Antibodies targeting CD147

Abstract

Providing antibodies that target CD147. [Solution] This specification provides novel antibody sequences that bind to CD147, inhibit viral or parasitic infiltration, reduce inflammation, and decrease cancer cell viability. This disclosure also provides methods for using these antibodies to treat viral infections and cancer. This disclosure provides novel antibodies, antibody fragments, or variants thereof that bind to CD147 expressed on cells to prevent viral infection, inhibit malaria infection, inhibit angiogenesis, and reduce cell viability.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 135,827, filed on 11 January 2021, the entirety of which is incorporated herein by reference.

[0002] Description of the electronically submitted text file The contents of the text file submitted electronically with this specification are incorporated herein by reference in their entirety: a computer-readable copy of the sequence listing (filename: IBEX_005_01WO_SeqList_ST25.txt, dated January 11, 2022, file size approximately 52 kilobytes).

[0003] Built-in by reference All cited publications, patents, and patent publications are incorporated herein by reference in their entirety for any purpose. [Background technology]

[0004] background The extracellular matrix metalloproteinase inducer CD147 (also known as basigin, emmprin, and neurothelin) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD147 is involved in tumorigenesis, plasma infiltration, and viral infection. Furthermore, CD147 has been studied as a potential therapeutic target for cancer and immunological disorders such as rheumatoid arthritis. [Overview of the Initiative] [Means for solving the problem]

[0005] Brief overview This disclosure provides novel antibodies, antibody fragments, or modifications thereof that bind to CD147 expressed on cells to prevent viral infection, inhibit malaria infection, inhibit angiogenesis, and reduce cell viability.

[0006] This specification provides anti-CD147 antibodies comprising a binding domain containing at least one CDR having at least 70% identity to an amino acid sequence selected from SEQ ID NOs. 16-39. In some embodiments, the anti-CD147 antibody comprises two CDRs, each independently having at least 70% identity to an amino acid sequence selected from SEQ ID NOs. 16-39. In some embodiments, the anti-CD147 antibody comprises three CDRs, each independently having at least 70% identity to an amino acid sequence selected from SEQ ID NOs. 16-39. In some embodiments, the anti-CD147 antibody comprises an amino acid sequence having at least 70% identity to a sequence selected from SEQ ID NOs. 4-15. In some embodiments, the anti-CD147 antibody comprises an amino acid sequence selected from SEQ ID NOs. 4-15. In some embodiments, the antibody is a full-length antibody, a monospecific antibody, a bispecific antibody, a trispecific antibody, an antigen-binding domain, a heavy chain, a light chain, VhH, Vh, a CDR, a variable domain, scFv, Fc, Fv, Fab, F(ab)2, IgG, reduced IgG (rIgG), monospecific Fab2, bispecific Fab2, trispecific Fab3, a diabody, a bispecific diabody, a trispecific triabody, a minibody, a nanobody, IgNAR, V-NAR, HcIgG, or a combination thereof. In some embodiments, the antibody is VhH. In some embodiments, the binding domain of the chimeric antigen receptor (CAR) includes at least one CDR having at least 70% identity to an amino acid sequence selected from SEQ ID NOs. 16-39. In some embodiments, the CAR is expressed on immune cells. In some embodiments, the immune cells are PBMCs, lymphocytes, T cells, or NK cells. In some embodiments, the anti-CD147 antibody binds to CD147 or a fragment thereof expressed on the surface of the cell. In some embodiments, the cells are epithelial cells, endothelial cells, or neuronal cells. In some embodiments, the anti-CD147 antibody reduces or eliminates the interaction between the virus and CD147. In some embodiments, the interaction includes the binding of CD147 by the virus.In some embodiments, the anti-CD147 antibody reduces or eliminates the binding of the viral spike protein to CD147. In some embodiments, the anti-CD147 antibody reduces or eliminates viral infiltration into cells. In some embodiments, the anti-CD147 antibody reduces or eliminates viral infiltration into cells by at least about 1-fold, as determined by a viral infectivity assay. In some embodiments, the virus is selected from the group consisting of measles, coronavirus, SARS, MERS, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella-zoster virus, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the cells are cancer cells. In some embodiments, the cells are tumor cells. In some embodiments, the cancer cells are derived from hematological cancers. In some embodiments, the tumor cells are derived from cancers selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL). In some embodiments, the anti-CD147 antibody reduces or eliminates tumor cell proliferation, metastasis, secretion of matrix metalloproteinases, degradation of the tumor matrix, tumor cell invasion, and / or angiogenesis. In some embodiments, anti-CD147 antibodies reduce or eliminate inflammation. In some embodiments, anti-CD147 antibodies are effective in reducing or eliminating inflammatory or autoimmune disorders.In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis. In some embodiments, the anti-CD147 antibody is humanized. In some embodiments, the anti-CD147 antibody binds to cells, thereby preventing, inhibiting, or reducing the infiltration of Plasmodium parasites into the cells. In some embodiments, the infiltration of Plasmodium parasites into the cells is at least about 1x. In some embodiments, the cells are red blood cells. In some embodiments, the Plasmodium parasite is selected from the group consisting of Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Plasmodium knowlesi.

[0007] In some embodiments, anti-CD147 antibodies are effective in reducing parasitemia in blood cells. In some embodiments, anti-CD147 antibodies reduce parasitemia in blood cells within approximately 48 hours. In some embodiments, anti-CD147 antibodies reduce parasitemia in blood cells within approximately 96 hours. In some embodiments, administration of anti-CD147 antibodies prevents, improves, or treats malaria in subjects.

[0008] This specification also provides methods for preventing, treating, or improving CD147 expression-related disorders in subjects requiring prevention, treatment, or improvement of such disorders, including the administration of an anti-CD147 antibody.

[0009] This specification also provides pharmaceutical compositions containing an effective amount of anti-CD147 antibody.

[0010] This specification also provides cells containing sequences encoding an anti-CD147 antibody.

[0011] This specification provides an anti-CD147 antibody comprising CDR1, CDR2, and CDR3 regions, wherein the CDR1 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 12 to 15, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 to 19, and the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 20 to 23, and the anti-CD147 antibody contains 0 to 5 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions. In some embodiments, the anti-CD147 antibody contains 0 to 3 amino acid modifications. In some embodiments, the CDR1 region corresponds to SEQ ID NOs: 18 or 22, the CDR2 region corresponds to SEQ ID NOs: 26 or 30, and the CDR3 region corresponds to SEQ ID NOs: 34 or 38. In some embodiments, the anti-CD147 antibody contains SEQ ID NOs: 12 or 14. In some embodiments, the anti-CD147 antibody is humanized.

[0012] This specification provides a treatment method comprising administering a pharmaceutical composition containing an effective amount of anti-CD147 antibody, wherein the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 regions, the CDR1 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 to 23, the CDR2 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 31, and the CDR3 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 to 39, and the anti-CD147 antibody comprising 0 to 2 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions. In some embodiments, administration is effective in reducing or eliminating inflammatory or autoimmune diseases. In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis. In some embodiments, administration is effective in reducing or eliminating viral infiltration into cells by the virus. In some embodiments, the virus is selected from the group consisting of measles, coronavirus, SARS, MERS, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella-zoster virus, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus includes SARS-CoV-2. In some embodiments, administration is effective in reducing or eliminating cancer metastasis.In some embodiments, cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL). In some embodiments, administration is effective in reducing or eliminating the infiltration of Plasmodium into cells.

[0013] This specification provides antibody-drug conjugates comprising an anti-CD147 antibody. In some embodiments, the drug is selected from the group consisting of anticancer drugs, antimalarial drugs, antiviral drugs, toxins, and anti-inflammatory drugs. In some embodiments, the drug comprises an antiviral drug, and the antiviral drug is an anti-SARS-CoV-2 drug. In some embodiments, the drug comprises an anticancer drug, and the anticancer drug comprises an immunotherapy. In some embodiments, the immunotherapy is selected from the group consisting of antibodies, checkpoint inhibitors, cell therapies, cytokines, oncolytic viruses, and vaccines. In some embodiments, the ADC comprises an antibody. In some embodiments, the antibody comprises SEQ ID NO: 12 or SEQ ID NO: 14.

[0014] In some embodiments, the disclosure provides anti-CD147 antibodies, antibody fragments, or variants thereof that bind to a CD147 polypeptide. In some embodiments, the disclosure provides anti-CD147 antibodies or fragments thereof comprising an amino acid sequence having at least one CDR included in any of SEQ ID NOs. 16-39. In some embodiments, the antibody comprises 2-6 CDRs included in any of SEQ ID NOs. 16-39. In some embodiments, the antibody comprises all CDRs included in any one of SEQ ID NOs. 16-39. In some embodiments, the antibody comprises an amino acid sequence that is at least 70% identical to any of SEQ ID NOs. 16-39. In some embodiments, the antibody comprises an amino acid sequence of any of SEQ ID NOs. 16-39.

[0015] In some embodiments, the anti-CD147 antibody is a full-length antibody, a monospecific antibody, a bispecific antibody, a trispecific antibody, an antigen-binding domain, a heavy chain, a light chain, VhH, Vh, Vl, CDR, a variable domain, scFv, Fc, Fv, Fab, F(ab)2, reduced IgG (rIgG), monospecific Fab2, bispecific Fab2, trispecific Fab3, a diabody, a bispecific diabody, a trispecific triabody, a minibody, a nanobody, IgNAR, V-NAR, HcIgG, or a combination thereof. In some embodiments, the anti-CD147 antibody is VhH. In some embodiments, the anti-CD147 antibody is contained in a chimeric antigen receptor (CAR). In some embodiments, the CAR is expressed from immune cells. In some embodiments, the immune cells are PBMCs, lymphocytes, T cells, or NK cells.

[0016] In some embodiments, an anti-CD147 antibody, antibody fragment, or variant binds to a CD147 polypeptide or fragment expressed on the surface of a cell. In some embodiments, the cell is an epithelial cell, endothelial cell, or neuron cell. In some embodiments, the cell is a tumor cell. In some embodiments, the tumor cell is derived from a solid tumor. In some embodiments, the tumor cell is derived from a hematological cancer. In some embodiments, the tumor cell is derived from cancers consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0017] In some embodiments, an anti-CD147 antibody, antibody fragment, or variant inhibits the interaction between the virus and CD147. In some embodiments, the anti-CD147 antibody prevents or reduces the binding of the virus to CD147. In some embodiments, the anti-CD147 antibody prevents or reduces the binding of the viral spike protein to CD147.

[0018] In some embodiments, anti-CD147 antibodies reduce or eliminate viral infiltration into cells. In some embodiments, anti-CD147 antibodies prevent or reduce viral infection. In some embodiments, the virus is selected from the group consisting of measles, coronavirus, SARS, MERS, SARS-CoV-2, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella-zoster virus, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is SARS-CoV-2.

[0019] In some embodiments, anti-CD147 antibodies, antibody fragments, or variants thereof prevent or reduce tumor cell proliferation, metastasis, secretion of matrix metalloproteinases, matrix degradation, tumor cell invasion, and / or angiogenesis.

[0020] In some embodiments, the anti-CD147 antibody, antibody fragment, or variant thereof prevents or reduces inflammation. In some embodiments, the antibody treats or ameliorates an inflammatory or autoimmune disorder. In some embodiments, the inflammatory or autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type I diabetes, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

[0021] In some embodiments, the present disclosure provides a method for preventing, treating, or ameliorating a disorder related to CD147 expression in a subject that requires preventing, treating, or ameliorating a disorder related to CD147 expression, comprising administering the anti-CD147 antibody, antibody fragment, or variant thereof described herein.

[0022] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the anti-CD147 antibody, antibody fragment, or variant thereof described herein.

[0023] In some embodiments, the present disclosure provides a cell comprising a sequence encoding the anti-CD147 antibody, antibody fragment, or variant thereof described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] [Figure 1] FIG. 1 shows an ELISA demonstrating the binding of the anti-CD147 antibody of the present disclosure to a CD147-coated plate.

[0025] [Figure 2] FIG. 2 shows that none of the tested antibodies bind to murine (mouse) mCD147.

[0026] [Figure 3] FIG. 3 shows a comparison of the binding of the tested antibodies to human CD147 and mouse CD147.

[0027] [Figure 4] Figure 4 shows a steady-state model of Ibx-77 binding to CD147.

[0028] [Figure 5] Figure 5 shows the dynamics model of the Ibx-77 coupling to CD147.

[0029] [Figure 6] Figure 6 shows the Kd / Ka dynamics model for the Ibx-77 coupling to CD147.

[0030] [Figure 7] Figure 7 shows a steady-state 1:1 fitting model of Ibx-77 binding to CD147.

[0031] [Figure 8] Figure 8 shows the Ibx-77 staining of HEK-293 cells.

[0032] [Figure 9] Figure 9 shows Ibx-77 staining of HCC-1954 cells.

[0033] [Figure 10] Figure 10 shows Ibx-77 staining of HeLa cells.

[0034] [Figure 11A] Figures 11A and 11B show the Ibx-11, Ibx-13, and Ibx-77 staining of HCC-1954 cells. [Figure 11B] Figures 11A and 11B show the Ibx-11, Ibx-13, and Ibx-77 staining of HCC-1954 cells.

[0035] [Figure 12A] Figures 12A and 12B show the staining of HeLa cells with Ibx-11, Ibx-13, and Ibx-77. [Figure 12B]Figures 12A and 12B show the staining of HeLa cells with Ibx-11, Ibx-13, and Ibx-77.

[0036] [Figure 13] Figure 13 shows Ibx-11 staining of Jurkat cells.

[0037] [Figure 14A] Figures 14A and 14B show Ibx-11 and Ibx-13 staining of Vero E6 cells. [Figure 14B] Figures 14A and 14B show Ibx-11 and Ibx-13 staining of Vero E6 cells.

[0038] [Figures 15A-15B] Figures 15A and 15B show the sensorgrams of Ibx-75(A) and Ibx-74(B).

[0039] [Figure 16] Figure 16 shows that Ibx-11 and Ibx-13 antibody-drug conjugates (ADCs) effectively kill MiaPaCa-2 cancer cells.

[0040] [Figure 17] Figure 17 shows the difference in aggregation patterns between Ibx-treated cells and control cells.

[0041] [Figure 18] Figure 18 shows image analysis to measure pixel size, indicating that the pixel size of particles (aggregates) increases over 24 hours with Ibx series antibodies ranging from 50 μg / ml to 25 μg / ml.

[0042] [Figure 19] Figure 19 shows images from this Jurkat agglutination assay counted at 18 and 24 hours.

[0043] [Figure 20]Figure 20 shows a significant decrease in the number of single cells in Ibx-77-treated cells after 24 hours.

[0044] [Figure 21] Figure 21 demonstrates that cells treated with either Ibx-76 or Ibx-77 showed inhibition of angiogenesis in the tube formation assay.

[0045] [Figure 22] Figure 22 shows the percentage of in vitro parasitemia 48 and 96 hours after administration of Ibx-13 (AB1), MIF-2-5 (AB2), or VhH-Fc (AB3).

[0046] [Figure 23A] Figures 23A and 23B show the percentage of parasitemia in vitro after administration of Ibx-13, MF22.3 (AB2), and h378GL (AB3) at 1 μg / mL, 10 μg / mL, and 100 μg / mL. Figure 23A shows the percentage of parasitemia 48 hours after administration, and Figure 23B shows the percentage of parasitemia 96 hours after administration. [Figure 23B] Figures 23A and 23B show the percentage of parasitemia in vitro after administration of Ibx-13, MF22.3 (AB2), and h378GL (AB3) at 1 μg / mL, 10 μg / mL, and 100 μg / mL. Figure 23A shows the percentage of parasitemia 48 hours after administration, and Figure 23B shows the percentage of parasitemia 96 hours after administration.

[0047] [Figure 24] Figure 24 shows the survival rates of A375 malignant melanoma cells after treatment with various concentrations of Ibx-11, Ibx-13, or control antibodies.

[0048] [Figure 25] Figure 25 shows a comparison of A375 malignant melanoma cell survival rates after treatment with 30 nM Ibx-11, Ibx-13, or a control antibody.

[0049] [Figure 26] Figure 26 shows the PC3 prostate cancer cell survival rates after treatment with various concentrations of Ibx-11, Ibx-13, or control antibodies.

[0050] [Figure 27] Figure 27 shows a comparison of PC3 prostate cancer cell survival rates after treatment with 30 nM Ibx-11, Ibx-13, or a control antibody. [Modes for carrying out the invention]

[0051] Detailed explanation CD147 in cancer CD147 is a highly glycosylated transmembrane protein of the immunoglobulin superfamily that acts as a major upstream stimulator of matrix metalloproteinases (MMPs). CD147 and MMP expression levels are often increased in inflammatory processes and tumors and are associated with cancer progression. Cancer stem cells characterized by high cell surface CD147 expression produce more hyaluronan, leading to stabilization of lipid rafts, as well as enhanced expression, resistance, and survival of MMPs and ABC drug transporters.

[0052] In some embodiments, the anti-CD147 antibody or fragment, or its variants, described herein may be used to treat cancer or prevent cancer growth. In some embodiments, the anti-CD147 antibody or fragment, or its variants, and modified versions (e.g., antibody-drug conjugates ADCs) treat or prevent the growth of hematological malignancies. In some embodiments, the anti-CD147 antibody or fragment, or its variants, treat or prevent the growth of solid tumors. In some embodiments, the anti-CD147 antibody or fragment, or its variants, treat or prevent the growth of hematological malignancies. In some embodiments, the anti-CD147 antibody or fragment, or its variants, treat or prevent the growth of metastatic cancers. In some embodiments, cancers include, but are not limited to, breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0053] Autoimmune disorders and inflammatory disorders Anti-CD147 antibodies, fragments thereof, or variants thereof may be used to treat or reduce inflammation in a subject. In some embodiments, the inflammation is associated with an autoimmune disorder or inflammatory disorder. In some embodiments, autoimmune disorders or inflammatory disorders include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

[0054] Virus infection Anti-CD147 antibodies, fragments thereof, or variants may be used to treat or reduce viral infection and / or viral load in a subject. In some embodiments, anti-CD147 antibodies, fragments thereof, or variants may be used to prevent, inhibit, or reduce viral infiltration into cells. CD147 is known to be important for viral infiltration into cells. For example, CD147 is known to be a functional entry receptor for measles virus infiltration into epithelial cells (Watanabe 2010). Furthermore, during HIV-1 infection, the CD147 molecule may promote infection of host cells by the HIV-1 virus through interaction with virus-associated CyPA (Chenglong 2020). In some embodiments, viral infections are caused by viruses including, but not limited to, measles, coronavirus, SARS, MERS, SARS-CoV-2, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella-zoster virus, poliovirus, immunodeficiency virus (e.g., HIV), enveloped viruses, RNA viruses, and hepatitis.

[0055] Malaria infection Anti-CD147 antibodies, fragments thereof, or variants may be used to treat or reduce the symptoms of malaria in a subject. In some embodiments, anti-CD147 antibodies, fragments thereof, or variants may be used to prevent, inhibit, or reduce the infiltration of one or more Plasmodium strains into cells. In some embodiments, the cells are erythrocytes. In some embodiments, the Plasmodium strains are selected from Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Plasmodium knowlesi. In some embodiments, anti-CD147 antibodies, fragments thereof, or variants prevent the infiltration of Plasmodium falciparum into cells. In some embodiments, anti-CD147 antibodies, fragments thereof, or variants prevent the infiltration of multiple Plasmodium strains into cells. In some embodiments, Plasmodium is Plasmodium falciparum. In some embodiments, Plasmodium is Plasmodium malariae.

[0056] In some embodiments, anti-CD147 antibodies or fragments or variants thereof reduce parasitemia. In some embodiments, anti-CD147 antibodies or fragments or variants thereof reduce parasitemia in blood cells. In some embodiments, anti-CD147 antibodies or fragments or variants thereof reduce parasitemia in blood cells within 10 minutes to 120 hours. In some embodiments, anti-CD147 antibodies or fragments or variants thereof reduce parasitemia in blood cells within approximately 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 20 hours, 24 hours, 25 hours, 30 hours, and 35 hours. The anti-CD147 antibody or a fragment or variant thereof reduces parasitemia in blood cells within approximately 48 hours. In some embodiments, the anti-CD147 antibody or a fragment or variant thereof reduces parasitemia in blood cells within approximately 96 hours. In some embodiments, the anti-CD147 antibody or a fragment or variant thereof reduces parasitemia in blood cells within approximately 96 hours. In some embodiments, the blood cells are red blood cells.

[0057] SARS-CoV-2 As of January 2022, SARS-CoV-2 has infected over 293 million people (over 55 million in the United States), claimed over 5.4 million lives worldwide (over 821,408 in the United States), and continues to spread at an alarming rate with no signs of slowing down. One of the factors contributing to SARS-CoV-2's high virulence and pathogenicity is its ability to infect multiple tissues, leading to organ failure and death in severe cases. Like other enveloped viruses, SARS-CoV-2 infiltrates host cells using host cell receptors, ultimately causing tissue necrosis, organ damage, and ultimately death. CD147 is one such host cell receptor that facilitates viral entry.

[0058] Angiotensin-converting enzyme 2 (ACE2) is generally recognized as the primary receptor for SARS-CoV-2 infection, but other molecules have been reported to significantly contribute to the cell-targeting nature of this virus. CD147 has recently attracted attention for its role in SARS-CoV-2 cell infiltration via direct interaction with the viral spike protein recognition-binding domain (RBD), and potential benefits have been observed in open-label clinical trials demonstrating early resolution of COVID-19 symptoms in patients treated with anti-CD147 antibodies.

[0059] Anti-CD147 antibody In some embodiments, this disclosure provides novel antibodies that bind to CD147 and their use in preventing or improving a condition or disease. In some embodiments, CD147 is expressed on the surface of a cell. In some embodiments, the anti-CD147 antibodies of this disclosure can exert their effects directly or indirectly. In some embodiments, the anti-CD147 antibody binds to CD147, thereby directly reducing or eliminating the binding of CD147 by something else (e.g., a virus or cancer cells). In some embodiments, the anti-CD147 antibody can exert its effect indirectly by sterically interfering with the binding of CD147 to the CD147 receptor. In some embodiments, the anti-CD147 antibody can deliver a blocking agent when complexed as part of an antibody-drug conjugate, thereby indirectly reducing or eliminating binding to the CD147 receptor. Any anti-CD147 antibody may be fully human, humanized, mouse, rat, rabbit, or any combination thereof. In some embodiments, the anti-CD147 antibody is humanized. In some embodiments, the anti-CD147 antibody is fully human.

[0060] In some embodiments, the anti-CD147 antibody binds to the human CD147 polypeptide, its isoform, or fragment. In some embodiments, human CD147 is an isoform. In some embodiments, the CD147 isoform is basigin or basigin-2 having two immunoglobulin domains. In some embodiments, the CD147 isoform is basigin-1 having three immunoglobulin domains. In some embodiments, the human CD147 polypeptide or fragment is a polypeptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the human CD147 polypeptide or fragment is a polypeptide containing at least about 70% sequence identity with SEQ ID NO: 1. In some embodiments, the human CD147 polypeptide or a fragment thereof is a polypeptide containing at least about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about or about 99.9% sequence identity with SEQ ID NO: 1. In some embodiments, the CD147 polypeptide, its isoform, or fragment is expressed on the surface of a cell. In some embodiments, the sequence of the portion of the CD147 polypeptide, its isoform, or fragment involved in binding is not altered. In some embodiments, the sequence of the portion of the CD147 polypeptide, its isoform, or fragment involved in binding is altered.

[0061] In some embodiments, the human CD147 polypeptide or fragment is a truncation of a polypeptide containing the amino acid sequence of SEQ ID NO: 1. In some embodiments, the polypeptide is truncated at the N-terminus. In some embodiments, the polypeptide is truncated at the C-terminus. In some embodiments, the polypeptide is truncated at both the N-terminus and the C-terminus. In some embodiments, the polypeptide is truncated by up to about 20 amino acids compared to the polypeptide of SEQ ID NO: 1. In some embodiments, the polypeptide is truncated by about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 amino acid compared to the polypeptide of SEQ ID NO: 1.

[0062] In some embodiments, an anti-CD147 antibody binds to a rodent CD147 polypeptide or a fragment thereof. In some embodiments, the rodent CD147 polypeptide or fragment thereof is rat CD147. In some embodiments, the rodent CD147 polypeptide or fragment thereof is mouse CD147. In some embodiments, the mouse CD147 polypeptide is a polypeptide containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the human CD147 polypeptide is a polypeptide containing at least about 70% sequence identity with SEQ ID NO: 2. In some embodiments, the human CD147 polypeptide is a polypeptide that contains at least about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about or about 99.9% sequence identity with SEQ ID NO: 2. In some embodiments, the sequence of the polypeptide portion involved in CD147 binding is not altered. In some embodiments, the sequence of the polypeptide portion involved in CD147 binding is altered.

[0063] In some embodiments, the mouse CD147 polypeptide or fragment is a truncation of a polypeptide containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the polypeptide is truncated at the N-terminus. In some embodiments, the polypeptide is truncated at the C-terminus. In some embodiments, the polypeptide is truncated at both the N-terminus and the C-terminus. In some embodiments, the polypeptide is truncated by up to about 20 amino acids compared to the polypeptide of SEQ ID NO: 2. In some embodiments, the polypeptide is truncated by about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 amino acid compared to the polypeptide of SEQ ID NO: 2.

[0064] In some embodiments, CD147 is expressed in endothelial cells, epithelial cells, neuronal cells, immune cells, blood cells, fibroblasts, T cells, peripheral blood mononuclear cells (PBMCs), monocytes, or mononuclear cells. In some embodiments, CD147 is abnormally expressed on the cell surface. In some embodiments, CD147 is overexpressed on the cell surface. In some embodiments, CD147 is expressed by cells in the tumor stroma.

[0065] In some embodiments, the antibody that binds to the CD147 polypeptide or a fragment thereof is a full-length antibody, a monospecific antibody, a bispecific antibody, a triplicate antibody, an antigen-binding domain, a heavy chain, a light chain, VhH, Vh, Vl, CDR, a variable domain, scFv, Fc, Fv, Fab, F(ab)2, reduced IgG (rIgG), monospecific Fab2, bispecific Fab2, triplicate Fab3, a diabody, a bispecific diabody, a triplicate triabody, a minibody, a nanobody, IgNAR, V-NAR, HcIgG, or a combination thereof.

[0066] In some embodiments, any of the described anti-CD147 antibodies may include one or more linkers, tags, or both linkers and tags. For example, any of the anti-CD147 antibody fusion constructs may be linked by one or more linkers (see, for example, the fusion constructs in Table 1). In some embodiments, the linkers are cleavage linkers. In some embodiments, the linkers are not cleavable. The linkers of this disclosure may be protease-sensitive, pH-sensitive, and / or glutathione-sensitive. Cleavable linkers may be used to more effectively release a drug at a target site (e.g., in tumors). Exemplary cleavable linkers include, but are not limited to, hydrazone, SPDB, SPP, vc, va, and combinations thereof. Exemplary non-cleavable linkers include mcc and mc. In some embodiments, flexible linkers, e.g., (GGGGS)3 (SEQ ID NO: 40) linker, may be used in the fusion construct. Another linker that may be used includes the sequence EPKIPQPQPKPQPQPQPQPQPKPQPEP (sequence number 41). In some embodiments, tags may be used. Exemplary tags may include flag tags such as DYKDDDDK (sequence number 42).

[0067] In some embodiments, the antibody that binds to the CD147 polypeptide or a fragment thereof comprises a VhH antibody. In some embodiments, the antibody that binds to the CD147 polypeptide or a fragment thereof is a VhH antibody. In some embodiments, the VhH antibody is selected from any of SEQ ID NOs: 4 to 15. In some embodiments, the VhH antibody has at least about 70% sequence identity to any of the sequences of SEQ ID NOs: 4 to 15. In some embodiments, the VhH antibody contains at least about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about or about 99.9% sequence identity to any of the sequences of SEQ ID NOs.

[0068] In some embodiments, the anti-CD147 antibody contains one or more CDRs found in any one or more of sequence numbers 4-15. In some embodiments, the anti-CD147 antibody contains one CDR found in any one or more of sequence numbers 4-15. In some embodiments, the anti-CD147 antibody contains two CDRs found in any one or more of sequence numbers 4-15. In some embodiments, the anti-CD147 antibody contains two CDRs found in any different sequences of sequence numbers 4-15. In some embodiments, the anti-CD147 antibody contains three CDRs found in any one or more of sequence numbers 4-15. In some embodiments, the anti-CD147 antibody contains three CDRs found in any one or more of sequence numbers 4-15. [Table 1-1] [Table 1-2] [Table 1-3]

[0069] In some embodiments, the anti-CD147 antibody contains a CDR that is at least 70% identical to one or more CDRs found in any of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody contains a CDR that is at least about 70% identical to one or more CDRs found in any of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody contains two CDRs that are at least about 70% identical to one or more CDRs found in any of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody contains two CDRs that are at least about 70% identical to one or more CDRs found in different sequences of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody contains three CDRs that are at least about 70% identical to one or more CDRs found in any of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody comprises three CDRs that are at least about 70% identical to one or more CDRs found in any one or more different sequences of SEQ ID NOs: 16-39. In some embodiments, one or more CDRs are found in one or more different sequences of any sequence numbers 16-39, and at least about 60%, about 65%, about 70%, about 75%, 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about or about 99.9%.

[0070] In some embodiments, the anti-CD147 antibody includes CDR1, which has at least about 60% identity to a sequence selected from the group consisting of SEQ ID NOs: 16-23. In some embodiments, the anti-CD147 antibody includes CDR2, which has at least about 60% identity to a sequence selected from the group consisting of SEQ ID NOs: 24-31. In some embodiments, the anti-CD147 antibody includes CDR3, which has at least about 60% identity to a sequence selected from the group consisting of SEQ ID NOs: 32-39. In some embodiments, the anti-CD147 antibody includes CDR1, CDR2, and CDR3, which each include SEQ ID NOs: 16, 24, and 32. In some embodiments, the anti-CD147 antibody includes CDR1, CDR2, and CDR3, which each include SEQ ID NOs: 17, 25, and 33. In some embodiments, the anti-CD147 antibody includes CDR1, CDR2, and CDR3, which each include SEQ ID NOs: 18, 26, and 34. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3, each including SEQ ID NOs. 19, 27, and 35, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3, each including SEQ ID NOs. 20, 28, and 36, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3, each including SEQ ID NOs. 21, 29, and 37, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3, each including SEQ ID NOs. 22, 30, and 38, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3, each including SEQ ID NOs. 23, 31, and 39, respectively. In some embodiments, the anti-CD147 antibody comprises three CDR1, CDR2, and / or CDR3 sequences in tandem. In embodiments, the anti-CD147 antibody comprises CDR1, CDR2, or CDR3 in a double or triple sequence, such as in one of the fusion constructs described herein. In some embodiments, the fusion construct may contain one of the CDR sequences described herein in tandem with one or more linkers. [Table 2-1]

[0071] In some embodiments, the anti-CD147 antibodies described herein may include modifications. In some embodiments, modifications include amino acid substitutions, deletions, and / or insertions. With respect to modifications, this may include any modifications such as amino acid substitutions, deletions, and / or insertions at any position in the sequence. Thus, modifications may include modifications of the sequence and / or length. In some embodiments, the sequence includes a CDR region. Thus, the CDR may be modified to vary in length over a range of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and up to about 35 amino acid residues. Similarly, any region of the CDR may be modified to include residue substitutions, deletions, and / or insertions over a range of length, as described above. In some embodiments, the modification may consist of modifications of about 0 to 2 residues. In some embodiments, the modification may consist of modifications of about 1 to 3, 2 to 4, 0 to 4, or 1 to 5 residues in any one of CDR1, CDR2, and / or CDR3. In some embodiments, any one of SEQ ID NOs. 16 to 39 may have one or more modifications described herein.

[0072] In some embodiments, the anti-CD147 antibody or a fragment thereof (e.g., VhH, CDR) is part of a chimeric antigen receptor (CAR). A CAR is a recombinant receptor composed of an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular signaling domain may include a signaling domain from immune cells. In some embodiments, the immune cells are mononuclear cells. In some embodiments, the mononuclear cells are PBMCs, PBLs, lymphocytes, B cells, T cells, natural killer (NK) cells, monocytes, dendritic cells, eosinophils, neutrophils, basophils, or antigen-presenting cells (APCs).

[0073] In some embodiments, the CAR binding region may include a CDR sequence disclosed herein. The binding region is typically fused with a transmembrane domain derived from, for example, CD8, which is also fused with an intracellular signaling domain. Suitable intracellular signaling domains may include intracellular signaling domain sequences of CD3 zeta (CD3ζ), CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCER1G), FcR beta (Fc epsilon R1b), CD79a, CD79b, Fc gamma RIIa, DAP10 and DAP12 molecules, or combinations thereof. In some embodiments, the intracellular signaling domain includes the signaling domain of the CD3ζ molecule.In some embodiments, the intracellular signaling domain also includes the following co-stimulatory signaling molecules: CD27, CD28, 4-1BB, OX40, CD30, CD40, CD2, Lymphocyte Function-Associated Antigen-1 (LFA-1), LIGHT, NKG2C, B7-H3, PD-1, ICOS, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, CD7, NKp80 (KLRF1), CD160, CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD It contains a co-stimulatory signaling domain that can be selected from ligands that specifically bind to 11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMFI, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, CD83, or any combination thereof. In some embodiments, the co-stimulatory signaling molecule is 4-1BB and / or CD28. In some embodiments, 0-2 co-stimulatory signaling molecules are included in the CAR.

[0074] As used herein, “binding affinity” generally refers to the sum of the strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, as used herein, “binding affinity” refers to the intrinsic binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be expressed by its dissociation constant (KD). Affinity can be measured and / or expressed by many methods known in the art, including but not limited to the equilibrium dissociation constant (KD) and the equilibrium association constant (KA). KD is k off / k on Calculated from the quotient, KA is k on / k off Calculated from the quotient, for example, the association rate constant of an antibody to an antigen, k off This refers, for example, to the dissociation of an antibody against an antigen. on and k off This can be determined by techniques known to those skilled in the art, such as BIACORE® or KinExA. In some embodiments, the antibody binds to CD147 with a KD of about 50 nM or less. In some embodiments, the antibody binds to CD147 with a KD in the range of about 250 pM to about 1 pM. In some embodiments, the antibody binds to CD147 with a KD in the range of about 100 pM to about 1 pM. In some embodiments, the antibody binds to CD147 with an IC50 of about 200 nM or less. In some embodiments, the antibody binds to CD147 with an IC50 of about 100 nM to about 1 nM. In some embodiments, the antibody binds to CD147 with an IC50 of about 10 nM to about 1 nM.

[0075] In some embodiments, the antibody or fragment of the disclosure binds to CD147 on the surface of a cell. In some embodiments, the antibody binds to CD147 on the surface of a cancer cell. In some embodiments, the antibody binds to CD147 on the surface of a cancer cell that has not yet become metastatic. In some embodiments, the antibody binds to CD147 on the surface of a metastatic cancer cell.

[0076] In some embodiments, the antibody or a fragment of the Disclosure binds to CD147 on the surface of a virus-infected cell. In some embodiments, the antibody binds to CD147 on the surface of a cell that is not infected with the virus. In some embodiments, the binding of the antibody to CD147 on the cell surface prevents viral infection. In some embodiments, the antibody interferes with the interaction between the virus and CD147 on the cell surface. In some embodiments, the antibody interferes with the interaction between the spike protein and CD147. In some embodiments, the spike protein is the coronavirus spike protein. In some embodiments, the spike protein is the SARS-CoV-2 spike protein. In some embodiments, the antibody interferes with the virus / CD147 interaction and inhibits viral infiltration and / or transmission between other cells.

[0077] In some embodiments, the antibody, antibody fragment, or a variant thereof completely blocks the interaction between the viral protein and CD147. In some embodiments, the antibody, antibody fragment, or a variant thereof reduces the interaction between the viral protein and CD147 compared to untreated cells. In some embodiments, the antibody, antibody fragment, or a variant thereof reduces the interaction between the viral protein and CD147 by about 99.9% to about 1% compared to untreated cells. In some embodiments, the antibody, antibody fragment, or a variant thereof reduces the interaction between the viral protein and CD147 by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, and about 94% compared to untreated cells. %, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 64%, approximately 63 %, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, approximately 32 Reduces by approximately %, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, the antibody, antibody fragment, or variant thereof reduces the interaction between the viral protein and CD147 approximately 10 minutes to 1 day after administration compared to untreated cells.In some embodiments, the antibody, antibody fragment, or a variant thereof reduces the interaction between the viral protein and CD147 at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to untreated cells.

[0078] In some embodiments, antibodies, antibody fragments, or their variants completely prevent viral infiltration into cells. In some embodiments, antibodies, antibody fragments, or their variants reduce viral infiltration into cells compared to untreated cells. In some embodiments, antibodies, antibody fragments, or their variants reduce viral infiltration into cells by about 99.9% to about 1% compared to untreated cells. In some embodiments, antibodies, antibody fragments, or their variants reduce viral infiltration into cells by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 64%, approximately 63%, approximately 62% Approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, approximately 32%, approximately Reduces by 31%, approximately 30%, approximately 29%, approximately 28%, approximately 27%, approximately 26%, approximately 25%, approximately 24%, approximately 23%, approximately 22%, approximately 21%, approximately 20%, approximately 19%, approximately 18%, approximately 17%, approximately 16%, approximately 15%, approximately 14%, approximately 13%, approximately 12%, approximately 11%, approximately 10%, approximately 9%, approximately 8%, approximately 7%, approximately 6%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, or approximately 1%. In some embodiments, the antibody reduces viral infiltration into cells approximately 10 minutes to approximately 1 day after administration compared to untreated cells.In some embodiments, the antibody reduces viral infiltration into cells compared to untreated cells at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration. In some embodiments, the cells are epithelial cells. In some embodiments, the anti-CD147 antibody, when determined by the viral infectivity assay described herein, reduces viral infiltration into cells by at least about 1x, 50x, 100x, 150x, 200x, 250x, 300x, 350x, 400x, 450x, 500x, 550x, 600x, 650x, 700x, 750x, 800x, and 850x. Reduce or eliminate by 900x, 950x, 1000x, 1050x, 1100x, 1150x, 1200x, 1250x, 1300x, 1350x, 1400x, 1450x, 1500x, 1550x, 1600x, 1650x, 1700x, 1750x, 1800x, 1850x, 1900x, 1950x, or up to approximately 2000x.

[0079] Viral infiltration or infection can be determined using in vitro assays. In some embodiments, viral load can be quantified by counting the viral RNA genome by qRT-PCR and measuring the number of infectious units in the tissue culture. A second approach involves incubating susceptible mammalian cells with a dilution of the target sample to determine the amount of sample required to kill 50% of the cells. Using this value, the infectivity titer in the sample is calculated in units of "50% tissue culture infectious dose" or TCID50, for example, by the Reed and Muench method.

[0080] In some embodiments, antibodies, antibody fragments, or their variants completely prevent intercellular viral transmission. In some embodiments, antibodies, antibody fragments, or their variants reduce intercellular viral transmission compared to untreated subjects or cell cultures. In some embodiments, antibodies, antibody fragments, or their variants reduce intercellular viral transmission by about 99.9% to about 1% compared to untreated subjects or cell cultures. In some embodiments, antibodies, antibody fragments, or their variants reduce intercellular viral transmission by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 64%, approximately 6 3%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, approximately 32% Reduces by approximately %, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, the antibody, antibody fragment, or variant thereof reduces intercellular viral transmission approximately 10 minutes to 1 day after administration compared to those in untreated subjects or cell cultures.In some embodiments, the antibody, antibody fragment, or a variant thereof reduces intercellular viral transmission at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to untreated subjects or cell cultures.

[0081] In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces inflammation in a subject. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces inflammation compared to the level of inflammation in a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces inflammation by about 99.9% to about 1% compared to the level of inflammation in a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces inflammation by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, and about 96% compared to the level of inflammation in a similar untreated subject or the same subject before administration of the antibody. Approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 6 4%, approximately 63%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, The levels are reduced by approximately 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces inflammation approximately 10 minutes to 1 day after administration compared to the level of inflammation in a similar untreated subject or the same subject before antibody administration.In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces inflammation at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to the level of inflammation in a similar untreated subject or the same subject before antibody administration.

[0082] In some embodiments, inflammation results in inflammatory lung injury. The reduction of inflammatory lung injury can be measured by any means known in the art. For example, inflammatory lung injury and / or its symptoms can be measured by evaluating changes in the patient's oxygen levels, exhaled nitric oxide, respiratory rate, or vital capacity measurements.

[0083] In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces proteinase activity in a subject. In some embodiments, the proteinase is a metalloproteinase. In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces proteinase activity compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces proteinase activity by about 99.9% to about 1% compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces proteinase activity by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, Approximately 64%, approximately 63%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33% Reduce by approximately 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces proteinase activity approximately 10 minutes to 1 day after administration, compared to the level in a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces proteinase activity approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to the level of proteinase activity in a similar untreated subject or the same subject before administration of the antibody. In some embodiments, the proteinase is produced and / or secreted by cells expressing CD147. In some embodiments, the proteinase is produced and / or secreted by cancer cells. In some embodiments, the proteinase is produced and / or secreted by cancer cells expressing CD147.

[0084] In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces matrix degradation in a subject. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces matrix degradation compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces matrix degradation by about 99.9% to about 1% compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces matrix degradation by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, and about 9% compared to a similar untreated subject or the same subject before administration of the antibody. 6%, approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 64%, approximately 63%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, The levels are reduced by approximately 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces matrix degradation approximately 10 minutes to 1 day after administration compared to levels in similar untreated subjects or the same subjects before antibody administration.In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces matrix degradation at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to the levels in a similar untreated subject or the same subject before antibody administration.

[0085] In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces cell infiltration in a subject. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces cell infiltration compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces cell infiltration by about 99.9% to about 1% compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces cell infiltration by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, compared to a similar untreated subject or the same subject before administration of the antibody. Approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 64% %, approximately 63%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, approximately The levels are reduced by approximately 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces cell infiltration approximately 10 minutes to 1 day after administration compared to levels in similar untreated subjects or the same subjects before antibody administration.In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces cell infiltration at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to the level in a similar untreated subject or the same subject before antibody administration.

[0086] In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces tumor cell metastasis in a subject. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces tumor cell metastasis compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces tumor cell metastasis by about 99.9% to about 1% compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces tumor cell metastasis by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, and about 96% compared to a similar untreated subject or the same subject before administration of the antibody. %, approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 6 4%, approximately 63%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, The levels are reduced by approximately 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces tumor cell metastasis approximately 10 minutes to 1 day after administration compared to levels in similar untreated subjects or the same subjects before antibody administration.In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces tumor cell metastasis at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to levels in a similar untreated subject or the same subject before antibody administration.

[0087] In some embodiments, administration of the antibodies, antibody fragments, or variants thereof of the Disclosure reduces tumor cell viability in a subject. In some embodiments, administration of the antibodies, antibody fragments, or their modifications reduces tumor cell viability compared to similar untreated subjects or the same subjects before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or their variants reduces tumor cell viability by about 99.9% to about 1% compared to similar untreated subjects or the same subjects before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or their variants reduces tumor cell viability by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, and about 96% compared to similar untreated subjects or the same subjects before administration of the antibody. %, approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 6 4%, approximately 63%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, The levels are reduced by approximately 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces tumor cell viability approximately 10 minutes to 1 day after administration compared to levels in similar untreated subjects or the same subjects before antibody administration.In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces tumor cell viability at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to levels in similar untreated subjects or the same subjects before antibody administration.

[0088] In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces angiogenesis in a subject. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces angiogenesis compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces angiogenesis by about 99.9% to about 1% compared to a similar untreated subject or the same subject before administration of the antibody. In some embodiments, administration of the antibodies, antibody fragments, or variants thereof reduces angiogenesis by about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99%, about 98%, about 97%, about 96%, compared to a similar untreated subject or the same subject before administration of the antibody. Approximately 95%, approximately 94%, approximately 93%, approximately 92%, approximately 91%, approximately 90%, approximately 89%, approximately 88%, approximately 87%, approximately 86%, approximately 85%, approximately 84%, approximately 83%, approximately 82%, approximately 81%, approximately 80%, approximately 79%, approximately 78%, approximately 77%, approximately 76%, approximately 75%, approximately 74%, approximately 73%, approximately 72%, approximately 71%, approximately 70%, approximately 69%, approximately 68%, approximately 67%, approximately 66%, approximately 65%, approximately 64% %, approximately 63%, approximately 62%, approximately 61%, approximately 60%, approximately 59%, approximately 58%, approximately 57%, approximately 56%, approximately 55%, approximately 54%, approximately 53%, approximately 52%, approximately 51%, approximately 50%, approximately 49%, approximately 48%, approximately 47%, approximately 46%, approximately 45%, approximately 44%, approximately 43%, approximately 42%, approximately 41%, approximately 40%, approximately 39%, approximately 38%, approximately 37%, approximately 36%, approximately 35%, approximately 34%, approximately 33%, approximately Reduces by 32%, approximately 31%, approximately 30%, approximately 29%, approximately 28%, approximately 27%, approximately 26%, approximately 25%, approximately 24%, approximately 23%, approximately 22%, approximately 21%, approximately 20%, approximately 19%, approximately 18%, approximately 17%, approximately 16%, approximately 15%, approximately 14%, approximately 13%, approximately 12%, approximately 11%, approximately 10%, approximately 9%, approximately 8%, approximately 7%, approximately 6%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, or approximately 1%. In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces angiogenesis approximately 10 minutes to 1 day after administration compared to levels in similar untreated subjects or the same subjects before antibody administration.In some embodiments, administration of an antibody, antibody fragment, or a variant thereof reduces angiogenesis at approximately 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 2 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration, compared to levels in a similar untreated subject or the same subject before antibody administration.

[0089] Antibody-drug conjugates (ADCs) In some embodiments, any of the provided anti-CD147 antibodies may be fused with a drug as part of an ADC. In some embodiments, the antibody comprises one of the aforementioned constructs listed in Table 1 or Table 2. Antibody-drug conjugates (ADCs) can be constructed by attaching a small molecule drug or another therapeutic agent to an antibody using either a permanent or unstable linker. The antibody typically targets a specific antigen found on target cells. Once it binds to the cell, it causes internalization of the antibody together with the drug. This delivers the drug to diseased or target cells with very high specificity, maximizing their efficacy and minimizing systemic exposure with the associated risk of side effects. In some embodiments, a linker is used to link the antibody with the drug. The linker is usually stabilized to avoid drug release around non-target tissues, and the linker can keep the conjugate in an inactive and non-toxic state while bound to the antibody. In some embodiments, the linker should have the property of releasing the drug upon internalization of the ADC into the target cell. In some embodiments, any of the linkers described above can be utilized in the ADC construct. In some embodiments, the drugs that are part of the ADC are selected from the group consisting of anticancer drugs, antimalarial drugs, antiviral drugs, anti-inflammatory drugs, and toxins.

[0090] In some embodiments, the drug is an antiviral agent. In some embodiments, the antiviral agent is an anti-SARS-CoV-2 agent. In some embodiments, the anti-SARS-CoV-2 agent includes, but is not limited to, monoclonal antibodies such as bamranivimab, etesevimab, cacilibimab, indevimab, and sotrovimab. In some embodiments, the anti-SARS-CoV-2 agent is not an antibody. In some embodiments, the drug is an anticancer agent. In some embodiments, the anticancer agent includes immunotherapy. In some embodiments, the immunotherapy is selected from the group consisting of antibodies, checkpoint inhibitors, cell therapies, cytokines, oncolytic viruses, and vaccines. In some embodiments, the anticancer agent includes a cytotoxic agent. In some embodiments, the immunotherapy includes an antibody. Antibodies intended include gemtuzumab, inotuzumab, anti-B4-bR, denileukin, and combinations thereof. In some embodiments, the drug includes a toxin. Suitable toxins include Pseudomonas exotoxin and / or diphtheria toxin. In some embodiments, the ADC contains the anti-CD147 antibody of SEQ ID NO: 14. In some embodiments, the ADC contains the anti-CD147 antibody of SEQ ID NO: 12. In some embodiments, the drug contains a growth factor. Exemplary growth factors include, but are not limited to, IL-2, IL-13, TGFα, GM-CSF, and combinations thereof.

[0091] Treatment method In some embodiments, the present disclosure provides methods for treating, improving, or preventing disorders associated with CD147 expression and / or its symptoms.

[0092] In some embodiments, the Disclosure provides a method for treating, improving, or preventing cancer, comprising administering a pharmaceutical composition of the anti-CD147 antibody, antibody fragment, or a variant thereof to a subject of interest. In some embodiments, administration of the anti-CD147 antibody, antibody fragment, or a variant thereof prevents or delays tumor growth or cancer cell proliferation in a subject. In some embodiments, administration of the anti-CD147 antibody, antibody fragment, or a variant thereof prevents or delays the progression of cancer cells in a subject. In some embodiments, administration of the anti-CD147 antibody, antibody fragment, or a variant thereof prevents or delays cancer cell metastasis in a subject. In some embodiments, administration of the anti-CD147 antibody, antibody fragment, or a variant thereof prevents or delays angiogenesis in a subject. In some embodiments, administration of the anti-CD147 antibody, antibody fragment, or a variant thereof prevents or delays cell invasion in a subject. In some embodiments, cancers include, but are not limited to, breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0093] In some embodiments, the Disclosure provides methods for treating, improving, or preventing inflammatory or autoimmune disorders, comprising administering a pharmaceutical composition of the anti-CD147 antibody, antibody fragment, or a variant thereof to a subject of interest. In some embodiments, autoimmune or inflammatory disorders include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

[0094] In some embodiments, the Disclosure provides a method for treating or preventing viral infection symptoms and / or related conditions, comprising administering a pharmaceutical composition comprising the anti-CD147 antibody, antibody fragment, or a variant thereof of the Disclosure to a subject of interest. In some embodiments, the viral infection is caused by viruses including, but not limited to, measles, coronavirus, SARS, MERS, SARS-CoV-2, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella-zoster virus, poliovirus, immunodeficiency virus (e.g., HIV), enveloped viruses, RNA viruses, and hepatitis. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the coronavirus infection is a SARS-CoV-2 infection. Any strain of SARS-CoV-2, including but not limited to alpha, beta, gamma, delta, epsilon, zeta, eta, theta, iota, kappa, lambda, mu, nu, xy, omicron, pi, rho, sigma, tau, upsilon, phi, chi, psi, or omega, can be treated with the antibodies of this disclosure. In some embodiments, the SARS-CoV-2 strain is one or more of alpha, beta, gamma, delta, and / or omicron.

[0095] In some embodiments, the symptom and / or associated condition is dyspnea and / or respiratory failure. In some embodiments, respiratory failure is defined on a resource utilization basis requiring at least one of the following: endotracheal intubation and mechanical ventilation; oxygen delivered by high-flow nasal cannula; heated, humidified oxygen delivered at a flow rate of >20 L / min via reinforced nasal cannula (percentage of oxygen delivered ≥0.5); non-invasive positive pressure ventilation; extracorporeal membrane oxygenation (ECMO); and / or a clinical diagnosis of respiratory failure (e.g., clinically requiring one of the preceding treatments, but the preceding treatment cannot be performed in a resource-limited situation).

[0096] Pharmaceutical composition and administration This disclosure provides pharmaceutical compositions comprising the anti-CD147 antibody, antibody fragment, or a variant thereof, having one or more pharmaceutically acceptable excipients and / or diluents. For example, such excipients include salts and other excipients that can act to stabilize hydrogen bonds. Any suitable excipient known in the art can be used. Exemplary excipients include, but are not limited to, amino acids such as histidine, glycine, or arginine; glycerol; sugars such as sucrose; surfactants such as polysorbate 20 and polysorbate 80; citric acid; sodium citrate; antioxidants; salts including alkaline earth metal salts such as sodium, potassium, and calcium; counterions such as chlorides and phosphates; preservatives; sugar alcohols (e.g., mannitol, sorbitol); and buffers. Exemplary salts include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dibasic sodium phosphate, monobasic sodium phosphate, monobasic potassium phosphate, and dibasic potassium phosphate. In certain embodiments, the pharmaceutical compositions disclosed herein have enhanced efficacy, bioavailability, therapeutic half-life, persistence, degradation resistance, and the like.

[0097] Pharmaceutical formulations can be stored frozen, refrigerated, or at room temperature. Storage conditions may be below the freezing point, for example, below about -10°C, or below about -20°C, or below about -40°C, or below about -70°C. In some embodiments, pharmaceutical formulations are stored at 2° to 8°C. For example, pharmaceutical formulations may be isotonic with blood or have ionic strengths that mimic physiological conditions. For example, a formulation may have an ionic strength of at least 25 mM sodium chloride, or at least 30 mM sodium chloride, or at least 40 mM sodium chloride, or at least 50 mM sodium chloride, or at least 75 mM sodium chloride, or at least 100 mM sodium chloride, or at least 150 mM sodium chloride. In certain embodiments, a formulation has an ionic strength equivalent to that of 0.9% saline (154 mM sodium chloride).

[0098] In some embodiments, the pharmaceutical formulation is formulated at a physiological pH. In some embodiments, the pharmaceutical formulation is formulated at a pH in the range of about 5.5 to about 8.5. In some embodiments, the pharmaceutical formulation is formulated at a pH in the range of about 6.0 to about 8.0. In some embodiments, the pharmaceutical formulation is formulated at a pH in the range of about 6.5 to about 7.5. In some embodiments, the pharmaceutical formulation is formulated at a pH of 7.5. In some embodiments, pharmaceutical formulations with a lower pH exhibit improved formulation stability compared to formulations with a higher pH. In some embodiments, pharmaceutical formulations with a higher pH exhibit improved formulation stability compared to formulations with a lower pH.

[0099] In some embodiments, the pharmaceutical formulation is stable under storage conditions. Stability can be measured using any suitable means in the art. Generally, a stable formulation is one in which the increase in degradation products or impurities is less than 5%. In some embodiments, the formulation is stable under storage conditions for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 1 year, or at least about 2 years or more. In some embodiments, the formulation is stable at 25°C for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or at least about 1 year or more.

[0100] In another embodiment, the Disclosure provides a method for delivering the pharmaceutical formulations disclosed herein. The method comprises administering the pharmaceutical formulation described herein to a target subject requiring the pharmaceutical formulation to be administered about 1 to about 31 times per month. In some embodiments, the pharmaceutical formulation is administered about 1, 2, 3 and / or 4 times per month. In some embodiments, the pharmaceutical composition is administered daily. In some embodiments, the pharmaceutical is administered weekly. In some embodiments, the pharmaceutical composition is administered weekly. In some embodiments, the pharmaceutical composition is administered 1 to 3 times per week. In some embodiments, the pharmaceutical composition is administered once every two weeks. In some embodiments, the pharmaceutical composition is administered 1 to 2 times per month. In some embodiments, the pharmaceutical composition is administered about once per month. In some embodiments, the pharmaceutical composition is administered about once every two months, about once every three months, about once every four months, about once every five months and / or about once every six months.

[0101] In some embodiments, the pharmaceutical compositions disclosed herein are administered until at least one or more symptoms of the disorder being treated are reduced and / or improved. In some embodiments, the pharmaceutical compositions disclosed herein are administered until at least one or more symptoms are improved. In some embodiments, the pharmaceutical compositions disclosed herein are administered until at least one or more symptoms of the disorder are delayed. In some embodiments, the pharmaceutical compositions disclosed herein are administered until the disorder is cured.

[0102] In some embodiments, the pharmaceutical compositions disclosed herein are administered before the patient begins to exhibit one or more symptoms. In some embodiments, the pharmaceutical compositions disclosed herein are administered at the time of symptom onset.

[0103] The pharmaceutical composition may be administered by any known route, for example, orally, intravenously, intramuscularly, nasally, subcutaneously, parenterally, by inhalation, or intradermally. In some embodiments, the formulation is generally for subcutaneous administration. In some embodiments, the formulation is generally for intravenous administration.

[0104] Those skilled in the art can determine the desired dose in each case, but a suitable dose of the pharmaceutical composition to achieve therapeutic benefits may be, for example, in the range of about 1 microgram (μg) to about 100 milligrams (mg) per kilogram of body weight of the recipient, preferably in the range of about 10 μg to about 50 mg per kilogram of body weight, and most preferably in the range of about 100 μg to about 10 mg per kilogram of body weight. In some embodiments, the pharmaceutical composition is administered in low doses. In some embodiments, the pharmaceutical composition is administered in doses of 0.1 mg / kilogram / body weight to about 9 mg / kilogram / body weight. In some embodiments, the pharmaceutical composition is administered at doses of approximately 0.05 mg / kg body weight, approximately 0.1 mg / kg body weight, approximately 0.2 mg / kg body weight, approximately 0.4 mg / kg body weight, approximately 0.5 mg / kg body weight, approximately 0.8 mg / kg body weight, approximately 1 mg / kg body weight, approximately 1.2 mg / kg body weight, approximately 2 mg / kg body weight, approximately 3 mg / kg body weight, and / or approximately 9 mg / kg body weight. The desired dose can be administered weekly.

[0105] Appropriate doses of the pharmaceutical composition to achieve therapeutic benefits may range, for example, from about 1 microgram (μg) to about 10 milligrams (mg) per kilogram of body weight of the recipient, preferably from about 10 μg to about 5 mg per kilogram of body weight, and most preferably from about 100 μg to about 2 mg per kilogram of body weight. In some embodiments, the pharmaceutical composition is administered in low doses. In some embodiments, the pharmaceutical composition is administered in doses of 0.1 mg / kilogram / body weight to about 9 mg / kilogram / body weight. In some embodiments, the pharmaceutical composition is administered in doses of about 0.05 mg / kilogram / body weight, about 0.1 mg / kilogram / body weight, about 0.2 mg / kilogram / body weight, about 0.4 mg / kilogram / body weight, about 0.5 mg / kilogram / body weight, about 0.8 mg / kilogram / body weight, about 1 mg / kilogram / body weight, about 1.2 mg / kilogram / body weight, about 2 mg / kilogram / body weight, about 3 mg / kilogram / body weight, and / or about 9 mg / kilogram / body weight. The desired dose may be presented as a single dose administered at appropriate intervals, or as two or more partial doses. These partial doses may be administered in unit dosage forms containing, for example, about 10 μg to about 1000 mg, preferably about 50 μg to about 500 mg, and most preferably about 50 μg to about 250 mg of the active ingredient per unit dosage form. Alternatively, if necessary depending on the recipient's condition, the dose may be administered as a series of infusions.

[0106] In some embodiments, the pharmaceutical composition is administered in a fixed dose of about 1 mg to about 1 g or more, regardless of the patient's body weight. In some embodiments, the pharmaceutical composition is approximately 1.0 mg, approximately 1.1 mg, approximately 1.2 mg, approximately 1.3 mg, approximately 1.4 mg, approximately 1.5 mg, approximately 1.6 mg, approximately 1.7 mg, approximately 1.8 mg, approximately 1.9 mg, approximately 2.0 mg, approximately 3.0 mg, approximately 4.0 mg, approximately 5.0 mg, approximately 6.0 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg , about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 26 0mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, The drug is administered in doses of approximately 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, or more. In some embodiments, the pharmaceutical composition is administered in doses of approximately 10 mg, 40 mg, or 100 mg.

[0107] The pharmaceutical composition may be administered for about 1 day to about 1 year or longer. In some embodiments, the pharmaceutical composition is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

[0108] In certain embodiments, the subject is a human, but in other embodiments, it may be a domesticated pet (e.g., a dog or a cat), or a non-human mammal such as livestock or farm animals (e.g., a horse, a cow, a sheep, or a pig).

[0109] Patient group The pharmaceutical compositions of this disclosure may be administered to any suitable subject. In some embodiments, the subject is at risk of developing a viral infection, cancer, or autoimmune or inflammatory disorder. In some embodiments, the patient is at risk of developing the adverse or life-threatening effects of the disorders described herein. In some embodiments, the subject is experiencing the adverse or life-threatening effects of the disorders described herein.

[0110] In some embodiments, the subject is infected with or suspected to be infected with SARS-CoV-2. In some embodiments, the subject has COVID-19, ARDS, and / or is experiencing symptoms associated with COVID-19 or ARDS. In some embodiments, the subject is hospitalized. In some embodiments, the patient has a mild case of COVID-19, ARDS, and / or is experiencing mild symptoms associated with COVID-19 or ARDS. In some embodiments, the subject has a moderate case of COVID-19, ARDS, and / or is experiencing moderate symptoms associated with COVID-19 or ARDS. In some embodiments, the subject has a severe case of COVID-19, ARDS, and / or is experiencing severe symptoms associated with COVID-19 (e.g., rapid clinical deterioration, ARDS, and / or death). In some embodiments, the patient requires assisted breathing. In some embodiments, the patient is receiving oxygen supplementation. In some embodiments, the patient is receiving oxygen supplementation via a face mask or nasal cannula with prongs. In some embodiments, the patient requires a ventilator to breathe. In some embodiments, the patient exhibits low oxygen saturation levels. In some embodiments, the patient exhibits an increased respiratory rate (e.g., more than 24 breaths / minute). In some embodiments, the patient has a fever (e.g., a body temperature above 100.4°F or 38°C). In some embodiments, the patient is at risk of progressing to more severe COVID-19, ARDS, or its symptoms, and the pharmaceutical compositions of this disclosure are administered before the symptoms worsen.

[0111] In some embodiments, a patient is determined to have mild COVID-19 by 1) testing positive by a standard RT-PCR assay or equivalent, 2) having symptoms of a mild illness with COVID-19, which may include fever, cough, sore throat, fatigue, headache, muscle pain, and gastrointestinal symptoms, but without shortness of breath or dyspnea; and / or 3) not having any clinical signs indicating moderate, severe, or critical COVID-19.

[0112] In some embodiments, a patient is determined to have moderate COVID-19 by: 1) a positive test by a standard RT-PCR assay or equivalent; 2) symptoms of moderate illness with COVID-19, which may include any symptoms of mild illness or shortness of breath associated with exercise; 3) clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥ 20 breaths / min, oxygen saturation (SpO2) > 93% in room air at sea level, heart rate ≥ 90 beats / min, and / or 4) the absence of clinical signs indicating severe or critical illness.

[0113] In some embodiments, a patient is determined to have severe COVID-19 by 1) a positive test result by a standard RT-PCR assay or equivalent; 2) symptoms suggestive of severe systemic disease with COVID-19, which may include moderate illness or any symptoms of shortness of breath or dyspnea at rest; 3) clinical signs indicating severe systemic disease with COVID-19, such as respiratory rate ≥ 30 breaths / min, heart rate ≥ 125 beats / min, SpO2 ≤ 93% in room air at sea level, or PaO2 / FiO2 < 300; and / or 4) the absence of criteria for critical severity.

[0114] In some embodiments, a patient is determined to have severe COVID-19 by evidence of a severe illness defined by: 1) a positive test result by a standard RT-PCR assay or equivalent; 2) a) respiratory failure defined on a resource basis requiring at least one of the following: endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula; heated, humidified oxygen delivered at a flow rate of >20 L / min via reinforced nasal cannula (percentage of oxygen delivered ≥0.5); non-invasive positive pressure ventilation; extracorporeal membrane oxygenation (ECMO); and / or a clinical diagnosis of respiratory failure (e.g., clinically requiring one of the preceding treatments, but the preceding treatment cannot be administered in a resource-constrained situation); b) shock (e.g., defined by systolic blood pressure <90 mmHg, or diastolic blood pressure <60 mmHg, or requiring a vasoconstrictor); and / or c) at least one of the following:

[0115] In some embodiments, the patient is an infant (e.g., including all ages from 0 to 2 years). In some embodiments, the patient is a pediatric patient (e.g., including all ages from 2 to 18 years). In some embodiments, the patient is between 18 and 100 years old. In some embodiments, the patient is between 18 and 85 years old. In some embodiments, the patient is between 50 and 100 years old. In some embodiments, the patient is over 65 years old. In some embodiments, the patient is 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 years old or over. In some embodiments, patients over 50 years of age are considered to be at higher risk of developing a serious illness (e.g., COVID-19 or ARDS). In some embodiments, patients over 65 years of age are considered to be at higher risk of developing a serious illness (e.g., COVID-19 or ARDS).

[0116] In some embodiments, patients with one or more comorbidities are considered to be at high risk of developing a serious illness (e.g., COVID-19 or ARDS). In some embodiments, comorbidities include, but are not limited to, obesity, hypertension, diabetes, autoimmune disorders (e.g., rheumatoid arthritis), heart disease, heart failure, atherosclerosis, cancer (e.g., lung cancer), exposure to lung-damaging agents, liver disease, alcoholism, other lung infections, and chronic kidney disease. In some embodiments, patients at risk show elevated markers of cardiac trauma or impairment (e.g., hsTnI, NT-proBNP). In some embodiments, race is a factor in patients considered to be at high risk of developing a serious illness (e.g., COVID-19 or ARDS). In some embodiments, socioeconomic status is a factor in patients considered to be at high risk of developing a serious illness (e.g., COVID-19 or ARDS).

[0117] In some embodiments, the patient continues to receive standard care for any comorbidities while being administered the pharmaceutical composition of the present disclosure.

[0118] Combination therapy The pharmaceutical compositions disclosed herein may be administered in conjunction with a variety of therapies used to treat, prevent, delay, or improve cancer, viral infections, inflammation, autoimmune disorders, inflammatory lung injury, COVID-19, and / or ARDS. In some embodiments, the pharmaceutical compositions are administered concurrently with standard therapeutic agents. One or more therapeutic agents may be any compound, molecule, or substance that exerts a therapeutic effect on the target requiring such effect.

[0119] In some embodiments, the pharmaceutical compositions disclosed herein are administered with therapeutic agents including, but not limited to, antiviral agents, antimalarial agents, agents that protect epithelial cells, defibrotide, convalescent plasma, chloroquine, hydroxychloroquine, remdesivir, desferal, favipiravir, corticosteroids, klevudin, anti-inflammatory agents, antioxidants, dapagliflozin, IFX-1, ruxolitinib, baricitinib, interferon beta-1a, azithromycin, tocilizumab, acalabrutinib, umifenovir, ciclesonide, sarilumab, anti-interleukin agents, and telmisartan.

[0120] In some embodiments, the subject has been previously treated with anti-SARS-CoV-2 therapy or COVID-19 therapy, or is receiving combination therapy with anti-SARS-CoV-2 therapy or COVID-19 therapy. Appropriate treatments include monoclonal antibodies (e.g., bamranivimab, evusheld, sotrovimab, Regen-Cov, and etesevimab), remdesivir, mechanical ventilation, oxygen therapy, and combinations thereof. In some embodiments, the subject in need of treatment is refractory to anti-SARS-CoV-2 therapy or COVID-19 therapy, e.g., appropriate treatments provided herein. In some embodiments, the subject in need of treatment, which is refractory to anti-SARS-CoV-2 therapy, is treated with the antibodies of this disclosure.

[0121] In some embodiments, the pharmaceutical compositions disclosed herein include methotrexate, daunomycin, mitomycin, cisplatin, vincristine, epirubicin, fluorouracil, verapamil, cyclophosphamide, cytosine arabinoside, aminopterin, bleomycin, mitomycin C, democolcine, etoposide, and mitomycin. It is administered with one or more chemotherapeutic agents, including but not limited to tramicin, chlorambucil, melphalan, daunorubicin, doxorubicin, tamoxifen, paclitaxel, vinblastine, camptothecin, actinomycin D, cytarabine, and combrestatin.

[0122] One or more therapeutic agents may be “co-administered” to a subject, either as separate pharmaceutical compositions or mixed into a single pharmaceutical composition; that is, they may be prepared and administered together. By “co-administering,” one or more therapeutic agents may also be administered simultaneously with the pharmaceutical composition, or separately, including at different times and at different frequencies. One or more therapeutic agents may be administered by any known route, such as subcutaneous, vaginal, or rectal, or, for example, orally, intravenously, intramuscularly, nasally, or via aerosol. The therapeutic agents may also be administered by any conventional route. In some embodiments, the pharmaceutical composition is administered subcutaneously.

[0123] When two or more therapeutic agents are used in combination, the dosage of each agent is generally the same as the dosage of the agent when used alone. However, if one agent interferes with the metabolism of another, the dosage of each agent is adjusted accordingly. Alternatively, if two or more agents exhibit a synergistic effect, one or more doses may be reduced. Each agent may be administered simultaneously or separately at appropriate time intervals.

[0124] definition When used in this disclosure, the singular forms "a," "an," and "the" refer to multiple subjects unless the context explicitly indicates otherwise.

[0125] Where used in this disclosure, the term “or” is understood to be inclusive and encompasses both “or” and “and.”

[0126] Where used in this disclosure, any concentration range, percentage range, ratio range, or integer range should be understood to include all integer values ​​within the enumerated range, and, where appropriate, fractions thereof (such as 1 / 10 and 1 / 100 of an integer), unless otherwise specified. Units, prefixes, and symbols used herein are provided in the form recognized by the International System of Units (SI). Numerical ranges include all numerical values ​​that define that range.

[0127] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to compounds containing amino acid residues covalently linked by peptide bonds. A protein or peptide contains at least two amino acids, and there is no limit to the maximum number of amino acids that can be included in a protein or peptide sequence. A polypeptide includes any peptide or protein containing two or more amino acids linked to each other by peptide bonds. As used herein, this term refers to both short chains, also commonly called peptides, oligopeptides, and oligomers in the art, and long chains, both commonly called proteins in the art, of which there are many types. Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, and fusion proteins. Polypeptides include native peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0128] To calculate the percentage of identity, the sequences being compared are typically aligned to give the maximum match between them. An example of a computer program that can be used to determine the percentage of identity is the GCG program package, which includes GAP (Devereux et al., 1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, Wis). The computer algorithm GAP is used to align two polypeptides or polynucleotides whose percentage sequence identity is determined. The sequences are aligned so that their respective amino acids or nucleotides best match (the "match span" determined by the algorithm). In certain embodiments, standard comparison matrices (see Dayhoff et al., 1978, Atlas of Protein Sequence and Structure 5:345-352 for the PAM250 comparison matrix; Henikoff et al., 1992, Proc. Natl. Acad. Sci. USA 89:10915-10919 for the BLOSUM 62 comparison matrix) are also used by the algorithm.

[0129] Examples of non-limiting embodiments of the present disclosure The embodiments of the subject matter disclosed herein may be useful on their own or in combination with one or more other embodiments. Without limiting the foregoing description, certain non-limiting embodiments of the disclosure are provided below. As will be apparent to those skilled in the art upon reading the disclosure, each individually numbered embodiment may be used or combined with any preceding or succeeding individually numbered embodiment. This is intended to provide support for all such combinations of embodiments, and is not limited to the combinations of embodiments expressly provided below.

[0130] Embodiments:

[0131] Embodiment 1. An anti-CD147 antibody comprising a binding domain containing at least one CDR having at least 70% identity with an amino acid sequence selected from SEQ ID NOs: 16-39.

[0132] Embodiment 2. The anti-CD147 antibody according to Embodiment 1, wherein the anti-CD147 antibody comprises two CDRs, each of which independently contains at least 70% identity to an amino acid sequence selected from SEQ ID NOs. 16-39.

[0133] Embodiment 3. The anti-CD147 antibody according to Embodiment 1 or 2, wherein the anti-CD147 antibody comprises three CDRs, each of which independently contains at least 70% identity to an amino acid sequence selected from SEQ ID NOs: 16-39.

[0134] Embodiment 4. The anti-CD147 antibody according to any one of Embodiments 1 to 3, wherein the anti-CD147 antibody comprises an amino acid sequence having at least 70% identity with a sequence selected from SEQ ID NOs: 4 to 15.

[0135] Embodiment 5. The anti-CD147 antibody according to any one of Embodiments 1 to 4, wherein the anti-CD147 antibody comprises an amino acid sequence selected from SEQ ID NOs. 4 to 15.

[0136] Embodiment 6. An anti-CD147 antibody according to any one of Embodiments 1 to 5, wherein the antibody is a full-length antibody, a monospecific antibody, a bispecific antibody, a triplicate antibody, an antigen-binding domain, a heavy chain, a light chain, VhH, Vh, CDR, a variable domain, scFv, Fc, Fv, Fab, F(ab)2, IgG, reduced IgG (rIgG), monospecific Fab2, bispecific Fab2, triplicate Fab3, a diabody, a bispecific diabody, a triplicate triabody, a minibody, a nanobody, IgNAR, V-NAR, HcIgG, or a combination thereof.

[0137] Embodiment 7. The anti-CD147 antibody according to Embodiment 6, wherein the antibody is VhH.

[0138] Embodiment 8. An anti-CD147 antibody according to any one of Embodiments 1 to 7, wherein the binding region of the chimeric antigen receptor (CAR) comprises at least one CDR having at least 70% identity with an amino acid sequence selected from SEQ ID NOs. 16 to 39.

[0139] Embodiment 9. The anti-CD147 antibody according to Embodiment 8, wherein the CAR is expressed on immune cells.

[0140] Embodiment 10. The anti-CD147 antibody according to Embodiment 9, wherein the immune cells are peripheral blood mononuclear cells (PBMCs), lymphocytes, T cells, or NK cells.

[0141] Embodiment 11. The anti-CD147 antibody according to any one of Embodiments 1 to 10, wherein the anti-CD147 antibody binds to CD147 or a fragment thereof expressed on the surface of a cell.

[0142] Embodiment 12. The anti-CD147 antibody according to Embodiment 11, wherein the cells are epithelial cells, endothelial cells, or neuronal cells.

[0143] Embodiment 13. The anti-CD147 antibody according to any one of Embodiments 1 to 12, wherein the anti-CD147 antibody reduces or eliminates the interaction between the virus and CD147.

[0144] Embodiment 14. The anti-CD147 antibody according to Embodiment 13, wherein the interaction includes the binding of CD147 by the virus.

[0145] Embodiment 15. The anti-CD147 antibody according to any one of Embodiments 1 to 14, wherein the anti-CD147 antibody reduces or eliminates the binding of the viral spike protein to CD147.

[0146] Embodiment 16. The anti-CD147 antibody according to any one of Embodiments 1 to 15, wherein the anti-CD147 antibody reduces or eliminates viral infiltration into cells.

[0147] Embodiment 17. The anti-CD147 antibody according to any one of Embodiments 1 to 16, wherein the anti-CD147 antibody reduces or eliminates viral infiltration into cells by at least about 1-fold, as determined by a viral infectivity assay.

[0148] Embodiment 18. An anti-CD147 antibody according to any one of Embodiments 13 to 17, wherein the virus is selected from the group consisting of measles, coronavirus, SARS, MERS, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella-zoster virus, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis.

[0149] Embodiment 19. The anti-CD147 antibody according to Embodiment 18, wherein the virus is the coronavirus.

[0150] Embodiment 20. The anti-CD147 antibody according to Embodiment 19, wherein the coronavirus is SARS-CoV-2.

[0151] Embodiment 21. The anti-CD147 antibody according to any one of Embodiments 11 to 20, wherein the cells are cancer cells.

[0152] Embodiment 22. The anti-CD147 antibody according to any one of Embodiments 11 to 20, wherein the cells are tumor cells.

[0153] Embodiment 23. The anti-CD147 antibody according to Embodiment 21, wherein the cancer cells are derived from hematological cancer.

[0154] Embodiment 24. The anti-CD147 antibody according to Embodiment 22, wherein the tumor cells are derived from cancer selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0155] Embodiment 25. The anti-CD147 antibody according to any one of Embodiments 1 to 24, wherein the anti-CD147 antibody reduces or eliminates tumor cell proliferation, metastasis, secretion of matrix metalloproteinases, degradation of the tumor matrix, tumor cell invasion, and / or angiogenesis.

[0156] Embodiment 26. The anti-CD147 antibody according to any one of Embodiments 1 to 24, wherein the anti-CD147 antibody reduces or eliminates inflammation.

[0157] Embodiment 27. The anti-CD147 antibody according to any one of Embodiments 1 to 24, wherein the anti-CD147 antibody is effective in reducing or eliminating inflammatory or autoimmune disorders.

[0158] Embodiment 28. The anti-CD147 antibody according to Embodiment 27, wherein the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

[0159] Embodiment 29. The anti-CD147 antibody according to any one of Embodiments 1 to 28, wherein the anti-CD147 antibody is humanized.

[0160] Embodiment 30. A method for preventing, treating, or improving a CD147 expression-related disorder in a subject requiring prevention, treatment, or improvement of a CD147 expression-related disorder, comprising administering an anti-CD147 antibody described in any one of Embodiments 1 to 29.

[0161] Embodiment 31. A pharmaceutical composition comprising an effective amount of the anti-CD147 antibody described in any one of Embodiments 1 to 29.

[0162] Embodiment 32. Cells containing a sequence encoding the anti-CD147 antibody described in any one of Embodiments 1 to 29.

[0163] Embodiment 33. An anti-CD147 antibody according to any one of Embodiments 1 to 29, wherein the anti-CD147 antibody binds to a cell, thereby preventing, inhibiting, or reducing the infiltration of Plasmodium parasites into the cell.

[0164] Embodiment 34. The anti-CD147 antibody according to Embodiment 33, wherein the infiltration of the Plasmodium parasite into the cell is at least about 1x.

[0165] Embodiment 35. The anti-CD147 antibody according to Embodiment 34, wherein the cells are red blood cells.

[0166] Embodiment 36. An anti-CD147 antibody according to any one of Embodiments 33 to 35, wherein the Plasmodium parasite is selected from the group consisting of Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Plasmodium knowlesi.

[0167] Embodiment 37. The anti-CD147 antibody according to any one of Embodiments 33 to 36, wherein the anti-CD147 antibody is effective in reducing parasitemia in blood cells.

[0168] Embodiment 38. The anti-CD147 antibody according to Embodiment 37, wherein the anti-CD147 antibody reduces parasitemia in blood cells within approximately 48 hours.

[0169] Embodiment 39. The anti-CD147 antibody according to Embodiment 37, wherein the anti-CD147 antibody reduces parasitemia in blood cells within approximately 96 hours.

[0170] Embodiment 40. The anti-CD147 antibody according to Embodiment 33, wherein administration of the anti-CD147 antibody prevents, improves, or treats malaria in a subject.

[0171] Embodiment 41. An anti-CD147 antibody comprising CDR1, CDR2, and CDR3 regions, wherein the CDR1 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 to 23, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 31, the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 to 39, and the anti-CD147 antibody comprises 0 to 5 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions.

[0172] Embodiment 42. The anti-CD147 antibody according to Embodiment 41, wherein the anti-CD147 antibody contains 0 to 3 amino acid modifications.

[0173] Embodiment 43. An anti-CD147 antibody according to any one of Embodiments 41 to 42, wherein the CDR1 region corresponds to SEQ ID NO: 18 or 22, the CDR2 region corresponds to SEQ ID NO: 26 or 30, and the CDR3 region corresponds to SEQ ID NO: 34 or 38.

[0174] Embodiment 44. The anti-CD147 antibody according to any one of Embodiments 41 to 43, wherein the anti-CD147 antibody comprises SEQ ID NO: 12 or SEQ ID NO: 14.

[0175] Embodiment 45. The anti-CD147 antibody according to any one of Embodiments 41 to 44, wherein the anti-CD147 antibody is humanized.

[0176] Embodiment 46. A treatment method comprising administering a pharmaceutical composition containing an effective amount of anti-CD147 antibody, wherein the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 regions, the CDR1 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 to 23, the CDR2 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 31, the CDR3 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 to 39, and the anti-CD147 antibody comprising 0 to 2 amino acid modifications in at least one of the CDR1, CDR, or CDR3 region.

[0177] Embodiment 47. The treatment method according to Embodiment 46, wherein the administration is effective in reducing or eliminating inflammatory or autoimmune diseases.

[0178] Embodiment 48. The treatment method according to any one of Embodiments 46 to 47, wherein the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

[0179] Embodiment 49. The treatment method according to any one of Embodiments 46 to 48, wherein the administration is effective in reducing or eliminating viral infiltration into cells by the virus.

[0180] Embodiment 50. The treatment method according to Embodiment 49, wherein the virus is selected from the group consisting of measles, coronavirus, SARS, MERS, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella-zoster virus, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis.

[0181] Embodiment 51. The treatment method according to Embodiment 50, wherein the virus is the coronavirus.

[0182] Embodiment 52. The treatment method according to Embodiment 51, wherein the coronavirus includes SARS-CoV-2.

[0183] Embodiment 53. The treatment method according to any one of Embodiments 46 to 48, wherein the administration is effective in reducing or eliminating cancer metastasis.

[0184] Embodiment 54. The treatment method according to Embodiment 53, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0185] Embodiment 55. The treatment method according to any one of Embodiments 46 to 48, wherein the administration is effective in reducing or eliminating the infiltration of Plasmodium into cells.

[0186] Embodiment 56. An antibody-drug conjugate comprising the anti-CD147 antibody described in any one of Embodiments 1 to 29.

[0187] Embodiment 57. The antibody-drug conjugate according to Embodiment 56, wherein the drug is selected from the group consisting of anticancer drugs, antimalarial drugs, antiviral drugs, and anti-inflammatory drugs.

[0188] Embodiment 58. The antibody-drug conjugate according to Embodiment 57, comprising the antiviral drug, wherein the antiviral drug is an anti-SARS-CoV-2 drug.

[0189] Embodiment 59. The antibody-drug conjugate according to Embodiment 57, comprising the anticancer drug, wherein the anticancer drug comprises immunotherapy.

[0190] Embodiment 60. The antibody-drug conjugate according to Embodiment 59, wherein the immunotherapy is selected from the group consisting of antibodies, checkpoint inhibitors, cell therapies, cytokines, oncolytic viruses, and vaccines.

[0191] Embodiment 61. The antibody-drug conjugate according to Embodiment 60, comprising the antibody.

[0192] Embodiment 62. The antibody-drug conjugate according to Embodiment 56, wherein the anti-CD147 antibody comprises SEQ ID NO: 12 or SEQ ID NO: 14. [Examples]

[0193] Example 1 - Production of VhH antibody that binds to human CD147 To produce VhH antibodies that bind to human CD147, llamas were immunized with recombinant CD147 (in a cocktail of 21 antigens) and given four booster immunizations. mRNA was extracted from blood lymphocytes, and a VhH antibody display library was constructed using a yeast surface expression system. Yeast clones expressing anti-CD147 VhH antibodies were enriched by two panning and FACS procedures, and 24 clones were analyzed for VhH secretion. Their anti-CD147 activity was measured by ELISA.

[0194] Of these 24 clones, four were selected for further study due to their unique sequences and high signal-to-noise ratios in ELISA. Two of these (Ibx-11 and Ibx-13) were well expressed as IgG Fc fusions in mammalian cells, and three tandem bivalent VhH constructs (without IgG Fc fusions) were also produced (Ibx-75, Ibx-76, and Ibx-75 VhH).

[0195] For ELISA, 100 ng of human CD147 was coated overnight in 1× coating buffer onto Nunc polysorb plates. The wells were washed once with TBST (0.01% Tween® 20) and then blocked for 1 hour at room temperature (RT) using a 1× fish gel in TBST. Ibx-11, Ibx-13, Ibx-75, Ibx-76, Ibx-77, and anti-HIS antibodies were incubated at RT for 1 hour at 0.01 ng / well to 100 ng / well per 100 μl, followed by three 5-minute washes for each wash. The wells were incubated at RT for 1 hour with a 1:1000 dilution, with anti-human antibody for Ibx-11 and Ibx-13 treatment wells, and with anti-flag antibody for Ibx-77, Ibx-75, and Ibx-76 treatment wells, followed by three 5-minute washes for each wash. The wells were incubated with 100 μl / well of TMBE for 30 minutes, and the reaction was stopped with 100 μl / well of 2N sulfuric acid. Optical density (OD) was measured using a Biotek Synergy 4 instrument for quantification.

[0196] The results of this assay are shown in Figure 1. The ELISA EC50 for the tested antibodies ranged from 2log (0.1 to 10 ng of VhH antibody / well). Tandem bivalent Ibx-75 (10 ng / well) showed the lowest binding to human CD147, followed by Ibx-76 and Ibx-77 at the same level (1 ng / well). IgG Best binding was observed with Fc fusions Ibx-11 and Ibx-13 (0.1 ng / well). The improved binding of IgG Fc fusions across tandem bivalents may be due to the different secondary reagents used (anti-Fc vs. anti-Flag, respectively) or differences in functional valency (i.e., the tandem bivalent structure may be binding effectively as a monovalent structure due to its shorter linker length).

[0197] Example 2 - Binding of VhH to mouse CD147 An ELISA was performed to test the ability of VhH described in Example 1 to bind to mouse CD147.

[0198] For ELISA, 100 ng of mouse CD147 was coated overnight in 1× coating buffer onto Nunc polysorb plates. The wells were washed once with TBST (0.01% Tween® 20) and then blocked for 1 hour at room temperature (RT) using a 1× fish gel in TBST. Ibx-11, Ibx-13, Ibx-75, Ibx-76, Ibx-77, and anti-HIS antibodies were incubated at RT for 1 hour at 0.01 ng / well to 100 ng / well per 100 μl, followed by three 5-minute washes for each wash. The wells were incubated at RT for 1 hour with a 1:1000 dilution, with anti-human antibodies for Ibx-11 and Ibx-13 treatment wells, and with anti-flag antibodies for Ibx-77, Ibx-75, and Ibx-76 treatment wells, followed by three 5-minute washes for each wash. The wells were incubated with 100 μl / well of TMBE for 30 minutes, and the reaction was stopped with 100 μl / well of 2N sulfuric acid. Optical density (OD) was measured using a Biotek Synergy 4 instrument for quantification.

[0199] Example 3 - SPR analysis of IBX-77 binding to CD147 For this assay, CD147 was injected at a concentration in the range of 0 nM to 900 nM at 10 μl / min for 600 seconds in HBS-EP buffer pH 7.4. For 0 nM, 9.22 nM, 0 nM, 23.04 nM, 57.6 nM, 144 nM, 360 nM, 900 nM, two CD147 injections were performed (2.5-fold dilution series). The chip surface was regenerated with 10 mM glycine pH 2.0 at 10 μl / min for 180 seconds.

[0200] Due to sudden air spikes and DIP during analyte injection, one technical replicate of 0 nm and 23.04 nM was excluded from the analysis. The data was analyzed with Q-Dat software provided by the instrument manufacturer. A steady-state 1:1 fitting model (Figure 4) was used for the initial steady-state binding analysis, and a simple Kd / Ka kinetic model (Figure 5) was used to estimate KD.

[0201] The two injections for each concentration were similar, but the response of the second injection was lower than that of the first injection. KD = 138.0 nM (±0.003 nM) was calculated at steady-state 1:1. The calculated kinetic model

[0202] Ka = 1.328×10 4 (±0.005) M-1s-1

[0203] Kd = 4.89×10 -4 (±0.001) s-1

[0204] KD = 36.1 nM (±0.001 nM).

[0205] Example 4 - SPR Analysis of Ibx-77 Binding to CD147 on a CMD Chip The CMD tip surface was activated by injecting a 1:1 mixture of NHS / EDC at 10 μl / min for 420 seconds. 100 μg / ml of CD147 was fixed in a 10 mM sodium acetate solution at pH 4.5 at 10 μl / min for 510 seconds. The unreacted CD147 and activated tip surface were washed and inactivated with ethanolamine at pH 8.5 at 10 μl / min for 420 seconds. A total of approximately 3800 RU of CD147 was fixed.

[0206] Ibx-77 was injected into HBS-EP buffer pH 7.4 at concentrations ranging from 9.22 nM to 360 nM at a rate of 10 μl / min for 420 seconds. The tip surface was regenerated using 10 mM glycine pH 2.0.

[0207] The data were analyzed using qDat software provided by the equipment manufacturer. A steady-state 1:1 fitting model was used for the initial steady-state coupled analysis (Figure 7). Subsequently, KD was estimated using a simple Kd / Ka dynamics model (Figure 6).

[0208] Example 5: Ibx-77 binds to HEK293 and HCC1954 cells. Flow cytometry was performed to test the ability of the VhH antibody of this disclosure to bind to CD147 expressed in cells. All cell lines were grown to confluence in the recommended medium in T-75 flasks (HCC1954-RPMI;SKBR3-McCoy's 5A;HEK293-DMEM;MCF-7-EMEM). Approximately 1 million cells were plated into 6-well plates and allowed to stand and grow overnight. Cells were removed by manual scraping using the broad, blunt tip of a 1 ml pipette, and the cells were prepared for flow cytometry analysis as before. 1 μg of Ibx-77, anti-CD147, rabbit isotype control, anti-Flag dylight was used to stain the cells on ice for 1 hour, followed by washing and centrifugation. The cells were then incubated with 1 μg of anti-rabbit Dylight488 and anti-Flag dylight488 as secondary antibodies for 30 minutes, followed by centrifugation and washing. Cells were resuspended in 1000 μl of flow source and given a final run on a flow cytometer. A total of 30,000 events were collected to analyze as many as possible within 300 seconds (5 minutes). Negative cells were gated out based on unstained cells for each individual cell line.

[0209] Conditions for each cell line: CST with positive controls only; Ibx-77 only; ISO-type control rabbits; UST; anti-Flag488 2° only - XF2.

[0210] Ibx-77 stained cells exhibit a different population of positively stained cells compared to unstained controls in the HEK293 cell line (Figure 8) and the HCC1954 cell line (Figure 9).

[0211] Example 6: Ibx-77 binds to CD147 expressed in HeLa cells. HELA cell lines were grown in the recommended medium in a T-75 flask until confluence. Approximately 1 million cells were plated into a 6-well plate and allowed to stand and grow overnight. Cells were removed by manual scraping using the broad, blunt tip of a 1 ml pipette, and the cells were prepared for flow cytometry analysis as before. The cells were washed once with the flow source, incubated on ice for 30 minutes with 1 μl / ml viability dye 660, and then washed twice. 10 μg and 5 μg of Ibx-77 were used to stain the cells on ice for 1 hour, and then washed twice. The cells were then incubated with 1 μg of anti-human Dylight488 and anti-Flag Dylight488 as secondary antibodies for 30 minutes, and then washed twice. The cells were resuspended in 1000 μl of flow source and subjected to a final run on the flow cytometer. A total of 50,000 events were collected to analyze as many as possible within 300 seconds (5 minutes). Negative cells were gated out based on unstained cells for each cell line. The conditions for each cell line were Ibx-77 only;UST, anti-flag488 secondary antibody only;Flag2 only.

[0212] As shown in Figure 10, 5 μg of Ibx-77 shows a different peak from the control and unstained cells treated with secondary antibody only.

[0213] Example 7 - Analysis of the ability of Ibx-77, Ibx-13, and Ibx-11 to bind to cells. HeLa and HCC-1954 cell lines were grown in the recommended medium in a T-75 flask until confluence. Approximately 1 million cells were plated into a 6-well plate and allowed to stand and grow overnight. Cells were removed by manual scraping using the broad, blunt tip of a 1 ml pipette, and the cells were prepared for flow cytometry analysis as before. Cells were washed once in the flow source (PBS, 1% FBS, and sodium azide). They were incubated on ice for 30 minutes with 1 μl / ml viability dye 660, followed by two washes. The cells were first blocked for reliable Fc receptors on ice for 10 minutes using 1 μg / 100 μl of Fc blocking reagent, followed by two washes. Cells were stained on ice for 1 hour with the indicated antibody amounts shown in the table, followed by two washes. Next, the cells were incubated for 30 minutes with anti-human Dylight488, anti-rabbit Dylight488, and anti-Flag Dylight488 as secondary antibodies, followed by two washes. The cells were resuspended in 2000 μl of flow source and subjected to a final run on a flow cytometer. A total of 50,000 events were collected to analyze as many as possible within 300 seconds (5 minutes). Negative cells were gated out based on the VhH-Fc-(h27-8GL) cells of the individual cell lines.

[0214] In this experiment, the following antibodies and controls were tested: Ibx-77 (10 μg); Ibx-13 (10 μg); Ibx-11 (10 μg); human isotype control (10 μg); anti-human secondary antibody only (1 μg; human 2); VhH-Fc-(h27-8GL) (10 μg); XF2 (anti-flag488) only; unstained.

[0215] Ibx-11 and Ibx-13 stain cells in a similar pattern, and histograms can be implied. Ibx-77 shows weaker staining, presumably because there is only one Flag epitope available for secondary antibody binding. Blocking with 1 μg of Fc block slightly reduced background noise for the human isotype control. The VhH-Fc(h27-8GL) control antibody clearly shows the staining difference between itself and Ibx-11 and Ibx-13. Therefore, such a control can be used for all experiments using VhH-Fc. Overall, HELA cells appear to express more CD147 than HCC1954.

[0216] Example 8: Analysis of the ability of Ibx-11 and Ibex-13 antibodies to bind to Jurkat T cells Jurkat cells were grown in recommended medium until confluence, and 4 million cells were collected and prepared for flow cytometry analysis as before. These cells were not treated with sodium azide. After washing the cells once with flow sources (PBS, 1% FBS, and sodium azide), they were incubated on ice for 30 minutes with 1 μl / mL viability dye 660 and washed twice. The Fc receptor was blocked for 10 minutes at room temperature using 1 μg / 100 μl of Fc blocking reagent, followed by two washes. The cells were stained on ice for 1 hour with the indicated amounts of antibody as shown in the table in Figure 13, followed by two washes. The specified tubes were incubated with spike RBD (1 μg / tube) for 1 hour and then washed twice. The cells were then incubated with anti-spike antibody, VhH-Fc control, human isotype antibody, or Ibx-11 at 4°C for 1 hour and then washed twice. Next, the cells were incubated with anti-human Dylight488, then anti-rabbit Dylight488, for 30 minutes, followed by two washes. The cells were resuspended in 1000 μl of flow source and given a final run on a flow cytometer. A total of 50,000 events were collected to analyze as many as possible within 300 seconds (5 minutes). Negative cells were gated out based on the VhH-Fc-(h27-8GL) cells of the individual cell lines.

[0217] Overall, Ibx-11 and Ibex-13 antibodies stained Jurkat cells.

[0218] Example 9: Analysis of the ability of Ibx-11 and Ibex-13 antibodies to bind to Vero E-6 cells. Jurkat and Vero E-6 cells were grown in recommended medium until confluence. Approximately 1 million cells per well were plated into 6-well dishes and prepared for flow cytometry analysis as before. Cells were not treated with sodium azide. Cells were washed once in the flow source (PBS, 1% FBS, and sodium azide). Fc receptors were blocked for 10 minutes at room temperature using 1 μg / 100 μl of Fc blocking reagent, followed by two washes. Cells were stained on ice for 1 hour with the indicated amounts of antibody shown in the table in Figure 14A-B, followed by two washes. Cells were then incubated with spike RBD (1 μg / tube) for 1 hour, followed by two washes. Cells were then incubated with anti-spike antibody, VhH-Fc control, human isotype antibody, or Ibx-11, Ibx-13, or Ibx-77 at 4°C for 1 hour, followed by two washes. Next, the cells were incubated with anti-human Dylight488, then anti-rabbit Dylight488, for 30 minutes, followed by two washes. The cells were resuspended in 1000 μl of flow source and given a final run on a flow cytometer. A total of 50,000 events were collected to analyze as many as possible within 300 seconds (5 minutes). Negative cells were gated out based on the VhH-Fc-(h27-8GL) cells of the individual cell lines.

[0219] Vero E6 cells were analyzed using the same flow cytometer voltage settings as those used for Jurkat cells. Jurkat cells showed good staining with Ibx-11, Ibx-13, and Ibx-77, clearly separating the negative control (VhH-Fc-(h27-8GL)) from the unstained control. See Figure 14A. Surprisingly, Vero E6 cells showed stronger staining with Ibx-13 than with Ibx-11. See Figure 14B. These differences may be due to differences in the CD147 sequence between humans and monkeys. Such amino acid differences may be part of an important epitope in the Ibx antibody lineage and can be used for potential epitope mapping. For non-human primate models, Ibx-13 and its dimerized version, Ibx-76, may be good candidates. Ibx-77 showed two peak populations that may indicate weaker staining of Vero E6 cells.

[0220] KD of Examples 10-Ibx-74 and Ibx-75 Approximately 45 μl of Ibx-74 and Ibx-75 were prepared at various purification stages. 35 μl of each sample was injected into a sensor tip, and a sensorgram was collected. The flow rate was 10 μl / min, and the tip was regenerated using 10 mM glycine at pH 1.5. The results are shown in Figures 15A and 15B.

[0221] The KD values ​​obtained here may be affected by impurities or concentration, but since the values ​​are mainly antibody-dependent, they can be used as a screening tool to identify strong binders. In this case, Ibx-75 is 1 × 10⁻⁶ -6 (±0.009)s -1 K d They are joined together, and Ibx-74 is 3 × 10 -5 (±0.001)s -1 K d They were joined together.

[0222] This comparison suggests that Ibx-75 may be a stronger binder with a lower off-rate than Ibx-74.

[0223] Example 11 - Antibody-drug conjugate (ADC) cytotoxicity assay MiaPaCa-2 cancer cells were seeded at 2500 cells / well in 96-well dishes, adhered, and grown overnight. Old medium was replaced with 50 μl of fresh medium. Ibx-11 and Ibx-13 antibodies were prepared by pre-mixing the antibodies with anti-human IgG Fc-MMAF. 50 microliters of Ibx-11 and Ibx-13 mixtures at various concentrations (final concentrations of 30 nM to 1.1 nM) were added to the wells. Controls consisting only of isotypes and secondary ADCs were included in the plates. The plates were then incubated for 72 hours. After this 72-hour incubation, cell viability was measured using a Rockland kit.

[0224] At the highest concentrations, Ibx-11 and Ibx-13 showed approximately 73% and 74% viable cells, respectively. See Figure 16. These antibodies effectively killed cancer cells.

[0225] Example 12 - Jurkat T cell aggregation assay Jurkat T cells were seeded at 20,000 cells / well, 100 μl, in 96 round-bottom wells. 100 μg / ml of Ibx-77, Ibx-11, or Ibx-13 was added to 100 μl of cells to a final volume of 200 μl per well and a final antibody concentration of 50 μg / ml. Images were collected at 0, 2, 4, 9, 18, and 24 hours. Pixels were measured using ImageJ at 2 hours, reaching a maximum value at 24 hours. No further differences were observed at 48 hours. Visual identification (Figure 17) revealed differences in aggregation patterns at 18 hours, with cells treated with 50 μg / ml of Ibx-series antibody exhibiting a more pronounced aggregation pattern, with denser aggregate clusters and fewer individual cells compared to the untreated control. Similar patterns were observed with lower doses of anti-CD147 control antibody and anti-CD98 antibody at 20 μg / ml. These data were also quantitatively analyzed by imaging analysis, counting pixel sizes from 8-bit images. Ibx-series antibodies at doses of 50 μg / ml to 25 μg / ml showed larger pixel sizes of particles (aggregates) over 24 hours. These differences varied subtly among the Ibx-series antibodies. See Figure 18.

[0226] In another cell aggregation assay, Jurkat T cells were seeded at 20,000 cells / well, 100 μl, in 96 round-bottom wells. 100 μg / ml of Ibx-77, Ibx-11, or Ibx-13 was added to 100 μl of cells to a final volume of 200 μl per well and a final antibody concentration of 50 μg / ml. Images were collected at 0, 2, 4, 9, 18, and 24 hours. Individual cells and cell groups with clear boundaries (less than 3 cells per group), rather than being part of larger aggregates, were manually counted at 18 and 24 hours. Figure 19. At 24 hours, there was a significant decrease in single cell count for Ibx-77 treated cells (p=0.071). Figures 20A–20B.

[0227] Example 13: Ibx-76 and Ibx-77 inhibit angiogenesis in a tubule formation assay. The ability of anti-CD147 VhH antibody to inhibit angiogenesis was investigated using a tubule formation assay. HuVEC cells were seeded on the surface of Matrigel coated wells. The day after seeding, the antibody and CD147 protein (added for competition) were added. After culturing for another day, the cells were stained with calcein AM. Tubulization was then evaluated by microscopy. In this case, a mouse antibody that binds to human CD147 (HIM6) was used as a positive control.

[0228] As shown in Figure 21, cells treated with either Ibx-76 or Ibx-77 showed inhibition of angiogenesis. In this case, CD147 is used as a stimulant for angiogenesis. Co-incubation of CD147 with Ibx-76 and Ibx-77 shows a reduction in angiogenesis that is not induced by CD147 alone.

[0229] Example 14-Ibx-13 inhibits the growth of Plasmodium falciparum in blood cells. The ability of different antibodies to block the growth of the NF54 strain of Plasmodium falciparum in red blood cells. Initial parasitemia was 1.3%, and this strain was cultured in 96-well plates at 2% hematocrit. Ibx-13 or MIF-2-5 antibody or VhH-Fc was administered to the wells at 1, 10, and 100 μg / mL. Parasites unexposed to any antibody were cultured as negative controls, and parasites cultured with the antimalarial drug chloroquine (CQ) were used as positive controls. Blood smears were prepared 48 and 96 hours after treatment, stained, and microscopically examined in a blind manner. The number of infected red blood cells (RBCs) was scored in a blind manner from approximately 1000 red blood cells and expressed as a percentage of parasitemia.

[0230] The results are shown in Figures 22 and 23 and Table 2.

[0231] In the positive control group, parasites grew normally after 48 hours, increasing to 1.3%–5.9%. In the negative control group, chloroquine treatment killed approximately 93% of parasites after 48 hours and approximately 98% after 96 hours. Treatment with Ibx-13 resulted in approximately 100% parasite inhibition even at the lowest concentration tested, while treatment with MIF-2-5 or VhH-Fc had no measurable effect. By 96 hours, parasites in the control, MIF-2-5, and VhH-Fc groups had died due to very high levels of parasitemia because the culture medium was not changed daily. [Table 2-2]

[0232] Example 15 - Antibody-drug conjugate assay against malignant melanoma cells 2,500 A375 (malignant melanoma) cells were seeded per well in a 96-well plate containing complete growth medium (DMEM, 10% FBS) and allowed to adhere overnight. The following day, the old medium was supplemented with 50 μl of fresh complete medium and 25 μl of Ibx-11, Ibx-13, or control antibody (diluted in complete medium). Antibodies were added in amounts ranging from 30 nM to 1.1 nM, decreasing threefold in concentration while maintaining a constant secondary ADC of 30 nM. These mixtures were incubated for 5 minutes. 25 μl of anti-Fc (human) secondary antibody drug conjugate reagent (diluted in complete medium) was added to the wells and incubated in a 5.0% CO2 incubator at 37°C for 72 hours. After 72 hours, viability was assessed using the Viability Kit® according to the manufacturer's protocol.

[0233] A375 cells exhibit sensitivity to primary antibodies Ibx-11 and Ibx-13 at escalating doses up to 3.3 nM. See Figures 24-25. The maximum effect observed was approximately a 55% reduction in viability at 3.3 nM, after which viability gradually decreased with higher antibody concentrations. Secondary ADCs of 30 nM themselves may have a small effect compared to untreated cells. Several effects of human isotype controls were also observed.

[0234] Example 16 - Antibody-drug conjugate assay against prostate cancer cells 2,500 PC-3 (prostate cancer) cells were seeded per well in a 96-well plate containing complete growth medium (F-12K, 10% FBS) and allowed to adhere overnight. The following day, the old medium was supplemented with 50 μl of fresh complete medium and 25 μl of Ibx-11, Ibx-13, or control antibody (diluted in complete medium). Antibodies were added in amounts ranging from 30 nM to 1.1 nM, decreasing threefold in concentration while maintaining a constant secondary ADC of 30 nM. These mixtures were incubated for 5 minutes. 25 μl of anti-Fc (human) secondary antibody drug conjugate reagent (diluted in complete medium) was added to the wells and incubated in a 5.0% CO2 incubator at 37°C for 72 hours. After 72 hours, viability was assessed using the Viability Kit® according to the manufacturer's protocol.

[0235] PC3 cells may be less sensitive to the ADC assay than A375 (malignant melanoma) cells taught in Example 15. See Figures 26 and 27. The maximum effect observed here was a loss of approximately 25% of survival. This difference in survival may be due to differences in the amount of surface CD147 present in the cells, the corresponding differences in the rate of endocytosis, and differences in the sensitivity of cancer to the toxic payload used in the assay. References Watanabe et al. (2010). CD147 / EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells. Journal of Virology Apr 2010, 84 (9) 4183-4193. Chenglong et al. (2020) Cyclophilin A and CD147: novel therapeutic targets for the treatment of COVID-19. Medicine in Drug Discovery, Volume 7:100056 In certain embodiments, for example, the following are provided: (Item 1) An anti-CD147 antibody comprising a binding domain containing at least one CDR having at least 70% identity with an amino acid sequence selected from SEQ ID NOs. 16-39. (Item 2) The anti-CD147 antibody according to item 1, wherein the anti-CD147 antibody comprises two CDRs, each of which independently contains at least 70% identity to an amino acid sequence selected from SEQ ID NOs. 16-39. (Item 3) The anti-CD147 antibody according to item 1 or 2, wherein the anti-CD147 antibody comprises three CDRs, each of which independently contains at least 70% identity to an amino acid sequence selected from SEQ ID NOs. 16-39. (Item 4) The anti-CD147 antibody according to item 1, wherein the anti-CD147 antibody comprises an amino acid sequence having at least 70% identity with a sequence selected from sequence numbers 4 to 15. (Item 5) The anti-CD147 antibody described in item 1, wherein the anti-CD147 antibody contains an amino acid sequence selected from SEQ ID NOs. 4 to 15. (Item 6) The anti-CD147 antibody described in item 1, wherein the antibody is a full-length antibody, a monospecific antibody, a bispecific antibody, a triplicate antibody, an antigen-binding domain, a heavy chain, a light chain, VhH, Vh, CDR, a variable domain, scFv, Fc, Fv, Fab, F(ab)2, IgG, reduced IgG (rIgG), monospecific Fab2, bispecific Fab2, triplicate Fab3, a diabody, a bispecific diabody, a triplicate triabody, a minibody, a nanobody, IgNAR, V-NAR, HcIgG, or a combination thereof. (Item 7) The aforementioned antibody is VhH, and is the anti-CD147 antibody described in item 6. (Item 8) An anti-CD147 antibody as described in item 1, wherein the binding region of the chimeric antigen receptor (CAR) contains at least one CDR having at least 70% identity with an amino acid sequence selected from SEQ ID NOs. 16-39. (Item 9) The aforementioned CAR is expressed on immune cells, and is an anti-CD147 antibody as described in item 8. (Item 10) The anti-CD147 antibody as described in item 9, wherein the immune cells are PBMCs, lymphocytes, T cells, or NK cells. (Item 11) The anti-CD147 antibody according to item 1, wherein the anti-CD147 antibody binds to CD147 or a fragment thereof expressed on the surface of a cell. (Item 12) The anti-CD147 antibody described in item 11, wherein the cells are epithelial cells, endothelial cells, or neuronal cells. (Item 13) The anti-CD147 antibody according to item 1, wherein the anti-CD147 antibody reduces or eliminates the interaction between the virus and CD147. (Item 14) The anti-CD147 antibody according to item 13, wherein the interaction includes the binding of CD147 by the virus. (Item 15) The anti-CD147 antibody described in item 1, wherein the anti-CD147 antibody reduces or eliminates the binding of the viral spike protein to CD147. (Item 16) The anti-CD147 antibody described in item 1, wherein the anti-CD147 antibody reduces or eliminates viral infiltration into cells. (Item 17) The anti-CD147 antibody described in item 1, which, when determined by a viral infectivity assay, reduces or eliminates viral infiltration into cells by at least approximately 1-fold. (Item 18) The anti-CD147 antibody according to item 13, wherein the virus is selected from the group consisting of measles virus, coronavirus, SARS, MERS, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella zoster, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis. (Item 19) The anti-CD147 antibody according to item 18, wherein the virus is the coronavirus. (Item 20) The anti-CD147 antibody according to item 19, wherein the coronavirus is SARS-CoV-2. (Item 21) The anti-CD147 antibody according to item 11, wherein the cell is a cancer cell. (Item 22) The anti-CD147 antibody according to item 11, wherein the cell is a tumor cell. (Item 23) The anti-CD147 antibody according to item 21, wherein the cancer cell is derived from a hematological cancer. (Item 24) The anti-CD147 antibody according to item 22, wherein the tumor cell is derived from a cancer selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL). (Item 25) The anti-CD147 antibody according to item 1, wherein the anti-CD147 antibody reduces or eliminates tumor cell proliferation, metastasis, secretion of matrix metalloproteinase, degradation of tumor matrix, tumor cell infiltration, and / or angiogenesis. (Item 26) The anti-CD147 antibody described in item 1, wherein the anti-CD147 antibody reduces or eliminates inflammation. (Item 27) The anti-CD147 antibody described in item 1, wherein the anti-CD147 antibody is effective in reducing or eliminating inflammatory or autoimmune disorders. (Item 28) The anti-CD147 antibody described in item 27, wherein the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis. (Item 29) The anti-CD147 antibody described in item 1, wherein the aforementioned anti-CD147 antibody has been humanized. (Item 30) A method for preventing, treating, or improving CD147 expression-related disorders in subjects requiring prevention, treatment, or improvement of such disorders, comprising administering the anti-CD147 antibody described in item 1. (Item 31) A pharmaceutical composition containing an effective amount of the anti-CD147 antibody described in item 1. (Item 32) Cells containing a sequence encoding the anti-CD147 antibody described in item 1. (Item 33) The anti-CD147 antibody according to item 1, wherein the anti-CD147 antibody binds to cells, thereby preventing, inhibiting, or reducing the infiltration of Plasmodium parasites into the cells. (Item 34) The anti-CD147 antibody according to item 33, wherein the infiltration of the Plasmodium parasite into the cell is at least about 1-fold. (Item 35) The aforementioned cells are red blood cells, and the anti-CD147 antibody is as described in item 34. (Item 36) The anti-CD147 antibody described in item 33, wherein the Plasmodium parasite is selected from the group consisting of Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, and Plasmodium knowlesi. (Item 37) The anti-CD147 antibody described in item 33 is effective in reducing parasitemia in blood cells. (Item 38) The anti-CD147 antibody described in item 37 reduces parasitemia in blood cells within approximately 48 hours. (Item 39) The anti-CD147 antibody described in item 37 reduces parasitemia in blood cells within approximately 96 hours. (Item 40) The anti-CD147 antibody described in item 33, wherein administration of the anti-CD147 antibody prevents, improves, or treats malaria in the subject. (Item 41) An anti-CD147 antibody comprising CDR1, CDR2, and CDR3 regions, wherein the CDR1 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 to 23, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 31, the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 to 39, and the anti-CD147 antibody contains 0 to 5 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions. (Item 42) The anti-CD147 antibody described in item 41, wherein the anti-CD147 antibody contains 0 to 3 amino acid modifications. (Item 43) The anti-CD147 antibody according to item 41, wherein the CDR1 region corresponds to SEQ ID NO: 18 or 22, the CDR2 region corresponds to SEQ ID NO: 26 or 30, and the CDR3 region corresponds to SEQ ID NO: 34 or 38. (Item 44) The anti-CD147 antibody according to item 41, wherein the anti-CD147 antibody comprises SEQ ID NO: 12 or SEQ ID NO: 14. (Item 45) The anti-CD147 antibody described in item 41, wherein the aforementioned anti-CD147 antibody has been humanized. (Item 46) A treatment method comprising administering a pharmaceutical composition containing an effective amount of anti-CD147 antibody, wherein the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 regions, the CDR1 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 to 23, the CDR2 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 31, the CDR3 region being an amino acid sequence selected from the group consisting of SEQ ID NOs: 32 to 39, and the anti-CD147 antibody comprising 0 to 5 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions. (Item 47) The treatment method described in item 46, wherein the administration is effective in reducing or eliminating inflammatory or autoimmune diseases. (Item 48) The treatment method described in item 47, wherein the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), celiac disease, inflammatory bowel disease, Hashimoto's disease, Addison's disease, Graves' disease, type 1 diabetes mellitus, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis. (Item 49) The treatment method described in item 46, wherein the administration is effective in reducing or eliminating viral infiltration into cells by the virus. (Item 50) The treatment method according to item 49, wherein the virus is selected from the group consisting of measles virus, coronavirus, SARS, MERS, infectious hematopoietic necrosis virus (IHNV), parvovirus, herpes simplex virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, mumps virus, rubella virus, HIV, influenza virus, rhinovirus, rotavirus A, rotavirus B, rotavirus C, respiratory syncytial virus (RSV), varicella zoster, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis. (Item 51) The treatment method according to item 50, wherein the virus is the coronavirus. (Item 52) The treatment method according to item 51, wherein the coronavirus includes SARS-CoV-2. (Item 53) The treatment method according to item 46, wherein the administration is effective for reducing or eliminating cancer metastasis. (Item 54) The treatment method according to item 53, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, kidney cancer, skin cancer, head and neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphoma, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL). (Item 55) The treatment method according to item 46, wherein the administration is effective for reducing or eliminating the invasion of Plasmodium into cells. (Item 56) An antibody-drug conjugate comprising the anti-CD147 antibody according to item 1. (Item 57) The antibody-drug conjugate according to item 56, wherein the drug is selected from the group consisting of anti-cancer drugs, anti-malarial drugs, anti-viral drugs, and anti-inflammatory drugs. (Item 58) The antibody-drug conjugate according to item 57, comprising the antiviral agent, wherein the antiviral agent is an anti-SARS-CoV-2 agent. (Item 59) The antibody-drug conjugate according to item 57, comprising the aforementioned anticancer drug, wherein the aforementioned anticancer drug comprises immunotherapy. (Item 60) The antibody-drug conjugate described in item 59, wherein the immunotherapy is selected from the group consisting of antibodies, checkpoint inhibitors, cell therapies, cytokines, oncolytic viruses, and vaccines. (Item 61) The antibody-drug conjugate described in item 60, comprising the aforementioned antibody. (Item 62) The antibody-drug conjugate according to item 56, comprising the anti-CD147 antibody SEQ ID NO: 12 or SEQ ID NO: 14.

Claims

[Claim 1] The invention described in the specification.

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