigs as defined above.

[0216] The cancer cell lines used in the study are as follows: - MeWo (human melanoma), and - A375 (Human melanoma).

[0217] First, the cross-CDC activity of XON5 was tested in these human tumor cell lines. The results are shown in Figure 21.

[0218] XON5 was able to induce CDC in these different human melanoma cell lines, and in particular, it was able to potently lyse these two melanomas with more than 80% specific cytotoxicity at 100 μg / mL.

[0219] To determine whether this mechanism can be activated by XON5 in different human cell lines, apoptosis was tested. The results are shown in Figure 22.

[0220] These results demonstrate that XON5 can induce apoptosis in two further distinct melanoma cell lines, with apoptotic activity exceeding 80% of cells at a concentration of 300 μg / mL.

[0221] (Example 7) In vitro efficacy of XON7 according to the present invention against various primary tumors and various human cancer cell lines derived from human patients. Cell titer-Glo® Cell Viability Assay Cells are harvested from logarithmic-phase cultures, counted, and seeded at a cell density corresponding to the cell lineage's growth rate (4,000 to 20,000 cells / well depending on the cell lineage, up to 60,000 for hematological cancer cell lines) in 96-well flat-bottom microtiter plates containing stable L-glutamine and 25 mM HEPES, supplemented with 10% (v / v) fetal bovine serum and 50 μg / mL gentamicin (150 μL / well).

[0222] The cultures are incubated at 37°C and 5% CO2 under a humidified atmosphere. After 24 hours, XON7 is added in the presence of rabbit complement (dil 1:12) at a concentration of 10 (ranging from 0.3 μg / mL to 1000 μg / mL), and the cells are left on the surface for another 24 hours.

[0223] Cell viability is quantified using the CellTiter-Glo® One Solution cell viability assay (Promega G8462). After incubating the cells, the CellTiter-Glo® One Solution assay reagent is brought to ambient temperature. Next, 100 μL of the CellTiter-Glo® One Solution assay reagent is added to each well.

[0224] The plate is shaken for 2 minutes to induce cell lysis, incubated for 20 minutes, and then the luminescence (LU) is read using an EnVision® Xcite multimode plate reader (Perkin Elmer).

[0225] XON7 is defined as described above, that is, a combination of anti-annexin A2 antibody, anti-SLC3A2 antibody, anti-CKAP4 antibody, and anti-PDIA4 antibody obtained from the double knockout pigs defined above.

[0226] Primary tumors and human cancer cell lines derived from human patients in the study. - Colon cancer: Three different primary tumors derived from human patients: CXF 1103, CXF 243, and CXF 280. - Gastric cancer: Three different primary tumors derived from human patients: CXF 3067, CXF 251, and CXF 1172. - Head and neck cancer: Three different primary tumors and three different human cancer cell lines derived from human patients, namely: HNXF 1853 and HNXF 1859, and CAL-27, SW579, SNU-1076, and FaDu, respectively. - Myeloma: Four different human cancer cell lines and one primary tumor derived from human patients, namely: MM.1R, MM.1S, RPMI 8226, and U-266, as well as primary tumor 1023. - Leukemia: Five different human cancer cell lines: MOLT-4 and RCH-ACV, PL-21, MEC-1 and MEG-01. - Liver cancer: Four different human cancer cell lines: LIXAH 575, LIXAH JHH-6, LIXAH SNU-449, and LIXFC TFK-1. - Non-small cell lung cancer: Seven different primary tumors derived from human patients: LXFA 1647, LXFA 289, LXFA 526, LXFA 586, LXFA 629, LXFA 677, and LXFA 737. - Lymphoma DLBCL (diffuse large B-cell lymphoma): One human cancer cell lineage: OCI-LY7. - Bladder cancer: Two different primary tumors derived from human patients: BXF 1036 and BXF 1218. - Triple-negative breast cancer (TNBC): Two different primary tumors and five human cancer cell lines derived from human patients: MAXFTN 401 and MX1, as well as BT20, CAL-51, HCC-1937, MCF 10A, and MDA-MB-468, respectively. - Melanoma: Six different primary tumors derived from human patients: MEXF 1341, MEXF 1792, MEXF 2090, MEXF 276, MEXF 462, and MEXF 622. - Ovarian cancer: Two different primary tumors and three human cancer cell lines derived from human patients: OVXF 1023 and OVXF 899, as well as EFO-27, OVCAR-3, and SF-OV-3, respectively. - Pancreatic cancer: Three different primary tumors and one human tumor cancer cell lineage derived from human patients: PAXF 1657, PAXF 1997, and PAXF 546, and PANC-1, respectively. - Prostate cancer: Six different human cancer cell lines: 22Rv1, BPH1, DU-145, PC-3, PC-3M, and VCaps. - Pleural mesothelioma: Three different primary tumors derived from human patients: PXF 1118, PXF 1752, and PXF 698. - Kidney cancer: Five different primary tumors derived from human patients: RXF 1183, RXF 2282, RXF 393, RXF 486, and RXF 786-O. - Sarcoma: Two primary tumors and seven human cancer cell lines derived from human patients: SXF0 678 and SXFS 1301 A-673, RD-ES, Saos-2, HT-1080, RH-30, SL-LMS-1, and TE671, respectively.

[0227] Consideration The cross-coupling test for XON7 is shown in the following figure.

[0228] Colon cancer (Figure 23), stomach cancer (Figure 24), head and neck cancer (Figure 25), myeloma (Figure 26), leukemia (Figure 27), liver cancer (Figure 28), non-small cell lung cancer (Figure 29), lymphoma DLBCL (diffuse large B-cell lymphoma) (Figure 30), bladder cancer (Figure 31), triple-negative breast cancer (TNBC) (Figure 32), melanoma (Figure 33), ovarian cancer (Figure 34), pancreatic cancer (Figure 35), prostate cancer (Figure 36), pleural mesothelioma (Figure 37), kidney cancer (Figure 38), and sarcoma (Figure 39).

[0229] Furthermore, the EC50 and ECmax values ​​of XON7 measured for each of these cancers are shown in Table 5 below.

[0230] [Table 5A]

[0231] [Table 5B]

[0232] Interestingly, XON7 can potently target all of these different human cancer cell lines, particularly various primary tumors derived from all of these human patients, and induce CDC against them.

[0233] (Example 8) In vivo efficacy of XON7 for metastasis in breast cancer 5 x 10 6 Human triple-negative cancer tumor cells:MDA-MB-231-Luc were intravenously injected into the tail vein of rats (n=10). This cell line stably expresses firefly luciferase. In the presence of luciferin, the cells bioluminescent, which can be imaged with a bioimager.

[0234] In this way, the extent of metastasis in the in situ can be monitored for both the XON7 group and the media group. Treatment is initiated on D1 post-vaccination and consists of 40 mg / kg doses of XON7 (as defined above) on D1, D4, D7, and D10.

[0235] After intraperitoneal injection of luciferin (75 mg / kg), bioluminescence was measured in cpm / cm². 2 It was measured in units.

[0236] The results are shown in Figure 40.

[0237] The results show that in the XON7 treatment group, a significant reduction in metastasis (75% reduction) was measured on D11 compared to the control group (p=0.05 - Mann-Whitney test).

[0238] (Example 9) In vitro efficacy and specificity of XON9 according to the present invention for tumor cell lines and healthy hepatocytes. A. Human hepatocellular carcinoma (Hep3B and HUH-7) cell lines, as well as non-tumor healthy human primary hepatocytes, were used in this study.

[0239] All cell lines were cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FCS).

[0240] The apoptosis-inducing ability of XON9 was investigated in these various tumor and non-tumor cell lines. XON9 is described in detail above.

[0241] Cells were cultured with an increased dose of XON9 for 20 hours ± 4 hours, and the induction of apoptosis was evaluated by annexin V analysis and PI staining.

[0242] The results obtained are shown in Figure 41.

[0243] Strong induction of cell death was observed after XON9 treatment. Log-1 XON9 alone resulted in more than 60% specific lysis of two hepatocellular carcinoma cell lines, while the same concentration resulted in less than 10% specific lysis in non-tumor healthy primary hepatocytes.

[0244] The corresponding EC50 values ​​obtained are shown in Table 6 below.

[0245] [Table 6]

[0246] These data demonstrate the extremely high selectivity of XON9 for liver cancer cells versus healthy primary hepatocytes (the ratio ranges from 11 to 14 times).

[0247] XON9-induced apoptosis is also present in HCT116 cell lines (colon cancer) and A549 cell lines (lung cancer), suggesting cross-reactivity of XON9 across various tumor cell lines (see Figure 42).

[0248] C. The activity of caspases 8 and 9 after treatment of various cancer cell lines with XON9 was further determined by caspase assay using a NucleoCounter NC3000 Cytometer (Chemometec) according to the manufacturer's instructions.

[0249] Human hepatocellular carcinoma cells (HepG2, Hep3B, and HUH-7), human lung cancer cell lineage (A549), human colon cancer cell lineage (HCT116), and human pancreatic adenocarcinoma cell lineages (CAPAN-1 and AsPC-1) were used in this study. HepG2, Hep3B, HUH-7, HCT116, A549, and CAPAN-1 cells were cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FCS). AsPC-1 cells were cultured in Roswell Park Memorial Laboratory (RPMI) 1640 medium supplemented with 10% FCS.

[0250] Cells were labeled with fluorescently labeled caspase inhibitors (FLICA) specific to caspase 8 (FAM-LETD-FMK, reference no. 99) or caspase 9 (FAM-LEHD-FMK, reference no. 912) (both obtained from ImmunoChemistry), as well as with 2 μg / ml of PI.

[0251] Overall caspase activity was determined by the green fluorescence level in PI+ or PI- cells.

[0252] The results obtained are shown in Figure 43.

[0253] In all cancer cell lines tested, a potent increase in the activity of both caspase-8 and caspase-9 was observed after treatment with XON9.

Claims

1. A combination of an antibody or its antigen-binding fragment for use in the treatment of cancer in human subjects where it is necessary, - At least one first antibody or its antigen-binding fragment, - At least one second antibody or its antigen-binding fragment, and - At least one third antibody or its antigen-binding fragment Includes, Each of these antibodies independently and specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, Annexin A2, GSTO1, Annexin A5, MX1, RTN4, FASN, and PDIA4. The first, second, and third antibodies or their antigen-binding fragments each bind to a different antigen selected from the group consisting of SLC3A2, CKAP4, annexin A2, GSTO1, annexin A5, MX1, RTN4, FASN, and PDIA4. At least one of the antibody combinations for use lacks at least one antigenic determinant selected from (i) N-glycolylneuraminic acid (Neu5Gc) and (ii) α-1,3-galactose, and in particular lacks two antigenic determinants, N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose. A combination of antibodies or their antigen-binding fragments for use.

2. The combination comprises at least one fourth antibody or its antigen-binding fragment that specifically binds to an antigen selected from the group consisting of SLC3A2, CKAP4, Annexin A2, GSTO1, Annexin A5, MX1, RTN4, FASN, and PDIA4. The antigen is, in particular, different from the three antigens to which the first, second, and third antibodies or their antigen-binding fragments bind. The combination for use described in claim 1.

3. The combination for use according to claim 1 or 2, wherein the antigen-binding fragments of the antibodies present in the combination are independently Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, or diabody.

4. Cancer is selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; esophageal cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers. More specifically, selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; and esophageal cancer. A combination for use as described in any one of claims 1 to 3.

5. - The first antibody or its antigen-binding fragment specifically binds to the antigen GSTO1, - The second antibody or its antigen-binding fragment specifically binds to the antigen annexin A5, - The third antibody or its antigen-binding fragment specifically binds to antigen MX1, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen RTN4, - Cancer is selected from the group consisting of melanoma; myeloma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; breast cancer; prostate cancer; colorectal cancer, especially colon cancer; and lung cancer, especially non-small cell lung cancer. More specifically, the group is selected from melanoma; prostate cancer; myeloma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; and lung cancer, especially non-small cell lung cancer. In particular, selected from the group consisting of melanoma; prostate cancer; myeloma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; and lung cancer, especially non-small cell lung cancer, and More specifically, selected from the group consisting of melanoma; myeloma and liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer, A combination for use as described in any one of claims 1 to 4.

6. - The first antibody or its antigen-binding fragment specifically binds to the antigen annexin A2, - The second antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, - The third antibody or its antigen-binding fragment specifically binds to the antigen CKAP4, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen PDIA4, - Cancer is selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; gastric cancer; head and neck cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers. More specifically, selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially T-cell lymphoma or B-cell lymphoma, especially T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; gastric cancer; head and neck cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers. A combination for use as described in any one of claims 1 to 4.

7. Cancer is selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; and epidermal carcinoma. More specifically, the group is selected from myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; pancreatic cancer; and lymphoma, especially T-cell lymphoma. More specifically, the group is selected from myeloma; melanoma; breast cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; pancreatic cancer; and lymphoma, especially T-cell lymphoma. More specifically, selected from the group consisting of myeloma; melanoma; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; and colorectal cancer, especially colon cancer, and In particular, selected from the group consisting of myeloma; melanoma; and liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer, A combination for use as described in claim 6.

8. - The first antibody or its antigen-binding fragment specifically binds to the antigen SLC3A2, - The second antibody or its antigen-binding fragment specifically binds to the antigen annexin A5, - The third antibody or its antigen-binding fragment specifically binds to the antigen RTN4, and - The fourth antibody or its antigen-binding fragment specifically binds to the antigen FASN, The combination further comprises a fifth antibody or its antigen-binding fragment that specifically binds to the antigen PDIA4, - Cancer is selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; gastric cancer; head and neck cancer; anal cancer; esophageal cancer; and prostate cancer. In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer; gastric cancer; head and neck cancer; anal cancer; and esophageal cancer, In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; colorectal cancer, especially colon cancer; and prostate cancer, In particular, selected from the group consisting of liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; myeloma; melanoma; and colorectal cancer, especially colon cancer, Furthermore, more specifically, liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer. A combination for use as described in any one of claims 1 to 4.

9. A combination for use according to any one of claims 1 to 8, wherein all antibodies in the combination for use lack at least one antigenic determinant selected from (i) N-glycolylneuraminic acid (Neu5Gc) and (ii) α-1,3-galactose, and in particular lack two antigenic determinants, N-glycolylneuraminic acid (Neu5Gc) and α-1,3-galactose.

10. A pharmaceutical composition for use in the treatment of cancer in a human subject requiring the use thereof, comprising a combination of an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 3 and 5 to 9, and a pharmaceutically acceptable carrier.

11. Cancer is selected from the group consisting of myeloma; melanoma; breast cancer, especially triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, especially colon cancer; lung cancer, especially non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, especially hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, especially B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, especially Ewing's sarcoma or soft tissue sarcoma; leukemia, especially leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; esophageal cancer; bladder cancer; pleural mesothelioma; kidney cancer; and circulating tumor cell (CTC) cancers. Furthermore, selected from the group consisting particularly of myeloma; melanoma; breast cancer, particularly triple-negative breast cancer (TNBC); prostate cancer; colorectal cancer, particularly colon cancer; lung cancer, particularly non-small cell lung cancer or small cell lung cancer, more specifically non-small cell lung cancer; liver cancer, particularly hepatocellular carcinoma, cholangiocarcinoma, or metastatic liver cancer; pancreatic cancer; lymphoma, particularly B-cell lymphoma or T-cell lymphoma, more specifically T-cell lymphoma or diffuse large B-cell lymphoma (DLBCL); gastric cancer; head and neck cancer; ovarian cancer; sarcoma, particularly Ewing's sarcoma or soft tissue sarcoma; leukemia, particularly leukemia ALL, leukemia AML, leukemia B-CLL, or leukemia CML; osteosarcoma; anal cancer; testicular cancer; uterine cancer; thyroid cancer; central nervous system cancer; gastrointestinal stromal cancer; epidermal carcinoma; and esophageal cancer. A pharmaceutical composition for use as described in claim 10.

12. The pharmaceutical composition for use according to claim 10 or 11, further comprising at least one additional anticancer drug different from the antibodies of the antibody combination according to any one of claims 1 to 3 and 5 to 9.

13. At least one additional anticancer drug is selected from a group consisting of monoclonal antibodies, in particular anti-CD137 monoclonal antibody, anti-CTLA4 monoclonal antibody, anti-TIM-3 monoclonal antibody, anti-B7-H3 monoclonal antibody, anti-CD134 monoclonal antibody, anti-CD154 monoclonal antibody, anti-LAG-3 monoclonal antibody, anti-CD227 monoclonal antibody, anti-BTNA3 monoclonal antibody, anti-CD39 monoclonal antibody, anti-CD73 monoclonal antibody, anti-CD115 monoclonal antibody, anti- A polyclonal antibody composition for use as specified in claim 12, selected from the group consisting of CD47 monoclonal antibody, anti-SIRP alpha monoclonal antibody, anti-SIRP gamma monoclonal antibody, anti-CD28 monoclonal antibody, anti-NCR monoclonal antibody, anti-NKp46 monoclonal antibody, anti-NKp30 monoclonal antibody, anti-NKp44 monoclonal antibody, anti-NKG2D monoclonal antibody, anti-PD1 monoclonal antibody, anti-PDL1 monoclonal antibody, and anti-DNAM-1 monoclonal antibody.

Images