Anti-CD147 antibodies and methods of using the same

Abstract

Provided are anti-CD147 antibodies, pharmaceutical compositions comprising the same, and methods of treating cancer comprising administering to a subject such anti-CD147 antibodies or pharmaceutical compositions.

Description

ANTI-CD147 ANTIBODIES AND METHODS OF USING THE SAME

[0001] Advances in methods and remedies for treating cancer have revealed that cancers previously considered to be incurable are treatable and even curable. For example, anti-CTLA4 antibodies and anti-PD1 antibodies, which have been developed as antibody drugs exhibiting high stability and specificity, exhibit high response rates against melanoma and some solid cancers through activation of immune cells, including T cells. Although treatments of many intractable solid cancers with these remedies have been attempted, many cancers, such as most pancreatic cancers and liver cancers, do not show sensitivity to these drugs.

[0002] CD147 is a single-pass transmembrane protein having 2 to 3 immunoglobulin-like domains, and is known to activate downstream signal-related molecules, such as FAK, MEK, Erk, JAK / STAT, AKT and MAPK family molecules. Moreover, it has been reported that a high CD147 expression level leads to a short survival period and a poor prognosis in cancer patients. Hence, CD147 can be considered a target molecule for cancer treatment.

[0003] In one aspect, provided is a method for treating a disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a humanized anti-CD147 antibody, wherein the humanized anti-CD147 antibody comprises a light chain comprising that comprises a CDRL1 having the sequence RASQGISNYLN (SEQ ID NO: 5), a CDRL2 having the sequence YTSNLQS (SEQ ID NO: 6), and a CDRL3 having the sequence QQYDSSPRT (SEQ ID NO: 7); and a heavy chain that comprises a CDRH1 having the sequence GYTFTSDFMH (SEQ ID NO: 8), a CDRH2 having the sequence WIYPGDGDTE (SEQ ID NO: 9), and a CDRH3 having the sequence GRGYVMDA (SEQ ID NO: 10), wherein the pharmaceutical composition is administered to the subject at a dosage from about 0.5 mg / kg to about 50.0 mg / kg, and wherein the pharmaceutical composition is administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed. In some embodiments, the anti-CD147 antibody comprises a heavy chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-CD147 antibody heavy chain amino acid sequence comprises SEQ ID NO: 12. In some embodiments, the anti-CD147 antibody comprises a light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-CD147 antibody light chain amino acid sequence comprises SEQ ID NO: 11.

[0004] In some embodiments, the pharmaceutical composition is administered to the subject at a dosage from about 1.0 mg / kg to about 40.0 mg / kg. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage from about 3.0 mg / kg to about 40.0 mg / kg. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 10.0 mg / kg, about 12.0 mg / kg, about 15.0 mg / kg, about 20.0 mg / kg, or about 40.0 mg / kg. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg.

[0005] In some embodiments, the pharmaceutical composition is administered intravenously, subcutaneously, intraperitoneally, intramuscularly, intramedullary, intrathecally, intratumorally, or intraocularly. In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed. In some embodiments, the pharmaceutical composition is administered once every two weeks. In some embodiments, the pharmaceutical composition is administered once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 10.0 mg / kg, about 12.0 mg / kg, about 20.0 mg / kg, or about 40.0 mg / kg once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every four weeks. In some embodiments, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every four weeks.

[0006] In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, breast cancer, uterine cancer, ovarian cancer, lung cancer, lymphoma, thyroid cancer, skin cancer, head and neck cancer, esophageal cancer, sarcoma, prostate cancer, bladder cancer, brain tumor, gastrointestinal stromal tumor (GIST), leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), malignant lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, and diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is selected from pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), malignant lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma or diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), renal cell carcinoma (RCC), squamous cell non-small cell lung cancer (sq-NSCLC), head and neck squamous cell carcinoma (HNSCC), and squamous esophageal cancer. In some embodiments, the cancer is PDAC. In some embodiments, the cancer comprises a SMAD4-positive tumor or a tumor having a decreased expression level of or lacking the expression of KLF5. In some embodiments, the duration of treatment is until disease progression or unacceptable toxicity occurs, for example, about one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about one year, about two years, about three years, about four years, about five years, or as needed. In some embodiments, the anti-CD147 antibody is administered with two, three, or more other therapeutic agents either sequentially or concurrently.

[0007] In some embodiments, following treatment, the size of a tumor in the subject is decreased. In some embodiments, following treatment, the size of a tumor in a subject is not increased. In some embodiments, following treatment, progression of tumor growth or formation is slowed.

[0008] Both the foregoing summary and the following description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the disclosure, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the disclosure.

[0009] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below are provided as being part of the inventive subject matter disclosed herein and may be employed in any combination to achieve the benefits described herein.

[0010] FIG. 1 is a graph showing the effect of administration of #110H1L4hIgG4P on tumor growth in a pancreatic cancer xenograft mouse model. Each data point represents the mean tumor volume (mm3) ± standard error (SE). n = 6.FIG. 2 is a graph showing the effect of administration of #110H1L4hIgG4P on receptor occupancy in a pancreatic cancer xenograft mouse model. Each bar represents the mean percent receptor occupancy ± standard error (SE). n = 3.FIG. 3 is a graph showing CD147 protein expression levels in hepatocytes and erythrocytes in cynomolgus monkeys and humans, in terms of sites per cell. Each bar represents the mean CD147 expression level ± standard error (SE). n = 2 (cynomolgus monkeys); n = 3 (humans).FIG. 4 is a graph depicting the concentration (μg / mL) over time of #110H1L4hIgG4P in the plasma of cynomolgus monkeys following intravenous (IV) administration of #110H1L4hIgG4P at the indicated concentrations.FIG. 5 is a graph depicting the receptor occupancy (%) over time of #110H1L4hIgG4P in the blood of cynomolgus monkeys following intravenous (IV) administration of #110H1L4hIgG4P at the indicated concentrations.FIG. 6 is a schematic illustrating a minimal physiologically-based pharmacokinetic model incorporating target-mediated drug disposition (TMDD) for #110H1L4hIgG4P in central and leaky tissue compartments. Vp: Volume of plasma; V1: Volume of tight tissues; V2: Volume of leaky tissues; Vlymph: Volume of lymph; L: Lymph flow; L1: Lymph flow for V1; L2: Lymph flow for V2; CLp: Systemic clearance; σ1 (Sigma1): Vascular reflection coefficients for tight tissues; σ2 (Sigma2): Vascular reflection coefficients for leaky tissues; R: Receptor (CD147); RC: Complex of receptor and #110H1L4hIgG4P; Ksyn: Antigen (CD147) synthesis rate constant; Kdeg: Antigen (CD147) degradation rate constant; and Kint: Complex (#110H1L4hIgG4P-CD147) internalization rate constant.FIG. 7 is a graph depicting the predicted plasma concentration-time profiles of #110H1L4hIgG4P in humans after a single intravenous (IV) administration of #110H1L4hIgG4P at the indicated concentrations.FIG. 8 is a graph depicting the predicted receptor occupancy-time profiles in leaky tissues (including tumor) in humans after a single intravenous (IV) administration of #110H1L4hIgG4P at the indicated concentrations.FIG. 9 is a schematic illustrating the experimental design of a phase 1 clinical trial for #110H1L4hIgG4P in the treatment of cancer in humans.

[0011] Embodiments according to the present disclosure will be described more fully hereinafter. Aspects of the disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0012] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the present application and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Although not explicitly defined below, such terms should be interpreted according to their common meaning.

[0013] The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other aspects are set forth within the claims that follow.

[0014] The practice of the present technology will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, chemical engineering, and cell biology, which are within the skill of the art.

[0015] Unless the context indicates otherwise, it is specifically intended that the various features described herein can be used in any combination. Moreover, the disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B, and C (or A, B, and / or C), it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination.

[0016] Unless explicitly indicated otherwise, all specified embodiments, features, and terms intend to include both the recited embodiment, feature, or term and biological equivalents thereof.

[0017] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations that can be varied ( + ) or ( - ) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of + / - 15%, or alternatively 10%, or alternatively 5%, or alternatively 2%. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”. Definitions

[0018] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0019] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined. Unless otherwise specified, materials and / or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein, based on the guidance provided herein.

[0020] The terms “substantially” and “about” are used herein to describe and account for small variations. When used in conjunction with an event or circumstance, the terms can refer to instances in which the event or circumstance occurs precisely as well as instances in which the event or circumstance occurs to a close approximation. When used in conjunction with a numerical value, the terms can refer to a range of variation of less than or equal to ±10% of that numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%. When referring to a first numerical value as “substantially” or “about” the same as a second numerical value, the terms can refer to the first numerical value being within a range of variation of less than or equal to ±10% of the second numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%. The terms or “acceptable,” “effective,” or “sufficient” when used to describe the selection of any components, ranges, dose forms, etc. disclosed herein intend that said component, range, dose form, etc. is suitable for the disclosed purpose.

[0021] Additionally, amounts, ratios, and other numerical values are sometimes presented herein in a range format. It is to be understood that such range format is used for convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly specified. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth.

[0022] Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0023] As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the composition or method. “Consisting of” shall mean excluding more than trace elements of other ingredients for claimed compositions and substantial method steps. Examples and implementations defined by each of these transition terms are within the scope of this disclosure. Accordingly, it is intended that the methods and compositions can include additional steps and components (comprising) or alternatively including steps and compositions of no significance (consisting essentially of) or alternatively, intending only the stated method steps or compositions (consisting of).

[0024] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0025] As used herein, the phrase “therapeutically effective amount” with reference to an anti-CD147 antibody means that dose of the antibody that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. For example, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate cancer or a tumor, or signs and symptoms thereof. It is emphasized that a therapeutically effective amount of an anti-CD147 antibody will not always be effective in treating the disease or condition (e.g., cancer) in every individual subject, even though such dose is deemed to be a therapeutically effective amount by those of skill in the art. Those skilled in the art can adjust what is deemed to be a therapeutically effective amount in accordance with standard practices as needed to treat a specific subject. A therapeutically effective amount may vary based on, for example, the age and weight of the subject, and / or the subject’s overall health, and / or the severity of the subject’s disease or condition (e.g., cancer).

[0026] The terms “treat,” “treatment” or “treating” as used herein with reference to a disease or disorder associated with CD147 (e.g., cancer) refer to reducing, ameliorating, or eliminating pathophysiological features of the disease or condition (e.g., cancer), reducing, ameliorating, or eliminating signs or symptoms of the disease or disorder, and / or otherwise improving quality of life in a subject. For example, in the case of cancer, treatment may entail decreasing tumor size or tumor burden, slowing the progression of tumor growth or formation, or a combination of any or all of the foregoing.

[0027] The terms “individual,” “subject,” and “patient” are used interchangeably herein, and refer to any individual mammalian subject, e.g., bovine, canine, feline, equine, or human. In specific embodiments, the subject, individual, or patient is a human.

[0028] The term “specifically binds” to an antigen or epitope is a term that is well understood in the art, and methods to determine such specific binding are also well known in the art. A molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a CD147 epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and / or with greater duration than it binds to other CD147 epitopes or non-CD147 epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding. “Specificity” refers to the ability of a binding protein to selectively bind an antigen.

[0029] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (for example, bispecific (such as Bi-specific T-cell engagers) and trispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0030] The term “CDR” denotes a complementarity determining region as defined by at least one manner of identification to one of skill in the art.

[0031] The term “heavy chain variable region” as used herein refers to a region comprising at least three heavy chain CDRs. In some embodiments, the heavy chain variable region includes the three CDRs and at least FR2 and FR3. In some embodiments, the heavy chain variable region includes at least heavy chain HCDR1, framework (FR) 2, HCDR2, FR3, and HCDR3. In some embodiments, a heavy chain variable region also comprises at least a portion of an FR1 and / or at least a portion of an FR4.

[0032] The term “heavy chain constant region” as used herein refers to a region comprising at least three heavy chain constant domains, CH1, CH2, and CH3. Of course, non-function-altering deletions and alterations within the domains are encompassed within the scope of the term “heavy chain constant region,” unless designated otherwise. Non-limiting exemplary heavy chain constant regions include γ, δ, and α. Non-limiting exemplary heavy chain constant regions also include ε and μ. Each heavy constant region corresponds to an antibody isotype. For example, an antibody comprising a γ constant region is an IgG antibody, an antibody comprising a δ constant region is an IgD antibody, and an antibody comprising an α constant region is an IgA antibody. Further, an antibody comprising a μ constant region is an IgM antibody, and an antibody comprising an ε constant region is an IgE antibody. Certain isotypes can be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (comprising a γ1constant region), IgG2 (comprising a γ2constant region), IgG3 (comprising a γ3constant region), and IgG4 (comprising a γ4constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (comprising an α1constant region) and IgA2 (comprising an α2constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2.

[0033] The term “heavy chain” as used herein refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full-length heavy chain” as used herein refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0034] The term “light chain variable region” as used herein refers to a region comprising at least three light chain CDRs. In some embodiments, the light chain variable region includes the three CDRs and at least FR2 and FR3. In some embodiments, the light chain variable region includes at least light chain LCDR1, framework (FR) 2, LCDR2, FR3, and LCDR3. For example, a light chain variable region may comprise light chain CDR1, framework (FR) 2, CDR2, FR3, and CDR3. In some embodiments, a light chain variable region also comprises at least a portion of an FR1 and / or at least a portion of an FR4.

[0035] The term “light chain constant region” as used herein refers to a region comprising a light chain constant domain, CL. Non-limiting exemplary light chain constant regions include λ and κ. Of course, non-function-altering deletions and alterations within the domains are encompassed within the scope of the term “light chain constant region,” unless designated otherwise.

[0036] The term “light chain” as used herein refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full-length light chain” as used herein refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0037] The term “identity” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. The term “identical” or “percent identity” is a numeric score determined for a pair of aligned amino acid or nucleic acid sequences. Percent identity measures the number of identical residues (“identity”) between two sequences in relation to the length of the alignment across a “comparison window.” The number shows the % of amino acid residues or nucleotides that are the same between two sequences and indicates the degree of primary structure similarity.

[0038] Methods for the calculation of a percent identity as between two provided polypeptide sequences are known. Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, may be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps may be introduced in one or both of a first and a second sequences for optimal alignment and non-identical sequences may be disregarded for comparison purposes). The nucleotides or amino acids at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, optionally considering the number of gaps, and the length of each gap, which may need to be introduced for optimal alignment of the two sequences. Comparison or alignment of sequences and determination of percent identity between two sequences may be accomplished using a mathematical algorithm, such as BLAST (basic local alignment search tool). In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical (e.g., 85-90%, 85-95%, 85-100%, 90-95%, 90-100%, or 95-100%).

[0039] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (for example, an antibody) and its binding partner (for example, an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art (such as, for example, ELISA KD, KinExA, bio-layer interferometry (BLI), and / or surface plasmon resonance devices (such as a device), including those described herein).

[0040] The term “KD”, as used herein, refers to the equilibrium dissociation constant of an antibody-antigen interaction.

[0041] A “humanized antibody” as used herein refers to an antibody in which at least one amino acid in a framework region of a non-human variable region has been replaced with the corresponding amino acid from a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or fragment thereof. In some embodiments, a humanized antibody is an antibody fragment, such as Fab, an scFv, a (Fab')2, etc. The term humanized also denotes forms of non-human (for example, murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab')2or other antigen-binding subsequences of antibodies) that contain minimal sequence of non-human immunoglobulin. Humanized antibodies can include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are substituted by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody can comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. In general, the humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. In some embodiments, the humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Other forms of humanized antibodies have one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, and / or CDR H3) which are altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody. As will be appreciated, a humanized sequence can be identified by its primary sequence and does not necessarily denote the process by which the antibody was created.

[0042] An “CDR-grafted antibody” as used herein refers to a humanized antibody in which one or more complementarity determining regions (CDRs) of a first (non-human) species have been grafted onto the framework regions (FRs) of a second (human) species.

[0043] A “human antibody” as used herein encompasses antibodies produced in humans, antibodies produced in non-human animals that comprise human immunoglobulin genes, such as mice, and antibodies selected using in vitro methods, such as phage display (Vaughan et al., 1996, Nature Biotechnology, 14:309-314; Sheets et al., 1998, Proc. Natl. Acad. Sci. (USA) 95:6157-6162; Hoogenboom and Winter, 1991, J. Mol. Biol., 227:381; Marks et al., 1991, J. Mol. Biol., 222:581), wherein the antibody repertoire is based on a human immunoglobulin sequence. The term “human antibody” denotes the genus of sequences that are human sequences. Thus, the term is not designating the process by which the antibody was created, but the genus of sequences that are relevant.

[0044] An amino acid substitution may include but are not limited to the replacement of one amino acid in a polypeptide with another amino acid. Exemplary conservative substitutions are shown in Table 1. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, for example, retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

[0045]

[0046] Amino acids may be grouped according to common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe.

[0047] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0048] The terms “pharmaceutical formulation” and “pharmaceutical composition” refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.

[0049] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed. CD147

[0050] CD147 is a single-pass transmembrane protein having 2 to 3 immunoglobulin-like domains, and is known to activate downstream signal-related molecules, such as FAK, MEK, Erk, JAK / STAT, AKT and MAPK family molecules through interactions between multiple CD147 proteins, or through interactions with extracellular or cell membrane surface molecules, such as CD44, Integrin family molecules, CD98, VEGFR, CypA / B, and MCT1 / 3 / 4 which are involved in growth, invasion, and inflammation, thereby accelerating the production of proteases such as MMPs, and cancer growth, metastasis, and invasion. Moreover, it has been reported that a high CD147 expression level leads to a short survival period and a poor prognosis. Hence, CD147 is considered as one of the target molecules for cancer treatment.

[0051] Three variants of human CD147 are known. Variant 1 is expressed in a retina-specific manner and is a single-pass transmembrane protein having 3 immunoglobulin-like domains (these domains may be referred to as D0, D1 and D2, respectively herein.). Variant 2 is expressed in T cells or various normal cells, and, is a single-pass transmembrane protein having 2 immunoglobulin-like domains (D1, D2), the increased expression of which in various cancer tissues has been reported. Variant 3 is a single-pass transmembrane protein having 1 immunoglobulin-like domain.

[0052] The amino acid sequence and the nucleotide sequence of variant 1 of human CD147 are available with reference to GenBank Accession Nos. NP_001719.2 and NM_001728.3, and, the amino acid sequence is disclosed herein as SEQ ID NO: 1, and the nucleotide sequence is disclosed herein as SEQ ID NO: 2. The three immunoglobulin-like domains of variant 1 range from amino acid number 22 to 138 (D0), amino acid number 140 to 218 (D1), and amino acid number 223 to 323 (D2), respectively, in SEQ ID NO: 1, (Redzic, J., J. Mol. Biol., 2011, 68-82) (Grass et al., Biosol. Rep, 2016, 1-16). The transmembrane region of variant 1 ranges from amino acid number 324 to 344 in SEQ ID NO: 1.

[0053] The amino acid sequence and the nucleotide sequence of variant 2 of human CD147 are available with reference to GenBank Accession Nos. NP_940991.1 and NM_198589.2, and the amino acid sequence is disclosed herein as SEQ ID NO: 3, and the nucleotide sequence is disclosed herein as SEQ ID NO: 4. The two immunoglobulin-like domains (D1, D2) of variant 2 range from amino acid number 24 to 102 (D1) and amino acid number 107 to 207 (D2), respectively, in SEQ ID NO: 3. The transmembrane region of variant 2 ranges from amino acid number 208 to 228 in SEQ ID NO: 3 (Grass et al., Biosol. Rep, 2016, 1-16).

[0054] The amino acid sequence and the nucleotide sequence of variant 3 of human CD147 are available with reference to GenBank Accession Nos. NP_940992.1 and NM_198590.2. The human CD147 gene is also available from a commercial source.

[0055] The amino acid sequence and the nucleotide sequence of cynomolgus monkey CD147 (also referred to as monkey CD147 herein) are available with reference to GenBank Accession Nos. XP_005587354.1 and XM_005587297.1. The monkey CD147 gene is also available from a commercial source. The amino acid sequence and the nucleotide sequence of mouse CD147 are available with reference to GenBank Accession Nos. NP_001070652.1 and NM_001077184. 1. The mouse CD147 gene is also available from a commercial source.

[0056] CD147 to be used in the present invention can be obtained by synthesizing CD147 in vitro, or by using genetically engineered host cells to produce CD147. Specifically, CD147 cDNA is incorporated into a vector capable of expressing it, and then CD147 is synthesized in a solution containing an enzyme, a substrate and energy substances required for transcription and translation, or host cells of other prokaryotes or eukaryotes are transformed to express CD147, so that the protein can be obtained.

[0057] The cDNA of CD147 can be obtained by a polymerase chain reaction (hereinafter, referred to as “PCR”), namely, a PCR method, using a cDNA library expressing the cDNA of CD147 as a template, and primers for specific amplification of the cDNA of CD147 (Saiki, R. K., et al., Science, (1988)239, 487-49), for example.

[0058] Examples of the cDNA of CD147 include a polynucleotide hybridizing under stringent conditions to a polynucleotide consisting of a nucleotide sequence complementary to a nucleotide sequence encoding human, monkey or mouse CD147, and, encoding a protein having biological activity equivalent to that of CD147. Further, examples of the cDNA of CD147 include a polynucleotide that is a splicing variant transcribed from the human, monkey or mouse CD147 gene locus or a polynucleotide hybridizing under stringent conditions thereto, and, encodes a protein having biological activity equivalent to that of CD147.

[0059] Examples of CD147 further include a protein: consisting of the amino acid sequence of human, monkey or mouse CD147, or an amino acid sequence in which one or several amino acids are substituted, deleted, or added in the amino acid sequence of human, monkey or mouse CD147 from which a signal sequence is removed; and having biological activity equivalent to that of CD147. Further, examples of CD147 include a protein: consisting of an amino acid sequence encoded by a splicing variant transcribed from the human, monkey or mouse CD147 gene locus, or the amino acid sequence in which one or several amino acids are substituted, deleted, or added; and having biological activity equivalent to that of CD147. Anti-CD147 antibodies

[0060] The present disclosure provides antibodies that bind to CD147 (i.e., “anti-CD147 antibodies”). The disclosed antibodies can bind selectively to CD147 and be used to treat diseases or disorders associated with CD147, including cancer.

[0061] Anti-CD147 antibodies described herein can be obtained by any means, including in vitro sources (e.g., a hybridoma or a cell line producing an antibody recombinantly) and in vivo sources (e.g., rodents, rabbits, humans, etc.). The disclosed antibodies may be human, humanized (partially or fully), or chimeric. Human, partially humanized, fully humanized, and chimeric antibodies can be made by methods known in the art, such as using a transgenic animal (e.g., a mouse) wherein one or more endogenous immunoglobulin genes are replaced with one or more human immunoglobulin genes. Examples of transgenic mice wherein endogenous antibody genes are effectively replaced with human antibody genes include, but are not limited to, the HUMAB-MOUSETM, the Kirin TC MOUSETM, and the KM-MOUSETM(see, e.g., Lonberg, Nat. Biotechnol., 23(9): 1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol., 181: 69-97 (2008)).

[0062] Anti-CD147 antibodies disclosed herein generally will be monoclonal, recombinant, or both. Monoclonal antibodies (mAbs) may obtained by methods known in the art, for example, by fusing antibody-producing cells with immortalized cells to obtain a hybridoma, and / or by generating mAbs from mRNA extracted from bone marrow, B cells, plasma cells and / or spleen cells of immunized animals using combinatorial antibody library technology and / or by isolating monoclonal antibodies from serum from subjects immunized with an CD147 antigen. Recombinant antibodies may be obtained by methods known in the art, for example, using phage display technologies, yeast surface display technologies (Chao et al., Nat. Protoc., 1(2): 755-68 (2006)), mammalian cell surface display technologies (Beerli et al., PNAS, 105(38): 14336-41 (2008), and / or expressing or co-expressing antibody polypeptides. Other techniques for making antibodies are known in the art, and can be used to obtain antibodies used in the methods described herein.

[0063] Typically, an antibody consists of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two copies of a light (L) chain polypeptide. Typically, each heavy chain contains one N-terminal variable (VH) region and three C-terminal constant (CH1, CH2 and CH3) regions, and each light chain contains one N- terminal variable (VL) region and one C-terminal constant (CL) region. The variable regions of each pair of light and heavy chains form the antigen binding site of an antibody.

[0064] The term “antibody fragment,” as used herein, refer to one or more portions of an CD147-binding antibody that exhibits the ability to bind CD147. Examples of binding fragments include (i) Fab fragments (monovalent fragments consisting of the VL, VH, CLand CH1 domains); (ii) F(ab′)2fragments (bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region); (iii) Fd fragments (comprising the VHand CH1 domains); (iv) Fv fragments (comprising the VLand VHdomains of a single arm of an antibody), (v) dAb fragments (comprising a VHdomain); and (vi) isolated complementarity determining regions (CDR), e.g., VHCDR3. Other examples include single chain Fv (scFv) and variable domain of heavy chain of heavy chain antibody (VHH) constructs. See e.g., Bird et al., Science, 242:423-26 (1988); Huston et al., Proc. Natl. Acad. Sci. USA, 85:5879-83 (1988). Other examples include CD147-binding domain immunoglobulin fusion proteins comprising (i) a CD147-binding domain polypeptide (such as a heavy chain variable region, a light chain variable region, or a heavy chain variable region fused to a light chain variable region via a linker peptide) fused to an immunoglobulin hinge region polypeptide, (ii) an immunoglobulin heavy chain CH2 constant region fused to the hinge region, and (iii) an immunoglobulin heavy chain CH3 constant region fused to the CH2 constant region, where the hinge region may be modified by replacing one or more cysteine residues with, for example, serine residues, to prevent dimerization.

[0065] The disclosed antibodies may belong to a class of antibody selected from IgG, IgM, IgA, IgE, and IgD. More specifically, the disclosed antibodies may be an IgG1, IgG2, IgG3, or IgG4. In some embodiments, the disclosed antibodies may comprise all or part of the constant regions, framework regions, or a combination thereof of an IgG, IgM, IgA, IgE, or IgD antibody. For instance, a disclosed antibody may comprise an IgG1 immunoglobulin structure that can be modified to replace (or “switch”) the IgG1 structure with the corresponding structure of another IgG-class immunoglobulin or an IgM, IgA, IgE, or IgD immunoglobulin. This type of modification or switching may be performed in order to augment the neutralization functions of the peptide, such as antibody dependent cell cytotoxicity (ADCC) and complement fixation (CDC), or signal activation. In some embodiments, the anti-CD147 antibody may be mammalian, human, or humanized.

[0066] In some embodiments, the disclosed anti-CD147 antibodies may comprise one or more mutations that make the antibody more suitable in a therapeutic context. Such mutations, alterations, or modifications may comprise, for example, changes to the Fc region to increase the ability of the peptide to mediate cellular cytotoxicity functions like antibody dependent cell cytotoxicity (ADCC), antibody dependent cell mediated phagocytosis (ADCP), and / or complement fixation (CDC). A wide number of mutations to the Fc domain that enhance binding to Fc receptors have been reported, for example, S239D / A330L / I332E, F243L, and G236A. Additionally or alternatively, mutations to the Fc region that increase the circulating half-life or maximum drug concentration may be incorporated into the structure. For example, mutations to engineer the pH-dependent interaction of the Fc domain with FcRn to increase affinity at pH 6.0 while retaining minimal binding at pH 7.4, can increase half-life and improve efficacy under physiological conditions. In some embodiments, the disclosed antibodies may be conjugated to polyethylene glycol (PEG) and / or albumin, which may increase the half-life and decrease the potential immunogenicity of the antibody.

[0067] In some embodiments, the disclosed anti-CD147 antibody may comprise a light chain variable region comprising the CDRs of SEQ ID NO: 5, SEQ IDNO: 6, and SEQ ID NO: 7, and a heavy chain variable region comprising the CDRs of SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10. In some embodiments, the disclosed anti-CD147 antibody may comprise a light chain comprising SEQ ID NO: 11, and a heavy chain comprising SEQ ID NO: 12.

[0068] In some embodiments, the anti-CD147 antibody may comprise a heavy chain comprising a CDRH1 comprising GYTFTSDFMH (SEQ ID NO: 8), a CDRH2 comprising WIYPGDGDTE (SEQ ID NO: 9), and a CDRH3 comprising GRGYVMDA (SEQ ID NO: 10); and a light chain comprising a CDRL1 comprising RASQGISNYLN (SEQ ID NO: 5), a CDRL2 comprising YTSNLQS (SEQ ID NO: 6), and a CDRL3 comprising QQYDSSPRT (SEQ ID NO: 7). In some embodiments, the anti-CD147 antibody is #110H1L4hIgG4P.

[0069] In some embodiments, an anti-CD147 antibody comprises a heavy chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-CD147 antibody heavy chain amino acid sequence comprises SEQ ID NO: 12. In some embodiments, a heavy chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD147 antibody comprising that sequence retains the ability to bind to CD147. In some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been substituted, inserted and / or deleted in SEQ ID NO: 12. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). Optionally, the anti-CD147 antibody comprises the heavy chain sequence of SEQ ID NO: 12, including post-translational modifications of that sequence.

[0070] In some embodiments, an anti-CD147 antibody comprises a light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-CD147 antibody light chain amino acid sequence comprises SEQ ID NO: 11. In some embodiments, a light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD147 antibody comprising that sequence retains the ability to bind to CD147. In some embodiments, a total of 1 to 10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been substituted, inserted and / or deleted in SEQ ID NO: 11. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). Optionally, the anti-CD147 antibody comprises the light chain sequence in SEQ ID NO: 11, including post-translational modifications of that sequence.

[0071] Any of the antibodies disclosed herein can be used for treating diseases and disorders associated with CD147, such as cancer. Optimal doses and routes of administration may vary, such as based on the route of administration and dosage form, the age and weight of the subject, and / or the subject’s condition, including the type and severity of the disease, and can be determined by the skilled practitioner. The antibodies can be formulated in a pharmaceutical composition suitable for administration to a subject by any intended route of administration, as discussed in more detail below. Pharmaceutical Compositions

[0072] Provided herein are pharmaceutical compositions for use in the treatment of disease and disorders associated with CD147, including cancer. The pharmaceutical compositions comprise an anti-CD147 antibody described herein as an active ingredient.

[0073] Pharmaceutical compositions of an anti-CD147 antibody of the present disclosure can be prepared as formulations according to standard methods (see, for example, Remington's Pharmaceutical Science, Mark Publishing Company, Easton, USA). The pharmaceutical compositions generally comprise a carrier and / or additive in addition to the antibody. For example, in some embodiments, the pharmaceutical composition comprises one or more surfactants (for example, PEG and Tween), excipients, antioxidants (for example, ascorbic acid), coloring agents, flavoring agents, preservatives, stabilizers, buffering agents (for example, phosphoric acid, citric acid, and other organic acids), chelating agents (for example, EDTA), suspending agents, isotonizing agents, binders, disintegrators, lubricants, fluidity promoters, corrigents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmelose calcium, carmelose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylacetaldiethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, corn starch, and inorganic salt. In some embodiments, the pharmaceutical composition comprises one or more other low-molecular-weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulin, and amino acids such as glycine, glutamine, asparagine, arginine, and lysine.

[0074] An anti-CD147 antibody may be prepared as an aqueous solution for injection, in which the anti-CD147 antibody can be dissolved in an isotonic solution containing, for example, physiological saline, dextrose, or other excipients or tonifiers (i.e., tonicity agents). The tonifier may include, for example, D-sorbitol, D-mannose, D-mannitol, and sodium chloride. In addition, appropriate solubilizing agents, for example, alcohols (for example, ethanol), polyalcohols (for example, propylene glycols and PEGs), and non-ionic detergents (polysorbate 80 and HCO-50) may be used concomitantly.

[0075] The disclosed pharmaceutical compositions may be formulated for any suitable route of administration, including intravenous, subcutaneous, intraperitoneal, intramuscular, intramedullar, intrathecal, intratumoral, intraocular, or oral administration. In typical embodiments, the anti-CD147 antibodies are formulated for intravenous, subcutaneous, intraperitoneal, or intramuscular administration, such as in a solution, suspension, emulsion, liposome formulation, etc. More specifically, the disclosed anti-CD147 antibodies can be formulated for intravenous, subcutaneous, or intramuscular administration.

[0076] Pharmaceutically acceptable carriers for various dosage forms and routes of administration are known in the art. For example, solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, and soothing agents for liquid preparations are known. In some embodiments, the pharmaceutical compositions include one or more additional components, such as one or more preservatives, antioxidants, colorants, sweetening / flavoring agents, adsorbing agents, wetting agents and the like.

[0077] The present invention also provides a pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of the anti-CD147 antibody, and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and / or adjuvant.

[0078] The present invention also provides a pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of the anti-CD147 antibody, a therapeutically and / or prophylactically effective amount of at least one antitumor therapeutic agent, and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and / or adjuvant.

[0079] Substances to be used for a preparation that are acceptable in the pharmaceutical composition of the present invention are preferably nontoxic to a subject to which the pharmaceutical composition is administered in terms of preferably dosage and concentration for administration.

[0080] The pharmaceutical composition of the present invention can contain substances for a preparation in order to vary or maintain the pH, osmotic pressure, viscosity, transparency, color, isotonicity, sterility, stability, solubility, sustained release rate, absorptivity, permeability, and the like. Examples of substances for a preparation can include the following, but are not limited to: amino acids such as glycine, alanine, glutamine, asparagine, arginine or lysine, antimicrobial agents, antioxidants such as ascorbic acid, sodium sulfate or sodium hydrogen sulfite, buffering agents such as a phosphate, citrate, or borate buffer, sodium hydrogen carbonate, and tris-hydrochloric acid (Tris-Hcl) solution, fillers such as mannitol and glycine, chelating agents such as ethylenediaminetetraacetic acid (EDTA), complexing agents such as caffeine, polyvinyl pyrrolysine, β-cyclodextrin, and hydroxypropyl-β-cyclodextrin, extending agents such as glucose, mannose or dextrin, carbohydrates such as monosaccharide and disaccharide, colorants, flavors, diluents, emulsifiers, hydrophilic polymers such as polyvinyl pyrrolysine, low-molecular-weight polypeptides, salt-forming counter ions, benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, antiseptics such as sorbic acid or hydrogen peroxide, glycerin, solvents such as propylene and glycol or polyethylene glycol, sugar alcohols such as mannitol or sorbitol, suspensions, sorbitan esters, polysorbates such as polysorbate 20 and polysorbate 80, triton, tromethamine, surfactants such as lecithin or cholesterol, stabilization enhancers such as sucrose and sorbitol, sodium chloride, potassium chloride, elasticity enhancers such as mannitol and sorbitol, transporting agents, excipients, and / or pharmaceutical adjuvants. The amount of such a substance for a preparation is preferably added in an amount 0.01 to 100 times, and particularly 0.1 to 10 times the weight of the anti-CD147 antibody. The composition of a suitable pharmaceutical composition in a preparation can be adequately determined by persons skilled in the art according to its applicable disease, applicable route of administration, and the like.

[0081] An excipient and a carrier in a pharmaceutical composition may be liquid or solid. An appropriate excipient and an appropriate carrier may be water or saline for injection, an artificial cerebrospinal fluid, or other substances that are generally used for parenteral administration. Neutral saline or saline containing serum albumin can also be used as a carrier. A pharmaceutical composition can contain a Tris buffer of pH7.0-8.5, an acetate buffer of pH4.0-5.5, or a citrate buffer of pH3.0-6.2. These buffers may contain sorbitol and other compounds. Examples of the pharmaceutical composition of the present invention can include a pharmaceutical composition comprising the anti-CD147 antibody and a pharmaceutical composition comprising the anti-CD147 antibody and at least one antitumor therapeutic agent. The pharmaceutical composition of the present invention is prepared as a drug having the selected composition and purity as required, a freeze-dried product or a liquid. A pharmaceutical composition comprising the anti-CD147 antibody and a pharmaceutical composition comprising the anti-CD147 antibody and at least one anticancer therapeutic agent can also be formulated as a freeze-dried product in which an appropriate excipient such as sucrose is used.

[0082] The pharmaceutical composition of the present invention can also be prepared for parenteral administration, or for oral administration for gastrointestinal absorption. The composition and the concentration of a preparation can be determined depending on the method of administration. When the antibody of the present invention is administered to a human, about 0.1 to 100 mg / kg of the antibody may be administered once or several times during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, about 5 to about 10000 mg of the antibody may be administered once or several times during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, about 5 to about 10000 mg of the antibody may be administered once or several times during 1 to 365 days. However, the dosage and the frequency of administration should be generally determined in consideration of the gender, body weight, and age of a patient, symptoms, severity, adverse reaction, and the like, and thus doses and methods therefor are not limited to the above examples.

[0083] In some embodiments, when the antibody of the present invention is administered to a human, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 40 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 8000 mg, about 9000 mg, or about 10000 mg of the antibody may be administered. In some embodiments, when the antibody of the present invention is administered to a human, at least about 5 mg, at least about 10 mg, at least about 20 mg, at least about 50 mg, at least about 100 mg, at least about 200 mg, at least about 300 mg, at least about 40 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 2000 mg, at least about 3000 mg, at least about 4000 mg, at least about 5000 mg, at least about 6000 mg, at least about 7000 mg, at least about 8000 mg, at least about 9000 mg, or at least about 10000 mg of the antibody may be administered. In some embodiments, when the antibody of the present invention is administered to a human, at least 5 mg, at least 10 mg, at least 20 mg, at least 50 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 40 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 2000 mg, at least 3000 mg, at least 4000 mg, at least 5000 mg, at least 6000 mg, at least 7000 mg, at least 8000 mg, at least 9000 mg, or at least 10000 mg of the antibody may be administered. In some embodiments, when the antibody of the present invention is administered to a human, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 40 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 2000 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, or 10000 mg of the antibody may be administered.

[0084] In some embodiments, when the antibody of the present invention is administered to a human, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0. about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, about 25.0 mg / kg, about 26.0 mg / kg, about 27.0 mg / kg, about 28.0 mg / kg, about 29.0 mg / kg, about 30.0 mg / kg, about 31.0 mg / kg, about 32.0 mg / kg, about 33.0 mg / kg, about 34.0 mg / kg, about 35.0 mg / kg, about 36.0 mg / kg, about 37.0 mg / kg, about 38.0 mg / kg, about 39.0 mg / kg, about 40.0 mg / kg, about 41.0 mg / kg, about 42.0 mg / kg, about 43.0 mg / kg, about 44.0 mg / kg, about 45.0 mg / kg, about 46.0 mg / kg, about 47.0 mg / kg, about 48.0 mg / kg, about 49.0 mg / kg, or about 50.0 mg / kg of the antibody may be administered once or several times during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0. about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, about 25.0 mg / kg, about 26.0 mg / kg, about 27.0 mg / kg, about 28.0 mg / kg, about 29.0 mg / kg, about 30.0 mg / kg, about 31.0 mg / kg, about 32.0 mg / kg, about 33.0 mg / kg, about 34.0 mg / kg, about 35.0 mg / kg, about 36.0 mg / kg, about 37.0 mg / kg, about 38.0 mg / kg, about 39.0 mg / kg, about 40.0 mg / kg, about 41.0 mg / kg, about 42.0 mg / kg, about 43.0 mg / kg, about 44.0 mg / kg, about 45.0 mg / kg, about 46.0 mg / kg, about 47.0 mg / kg, about 48.0 mg / kg, about 49.0 mg / kg, or about 50.0 mg / kg of the antibody may be administered once during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0. about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, about 25.0 mg / kg, about 26.0 mg / kg, about 27.0 mg / kg, about 28.0 mg / kg, about 29.0 mg / kg, about 30.0 mg / kg, about 31.0 mg / kg, about 32.0 mg / kg, about 33.0 mg / kg, about 34.0 mg / kg, about 35.0 mg / kg, about 36.0 mg / kg, about 37.0 mg / kg, about 38.0 mg / kg, about 39.0 mg / kg, about 40.0 mg / kg, about 41.0 mg / kg, about 42.0 mg / kg, about 43.0 mg / kg, about 44.0 mg / kg, about 45.0 mg / kg, about 46.0 mg / kg, about 47.0 mg / kg, about 48.0 mg / kg, about 49.0 mg / kg, or about 50.0 mg / kg of the antibody may be administered at least twice during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0. about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, about 25.0 mg / kg, about 26.0 mg / kg, about 27.0 mg / kg, about 28.0 mg / kg, about 29.0 mg / kg, about 30.0 mg / kg, about 31.0 mg / kg, about 32.0 mg / kg, about 33.0 mg / kg, about 34.0 mg / kg, about 35.0 mg / kg, about 36.0 mg / kg, about 37.0 mg / kg, about 38.0 mg / kg, about 39.0 mg / kg, about 40.0 mg / kg, about 41.0 mg / kg, about 42.0 mg / kg, about 43.0 mg / kg, about 44.0 mg / kg, about 45.0 mg / kg, about 46.0 mg / kg, about 47.0 mg / kg, about 48.0 mg / kg, about 49.0 mg / kg, or about 50.0 mg / kg of the antibody may be administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, or once per year.

[0085] In some embodiments, when the antibody of the present invention is administered to a human, at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1.0 mg / kg, at least about 2.0 mg / kg, at least about 3.0 mg / kg, at least about 4.0 mg / kg, at least about 5.0 mg / kg, at least about 6.0. at least about 7.0 mg / kg, at least about 8.0 mg / kg, at least about 9.0 mg / kg, at least about 10.0 mg / kg, at least about 11.0 mg / kg, at least about 12.0 mg / kg, at least about 13.0 mg / kg, at least about 14.0 mg / kg, at least about 15.0 mg / kg, at least about 16.0 mg / kg, at least about 17.0 mg / kg, at least about 18.0 mg / kg, at least about 19.0 mg / kg, at least about 20.0 mg / kg, at least about 21.0 mg / kg, at least about 22.0 mg / kg, at least about 23.0 mg / kg, at least about 24.0 mg / kg, at least about 25.0 mg / kg, at least about 26.0 mg / kg, at least about 27.0 mg / kg, at least about 28.0 mg / kg, at least about 29.0 mg / kg, at least about 30.0 mg / kg, at least about 31.0 mg / kg, at least about 32.0 mg / kg, at least about 33.0 mg / kg, at least about 34.0 mg / kg, at least about 35.0 mg / kg, at least about 36.0 mg / kg, at least about 37.0 mg / kg, at least about 38.0 mg / kg, at least about 39.0 mg / kg, at least about 40.0 mg / kg, at least about 41.0 mg / kg, at least about 42.0 mg / kg, at least about 43.0 mg / kg, at least about 44.0 mg / kg, at least about 45.0 mg / kg, at least about 46.0 mg / kg, at least about 47.0 mg / kg, at least about 48.0 mg / kg, at least about 49.0 mg / kg, or at least about 50.0 mg / kg of the antibody may be administered once or several times during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1.0 mg / kg, at least about 2.0 mg / kg, at least about 3.0 mg / kg, at least about 4.0 mg / kg, at least about 5.0 mg / kg, at least about 6.0. at least about 7.0 mg / kg, at least about 8.0 mg / kg, at least about 9.0 mg / kg, at least about 10.0 mg / kg, at least about 11.0 mg / kg, at least about 12.0 mg / kg, at least about 13.0 mg / kg, at least about 14.0 mg / kg, at least about 15.0 mg / kg, at least about 16.0 mg / kg, at least about 17.0 mg / kg, at least about 18.0 mg / kg, at least about 19.0 mg / kg, at least about 20.0 mg / kg, at least about 21.0 mg / kg, at least about 22.0 mg / kg, at least about 23.0 mg / kg, at least about 24.0 mg / kg, at least about 25.0 mg / kg, at least about 26.0 mg / kg, at least about 27.0 mg / kg, at least about 28.0 mg / kg, at least about 29.0 mg / kg, at least about 30.0 mg / kg, at least about 31.0 mg / kg, at least about 32.0 mg / kg, at least about 33.0 mg / kg, at least about 34.0 mg / kg, at least about 35.0 mg / kg, at least about 36.0 mg / kg, at least about 37.0 mg / kg, at least about 38.0 mg / kg, at least about 39.0 mg / kg, at least about 40.0 mg / kg, at least about 41.0 mg / kg, at least about 42.0 mg / kg, at least about 43.0 mg / kg, at least about 44.0 mg / kg, at least about 45.0 mg / kg, at least about 46.0 mg / kg, at least about 47.0 mg / kg, at least about 48.0 mg / kg, at least about 49.0 mg / kg, or at least about 50.0 mg / kg of the antibody may be administered once during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1.0 mg / kg, at least about 2.0 mg / kg, at least about 3.0 mg / kg, at least about 4.0 mg / kg, at least about 5.0 mg / kg, at least about 6.0. at least about 7.0 mg / kg, at least about 8.0 mg / kg, at least about 9.0 mg / kg, at least about 10.0 mg / kg, at least about 11.0 mg / kg, at least about 12.0 mg / kg, at least about 13.0 mg / kg, at least about 14.0 mg / kg, at least about 15.0 mg / kg, at least about 16.0 mg / kg, at least about 17.0 mg / kg, at least about 18.0 mg / kg, at least about 19.0 mg / kg, at least about 20.0 mg / kg, at least about 21.0 mg / kg, at least about 22.0 mg / kg, at least about 23.0 mg / kg, at least about 24.0 mg / kg, at least about 25.0 mg / kg, at least about 26.0 mg / kg, at least about 27.0 mg / kg, at least about 28.0 mg / kg, at least about 29.0 mg / kg, at least about 30.0 mg / kg, at least about 31.0 mg / kg, at least about 32.0 mg / kg, at least about 33.0 mg / kg, at least about 34.0 mg / kg, at least about 35.0 mg / kg, at least about 36.0 mg / kg, at least about 37.0 mg / kg, at least about 38.0 mg / kg, at least about 39.0 mg / kg, at least about 40.0 mg / kg, at least about 41.0 mg / kg, at least about 42.0 mg / kg, at least about 43.0 mg / kg, at least about 44.0 mg / kg, at least about 45.0 mg / kg, at least about 46.0 mg / kg, at least about 47.0 mg / kg, at least about 48.0 mg / kg, at least about 49.0 mg / kg, or at least about 50.0 mg / kg of the antibody may be administered at least twice during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1.0 mg / kg, at least about 2.0 mg / kg, at least about 3.0 mg / kg, at least about 4.0 mg / kg, at least about 5.0 mg / kg, at least about 6.0. at least about 7.0 mg / kg, at least about 8.0 mg / kg, at least about 9.0 mg / kg, at least about 10.0 mg / kg, at least about 11.0 mg / kg, at least about 12.0 mg / kg, at least about 13.0 mg / kg, at least about 14.0 mg / kg, at least about 15.0 mg / kg, at least about 16.0 mg / kg, at least about 17.0 mg / kg, at least about 18.0 mg / kg, at least about 19.0 mg / kg, at least about 20.0 mg / kg, at least about 21.0 mg / kg, at least about 22.0 mg / kg, at least about 23.0 mg / kg, at least about 24.0 mg / kg, at least about 25.0 mg / kg, at least about 26.0 mg / kg, at least about 27.0 mg / kg, at least about 28.0 mg / kg, at least about 29.0 mg / kg, at least about 30.0 mg / kg, at least about 31.0 mg / kg, at least about 32.0 mg / kg, at least about 33.0 mg / kg, at least about 34.0 mg / kg, at least about 35.0 mg / kg, at least about 36.0 mg / kg, at least about 37.0 mg / kg, at least about 38.0 mg / kg, at least about 39.0 mg / kg, at least about 40.0 mg / kg, at least about 41.0 mg / kg, at least about 42.0 mg / kg, at least about 43.0 mg / kg, at least about 44.0 mg / kg, at least about 45.0 mg / kg, at least about 46.0 mg / kg, at least about 47.0 mg / kg, at least about 48.0 mg / kg, at least about 49.0 mg / kg, or at least about 50.0 mg / kg of the antibody may be administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, or once per year.

[0086] In some embodiments, when the antibody of the present invention is administered to a human, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, at least 0.5 mg / kg, at least 0.6 mg / kg, at least 0.7 mg / kg, at least 0.8 mg / kg, at least 0.9 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0. at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10.0 mg / kg, at least 11.0 mg / kg, at least 12.0 mg / kg, at least 13.0 mg / kg, at least 14.0 mg / kg, at least 15.0 mg / kg, at least 16.0 mg / kg, at least 17.0 mg / kg, at least 18.0 mg / kg, at least 19.0 mg / kg, at least 20.0 mg / kg, at least 21.0 mg / kg, at least 22.0 mg / kg, at least 23.0 mg / kg, at least 24.0 mg / kg, at least 25.0 mg / kg, at least 26.0 mg / kg, at least 27.0 mg / kg, at least 28.0 mg / kg, at least 29.0 mg / kg, at least 30.0 mg / kg, at least 31.0 mg / kg, at least 32.0 mg / kg, at least 33.0 mg / kg, at least 34.0 mg / kg, at least 35.0 mg / kg, at least 36.0 mg / kg, at least 37.0 mg / kg, at least 38.0 mg / kg, at least 39.0 mg / kg, at least 40.0 mg / kg, at least 41.0 mg / kg, at least 42.0 mg / kg, at least 43.0 mg / kg, at least 44.0 mg / kg, at least 45.0 mg / kg, at least 46.0 mg / kg, at least 47.0 mg / kg, at least 48.0 mg / kg, at least 49.0 mg / kg, or at least 50.0 mg / kg of the antibody may be administered once or several times during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, at least 0.5 mg / kg, at least 0.6 mg / kg, at least 0.7 mg / kg, at least 0.8 mg / kg, at least 0.9 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0. at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10.0 mg / kg, at least 11.0 mg / kg, at least 12.0 mg / kg, at least 13.0 mg / kg, at least 14.0 mg / kg, at least 15.0 mg / kg, at least 16.0 mg / kg, at least 17.0 mg / kg, at least 18.0 mg / kg, at least 19.0 mg / kg, at least 20.0 mg / kg, at least 21.0 mg / kg, at least 22.0 mg / kg, at least 23.0 mg / kg, at least 24.0 mg / kg, at least 25.0 mg / kg, at least 26.0 mg / kg, at least 27.0 mg / kg, at least 28.0 mg / kg, at least 29.0 mg / kg, at least 30.0 mg / kg, at least 31.0 mg / kg, at least 32.0 mg / kg, at least 33.0 mg / kg, at least 34.0 mg / kg, at least 35.0 mg / kg, at least 36.0 mg / kg, at least 37.0 mg / kg, at least 38.0 mg / kg, at least 39.0 mg / kg, at least 40.0 mg / kg, at least 41.0 mg / kg, at least 42.0 mg / kg, at least 43.0 mg / kg, at least 44.0 mg / kg, at least 45.0 mg / kg, at least 46.0 mg / kg, at least 47.0 mg / kg, at least 48.0 mg / kg, at least 49.0 mg / kg, or at least 50.0 mg / kg of the antibody may be administered once during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, at least 0.5 mg / kg, at least 0.6 mg / kg, at least 0.7 mg / kg, at least 0.8 mg / kg, at least 0.9 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0. at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10.0 mg / kg, at least 11.0 mg / kg, at least 12.0 mg / kg, at least 13.0 mg / kg, at least 14.0 mg / kg, at least 15.0 mg / kg, at least 16.0 mg / kg, at least 17.0 mg / kg, at least 18.0 mg / kg, at least 19.0 mg / kg, at least 20.0 mg / kg, at least 21.0 mg / kg, at least 22.0 mg / kg, at least 23.0 mg / kg, at least 24.0 mg / kg, at least 25.0 mg / kg, at least 26.0 mg / kg, at least 27.0 mg / kg, at least 28.0 mg / kg, at least 29.0 mg / kg, at least 30.0 mg / kg, at least 31.0 mg / kg, at least 32.0 mg / kg, at least 33.0 mg / kg, at least 34.0 mg / kg, at least 35.0 mg / kg, at least 36.0 mg / kg, at least 37.0 mg / kg, at least 38.0 mg / kg, at least 39.0 mg / kg, at least 40.0 mg / kg, at least 41.0 mg / kg, at least 42.0 mg / kg, at least 43.0 mg / kg, at least 44.0 mg / kg, at least 45.0 mg / kg, at least 46.0 mg / kg, at least 47.0 mg / kg, at least 48.0 mg / kg, at least 49.0 mg / kg, or at least 50.0 mg / kg of the antibody may be administered at least twice during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, at least 0.5 mg / kg, at least 0.6 mg / kg, at least 0.7 mg / kg, at least 0.8 mg / kg, at least 0.9 mg / kg, at least 1.0 mg / kg, at least 2.0 mg / kg, at least 3.0 mg / kg, at least 4.0 mg / kg, at least 5.0 mg / kg, at least 6.0. at least 7.0 mg / kg, at least 8.0 mg / kg, at least 9.0 mg / kg, at least 10.0 mg / kg, at least 11.0 mg / kg, at least 12.0 mg / kg, at least 13.0 mg / kg, at least 14.0 mg / kg, at least 15.0 mg / kg, at least 16.0 mg / kg, at least 17.0 mg / kg, at least 18.0 mg / kg, at least 19.0 mg / kg, at least 20.0 mg / kg, at least 21.0 mg / kg, at least 22.0 mg / kg, at least 23.0 mg / kg, at least 24.0 mg / kg, at least 25.0 mg / kg, at least 26.0 mg / kg, at least 27.0 mg / kg, at least 28.0 mg / kg, at least 29.0 mg / kg, at least 30.0 mg / kg, at least 31.0 mg / kg, at least 32.0 mg / kg, at least 33.0 mg / kg, at least 34.0 mg / kg, at least 35.0 mg / kg, at least 36.0 mg / kg, at least 37.0 mg / kg, at least 38.0 mg / kg, at least 39.0 mg / kg, at least 40.0 mg / kg, at least 41.0 mg / kg, at least 42.0 mg / kg, at least 43.0 mg / kg, at least 44.0 mg / kg, at least 45.0 mg / kg, at least 46.0 mg / kg, at least 47.0 mg / kg, at least 48.0 mg / kg, at least 49.0 mg / kg, or at least 50.0 mg / kg of the antibody may be administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, or once per year.

[0087] In some embodiments, when the antibody of the present invention is administered to a human, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0. 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10.0 mg / kg, 11.0 mg / kg, 12.0 mg / kg, 13.0 mg / kg, 14.0 mg / kg, 15.0 mg / kg, 16.0 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, 25.0 mg / kg, 26.0 mg / kg, 27.0 mg / kg, 28.0 mg / kg, 29.0 mg / kg, 30.0 mg / kg, 31.0 mg / kg, 32.0 mg / kg, 33.0 mg / kg, 34.0 mg / kg, 35.0 mg / kg, 36.0 mg / kg, 37.0 mg / kg, 38.0 mg / kg, 39.0 mg / kg, 40.0 mg / kg, 41.0 mg / kg, 42.0 mg / kg, 43.0 mg / kg, 44.0 mg / kg, 45.0 mg / kg, 46.0 mg / kg, 47.0 mg / kg, 48.0 mg / kg, 49.0 mg / kg, or 50.0 mg / kg of the antibody may be administered once or several times during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0. 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10.0 mg / kg, 11.0 mg / kg, 12.0 mg / kg, 13.0 mg / kg, 14.0 mg / kg, 15.0 mg / kg, 16.0 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, 25.0 mg / kg, 26.0 mg / kg, 27.0 mg / kg, 28.0 mg / kg, 29.0 mg / kg, 30.0 mg / kg, 31.0 mg / kg, 32.0 mg / kg, 33.0 mg / kg, 34.0 mg / kg, 35.0 mg / kg, 36.0 mg / kg, 37.0 mg / kg, 38.0 mg / kg, 39.0 mg / kg, 40.0 mg / kg, 41.0 mg / kg, 42.0 mg / kg, 43.0 mg / kg, 44.0 mg / kg, 45.0 mg / kg, 46.0 mg / kg, 47.0 mg / kg, 48.0 mg / kg, 49.0 mg / kg, or 50.0 mg / kg of the antibody may be administered once during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0. 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10.0 mg / kg, 11.0 mg / kg, 12.0 mg / kg, 13.0 mg / kg, 14.0 mg / kg, 15.0 mg / kg, 16.0 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, 25.0 mg / kg, 26.0 mg / kg, 27.0 mg / kg, 28.0 mg / kg, 29.0 mg / kg, 30.0 mg / kg, 31.0 mg / kg, 32.0 mg / kg, 33.0 mg / kg, 34.0 mg / kg, 35.0 mg / kg, 36.0 mg / kg, 37.0 mg / kg, 38.0 mg / kg, 39.0 mg / kg, 40.0 mg / kg, 41.0 mg / kg, 42.0 mg / kg, 43.0 mg / kg, 44.0 mg / kg, 45.0 mg / kg, 46.0 mg / kg, 47.0 mg / kg, 48.0 mg / kg, 49.0 mg / kg, or 50.0 mg / kg of the antibody may be administered at least twice during 1 to 180 days. In some embodiments, when the antibody of the present invention is administered to a human, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0. 7.0 mg / kg, 8.0 mg / kg, 9.0 mg / kg, 10.0 mg / kg, 11.0 mg / kg, 12.0 mg / kg, 13.0 mg / kg, 14.0 mg / kg, 15.0 mg / kg, 16.0 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, 25.0 mg / kg, 26.0 mg / kg, 27.0 mg / kg, 28.0 mg / kg, 29.0 mg / kg, 30.0 mg / kg, 31.0 mg / kg, 32.0 mg / kg, 33.0 mg / kg, 34.0 mg / kg, 35.0 mg / kg, 36.0 mg / kg, 37.0 mg / kg, 38.0 mg / kg, 39.0 mg / kg, 40.0 mg / kg, 41.0 mg / kg, 42.0 mg / kg, 43.0 mg / kg, 44.0 mg / kg, 45.0 mg / kg, 46.0 mg / kg, 47.0 mg / kg, 48.0 mg / kg, 49.0 mg / kg, or 50.0 mg / kg of the antibody may be administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, or once per year.

[0088] Examples of the form of the pharmaceutical composition of the present invention can include injection preparations including preparations for infusion, suppositories, nasal agents, sublingual agents, and transdermal absorbents. Examples of the route of administration include oral administration or parenteral administration. Examples of parenteral administration include intravenous, intraarterial, intramuscular, rectal, transmucosal or intramucosal, and intradermal administrations.

[0089] The antibody of the present invention or a pharmaceutical composition comprising them can be provided in combination with a biomarker for selecting patients to which they are administered. Such an antibody or a pharmaceutical composition may also be provided as a kit in combination with a means for detecting a biomarker, or, such an antibody or a pharmaceutical composition may be provided separately with a biomarker. Through the use of a biomarker, the antibody or the pharmaceutical composition of the present invention can be administered to a patient group for whom the antibody of the present invention is expected to be highly effective.

[0090] The present disclosure provides a pharmaceutical composition for use in the treatment of diseases and disorders associated with CD147, such as cancer, in a subject, wherein the pharmaceutical composition comprises an anti-CD147 antibody disclosed herein as an active ingredient.

[0091] Any of the pharmaceutical compositions disclosed herein can be used for treating diseases and disorders associated with CD147, such as cancer. Methods of Treatment

[0092] The present disclosure provides methods of treating diseases and disorders associated with CD147, such as cancer. Additionally, the present disclosure provides uses of the disclosed anti-CD147 antibodies for treating diseases and disorders associated with CD147, such as cancer.

[0093] In general, the treatments disclosed herein comprise administering to a subject a therapeutically effective amount of an anti-CD147 antibody (e.g., #110H1L4hIgG4P). In particular, the present disclosure provides methods of treating cancer, comprising administering to a subject with cancer an anti-CD147 antibody (e.g., #110H1L4hIgG4P) disclosed herein.

[0094] An effective amount of a disclosed anti-CD147 antibody can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the anti-CD147 antibodies of the present disclosure for any particular subject may depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. Typically, dosage-effect relationships from in vitro and / or in vivo tests initially can provide useful guidance on the proper doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro.

[0095] Administration of the anti-CD147 antibody (e.g., #110H1L4hIgG4P) may be intravenous, subcutaneous, intramuscular, intradermal, or intraperitoneal. In general, injections or infusions of the antibody will be the most common route of administration. Administration may comprise a single dose or repeated dosing over a period of treatment.

[0096] That is, the anti-CD147 antibody of the present invention can be selectively used as an anti-cancer drug, and as a result, can delay development of cancer cells, inhibit growth thereof, and further kill the cancer cells. This can allow cancer patients to be free from symptoms caused by cancer or achieve improvement in QOL of cancer patients and attains a therapeutic effect by sustaining the lives of the cancer patients. Even if the anti-CD147 antibody of the resent invention does not accomplish killing cancer cells, it can achieve higher QOL of cancer patients while achieving their longer-term survival, by inhibiting or controlling the growth of cancer cells.

[0097] In such drug therapy, it can be used as a drug alone as well as a drug in combination with an additional therapy in adjuvant therapy and can be combined with radiotherapy, hormone therapy, or the like. Furthermore, it can also be used as a drug for drug therapy in neoadjuvant therapy.

[0098] In some embodiments of the disclosed methods and uses, an anti-CD147 antibody is administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed. In some embodiments of the disclosed methods and uses, an anti-CD147 antibody is administered once every two weeks. In some embodiments of the disclosed methods and uses, an anti-CD147 antibody is administered once every four weeks.

[0099] In some embodiments of the disclosed methods and uses, the duration of treatment is until disease progression or unacceptable toxicity occurs, for example, about one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about one year, about two years, about three years, about four years, about five years, or as needed.

[0100] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 10.0 mg / kg, about 12.0 mg / kg, about 20.0 mg / kg, or about 40.0 mg / kg daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed.

[0101] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg daily. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg every other day. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg twice per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg three times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg four times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg five times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg six times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every two weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every three weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every four weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every five weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every six weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every seven weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every eight weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every nine weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every 10 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every 11 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every 12 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg twice per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg as needed.

[0102] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg daily. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg every other day. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg twice per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg three times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg four times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg five times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg six times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every two weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every three weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every four weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every five weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every six weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every seven weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every eight weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every nine weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every 10 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every 11 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every 12 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg twice per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg as needed.

[0103] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg daily. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg every other day. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg twice per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg three times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg four times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg five times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg six times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every two weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every three weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every four weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every five weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every six weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every seven weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every eight weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every nine weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every 10 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every 11 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every 12 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg twice per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg as needed.

[0104] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg daily. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg every other day. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg twice per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg three times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg four times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg five times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg six times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every two weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every three weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every four weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every five weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every six weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every seven weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every eight weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every nine weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every 10 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every 11 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every 12 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg twice per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg as needed.

[0105] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg daily. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg every other day. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg twice per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg three times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg four times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg five times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg six times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every two weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every three weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every four weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every five weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every six weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every seven weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every eight weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every nine weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every 10 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every 11 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every 12 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg twice per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg as needed.

[0106] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg daily. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg every other day. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg twice per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg three times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg four times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg five times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg six times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every two weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every three weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every four weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every five weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every six weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every seven weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every eight weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every nine weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every 10 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every 11 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every 12 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg twice per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg as needed.

[0107] In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg daily. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg every other day. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg twice per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg three times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg four times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg five times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg six times per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once per week. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every two weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every three weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every four weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every five weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every six weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every seven weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every eight weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every nine weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every 10 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every 11 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every 12 weeks. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg twice per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once per year. In some embodiments of the disclosed methods and uses, the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg as needed.

[0108] The present disclosure provides uses of an anti-CD147 antibody in the manufacture of a medicament for the treatment of diseases and disorders associated with CD147, such as cancer.

[0109] The anti-CD147 antibody of the present invention exhibits strong antitumor efficacy and is useful as a remedy for treating a tumor or cancer. The anti-CD147 antibody of the present invention exhibits excellent antitumor efficacy on gemcitabine-resistant cancer cells and cancer cells having low sensitivity to sorafenib. The anti-CD147 antibody of the present invention exhibited significantly stronger efficacy on chronic myeloid leukemia cells, than those of imatinib.

[0110] Examples of tumors that can be treated using the anti-CD147 antibody of the present invention or a drug comprising the antibody are not particularly limited, as long as they are tumors expressing CD147. Such cancers include but are not limited to pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, breast cancer, uterine cancer, ovarian cancer, lung cancer, thyroid cancer, skin cancer, head and neck cancer, esophageal cancer, sarcoma, prostate cancer, bladder cancer, brain tumor, gastrointestinal stromal tumor (GIST), leukemia (for example, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL) or acute lymphocytic leukemia (ALL)), lymphoma or malignant lymphoma (for example, B-cell lymphoma, non-Hodgkin's lymphoma or diffuse large B-cell lymphoma (DLBCL)), and preferably, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), malignant lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma or diffuse large B-cell lymphoma (DLBCL). Other examples of tumors that can be treated using the anti-CD147 antibody of the present invention include hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), renal cell carcinoma (RCC), squamous cell non-small cell lung cancer (sq-NSCLC), head and neck squamous cell carcinoma (HNSCC) and squamous esophageal cancer. In some embodiments, the cancer to be treated is HCC. In some embodiments, the cancer to be treated is CRC. In some embodiments, the cancer to be treated is PDAC. In some embodiments, the cancer to be treated is RCC. In some embodiments, the cancer to be treated is sq-NSCLC. In some embodiments, the cancer to be treated is HNSCC.

[0111] Examples of tumors that can be treated using the antibody of the present invention or a drug comprising the antibody include SMAD-positive CD147-expressing tumors. Examples of SMAD-positive CD147-expressing tumors include SMAD-positive CD147-expressing liver cancer and pancreatic cancer. The anti-CD147 antibody of the present invention or a drug comprising the antibody is administered to, preferably, patients confirmed for the expression of CD147 and / or SMAD. Examples of SMAD include, preferably, SMAD2, SMAD3 and / or SMAD4, and more preferably SMAD4. Preferably, together with confirmation of the expression of SMAD4, the expression of at least one of SMAD2 and SMAD3 is confirmed.

[0112] Alternatively, examples of a tumor that can be treated with the antibody of the present invention or a drug comprising the antibody include a tumor exhibiting decreased expression of KLF5 or lacking the expression of KLF5. Examples of a tumor exhibiting decreased expression of KLF5 or lacking the expression of KLF5 include liver cancer, ALL, lymphoma, gastrointestinal stromal tumor (GIST), skin cancer, sarcoma, AML, and renal cancer. The anti-CD147 antibody of the present invention or a drug comprising the antibody is preferably administered to a patient confirmed to exhibit decreased expression of KLF5 or lack the expression of KLF5.

[0113] The anti-CD147 antibody of the present invention can also be administered with two, three, or more other therapeutic agents depending on the purpose of treatment. The other therapeutic agents can be encapsulated in the same preparation and administered simultaneously. Other therapeutic agents and the anti-CD147 antibody may also be encapsulated in the same preparation and thus can be administered simultaneously. The anti-CD147 antibody and other therapeutic agents may be separately encapsulated in preparations and can then be administered simultaneously. Further, other drugs and the anti-CD147 antibody can also be administered separately, specifically the drugs can be administered before or after the administration of the anti-CD147 antibody. Specifically, after administration of other therapeutic agents, a therapeutic agent comprising the anti-CD147 antibody or an antigen-binding fragment of the antibody as an active component is administered, or, after administration of a therapeutic agent comprising the anti-CD147 antibody or an antigen-binding fragment of the antibody as an active component, other therapeutic agents may be administered.

[0114] The term “biological sample(s)” as used herein refers to a tissue, a liquid, and cells isolated from an individual and a mixture thereof, and examples thereof can include, but are not limited to, a tumor biopsy, spinal fluids, pleural fluids, intraperitoneal fluids, lymph, skin sections, blood, urine, feces, sputum, respiratory organs, intestinal tract, genitourinary organs, saliva, breast milk, digestive organs, and cells collected therefrom. Examples of the “biological sample(s)” include preferably a sample containing cancer cells, more preferably a tissue or cells obtained by excision or biopsy, or cells derived from a pleural fluid or an intraperitoneal fluid. Further preferred biological samples are samples containing cancer cells or cancerous tissue.

[0115] The “expression of SMAD4” can be detected or measured using the genome sequence, the gene expression or the protein expression of SMAD4 according to a method known by persons skilled in the art. Examples of such a method include RNA sequencing, microarray, genome sequencing, and immunoassay.

[0116] The “expression of KLF5” can be detected or measured using the genome sequence, the gene expression or the protein expression of KLF5 according to a method known by persons skilled in the art. Examples of such a method include IHC, RNA sequencing, microarray, genome sequencing, and immunoassay. The term “decreased expression of KLF5” means that when compared with a control (for example, the expression level in a healthy subject or the expression level in a non-cancerous tissue of the same patient), the expression level is found to be lower than that of the control. Alternatively, the degree of the decreased expression of KLF5 at which the responsiveness to cancer treatment resulting from the use of the antibody or the pharmaceutical composition of the present invention can be confirmed, can be determined by performing a method known by persons skilled in the art and appropriate clinical trials. For example, patients for which an effect can be obtained and patients for which no effect can be obtained are compared for KLF5 expression levels, thereby setting an appropriate threshold. Therefore, the term “decreased expression of KLF5” refers to an expression level lower than the thus determined threshold, for example.

[0117] In some embodiments, following treatment by one or more of the foregoing treatment methods described herein, a tumor in a subject is not increased in size. In some embodiments, following treatment by one or more of the foregoing treatment methods described herein, a tumor in a subject decreased in size. EXAMPLES OF EMBODIMENTS

[0118] The following examples are given to illustrate the present disclosure. It should be understood, however, that the disclosure is not to be limited to the specific conditions or details described in these examples.

[0119] Embodiment 1: A method for treating a disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a humanized anti-CD147 antibody, wherein the humanized anti-CD147 antibody comprises a light chain comprising that comprises a CDRL1 having the sequence RASQGISNYLN (SEQ ID NO: 5), a CDRL2 having the sequence YTSNLQS (SEQ ID NO: 6), and a CDRL3 having the sequence QQYDSSPRT (SEQ ID NO: 7); and a heavy chain that comprises a CDRH1 having the sequence GYTFTSDFMH (SEQ ID NO: 8), a CDRH2 having the sequence WIYPGDGDTE (SEQ ID NO: 9), and a CDRH3 having the sequence GRGYVMDA (SEQ ID NO: 10), wherein the pharmaceutical composition is administered to the subject at a dosage from about 0.5 mg / kg to about 50.0 mg / kg, and wherein the pharmaceutical composition is administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed.

[0120] Embodiment 2: The method of embodiment 1, wherein the anti-CD147 antibody comprises a heavy chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 12.

[0121] Embodiment 3: The method of embodiment 1, wherein the anti-CD147 antibody heavy chain amino acid sequence comprises SEQ ID NO: 12.

[0122] Embodiment 4: The method of any one of embodiments 1-3, wherein the anti-CD147 antibody comprises a light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11.

[0123] Embodiment 5: The method of embodiment 1, wherein the anti-CD147 antibody light chain amino acid sequence comprises SEQ ID NO: 11.

[0124] Embodiment 6: The method of any one of embodiments 1-5, wherein the pharmaceutical composition is administered to the subject at a dosage from about 1.0 mg / kg to about 40.0 mg / kg.

[0125] Embodiment 7: The method of any one of embodiments 1-6, wherein the pharmaceutical composition is administered to the subject at a dosage from about 3.0 mg / kg to about 40.0 mg / kg.

[0126] Embodiment 8: The method of any one of embodiments 1-5, wherein the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 10.0 mg / kg, about 12.0 mg / kg, about 15.0 mg / kg, about 20.0 mg / kg, or about 40.0 mg / kg.

[0127] Embodiment 9: The method of embodiment 8, wherein the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg.

[0128] Embodiment 10: The method of embodiment 8, wherein the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg.

[0129] Embodiment 11: The method of embodiment 8, wherein the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg.

[0130] Embodiment 12: The method of any one of embodiments 1-7, wherein the pharmaceutical composition is administered intravenously, subcutaneously, intraperitoneally, intramuscularly, intramedullary, intrathecally, intratumorally, or intraocularly.

[0131] Embodiment 13: The method of embodiment 12, wherein the pharmaceutical composition is administered intravenously.

[0132] Embodiment 14: The method of any one of embodiments 1-13, wherein the pharmaceutical composition is administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed.

[0133] Embodiment 15: The method of embodiment 14, wherein the pharmaceutical composition is administered once every two weeks.

[0134] Embodiment 16: The method of embodiment 14, wherein the pharmaceutical composition is administered once every four weeks.

[0135] Embodiment 17: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 10.0 mg / kg, about 12.0 mg / kg, about 20.0 mg / kg, or about 40.0 mg / kg once every four weeks.

[0136] Embodiment 18: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every four weeks.

[0137] Embodiment 19: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every four weeks.

[0138] Embodiment 20: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every four weeks.

[0139] Embodiment 21: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every four weeks.

[0140] Embodiment 22: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every four weeks.

[0141] Embodiment 23: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every four weeks.

[0142] Embodiment 24: The method of any one of embodiments 1-16, wherein the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every four weeks.

[0143] Embodiment 25: The method of any one of embodiments 1-24, wherein the disease is cancer.

[0144] Embodiment 26: The method of embodiment 25, wherein the cancer is selected from pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, breast cancer, uterine cancer, ovarian cancer, lung cancer, lymphoma, thyroid cancer, skin cancer, head and neck cancer, esophageal cancer, sarcoma, prostate cancer, bladder cancer, brain tumor, gastrointestinal stromal tumor (GIST), leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), malignant lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0145] Embodiment 27: The method of embodiment 25, wherein the cancer is selected from pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), malignant lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma or diffuse large B-cell lymphoma (DLBCL).

[0146] Embodiment 28: The method of embodiment 25, wherein the cancer is selected from hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), renal cell carcinoma (RCC), squamous cell non-small cell lung cancer (sq-NSCLC), head and neck squamous cell carcinoma (HNSCC), and squamous esophageal cancer.

[0147] Embodiment 29: The method of embodiment 28, wherein the cancer is PDAC.

[0148] Embodiment 30: The method of embodiment 25, wherein the cancer comprises a SMAD4-positive tumor or a tumor having a decreased expression level of or lacking the expression of KLF5.

[0149] Embodiment 31: The method of any one of embodiments 1-30, wherein the duration of treatment is about one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about one year, about two years, about three years, about four years, about five years, or as needed.

[0150] Embodiment 32: The method of any one of embodiments 1-31, wherein the anti-CD147 antibody is administered with two, three, or more other therapeutic agents either sequentially or concurrently.

[0151] Embodiment 33: The method of any one of embodiments 1-32, wherein following treatment, the size of a tumor in the subject is decreased.

[0152] Embodiment 34: The method of any one of embodiments 1-32, wherein following treatment, the size of a tumor in a subject is not increased.

[0153] Embodiment 35: The method of any one of embodiments 1-32, wherein following treatment, progression of tumor growth or formation is slowed. EXAMPLES

[0154] The examples discussed below are intended to be purely exemplary of the invention and should not be considered to limit the invention in any way. The examples are not intended to represent that the experiments below are all or the only experiments performed.

[0155] Example 1. Preparation of #110H1L4hIgG4P

[0156] #110H1L4hIgG4P (which is described in US20200362033A1) was prepared according to US20200362033A1, which is incorporated herein by reference in its entirety.

[0157] Briefly, humanized antibody light chains were constructed by connecting the variable region designed above with the human κ chain constant region and named #110L4h. SEQ ID NO: 11 represents the full-length amino acid sequence of light chain #110L4h. Humanized antibody heavy chains were constructed by connecting the variable region designed above with the human gamma chain constant region of IgG4P and named #110H1hIgG4P. SEQ ID NO: 12 represents the full-length amino acid sequence of #110H1hIgG4P. the humanized antibody #110H1L4hIgG4P was designed by combining the heavy chain of SEQ ID NO: 12 and the light chain SEQ ID NO: 11. The heavy chain and light chain amino acid sequences are shown below in Table 2. CDR sequences are shown in bold and underline.

[0158]

[0159] Example 2. Toxicity profile of #110H1L4hIgG4P in cynomolgus monkeys

[0160] To assess the general toxicity profile of #110H1L4hIgG4P, a 1-month intermittent dose toxicity study of #110H1L4hIgG4P was conducted in cynomolgus monkeys. #110H1L4hIgG4P was intravenously administered every two weeks (twice in total) at dose levels of 0, 10, 40, and 158.4 mg / kg to monkeys (3 monkeys / sex / group). During the study, clinical signs, body weight, food consumption, electrocardiogram, ophthalmology, urinalysis, hematology, lymphocyte subsets, blood chemistry, plasma cytokines, organ weight, necropsy, histopathology, and toxicokinetics were examined.

[0161] As a result of the administration of #110H1L4hIgG4P, no deaths or moribundity was observed at any dose levels. On electrocardiogram examination, prolonged QT and QTc were noted in 1 female at 158.4 mg / kg. The cytokine measurements revealed transient increases in IL-6 and MIP-1β at ≧ 10 mg / kg. Other than these changes, no treatment-related changes were noted.

[0162] In conclusion, #110H1L4hIgG4P was well-tolerated at up to 158.4 mg / kg, the maximum feasible dose, in monkeys.

[0163] Example 3. Pharmacological activity in xenograft model mice

[0164] A preclinical pharmacological study was conducted in xenograft model mice transplanted with a pancreatic cancer cell line, MIA PaCa-2 cells, by intravenous administration of #110H1L4hIgG4P. Receptor occupancy of CD147 in tumors was measured using flowcytometry of tumor cells prepared from the pancreatic cancer xenograft-tumors after administration of #110H1L4hIgG4P at 1 and 3 mg / kg on Day 1, 3, 7, 10 and 14 (n=3 / treatment). Tumor cells without antibody treatment was analyzed as a control using the same procedure as applied to analysis of #110H1L4hIgG4P -treated tumors. #110H1L4hIgG4P exhibited partial and potent antitumor activity at 1 and 3 mg / kg, respectively (FIG. 1). At these doses, receptor occupancy in tumors on the day after dosing was 18% (1 mg / kg) and 89% (3 mg / kg) (FIG. 2).

[0165] Example 4. CD147 expression in humans and monkeys

[0166] The protein expression levels of CD147 in hepatocytes and erythrocytes in cynomolgus monkeys and humans were quantified by a flow cytometer-based assay using QIFIKIT (Agilent) to determine species-specific differences. Freshly isolated monkey erythrocytes and hepatocytes were prepared from cynomolgus monkeys. Freshly isolated human-erythrocytes, hepatocytes were provided from suppliers. The results showed the expression levels of monkey CD147 in erythrocytes and hepatocytes were approximately 40000 and 100000 site / cells, respectively. Mean human CD147 sites per cell were determined to be approximately 300000 and 1000 for freshly isolated hepatocytes, and erythrocytes, respectively. Compared to the findings in monkeys, the expression level of CD147 in humans was lower in erythrocytes and higher in hepatocytes (FIG. 3).

[0167] Example 5. Pharmacokinetics and receptor occupancy in blood in cynomolgus monkeys

[0168] A pharmacokinetic study was conducted in male cynomolgus monkeys following single intravenous administration of #110H1L4hIgG4P at 0.3, 1, 3, 6, 10, 40 and 158.4 mg / kg. Blood samples were collected up to 28 days after administration in the groups receiving doses of 0.3, 1, 3, 6 and 10 mg / kg. In the groups receiving doses of 40 and 158.4 mg / kg, blood samples were collected up to 7 days after administration. #110H1L4hIgG4P concentrations in plasma were quantified using a ligand binding assay. In cynomolgus monkeys, the mean area under the plasma concentration-time curves up to infinity increased more than dose-proportionally from 1 to 158.4 mg / kg (FIG. 4).

[0169] CD147 receptor occupancy in blood was measured by a flow cytometry assay following a single intravenous administration of #110H1L4hIgG4P at 10 or 30 mg / kg in male cynomolgus monkeys (FIG. 5). Receptor occupancy in blood reached over 80% at 4 hours after administration of #110H1L4hIgG4P (10 mg / kg and 30 mg / kg), being sustained for 7 days (10 mg / kg) and 10 days (30 mg / kg), and then declined gradually until the last observed time point (day 49).

[0170] Example 6. Human pharmacokinetics-pharmacodynamics prediction by physiologically based pharmacokinetics model

[0171] A minimal physiologically based pharmacokinetic model for monkeys was constructed, incorporating target-mediated drug disposition in blood and leaky tissues including tumors and liver where CD147 expression is expected. This model utilized monkey pharmacokinetics, receptor occupancy, and CD147 expression levels in erythrocytes and hepatocytes (FIG. 6). Subsequently, pharmacokinetics and receptor occupancy profiles were predicted in humans for a single intravenous administration of #110H1L4hIgG4P. The physiological parameters were replaced with relevant human values (Cao Y, Jusko WJ. Incorporating target-mediated drug disposition in a minimal physiologically-based pharmacokinetic model for monoclonal antibodies. Journal of Pharmacokinetics and Pharmacodynamics. 2014;41:375-387). The CD147 expression levels in erythrocytes and hepatocytes were replaced with human values measured by a flow cytometer-based assay. The nonspecific clearance was scaled allometrically from monkeys to humans (Zhao J, Cao Y, Jusko WJ. Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model. Pharmaceutical Research. 2015; 32:3269-3281.). Other estimated parameters were assumed to be same between monkeys and humans.

[0172] The plasma concentration-time profiles of #110H1L4hIgG4P in human were simulated to have a longer half-life compared to monkeys due to the lower expression of CD147 on human erythrocytes (FIG. 7). Receptor occupancy in leaky tissue (including tumors) after single intravenous administration of #110H1L4hIgG4P to humans was estimated to reach 89% at 1 day after injection at 3 mg / kg (FIG. 8). Considering the receptor occupancy in the tumor at an effective dose was 89% in xenograft model mice, it was expected that an anti-tumor effect would be achieved at doses over 3 mg / kg in humans.

[0173] Example 7. Initial Phase 1 Clinical Study

[0174] This Phase 1 study is an open-label, multicenter, and first-in-human study which enrolls subjects with advanced solid tumors in Japan.

[0175] The study includes both a dose escalation phase and a dose expansion phase, as depicted in FIG 9.

[0176] #110H1L4hIgG4P is administered every 4 weeks at the dose levels as shown FIG. 9 in the dose escalation phase and at recommended doses for expansion (RDE)(s) in the dose expansion phase.

[0177] In the dose escalation phase, dose-limited toxicity (DLT) is assessed during DLT evaluation period (Cycle 1).

[0178] The primary objective of the dose escalation phase is to evaluate the safety and tolerability of #110H1L4hIgG4P and determine the maximum tolerated dose (MTD) and / or RDE(s).

[0179] The primary objective of the dose expansion phase is to evaluate the overall safety of #110H1L4hIgG4P at the RDE(s).

[0180] Secondary objectives include investigation of the antitumor activity of #110H1L4hIgG4P using RECIST ver.1.1, characterization of the pharmacokinetic (PK) profile of #110H1L4hIgG4P, and assessment of the immunogenicity of #110H1L4hIgG4P.

[0181] Exploratory objectives include investigation of antitumor activity by g-score that is a measurement to describe tumor growth rate and investigation of the antitumor activity of #110H1L4hIgG4P using modified RECIST.

[0182] Inclusion criteria include: subjects aged ≧ 18 years with histologically or cytologically documented, locally advanced, metastatic, or unresectable solid tumor; tumor refractory to standard treatment, subjects unable to tolerate standard treatment, or standard treatment not available; ≧ 1 measurable lesion per RECIST ver. 1.1; Eastern Cooperative Oncology Group performance status 0 or 1.

[0183] Exclusion criteria include: prior or current untreated CNS metastases, or prior leptomeningeal carcinomatosis; prior or current interstitial lung disease (ILD), or suspected ILD that cannot be excluded on imaging.

[0184] Patient assessments include echocardiogram or multigated acquisition scan, 12-lead electrocardiogram, adverse event (AE)s, PK, human anti-human antibodies, biomarkers, and tumor assessments at prespecified visits.

[0185] MTD and / or the RDE(s) are guided by the Bayesian logistic regression model along with escalation with overdose control principle.

[0186] Accelerated titration - treating a single subject at a dose level below pharmacologically active dose - is performed until any DLT and / or ≧ Grade 2 AE at least possibly related to #110H1L4hIgG4P (excluding infusion-related reactions) during cycle 1 is observed.

[0187] The efficacy endpoints are reported as listings only for the Dose-escalation Phase.

[0188] In dose expansion phase, the objective response rate and disease control rate are summarized with 95% confidence intervals using the Clopper-Pearson method; time to event variables including duration of response, progression-free survival, and overall survival will be summarized and presented graphically using the Kaplan Meier method.

[0189] Safety endpoints, PK parameters of #110H1L4hIgG4P, anti-#110H1L4hIgG4P antibody, and biomarkers are summarized using descriptive statistics. * * * *

[0190] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0191] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0192] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified.

[0193] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0194] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0195] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof, inclusive of the endpoints. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0196] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0197] Other embodiments are set forth in the following claims.

Claims

1. A method for treating a disease in a subject, comprising administering to the subject a pharmaceutical composition comprising a humanized anti-CD147 antibody, wherein the humanized anti-CD147 antibody comprises a light chain comprising that comprises a CDRL1 having the sequence RASQGISNYLN (SEQ ID NO: 5), a CDRL2 having the sequence YTSNLQS (SEQ ID NO: 6), and a CDRL3 having the sequence QQYDSSPRT (SEQ ID NO: 7); and a heavy chain that comprises a CDRH1 having the sequence GYTFTSDFMH (SEQ ID NO: 8), a CDRH2 having the sequence WIYPGDGDTE (SEQ ID NO: 9), and a CDRH3 having the sequence GRGYVMDA (SEQ ID NO: 10), wherein the pharmaceutical composition is administered to the subject at a dosage from about 0.5 mg / kg to about 50.0 mg / kg, and wherein the pharmaceutical composition is administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed.

2. The method of claim 1, wherein the anti-CD147 antibody comprises a heavy chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 12.

3. The method of claim 1, wherein the anti-CD147 antibody heavy chain amino acid sequence comprises SEQ ID NO: 12.

4. The method of any one of claims 1-3, wherein the anti-CD147 antibody comprises a light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11.

5. The method of claim 1, wherein the anti-CD147 antibody light chain amino acid sequence comprises SEQ ID NO: 11.

6. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage from about 1.0 mg / kg to about 40.0 mg / kg.

7. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage from about 3.0 mg / kg to about 40.0 mg / kg.

8. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 10.0 mg / kg, about 12.0 mg / kg, about 15.0 mg / kg, about 20.0 mg / kg, or about 40.0 mg / kg.

9. The method of claim 8, wherein the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg.

10. The method of claim 8, wherein the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg.

11. The method of claim 8, wherein the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg.

12. The method of claim 1, wherein the pharmaceutical composition is administered intravenously, subcutaneously, intraperitoneally, intramuscularly, intramedullary, intrathecally, intratumorally, or intraocularly.

13. The method of claim 12, wherein the pharmaceutical composition is administered intravenously.

14. The method of claim 1, wherein the pharmaceutical composition is administered daily, every other day, twice per week, three times per week, four times per week, five times per week, six times per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice per year, once per year, and / or as needed.

15. The method of claim 14, wherein the pharmaceutical composition is administered once every two weeks.

16. The method of claim 14, wherein the pharmaceutical composition is administered once every four weeks.

17. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 10.0 mg / kg, about 12.0 mg / kg, about 20.0 mg / kg, or about 40.0 mg / kg once every four weeks.

18. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 1.0 mg / kg once every four weeks.

19. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 3.0 mg / kg once every four weeks.

20. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 6.0 mg / kg once every four weeks.

21. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 10.0 mg / kg once every four weeks.

22. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 12.0 mg / kg once every four weeks.

23. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 20.0 mg / kg once every four weeks.

24. The method of claim 1, wherein the pharmaceutical composition is administered to the subject at a dosage of about 40.0 mg / kg once every four weeks.

25. The method of claim 1, wherein the disease is cancer.

26. The method of claim 25, wherein the cancer is selected from pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, breast cancer, uterine cancer, ovarian cancer, lung cancer, lymphoma, thyroid cancer, skin cancer, head and neck cancer, esophageal cancer, sarcoma, prostate cancer, bladder cancer, brain tumor, gastrointestinal stromal tumor (GIST), leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), malignant lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, and diffuse large B-cell lymphoma (DLBCL).

27. The method of claim 25, wherein the cancer is selected from pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, renal cancer, leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), malignant lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma or diffuse large B-cell lymphoma (DLBCL).

28. The method of claim 25, wherein the cancer is selected from hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), renal cell carcinoma (RCC), squamous cell non-small cell lung cancer (sq-NSCLC), head and neck squamous cell carcinoma (HNSCC), and squamous esophageal cancer.

29. The method of claim 28, wherein the cancer is PDAC.

30. The method of claim 25, wherein the cancer comprises a SMAD4-positive tumor or a tumor having a decreased expression level of or lacking the expression of KLF5.

31. The method of claim 1, wherein the duration of treatment is about one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about one year, about two years, about three years, about four years, about five years, or as needed.

32. The method of claim 1, wherein the anti-CD147 antibody is administered with two, three, or more other therapeutic agents either sequentially or concurrently.

33. The method of claim 1, wherein following treatment, the size of a tumor in the subject is decreased.

34. The method of claim 1, wherein following treatment, the size of a tumor in a subject is not increased.

35. The method of claim 1, wherein following treatment, progression of tumor growth or formation is slowed.

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