CN113925963B - Stable pharmaceutical formulation comprising anti-CD 147 monoclonal antibody - Google Patents
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Abstract
The application discloses a pharmaceutical preparation, which comprises an anti-CD 147 monoclonal antibody, a buffer solution and a protein protecting agent. The pharmaceutical preparation can maintain the stability of the anti-CD 147 monoclonal antibody for a long time, and has the advantages of simple auxiliary materials and stable medicine.
Description
Technical Field
The present application relates to pharmaceutical formulations, in particular to stable pharmaceutical formulations comprising anti-CD 147 monoclonal antibodies and methods of making the same.
Background
Studies have shown that CD147 molecules mediate a variety of biological functions during tumor progression: (1) promote tumor cell pseudopodia formation, spreading and adhesion; (2) promoting tumor cell motility; (3) Promoting VEGF expression of tumor endothelial cells and promoting tumor neovascularization; (4) affecting downstream molecule expression; (5) Inhibiting apoptosis of tumor cells induced by endoplasmic reticulum stress and reduction of sensitivity to chemical drugs; (6) influencing EMT formation via TGF- β1-slot signaling pathways; (7) involvement in T cell activation and immune synapse formation; (8) Promoting tumor cell invasion and metastasis (Zhang DW et al, J hepatol.2012; chen YK et al, PLoS One,7 (7), 2012; tang J et al, cell Death Differ,19 (11), 2012; li Y et al, J Biol Chem,287 (7), 2012; wu J et al, oncogene,2011; zhao P et al, hepatology,54 (6), 2011; zhao P et al, cancer Sci.101 (2), 2010; gou XC et al, cancer Sci.100 (5), 2009; chen YK et al, cancer Letters,278 (1), 2009).
The HcHAb18 monoclonal antibody is a humanized modified chimeric IgG1 monoclonal antibody, can specifically bind to CD147 molecules on the surfaces of epithelial tumor tissue cells such as lung cancer and the like, and blocks the biological effect mediated by the molecules, thereby inhibiting the growth and invasion and metastasis of tumor cells.
Because antibody molecules have complex protein multi-stage structures and tend to physically bind together, possibly resulting in undesired immune responses, or may clog syringes or pumps during administration to be unsafe to patients, one of the long-standing problems with liquid formulations of antibodies is stability problems caused by aggregation, whether storage or clinical use is relatively inconvenient, whereas freeze-drying techniques can uniformly fix antibodies in the formulation, reducing aggregation of antibodies, and thus improving antibody stability. However, too many excipients in the formulation tend to produce undesirable toxic side effects, and therefore, there is a need for a pharmaceutical formulation of an anti-CD 147 antibody (e.g., hcHAb18 monoclonal antibody) that is simple but still stable with respect to the excipients.
Summary of The Invention
The application provides a stable pharmaceutical formulation comprising an anti-CD 147 monoclonal antibody, which has the advantage of simple adjuvant and can remain homogeneous and stable for a long period of time.
In one aspect, the application provides a pharmaceutical formulation comprising an anti-CD 147 monoclonal antibody, a buffer solution and a protein protectant, wherein the concentration of the anti-CD 147 monoclonal antibody is 1-40 mg/ml, the concentration of the buffer solution is 5-50 mmol/L, the concentration of the protein protectant is 10-200 mg/ml, wherein the buffer solution is succinic acid buffer solution, histidine buffer solution or citric acid buffer solution, and the protein protectant is sucrose, trehalose or a combination thereof.
In certain embodiments, the anti-CD 147 monoclonal antibody comprises the amino acid sequence set forth in SEQ ID NO:1 and/or the heavy chain of the amino acid sequence shown as SEQ ID NO:2, and a light chain of the amino acid sequence shown in FIG. 2.
In certain embodiments, the anti-CD 147 monoclonal antibody is present in the pharmaceutical formulation at a concentration of 10 to 30mg/ml.
In certain embodiments, the concentration of the anti-CD 147 monoclonal antibody in the pharmaceutical formulation is 20mg/ml.
In certain embodiments, the buffer is a histidine buffer.
In certain embodiments, the histidine buffer is present in the pharmaceutical formulation at a concentration of 5 to 15mmol/L.
In certain embodiments, the histidine buffer is present at a concentration of 10mmol/L in the pharmaceutical formulation.
In certain embodiments, the protein protectant is sucrose.
In certain embodiments, the sucrose is present in the pharmaceutical formulation at a concentration of 80 to 120mg/ml.
In certain embodiments, the sucrose is present in the pharmaceutical formulation at a concentration of 100mg/ml.
In certain embodiments, the pharmaceutical formulation consists of 20mg/mL of anti-CD 147 monoclonal antibody, 10mmol/L histidine buffer, and 100mg/mL sucrose.
In certain embodiments, the pharmaceutical formulation is in lyophilized form.
Detailed Description
The following description of the application is intended only to illustrate various embodiments of the application. The specific embodiments described should not be considered as limiting the scope of the application. Various equivalents, modifications, or variations may be made by those skilled in the art without departing from the spirit and nature of the application, and it is to be understood that such equivalents are also included herein. All documents cited herein, including publications, patents, and patent applications, and the like, are incorporated by reference in their entirety.
Where a method referred to in this disclosure includes two or more defined steps, the defined steps may be performed in any order or concurrently (unless the context excludes the possibility), and the method may include one or more other steps, which may be performed before any defined step, between two defined steps, or after all defined steps (unless the context excludes the possibility).
Antibodies to
As used herein, the term "monoclonal antibody" refers to a population of antibodies that contain a homogeneous or substantially homogeneous single identical antibody. Monoclonal antibodies can be obtained from a single hybridoma cell clone (Milstein, C (1999), "The hybridoma revolution: an offshoot ofbasic research". BioEssays.21 (11): 966-73). The intact monoclonal antibody comprises two heavy chains and two light chains. Each heavy chain is composed of a heavy chain variable region (VH) and heavy chain first, second and third constant regions (C H1 、C H2 、C H3 ) And each light chain consists of a light chain variable region (V L ) And a light chain constant region (G) L ) Composition is prepared. V of heavy and light chains H And V L There are also three Complementarity Determining Regions (CDRs) in each region, the three CDRs being separated by a contiguous portion called the Framework Region (FR), which is more highly conserved than the CDRs and forms a scaffold supporting the hypervariable loops. The 6 CDRs of a heavy chain and a light chain together form the antigen binding site of an antibody, determining the specificity of the antibody. The monoclonal antibodies described herein also include fragments or derivatives of the intact monoclonal antibodies that have the same antigen binding specificity as the intact monoclonal antibodies, but may have the same or different affinity for binding to their specific antigen as the intact monoclonal antibodies.
In some embodiments, monoclonal antibodies described herein include antigen binding fragments. An antigen binding fragment refers to one or more antibody fragments that retain the ability to specifically bind to an antigen. Examples of antigen binding fragments include, but are not limited to, (i) Fab fragments, which refer to those fragments derived from V L 、V H 、C L And C H1 A monovalent fragment of a domain; (ii) Fab' fragments, which refer to Fab fragments comprising a portion of the hinge region; (iii) F (ab') 2 A fragment, which refers to a bivalent fragment comprising 2 Fab fragments linked by a disulfide bond of the hinge region; (iv) From V H And C H1 Fd fragments of domain composition; (v) V by antibody single arm L And V H An Fv fragment consisting of domains, (vi) a dAb fragment (Ward et al Nature 341:544-546 (1989); PCT publication WO 90/05144) comprising a single variable domain; (vii) isolated CDRs; (viii) Single chain Fv fragment, which refers to V L And V H The domains are linked directly or via a peptide chain to form monovalent fragments (Huston JS et al Proc Natl Acad Sci USA,85:5879 (1988)).
In some embodiments, monoclonal antibodies described herein include chimeric monoclonal antibodies, portions of the heavy and/or light chains of which are identical or homologous to corresponding sequences of antibodies derived from a particular class or subclass of antibody, while the remaining chains are identical or homologous to corresponding sequences of antibodies derived from another class or class of antibody, and fragments of such antibodies, so long as they exhibit the desired functional activity.
In some embodiments, the monoclonal antibodies described herein include human murine chimeric monoclonal antibodies having murine heavy and light chain variable regions and human heavy and light chain constant regions.
In some embodiments, the monoclonal antibodies described herein comprise humanized monoclonal antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (e.g., fv, fab, fab ', F (ab') 2 Or other antigen binding sequences of antibodies). In some examples, the humanized antibody may be a CDR-grafted antibody in which the amino acid sequence of a humanized CDR is introduced into a non-humanized V H And V L To replace the amino acid sequence of a corresponding non-human CDR. In other examples, the majority of the amino acid sequence of the humanized antibody may be derived from a human immunoglobulin (recipient antibody) in which the amino acid residues of the CDRs of the recipient are replaced with amino acid residues of CDRs of a non-human (e.g., mouse, rat, rabbit) antibody having the desired specificity, affinity, and capacity. Typically, humanized antibodies will comprise substantially all of at least one, and typically will comprise 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 Framework (FR) regions are those of a human immunoglobulin. In some examples, framework region residues of the variable region of a human immunoglobulin are replaced with corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are absent from both the recipient antibody and the imported CDR or framework region sequences.
The anti-CD 147 monoclonal antibodies described herein refer to monoclonal antibodies capable of specifically binding to CD147 protein.
The CD147 protein described herein refers to a single transmembrane glycoprotein belonging to the immunoglobulin superfamily, the full-length sequence of which has 269 amino acid residues, the first 21 amino acid residues from the N-terminus are signal peptides, 22 to 205 amino acid residues constitute extracellular regions, 206 to 229 amino acid residues constitute transmembrane regions, and has a typical leucine zipper structure, and 230 to 269 amino acid residues near the C-terminus constitute intracellular regions. Extracellular 4 cysteines form 2 disulfide bonds, constituting two Ig-like domains. Representative sequences of CD147 proteins can be, for example, as shown in GenBank number BAC76828.1, and can also be referenced, for example, zhang DW et al, J hepatol 2012; chen YK et al, PLoS One,7 (7), 2012; tang J et al Cell Death Differ,19 (11), 2012; li Y et al, J Biol Chem,287 (7), 2012; wu J et al Oncogene,2011; zhao P et al, hepatology,54 (6), 2011; zhao P et al, cancer sci.101 (2), 2010; gou XC et al, cancer Sci.100 (5), 2009; chen YK et al, cancer Letters,278 (1), 2009.
In some embodiments, an anti-CD 147 monoclonal antibody described herein further comprises an immunoglobulin constant region. In some embodiments, the immunoglobulin constant region comprises a heavy chain and/or a light chain constant region. The heavy chain constant region comprises C H1 、C H1 -C H2 Or C H1 -C H3 A light chain constant region comprising C L A zone.
In some embodiments, the anti-CD 147 monoclonal antibodies described herein include chimeric anti-CD 147 monoclonal antibodies, particularly human murine chimeric anti-CD 147 monoclonal antibodies.
In some embodiments, the anti-CD 147 monoclonal antibodies described herein are HcHAb18 monoclonal antibodies. The HcHAb18 monoclonal antibody was expressed in CHO cells by genetic engineering means and purified by a series of standard chromatographic steps. The HcHAb18 monoclonal antibody is a humanized modified chimeric IgG1 antibody, has a molecular weight of 147kDa, consists of 2 IgG1 heavy chains and 2 kappa light chains, each heavy chain contains 447 amino acids, has a molecular weight of 49kDa, and has a heavy chain amino acid sequence shown in SEQ ID NO:1 is shown in the specification; each light chain contains 214 amino acids, the molecular weight is 24kDa, and the amino acid sequence of the light chain is shown in SEQ ID NO:2.
TABLE 1 amino acid sequence of HcHAb18 monoclonal antibody
The present application relates to pharmaceutical formulations comprising anti-CD 147 monoclonal antibodies. The concentration of anti-CD 147 monoclonal antibodies included in the pharmaceutical formulations of the application will vary depending on the particular properties desired for the pharmaceutical formulation and the particular environment and purpose for which the pharmaceutical formulation is intended to be used. In some embodiments, the pharmaceutical formulation of the application is a solid formulation. In certain embodiments, the solid formulation may comprise the anti-CD 147 monoclonal antibody at a concentration of 1-40 mg/ml after reconstitution. In certain embodiments, the concentration of anti-CD 147 monoclonal antibodies can be any concentration value suitable for treatment. For example, the concentration of anti-CD 147 monoclonal antibody in a pharmaceutical formulation of the application may be at least 1mg/ml, at least 2mg/ml, at least 3mg/ml, at least 4mg/ml, at least 5mg/ml, at least 6mg/ml, at least 7mg/ml, at least 8mg/ml, at least 9mg/ml, at least 10mg/ml, at least 11mg/ml, at least 12mg/ml, at least 13mg/ml, at least 14mg/ml, at least 15mg/ml, at least 16mg/ml, at least 17mg/ml, at least 18mg/ml, at least 19mg/ml, at least 20mg/ml, at least 21mg/ml, at least 22mg/ml, at least 23mg/ml, at least 24mg/ml, at least 25mg/ml, at least 26mg/ml, at least 27mg/ml, at least 28mg/ml, at least 29mg/ml, or at least 30mg/ml, and/or at most 40mg/ml, at most 39mg/ml, at most 38mg/ml, at most 337mg/ml, at most 36mg/ml, at most 35mg/ml, at most 34mg/ml, at most 33mg/ml, at most 32mg/ml, at most 31mg/ml, at most 30mg/ml, at most 29mg/ml, at most 28mg/ml, at most 27mg/ml, at most 26mg/ml, at most 25mg/ml, at most 24mg/ml, at most 23mg/ml, at most 22mg/ml, at most 21mg/ml, or at most 20mg/ml. In certain embodiments, the concentration of HcHAb18 monoclonal antibody in the pharmaceutical formulation of the present application is between 10 and 30mg/ml.
The pharmaceutical formulation of the present application may comprise one or more excipients. The term "adjuvant" as used herein generally refers to any non-therapeutic agent added to a formulation to provide a desired consistency, viscosity or stabilization.
Buffer solution
The term "buffer" generally refers to a buffer solution that is resistant to changes in pH by the action of its acid-base conjugate components. As used herein, "buffer" refers to a solution of a compound known to be safely used in pharmaceutical formulations having the ability to maintain or control the pH of the formulation within a desired range.
The stable pharmaceutical formulation of the application may comprise a buffer such that the pharmaceutical formulation has a pH of 5.0 to 8.0, for example a pH of 5.0 to 6.0, 6.0 to 7.0 or 7.0 to 8.0. In some embodiments, suitable buffers provide the pharmaceutical formulations of the present application with a pH of 5.0 to 6.0. In particular, the pH of the pharmaceutical formulation of the application may be any pH within the pH ranges as listed above, for example 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6. 1. 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0.
Examples of buffers that can control the pH of the pharmaceutical formulation within the desired range include succinic acid buffers, histidine buffers, citric acid buffers, and other organic or inorganic acid buffers. These buffers may be used alone or in combination of two or more kinds. Preferably, the pharmaceutical formulation of the application comprises a succinic acid buffer, a histidine buffer or a citric acid buffer. More preferably, the pharmaceutical formulation of the application comprises histidine buffer.
A "succinic acid buffer" is a buffer comprising succinate ions. The succinic acid buffer may comprise one or more of succinic acid, monosodium succinate, disodium succinate, monopotassium succinate, dipotassium succinate, sodium chloride, potassium chloride, and the like. In some embodiments, the succinic acid buffer may be a succinic acid-disodium succinate buffer. In some embodiments, the pH of the succinic buffer may be any pH in the range of 5.0 to 6.0, such as 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0.
A "histidine buffer" is a buffer comprising histidine ions. The histidine buffer may include one or more of histidine, histidine hydrochloride, histidine acetate, histidine phosphate, histidine sulfate, and the like. In some embodiments, the histidine buffer may be a histidine-histidine hydrochloride buffer. In some embodiments, the pH of the histidine buffer may be any pH in the range of 5.0 to 6.0, for example 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0.
A "citrate buffer" is a buffer containing citrate ions. The citric acid buffer may comprise one or more of citric acid, monosodium citrate, disodium citrate, trisodium citrate, monopotassium citrate, dipotassium citrate, tripotassium citrate, sodium chloride, potassium chloride, and the like. In some embodiments, the citrate buffer is a citrate-trisodium citrate buffer. In some embodiments, the pH of the citrate buffer may be any pH in the range of 5.0 to 6.0, such as 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0.
The concentration of the buffer as described herein refers to the concentration of buffer ions in the buffer. In some embodiments, suitable buffers for use in the pharmaceutical formulations of the present application may be present at a concentration of 5 to 50mmol/L. In some embodiments, the concentration of the buffer is any concentration value within the above range. For example, the buffer may have a concentration of at least 5mmol/L, at least 6mmol/L, at least 7mmol/L, at least 8mmol/L, at least 9mmol/L, at least 10mmol/L, at least 11mmol/L, at least 12mmol/L, at least 13mmol/L, at least 14mmol/L, at least 15mmol/L, at least 16mmol/L, at least 17mmol/L, at least 18mmol/L, at least 19mmol/L, at least 20mmol/L, at least 21mmol/L, at least 22mmol/L, at least 23mmol/L, at least 24mmol/L, at least 25mmol/L, at least 30mmol/L, at least 35mmol/L, at least 40mmol/L, or at least 45mmol/L, and/or up to 50mmol/L, up to 45mmol/L, up to 40mmol/L, up to 35mmol/L, up to 30mmol/L, up to 25mmol/L, up to 24mmol/L, up to 23mmol/L, up to 22mmol/L, up to 21mmol/L, up to 20mmol/L, up to 19mmol/L, up to 18mmol/L, up to 17mmol/L, up to 16mmol/L, up to 15mmol/L, up to 14mmol/L, up to 13mmol/L, up to 12mmol/L, up to 11mmol/L, up to 10mmol/L, up to 9mmol/L, up to 8mmol/L, up to 7mmol/L, or up to 6mmol/L, depending on the particular buffer and the desired stability of the pharmaceutical formulation. In some embodiments, the buffer used in the pharmaceutical formulations of the present application is a histidine buffer, including histidine-histidine hydrochloride buffer, at a concentration of 5 to 15mmol/L. In some embodiments, the histidine buffer concentration may be 6 to 14mmol/L, 7 to 13mmol/L, 8 to 12mmol/L, 9 to 11mmol/L, or 10mmol/L.
Protein protectant
As used herein, the term "protein protectant" refers to an agent that, when bound to a protein of interest, prevents or reduces chemical and/or physical instability of the protein. Examples of protein protectants include saccharides, alcohols, acids, salts, polymers, and the like. Examples of the saccharides include non-reducing saccharides such as starch, cellulose, glycogen, arabinan, galactan, levan, xylan, dextran, arabinoxylan, arabinogalactan, chitin, laminarin, fucan, hyaluronic acid, chondroitin sulfate, trehalose, sucrose, raffinose, melezitose, dihydroxyacetone. In some embodiments, the protein protectant is selected from glucose, sucrose, trehalose, lactose, and dextran. Examples of alcohols include sorbitol and the like. Examples of acids include citric acid, phosphoric acid, tartaric acid, amino acids, ethylenediamine tetraacetic acid, and the like. Examples of salts include sodium sulfate, sodium glutamate, sodium chloride, potassium chloride, ammonium acetate, and the like. Examples of the polymer include polyethylene glycol, povidone, and the like.
In some embodiments, the protein protectant used in the pharmaceutical formulation of the application is selected from saccharides. In some embodiments, the protein protectant used in the pharmaceutical formulation of the application is a non-reducing sugar (e.g., starch, cellulose, glycogen, arabinan, galactan, levan, xylan, dextran, arabinoxylan, arabinogalactan, chitin, laminarin, fucan, hyaluronic acid, chondroitin sulfate, trehalose, sucrose, raffinose, melezitose, dihydroxyacetone). In some embodiments, the protein protectant used in the pharmaceutical formulation of the application is selected from sucrose, trehalose, or a combination thereof. In some embodiments, the protein protectant used in the pharmaceutical formulation of the application is sucrose.
In some embodiments, the concentration of the protein protectant used in the pharmaceutical formulation of the application may be in the range of 10 to 200mg/ml in the pharmaceutical formulation. In some embodiments, the concentration of the protein protectant is any concentration value within the ranges described above. For example, the concentration of the protein protectant in the pharmaceutical formulation may be at least 10mg/ml, at least 20mg/ml, at least 30mg/ml, at least 40mg/ml, at least 50mg/ml, at least 60mg/ml, at least 70mg/ml, at least 80mg/ml, at least 90mg/ml, and/or at most 200mg/ml, at most 150mg/ml, at most 100mg/ml, at most 90mg/ml, at most 80mg/ml, at most 70mg/ml, at most 60mg/ml, at most 50mg/ml, at most 40mg/ml, at most 30mg/ml, at most 20mg/ml, or at most 10mg/ml, depending on the particular protein protectant and the desired stability of the pharmaceutical formulation.
In some embodiments, the protein protectant used in the pharmaceutical formulation of the application is sucrose, which may be present in the pharmaceutical formulation at a concentration of 10-200 mg/ml. In some embodiments, the concentration of sucrose in the pharmaceutical formulation may be 20 to 180mg/ml, 40 to 160mg/ml, 60 to 140mg/ml, 80 to 120mg/ml, or 100mg/ml.
Formulations
In one aspect, the application provides stable pharmaceutical formulations comprising an anti-CD 147 monoclonal antibody, a buffer, and a protein protectant. The pharmaceutical formulation has a pH of 5.0 to 8.0, in some embodiments, pH 5.0 to 6.0 to achieve adequate stability.
In some embodiments, the pharmaceutical formulation of the application comprises:
HcHAb18 monoclonal antibody, its concentration is 1-40 mg/ml, preferably 5-35 mg/ml, 10-30 mg/ml, 15-25 mg/ml or 20mg/ml;
a buffer, preferably a succinic acid buffer, a histidine buffer or a citric acid buffer, most preferably a histidine buffer, and the concentration of said buffer in said pharmaceutical formulation is 5-50 mmol/L, preferably 5-15 mmol/L or 10mmol/L;
a protein protecting agent, which is preferably sucrose or trehalose, most preferably sucrose, and the concentration of the protein protecting agent in the pharmaceutical formulation is 10 to 200mg/ml, preferably 20 to 180mg/ml, 40 to 160mg/ml, 60 to 140mg/ml, 80 to 120mg/ml or 100mg/ml.
In some embodiments, the pharmaceutical formulation of the application comprises HcHAb18 monoclonal antibody at a concentration of 1-40 mg/ml, histidine buffer at a concentration of 5-50 mmol/L, and sucrose at a concentration of 10-200 mg/ml. In some embodiments, the pharmaceutical formulation comprises HcHAb18 monoclonal antibody at a concentration of 5-35 mg/ml, 10-30 mg/ml, 15-25 mg/ml or 20mg/ml.
In some embodiments, the pharmaceutical formulation of the application comprises HcHAb18 monoclonal antibody at a concentration of about 10 to 30mg/ml, histidine buffer at a concentration of about 5 to 15mmol/L, and sucrose at a concentration of about 80 to 120mg/ml.
In some embodiments, the pharmaceutical formulation of the application comprises HcHAb18 monoclonal antibody at a concentration of about 20mg/ml, histidine buffer at a concentration of about 10mmol/L, and sucrose at a concentration of about 100mg/ml.
The chemical degradation, or aggregation of the antibody molecule to form a polymer, or deglycosylation, glycosylation modification, oxidation, or other structural modification of the antibody molecule that may result in a decrease in at least one functional activity of the monomeric protein, etc., may cause instability of the antibody formulation. For pharmaceutical formulations comprising anti-CD 147 monoclonal antibodies, the anti-CD 147 monoclonal antibody may undergo chemical degradation during storage of the pharmaceutical formulation, resulting in a decrease in the concentration of the antibody; anti-CD 147 monoclonal antibodies may also aggregate to form polymers that are sometimes insoluble in the form of multimeric molecules containing multiple antibody molecules, resulting in a reduced monomer content containing a single antibody molecule. Thus, an increase in the content of polymer antibodies will result in a decrease in the purity of the monomer antibodies. Moreover, turbidity of the pharmaceutical formulation may increase due to the formation of insoluble polymers.
In some embodiments, the pharmaceutical formulations of the application comprising an anti-CD 147 monoclonal antibody can remain stable over time, wherein the physical and/or chemical stability and/or functional activity, etc., of the anti-CD 147 monoclonal antibody remains relatively constant over time. In some embodiments, the concentration of antibody protein, protein purity, protein activity, appearance of the formulation, insoluble particles in the formulation, moisture of the formulation, etc., can be used as an indicator of the stability of the pharmaceutical formulation. There are a number of analytical techniques in the art for determining protein stability, which are described in Peptide and Protein Drug Delivery,247-301, edited by vincent Lee, marcel Dekker inc., new york press (1991) and Jones, a.adv. Drug Delivery rev.10:29-90 (1993). In some embodiments, the stability of a pharmaceutical formulation can be measured by methods known in the art under selected conditions and for a time.
In studying the long-term stability of the formulation, the preset criteria used in the present application to indicate the stability of the formulation are: the protein concentration change is not more than +/-2.0 mg/ml (for the initial protein concentration of 20 mg/ml), the protein purity measured by a CE-SDS method is not less than 95.0%, the monomer content in the protein purity measured by a SE-HPLC method is not less than 99.0%, the polymer content is not more than 1.0%, the moisture content is not more than 3.0%, the binding activity of the antibody is not less than 1:8000, and the functional activity is positive.
The protein concentration can be measured by ultraviolet-visible spectrophotometry according to the Chinese pharmacopoeia 2015 edition, the three parts, the general rule 0401.
The water content can be measured according to the method of the Chinese pharmacopoeia 2015 edition, the three parts, general rule 0832 and Fei Xiushi.
The binding activity represents the specific binding activity of the antibody and the target spot, and can be measured by an enzyme-linked immunosorbent assay according to the Chinese pharmacopoeia 2015 edition, three general rules 3418. In the application, A549 cell climbing tablet is added with an antibody diluted by 5% normal sheep serum PBS solution according to 1:4000, 1:8000 and 1:16000 (based on 1 mg/ml) to react with fluorescent secondary antibody (sheep anti-human IgG-FITC), and the specific fluorescence intensity of cells is observed under a fluorescence microscope and is not lower than 1:8000.
The functional activity refers to the ability of a pharmaceutical formulation to produce killing or inhibition against a particular target cell and can be measured by a cytotoxicity assay. The method uses frozen human spleen cells as effector cells, and uses MTS and living cells to generate soluble first to detect the content of living cells and draw a curve, and observes that the concentration of monoclonal antibody is not higher than 1/10 of the concentration of negative control antibody under a certain killing rate. A positive functional activity of a pharmaceutical formulation indicates that the pharmaceutical formulation has killing activity against a particular target cell.
The pharmaceutical formulations described herein, preferably lyophilized formulations, although simple (comprising only buffering agents and protein protectants) and inexpensive to prepare, have little toxic side effects due to the excipients, and have unexpected long-term stability that can be stored at 5 ℃ for up to 12 months, 24 months, 36 months, 48 months, or even 60 months.
Preparation of the formulation
In another aspect, the present application provides a method of preparing a pharmaceutical formulation comprising:
1) Providing a formulation vehicle and an anti-CD 147 monoclonal antibody (e.g., hcHAb18 monoclonal antibody), wherein the formulation vehicle comprises a buffer at a concentration of about 5 to 50mmol/L, about 5 to 15mmol/L, or about 10mmol/L, and a protein protectant at a concentration of about 10 to 200mg/ml, about 80 to 120mg/ml, or about 100 mg/ml;
2) The stock anti-CD 147 monoclonal antibody (e.g., hcHAb18 monoclonal antibody stored in a phosphate buffer system) is filtered using the formulation vehicle to obtain a pharmaceutical formulation as described herein. In some embodiments, the filtration is ultrafiltration, diafiltration, gel filtration, and/or other filtration methods known to those of skill in the art.
As used herein, the term "ultrafiltration" refers to a process in which a mixture (e.g., an anti-CD 147 monoclonal antibody stock solution) moves through a membrane (e.g., an ultrafiltration membrane) under, for example, pressure drive, and in which different substances (e.g., solvents and solutes) are separated as a result of their differences in the rate at which they filter through the membrane in response to a given pressure drive force.
As used herein, the term "diafiltration" refers to a process in which a mixture (e.g., an anti-CD 147 monoclonal antibody stock solution) is separated according to the molecular size of the components therein using, for example, a permeable membrane filter. Typically, the protein stock is diafiltered through a membrane that retains the protein and allows buffer exchange, whereby over time the protein-containing stock is replaced with new buffer.
As used herein, the term "gel filtration" refers to a process whereby larger molecules and smaller molecules are separated by gel by repelling molecules (e.g., proteins) larger than the resin pores, through the solid phase faster than smaller molecules that diffuse into the resin pores and are thus retained and move slower through the solid phase.
In some embodiments, the method further comprises lyophilizing the pharmaceutical formulation to obtain a lyophilized powder injection or other lyophilized form as described herein.
Application of
In another aspect, the application also provides a method of treating a disease in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the application, wherein the subject has or is likely to have a disease in need of treatment with an antibody directed against a CD147 molecule.
As used herein, the term "treating" refers to reducing or ameliorating the severity and/or duration of a disorder or one or more symptoms thereof, inhibiting or preventing the progression of the disorder, causing the disorder to resolve, inhibiting or preventing the recurrence, development, onset, or progression of one or more symptoms associated with the disorder. Subjects in need of treatment include subjects already with the disease.
The term "therapeutically effective amount" refers to the minimum concentration required to achieve a measurable improvement or prevention of a particular disorder.
The pharmaceutical formulations of the application are useful for the treatment of CD147 molecule related diseases, including chronic and acute diseases. CD147 molecule related diseases include malaria, cancer, inflammation, and the like. In some embodiments, the CD147 molecule related disease is malaria. In some embodiments, the CD147 molecule associated disease is meta-daily, tri-daily, oval, or malignant.
The pharmaceutical formulations of the application may be administered to a subject by any suitable route. For example, the pharmaceutical formulation may be administered to a subject by intravenous injection.
In a further aspect, the application provides the use of a pharmaceutical formulation in the manufacture of a medicament for the prophylaxis and/or treatment of a CD147 molecule related disease.
Examples
The application will be better understood by reference to the following examples, which are intended to illustrate the application and are not to be construed as limiting the scope of the application. Modifications and variations are possible in light of the teachings herein and are therefore within the scope of the present application.
The various reagents, equipment and measurement methods used in the examples were as follows:
reagent(s)
anti-CD 147 monoclonal antibody: an HcHAb18 monoclonal antibody comprising the amino acid sequence as set forth in SEQ ID NO:1 and a heavy chain as set forth in SEQ ID NO:2, and a light chain as shown in FIG. 2.
Histidine buffer: is prepared from histidine solution and histidine hydrochloride solution.
Test method
In studying the long-term stability of the formulation, the preset criteria used in the present application to indicate the stability of the formulation are: the protein concentration does not change more than 4.0mg/ml (for the initial protein concentration of 20 mg/ml), the protein purity measured by a denaturing capillary electrophoresis (CE-SDS) method is more than or equal to 95.0%, the monomer content in the protein purity measured by a high performance liquid gel chromatography (SE-HPLC method) method is more than or equal to 99.0%, the polymer content is less than or equal to 1.0%, the water content is less than or equal to 3.0%, the binding activity of the antibody is not less than 1:8000, and the functional activity is positive.
Example 1: formulation of HcHAb18 monoclonal antibody preparation
The formulation of the monoclonal antibody preparation used in this example is as follows:
TABLE 2 formulation of HcHAb18 monoclonal antibody preparation
The preparation method of the monoclonal antibody preparation comprises the following steps:
1) Preparing a preparation solvent containing a buffering agent and a protein protecting agent, wherein the solvent comprises the following components:
TABLE 3 solvent components of the formulations
| Component (A) | Mass/volume used in formulation |
| Histidine | 0.81g |
| Histidine hydrochloride | 1.0g |
| Sucrose | 100g |
| Water for injection | Proper amount of |
| Full amount of | 1L |
2) And filtering and replacing the purified HcHAb18 monoclonal antibody stock solution by using the prepared preparation solvent.
3) And (3) obtaining a semi-finished product, filling the semi-finished product into a penicillin bottle in an aseptic manner, freeze-drying, covering a rubber plug and an aluminum plastic cover to obtain cake powder, and obtaining the freeze-dried powder injection.
Example 2: long term stability test
Two batches of lyophilized powder for injection (batch A and batch B) were placed at 5deg.C for stability experiments, the results of which are shown in Table 4. As can be seen from Table 4, the preparation of the present application, although having a simple formulation, uses only two auxiliary materials, namely histidine buffer solution prepared from histidine and histidine hydrochloride, and sucrose, the resulting liquid semi-finished product can still form good cake powder after freeze-drying, and even after 3 years, the protein concentration in the lyophilized powder injection preparation of the present application does not change more than 4.0mg/ml, the protein purity is not less than 95.0%, even more than 96.0%, the monomer content in the protein purity is not less than 99.0%, the polymer content is not more than 1.0%, even not more than 0.6%, the moisture content is not more than 3.0%, the binding activity of the antibody is 1:8000, the functional activity is positive, and unexpectedly good long-term stability is provided.
The antibody preparation has the advantages of simple auxiliary material components, high safety and remarkable long-term stability, and has substantial progress and good application prospect in the aspects of preparation process and economy.
The present application is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications and variations of the application will be apparent to those skilled in the art in light of the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims.
Claims (2)
1. A pharmaceutical formulation consisting of 20mg/mL of an anti-CD 147 monoclonal antibody, 10mmol/L of histidine buffer and 100mg/mL of sucrose, wherein the anti-CD 147 monoclonal antibody comprises a heavy chain of the amino acid sequence shown in SEQ ID No. 1 and a light chain of the amino acid sequence shown in SEQ ID No. 2.
2. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is in lyophilized form.
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| CN202111207580.8A CN113925963B (en) | 2021-10-15 | 2021-10-15 | Stable pharmaceutical formulation comprising anti-CD 147 monoclonal antibody |
| PCT/CN2022/125278 WO2023061462A1 (en) | 2021-10-15 | 2022-10-14 | Stable pharmaceutical formulation comprising anti-cd147 monoclonal antibody |
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| CN108261391A (en) * | 2016-12-30 | 2018-07-10 | 江苏太平洋美诺克生物药业有限公司 | The stable pharmaceutical preparation for including CD147 monoclonal antibodies |
| CN108261544A (en) * | 2016-12-30 | 2018-07-10 | 陈小春 | The stable pharmaceutical preparation for including CD147 monoclonal antibodies |
| CN111971062A (en) * | 2018-04-28 | 2020-11-20 | 齐鲁制药有限公司 | Monoclonal antibody preparation for resisting human PD-1, combined medicament and application thereof |
| CN112972674A (en) * | 2021-03-10 | 2021-06-18 | 江苏太平洋美诺克生物药业有限公司 | Stable pharmaceutical formulation comprising CD147 monoclonal antibody |
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| WO2007076354A2 (en) * | 2005-12-20 | 2007-07-05 | Bristol-Myers Squibb Company | Stable protein formulations |
| CN105820250B (en) * | 2016-04-29 | 2019-04-30 | 中国人民解放军第四军医大学 | A kind of anti-BASIGIN humanized antibody and its application |
| CN113925963B (en) * | 2021-10-15 | 2023-08-11 | 江苏太平洋美诺克生物药业股份有限公司 | Stable pharmaceutical formulation comprising anti-CD 147 monoclonal antibody |
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| CN108261391A (en) * | 2016-12-30 | 2018-07-10 | 江苏太平洋美诺克生物药业有限公司 | The stable pharmaceutical preparation for including CD147 monoclonal antibodies |
| CN108261544A (en) * | 2016-12-30 | 2018-07-10 | 陈小春 | The stable pharmaceutical preparation for including CD147 monoclonal antibodies |
| CN111971062A (en) * | 2018-04-28 | 2020-11-20 | 齐鲁制药有限公司 | Monoclonal antibody preparation for resisting human PD-1, combined medicament and application thereof |
| CN112972674A (en) * | 2021-03-10 | 2021-06-18 | 江苏太平洋美诺克生物药业有限公司 | Stable pharmaceutical formulation comprising CD147 monoclonal antibody |
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