WO2023019556A1 - 一种高浓度抗her2的抗体制剂及其用途 - Google Patents
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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Definitions
- the invention belongs to the field of antibody preparations, and in particular relates to a high-concentration anti-HER2 antibody preparation and its application.
- Antibodies of choice have been increasingly administered intravenously (IV) over the past few years.
- the amount of antibody that can be injected intravenously is however limited by the physico-chemical properties of the antibody, in particular by its solubility and stability in suitable liquid formulations and by the volume of infused liquid.
- Alternative routes of administration are subcutaneous or intramuscular injections, which require higher protein concentrations in the final solution to be injected [Shire, S.J., Shahrokh, Z. et al. "Challenges in the development of high protein Concentration formulations", J 2004; 93(6): 1390-1402; Roskos, L.K., Davis C.G.
- (Trastuzumab) is a monoclonal antibody against the HER2 receptor (anti-HER2 antibody), which is currently available in Europe as a 150 mg lyophilized powder (containing antibody, dihydrate ⁇ , ⁇ -trehalose, L - Sold in the form of histidine and L-histidine hydrochloride and polysorbate 20), the lyophilized powder should be reconstituted with water for injection to produce an antibody solution of about 21 mg/ml.
- Bevacizumab a monoclonal antibody against vascular endothelial growth factor (VEGF), is currently marketed in Europe as a liquid formulation in two vials: 100 mg bevacizumab in 4 ml each mAb and 400mg bevacizumab in 16ml.
- VEGF vascular endothelial growth factor
- subcutaneous injection allows the medical practitioner to administer it in a relatively short intervention with the patient.
- patients can be instructed to administer subcutaneous injections themselves.
- subcutaneous drugs are particularly beneficial during administration of maintenance doses, since hospital care is not required and utilization of medical resources is reduced.
- injection volumes are less than about 2 ml by the subcutaneous route.
- multiple unit dose formulations may be injected at multiple sites on the body surface.
- TNF ⁇ tumor necrosis factor alpha
- Optizumab is a monoclonal antibody against immunoglobulin E (anti-IgE antibody), which is currently available as a 150 mg lyophilized powder (containing antibody, sucrose, histidine and histidine hydrochloride monohydrate and polysorbate 20), the lyophilized powder is reconstituted with water for injection to yield a 125 mg/ml injection dose.
- anti-IgE antibody immunoglobulin E
- Parenteral drugs are generally limited to volumes less than 2 ml for subcutaneous injection because of counterpressure in the subcutaneous (SC) tissue following injection due to viscoelastic resistance to hydraulic transmission and due to the sensation of pain [Aukland K. and Reed R ., "Interstitial-Lymphatic Mechanisms in the control of Extracellular Fluid Volume", Physiology Reviews", 1993;73:1-78].
- Finding a suitable buffer is especially important for pharmaceutical proteins.
- the conformation and activity of proteins critically depend on pH. Proteins are susceptible to various pH effects, much more so than small molecule drugs. For example, the side chain amides of asparagine and glutamine are deamidated at low pH (less than 4.0) and at neutral or higher pH (greater than 6.0). Aspartic acid residues promote the hydrolysis of adjacent peptide bonds at low pH. Especially in the presence of thiols, the stability and distribution of disulfide bonds is pH dependent. Solubility, flocculation, aggregation, precipitation and fibrillation of proteins are precisely pH dependent. The crystallization habit, which is important for some pharmaceutical formulations, is also critically pH dependent.
- Buffers for pharmaceutical use must not only satisfy the buffering capacity to maintain the correct pH, but they must be such that their administration does not strongly perturb the physiological pH of the subject. Buffers for pharmaceutical formulations must also not interfere with the typically complex formulation process. For example, sublimation or evaporation buffers, such as acetate and imidazole, cannot usually be relied upon to maintain pH during lyophilization and in reconstituted lyophilized products. Other buffers that crystallize out of the protein's amorphous phase, such as sodium phosphate, do not maintain pH in processes that require freezing.
- Buffers used to maintain pH in the final drug product must also not only be effective at the maintained pH, but also must be safe and suitable for the patient. For example citrate at low or high concentrations and acetate at high concentrations of some other useful buffers are undesirable for parenteral administration.
- Some buffers such as acetate, succinate, citrate, histidine (imidazole), phosphate, and Tris have been found to be useful in formulating pharmaceutical proteins, all of which have undesired limitations and disadvantages, and they all Has the inherent disadvantage of being an additional component in the formulation which complicates the formulation process, increases the risk of detrimental components, affects other stability, shelf life and end user acceptability.
- histidine was photo-oxidized to generate a photosensitizer, thereby mediating the photodegradation of monoclonal antibodies. Histidine can also be oxidized by hydrogen peroxide and metal cations . Singlet oxygen attacks the imidazole ring of histidine, triggering the photooxidation of histidine to form an endoperoxide intermediate, which is further decomposed to generate a variety of end products, including aspartic acid and urea.
- the imidazole ring is also susceptible to metal-catalyzed oxidation, mainly producing 2-oxohistidine and its ring-opening products, such as aspartate and formamide.
- amino acid functional groups can be oxidized to produce carbon dioxide, ammonia, aldehydes, and carboxylic acids containing imidazole moieties. It was observed that the activity of the monoclonal antibody in a solution containing histidine was weakened, and its histidine oxidation product was identified as formyl imidazole [Chunlei Wang, Aaron Yamniuk, Jun Dai, Investigation of a Degradant in a Biologics Formulation Buffer Containing L- Histidine].
- the inventor obtained a high-concentration anti-HER2 preparation through concentration, and obtained a high-concentration anti-HER2 preparation for subcutaneous injection that is easier to prepare and more effective than Roche’s PHESGO and other high-concentration products .
- the present invention has no additional buffering agent, but high-concentration protein self-buffering, which reduces the influence of histidine oxidation products such as aspartate and formamide on antibody activity.
- the present invention has further explored and studied the prescription of high-concentration preparations, and found that methionine has a significant effect on preventing high-concentration antibody aggregation and degradation; at the same time, it has also been found that polysorbate 20 is used as a cosolvent in pharmaceutical preparations, which has a significant effect on There are obvious benefits in improving drug solubility, enhancing drug pharmacological effects or reducing side effects.
- hyaluronidase is added to the high-concentration preparation to achieve smooth subcutaneous injection.
- the present invention provides a high-concentration anti-HER2 preparation for subcutaneous injection, and can store the high-concentration preparation stably. The preparation can fully prevent protein aggregation, degradation, oxidation or denaturation, etc., thereby maintaining its active components Biological activity, suitable for clinical use.
- the term “about” is meant to include ⁇ 20%, or in some cases ⁇ 10%, or in some cases ⁇ 5%, or within ⁇ 1% in some cases, or ⁇ 0.1% in some cases.
- anti-HER2 antibody refers to an antibody capable of recognizing and binding to a human-derived HER2 molecule.
- antibody typically refers to a Y-shaped tetramer comprising two heavy (H) polypeptide chains and two light (L) polypeptide chains held together by covalent disulfide bonds and non-covalent interactions.
- Natural IgG antibodies have such a structure. Each light chain consists of a variable domain (VL) and a constant domain (CL). Each heavy chain comprises a variable domain (VH) and constant regions.
- antibodies in a broad sense may include, for example, polyclonal antibodies (polyclonal antibodies), monoclonal antibodies, chimeric antibodies, humanized antibodies and primatized antibodies, CDR-grafted antibodies (CDR- grafted antibody), human antibody (including recombinantly produced human antibody), recombinantly produced antibody, intrabody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, anti-idiotype antibody, synthetic antibody ( Including muteins and variants thereof) and the like.
- polyclonal antibodies polyclonal antibodies
- monoclonal antibodies monoclonal antibodies
- chimeric antibodies humanized antibodies and primatized antibodies
- CDR-grafted antibodies CDR-grafted antibody
- human antibody including recombinantly produced human antibody
- recombinantly produced antibody intrabody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, anti-idiotype antibody, synthetic antibody ( Including muteins and variants thereof) and the like.
- monoclonal antibody refers to a substantially homogeneous antibody produced by a single cell clone that only targets a specific epitope.
- Monoclonal antibodies can be prepared using various techniques known in the art, including hybridoma technology, recombinant technology, phage display technology, transgenic animals, synthetic technology or a combination of the above technologies, etc.
- antibody fragment includes at least a portion of an intact antibody.
- a "fragment" of an antibody molecule includes an "antigen-binding fragment” of an antibody, and the term “antigen-binding fragment” refers to a fragment of an immunoglobulin or antibody that specifically binds to a selected antigen or an immunogenic determining portion thereof. Or reacted polypeptide fragments, or fusion protein products further derived from such fragments, such as single-chain antibodies, extracellular binding regions in chimeric antigen receptors, etc.
- Exemplary antibody fragments or antigen-binding fragments thereof include, but are not limited to: variable light chain fragments, variable heavy chain fragments, Fab fragments, F(ab') 2 fragments, Fd fragments, Fv fragments, single domain antibodies, linear Antibodies, single-chain antibodies (scFv), bispecific antibodies or multispecific antibodies formed from antibody fragments, etc.
- an antigen refers to a substance that is recognized and specifically bound by an antibody or antibody-binding fragment.
- an antigen can include any immunogenic fragment or determinant of a selected target, including single-epitope, multi-epitope, single-structure domains, multiple domains, complete extracellular domains (ECDs), or proteins.
- ECDs extracellular domains
- Peptides, proteins, glycoproteins, polysaccharides and lipids, parts thereof and combinations thereof can constitute antigens.
- Non-limiting exemplary antigens include tumor antigens or pathogen antigens, among others.
- Antigen can also refer to a molecule that elicits an immune response.
- antigen or cells or preparations containing the antigen can be used to generate antibodies specific for an antigenic determinant.
- the antigen can be an isolated full-length protein, a cell surface protein (e.g., immunized with a cell expressing at least a portion of the antigen on its surface), or a soluble protein (e.g., immunized with only the ECD portion of the protein) or protein Constructs (eg, Fc antigens).
- the antigen can be produced in genetically modified cells. Any of the foregoing antigens may be used alone or in combination with one or more immunogenicity enhancing adjuvants known in the art.
- the DNA encoding the antigen may be genomic or non-genomic (eg, cDNA), and may encode at least a portion of the ECD sufficient to elicit an immunogenic response.
- Any vector may be used to transform the cells in which the antigen is expressed, including but not limited to adenoviral vectors, lentiviral vectors, plasmids, and non-viral vectors such as cationic lipids.
- affinity refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen).
- KD refers to the dissociation constant for a particular antibody-antigen interaction. Binding affinity can be determined using various techniques known in the art, such as surface plasmon resonance, biolayer interferometry, dual polarization interferometry, static light scattering, dynamic light scattering, isothermal titration calorimetry, ELISA, analytical ultrafast centrifugation and flow cytometry, etc.
- biological activity refers to the ability of an antibody to bind antigen and cause a measurable biological response, which can be measured in vitro or in vivo.
- pharmaceutical preparation or “preparation” or “preparation formulation” means a preparation that is present in a form that allows the biological activity of the active ingredient to be effective and that contains no other components that are toxic to the subject to which the formulation is administered .
- solution formulation means a formulation that is liquid at a temperature of at least about 2°C to about 8°C at atmospheric pressure.
- deamidation means that one or more asparagine residues in an antibody have been derivatized to, for example, aspartic acid or iso-aspartic acid.
- aggregated antibody is one that has been found to aggregate with other antibody molecules, particularly after freezing and/or agitation.
- stable formulation is one in which the protein substantially retains its physical and/or chemical stability and/or biological activity after storage.
- the formulation substantially retains its physical and chemical stability, as well as its biological activity after storage.
- the shelf life is generally selected based on the shelf life of the formulation.
- Various analytical techniques for measuring protein stability are available in the art. Stability can be measured at a selected temperature for a selected time.
- Stability can be assessed qualitatively and/or quantitatively in a number of different ways, including assessing aggregate formation (e.g., using size exclusion chromatography, by measuring turbidity, and/or by visual inspection); by using cation exchange chromatography; or capillary partitioned electrophoresis to assess charge heterogeneity; amino- or carboxy-terminal sequence analysis; mass spectrometry; SDS-PAGE analysis to compare reduced and intact antibodies; peptide mapping; to assess biological activity or antigen-binding function of antibodies; etc.
- aggregate formation e.g., using size exclusion chromatography, by measuring turbidity, and/or by visual inspection
- capillary partitioned electrophoresis to assess charge heterogeneity
- amino- or carboxy-terminal sequence analysis e.g., amino- or carboxy-terminal sequence analysis
- mass spectrometry mass spectrometry
- SDS-PAGE analysis to compare reduced and intact antibodies
- peptide mapping to assess biological activity or antigen-bind
- Instability can include any one or more of the following: aggregation, deamidation (eg, Asn deamidation), oxidation (eg, Met oxidation), isomerization (eg, Asp isomerization), shearing Cleavage/hydrolysis/fragmentation (e.g. hinge fragmentation), succinimide formation, unpaired cysteines, N-terminal extension, C-terminal processing, differential glycosylation, etc.
- deamidation eg, Asn deamidation
- oxidation eg, Met oxidation
- isomerization eg, Asp isomerization
- shearing Cleavage/hydrolysis/fragmentation e.g. hinge fragmentation
- succinimide formation unpaired cysteines, N-terminal extension, C-terminal processing, differential glycosylation, etc.
- buffer or “buffer” means a pharmaceutically acceptable excipient that stabilizes the pH of a pharmaceutical formulation.
- Suitable buffers are well known in the art and can be found in the literature.
- Preferred pharmaceutically acceptable buffers include, but are not limited to: histidine buffer, citrate buffer, succinate buffer, acetate buffer, arginine buffer, phosphate buffer, or mixtures and more.
- the buffer is pH adjusted with acids or bases known in the art, the pH may be adjusted to a value in the range 4.5-6.5, especially to a value in the range 5.0-6.0, most particularly to pH 5. 5.
- stabilizer denotes a pharmaceutically acceptable excipient which protects the active pharmaceutical ingredient and/or formulation against chemical and/or physical degradation during manufacture, storage and application.
- Stabilizers include, but are not limited to, sugars, amino acids, polyols, cyclodextrins, and the like.
- surfactant denotes a pharmaceutically acceptable excipient used to protect protein formulations against physical stress, such as agitation and shearing.
- Pharmaceutically acceptable surfactants include: polyoxyethylene sorbitan fatty acid esters (Tween), polyoxyethylene alkyl ethers (such as those sold under the trademark Brij TM ), and polyoxyethylene-polyoxypropylene Copolymer (poloxamer, Pluronic).
- Polyoxyethylene sorbitan-fatty acid esters include polysorbate 20 (sold under the trademark Tween 20 TM ) and polysorbate 80 (sold under the trademark Tween 80 TM ).
- combination drug refers to a combination comprising two or more pharmaceutical preparations each having an active ingredient, which need to be used in combination when administered to a subject.
- the active ingredients can be mixed together to form a single administration unit, or can be used independently as a administration unit and used separately.
- an effective amount refers to the dose of a pharmaceutical formulation of an antibody or fragment of the present invention which, after administration to a patient in single or multiple doses, produces the desired effect in the treated patient.
- An effective amount can be readily determined by the attending physician, who is skilled in the art, by considering various factors such as ethnic differences; body weight, age and health; the particular disease involved; the severity of the disease; the response of the individual patient; The specific antibody administered; the mode of administration; the bioavailability characteristics of the formulation administered; the chosen dosing regimen; and the use of any concomitant therapy.
- the engineered antibodies or antigen-binding fragments thereof of the present invention can be prepared and purified by conventional methods.
- cDNA sequences encoding heavy and light chains can be cloned and recombined into expression vectors.
- the recombinant immunoglobulin expression vector can stably transfect CHO cells.
- mammalian expression systems lead to glycosylation of antibodies, especially at the highly conserved N-terminus of the Fc region.
- Stable clones are obtained by expressing antibodies that specifically bind to human antigens. Positive clones are expanded in serum-free medium in bioreactors for antibody production.
- the culture fluid that secretes the antibody can be purified and collected using conventional techniques.
- Antibodies can be concentrated by filtration using conventional methods. Soluble mixtures and aggregates can also be removed by conventional methods such as molecular sieves and ion exchange.
- Subjects of the invention refers to any animal, such as a mammal or a marsupial.
- Subjects of the invention include, but are not limited to, humans, non-human primates (such as cynomolgus or rhesus or other types of rhesus monkeys), mice, pigs, horses, donkeys, cows, sheep, rats, and any species poultry.
- neoplastic refers to a disease characterized by the pathological proliferation of cells or tissues, and their subsequent migration or invasion of other tissues or organs. Tumor growth is usually uncontrolled and progressive, without inducing or inhibiting normal cell proliferation.
- Tumors can affect a variety of cells, tissues, or organs, including but not limited to those selected from bladder, bone, brain, breast, cartilage, glial cells, esophagus, fallopian tubes, gallbladder, heart, intestine, kidney, liver, lung, lymph nodes, Nervous tissue, ovary, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testis, thymus, thyroid, trachea, urethra, ureter, urethra, uterus, vaginal organs, or tissues or corresponding cells.
- Tumors include cancers such as sarcomas, carcinomas, or plasmacytomas (malignancies of plasma cells).
- the tumors described in the present invention may include, but are not limited to, leukemia (such as acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, Acute monocytic leukemia, chronic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, polycythemia vera), lymphoma (Hodgkin's disease, non-Hodgkin's disease), primary macroglobulinemia, severe Chain diseases, solid tumors such as sarcomas and cancers (eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, endothelial sarcoma, lymphangiosarcoma, angiosarcoma, lymphangioendothelial sarcoma,
- the "tumor” includes, but is not limited to: pancreatic cancer, liver cancer, lung cancer, gastric cancer, esophageal cancer, squamous cell carcinoma of the head and neck, prostate cancer, colon cancer, breast cancer, lymphoma, gallbladder cancer, Kidney cancer, leukemia, multiple myeloma, ovarian cancer, cervical cancer, and glioma.
- the term “disease” or “condition” or “disorder” and the like refers to any change or disorder that damages or interferes with the normal function of a cell, tissue or organ.
- the “disease” includes, but is not limited to: tumor, pathogenic infection, autoimmune disease, T cell dysfunction disease, or immune tolerance deficiency (such as transplant rejection).
- treatment refers to clinical intervention in an attempt to alter the course of a disease caused by an individual or a cell, either for prevention or for intervention in the course of clinical pathology.
- Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, relieving symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing down the progression of the disease, improving or mitigating the condition, mitigating or improving the prognosis, etc.
- Such formulations comprise a stabilizer or a mixture of two or more stabilizers, a non-ionic surfactant and an effective amount of at least one hyaluronidase in addition to higher concentrations of anti-HER2 antibody or mixture thereof.
- the preparation of highly concentrated antibody formulations is challenging due to the potential increase in viscosity at higher protein concentrations and the potential increase in protein aggregation, an inherently concentration-dependent phenomenon. High viscosity negatively affects the processability (eg, aspiration and filtration steps) and application (eg, syringeability) of antibody formulations.
- High viscosity can be reduced in some cases by adding excipients.
- the control and analysis of protein aggregation is increasingly challenging. Aggregation is potentially encountered during various steps of the manufacturing process (which include fermentation, purification, formulation) and during storage. Various factors, such as temperature, protein concentration, agitation stress, freezing and thawing, solvent and surfactant effects, and chemical modifications can affect the aggregation phenomenon of therapeutic proteins. During the development of highly concentrated antibody formulations, the tendency of proteins to aggregate must be monitored and controlled through the addition of various excipients and surfactants.
- a challenge in preparing suitable highly concentrated stable pharmaceutical formulations of pharmaceutically active anti-HER2 antibodies according to the invention is that two different high concentrations of proteins must be formulated in one liquid formulation so that the formulation remains stable over several weeks and the pharmaceutically active ingredient Remains active during proper storage.
- Soluble hyaluronidase glycoprotein (sHASEGP), methods for its preparation and its use in pharmaceutical compositions have been described in WO 2004/078140.
- the hyaluronidase in the formulations of the invention enhances the absorption of anti-HER2 antibodies, for example by increasing the absorption of the active substance (it acts as a penetration enhancer).
- Hyaluronidase also enhances the delivery of therapeutic anti-HER2 antibodies to the systemic circulation via the subcutaneous route of application by reversibly hydrolyzing hyaluronan, an extracellular component of SC interstitium.
- Subcutaneous hyaluronan hydrolysis temporarily opens channels in the interstitial space of the subcutaneous tissue and thereby improves delivery of therapeutic anti-HER2 antibodies to the systemic circulation. Additionally, administration of this technology can reduce and reduce pain and swelling of the subcutaneous tissue in a person.
- Hyaluronidase is locally inactivated and metabolized within minutes, and no systemic or long-term effects have been noted. This property also raises potential systemic safety, since hyaluronidase products cannot act at remote injection sites.
- a unifying feature of all hyaluronidases is their ability to depolymerize hyaluronan regardless of differences in chemical structure, species origin, tissue origin, or batches of drug product derived from the same species and tissue. What sets them apart is that, despite their different structures, their activity is the same (aside from potency).
- hyaluronidases there are many suitable hyaluronidases according to the invention.
- a preferred enzyme is human hyaluronidase, most preferably the enzyme known as rHuPH20.
- rHuPH20 depolymerizes the neutral and acidic active ⁇ -1,4 glycosyl groups of hyaluronan by hydrolyzing the ⁇ -1,4 linkage between the C1 position of N-acetylglucosamine and the C4 position of glucuronic acid Member of the hydrolase family.
- Hyaluronan is a polysaccharide found in connective tissues, such as subcutaneous mesenchymal tissue, and the intracellular matrix of certain specialized tissues, such as the umbilical cord and vitreous humor.
- Hydrolysis of hyaluronan temporarily reduces the viscosity of the interstitial tissue and facilitates the dispersion of injected fluid or local transudate or exudate, thus facilitating its absorption.
- the effect of hyaluronidase is localized and reversible with complete tissue hyaluronan reconstitution occurring within 24 to 48 hours.
- Increased connective tissue permeability via hydrolysis of hyaluronan correlates with the efficacy of hyaluronidase in its ability to increase the dispersion and absorption of co-administered molecules.
- the present invention provides protein formulations comprising proteins, especially pharmaceutically acceptable formulations comprising pharmaceutical proteins, which provide buffering by the protein itself, and which do not require additional buffering agent to maintain the desired pH, and wherein the protein is substantially the only buffering agent (ie other components, if any, do not substantially function as buffering agents in the formulation).
- the present invention provides self-buffering formulations of proteins, particularly pharmaceutical proteins, characterized in that the formulated protein concentration provides the desired buffering capacity.
- a technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection without additional buffer, and the components include:
- the anti-HER2 antibody is trastuzumab, pertuzumab and/or their antigen-binding fragments.
- the concentration of the anti-HER2 antibody is 100-150 mg/ml, preferably 120 mg/ml.
- the pH of the preparation is 5.0-6.0, preferably 5.5.
- the stabilizer is sucrose, mannitol and/or trehalose, preferably sucrose, and the concentration of the stabilizer is preferably 70 mg/ml.
- the surfactant is polysorbate 20 or polysorbate 80, and the concentration is 0.3-1.5 mg/ml, preferably 1.0 mg/ml.
- methionine is used as the second stabilizer, and the concentration of methionine is 5 to 20 mM.
- the hyaluronidase content is 1000 to 16000 U/ml, preferably 2000 U/ml.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection without additional buffer, the components include: 100-150 mg/ml anti-HER2 antibody, 60-90 mg/ml Sucrose, 0.3-1.5 mg/ml polysorbate 20, 0-50 mM methionine, 2000 U/ml hyaluronidase, pH range 5.0-6.0.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 120mg/ml trastuzumab and pertuzumab antibodies, 70mg/ml sucrose, 1mg/ml Polysorbate 20, 10 mM methionine, 2000 U/ml hyaluronidase, pH 5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 34.2mg/ml sucrose , 39.7mg/ml trehalose, 1mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose , 26.5mg/ml trehalose, 1mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 34.2mg/ml sucrose , 39.7mg/ml trehalose, 0.3mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose , 26.5mg/ml trehalose, 0.3mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection the components are: 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 25-50mg/ml Sucrose, 25-50 mg/ml trehalose, 0.3-1 mg/ml polysorbate 20, 5-50 mM methionine, 2000 U/ml hyaluronidase, pH 5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 33.3-66.7mg/ml ml sucrose, 16.7-33.3 mg/ml trehalose, 0.3-1 mg/ml polysorbate 20, 5-50 mM methionine, 2000 U/ml hyaluronidase, pH 5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 34.2mg/ml sucrose , 39.7mg/ml trehalose, 0.3 ⁇ 1mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose , 26.5mg/ml trehalose, 0.3 ⁇ 1mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 34.2mg/ml sucrose , 39.7mg/ml trehalose, 0.4mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- Another technical solution provided by the present invention is: a stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection, the components are: 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose , 26.5mg/ml trehalose, 0.4mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronidase, pH5.5.
- the present invention also provides the application of the above-mentioned preparation in the preparation of a medicament for treating cancer, and the cancer is selected from lung cancer, gastric cancer, melanoma, kidney cancer, breast cancer, intestinal cancer, liver cancer, ovarian cancer, cervical cancer, bladder cancer, Esophageal cancer, pancreatic cancer and head and neck tumors; preferably selected from breast cancer, non-small cell lung cancer, melanoma and renal cancer.
- the stable anti-HER2 high-concentration solution preparation suitable for subcutaneous injection described in the present invention has the following beneficial effects:
- the preparation of the present invention can effectively inhibit the aggregation and deamidation of antibodies without adding additional buffers, thereby preventing the degradation of antibody products therein, and obtaining a stable high-concentration composition. Moreover, the preparation of the present invention has a protective effect on protein oxidative degradation, is compatible with glass and stainless steel containers, and can also exist stably in these containers.
- Figure 1 is a graph showing the transformation trend of C/D/E SEC aggregates in prescriptions at 2-8°C.
- Figure 2 is a trend chart of the SEC purity transformation of C/D/E prescriptions at 2-8°C.
- Figure 3 is the visual inspection pictures of prescriptions a and b.
- Stabilizers and surfactants involved in the present invention are used in combination of several substances during practical application.
- changes in its concentration or addition of some other substances, but changes that have no significant effect on improving the protein stability of the anti-Her2 high-concentration antibody, are still considered a part of the present invention.
- the protein content was determined by Lunatic micro-spectroscopy analyzer. Purified water was used for blank subtraction, and 280nm ultraviolet light absorption was corrected by 330nm light scattering, and the protein concentration was calculated according to formula 1, wherein the extinction coefficient ⁇ was 1.5 (L/g ⁇ cm -1 ).
- Size exclusion chromatography was used to quantify aggregates, monomers, and fragments.
- the method utilizes the Waters Xbridge BEH SEC 7.8 x 300mm column and run on a Waters e2695-2489 HPLC system.
- the mobile phase was 200 mM potassium phosphate salt, 250 mM potassium chloride, pH 6.2. Dilute the sample to 5 mg/mL with mobile phase, and the injection volume is 6 ⁇ L. Isocratic elution was carried out at a flow rate of 0.5 mL/min for 30 min, and the detection wavelength was 280 nm.
- Empower 3 software was used for integral processing, and the percentage content of each component was calculated according to the area normalization method.
- the carrier ampholyte establishes a uniform pH gradient from small to large in the capillary from the anode to the cathode under the action of an electric field. Focused separation was performed in an ampholyte pH gradient. The whole-column focusing process is monitored in real time at a wavelength of 280nm.
- FC-coated fused silica capillary 100 ⁇ m inner diameter FC-coated fused silica capillary is used, and the effective separation length is 5cm; when the sample is processed, a final concentration of 3.5% of GE Pharmalyte 3-10, 0.5% of GE Pharmalyte 8-10.5, 0.35% of HPMC, and 2M urea are added, The final concentration of the sample is 0.25mg/ml; the focus separation voltage and time are 1.5kV-1min, 3kV-7min.
- Compass for iCE software was used for data acquisition, and Empower 3 software was used to integrate the spectra. Calculate the content of acid region, main peak and alkali region by peak area percentage, and calculate the pI value of the target peak by Marker pI value.
- Hyaluronidase can enzymatically degrade the hyaluronic acid substrate. Excess hyaluronic acid solution can form a stable colloidal solution with acidified serum. A standard curve is drawn by measuring different concentrations of standard substances and their corresponding absorbance, so as to obtain hyaluronic acid. Acidase activity.
- Embodiment 1 preparation prescription preparation
- Trastuzumab and Pertuzumab are buffer-exchanged with the intended excipient solutions and, if required, concentrated by ultrafiltration to the desired antibody concentration. After the ultrafiltration concentration is completed, the excipients to be added are added to the antibody solution in the form of mother liquor, and finally the protein concentration is adjusted to about 110mg/ml, 120mg/ml, 130mg/ml, 140mg/ml, 150mg/ml with buffer. All formulations were sterile filtered through a 0.22 ⁇ m low protein binding filter and filled under aseptic conditions into sterile 2 ml vials, sealed with a film-coated rubber stopper and a combination aluminum-plastic cap. These preparation solutions were placed under the conditions of 2-8°C, 25°C, 40°C and light to examine the stability of the samples. The following are different preparation formulations and stability results:
- Prescription A 120 mg/ml trastuzumab antibody, 70 mg/ml sucrose, 1 mg/ml polysorbate 20, 10 mM methionine, pH 5.5.
- N/A means not detected.
- Prescription B 120 mg/ml Pertuzumab, 70 mg/ml sucrose, 1 mg/ml polysorbate 20, 10 mM methionine, pH 5.5.
- N/A means not detected.
- Prescription C 120 mg/ml trastuzumab and pertuzumab antibodies, 70 mg/ml sucrose, 1 mg/ml polysorbate 20, 10 mM methionine, pH 5.5.
- N/A means not detected.
- Prescription D 120 mg/ml trastuzumab and pertuzumab antibodies, 70 mg/ml sucrose, 20 mM histidine hydrochloride, 1 mg/ml polysorbate 20, 10 mM methionine, pH 5.5.
- N/A means not detected.
- Prescription E 120mg/ml trastuzumab and pertuzumab antibodies, 70mg/ml sucrose, 1mg/ml polysorbate 20, 20mM sodium acetate buffer solution, 10mM methionine, pH5.5.
- N/A means not detected.
- Prescription F 150 mg/ml trastuzumab and pertuzumab antibodies, 70 mg/ml sucrose, 1 mg/ml polysorbate 20, pH 5.5.
- Prescription G 150mg/ml trastuzumab and pertuzumab antibodies, 70mg/ml sucrose, 1mg/ml polysorbate 20, 20mM histidine hydrochloride, pH 5.5.
- Prescription H 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 34.2mg/ml sucrose, 39.7mg/ml trehalose, 1mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronic acid Acidase, pH5.5.
- N/A means not detected.
- Prescription I 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose, 26.5mg/ml trehalose, 1mg/ml polysorbate 20, 10mM methionine, 2000U/ml hyaluronic acid Acidase, pH5.5.
- Prescription J 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 34.2mg/ml sucrose, 39.7mg/ml trehalose, 0.3mg/ml polysorbate 20, 10mM methionine, 2000U/ml clear Protonidase, pH 5.5.
- Prescription K 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose, 26.5mg/ml trehalose, 0.3mg/ml polysorbate 20, 10mM methionine, 2000U/ml clear Protonidase, pH 5.5.
- Prescription L 60 mg/ml trastuzumab and 60 mg/ml pertuzumab antibody, 34.2 mg/ml sucrose, 39.7 mg/ml trehalose, 0.4 mg/ml polysorbate 20, 10 mM methionine, pH 5.5.
- Prescription M 40 mg/ml trastuzumab and 80 mg/ml pertuzumab antibody, 45.5 mg/ml sucrose, 26.5 mg/ml trehalose, 0.4 mg/ml polysorbate 20, 10 mM methionine, pH 5.5.
- Prescription N 60mg/ml trastuzumab and 60mg/ml pertuzumab antibody, 34.2mg/ml sucrose, 39.7mg/ml trehalose, 0.4mg/ml polysorbate 20, 10mM methionine, 2000U/ml clear Protonidase, pH 5.5.
- Prescription O 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose, 26.5mg/ml trehalose, 0.4mg/ml polysorbate 20, 10mM methionine, 2000U/ml clear Protonidase, pH 5.5.
- Prescription P 60 mg/ml trastuzumab and 60 mg/ml pertuzumab antibody, 34.2 mg/ml sucrose, 39.7 mg/ml trehalose, 0.4 mg/ml polysorbate 20, 10 mM methionine, 20 mM histidine Hydrochloric acid, 2000U/ml hyaluronidase, pH5.5.
- Prescription Q 40mg/ml trastuzumab and 80mg/ml pertuzumab antibody, 45.5mg/ml sucrose, 26.5mg/ml trehalose, 0.4mg/ml polysorbate 20, 10mM methionine, 20mM histidine Hydrochloric acid, 2000U/ml hyaluronidase, pH5.5.
- the stability test of the above L, M, N, O, P, Q prescriptions shows that hyaluronidase has no effect on the purity of the antibody, and the antibody has no effect on the enzyme activity, and the activity of the hyaluronidase and the antibody are relatively stable.
- there is no difference in the purity of the prescription antibody containing histidine and the enzyme activity of hyaluronidase but the corresponding ingredient process is reduced in the preparation process, which saves production costs and can avoid the photosensitivity of histidine induced by light.
- Embodiment 2 contains the preparation oxidation analysis of buffer salt
- the high-concentration preparation was formulated and diluted 5 times to detect the histidine content and perform visual inspection.
- Prescription a 120 mg/ml trastuzumab and pertuzumab antibodies, 70 mg/ml sucrose, 1 mg/ml polysorbate 20, 10 mM methionine, pH 5.5.
- Prescription b 120mg/ml trastuzumab and pertuzumab antibodies, 70mg/ml sucrose, 1mg/ml polysorbate 20, 20mM histidine hydrochloride, 10mM methionine, pH5.5.
- the post-translational modification analysis was carried out at the peptide map level by LC-MS/MS on the samples of prescription a and prescription b without light and light for 4 weeks.
- the results of the post-translational modification analysis are shown in Table 20.
- After 4 weeks of exposure to prescription a and prescription b there were no significant changes in deamidation, deamination, glycosylation, D isomerization, K deletion and N-terminal E cyclization, but methionine (M) and tryptophan (W ) oxidation modification increased significantly, and the methionine and tryptophan oxidation modification of the prescription b antibody increased more than that of the prescription a antibody.
- the ratio of tryptophan modification in prescription a after H1:W 99 light for 4 weeks was 3.17
- the modification ratio of tryptophan in prescription b was 18.13
- the ratio of methionine modification in prescription a was 52.80 after H1:M 361 /H2:M 360 light for 4 weeks
- the ratio of methionine modification in prescription b was 79.10.
- H1 and “L1” are the heavy chain and light chain of Trastuzumab
- H2 and “L2” are the heavy chain and light chain of Pertuzumab
- the ratio of glycation modification is only used for comparison between samples.
- NQ means the content is too low to be quantified; ND means not detected; italics are modification positions.
Abstract
本发明涉及一种高浓度抗HER2的抗体制剂及其用途。本发明的抗体制剂无额外缓冲剂,而是高浓度的蛋白自缓冲,减少组氨酸氧化产物如天冬氨酸盐和甲酰胺等对抗体活性影响。该制剂能够充分防止蛋白聚集、降解、氧化或者变性等,从而保持其有效组分的生物学活性,适合于临床使用。
Description
本发明属于抗体制剂领域,具体的涉及一种高浓度抗HER2的抗体制剂及其用途。
过去数年来越来越多的抗体选择由静脉(IV)注射。然而可以经由静脉注射的抗体量受限于抗体的物理-化学特性,特别地受限于其在合适的液体配制剂中的溶解度和稳定性及受限于输注液体的体积。备选的施用途径是皮下或肌肉内注射,这些注射途径要求要注射的最终溶液中的蛋白质浓度较高[Shire,S.J.,Shahrokh,Z.等“Challenges in the development of high protein Concentration formulations”,J.Pharm.Sci.2004;93(6):1390-1402;Roskos,L.K.,Davis C.G.等,“The clinical pharmacology of therapeutic antibodies”,Drug Development Research 2004;61(3):108-120]。为了增加用药体积,以及由此增加治疗剂量,有文献已经报道使用透明质酸酶可以增加抗体药物的施用空间,例如参见:WO2006/091871。
目前出售的治疗用途的药学活性抗体的稳定的配制剂的例子如下:
(曲妥珠单抗(Trastuzumab))是一种针对HER2受体的单克隆抗体(抗HER2抗体),其目前在欧洲以150mg冻干粉(含有抗体、二水合α,α-海藻糖、L-组氨酸和L-盐酸组氨酸和聚山梨酯20)形式销售,所述冻干粉应加入注射用水重建产生约21mg/ml抗体溶液。
(贝伐珠单抗(Bevacizumab))是一种针对血管内皮生长因子(VEGF)的单克隆抗体,其目前在欧洲以两类管制瓶中的液体制剂销售:分别为4ml中的100mg贝伐珠单抗和16ml中的400mg贝伐珠单抗。
虽然已经发现了上述抗体制剂适合于静脉内施用,但是期望获得皮下注射用的治疗活性抗体的高度浓缩的稳定药物制剂。皮下注射的优点在于它容许医学从业人员在对患者相当短的干预中将其实施。此外,可以指导患者自己实施皮下注射。此类皮下注射药物在维持剂量的给药期间特别有益,因为不需要医院护理,医学资源利用降低。通常,由皮下注射途径的注射体积低于约2ml。对于需要多剂的患者,可以在身体表面的多个部位注射多个单位剂量配制剂。
皮下施用的下列两种抗体产品已经出售。
(奥马珠单抗(Omalizumab))是一种针对免疫球蛋白E的单克隆抗体(抗IgE抗体),其目前以150mg冻干粉(含有抗体、蔗糖、组氨酸和一水合盐酸组氨酸和聚山梨酯20)形式销售,所述冻干粉使用注射用水重建以产生125mg/ml注射剂量。
对皮下注射胃肠外药物一般限于小于2ml的体积,这是因为注射后皮下(SC)组织中对水力传导的粘弹性阻力形成的反压力及由于疼痛的感觉所致[Aukland K.和Reed R.,“Interstitial-Lymphatic Mechanisms in the control of Extracellular Fluid Volume”,Physiology Reviews”,1993;73:1-78]。
找到一种合适的缓冲剂对药物蛋白来说是尤其重要的。蛋白质的构象和活性关键地取决于pH值。蛋白质易受各种pH的影响,比小分子药物受影响要严重很多。例如,天门冬酰胺和谷氨酰胺的侧链酰胺在低pH值(小于4.0)以及在中性或更高的pH值(大于6.0)时被脱去酰胺基。天冬氨酸残基在低pH值时促进相邻肽键的水解。特别是在硫醇存在下,二硫键的稳定性和分布取决于pH值。蛋白质的溶解度、絮凝、凝集、沉淀和纤丝化精确地取决于pH值。对一些药物制剂来说重要的结晶习性也关键地取决于pH值。药物用途的缓冲剂必须不仅满足缓冲能力以维持正确的pH值,而且它们必须是这样的一种缓冲剂,即它们的给予不会强烈地扰乱受试者的生理pH值。药物制剂的缓冲剂还必须与典型地复杂的配制过程不矛盾。例如升华或蒸发的缓冲剂,例如乙酸盐和咪唑,通常在冷冻干燥期间和在重新构成的冷冻干燥产品中不能依赖其保持pH值。其它从蛋白质无定形相中结晶出来的缓冲剂,例如磷酸钠,在需要冷冻的工艺中不能保持pH值。
在药物终产品中用于保持pH的缓冲剂还必须不仅在保持的pH下是有效的,而且必须是安全的和适合于患者。例如一些其它有用的缓冲剂在低或高浓度下的柠檬酸盐和在高浓度下的乙酸盐对胃肠外给药时是不希望产生痛苦的。一些缓冲剂例如乙酸盐、琥珀酸盐、柠檬酸盐、组氨酸(咪唑)、磷酸盐和Tris已经被发现用于配制药物蛋白,它们所有都具有不希望的限制和缺点,并且它们都具有固有的缺点,即是制剂中的额外的组分,其使配制过程变得复杂,增加了有害的组分、影响其它稳定性、贮存期限和最终用户可接受性的风险。
组氨酸的氧化降解已被广泛报道,在一项研究中,组氨酸通过光氧化产生光敏剂,从而介导单克隆抗体的光降解,组氨酸还可以被过氧化氢和金属阳离子氧化。单线态氧攻击组氨酸的咪唑环,引发组氨酸的光氧化反应,形成一种内过氧化物中间体,该中间体进一步分解,生成多种最终产物,包括天冬氨酸和尿素。咪唑环也易受金属催化氧化,主要生成2-氧组氨 酸及其开环产物,如天冬氨酸盐和甲酰胺。另一方面,氨基酸官能团可以氧化产生二氧化碳、氨、醛和含有咪唑部分的羧酸。观察到在含有组氨酸溶液中的单克隆抗体的活性减弱,鉴定其组氨酸氧化产物为甲酰基咪唑[Chunlei Wang,Aaron Yamniuk,Jun Dai,Investigation of a Degradant in a Biologics Formulation Buffer Containing L-Histidine]。
发明内容
为了追求更佳的临床效果,发明人经过浓缩得到高浓度的抗HER2制剂,获得了一种相较于罗氏公司的PHESGO等高浓度产品制备简单、效果更优的皮下注射的抗HER2高浓度制剂。本发明无额外的缓冲剂,而是高浓度的蛋白自缓冲,减少组氨酸氧化产物如天冬氨酸盐和甲酰胺等对抗体活性影响。本发明进一步地对高浓度制剂处方进行了摸索和研究,发现甲硫氨酸对阻止高浓度抗体聚集、降解有明显作用;同时,还发现聚山梨酯20在药物制剂中用作助溶剂,对提高药物溶解度,增强药物的药理作用或减少副作用有明显益处。另外高浓度制剂中添加了透明质酸酶可以顺利实现皮下注射。综上,本发明提供了一种针对皮下注射的抗HER2高浓度制剂,且能稳定保存所述高浓度制剂,该制剂能够充分防止蛋白聚集、降解、氧化或者变性等,从而保持其有效组分的生物学活性,适合于临床使用。
发明详述
1、术语
本说明书中提及的所有公布、专利和专利申请都以引用的方式并入本文,所述引用的程度就如同已特定地和个别地指示将各个别公布、专利或专利申请以引用的方式并入本文。
在下文详细描述本发明前,应理解本发明不限于本文中描述的特定方法学、方案和试剂,因为这些可以变化。还应理解本文中使用的术语仅为了描述具体实施方案,而并不意图限制本发明的范围。除非另外定义,本文中使用的所有技术和科学术语与本发明所属领域中普通技术人员通常的理解具有相同的含义。
本文所公开的某些实施方案包含了数值范围,并且本发明的某些方面可采用范围的方式描述。除非另有说明,应当理解数值范围或者以范围描述的方式仅是出于简洁、便利的目的,并不应当认为是对本发明的范围的严格限定。因此,采用范围方式的描述应当被认为具体地公开了所有可能的子范围以及在该范围内的所有可能的具体数值点,正如这些子范围和数值点在本文中已经明确写出。不论所述数值的宽窄,上述原则均同等适用。当采用范围描述时,该范围包括范围的端点。
当涉及可测量值比如量、暂时持续时间等时,术语“约”是指包括指定值的±20%、或在某些情况下±10%、或在某些情况下±5%、或在某些情况下±1%、或在某些情况下±0.1%的变化。
术语“抗HER2抗体”是指能够识别、结合来自于人的HER2分子的抗体。
本文所用的术语“抗体”,典型是指包含通过共价二硫键和非共价相互作用保持在一起的两条重(H)多肽链和两条轻(L)多肽链的Y型四聚蛋白。天然IgG抗体即具有这样的结构。每条轻链由一个可变结构域(VL)和一个恒定结构域(CL)组成。每条重链包含一个可变结构域(VH)和恒定区。
如在此使用的,广义上的“抗体”的类型可包括如多克隆抗体(polyclonal antibodies)、单克隆抗体、嵌合抗体、人源化抗体及灵长类化抗体、CDR移植抗体(CDR-grafted antibody)、人类抗体(包括重组产生的人类抗体)、重组产生的抗体、胞内抗体、多特异性抗体、双特异性抗体、单价抗体、多价抗体、抗个体基因型抗体、合成抗体(包括突变蛋白及其变体)等等。
术语“单克隆抗体”(或称“单抗”)指由单一细胞克隆产生的基本均质、仅针对某一特定抗原表位的抗体。单克隆抗体可以使用本领域中已知的多种技术制备,包括杂交瘤技术、重组技术、噬菌体展示技术、转基因动物、合成技术或上述技术的组合等。
术语“抗体片段”包含完整抗体的至少一部分。如在此所使用,抗体分子的“片段”包括抗体的“抗原结合片段”,并且术语“抗原结合片段”是指免疫球蛋白或抗体中与所选抗原或其免疫原性决定部分特异性结合或反应的多肽片段,或由此片段进一步衍生的融合蛋白产物,例如单链抗体,嵌合抗原受体中的胞外结合区等。示例性的抗体片段或其抗原结合片段包括但不限于:可变轻链片段、可变重链片段、Fab片段、F(ab’)
2片段、Fd片段、Fv片段、单结构域抗体、线性抗体、单链抗体(scFv)及由抗体片段形成的双特异性抗体或多特异性抗体等。
术语“抗原”是指被抗体或抗体结合片段识别并特异性结合的物质,广义上,抗原可以包括所选靶标的任何免疫原性片段或决定簇,包括单表位、多表位、单结构域、多结构域、完整的胞外结构域(ECD)或蛋白质。肽、蛋白质、糖蛋白、多糖和脂质,其部分及其组合均可构成抗原。非限制性示例性抗原包括肿瘤抗原或病原体抗原等。“抗原”也可以指引发免疫反应的分子。任何形式的抗原或含有该抗原的细胞或制剂都可以用于生成对抗原决定簇具有特异性的抗体。抗原可以是分离的全长蛋白质、细胞表面蛋白(例如,用在其表面上表 达至少一部分抗原的细胞进行免疫的)、或可溶性蛋白质(例如,仅用该蛋白质的ECD部分进行免疫的)或蛋白质构建体(例如,Fc抗原)。该抗原可以在基因修饰的细胞中产生。前述任何抗原可以单独或与本领域已知的一种或多种免疫原性增强佐剂组合使用。编码该抗原的DNA可以是基因组的或非基因组的(例如,cDNA),并且可以编码足以引起免疫原性应答的至少一部分ECD。可以使用任何载体来转化其中表达抗原的细胞,所述载体包括但不限于腺病毒载体、慢病毒载体、质粒以及非病毒载体如阳离子脂质。
术语“亲和力”或“结合亲和力”指分子(例如抗体)的单一结合位点与其结合配偶体(例如抗原)之间全部非共价相互作用总和的强度。术语“K
D”是指特定的抗体-抗原相互作用的解离常数。可以使用本领域已知的各种技术来确定结合亲和力,例如表面等离子体共振、生物层干涉法、双极化干涉法、静态光散射、动态光散射、等温滴定量热法、ELISA、分析超速离心和流式细胞术等。
术语“生物学活性”指抗体结合抗原并导致可测量的生物学反应的能力,所述生物学反应可以在体外或体内进行测量。
术语“药物制剂”或“制剂”或“制剂处方”,表示这样的制品:其存在形式允许活性成分的生物学活性有效,并且不含有对所述制剂要施用的受试者有毒的其他组分。
术语“溶液制剂”表示,在大气压下至少约2℃至约8℃的温度为液体的制剂。
术语“脱酰胺”表示,抗体中的一个或多个天冬酰胺残基已经被衍生成,例如,天冬氨酸或异-天冬氨酸。
术语“聚集”的抗体是这样一种抗体,其已经被发现与其它抗体分子一起聚集,特别是在冷冻和/或搅动之后。
术语“稳定的”制剂是这样的制剂,其中的蛋白质在保存后基本上保持其物理稳定性和/或化学稳定性和/或生物学活性。优选地,该制剂在保存后基本上保持其物理和化学稳定性,以及其生物学活性。一般基于制剂保质期来选择贮存期。用来测量蛋白质稳定性的各种分析技术是本领域已有的。可以在选定的温度下测量稳定性持续选定的时间。稳定性能够以许多不同的方式进行定性和/或定量地评估,包括评估聚集物形成(例如利用大小排阻层析,通过测量浊度,和/或通过肉眼观察);通过利用阳离子交换层析或毛细管分区电泳评估电荷异质性;氨基末端或羧基末端序列分析;质谱分析;SDS-PAGE分析以比较减小的和完整的抗体;肽图谱分析;评估生物学活性或抗体的抗原结合功能;等等。不稳定性可以包括下列的任一种或多种:聚集,脱酰胺作用(例如Asn脱酰胺作用),氧化作用(例如Met氧化作用),异 构化作用(例如Asp异构化作用),剪切/水解/片段化(例如铰链区片段化),琥珀酰亚胺形成,未配对的半胱氨酸,N-末端延伸,C-末端加工,糖基化作用差异,等等。
术语“缓冲剂”或“缓冲液”表示稳定药物制剂pH的药学上可接受的赋形剂。合适的缓冲剂是本领域公知的,且可以在文献中找到的。优选的药学上可接受的缓冲液包括但不限于:组氨酸缓冲液、柠檬酸盐缓冲液、琥珀酸盐缓冲液、醋酸盐缓冲液、精氨酸缓冲液、磷酸盐缓冲液或其混合物等等。缓冲液用本领域已知的酸或碱进行pH调节,可以将pH调至在4.5-6.5范围内的值,特别是调至在5.0-6.0范围内的值,最特别地是调至pH5.5。
术语“稳定剂”表示药学可接受的赋形剂,其在制造,储存和应用过程中保护活性药物成分和/或制剂免受化学和/或物理降解。稳定剂包括但不限于糖,氨基酸,多元醇,环糊精等。
术语“表面活性剂”表示,用于保护蛋白制剂抵抗物理应力(如搅拌和剪切)的药学上可接受的赋形剂。药学上可接受的表面活性剂包括:聚氧乙烯脱水山梨糖醇脂肪酸酯(吐温)、聚氧乙烯烷基醚(例如在商标Brij
TM下销售的那些)和聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆,Pluronic)。聚氧乙烯脱水山梨糖醇-脂肪酸酯包括聚山梨酯20(在商标吐温20
TM下销售)和聚山梨酯80(在商标吐温80
TM下销售)。
术语“联合用药物”指包含各自具有活性成分的两种或两种以上药物制剂的组合,在施用于受试者时需要联合使用。活性成分可以混合在一起形成单一的给药单元,也可分别独立成为给药单元,分别使用。
术语“有效量”指本发明的抗体或片段的药物制剂的剂量,其以单一或多次剂量施用患者后,在治疗的患者中产生预期效果。有效量可以由作为本领域技术人员的主治医师通过考虑以下多种因素来容易地确定:诸如人种差异;体重、年龄和健康状况;涉及的具体疾病;疾病的严重程度;个体患者的应答;施用的具体抗体;施用模式;施用制剂的生物利用率特征;选择的给药方案;和任何伴随疗法的使用。
生产和纯化抗体和抗原结合片段的方法在现有技术中能够熟知和获得,如冷泉港的抗体实验技术指南,5-8章和15章。
本发明工程化的抗体或其抗原结合片段可用常规方法制备和纯化。比如,编码重链和轻链的cDNA序列,可以克隆并重组至表达载体。重组的免疫球蛋白表达载体可以稳定地转染CHO细胞。作为一种更推荐的现有技术,哺乳动物类表达系统会导致抗体的糖基化,特别是在Fc区的高度保守N端。通过表达与人源抗原特异性结合的抗体得到稳定的克隆。阳性的 克隆在生物反应器的无血清培养基中扩大培养以生产抗体。分泌了抗体的培养液可以用常规技术纯化、收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体,也可以用常规方法去除,比如分子筛、离子交换。
本文所用的术语“个体”或“受试者”是指任何动物,例如哺乳动物或有袋动物。本发明的个体包括但不限于人类、非人类灵长类动物(例如食蟹猴或恒河猴或其他类型的猕猴)、小鼠、猪、马、驴、牛、绵羊、大鼠和任何种类的家禽。
本文所用的术语“肿瘤”指的是一种以细胞或组织的病理性增生为特征的疾病,及其随后的迁移或侵袭其他组织或器官。肿瘤生长通常是不受控制的和进行性的,不诱导或抑制正常细胞增殖。肿瘤可影响多种细胞、组织或器官,包括但不限于选自膀胱、骨、脑、乳腺、软骨、神经胶质细胞、食管、输卵管、胆囊、心脏、肠、肾、肝、肺、淋巴结、神经组织、卵巢、胰腺、前列腺、骨骼肌、皮肤、脊髓、脾、胃、睾丸、胸腺、甲状腺、气管、尿道、输尿管、尿道、子宫、阴道器官,或组织或相应的细胞。肿瘤包括癌症,如肉瘤,癌,或浆细胞瘤(浆细胞的恶性肿瘤)。本发明所述的肿瘤,可包括,但不限于白血病(如急性白血病、急性淋巴细胞白血病、急性髓细胞性白血病,急性粒细胞白血病,急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、慢性白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、真性红细胞增多症),淋巴瘤(霍奇金病、非霍奇金病)、原发性巨球蛋白血症,重链病,实体瘤如肉瘤和癌症(如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、血管肉瘤、淋巴管内皮肉瘤,间皮瘤,尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、癌、支气管癌、髓样癌、肾细胞癌、肝癌,尼罗河管癌,绒癌、精原细胞瘤、胚胎癌、肾母细胞瘤、宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤,颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤,听神经瘤,少突胶质瘤、神经鞘瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤)、食管癌、胆囊癌、肾癌、多发性骨髓瘤。较佳地,所述的“肿瘤”包括但不限于:胰腺癌、肝癌、肺癌、胃癌、食管癌、头颈部鳞状细胞癌、前列腺癌、结肠癌、乳腺癌、淋巴瘤、胆囊癌、肾癌、白血病、多发性骨髓瘤、卵巢癌、宫颈癌和胶质瘤。
本文所用的术语“疾病”或“病症”或“紊乱”等是指任何损害或干扰细胞、组织或器官的正常功能的改变或失调。例如,所述的“疾病”包括但不限于:肿瘤、病原体感染、自身免疫性疾病、T细胞功能障碍性疾病、或免疫耐受能力缺陷(如移植排斥)。
本文所用的术语“治疗”是指在试图改变个人或处理细胞引起的的疾病过程中的临床干预,既可以进行预防也可以在临床病理过程干预。治疗效果包括但不限于,防止疾病的发生或复发、减轻症状、减少任何疾病直接或间接的病理后果、防止转移、减慢疾病的进展速度、改善或缓解病情、缓解或改善预后等。
2、发明内容
本发明的目的是提供皮下注射的药学活性抗HER2抗体或此类抗体分子的混合物,且高浓度的皮下制剂中无额外的缓冲剂。在较高浓度的抗HER2抗体或其混合物外,此类配制剂包含稳定剂或两种或更多种稳定剂的混合物、非离子型表面活性剂和有效量的至少一种透明质酸酶。高度浓缩的抗体配制剂的制备是有挑战性的,这是由于较高蛋白质浓度的粘性的潜在升高和蛋白质聚集的潜在升高,即一种本质上浓度依赖性的现象。高粘性负面地影响抗体配制剂的工艺能力(例如,抽吸和过滤步骤)和施用(例如注射器能力)。通过添加赋形剂,可以在一些情况中降低高粘性。对蛋白质聚集的控制和分析越来越多有挑战。在制造工艺的各个步骤(其包括发酵、纯化、配制)期间和贮存期间潜在地遇到聚集。不同因素,诸如温度、蛋白质浓度、搅动应力、冷冻和融化、溶剂和表面活性剂效应、和化学修饰可以影响治疗性蛋白质的聚集现象。在高度浓缩的抗体配制剂的开发期间,必须监测蛋白质的聚集趋势,并通过添加各种赋形剂和表面活性剂来控制。制备依照本发明的药学活性抗HER2抗体合适的高度浓缩稳定的药物配制剂的挑战是必须在一种液体制剂中配制两种不同高浓度蛋白质,使得制剂在数周里仍然稳定,并且药学活性成分在适当的贮存期间仍然有活性。
可溶性透明质酸酶糖蛋白(sHASEGP)、其制备方法及其在药物组合物中的用途已经记载于WO 2004/078140。已经在WO 2006/091871中提及与多种例示性抗体,例如曲妥珠单抗组合使用可溶性透明质酸酶糖蛋白。
本发明制剂中的透明质酸酶增强抗HER2抗体的吸收,例如通过增加活性物质的吸收来实现(它充当渗透增强剂)。透明质酸酶还通过可逆水解乙酰透明质酸(即SC间质组织的一种胞外组分)来提高治疗性抗HER2抗体经由皮下应用路径对系统循环的投递。皮下的乙酰透明质酸水解暂时打开皮下组织的间质空间中的通道,并且由此改善治疗性抗HER2抗体对系统循环的投递。另外,此技术的施用可以降低和减少人的疼痛和皮下组织的肿胀。
透明质酸酶在数分钟中局部失活并代谢,而且尚未注意到具有系统或长期效应。此特性还使潜在的系统安全性升高,这是因为透明质酸酶产品不能在远离的注射部位起作用。
所有透明质酸酶的统一特征是其解聚乙酰透明质酸的能力,不管化学结构、物种来源、组织来源、或源自相同物种和组织的药物产品的批次的差异。它们的与众不同之处在于,尽 管具有不同结构,它们的活性是相同的(除了效力外)。
依照本发明的许多合适的透明质酸酶。优选的酶是人透明质酸酶,最优选地称为rHuPH20的酶。rHuPH20是通过水解N-乙酰基葡糖胺的C1位置与葡糖醛酸的C4位置间的β-1,4连接来解聚乙酰透明质酸的中性和酸性活性β-1,4糖基水解酶家族成员。乙酰透明质酸是一种在结缔组织,诸如皮下间质组织和某些特化组织,诸如脐带和玻璃体液的胞内基质中找到的多糖。乙酰透明质酸的水解暂时地降低间质组织的粘性,并且促进注射流体或局部漏出液或渗出物的分散,如此便于其吸收。透明质酸酶的效果是局部的,并且在24至48小时内发生的组织乙酰透明质酸完全重建的情况中可逆。经由水解乙酰透明质酸的结缔组织渗透性升高与透明质酸酶在其提高共施用分子的分散和吸收能力方面的功效相关联。
因此在本发明中,在某些优选的实施方案中,本发明提供包含蛋白质的蛋白制剂,特别是包含药物蛋白质的药学上可接受的制剂,其通过蛋白本身提供缓冲作用,并且其不需要额外的缓冲剂以维持所需的pH,并且其中所述的蛋白基本上是唯一的缓冲剂(即其它组分,如果有的话在该制剂中基本上不作为缓冲剂起作用)。在某些优选实施方案中,本发明提供蛋白的自缓冲制剂,特别是药物蛋白的自缓冲制剂,其特征在于所配制的蛋白浓度提供所需的缓冲能力。
本发明提供的一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,无额外的缓冲剂,组分包含:
1)100~200mg/ml抗HER2抗体;
2)60~90mg/ml稳定剂,其中所述稳定剂是糖类;
3)0.3~2mg/ml非离子表面活性剂;
4)0~50mM甲硫氨酸;
5)150至16000U/ml透明质酸酶。
优选的,所述的抗HER2抗体为曲妥珠单抗、帕妥珠单抗和/或它们的抗原结合片段。
优选的,所述的抗HER2抗体的浓度为100~150mg/ml,优选为120mg/ml。
优选的,所述制剂的pH值为5.0~6.0,优选pH值为5.5。
优选的,所述稳定剂为蔗糖、甘露醇和/或海藻糖,优选为蔗糖,所述稳定剂的浓度优选为70mg/ml。
优选的,所述表面活性剂为聚山梨酯20或聚山梨酯80,所述浓度为0.3~1.5mg/ml,浓度优选为1.0mg/ml。
优选的,甲硫氨酸作为第二稳定剂使用,甲硫氨酸的浓度为5至20mM。
优选的,所述透明质酸酶含量为1000至16000U/ml,优选为2000U/ml。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,无额外的缓冲剂,组分包含:100~150mg/ml抗HER2抗体、60~90mg/ml蔗糖、0.3~1.5mg/ml聚山梨酯20、0至50mM甲硫氨酸、2000U/ml透明质酸酶,pH范围是5.0~6.0。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:120mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶,pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.3mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.3mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、25~50mg/ml蔗糖、25~50mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、5~50mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、33.3~66.7mg/ml蔗糖、16.7~33.3mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、5~50mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制 剂,组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明提供的另一个技术方案是:一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
本发明还提供上述制剂在用于制备治疗癌症的药物中的用途,所述癌症选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌和头颈肿瘤;优选地选自乳腺癌、非小细胞肺癌、黑色素瘤和肾癌。
本发明所述的稳定的适用于皮下注射的抗HER2高浓度溶液制剂,具有以下有益效果:
本发明的制剂不用额外添加缓冲剂,可以有效抑制抗体的聚集和脱酰胺作用,从而阻止其中抗体产品的降解,得到稳定性的高浓度组合物。并且,本发明的制剂对于蛋白氧化降解具有保护作用,还能够与玻璃、不锈钢容器相容,在这些容器中也能够稳定存在。
图1为2~8℃处方C/D/E SEC聚体变换趋势图。
图2为2~8℃处方C/D/E SEC纯度变换趋势图。
图3为处方a和b目检图片。
通过以下实施例进一步详细说明本发明。本发明所涉及的稳定剂、表面活性剂在实际应用时是几种物质组合使用。在本发明的基础上改变其浓度或加入其它一些物质,但对提高抗Her2高浓度抗体的蛋白稳定性没有显著作用的改变,仍被视为本发明的一部分。
蛋白质含量测定
采用Lunatic微量光谱分析仪对蛋白质含量进行测定。以纯化水进行空白扣除,以330nm的光散射校正280nm的紫外光吸收,依照公式1计算蛋白质浓度,其中消光系数ε为1.5(L/g·cm
-1)。
分子排阻色谱(SEC-HPLC)
采用分子排阻色谱法来量化聚集体、单体和片段。该方法利用Waters Xbridge BEH SEC
7.8×300mm色谱柱并在Waters e2695-2489 HPLC系统上运行。流动相为200mM磷酸钾盐,250mM氯化钾,pH6.2。用流动相稀释样品到5mg/mL,进样体积为6μL。以0.5mL/min的流速等度洗脱30min,检测波长为280nm。利用Empower 3软件进行积分处理,并按面积归一化法计算各组分的百分含量。
成像毛细管等电聚焦电泳(iCIEF)
成像毛细管等电聚焦电泳中,载体两性电解质在电场作用下在毛细管内从阳极到阴极端建立由小到大的均匀pH梯度,带不同电荷的蛋白电荷异质体根据其等电点的不同在两性电解质pH梯度中进行聚焦分离。全柱聚焦过程在280nm波长下实时监测。采用100μm内径FC涂层熔融石英毛细管,有效分离长度5cm;样品处理时分别加入终浓度为3.5%的GE Pharmalyte 3-10、0.5%的GE Pharmalyte 8-10.5、0.35%的HPMC、2M的尿素,样品终浓度0.25mg/ml;聚焦分离电压和时间为1.5kV-1min,3kV-7min。使用Compass for iCE软件进行数据采集,利用Empower 3软件对图谱进行积分处理。以峰面积百分比计算酸区、主峰与碱区含量,并以Marker pI值计算目标峰的pI值。
透明质酸酶活检测
应用浊度法对透明质酸酶进行活性检测。透明质酸酶可酶解透明质酸底物,过量的透明质酸溶液能够与酸化血清形成稳定的胶体状溶液,通过测定不同浓度的标准品与其对应的吸光度绘制标准曲线,从而得出透明质酸酶的活性。将含供试品、标准品的低蛋白吸附的96孔样品板和含透明质酸工作液的96孔底物板分别置于37℃孵育,从样品板取供试品、标准品至底物板进行反应,再加入血清工作液至底物板终止反应,于640nm处读板测定吸光度,根据标准曲线计算供试品活性。
以下列举具体实施例来阐明本发明,应理解这些例子仅仅是为了说明本发明,而非限制本发明的范围。
实施例1 制剂处方制备
为配制制剂处方溶液,将曲妥珠和帕妥珠使用预期的辅料溶液进行缓冲液交换,并在需要时通过超滤浓缩至所需抗体浓度。完成超滤浓缩后,将要添加的辅料以母液形式添加至抗体溶液,最后用缓冲液将蛋白质浓度调节约110mg/ml、120mg/ml、130mg/ml、140mg/ml、 150mg/ml。将所有配制剂通过0.22μm低蛋白质结合滤器无菌过滤,并在无菌条件下灌装至无菌2ml管制瓶中,使用覆膜胶塞和铝塑组合盖密封。这些制剂溶液放在2~8℃、25℃、40℃、光照条件下考察样品稳定性。以下是不同的制剂处方及稳定性结果:
处方A:120mg/ml曲妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、pH5.5。
表1:处方A的稳定性数据
注:N/A表示未检测。
处方B:120mg/ml帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、pH5.5。
表2:处方B的稳定性数据
注:N/A表示未检测。
处方C:120mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、10mM甲硫氨酸,pH5.5。
表3:处方C的稳定性数据
注:N/A表示未检测。
处方D:120mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、20mM组氨酸盐酸、1mg/ml聚山梨酯20、10mM甲硫氨酸、pH5.5。
表4:处方D的稳定性数据
注:N/A表示未检测。
处方E:120mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、20mM醋酸钠缓冲溶液、10mM甲硫氨酸、pH5.5。
表5:处方E的稳定性数据
注:N/A表示未检测。
通过以上5个处方可以发现:无缓冲盐处方C与有组氨酸缓冲盐处方D和有醋酸钠缓冲盐的处方E在SEC聚体含量方面没有明显差别,参见附图1和附图2。另外发现在iCIEF方面无缓冲盐的处方C主峰高于含有组氨酸缓冲盐制剂的主峰,酸区更低,优于含有缓冲盐的处方D和E。另外在制备工艺过程中无缓冲盐的高浓度制剂制备更加简单和节约成本。
处方F:150mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、pH5.5。
表6:处方F的稳定性数据
处方G:150mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、20mM组氨酸盐酸、pH5.5。
表7:处方G的稳定性数据
通过处方F和处方G发现:经过稳定性放置,未含有缓冲盐的高浓度制剂处方F和含有组氨酸缓冲盐的高浓度制剂处方G的聚体变化趋势是一致的;iCIEF显示,未含有缓冲盐的高浓度制剂主峰高于含有组氨酸缓冲盐制剂的主峰,酸区低于含有缓冲盐的高浓度制剂酸区,都优于含有缓冲体系的处方。
处方H:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
表8:处方H的稳定性数据
注:N/A表示未检测。
处方I:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
表9:处方I的稳定性数据
处方J:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.3mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
表10:处方J的稳定性数据
处方K:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.3mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
表11:处方K的稳定性数据
通过H、I、J、K处方可知,进一步探索聚山梨酯20的含量范围,发现其浓度在0.3~1mg/ml范围内,产品的稳定性均保持在很好的水平上。
处方L:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、pH5.5。
表12:处方L的稳定性数据
N/A表示未检测
处方M:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、pH5.5。
表13:处方M的稳定性数据
N/A表示未检测
处方N:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
表14:处方N的稳定性数据
处方O:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
表15:处方O的稳定性数据
处方P:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、20mM组氨酸盐酸、2000U/ml透明质酸酶、pH5.5。
表16:处方P的稳定性数据
处方Q:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、20mM组氨酸盐酸、2000U/ml透明质酸酶、pH5.5。
表17:处方Q的稳定性数据
以上L、M、N、O、P、Q处方经过稳定性考查可知,透明质酸酶对抗体纯度没有影响,抗体对酶活同样没有影响,且透明质酸酶酶活及抗体较为稳定。此外对比含有组氨酸的处方抗体纯度及透明质酸酶酶活没有差异,但是在制备过程中减少了相应的配料过程,节约了生产成本,同时可以避免组氨酸在光照诱导下产生的光敏剂对单克隆抗体的降解等。
实施例2含有缓冲盐的制剂氧化分析
超滤浓缩后高浓度制剂处方和稀释5倍后检测组氨酸含量,并且进行目检。
处方a:120mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、pH5.5。
光照(4500±500lx)条件下放置4周进行目检。
表18 处方a组氨酸含量检测和目检结果
注:N/D为未检测
处方b:120mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、20mM组氨酸盐酸、10mM甲硫氨酸、pH5.5。
光照(4500±500lx)条件下放置4周进行目检。
表19 处方b组氨酸含量检测和目检结果
组氨酸含量 | 色号 | |
处方b | 20mM | Y1~Y2 |
含有组氨酸的高浓度制剂在光照条件下放置,颜色明显变成棕黄色。
通过以上试验发现:参见附图3,在光照4周后含有组氨酸缓冲盐的处方b颜色明显变黄,未含有缓冲盐的处方a则无明显变化。组氨酸的氧化降解已被广泛报道,在一项研究中,组氨酸通过光氧化产生光敏剂,从而介导单克隆抗体的光降解,组氨酸还可以被过氧化氢和金属阳离子氧化。单线态氧攻击组氨酸的咪唑环,引发组氨酸的光氧化反应,形成一种内过氧化物中间体,该中间体进一步分解,生成多种最终产物,包括天冬氨酸和尿素。
对处方a与处方b未光照与光照4周样品通过LC-MS/MS在肽图水平进行翻译后修饰分析,翻译后修饰分析结果见表20。处方a与处方b光照4周后,脱酰胺、脱氨基、糖化、D异构、K缺失与N-端E环化均没有明显变化,但是甲硫氨酸(M)与色氨酸(W)氧化修饰均明显增加,其中处方b抗体的甲硫氨酸与色氨酸氧化修饰增加比处方a抗体更多,如H1:W
99光照4周后的处方a中色氨酸修饰比例为3.17,处方b中色氨酸修饰比例为18.13;H1:M
361/H2:M
360光照4周后的处方a甲硫氨酸修饰比例为52.80,处方b甲硫氨酸修饰比例为79.10。
表20 翻译后修饰分析结果
注:“H1”、“L1”为曲妥珠单抗重链与轻链,“H2”、“L2”为帕妥珠单抗重链与轻链;糖化修饰比例仅用于样品间对比,NQ表示含量太低,不能定量;ND表示未检测;斜体为修饰位。
以上,对本发明示例性的实施方式进行了说明。但是,本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (21)
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:无额外的缓冲剂,组分包含:1)100~200mg/ml抗HER2抗体;2)60~90mg/ml稳定剂,其中所述稳定剂是糖类;3)0.3~2mg/ml非离子表面活性剂;4)0~50mM甲硫氨酸;5)150至16000U/ml透明质酸酶。
- 如权利要求1所述的制剂,其特征在于:所述的抗HER2抗体为曲妥珠单抗、帕妥珠单抗和/或它们的抗原结合片段。
- 如权利要求1所述的制剂,其特征在于:所述的抗HER2抗体的浓度为100~150mg/ml,优选为120mg/ml。
- 如权利要求1所述的制剂,其特征在于:所述制剂的pH值为5.0~6.0,优选pH值为5.5。
- 如权利要求1所述的制剂,其特征在于:所述稳定剂为蔗糖、甘露醇和/或海藻糖,优选为蔗糖,所述稳定剂的浓度优选为70mg/ml。
- 如权利要求1所述的制剂,其特征在于:所述表面活性剂为聚山梨酯20或聚山梨酯80,所述浓度为0.3~1.5mg/ml,浓度优选为1.0mg/ml。
- 如权利要求1所述的制剂,其特征在于:甲硫氨酸作为第二稳定剂使用,甲硫氨酸的浓度为5至20mM。
- 如权利要求1所述的制剂,其特征在于:所述透明质酸酶含量为1000至16000个U/ml,优选为2000U/ml。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:无额外的缓冲剂,组分包含:100~150mg/ml抗HER2抗体、60~90mg/ml蔗糖、0.3~1.5mg/ml聚山梨酯20、0至50mM甲硫氨酸、2000U/ml透明质酸酶,pH范围是5.0~6.0。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、25~50mg/ml蔗糖、25~50mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、5~50mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、33.3~66.7mg/ml蔗糖、16.7~33.3mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、5~50mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:120mg/ml曲妥珠和帕妥珠抗体、70mg/ml蔗糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶,pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.3mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.3mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.3~1mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:60mg/ml曲妥珠和60mg/ml帕妥珠抗体、34.2mg/ml蔗糖、39.7mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 一种稳定的适用于皮下注射的抗HER2高浓度溶液制剂,其特征在于:组分为:40mg/ml曲妥珠和80mg/ml帕妥珠抗体、45.5mg/ml蔗糖、26.5mg/ml海藻糖、0.4mg/ml聚山梨酯20、10mM甲硫氨酸、2000U/ml透明质酸酶、pH5.5。
- 权利要求1-20任一项所述的制剂在用于制备治疗癌症的药物中的用途,其特征在于:所述癌症选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌和头颈肿瘤;优选地选自乳腺癌、非小细胞肺癌、黑色素瘤和肾癌。
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CN1539505A (zh) * | 1995-07-27 | 2004-10-27 | �����ɷ� | 稳定等渗的冻干蛋白质制剂 |
CN102573789A (zh) * | 2009-07-31 | 2012-07-11 | 霍夫曼-拉罗奇有限公司 | 皮下抗her2抗体配制剂 |
CN110167594A (zh) * | 2017-01-17 | 2019-08-23 | 基因泰克公司 | 皮下her2抗体配制剂 |
TW202123965A (zh) * | 2019-09-09 | 2021-07-01 | 德商百靈佳殷格翰國際股份有限公司 | 抗-il-23p19抗體調配物 |
CN114129723A (zh) * | 2020-09-03 | 2022-03-04 | 齐鲁制药有限公司 | 一种高浓度抗her2的抗体制剂及其用途 |
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CN1539505A (zh) * | 1995-07-27 | 2004-10-27 | �����ɷ� | 稳定等渗的冻干蛋白质制剂 |
CN102573789A (zh) * | 2009-07-31 | 2012-07-11 | 霍夫曼-拉罗奇有限公司 | 皮下抗her2抗体配制剂 |
CN110167594A (zh) * | 2017-01-17 | 2019-08-23 | 基因泰克公司 | 皮下her2抗体配制剂 |
TW202123965A (zh) * | 2019-09-09 | 2021-07-01 | 德商百靈佳殷格翰國際股份有限公司 | 抗-il-23p19抗體調配物 |
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