Antibodies targeting CD147

Abstract

Provided herein is a novel antibody sequence that binds to CD147, inhibits viral or parasitic invasion, reduces inflammation, and reduces cancer cell viability.The present disclosure also provides a method of using these antibodies to treat viral infection and cancer.The present disclosure provides a novel antibody, antibody fragment, or variant thereof that binds to CD147 expressed on cells to prevent viral infection, inhibit malaria infection, inhibit angiogenesis, and reduce cell viability.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 135,827, filed January 11, 2021, the entire contents of which are incorporated herein by reference.

[0002] Description of electronically submitted text files The contents of the text file submitted electronically herewith are incorporated by reference in their entirety into this specification: A computer-readable copy of the Sequence Listing (filename: IBEX_005_01WO_SeqList_ST25.txt, recorded on January 11, 2022, file size approximately 52 kilobytes).

[0003] Incorporation by Reference All cited publications, patents and patent publications are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0004] background Extracellular matrix metalloproteinase inducer CD147 (also known as Basigin, EMMPRIN, and Neurothelin) is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. CD147 is involved in tumor development, Plasmodium invasion, and viral infection. Furthermore, CD147 has been investigated as a potential therapeutic target for cancer and immunological disorders such as rheumatoid arthritis. Summary of the Invention [Means for solving the problem]

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

[0006] Provided herein are anti-CD147 antibodies comprising a binding domain comprising at least one CDR comprising 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 of the two CDRs independently comprising 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 of the three CDRs independently comprising 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 region, a heavy chain, a light chain, a VhH, a Vh, a CDR, a variable domain, a scFv, an Fc, an Fv, a Fab, an F(ab)2, an IgG, a reduced IgG (rIgG), a monospecific Fab2, a bispecific Fab2, a trispecific Fab3, a diabody, a bispecific diabody, a trispecific triabody, a minibody, a nanobody, an IgNAR, a V-NAR, an HcIgG, or a combination thereof. In some embodiments, the antibody is a VhH. In some embodiments, the binding region of the chimeric antigen receptor (CAR) comprises at least one CDR that comprises at least 70% identity to an amino acid sequence selected from SEQ ID NOs: 16-39. In some embodiments, the CAR is expressed on an immune cell. In some embodiments, the immune cell is a PBMC, a lymphocyte, a T cell, or a NK cell. In some embodiments, the anti-CD147 antibody binds to CD147 or a fragment thereof expressed on the surface of a cell. In some embodiments, the cell is an epithelial cell, an endothelial cell, or a neuronal cell. In some embodiments, the anti-CD147 antibody reduces or eliminates the interaction between the virus and CD147. In some embodiments, the interaction comprises the binding of CD147 by the virus.In some embodiments, the anti-CD147 antibody reduces or eliminates the binding of viral spike proteins 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, 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 cell is a cancer cell. In some embodiments, the cell is a tumor cell. In some embodiments, the cancer cell is from a hematological cancer. In some embodiments, the tumor cell is 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, lymphatic cancer, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic 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, tumor matrix degradation, tumor cell invasion, and / or angiogenesis. In some embodiments, the anti-CD147 antibody reduces or eliminates inflammation, hi some embodiments, the anti-CD147 antibody is effective in reducing or eliminating an inflammatory or autoimmune disorder.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 I diabetes, 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 a cell, thereby preventing, inhibiting, or reducing invasion of Plasmodium parasites into the cell. In some embodiments, invasion of Plasmodium parasites into the cell is at least about 1-fold. In some embodiments, the cell is a red blood cell. 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, the anti-CD147 antibody is effective in reducing parasitemia in blood cells. In some embodiments, the anti-CD147 antibody reduces parasitemia in blood cells within about 48 hours. In some embodiments, the anti-CD147 antibody reduces parasitemia in blood cells within about 96 hours. In some embodiments, administration of the anti-CD147 antibody prevents, ameliorates, or treats malaria in a subject.

[0008] Also provided herein are methods for preventing, treating, or ameliorating a disorder associated with CD147 expression in a subject in need thereof, comprising administering an anti-CD147 antibody.

[0009] Also provided herein is a pharmaceutical composition comprising an effective amount of an anti-CD147 antibody.

[0010] Also provided herein are cells comprising sequences encoding anti-CD147 antibodies.

[0011] Provided herein is an anti-CD147 antibody comprising a CDR1, CDR2, and CDR3 region, wherein the CDR1 region is an amino acid sequence selected from the group consisting of SEQ ID NO: 12-15, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NO: 16-19, and the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NO: 20-23, and the anti-CD147 antibody comprises 0-5 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions. In some embodiments, the anti-CD147 antibody comprises 0-3 amino acid modifications. In some embodiments, 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. In some embodiments, the anti-CD147 antibody comprises SEQ ID NO: 12 or SEQ ID NO: 14. In some embodiments, the anti-CD147 antibody is humanized.

[0012] Provided herein is a method of treatment comprising administering an effective amount of a pharmaceutical composition comprising an anti-CD147 antibody, wherein the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 regions, wherein the CDR1 region is an amino acid sequence selected from the group consisting of SEQ ID NO:16-23, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NO:24-31, and the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NO:32-39, and the anti-CD147 antibody comprises 0-2 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions. In some embodiments, the administering is effective to reduce or eliminate an inflammatory or autoimmune disease. 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 I diabetes, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis. In some embodiments, the administering is effective to reduce or eliminate viral infiltration of 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, 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 comprises SARS-CoV-2. In some embodiments, the administering is effective to reduce or eliminate metastasis of the cancer.In some embodiments, 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, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL). In some embodiments, administering is effective to reduce or eliminate the infiltration of Plasmodium into cells.

[0013] Provided herein is an antibody-drug conjugate comprising an anti-CD147 antibody. In some embodiments, the drug is selected from the group consisting of an anti-cancer drug, an anti-malarial drug, an anti-viral drug, a toxin, and an anti-inflammatory drug. In some embodiments, the drug comprises an anti-viral drug, and the anti-viral drug is an anti-SARS-CoV-2 drug. In some embodiments, the drug comprises an anti-cancer drug, and the anti-cancer drug comprises an immunotherapy. In some embodiments, the immunotherapy is selected from the group consisting of an antibody, a checkpoint inhibitor, a cell therapy, a cytokine, an oncolytic virus, and a vaccine. 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 an anti-CD147 antibody, antibody fragment, or variant thereof that binds to a CD147 polypeptide. In some embodiments, the disclosure provides an anti-CD147 antibody or fragment thereof comprising an amino acid sequence having at least one CDR comprised in any one of SEQ ID NOs: 16-39. In some embodiments, the antibody comprises two to six CDRs comprised in any one of SEQ ID NOs: 16-39. In some embodiments, the antibody comprises all CDRs comprised in any one of SEQ ID NOs: 16-39. In some embodiments, the antibody comprises an amino acid sequence at least 70% identical to any one of SEQ ID NOs: 16-39. In some embodiments, the antibody comprises the amino acid sequence of any one 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 region, a heavy chain, a light chain, a VhH, a Vh, a Vl, a CDR, a variable domain, a scFv, an Fc, an Fv, a Fab, a F(ab)2, a reduced IgG (rIgG), a monospecific Fab2, a bispecific Fab2, a trispecific Fab3, a diabody, a bispecific diabody, a trispecific triabody, a minibody, a nanobody, an IgNAR, a V-NAR, an HcIgG, or a combination thereof. In some embodiments, the anti-CD147 antibody is a VhH. In some embodiments, the anti-CD147 antibody is included in a chimeric antigen receptor (CAR). In some embodiments, the CAR is expressed from an immune cell. In some embodiments, the immune cell is a PBMC, a lymphocyte, a T cell, or a NK cell.

[0016] In some embodiments, the anti-CD147 antibody, antibody fragment, or variant binds to a CD147 polypeptide or fragment thereof expressed on the surface of a cell. In some embodiments, the cell is an epithelial cell, an endothelial cell, or a neuronal cell. In some embodiments, the cell is a tumor cell. In some embodiments, the tumor cell is from a solid tumor. In some embodiments, the tumor cell is from a hematological cancer. In some embodiments, the tumor cell is from a cancer 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, lymphatic cancer, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

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

[0018] In some embodiments, the anti-CD147 antibody reduces or eliminates viral infiltration into cells. In some embodiments, the anti-CD147 antibody prevents or reduces 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, 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, the anti-CD147 antibody, antibody fragment, or variant thereof prevents or reduces 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 of preventing, treating, or ameliorating a disorder associated with CD147 expression in a subject in need thereof comprising administering an anti-CD147 antibody, antibody fragment, or variant thereof described herein.

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

[0023] In some embodiments, the disclosure provides cells comprising sequences encoding an anti-CD147 antibody, antibody fragment, or variant thereof described herein. [Brief description of the drawings]

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

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

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

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

[0028] [Diagram 5] FIG. 5 shows a kinetic model of Ibx-77 binding to CD147.

[0029] [Figure 6] FIG. 6 shows the Kd / Ka kinetic model of Ibx-77 binding to CD147.

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

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

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

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

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

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

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

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

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

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

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

[0041] [Figure 18] FIG. 18 shows image analysis measuring pixel size, showing that the pixel size of particles (aggregates) increased over 24 hours with Ibx series antibodies at 50 μg / ml to 25 μg / ml.

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

[0043] [Figure 20]FIG. 20 shows that at 24 hours there was a significant reduction in single cell numbers for Ibx-77 treated cells.

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

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

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

[0047] [Figure 24] FIG. 24 shows A375 melanoma cell viability following treatment with various concentrations of Ibx-11, Ibx-13, or control antibody.

[0048] [Diagram 25] FIG. 25 shows a comparison of A375 melanoma cell viability following treatment with 30 nM Ibx-11, Ibx-13, or control antibody.

[0049] [Figure 26] FIG. 26 shows PC3 prostate cancer cell viability following treatment with various concentrations of Ibx-11, Ibx-13, or control antibody.

[0050] [Figure 27] FIG. 27 shows a comparison of PC3 prostate cancer cell viability following treatment with 30 nM Ibx-11, Ibx-13, or control antibody. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] Detailed Description 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). Expression levels of CD147 and MMPs 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 and enhanced expression, resistance, and survival of MMPs and ABC drug transporters.

[0052] In some embodiments, the anti-CD147 antibodies or fragments, or variants thereof, described herein may be used to treat or prevent the growth of cancer. In some embodiments, the anti-CD147 antibodies or fragments, or variants thereof, and modified versions (e.g., antibody-drug conjugate ADCs) treat or prevent the growth of hematological cancers. In some embodiments, the anti-CD147 antibodies or fragments, or variants thereof, treat or prevent the growth of solid cancers. In some embodiments, the anti-CD147 antibodies or fragments, or variants thereof, treat or prevent the growth of hematological cancers. In some embodiments, the anti-CD147 antibodies or fragments, or variants thereof, treat or prevent the growth of metastatic cancers. In some embodiments, the cancer includes, but is 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, lymphatic cancer, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0053] Autoimmune and Inflammatory Disorders Anti-CD147 antibody, its fragment or variant can be used to treat or reduce inflammation in a subject. In some embodiments, inflammation is associated with autoimmune or inflammatory disorders. 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 I diabetes, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

[0054] Viral infection Anti-CD147 antibodies, fragments, or variants thereof can be used to treat or reduce viral infection and / or viral load in a subject. In some embodiments, anti-CD147 antibodies, fragments, or variants thereof can be used to prevent, inhibit, or reduce viral infiltration into cells. CD147 is known to be important for viral infiltration into cells. For example, it is known that CD147 is a functional entry receptor for measles virus infiltration of epithelial cells (Watanabe 2010). Furthermore, during HIV-1 infection, CD147 molecules can promote the infection of host cells by HIV-1 virus through interaction with virus-associated CyPA (Chenglong 2020). In some embodiments, the viral infection is caused by a virus, 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, poliovirus, immunodeficiency viruses (e.g., HIV), enveloped viruses, RNA viruses, and hepatitis.

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

[0056] In some embodiments, the anti-CD147 antibody or fragment or variant thereof reduces parasitemia. In some embodiments, the anti-CD147 antibody or fragment or variant thereof reduces parasitemia in blood cells. In some embodiments, the anti-CD147 antibody or fragment or variant thereof reduces parasitemia in blood cells within 10 minutes to 120 hours. In some embodiments, the anti-CD147 antibody or fragment or variant thereof reduces parasitemia in blood cells within about 10 minutes, within about 20 minutes, within about 30 minutes, within about 40 minutes, within about 50 minutes, within about 1 hour, within about 2 hours, within about 3 hours, within about 4 hours, within about 5 hours, within about 6 hours, within about 7 hours, within about 8 hours, within about 9 hours, within about 10 hours, within about 12 hours, within about 15 hours, within about 20 hours, within about 24 hours, within about 25 hours, within about 30 hours, within about 35 hours, within about 40 ... In some embodiments, the anti-CD147 antibody or fragment or variant thereof reduces parasitemia in blood cells within about 48 hours, about 36 hours, about 40 hours, about 45 hours, about 48 hours, about 50 hours, about 55 hours, about 60 hours, about 65 hours, about 70 hours, about 75 hours, about 80 hours, about 85 hours, about 90 hours, about 95 hours, about 96 hours, about 100 hours, about 105 hours, about 110 hours, about 115 hours, or about 120 hours. In some embodiments, the anti-CD147 antibody or fragment or variant thereof reduces parasitemia in blood cells within about 48 hours. In some embodiments, the anti-CD147 antibody or fragment or variant thereof reduces parasitemia in blood cells within about 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 the high virulence and pathogenicity of SARS-CoV-2 is its ability to infect multiple tissues, which in severe cases can lead to organ failure and death. Like other enveloped viruses, SARS-CoV-2 utilizes host cell receptors to invade host cells, ultimately causing tissue necrosis, organ damage, and eventual death. CD147 is one such host cell receptor that facilitates viral entry.

[0058] Although angiotensin-converting enzyme 2 (ACE2) is generally recognized as the primary receptor for SARS-CoV-2 infection, other molecules have been reported to contribute significantly to the cell tropism of this virus. CD147 has recently attracted attention for its role in SARS-CoV-2 cell invasion via direct interaction with the viral spike protein recognition binding domain (RBD), with potential benefit observed in an open-label clinical trial that demonstrated early resolution of COVID-19 symptoms in patients treated with anti-CD147 antibodies.

[0059] Anti-CD147 antibody In some embodiments, the present disclosure provides novel antibodies that bind to CD147 and their use in preventing or ameliorating conditions or diseases. In some embodiments, CD147 is expressed on the surface of a cell. In some embodiments, the anti-CD147 antibodies of the present disclosure can exert their effect directly or indirectly. In some embodiments, the anti-CD147 antibodies bind to CD147, thereby directly reducing or eliminating the binding of CD147 by something else (e.g., a virus or a cancer cell). In some embodiments, the anti-CD147 antibodies can sterically hinder the binding of the CD147 receptor, thereby indirectly exerting their effect. In some embodiments, the anti-CD147 can deliver a blocking agent when complexed as part of an antibody-drug conjugate, thereby indirectly reducing or eliminating the binding to the CD147 receptor. Any anti-CD147 antibody can be fully human, humanized, mouse, rat, rabbit, and 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 a human CD147 polypeptide, an isoform, or a fragment thereof. In some embodiments, the human CD147 is an isoform. In some embodiments, the CD147 isoform is basigin or basigin-2, which has two immunoglobulin domains. In some embodiments, the CD147 isoform is basigin-1, which has three immunoglobulin domains. In some embodiments, the human CD147 polypeptide or a fragment thereof is a polypeptide comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, the human CD147 polypeptide or a fragment thereof is a polypeptide comprising at least about 70% sequence identity to SEQ ID NO:1. In some embodiments, the human CD147 polypeptide or fragment thereof is a polypeptide that comprises 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 SEQ ID NO:1. In some embodiments, the CD147 polypeptide, its isoform, or fragment is expressed on the surface of the cell. In some embodiments, the sequence of the portion of the CD147 polypeptide, its isoform, or fragment that is involved in binding is not altered. In some embodiments, the sequence of the portion of the CD147 polypeptide, its isoform, or fragment that is involved in binding is altered.

[0061] In some embodiments, the human CD147 polypeptide or fragment is a truncation of a polypeptide comprising 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, the anti-CD147 antibody binds to a rodent CD147 polypeptide or 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 comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the human CD147 polypeptide is a polypeptide comprising at least about 70% sequence identity to SEQ ID NO:2. In some embodiments, the human CD147 polypeptide is a polypeptide that comprises 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 SEQ ID NO:2. In some embodiments, the sequence of the portion of the polypeptide involved in binding CD147 is not altered, hi some embodiments, the sequence of the portion of the polypeptide involved in binding CD147 is altered.

[0063] In some embodiments, the mouse CD147 polypeptide or fragment is a truncation of a polypeptide comprising 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 on endothelial cells, epithelial cells, neuronal cells, immune cells, blood cells, fibroblasts, T cells, peripheral blood mononuclear cells (PBMCs), monocytic cells, or mononuclear cells. In some embodiments, CD147 is aberrantly expressed on the surface of cells. In some embodiments, CD147 is overexpressed on the surface of cells. In some embodiments, CD147 is expressed by cells of the tumor stroma.

[0065] In some embodiments, an antibody that binds to a CD147 polypeptide or a fragment thereof is a full length antibody, a monospecific antibody, a bispecific antibody, a trispecific antibody, an antigen binding region, a heavy chain, a light chain, VhH, Vh, Vl, CDR, a variable domain, scFv, Fc, Fv, Fab, F(ab)2, reduced IgG (rIgG), a monospecific Fab2, a bispecific Fab2, a trispecific Fab3, a diabody, a bispecific diabody, a trispecific triabody, a minibody, a nanobody, an IgNAR, a V-NAR, an 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 linker is a cleavable linker. In some embodiments, the linker is not cleavable. The linkers of the present disclosure may be protease-sensitive, pH-sensitive, and / or glutathione-sensitive. Cleavable linkers may be utilized to more effectively release the drug at the target site (e.g., in a tumor). 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, such as (GGGGS)3 (SEQ ID NO: 40) linkers, may be utilized in the fusion constructs. Another linker that may be utilized includes the sequence EPKIPQPQPKPQPQPQPQPQPKPQPEP (SEQ ID NO: 41). In some embodiments, a tag may be utilized. An exemplary tag may include a flag tag, such as DYKDDDDK (SEQ ID NO: 42).

[0067] In some embodiments, the antibody that binds to a CD147 polypeptide or fragment thereof comprises a VhH antibody. In some embodiments, the antibody that binds to a CD147 polypeptide or fragment thereof is a VhH antibody. In some embodiments, the VhH antibody is selected from any of SEQ ID NOs: 4-15. In some embodiments, the VhH antibody comprises at least about 70% sequence identity to any of SEQ ID NOs: 4-15. In some embodiments, the VhH antibody comprises 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 SEQ ID NOs:4-15.

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

[0069] In some embodiments, the anti-CD147 antibody comprises a CDR that is at least 70% identical to one or more CDRs found in any one of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody comprises one CDR that is at least about 70% identical to one or more CDRs found in any one or more of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody comprises two CDRs that are at least about 70% identical to one or more CDRs found in any one or more of SEQ ID NOs: 16-39. In some embodiments, the anti-CD147 antibody comprises two CDRs that are at least about 70% identical to one or more CDRs found in different sequences of 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 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 one or more different sequences of any of SEQ ID NOs: 16-39. In some embodiments, one or more CDRs are 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% identical to one or more CDRs found in one or more different sequences of any of SEQ ID NOs: 16-39.

[0070] In some embodiments, the anti-CD147 antibody comprises a CDR1 comprising 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 comprises a CDR2 comprising 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 comprises a CDR3 comprising 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 comprises a CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 16, 24, and 32, respectively. In some embodiments, the anti-CD147 antibody comprises a CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 17, 25, and 33, respectively. In some embodiments, the anti-CD147 antibody comprises a CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 18, 26, and 34, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 19, 27, and 35, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 20, 28, and 36, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 21, 29, and 37, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 22, 30, and 38, respectively. In some embodiments, the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 comprising 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 a duplex or triplet of CDR1, CDR2, or CDR3, such as in any of the fusion constructs described herein. In some embodiments, the fusion construct may comprise any 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, the 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 of the sequence. Thus, the modifications may include sequence and / or length modifications. In some embodiments, the sequence includes the CDR region. Thus, the CDR may be modified to vary in length ranging from 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 lengths as described above. In some embodiments, the modification may include modification of about 0-2 residues. In some embodiments, the modification may include modification of about 1-3, 2-4, 0-4, or 1-5 residues in any one of CDR1, CDR2, and / or CDR3. In some embodiments, any one of SEQ ID NO:16 to SEQ ID NO:39 may have one or more modifications as described herein.

[0072] In some embodiments, the anti-CD147 antibody or 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 an immune cell. In some embodiments, the immune cell is a mononuclear cell. In some embodiments, the mononuclear cell is a PBMC, PBL, lymphocyte, B cell, T cell, natural killer (NK) cell, monocyte, dendritic cell, eosinophil, neutrophil, basophil, or antigen presenting cell (APC).

[0073] In some embodiments, the binding region of the CAR may comprise the CDR sequence disclosed herein. The binding region is usually fused with a transmembrane region, for example from CD8, which is also fused with an intracellular signaling domain. Suitable intracellular signaling domains may comprise intracellular signaling region sequences of CD3 zeta (CD3zeta), 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 comprises the signaling domain of CD3zeta molecule.In some embodiments, the intracellular signal domain also comprises one or more of the following co-stimulatory signal 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 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, a ligand that specifically binds to CD83, or any combination thereof. In some embodiments, the costimulatory signaling molecule is 4-1BB and / or CD28. In some embodiments, 0 to 2 costimulatory signaling molecules are included in the CAR.

[0074] As used herein, "binding affinity" generally refers to the strength of the sum 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 a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (KD). Affinity can be measured and / or expressed in many ways known in the art, including, but not limited to, the equilibrium dissociation constant (KD) and the equilibrium association constant (KA). KD is the k off / k on Calculated from the quotient of k on / k off It is calculated from the quotient of, for example, the association rate constant of an antibody to an antigen, k off For example, k refers to the dissociation of an antibody against an antigen. on and k off can be determined by techniques known to those of skill 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 ranging from about 250 pM to about 1 pM. In some embodiments, the antibody binds to CD147 with a KD ranging from 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 thereof of the present 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 fragment thereof of the present 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, binding of the antibody to CD147 on the surface of the cell prevents viral infection. In some embodiments, the antibody interferes with the interaction of the virus with CD147 on the surface of the cell. In some embodiments, the antibody interferes with the interaction of a spike protein with CD147. In some embodiments, the spike protein is a coronavirus spike protein. In some embodiments, the spike protein is a SARS-CoV2 spike protein. In some embodiments, the antibody interferes with the virus / CD147 interaction and inhibits viral invasion and / or spread between other cells.

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

[0078] In some embodiments, the antibody, antibody fragment, or variant thereof completely prevents viral infiltration into cells. In some embodiments, the antibody, antibody fragment, or variant thereof reduces viral infiltration into cells compared to untreated cells. In some embodiments, the antibody, antibody fragment, or variant thereof reduces viral infiltration into cells by about 99.9% to about 1% compared to untreated cells. In some embodiments, the antibody, antibody fragment, or variant thereof reduces 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%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 64%, about 63%, about 62% ,About 61%,About 60%,About 59%,About 58%,About 57%,About 56%,About 55%,About 54%,About 53%,About 52%,About 51%,About 50%,About 49%,About 48%,About 47%,About 46%,About 45%,About 44%,About 43%,About 42%,About 41%,About 40%,About 39%,About 38%,About 37%,About 36%,About 35%,About 34%,About 33%,About 32%,About 31%, about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, 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%. In some embodiments, the antibody reduces viral infiltration into cells from about 10 minutes to about 1 day after administration compared to untreated cells.In some embodiments, the antibody reduces viral infiltration into the cell at about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration compared to untreated cells. In some embodiments, the cell is an epithelial cell. In some embodiments, the anti-CD147 antibody inhibits viral infiltration into cells by at least about 1 fold, 50 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 350 fold, 400 fold, 450 fold, 500 fold, 550 fold, 600 fold, 650 fold, 700 fold, 750 fold, 800 fold, 850 fold, or more than ...500 fold, 550 fold, 500 fold, 50 , 900-fold, 950-fold, 1000-fold, 1050-fold, 1100-fold, 1150-fold, 1200-fold, 1250-fold, 1300-fold, 1350-fold, 1400-fold, 1450-fold, 1500-fold, 1550-fold, 1600-fold, 1650-fold, 1700-fold, 1750-fold, 1800-fold, 1850-fold, 1900-fold, 1950-fold, or up to about 2000-fold reduction or elimination.

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

[0080] In some embodiments, the antibody, antibody fragment, or variant thereof completely prevents cell-to-cell viral transmission. In some embodiments, the antibody, antibody fragment, or variant thereof reduces cell-to-cell viral transmission compared to that in an untreated subject or cell culture. In some embodiments, the antibody, antibody fragment, or variant thereof reduces cell-to-cell viral transmission by about 99.9% to about 1% compared to that in an untreated subject or cell culture. In some embodiments, the antibody, antibody fragment, or variant thereof reduces cell-to-cell 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%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 64%, about 6 3%, about 62%, about 61%, about 60%, about 59%, about 58%, about 57%, about 56%, about 55%, about 54%, about 53%, about 52%, about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, about 45%, about 44%, about 43%, about 42%, about 41%, about 40%, about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32 %, about 31%, about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, 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%. In some embodiments, the antibody, antibody fragment, or variant thereof reduces cell-to-cell viral spread from about 10 minutes to about 1 day after administration compared to that in untreated subjects or cell cultures.In some embodiments, the antibody, antibody fragment, or variant thereof reduces cell-to-cell viral spread at about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration compared to that in untreated subjects or cell cultures.

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

[0082] In some embodiments, inflammation leads to 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 the change in patient's oxygen level, exhaled nitric oxide, respiratory rate, or spirometry measurement.

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

[0085] In some embodiments, administration of an antibody, antibody fragment, or variant thereof of the present disclosure reduces cellular infiltration in a subject. In some embodiments, administration of an antibody, antibody fragment, or variant thereof reduces cellular infiltration compared to levels in an analogous untreated subject or the same subject prior to administration of the antibody. In some embodiments, administration of an antibody, antibody fragment, or variant thereof reduces cellular infiltration by about 99.9% to about 1% compared to levels in an analogous untreated subject or the same subject prior to administration of the antibody. In some embodiments, administration of an antibody, antibody fragment, or variant thereof reduces cellular 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%, or less compared to levels in an analogous untreated subject or the same subject prior to 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% %, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 35 ... 32%, about 31%, about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, 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%. In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces cellular infiltration from about 10 minutes to about 1 day after administration, compared to levels in a similar untreated subject or in the same subject prior to administration of the antibody.In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces cellular infiltration at about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration, compared to levels in a similar untreated subject or the same subject prior to administration of the antibody. In some embodiments, the cells are tumor cells.

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

[0087] In some embodiments, administration of an antibody, antibody fragment, or variant thereof of the present disclosure reduces tumor cell viability in a subject. In some embodiments, administration of the antibody, antibody fragment, or modification thereof reduces tumor cell viability as compared to levels in an analogous untreated subject or the same subject prior to administration of the antibody. In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces tumor cell viability by about 99.9% to about 1% as compared to levels in an analogous untreated subject or the same subject prior to administration of the antibody. In some embodiments, administration of the antibody, antibody fragment, or variant thereof 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%, about 96%, or about 100% as compared to levels in an analogous untreated subject or the same subject prior to administration of the antibody. %, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, about 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 6 4%, about 63%, about 62%, about 61%, about 60%, about 59%, about 58%, about 57%, about 56%, about 55%, about 54%, about 53%, about 52%, about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, about 45%, about 44%, about 43%, about 42%, about 41%, about 40%, about 39%, about 38%, about 37%, about 36%, about 35%, about 34%, about 33%, about 32%, about 31%, about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, 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%. In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces tumor cell viability from about 10 minutes to about 1 day after administration, compared to levels in similar untreated subjects or in the same subject prior to administration of the antibody.In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces tumor cell viability at about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration compared to levels in a similar untreated subject or the same subject prior to administration of the antibody.

[0088] In some embodiments, administration of an antibody, antibody fragment, or variant thereof of the present disclosure reduces angiogenesis in a subject. In some embodiments, administration of an antibody, antibody fragment, or variant thereof reduces angiogenesis compared to levels in a similar untreated subject or the same subject prior to administration of the antibody. In some embodiments, administration of an antibody, antibody fragment, or variant thereof reduces angiogenesis by about 99.9% to about 1% compared to levels in a similar untreated subject or the same subject prior to administration of the antibody. In some embodiments, administration of an antibody, antibody fragment, or variant 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%, or less compared to levels in a similar untreated subject or the same subject prior to 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% %, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 35 ... 32%, about 31%, about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, 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%. In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces angiogenesis about 10 minutes to about 1 day after administration, compared to levels in a similar untreated subject or in the same subject prior to administration of the antibody.In some embodiments, administration of the antibody, antibody fragment, or variant thereof reduces angiogenesis at about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration, compared to the level in a similar untreated subject or the same subject before administration of the antibody. In some embodiments, the subject has cancer. In some embodiments, the angiogenesis is tumor-specific angiogenesis.

[0089] Antibody-drug conjugates (ADCs) In some embodiments, any of the anti-CD147 antibodies provided may be fused to a drug as part of an ADC. In some embodiments, the antibody comprises any of the aforementioned constructs described 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 labile linker. The antibody targets a specific antigen that is typically found on the target cell. Once it binds to the cell, it triggers internalization of the antibody along with the drug. This allows delivery of the drug with extremely high specificity to the diseased or target cell, maximizing their efficacy and minimizing systemic exposure with associated risks of side effects. In some embodiments, a linker is utilized to link the antibody to the drug. The linker is typically stabilized to avoid release of the drug in the surrounding non-target tissues, and the linker may maintain the conjugate in an inert and non-toxic state while attached 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 may be utilized in the ADC construct. In some embodiments, the drug that is part of the ADC is selected from the group consisting of an anti-cancer drug, an anti-malarial drug, an anti-viral drug, an anti-inflammatory drug, and a toxin.

[0090] In some embodiments, the drug is an antiviral drug. In some embodiments, the antiviral drug is an anti-SARS-CoV-2 drug. In some embodiments, the anti-SARS-CoV-2 drug comprises a monoclonal antibody, including but not limited to bamlanivimab, etesevimab, casirivimab, imdevimab, and sotrovimab. In some embodiments, the anti-SARS-CoV-2 drug is not an antibody. In some embodiments, the drug is an anti-cancer drug. In some embodiments, the anti-cancer drug comprises an immunotherapy. In some embodiments, the immunotherapy is selected from the group consisting of an antibody, a checkpoint inhibitor, a cell therapy, a cytokine, an oncolytic virus, and a vaccine. In some embodiments, the anti-cancer drug comprises a cytotoxic agent. In some embodiments, the immunotherapy comprises an antibody. Contemplated antibodies include gemtuzumab, inotuzumab, anti-B4-bR, denileukin, and combinations thereof. In some embodiments, the drug comprises a toxin. Suitable toxins include Pseudomonas exotoxin and / or diphtheria toxin. In some embodiments, the ADC comprises an anti-CD147 antibody of SEQ ID NO: 14. In some embodiments, the ADC comprises an anti-CD147 antibody of SEQ ID NO: 12. In some embodiments, the drug comprises a growth factor. Exemplary growth factors include, but are not limited to, IL-2, IL-13, TGFα, GM-CSF, and combinations thereof.

[0091] Treatment In some embodiments, the present disclosure provides methods of treating, ameliorating, or preventing a disorder associated with CD147 expression and / or its symptoms.

[0092] In some embodiments, the present disclosure provides a method of treating, ameliorating, or preventing cancer, comprising administering to a subject in need thereof a pharmaceutical composition of an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure. In some embodiments, administration of an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure prevents or delays tumor growth or cancer cell proliferation in the subject. In some embodiments, administration of an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure prevents or delays cancer cell progression in the subject. In some embodiments, administration of an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure prevents or delays cancer cell metastasis in the subject. In some embodiments, administration of an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure prevents or delays angiogenesis in the subject. In some embodiments, administration of an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure prevents or delays cell invasion in the subject. In some embodiments, the cancer includes, but is 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, lymphatic cancer, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0093] In some embodiments, the present disclosure provides a method of treating, ameliorating, or preventing an inflammatory or autoimmune disorder comprising administering to a subject in need thereof a pharmaceutical composition of an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure. In some embodiments, the autoimmune or inflammatory disorder includes, but is not limited to, 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.

[0094] In some embodiments, the present disclosure provides a method for treating or preventing a viral infection symptom and / or associated condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising an anti-CD147 antibody, antibody fragment, or variant thereof of the present disclosure. In some embodiments, the viral infection is caused by a virus, 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, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, 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 can be treated with an antibody of the disclosure, including, but not limited to, alpha, beta, gamma, delta, epsilon, gamma, eta, theta, iota, kappa, lambda, mu, nu, xi, omicron, pi, rho, sigma, tau, upsilon, phi, chi, psi, or omega. 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 based on resource utilization requiring at least one of the following: endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula; heated and humidified oxygen delivered at a flow rate of >20 L / min via enhanced nasal cannula (percentage of oxygen delivered >0.5), non-invasive positive pressure ventilation, extracorporeal membrane oxygenation (ECMO), and / or clinical diagnosis of respiratory failure (e.g., clinically requiring one of the preceding therapies, but the preceding therapies cannot be administered in a resource-limited setting).

[0096] Pharmaceutical Compositions and Administration The present disclosure provides pharmaceutical compositions comprising the anti-CD147 antibodies, antibody fragments, or variants thereof of the present disclosure with one or more pharma- ceutically acceptable excipients and / or diluents. For example, such excipients include salts and other excipients that can act to stabilize hydrogen bonds. Any suitable excipients 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 chloride and phosphate; 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, durability, resistance to degradation, and the like.

[0097] The pharmaceutical formulation can be stored frozen, refrigerated or at room temperature. Storage conditions can 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, the pharmaceutical formulation is stored at 2°-8°C. For example, the pharmaceutical formulation can be isotonic with blood or have an ionic strength that mimics physiological conditions. For example, the formulation can have an ionic strength of at least 25 mM sodium chloride, or an ionic strength of at least 30 mM sodium chloride, or an ionic strength of at least 40 mM sodium chloride, or an ionic strength of at least 50 mM sodium chloride, or an ionic strength of at least 75 mM sodium chloride, or an ionic strength of at least 100 mM sodium chloride, or an ionic strength of at least 150 mM sodium chloride. In certain embodiments, the formulation has an ionic strength equivalent to the ionic strength 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 ranging from about 5.5 to about 8.5. In some embodiments, the pharmaceutical formulation is formulated at a pH ranging from about 6.0 to about 8.0. In some embodiments, the pharmaceutical formulation is formulated at a pH ranging from about 6.5 to about 7.5. In some embodiments, the pharmaceutical formulation is formulated at a pH of 7.5. In some embodiments, the pharmaceutical formulation having a lower pH exhibits improved formulation stability compared to formulations with a higher pH. In some embodiments, the pharmaceutical formulation having a higher pH exhibits 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. In general, a stable formulation is one that exhibits less than 5% increase in degradation products or impurities. 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 a pharmaceutical formulation disclosed herein. The method includes administering to a subject in need thereof a pharmaceutical formulation described herein, wherein the pharmaceutical formulation is administered about 1 to about 31 times per month. In some embodiments, the pharmaceutical formulation is administered about 1, about 2, about 3, and / or about 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 ameliorated. In some embodiments, the pharmaceutical compositions disclosed herein are administered until at least one or more symptoms are ameliorated. In some embodiments, the pharmaceutical compositions disclosed herein are administered until at least one or more symptoms thereof 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, hi some embodiments, the pharmaceutical compositions disclosed herein are administered at the onset of symptoms.

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

[0104] Although one skilled in the art can determine the desired dosage in each case, an appropriate dosage of the pharmaceutical composition to achieve a therapeutic benefit may be, for example, in the range of about 1 microgram (μg) to about 100 milligrams (mg) per kilogram of recipient body weight, 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 a low dose. In some embodiments, the pharmaceutical composition is administered in a dose of 0.1 mg / kilogram / body weight to about 9 mg / kilogram / body weight. In some embodiments, the pharmaceutical composition is administered at 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 can be administered weekly.

[0105] An appropriate dose of the pharmaceutical composition to achieve a therapeutic benefit may be, for example, in the range of about 1 microgram (μg) to about 10 milligrams (mg) per kilogram of recipient body weight, preferably in the range of about 10 μg to about 5 mg per kilogram of body weight, and most preferably in the range of about 100 μg to about 2 mg per kilogram of body weight. In some embodiments, the pharmaceutical composition is administered at a low dose. In some embodiments, the pharmaceutical composition is administered at a dose of 0.1 mg / kilogram / body weight to about 9 mg / kilogram / body weight. In some embodiments, the pharmaceutical composition is administered at 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 one dose or two or more partial doses administered at appropriate intervals. These partial doses may be administered, for example, in unit dosage forms containing 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 active ingredient per unit dosage form. Alternatively, the dose may be administered as a continuous infusion, if required by the condition of the recipient.

[0106] In some embodiments, the pharmaceutical compositions are administered in a fixed dose of about 1 mg to about 1 g or more, regardless of the patient's weight. In some embodiments, the pharmaceutical composition comprises about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 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 pharmaceutical composition is administered in a dose of about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g or more. In some embodiments, the pharmaceutical composition is administered in a dose of about 10 mg, 40 mg, or 100 mg.

[0107] The pharmaceutical composition may be administered for about 1 day to about 1 year or more, 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 more.

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

[0109] Patient population Any suitable subject may be administered the pharmaceutical composition of the present disclosure. In some embodiments, the subject is at risk of viral infection, developing cancer, or developing an autoimmune or inflammatory disorder. In some embodiments, the patient is at risk of developing the harmful or life-threatening effects of the disorder described herein. In some embodiments, the subject is experiencing the harmful or life-threatening effects of the disorder described herein.

[0110] In some embodiments, the subject is infected 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 supplemental oxygen. In some embodiments, the patient is receiving supplemental oxygen via a face mask or pronged nasal cannula. 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., greater than 24 breaths per minute). In some embodiments, the patient is accompanied by a fever (e.g., a temperature greater than 100.4° F. or 38° C.). In some embodiments, the patient is at risk of progressing to more severe COVID-19, ARDS, or symptoms thereof, and the pharmaceutical composition of the present disclosure is administered before symptoms worsen.

[0111] In some embodiments, a patient is determined to have mild COVID-19 by: 1) a positive test by a standard RT-PCR assay or equivalent; 2) mild symptoms of illness with COVID-19 without shortness of breath or difficulty in breathing, which may include fever, cough, sore throat, fatigue, headache, myalgia, gastrointestinal symptoms; and / or 3) an absence of clinical signs indicative of moderate, severe, or severe 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 with exertion; 3) clinical signs suggestive of moderate illness with COVID-19, such as a respiratory rate of >20 breaths per minute, oxygen saturation (SpO2) >93% on room air at sea level, heart rate >90 beats per minute, and / or 4) the absence of clinical signs indicative of severe or critical illness.

[0113] In some embodiments, a patient is determined to have severe COVID-19 by 1) a positive test by a standard RT-PCR assay or equivalent, 2) symptoms suggestive of severe systemic illness with COVID-19, which may include moderate illness or shortness of breath at rest, or any symptoms of dyspnea; 3) clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate > 30 breaths / min, heart rate > 125 breaths / min, SpO2 < 93% on 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 1) a positive test by a standard RT-PCR assay or equivalent; 2) evidence of severe illness defined by at least one of the following: a) respiratory failure defined based on resource utilization 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 enhanced nasal cannula (fraction of oxygen delivered ≧0.5), noninvasive positive pressure ventilation, extracorporeal membrane oxygenation (ECMO), and / or a clinical diagnosis of respiratory failure (e.g., clinically requiring one of the preceding therapies, but the preceding therapies cannot be administered in a resource-limited setting); b) shock (e.g., defined by systolic blood pressure <90 mmHg, or diastolic blood pressure <60 mmHg, or requiring vasopressors); and / or c) multiple organ dysfunction / failure.

[0115] In some embodiments, the patient is an infant (e.g., 0 to 2 years of age, inclusive). In some embodiments, the patient is a pediatric patient (e.g., 2 to 18 years of age, inclusive). In some embodiments, the patient is between 18 and 100 years of age. In some embodiments, the patient is between 18 and 85 years of age. In some embodiments, the patient is between 50 and 100 years of age. In some embodiments, the patient is over 65 years of age. 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 of age or older. In some embodiments, patients over the age of 50 are considered to be at higher risk for developing severe disease (e.g., COVID-19 or ARDS). In some embodiments, patients over the age of 65 are considered to be at higher risk for developing severe disease (e.g., COVID-19 or ARDS).

[0116] In some embodiments, patients with one or more comorbidities are considered to be at higher risk for developing severe disease (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, at-risk patients exhibit elevated markers of cardiac injury or dysfunction (e.g., hsTnI, NT-proBNP). In some embodiments, race is a factor in patients considered at higher risk for developing severe disease (e.g., COVID-19 or ARDS). In some embodiments, socioeconomic status is a factor in patients considered at higher risk for developing severe disease (e.g., COVID-19 or ARDS).

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

[0118] Combination therapy The pharmaceutical compositions disclosed herein may be administered with various therapies used to treat, prevent, delay, or ameliorate cancer, viral infection, inflammation, autoimmune disorders, inflammatory lung injury, COVID-19, and / or ARDS. In some embodiments, the pharmaceutical compositions are administered simultaneously with standard therapeutic agents. The one or more therapeutic agents may be any compound, molecule, or substance that exerts a therapeutic effect on a subject in need thereof.

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

[0120] In some embodiments, the subject has previously been treated with an anti-SARS-CoV-2 or COVID-19 therapy or is receiving a combination therapy with an anti-SARS-CoV-2 or COVID-19 therapy. Suitable therapies include monoclonal antibodies (e.g., bamlanivimab, 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 an anti-SARS-CoV-2 or COVID-19 therapy, such as a suitable treatment provided herein. In some embodiments, a subject in need of treatment who is refractory to an anti-SARS-CoV-2 therapy is treated with an antibody of the present disclosure.

[0121] In some embodiments, the pharmaceutical compositions disclosed herein are administered with one or more chemotherapeutic agents, including but not limited to methotrexate, daunomycin, mitomycin, cisplatin, vincristine, epirubicin, fluorouracil, verapamil, cyclophosphamide, cytosine arabinoside, aminopterin, bleomycin, mitomycin C, democolcine, etoposide, mithramycin, 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 as separate pharmaceutical compositions or mixed in a single pharmaceutical composition, i.e., may be administered together in a coordinated manner. By "co-administered", one or more therapeutic agents may also be administered simultaneously with the pharmaceutical composition, or may be administered separately, including at different times and with different frequencies. One or more therapeutic agents may be administered by any known route, such as, for example, orally, intravenously, intramuscularly, nasally, via aerosol, subcutaneously, intravaginally, intrarectally, etc. 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 therapeutic agent is generally the same as the dosage of the agent when used independently.However, if a therapeutic agent interferes with the metabolism of other therapeutic agents, the dosage of each therapeutic agent is adjusted accordingly.Alternatively, if two or more therapeutic agents show synergistic effects, one or more doses may be reduced.Each therapeutic agent may be administered simultaneously or separately at appropriate time intervals.

[0124] definition As used in this disclosure, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0125] As used in this disclosure, the term "or" is understood to be inclusive, encompassing both "or" and "and."

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

[0127] The terms "peptide", "polypeptide" and "protein" are used interchangeably and refer to compounds that contain amino acid residues covalently linked by peptide bonds. A protein or peptide contains at least two amino acids, with no limit on the maximum number of amino acids that can comprise the sequence of a protein or peptide. A polypeptide includes any peptide or protein that contains two or more amino acids linked together by peptide bonds. As used herein, the term refers to both short chains, also commonly referred to in the art as peptides, oligopeptides and oligomers, for example, and longer chains, also commonly referred to in the art as proteins, of which there are many varieties. "Polypeptides" include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0128] To calculate percent identity, the sequences to be compared are typically aligned to give the maximum match between sequences.One example of a computer program that can be used to determine percent 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 the two polypeptides or polynucleotides whose percent sequence identity is to be determined.The sequences are aligned to best match their respective amino acids or nucleotides (the "match span" determined by the algorithm). In certain embodiments, standard comparison matrices (for the PAM250 comparison matrix, see Dayhoff et al., 1978, Atlas of Protein Sequence and Structure 5:345-352; for the BLOSUM 62 comparison matrix, see Henikoff et al., 1992, Proc. Natl. Acad. Sci. USA 89:10915-10919) are also used by the algorithm.

[0129] Non-Limiting Example Embodiments of the Disclosure The subject matter disclosed herein may be useful alone or in combination with one or more other embodiments.Without limiting the above description, certain non-limiting embodiments of the present disclosure are provided below.As will be clear to those skilled in the art upon reading this disclosure, each of the individually numbered embodiments may be used or combined with any of the preceding or succeeding individually numbered embodiments.This is intended to provide support for all such combinations of embodiments, and is not limited to the combinations of embodiments explicitly provided below.

[0130] Embodiments:

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

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

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

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

[0135] Embodiment 5. The anti-CD147 antibody of 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. The anti-CD147 antibody of any one of embodiments 1 to 5, wherein the antibody is a full length antibody, a monospecific antibody, a bispecific antibody, a trispecific antibody, an antigen binding region, a heavy chain, a light chain, a VhH, a Vh, a CDR, a variable domain, a scFv, an Fc, an Fv, an Fab, an F(ab)2, an IgG, a reduced IgG (rIgG), a monospecific Fab2, a bispecific Fab2, a trispecific Fab3, a diabody, a bispecific diabody, a trispecific triabody, a minibody, a nanobody, an IgNAR, a V-NAR, an HcIgG, or a combination thereof.

[0137] Embodiment 7. The anti-CD147 antibody of embodiment 6, wherein the antibody is a VhH.

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

[0139] Embodiment 9 The anti-CD147 antibody of embodiment 8, wherein the CAR is expressed on an immune cell.

[0140] Embodiment 10. The anti-CD147 antibody of embodiment 9, wherein the immune cell is a peripheral blood mononuclear cell (PBMC), a lymphocyte, a T cell, or a NK cell.

[0141] Embodiment 11. The anti-CD147 antibody of 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 of embodiment 11, wherein the cell is an epithelial cell, an endothelial cell, or a neuronal cell.

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

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

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

[0146] Embodiment 16 The anti-CD147 antibody of 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 of 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. The anti-CD147 antibody of 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, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis.

[0149] Embodiment 19 The anti-CD147 antibody of embodiment 18, wherein the virus is a coronavirus.

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

[0151] Embodiment 21. The anti-CD147 antibody of any one of embodiments 11 to 20, wherein the cell is a cancer cell.

[0152] Embodiment 22. The anti-CD147 antibody of any one of embodiments 11 to 20, wherein the cell is a tumor cell.

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

[0154] Embodiment 24. The anti-CD147 antibody of embodiment 22, wherein the tumor cells are 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, lymphatic cancer, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

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

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

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

[0158] Embodiment 28. The anti-CD147 antibody of 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 I diabetes, 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 of any one of embodiments 1 to 28, wherein the anti-CD147 antibody is humanized.

[0160] Embodiment 30. A method for preventing, treating, or ameliorating a disorder associated with CD147 expression in a subject in need thereof 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 an anti-CD147 antibody of any one of Embodiments 1 to 29.

[0162] Embodiment 32. A cell comprising a sequence encoding an anti-CD147 antibody according to any one of embodiments 1 to 29.

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

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

[0165] Embodiment 35 The anti-CD147 antibody of embodiment 34, wherein the cell is a red blood cell.

[0166] Embodiment 36. The anti-CD147 antibody of 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 of 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 of embodiment 37, wherein the anti-CD147 antibody reduces parasitemia in blood cells within about 48 hours.

[0169] Embodiment 39 The anti-CD147 antibody of embodiment 37, wherein the anti-CD147 antibody reduces parasitemia in blood cells within about 96 hours.

[0170] Embodiment 40 The anti-CD147 antibody of embodiment 33, wherein administration of the anti-CD147 antibody prevents, ameliorate, 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 NO: 16 to SEQ ID NO: 23, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NO: 24 to SEQ ID NO: 31, and the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NO: 32 to SEQ ID NO: 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 of embodiment 41, wherein the anti-CD147 antibody comprises 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 of 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 of any one of embodiments 41 to 44, wherein the anti-CD147 antibody is humanized.

[0176] Embodiment 46. A method of treatment comprising administering a pharmaceutical composition comprising an effective amount of an anti-CD147 antibody, wherein the anti-CD147 antibody comprises CDR1, CDR2, and CDR3 regions, the CDR1 region is an amino acid sequence selected from the group consisting of SEQ ID NO:16 to SEQ ID NO:23, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NO:24 to SEQ ID NO:31, and the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NO:32 to SEQ ID NO:39, and the anti-CD147 antibody comprises 0 to 2 amino acid modifications in at least one of the CDR1, CDR, or CDR3 regions.

[0177] Embodiment 47. The method of treatment of embodiment 46, wherein said administering is effective to reduce or eliminate an inflammatory or autoimmune disease.

[0178] Embodiment 48. The method of 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 I diabetes, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

[0179] Embodiment 49. The method of any one of embodiments 46 to 48, wherein the administering is effective to reduce or eliminate viral infiltration of cells by the virus.

[0180] Embodiment 50. The method of 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, poliovirus, immunodeficiency virus (e.g., HIV), enveloped virus, RNA virus, and hepatitis.

[0181] Embodiment 51 The method of treatment of embodiment 50, wherein the virus is a coronavirus.

[0182] Embodiment 52. The method of treatment of embodiment 51, wherein the coronavirus comprises SARS-CoV-2.

[0183] Embodiment 53. The method of any one of embodiments 46-48, wherein the administering is effective to reduce or eliminate metastasis of the cancer.

[0184] Embodiment 54. The method of treatment of 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, lymphatic cancer, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

[0185] Embodiment 55. The method of any one of embodiments 46 to 48, wherein the administering is effective to reduce or eliminate the infiltration of Plasmodium into cells.

[0186] Embodiment 56. An antibody-drug conjugate comprising an anti-CD147 antibody according to any one of embodiments 1 to 29.

[0187] Embodiment 57. The antibody-drug conjugate of embodiment 56, wherein the drug is selected from the group consisting of anti-cancer drugs, anti-malarial drugs, anti-viral drugs, and anti-inflammatory drugs.

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

[0189] Embodiment 59. The antibody-drug conjugate of embodiment 57, comprising an anti-cancer drug, wherein the anti-cancer drug comprises an immunotherapy.

[0190] Embodiment 60. The antibody-drug conjugate of embodiment 59, wherein the immunotherapy is selected from the group consisting of an antibody, a checkpoint inhibitor, a cell therapy, a cytokine, an oncolytic virus, and a vaccine.

[0191] Embodiment 61. The antibody-drug conjugate of embodiment 60, comprising the antibody.

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

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

[0194] Of these 24, four clones with unique sequences and high signal-to-noise ratios in ELISA were selected for further study: two of these (Ibx-11 and Ibx-13) were successfully 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, Ibx-75 VhH).

[0195] For ELISA, 100 ng of human CD147 was coated overnight in 1× coating buffer on Nunc polysorb plates. Wells were washed once with TBST (0.01% Tween® 20) and then blocked for 1 hour using 1× fish gel in TBST at room temperature (RT). Ibx-11, Ibx-13, Ibx-75, Ibx-76, Ibx-77, and anti-HIS antibodies were incubated at 0.01 ng / well to 100 ng / well in 100 μl for 1 hour at RT, followed by three 5-minute washes. Wells were incubated with anti-human antibodies for Ibx-11 and Ibx-13 treated wells, and anti-flag antibodies for Ibx-77, Ibx-75, Ibx-76 treated wells at 1:1000 dilution for 1 hour at RT, then washed three times for 5 minutes each wash. Wells were incubated with 100 μl / well TMBE for 30 min and the reaction was stopped with 100 μl / well 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. ELISA EC50s for the antibodies tested ranged over 2 logs (0.1-10 ng of VhH antibody / well). Tandem bivalent Ibx-75 (10 ng / well) had the lowest binding to human CD147, followed by Ibx-76 and Ibx-77, which bound at similar levels (1 ng / well). Best binding was observed with IgG Fc fusions Ibx-11 and Ibx-13 (0.1 ng / well). The improved binding of IgG Fc fusions over 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 structures may be binding effectively as monovalent structures due to the short linker length).

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

[0198] For ELISA, 100 ng of mouse CD147 was coated overnight in 1× coating buffer on Nunc polysorb plates. Wells were washed once with TBST (0.01% Tween® 20) and then blocked for 1 hour using 1× fish gel in TBST at room temperature (RT). Ibx-11, Ibx-13, Ibx-75, Ibx-76, Ibx-77, and anti-HIS antibodies were incubated at 0.01 ng / well to 100 ng / well in 100 μl for 1 hour at RT, followed by three 5-minute washes. Wells were incubated with anti-human for Ibx-11 and Ibx-13 treated wells and anti-flag for Ibx-77, Ibx-75, Ibx-76 treated wells at 1:1000 dilution for 1 hour at RT, then washed three times for 5 minutes each wash. Wells were incubated with 100 μl / well TMBE for 30 min and the reaction was stopped with 100 μl / well 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 concentrations ranging from 0 nM to 900 nM in HBS-EP buffer pH 7.4 at 10 μl / min for 600 seconds. Two CD147 injections were performed (2.5-fold dilution series) for 0 nM, 9.22 nM, 0 nM, 23.04 nM, 57.6 nM, 144 nM, 360 nM, and 900 nM. 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 DIPs during analyte injection, one technical replicate at 0 nM and 23.04 nM was excluded from the analysis. Data were 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 second response was lower than the first. At steady state 1:1, a KD of 138.0 nM (± 0.003 nM) was calculated. 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 chip surface was activated by injecting a 1:1 mixture of NHS / EDC at 10 μl / min for 420 seconds. 100 μg / ml CD147 was immobilized with 10 mM sodium acetate solution pH 4.5 at 10 μl / min for 510 seconds. Unreacted CD147 and the activated chip surface were washed and inactivated with ethanolamine pH 8.5 at 10 μl / min for 420 seconds. A total of approximately 3800 RU of CD147 was immobilized.

[0206] Ibx-77 was injected at 10 μl / min for 420 s at concentrations ranging from 9.22 nM to 360 nM in HBS-EP buffer pH 7.4. The chip surface was regenerated with 10 mM glycine pH 2.0.

[0207] Data was analyzed with qDat software provided by the instrument manufacturer. A steady-state 1:1 fitting model was used for initial steady-state binding analysis (Figure 7). KD was then estimated using a simple Kd / Ka kinetic 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 antibodies of the present disclosure to bind to CD147 expressed on 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 in 6-well plates, allowed to settle, and grown overnight. Cells were removed by manual scraping with the wide, blunt end of a 1 ml pipette tip, and cells were prepared for flow cytometry analysis as before. 1 μg of Ibx-77, anti-CD147, rabbit isotype control, anti-Flag dylight were used to stain cells for 1 hour on ice, followed by washing and centrifugation. Cells were then incubated with 1 μg of anti-rabbit Dylight488 and anti-Flag dyligth488 as secondary antibodies for 30 minutes, followed by centrifugation and washing. Cells were resuspended in 1000 μl of flow source and a final run was performed on the flow cytometer. A total of 30,000 events were collected for analysis within 300 seconds (5 minutes) if possible. Negative cells were gated out based on unstained cells for each individual cell line.

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

[0210] Ibx-77 stained cells show a distinct positive staining cell population compared to unstained controls in HEK293 (Figure 8) and HCC1954 (Figure 9) cell lines.

[0211] Example 6 - Ibx-77 binds to CD147 expressed on HeLa cells HELA cell lines were grown to confluence in recommended medium in T-75 flasks. Approximately 1 million cells were plated in 6-well plates and allowed to settle and grow overnight. Cells were removed by manual scraping with the wide, blunt end of a 1 ml pipette tip, and cells were prepared for flow cytometry analysis as before. Cells were washed once with flow source and incubated with 1 μl / ml viability dye 660 for 30 minutes on ice, then washed twice. 10 μg and 5 μg of Ibx-77 were used to stain cells for 1 hour on ice, followed by two washes. Cells were then incubated with 1 μg of anti-human Dylight488 and anti-Flag dyligth488 as secondary antibodies for 30 minutes, followed by two washes. Cells were resuspended in 1000 μl of flow source and a final run on the flow cytometer. A total of 50,000 events were collected for analysis within 300 seconds (5 minutes) as much as possible. Negative cells were gated out based on unstained cells for each individual cell line. The conditions for each cell line were: Ibx-77 only; UST, anti-flag488 secondary antibody only-Flag2 only.

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

[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 to confluence in the recommended medium in T-75 flasks. Approximately 1 million cells were plated in 6-well plates and allowed to settle and grow overnight. Cells were removed by manual scraping with the wide, blunt end of a 1 ml pipette tip and cells were prepared for flow cytometry analysis as before. Cells were washed once in flow source (PBS, 1% FBS and Na azide). Incubated with 1 μl / ml viability dye 660 for 30 minutes on ice and then washed twice. Valid Fc receptors were first blocked using 1 μg / 100 μl Fc block reagent for 10 minutes on ice. This was followed by two washes. Cells were stained for 1 hour on ice using the indicated amounts of antibodies shown in the table and then washed twice. The cells were then incubated with anti-human Dylight488, anti-rabbit Dylight488 and anti-Flag dyligth488 as secondary antibodies for 30 minutes, followed by two washes. The cells were resuspended in 2000 μl of flow source and run on the flow cytometer for the final time. A total of 50,000 events were collected to analyze as much as possible within 300 seconds (5 minutes). Negative cells were gated out based on VhH-Fc-(h27-8GL) cells of individual cell lines.

[0214] The following antibodies and controls were tested in this experiment: 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 the cells in a similar pattern and the histograms are imposable. Ibx-77 shows weaker staining, probably because there is one Flag epitope available for the secondary antibody to bind. Blocking with 1 μg of Fc block slightly reduced the background noise of the human isotype control. The VhH-Fc (h27-8GL) control antibody clearly shows differences in staining between itself and Ibx-11 and Ibx-13. Thus, 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 to confluence in the recommended medium and 4 million cells were harvested and prepared for flow cytometry analysis as before. These cells were not treated with sodium azide. Cells were washed once with flow source (PBS, 1% FBS and Na azide) and then incubated with 1 μl / mL viability dye 660 for 30 min on ice and washed twice. Fc receptors were blocked using 1 μg / 100 μl of Fc block reagent for 10 min at room temperature followed by two washes. Cells were stained with the indicated amounts of antibodies as shown in the table in Figure 13 for 1 h on ice followed by two washes. Designated tubes were incubated with spiked RBD (1 μg / tube) for 1 h and then washed twice. Cells were then incubated with anti-spike antibody, VhH-Fc control, human isotype antibody or Ibx-11 for 1 h at 4°C and then washed twice. The cells were then incubated with anti-human Dylight488 followed by anti-rabbit Dylight488 for 30 minutes, followed by two washes. The cells were resuspended in 1000 μl of flow source and run on the flow cytometer for the final time. A total of 50,000 events were collected to analyze as much as possible within 300 seconds (5 minutes). Negative cells were gated out based on 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 to confluence in the recommended medium. Approximately 1 million cells per well were plated in 6-well dishes and prepared for flow cytometry analysis as before. Cells were not sodium azide treated. Cells were washed once in flow source (PBS, 1% FBS and Na azide). Fc receptors were blocked using 1 μg / 100 μl of Fc block reagent for 10 min at room temperature followed by two washes. Cells were stained with the indicated amounts of antibodies as shown in the table in Figure 14A-B for 1 h on ice followed by two washes. Cells were then incubated with spiked RBD (1 μg / tube) for 1 h and then washed twice. Cells were then incubated with anti-spike antibodies, VhH-Fc control, human isotype antibodies or Ibx-11, Ibx-13, or Ibx-77 for 1 h at 4°C and then washed twice. The cells were then incubated with anti-human Dylight488 followed by anti-rabbit Dylight488 for 30 minutes, followed by two washes. The cells were resuspended in 1000 μl of flow source and run on the flow cytometer for the final time. A total of 50,000 events were collected to analyze as much as possible within 300 seconds (5 minutes). Negative cells were gated out based on VhH-Fc-(h27-8GL) cells of the individual cell lines.

[0219] Vero E6 cells were analyzed using the same voltage settings of the flow cytometer as those set for Jurkat cells. Jurkat cells show good staining with Ibx-11, Ibx-13 and Ibx-77, with clear separation between the negative control (VhH-Fc-(h27-8GL) and the unstained control. See Figure 14A. Surprisingly, Vero E6 cells show that Ibx-13 stains more strongly than Ibx-11. See Figure 14B. These differences may be due to differences in the sequences of human and monkey CD147. Such amino acid differences may be part of the important epitopes of the Ibx antibody series 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 show weaker staining of Vero E6 cells.

[0220] Example 10 - KD of 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 onto the sensor chip and sensorgrams were collected. The flow rate was 10 μ / min and the chip was regenerated with 10 mM glycine at pH 1.5. The results are shown in Figures 15A-B.

[0221] Although the KD values ​​obtained here may be affected by impurities or concentration, the values ​​are primarily antibody dependent and can therefore be used as a screening tool to identify strong binders. In this case, Ibx-75 was at 1 × 10 -6 (±0.009)s -1 K d and Ibx-74 binds at 3 × 10 -5 (±0.001)s -1 K d was bonded with.

[0222] This comparison indicates 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 and allowed to attach and grow overnight. Old medium was replaced with 50 μl of fresh medium. Ibx-11 and Ibx-13 were prepared by premixing the antibodies with anti-human IgG Fc-MMAF. 50 microliters of Ibx-11 and Ibx-13 mixtures at various concentrations (30 nM to 1.1 nM final concentration) were added to the wells. Isotype and secondary ADC only controls were included in the plate. The plate was 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 in 96 round bottom wells at 20,000 cells / well in 100 μl. 100 μg / ml Ibx-77, Ibx-11, or Ibx-13 was added to 100 μl of cells for a final volume of 200 μl per well and a final concentration of antibody of 50 μg / ml. Images were collected at 0, 2, 4, 9, 18, and 24 hours. Pixels were measured using ImageJ for 2 hours, reaching a maximum value at 24 hours. No further differences were observed at 48 hours. Visual identification (FIG. 17) showed that differences in aggregation patterns became evident at 18 hours, with cells treated with 50 μg / ml Ibx series antibodies showing a clear aggregation pattern with denser clusters of aggregates and fewer individual cells compared to untreated controls. A similar pattern was observed with the anti-CD147 control antibody and the anti-CD98 antibody at a lower dose of 20 μg / ml. These data were also quantitatively analyzed by imaging analysis counting pixel size from 8-bit images. Ibx series antibodies at 50 μg / ml to 25 μg / ml show larger pixel size of particles (aggregates) at 24 hours. These differences are subtle between the Ibx series antibodies. See Figure 18.

[0226] In another cell aggregation assay, Jurkat T cells were seeded in 96 round-bottom wells at 20,000,000 cells / well in 100 μl. 100 μg / ml Ibx-77, Ibx-11, or Ibx-13 was added to 100 μl of cells for a final volume of 200 μl per well and a final concentration of antibody of 50 μg / ml. Images were collected at 0, 2, 4, 9, 18, and 24 hours. Individual cells and groups of cells (<3 cells per group) with clear boundaries that were not part of larger aggregates were counted manually at 18 and 24 hours. Figure 19. At 24 hours, there was a significant decrease in single cell numbers for Ibx-77 treated cells (p=0.071). Figures 20A-B.

[0227] Example 13 - Ibx-76 and Ibx-77 inhibit angiogenesis in a tubule formation assay The ability of anti-CD147 VhH antibodies 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, antibodies and CD147 protein (added for competition) were added. After a further day of culture, cells were stained with calcein AM. Tube formation was then assessed 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 stimulator for angiogenesis. Co-incubation of CD147 with Ibx-76 and Ibx-77 shows a reduction in angiogenesis induced by CD147 alone.

[0229] Example 14 - Ibx-13 prevents the growth of Plasmodium falciparum in blood cells 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 the strain was cultured at 2% hematocrit in 96-well plates. Ibx-13 or MIF-2-5 antibodies or VhH-Fc were administered to the wells at 1, 10, and 100 μg / mL. Parasites not exposed 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 examined microscopically in a blinded fashion. The number of infected red blood cells (RBCs) was scored in a blinded fashion 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 treatment, parasites grew normally after 48 hours and increased to 1.3%-5.9%. In the negative control, treatment with chloroquine killed approximately 93% of the parasites at 48 hours and approximately 98% at 96 hours. Treatment with Ibx-13 resulted in approximately 100% parasitemia 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 were dead due to extremely high parasitemia because the medium was not changed daily. [Table 2-2]

[0232] Example 15 - Antibody drug conjugate assay for malignant melanoma cells 2,500 A375 (malignant melanoma) cells were seeded per well in a 96-well plate with complete growth medium (DMEM, 10% FBS) and allowed to adhere overnight. The next 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 3-fold decreasing amounts ranging from 30 nM to 1.1 nM, while the secondary ADC was kept constant at 30 nM. These mixtures were incubated for 5 min. 25 μl of anti-Fc (human) secondary antibody drug conjugate reagent (diluted in complete medium) was added to the wells and incubated for 72 h at 37 °C in a 5.0% CO2 incubator. After 72 h, viability was assessed using the Viability Kit® according to the manufacturer's protocol.

[0233] A375 cells show sensitivity to increasing doses of primary antibodies Ibx-11 and Ibx-13 up to 3.3 nM. See Figures 24-25. The maximum effect observed was a reduction in viability of about 55% at 3.3 nM, followed by a gradual decrease in viability at higher antibody concentrations. The secondary ADC at 30 nM itself may have a small effect compared to untreated cells. Some effect of the human isotype control was also observed.

[0234] Example 16 - Antibody drug conjugate assay for prostate cancer cells 2,500 PC-3 (prostate cancer) cells were seeded per well in a 96-well plate in complete growth medium (F-12K, 10% FBS) and allowed to adhere overnight. The next 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 3-fold decreasing amounts ranging from 30 nM to 1.1 nM, while the secondary ADC was kept constant at 30 nM. These mixtures were incubated for 5 min. 25 μl of anti-Fc (human) secondary antibody drug conjugate reagent (diluted in complete medium) was added to the wells and incubated for 72 h at 37 °C in a 5.0% CO2 incubator. After 72 h, 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 as taught in Example 15. See Figure 26 and Figure 27. The maximum effect observed here was about 25% loss of viability. This difference in viability may be due to the amount of surface CD147 present on the cells and the corresponding difference in the rate of endocytosis and the difference in the sensitivity of the 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

Claims

1. An anti-CD147 antibody comprising a CDR1 region, a CDR2 region, and a CDR3 region, wherein the CDR1 region is an amino acid sequence selected from the group consisting of SEQ ID NO:16 to SEQ ID NO:23, the CDR2 region is an amino acid sequence selected from the group consisting of SEQ ID NO:24 to SEQ ID NO:31, and the CDR3 region is an amino acid sequence selected from the group consisting of SEQ ID NO:32 to SEQ ID NO:39, and the anti-CD147 antibody comprises 0 to 5 amino acid modifications in at least one of the CDR1 region, the CDR2 region, or the CDR3 region.

2. An anti-CD147 antibody as described in claim 1, wherein the CDR1 region corresponds to sequence number 18 or 22, the CDR2 region corresponds to sequence number 26 or 30, and the CDR3 region corresponds to sequence number 34 or 38.

3. The anti-CD147 antibody of claim 1, wherein the antibody is a full-length antibody, a monospecific antibody, a bispecific antibody, a trispecific antibody, an antigen-binding region, a heavy chain, a light chain, a VhH, a Vh, a variable domain, a scFv, an Fc, an Fv, an Fab, an F(ab)2, an IgG, a reduced IgG (rIgG), a monospecific Fab2, a bispecific Fab2, a trispecific Fab3, a diabody, a bispecific diabody, a trispecific triabody, a minibody, a nanobody, an IgNAR, a V-NAR, an HcIgG, or a combination thereof.

4. An anti-CD147 antibody described in claim 3, wherein the antibody is VhH.

5. The anti-CD147 antibody described in claim 1, wherein the anti-CD147 antibody comprises sequence number 12 or sequence number 14.

6. The anti-CD147 antibody described in claim 1, wherein the anti-CD147 antibody comprises an amino acid sequence selected from SEQ ID NOs: 4 to 15.

7. An anti-CD147 antibody described in claim 3, wherein the antibody is an scFv.

8. The anti-CD147 antibody described in claim 7, wherein the scFv is expressed on an immune cell selected from the group consisting of PBMCs, lymphocytes, T cells, B cells, monocytes, dendritic cells, neutrophils, basophils, antigen-presenting cells, eosinophils, and NK cells.

9. A pharmaceutical composition comprising an effective amount of the anti-CD147 antibody described in claim 1.

10. A cell comprising an array encoding the anti-CD147 antibody described in claim 1.

11. An antibody-drug conjugate comprising the anti-CD147 antibody described in claim 1.

12. A composition for use in preventing, treating, or ameliorating a disorder associated with CD147 expression in a subject in need of such prevention, treatment, or amelioration, the composition comprising an anti-CD147 antibody described in claim 1.

13. The composition described in claim 12, wherein the disorder is cancer.

14. The composition of claim 13, 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, lymphatic cancer, gastric cancer, pancreatic cancer, testicular cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and mantle cell lymphoma (MCL).

15. The composition described in claim 12, wherein the disorder includes viral infiltration of a cell by a virus.

16. The composition of claim 15, 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 (HIV), enveloped virus, RNA virus, and hepatitis virus.

17. A pharmaceutical composition for use in the treatment of an inflammatory or autoimmune disease, said pharmaceutical composition comprising an anti-CD147 antibody, said anti-CD147 antibody comprising a CDR1 region, a CDR2 region, and a CDR3 region, said CDR1 region being an amino acid sequence selected from the group consisting of SEQ ID NO:16 to SEQ ID NO:23, said CDR2 region being an amino acid sequence selected from the group consisting of SEQ ID NO:24 to SEQ ID NO:31, and said CDR3 region being an amino acid sequence selected from the group consisting of SEQ ID NO:32 to SEQ ID NO:39, and said anti-CD147 antibody comprising 0 to 5 amino acid modifications in at least one of the CDR1 region, the CDR2 region, or the CDR3 region.

18. The pharmaceutical composition of claim 17, 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 I diabetes, autoimmune thrombocytopenic purpura (ATP), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), Crohn's disease, multiple sclerosis, and myasthenia gravis.

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