CN101410137A - Anti-IGF-1R human monoclonal antibody formulation - Google Patents
Anti-IGF-1R human monoclonal antibody formulation Download PDFInfo
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- CN101410137A CN101410137A CNA2007800114320A CN200780011432A CN101410137A CN 101410137 A CN101410137 A CN 101410137A CN A2007800114320 A CNA2007800114320 A CN A2007800114320A CN 200780011432 A CN200780011432 A CN 200780011432A CN 101410137 A CN101410137 A CN 101410137A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- 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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- 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
- A61K47/16—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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
Abstract
The present invention relates to an anti-IGF-1R human monoclonal antibody formulation, a process for the preparation and uses thereof.
Description
The present invention relates to a kind of resisting-the IGF-1R human monoclonal antibody formulation, prepare and use its method.
On the one hand, the present invention relates to the IGF-1R preparation, it comprises:
-Yue 1 to about 150mg/mL huMab IGF-1R,
-Yue 0.001 to about 1% at least a surfactant and
-Yue 1 to about 100mM buffer,
-Yue 5.0 to about 7.0 pH.
Described IGF-IR (1 type IGF-1) has participated in promoting the tumorigenesis of cancerous cell to transform, growing and survival.The IGF-IR of report excessive level expresses in people's malignant diseases of wide region.In addition, in tumor and relevant stromal cell, notice that high-caliber IGF-I and IGF-II express, and it may stimulate growth of cancer cells in the mode of autocrine or paracrine.Epidemiological study last five minute of the blood plasma level (upper quintileplasma levels) with IGF-I is relevant with the danger of the carcinoma of prostate, colon cancer, pulmonary carcinoma and the breast carcinoma that increase.Except its effect in cancer cell multiplication, IGF-IR protection cell avoids treating the programmed cell death that causes by somatomedin scarcity, adherent not dependency or cytotoxic drug.
The strategy a kind of likely of the function of IGF-IR is the anti-IGF-IR antibodies of should choosing in the anticancer, and it is in conjunction with extracellular domain and the inhibition receptor activation of IGF-IR.Developed human monoclonal antibodies such antagonism, complete, called after huMab IGF-1R, its specificity are in conjunction with human insulin-like growth factor I receptor (IGF-IR), and signal conduction and the propagation function of inhibition this receptor in cancerous cell.
Antibody included in preparation of the present invention is described in PCT number of patent application WO2005/005635 at first, and the applicant of this application is everyone, and the content of this application, and particularly claim is incorporated herein by reference.As described in the WO2005/005635, described antibodies IGF-IR, and suppress IGF-I and IGF-II in conjunction with IGF-IR, and it is characterized in that, it:
A) be the IgG1 isotype,
B) show 1: 3 to 3: 1 inhibition IGF-I in conjunction with the IC of IGF-IR
50Value combines the IC of IGF-IR with inhibition IGF-II
50The ratio of value,
C) in the culture medium that contains 0.5% heat-inactivated hyclone (FCS), during the cells phosphorylation that carries out with the HT29 cell is measured, when with such mensuration that need not described antibody relatively the time, it is with the concentration of 5nM, suppress at least 80%, preferably at least 90% IGF-IR phosphorylation and
D) in the culture medium that contains 0.5% heat-inactivated hyclone (FCS), use the 3T3 cell, provide 400,000 to 600,000 molecule I GF-IR/ cell, and during the cells phosphorylation that carries out measures is when with mensuration that need not described antibody relatively the time, in the concentration of 10 μ M, it does not show the IGF-IR stimulating activity of measuring as the pkB phosphorylation.
Antibody included in preparation of the present invention demonstrates benefit to the patient who needs antineoplaston, and the minimizing of tumor growth is provided and has reached the significant prolongation of the time of development.Included antibody has novel and creationary feature in preparation of the present invention, and it is that the patient who suffers from the disease, particularly tumor disease unusual relevant with IGF brings benefit.Included antibody is characterised in that above-mentioned feature in preparation of the present invention.Therefore, described feature particularly specificity suppresses IGF-I and IGF-II in conjunction with IGF-IR in conjunction with IGF-IR with aforementioned proportion, is the IgG1 isotype, and even is being its IC
50Do not activate the conduction of IGF-IR signal in the cell of the overexpression IGF-IR of 200 times of concentration of value yet.When as therapeutic agent, the antibody that does not have " IGF-I simulates active " provides very strong advantage.
Term " anti--IGF-1R human monoclonal antibodies " or " huMAb IGF-IR " expression as described in the WO2005/005635 and claimed antibody, the content of WO2005/005635, particularly claim, incorporated herein by reference.
Term " antibody " comprises multi-form antibody, includes but not limited to the antibody of complete antibody, antibody fragment, people's antibody, humanized antibody and heredity processing, as long as keep characteristic features of the present invention.
" antibody fragment " comprises the part of full length antibody, usually its antigen-binding portion thereof or variable region at least.The example of antibody fragment comprises double antibody, single-chain antibody molecule, immunotoxin and the multi-specificity antibody that is formed by antibody fragment.In addition, antibody fragment comprises single chain polypeptide, described single chain polypeptide has the feature of VH chain, promptly can fit together with the VL chain, perhaps has feature in conjunction with the VL chain of IGF-1R, promptly can fit together with the VH chain becomes the functional antigen binding pocket, and provides thus and suppress IGF-I and the IGF-II feature in conjunction with IGF-IR.
" antibody fragment " also comprises such fragment, and effector functions (ADCC/CDC) can not be provided itself, but providing this function with suitable antibody constant domain combination is back in mode of the present invention.
When being used for this paper, term " monoclonal antibody " or " monoclonal antibody combination " are meant the preparation of the antibody molecule that single amino acid is formed.Therefore, term " human monoclonal antibodies " refers to show the antibody of single binding characteristic, and it has the variable and constant region that the ethnic group of deriving from is an immunoglobulin sequences.In one embodiment, described human monoclonal antibodies produces by hybridoma, and the B cell that it comprises available from transgenic nonhuman animal such as transgenic mice has and comprises people's heavy chain transgenic and the genetically modified genome of light chain people that is fused in the infinite multiplication cell.
Term " chimeric antibody " refers to such monoclonal antibody, and it comprises the variable region from a kind of source or species, promptly the land and from separate sources or species to the small part constant region, prepare by recombinant DNA technology usually.The chimeric antibody that comprises variable region, Mus source and human constant region is particularly preferred.Such Mus source/people's chimeric antibody is the product of the immunoglobulin gene of expression, and the immunoglobulin gene of described expression comprises the dna fragmentation of coding Mus source immune globulin variable region and the dna fragmentation of coding human normal immunoglobulin constant region." chimeric antibody " of other form that the present invention is included be wherein kind or subclass modified from original antibody or change those." chimeric " antibody so also is called " kind-conversion antibody ".The method that produces chimeric antibody comprises present conventional recombinant DNA well known in the art and gene transfection technology.Referring to, for example, Morrison, S.L., etc., Proc.Natl.Acad Sci.USA (NAS's journal) 81 (1984) 6851-6855; U.S. Patent number 5,202,238 and 5,204,244.
Term " humanized antibody " refers to such antibody, and wherein framework or " complementary determining region " (CDR) have been modified to and comprise comparing with parent's immunoglobulin to have the not CDR of homospecific immunoglobulin.In preferred embodiments, Mus source CDR is transplanted to the framework region of people's antibody, with preparation " humanized antibody ".Referring to, for example, Riechmann, L., etc., Nature (nature) 332 (1988) 323-327; And Neuberger, M.S., etc., Nature (nature) 314 (1985) 268-270.The corresponding identification of particularly preferred CDRs is above-mentioned about chimeric and antigenic those representative series bifunctional antibody.
Term " people's antibody " when being used for this paper, is intended to comprise that having from ethnic group is the variable region of immunoglobulin sequences and the antibody of constant region.It kind is sequence D P-50 (GenBank LO6618) that variable heavy chain preferably derives from, and variable light chain preferably to derive from kind be sequence L6 (GenBank X01668).The constant region of described antibody is the constant region of human IgG1's type.Such zone can be allotypic, and by for example Johnson, G., and Wu, T.T., NucleicAcids Res. (nucleic acids research) 28 (2000) 214-218 and the data base that wherein quotes are described, and are useful, as long as keep ADCC and the feature of CDC preferably of inducing of the present invention.
Term " recombinant human antibody ", when being used for this paper, be intended to comprise by recombination form preparation, expression, generation or isolating everyone antibody, such as from host cell such as SP2-0, NS0 or Chinese hamster ovary celI or from for the human immunoglobulin gene be genetically modified animal (for example, mice) isolated antibody, perhaps use transfection in the host cell the recombinant expression carrier antibody of expressing.Such recombinant human antibody has the variable and constant region that the ethnic group of deriving from is an immunoglobulin sequences in the mode of resetting.Recombinant human antibody of the present invention has carried out intravital somatic hypermutation.Therefore, the aminoacid sequence in the VH of described recombinant antibodies and VL zone is such sequence, that is, although derive from and be that VH is relevant with the VL sequence with ethnic group, it can not the natural in vivo people's of being present in antibody kind be among all members.
When being used for this paper, " combination " is meant with about 10
-13To 10
-8M (K
D), preferably about 10
-13To 10
-9The affinity of M is in conjunction with the antibody of IGF-IR.
Term " nucleic acid molecules " when being used for this paper, is intended to comprise dna molecular and RNA molecule.Nucleic acid molecules can be strand or double-stranded, but double-stranded DNA preferably.
" constant domain " do not participated in antibody directly and combined with antigenic, but participates in effector functions (ADCC, complementary combination, and CDC).The constant domain of antibody of the present invention is the IgG1 type.People's constant domain with these features is at Kabat etc., Sequences ofProteins of Immunological Interest (protein sequence of immunology purpose), the 5th edition .Public Health Service (public health care service), National Institutes of Health (national health institute), Bethesda, MD. (1991), with Br ü ggemann, M., etc., J.Exp.Med. (The Journal of Experimental Medicine) 166 (1987) 1351-1361; Love, T.W., etc., describe in detail among MethodsEnzymol. (Enzymology method) 178 (1989) 515-527.Example is shown as SEQ ID NOS:5-8 in WO2005/005635.Other useful and preferred constant domain is can be available from the constant domain of the antibody of the hybridoma cell line that is kept at DSMZ for this invention.Be used for constant domain of the present invention complementary combination is provided.ADCC and randomly CDC provide by variable and combination constant domain.
When being used for this paper, right each of antibody and the bonded light chain of antigen and heavy chain is participated in " variable region " (variable region of light chain (VL), the variable region of heavy chain (VH)) expression directly.The domain of variable people's light chain and heavy chain has identical general structure (general structure), and each domain comprises 4 frameworks (FR) district that sequence is extensively conservative, and they are by 3 " super variable region " (or complementary determining region, CDRs) connection.This framework region adopts the beta sheet conformation, and CDRs can form the ring that connects described beta sheet structure.CDRs in every chain is contained in their three dimensional structure by described framework region, and forms antigen binding site with CDRs from another chain.Particular importance plays in heavy chain of antibody and light chain CDR3 district in the binding specificity/affinity of antibody of the present invention, and therefore provides another object of the present invention.
When being used for this paper, term " super variable region " or " antigen-bound fraction of antibody " are meant the amino acid residue of the antibody of being responsible for conjugated antigen.Described super variable region comprises the amino acid residue from " complementary determining region " or " CDRs "." framework " or " FR " district is those variable domains districts except super variable region residue defined herein.Therefore, the light chain of antibody and heavy chain comprise domain FR1, CDR1, and FR2, CDR2, FR3, the N of CDR3 and FR4 holds to C.Especially, the CDR3 of heavy chain helps the bonded zone of antigen most.CDR and FR district are according to Kabat etc., (protein sequence of immunology purpose), the 5th edition .Public Health Service (public health care service), National Institutes of Health (national health institute), Bethesda, MD. (1991)) standard definition determine, and/or be those residues from " super variable loop ".
When being used for this paper, term " combines with IGF-IR " and means in external test, during preferably antibodies combination was from the teeth outwards therein measured, described antibody combined with IGF-IR's, and the combination of IGF-IR is measured by surface plasma resonance (SPR).In conjunction with meaning binding affinity (K
D) 10
-8M or littler, preferred 10
-13To 10
-9M.
Combine with IGF-IR and can measure (Pharmacia Biosensor AB (Pharmacia biosensor AB), Uppsala, Sweden) research by BIAcore.Bonded affinity is by term ka (antibody from antibody/antigen complex on associating speed constant), kd (dissociation constant) and K
D(kd/ka) definition.Antibody of the present invention shows 10
-10M or littler K
D
The antibody inhibition that IGF-I and IGF-II are also described by the present invention with combining of IGF-IR.In the described bonded mensuration of IGF-IR that is suppressed on IGF-I/IGF-II and the tumor cell with IC
50Measure.Being determined among the embodiment 7 like this described.In such mensuration, (for example, radiolabeled IGF-I or IGF-II or its segmental amount in conjunction with IGF-IR in conjunction with the IGF-IR that HT29) provide on the surface need not or be measured with the antibody that increases concentration at described tumor cell.Antibody of the present invention is for IGF-I and IGF-II and the bonded IC of IGF-IR
50Value is not more than 2nM, and about IGF-I/IGF-II and the bonded IC of IGF-IR
50The ratio of value is about 1: 3 to 3: 1.IC
50Value is measured as the meansigma methods or the intermediate value of at least three independent measurements.Single IC
50Value may go beyond the scope.
When being used for this paper, term " to IGF-I and IGF-II and the bonded inhibition of IGF-IR " refers in external test, suppresses I
125The IGF-I of-labelling or IGF-II with present combining of IGF-IR on HT29 (ATCCHTB-38) tumor cell surface.Suppress to mean 2nM or lower IC
50Value.
When being used for this paper, term " surfactant " expression medicinal surfactant.In preparation of the present invention, the amount of surfactant is described as the percent represented with weight/volume.The most frequently used weight/volume unit is mg/mL.Suitable medicinal surfactant includes but not limited to, polyethylene-sorbitan-fatty acid ester, polyethylene-polypropylene glycol, polyoxyethylene-stearate and sodium lauryl sulphate.Preferred polyethylene-anhydro sorbitol is that polyethylene (20)-anhydro sorbitol-ester is (with the Polysorbate 20 synonym, with the trade (brand) name polysorbas20
TMSell) and polyoxyethylene (20) Arlacel-80 (with the polysorbate 80 synonym, with the trade (brand) name Tween 80
TMSell).Preferred polyethylene-polypropylene glycol is with title Pluronic
F68 or Poloxamer 188
TMThose that sell.Preferred polyoxyethylene-stearate is with trade (brand) name Myrj
TMThose that sell.Preferred Vinlub 73 is with trade (brand) name Brij
TMThose that sell.When using polyethylene-anhydro sorbitol-polyethylene (20)-anhydro sorbitol-ester (polysorbas20
TM) and polyoxyethylene (20) Arlacel-80 (Tween 80
TM) time, they use with about 0.001 to about 1%, preferably about 0.005 to about 0.1% and also preferably about 0.01 to about 0.02%w/v amount usually.
When being used for when of the present invention, medicinal buffer represented in term " buffer ".Suitable medicinal buffer includes but not limited to histidine-buffer, citric acid-buffer, succinic acid-buffer, acetic acid-buffer and phosphoric acid-buffer.Preferred buffer comprises the mixture of L-histidine or L-histidine and L-histidine hydrochloride and isotonic agent, carries out pH regulator with acid known in the art or alkali.Above-mentioned histidine-buffer arrives about 100mM with about 1mM usually, and preferably about 5mM is to about 50mM and the also more preferably amount of about 20mM use.Do not rely on used buffer, pH will comprise about 5.0 to about 7.0 and preferably about 5.5 to about 6.5, and preferably about 6.0 value is regulated.
When being used for this paper, medicinal isotonic agent represented in term " isotonic agent ".Isotonic agent is used to provide etc. opens preparation.Deng opening a preparation is liquid or by solid form, the liquid rebuild of lyophilized form for example, and expression has other solution such as the physiological solt solution tensile solution identical with blood serum that is compared with it.Suitable isotonic agent includes but not limited to sodium chloride, potassium chloride, glucose, glycerol and any composition from the aminoacid group, sugar and their combination.Isotonic agent uses to the total amount of about 350mM with about 5mM usually.
When being used for this paper, it is the preparation of liquid to about 8 ℃ temperature that term " liquid " and preparation contacts list of the present invention are shown at least about 2.
When being used for this paper, term " freeze dried " is got in touch expression by freezing described preparation and subsequently by any freeze-drying method known in the art with preparation of the present invention, the freeze-dried device that for example is purchased will be iced the preparation that distils from refrigerated content.
When being used for this paper, the aminoacid of the amount of term " aminoacid " expression about 1 to about 100mg/mL includes but not limited to arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, proline.
When being used for this paper, the medicinal sugar that term " sugar " expression is used to the amount of about 500mM with about 25mM.Suitable sugar includes but not limited to trehalose, sucrose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, Raffinose, glycosamine, N-methylglucosamine (so-called " meglumine "), galactosamine and neuraminic acid.
Term " stabilizing agent " refers to medicinal stabilizing agent, such as but not limited to, the cyclodextrin that is purchased and the glucosan of the described aminoacid in top and sugar and any kind of known in the art and molecular weight.
Medicinal antioxidant represented in term " antioxidant ".
As mentioned, on the one hand, the present invention relates to the IGF-1R preparation, it comprises:
-Yue 1 to about 150mg/mL huMab IGF-1R,
-Yue 0.001 to about 1% at least a surfactant and
-Yue 1 to about 100mM buffer,
-Yue 5.0 to about 7.0 pH.
Preparation of the present invention preferably includes about 0.001 to about 1% at least a surfactant.
In a specific embodiment, preparation of the present invention comprises:
-Yue 1 to about 150mg/mL huMab IGF-1R,
-Yue 0.005 to about 0.05% at least a surfactant and
-Yue 1 to about 100mM buffer,
-Yue 5.0 to about 7.0 pH.
Preparation of the present invention can be to be liquid form, freeze dried form or by the liquid form of lyophilized form reconstruct.
In a specific embodiment, preparation of the present invention is freeze dried preparation.About the granule of higher molecular weight and the preparation of aggregation, it is difficult in usually with the identical concentration of described resisting-IGF-1R human monoclonal antibodies and obtains liquid preparation, and freeze dried preparation of the present invention has the advantage of the stability of raising.
Preparation of the present invention can be used such as known those of drug world by intravenous (i.v.), subcutaneous (s.c.) or any other parenteral (parental) method of application.
Preparation of the present invention may further include the isotonic agent of one or more about 5mM to the amount of about 350mM.Suitable isotonic agent can be selected from by sodium chloride (NaCl), potassium chloride, and sugar comprises glucose, glycerol, aminoacid, and the group of their combination composition.
Preparation of the present invention may further include the sugar of about 25mM to the amount of about 500mM.Suitable sugar can be selected from the group of being made up of trehalose, sucrose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, Raffinose, glycosamine, N-methylglucosamine, galactosamine, neuraminic acid and its combination.
Preparation of the present invention may further include one or more following components: antioxidant, ascorbic acid, glutathion, antiseptic, for example ,-cresol, phenol, benzyl alcohol, methyl butex, propyl parabene, methaform, thiomersal, benzalkonium chloride, cyclodextrin, HP-for example, sulfo-butyl ethyl-beta-schardinger dextrin-, beta-schardinger dextrin-, Polyethylene Glycol, for example PEG 3000,3350,4000,6000, albumin, human serum albumin (HSA), bovine serum albumin (BSA), polyhydroxy-alcohol, glycerol, ethanol, mannitol, salt, acetate, (for example sodium acetate), magnesium chloride, calcium chloride, trometamol, EDTA (for example Na-EDTA).
Preparation of the present invention may further include one or more stabilizing agents defined above and also is known in the industry as the composition of " solvent protective agent (lyoprotectants) ", such as sugar known in the art, sugar alcohol, aminoacid and glucosan.
In a specific embodiment, preparation of the present invention comprises following preparation, with liquid, freeze dried or by the liquid of lyophilized form reconstruct:
-Yue 1 to about 150mg/mL huMab IGF-1R,
-0.01% polysorbas20 w/v,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0。
Preparation of the present invention also comprises following concrete preparation:
-25mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-0.03% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-0.05% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-10mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-10mg/mL huMab IGF-1R，
-0.03% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-10mg/mL huMab IGF-1R，
-0.05% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-140mM NaCl，
-pH 5.5；
Or
-25mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-pH 5.5；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-0.05% Polysorbate 20,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-60mM trehalose dihydrate compound,
-0.01% Polysorbate 20,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM succinate (succinate),
-250mM trehalose dihydrate compound,
-0.01% Polysorbate 20,
-pH 5.5；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-60mM trehalose dihydrate compound,
-0.01% Polysorbate 20,
-pH 6.0。
In the preferred embodiment of preparation of the present invention, described preparation is with freeze dried form, and comprises after an amount of water reconstruct that is used to inject:
-25mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-pH 5.5。
When 2-8 ℃ and 25 ℃ were preserved about 6 months, this preparation showed good stable, had to be lower than 1.5% high molecular weight species, and did not form visible and at microscopically visible granule.Shake and repeatedly freeze thawing step be used for this liquid preparation, with the simulation in preparation process, for example by in filter pressing and filling, lyophilizing and the complete operation process, the physical property stress condition of potential generation.Find that this preparation is stable at 5 ℃ and 25 ℃ after shaking a week.Can not detect visible and just visible particulate formation of microscopically, and in the fraction that shows the high molecular weight species that forms soluble aggregation, not observe remarkable increase.
Shake with freeze thawing after high molecular weight species
Embodiment
Following exploitation is of the present invention to be used for liquid and the freeze dried formulation of pharmaceutical products that intravenous is used:
The preparation liquid preparation
To dialyse with final preparation buffer salt system (referring to the form of accurate composition) separately at the water of large volume at about 10 and the 25mg/mL huMab IGF-1R solution produced in the buffer (about 10mM histidine buffering liquid has about 150mM NaCl) with preparation.If desired, before dialysis, protein concentration is purchased the centrifugal filter device filtration by use to be increased, and then by adjusting to the protein concentration that needs with the dilution of dialysis buffer liquid.When needing, will be used for stable protein and join dialysis buffer liquid with the sugar and the salt that are used for tension adjustment.After dialysis, surfactant is joined in the described preparation with 2-40 liquid storage doubly.Alternatively, buffer-exchanged and concentrate to use the grossflow filtration device (tangential flow filtrationdevice) that is purchased for example has Sartorius Hydrosart film (30 ' 000Da molecular cut off)
CF (GE health care (GE Healthcare)) carries out.Composition adds by the concentrated liquid storage that uses appropriate amount after buffer-exchanged such as sugar, salt or surfactant.All preparations all are to carry out aseptic filtration by the low protein binding filter of 0.22 μ m, and aseptic whole assigning in the aseptic 6mL vial, and this vial is with the rubber stopper and the alucrimp cap closure of special teflon-Bao quilt.These preparations are preserved different intervals under different temperatures, and take out at the specified time point of each section and to analyze, and analyze by 1) the UV spectrophotometry, 2) size exclusion chromatograph (SEC) and 3) the dark property of light carries out, with the turbidity of definite solution.In addition, use Seidenader V90-T instrument that every kind of sample is carried out the analysis of visible particle.The microscopically just appearance of visible particle is assessed by HIAC Royco device.
Prepare freeze dried preparation
Prepare 25mg/mL huMab IGF-1R solution by above-mentioned about liquid preparation.All preparations all are to carry out aseptic filtration by the low protein binding filter of 0.22 μ m, and aseptic whole assigning in the aseptic vial.This bottle part is partially enclosed with the rubber stopper of special teflon-Bao quilt, is applicable in freeze-drying process and uses, and transfer in the hothouse of lyophil apparatus.Any known freeze drying process in this area all is intended to comprise within the scope of the invention.For example, the freeze drying process that is used for this research comprises described preparation is cooled to about 5 ℃ (pre-coolings) from room temperature, then by freezing at-40 ℃ (freezing I), carries out with the rate of descent of about 1 ℃/min to 5 ℃/min.First drying steps can 0.3 to 0.5 ℃ rate of descent use from-40 ℃ to-30 ℃, under the constant pressure of about 75 to 80m Torr, remain on then-30 ℃ at least 50 hours.Second drying nest can be with rate of descent generation from-30 ℃ to 25 ℃ of 0.1 to 0.3 ℃/min, and about 50 under the constant pressure of 80m Torr 25 ℃ of maintenances at least 5 hours.Find to use the exsiccant huMab IGF-1R of above-mentioned freeze drying process preparation to have approximately＜time of quick reconfiguration expediently of 5 minutes.Lyophilizing is carried out in LyoStar II lyophil apparatus (FTS system, StoneRidge, New York, the U.S. and Usifroid Orion, Maurepas, France).When determining by the Karl-Fischer method, all freeze dried cakes have the residual water content of about 0.1-5.0% in this research.Freeze dried bottle is preserved different intervals under different temperatures.Before analyzing, described freeze dried preparation with separately injection water volume (WFI) reconstruct, is analyzed by 1) the UV spectrophotometry, 2) determine reconstitution time, 3) size exclusion chromatograph (SEC) and 4) the dark property of light carries out, with the turbidity of definite solution.In addition, use Seidenader V90-T instrument (Seidenader, Marktschwaben, Germany) every kind of sample to be carried out the analysis of visible particle.The microscopically just appearance of visible particle is assessed by HIAC Royco device.
Carry out size exclusion chromatography (SEC) to detect soluble high molecular weight species (aggregation) and low-molecular-weight hydrolyzate in the said preparation.This method is used Merck Hitachi's 7000 HPLC instruments or is had the Waters Alliance 2795 of UV detector (detecting wavelength X (280nm)).These two kinds of instruments all are equipped with TSK G3000 SWXL post; This method is used 0.2M K
2HPO
4/ 0.25MKCL, pH 7.0 is as mobile phase.Flow velocity is 0.5mL/min (equality), and 30 minutes running times, column temperature is at 25 ℃.With diluted sample to the 0.5mg/mL antibody concentration, go up at 278nm and determine the UV spectrophotomelric assay of protein concentration at Varian Cary Bio UV spectrophotometer at 280nm at Uvikon932 (Kontron instrument) respectively.Determine for turbidity, use HACH 2100AN scopometer in room temperature with the dark property of FTU (turbidity unit) measuring light.
The composition of liquid huMAb IGF-1R of the present invention pharmaceutical preparation and at the 2-8 ℃ of stability data after preserving 3 months
Preparation A is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 140mM NaCl, 0.01% Polysorbate 20 is at the composition of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU (turbidity) |
| Initially | 24.47 | 0.82 | 9.94 |
| 4 weeks | 22.35 | 1.0 | 10.3 |
| 8 weeks | 23.02 | 1.31 | 9.83 |
| 12 weeks | 23.59 | 1.46 | 9.22 |
Preparation B is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 140mM NaCl, 0.03% Polysorbate 20 is at the composition of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 24.98 | 0.84 | 9.79 |
| 4 weeks | 23.58 | 1.01 | 9.97 |
| 8 weeks | 25.43 | 1.37 | 10.5 |
| 12 weeks | 23.68 | 1.49 | 10.3 |
Formulation C is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 140mM NaCl, 0.05% Polysorbate 20 is at the composition of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 24.42 | 0.85 | 10.1 |
| 4 weeks | 21.57 | 1.02 | 10.5 |
| 8 weeks | 25.0 | 1.36 | 10.6 |
| 12 weeks | 23.97 | 1.51 | 10.2 |
Preparation D is a liquid preparation, and it has 10mg/mL huMab IGF-1R, 20mM L-histidine, and 140mM NaCl, 0.01% Polysorbate 20 is at the composition of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 9.87 | 0.63 | 4.42 |
| 4 weeks | 9.61 | 0.75 | 4.44 |
| 8 weeks | 9.72 | 0.97 | 4.53 |
| 12 weeks | 9.63 | 1.11 | 4.24 |
Preparation E is a liquid preparation, and it has 10mg/mL huMab IGF-1R, 20mM L-histidine, and 140mM NaCl, 0.03% Polysorbate 20 is at the composition of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 9.98 | 0.69 | 4.26 |
| 4 weeks | 9.68 | 0.79 | 4.72 |
| 8 weeks | 9.68 | 1.05 | 4.54 |
| 12 weeks | 9.62 | 1.59 | 4.26 |
Preparation F is a liquid preparation, and it has 10mg/mL huMab IGF-1R, 20mM L-histidine, and 140mM NaCl, 0.05% Polysorbate 20 is at the composition of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 9.81 | 0.67 | 4.45 |
| 4 weeks | 9.69 | 0.83 | 4.36 |
| 8 weeks | 9.62 | 1.19 | 5.01 |
| 12 weeks | 9.18 | 1.45 | 4.44 |
Preparation G is a liquid preparation, and it has 10mg/mL huMab IGF-1R, 20mM L-histidine, and 140mM NaCl is at the composition of pH 5.5.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 24.7 | 0.8 | 4.9 |
| 4 weeks | 24.6 | 1.0 | 3.9 |
| 8 weeks | n.d. | n.d. | n.d. |
| 12 weeks | 24.8 | 0.8 | 6.1 |
Preparation H is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 250mM trehalose dihydrate compound, 0.01% Polysorbate 20 is at the composition of pH 5.5.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 27.1 | 1.29 | 3.58 |
| 4 weeks | 26.9 | 1.27 | 3.74 |
| 8 weeks | 29.33 | 1.43 | 5.03 |
| 12 weeks | 26.44 | 1.38 | 4.10 |
Preparation I is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 250mM trehalose dihydrate compound is at the composition of pH 6.0.
Preparation J is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 250mM trehalose dihydrate compound, 0.01% Polysorbate 20 is at the composition of pH 6.0.
Formulation K is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 250mM trehalose dihydrate compound, 0.05% Polysorbate 20 is at the composition of pH 6.0.
Preparation L is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 60mM trehalose dihydrate compound, 0.01% Polysorbate 20 is at the composition of pH 6.0.
Preparation M is a liquid preparation, and it has 25mg/mL huMab IGF-1R, 20mMsuccinate, and 250mM trehalose dihydrate compound, 0.01% Polysorbate 20 is at the composition of pH 5.5.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 26.13 | 1.49 | 7.06 |
| 4 weeks | 27.93 | 1.46 | 7.25 |
| 8 weeks | 26.59 | 1.62 | 8.20 |
| 12 weeks | 26.89 | 1.62 | 7.10 |
The composition of freeze dried huMAb IGF-1R drug products of the present invention and at the 2-8 ℃ of stability data after preserving 3 months
Preparation N is freeze dried preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 60mM trehalose dihydrate compound, 0.01% Polysorbate 20 is formed in the reconstituted solutions of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 27.40 | 1.37 | 3.99 |
| 4 weeks | 27.89 | 1.36 | 4.20 |
| 8 weeks | 27.93 | 1.43 | 5.04 |
| 12 weeks | 27.34 | 1.38 | 4.31 |
Preparation O is freeze dried preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 60mM sucrose, 0.01% Polysorbate 20 is formed in the reconstituted solutions of pH 6.0.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 24.77 | 0.93 | 5.77 |
| 4 weeks | 24.81 | 0.93 | 6.79 |
| 8 weeks | 24.11 | 0.88 | 5.38 |
| 12 weeks | 24.32 | 1.03 | 3.93 |
Preparation P is freeze dried preparation, and it has 25mg/mL huMab IGF-1R, 20mMsuccinate, and 250mM trehalose dihydrate compound, 0.01% Polysorbate 20 is formed in the reconstituted solutions of pH 5.5.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 26.9 | 1.45 | 7.17 |
| 4 weeks | 27.71 | 1.55 | 7.44 |
| 8 weeks | 26.59 | 1.43 | 7.13 |
| 12 weeks | 26.89 | 1.36 | 7.07 |
Preparation Q is freeze dried preparation, and it has 25mg/mL huMab IGF-1R, 20mM L-histidine, and 250mM trehalose dihydrate compound, 0.01% Polysorbate 20 is formed in the reconstituted solutions of pH 5.5.
| Time point | Protein concentration | High molecular weight species (%) | Turbidity FTU |
| Initially | 27.11 | 1.33 | 3.59 |
| 4 weeks | 28.28 | 1.22 | 3.49 |
| 8 weeks | 27.81 | 1.30 | 4.65 |
| 12 weeks | 28.22 | 1.18 | 4.04 |
Claims (14)
1. preparation, it comprises:
-Yue 1 to about 150mg/mL huMab IGF-1R,
-Yue 0.001 to about 1% at least a surfactant and
-Yue 1 to about 100mM buffer,
-Yue 5.0 to about 7.0 pH.
2. the described preparation of claim 1, it comprises about 0.001 to about 1% at least a surfactant.
3. the described preparation of claim 1, it is with liquid form, with freeze dried form, or with the liquid form by lyophilized form reconstruct.
4. claim 1 or 3 each described preparations, it can be used by intravenous (i.v.) or subcutaneous (s.c.) or any other parenteral administration.
5. each described preparation of claim 1 to 4, it also comprises one or more isotonic agents to the amount of about 350mM with about 5mM.
6. the described preparation of claim 5, wherein said isotonic agent is selected from by sodium chloride (NaCl), potassium chloride, sugar comprises glucose, glycerol, the group that aminoacid and their combination are formed.
7. each described preparation of claim 1 to 6, it also comprises the sugar to the amount of about 500mM with about 25mM.
8. the described preparation of claim 7, wherein said sugar is selected from the group of being made up of trehalose, sucrose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, Raffinose, glycosamine, N-methylglucosamine (" meglumine "), galactosamine and neuraminic acid.
9. each described preparation of claim 1 to 8, it comprises that also one or more are selected from the composition of the group of being made up of following medicinal thing: antioxidant, ascorbic acid, glutathion, antiseptic, especially ,-cresol, phenol, benzyl alcohol, methyl butex, propyl parabene, methaform, thimersal, benzalkonium chloride, cyclodextrin, particularly HP-, sulfo-butyl ethyl-beta-schardinger dextrin-, beta-schardinger dextrin-, Polyethylene Glycol, particularly PEG 3000,3350,4000,6000, albumin, human serum albumin (HSA), bovine serum albumin (BSA), polyhydroxy-alcohol, glycerol, ethanol, mannitol, salt, acetate, sodium acetate particularly, magnesium chloride, calcium chloride, trometamol, EDTA, particularly Na-EDTA.
10. each described preparation of claim 1 to 9, wherein it comprises:
-Yue 1 to about 150mg/mL huMab IGF-1R,
-0.01% polysorbas20 w/v,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0。
11. each described preparation of claim 1 to 9, wherein it comprises:
-25mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-0.03% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-0.05% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-10mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-10mg/mL huMab IGF-1R，
-0.03% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-10mg/mL huMab IGF-1R，
-0.05% Polysorbate 20,
-20mM L-histidine,
-140mM NaCl，
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-140mM NaCl，
-pH 5.5；
Or
-25mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-pH 5.5；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-0.01% Polysorbate 20,
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-250mM trehalose dihydrate compound,
-0.05% Polysorbate 20,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-60mM trehalose dihydrate compound,
-0.01% Polysorbate 20,
-pH 6.0；
Or
-25mg/mL huMab IGF-1R，
-20mM succinate (ester),
-250mM trehalose dihydrate compound,
-0.01% Polysorbate 20,
-pH 5.5；
Or
-25mg/mL huMab IGF-1R，
-20mM L-histidine,
-60mM trehalose dihydrate compound,
-0.01% Polysorbate 20,
-pH 6.0。
12. each described preparation of claim 1 to 11 is used for preparing the application that is used for treating by the medicine of the disease of IGF-IR receptor modulators.
13. the described application of claim 12, wherein said disease are selected from the group of being made up of breast carcinoma, colorectal carcinoma, nonsmall-cell lung cancer (NSCLC) and carcinoma of prostate.
14. the present invention as indicated above.
***
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06111848 | 2006-03-28 | ||
| EP06111848.5 | 2006-03-28 |
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| CN101410137A true CN101410137A (en) | 2009-04-15 |
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| CNA2007800114320A Pending CN101410137A (en) | 2006-03-28 | 2007-03-19 | Anti-IGF-1R human monoclonal antibody formulation |
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| JP (1) | JP2009531371A (en) |
| KR (1) | KR20080104160A (en) |
| CN (1) | CN101410137A (en) |
| AR (1) | AR060130A1 (en) |
| AU (1) | AU2007229554A1 (en) |
| BR (1) | BRPI0709229A2 (en) |
| CA (1) | CA2647111A1 (en) |
| CL (1) | CL2007000797A1 (en) |
| CR (1) | CR10295A (en) |
| EC (1) | ECSP088778A (en) |
| IL (1) | IL193904A0 (en) |
| MA (1) | MA30345B1 (en) |
| MX (1) | MX2008012295A (en) |
| NO (1) | NO20083895L (en) |
| RU (1) | RU2008142359A (en) |
| TW (1) | TW200815029A (en) |
| WO (1) | WO2007110339A1 (en) |
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| CN102905692A (en) * | 2010-05-28 | 2013-01-30 | 诺沃—诺迪斯克有限公司 | Stable multi-dose compositions comprising antibody and preservative |
| CN103505729A (en) * | 2013-05-24 | 2014-01-15 | 华北制药集团新药研究开发有限责任公司 | Stable rabies virus humanized antibody combined reagent |
| CN104707146A (en) * | 2013-12-16 | 2015-06-17 | 浙江海正药业股份有限公司 | Adalimumab-containing pharmaceutical composition |
| CN106199007A (en) * | 2016-08-03 | 2016-12-07 | 烟台普罗吉生物科技发展有限公司 | Protein protective agent |
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| EP2094729A1 (en) * | 2006-12-11 | 2009-09-02 | F.Hoffmann-La Roche Ag | Abeta antibody parenteral formulation |
| GB0702888D0 (en) * | 2007-02-14 | 2007-03-28 | Glaxo Group Ltd | Novel Antibodies |
| EA200970880A1 (en) * | 2007-03-22 | 2010-02-26 | Имклоун Элэлси | STABLE COMPOSITIONS BASED ON ANTIBODIES |
| WO2009007272A1 (en) * | 2007-07-10 | 2009-01-15 | F. Hoffmann-La Roche Ag | Novel formulation |
| CN101874040A (en) * | 2007-11-29 | 2010-10-27 | 弗·哈夫曼-拉罗切有限公司 | Immunoglobulin aggregates |
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| US9345661B2 (en) | 2009-07-31 | 2016-05-24 | Genentech, Inc. | Subcutaneous anti-HER2 antibody formulations and uses thereof |
| AR078161A1 (en) | 2009-09-11 | 2011-10-19 | Hoffmann La Roche | VERY CONCENTRATED PHARMACEUTICAL FORMULATIONS OF AN ANTIBODY ANTI CD20. USE OF THE FORMULATION. TREATMENT METHOD |
| KR20120110175A (en) * | 2009-12-29 | 2012-10-09 | 에프. 호프만-라 로슈 아게 | Antibody formulation |
| KR102289394B1 (en) | 2011-03-31 | 2021-08-13 | 머크 샤프 앤드 돔 코포레이션 | Stable formulations of antibodies to human programmed death receptor pd-1 and related treatments |
| ES2746136T3 (en) | 2013-04-29 | 2020-03-04 | Hoffmann La Roche | Modified Human FcRn Binding Antibodies and Methods of Use |
| KR20160104636A (en) | 2014-01-15 | 2016-09-05 | 에프. 호프만-라 로슈 아게 | Fc-region variants with improved protein a-binding |
| WO2015181757A1 (en) * | 2014-05-28 | 2015-12-03 | Nono Inc. | Lyophilized formulation of tat-nr2b9c with acetylation scavenger |
| AR102198A1 (en) | 2014-10-09 | 2017-02-08 | Regeneron Pharma | PROCESS TO REDUCE SUBVISIBLE PARTICLES IN A PHARMACEUTICAL FORMULATION |
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| CA2999079A1 (en) * | 2015-09-28 | 2017-04-06 | Jiangsu Hengrui Medicine Co., Ltd. | Stable anti-pd-1 antibody pharmaceutical preparation and application thereof in medicine |
| AR106189A1 (en) | 2015-10-02 | 2017-12-20 | Hoffmann La Roche | BIESPECTIFIC ANTIBODIES AGAINST HUMAN A-b AND THE HUMAN TRANSFERRINE RECEIVER AND METHODS OF USE |
| TWI747843B (en) | 2015-10-02 | 2021-12-01 | 瑞士商赫孚孟拉羅股份公司 | Bispecific anti-human cd20/human transferrin receptor antibodies and methods of use |
| IL309453A (en) | 2016-08-16 | 2024-02-01 | Regeneron Pharma | Methods for quantitating individual antibodies from a mixture |
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-
2007
- 2007-03-19 JP JP2009502016A patent/JP2009531371A/en active Pending
- 2007-03-19 CN CNA2007800114320A patent/CN101410137A/en active Pending
- 2007-03-19 EP EP07727047A patent/EP1998806A1/en not_active Withdrawn
- 2007-03-19 RU RU2008142359/15A patent/RU2008142359A/en not_active Application Discontinuation
- 2007-03-19 CA CA002647111A patent/CA2647111A1/en not_active Abandoned
- 2007-03-19 MX MX2008012295A patent/MX2008012295A/en active IP Right Grant
- 2007-03-19 WO PCT/EP2007/052569 patent/WO2007110339A1/en active Application Filing
- 2007-03-19 KR KR1020087023673A patent/KR20080104160A/en not_active Application Discontinuation
- 2007-03-19 AU AU2007229554A patent/AU2007229554A1/en not_active Abandoned
- 2007-03-19 BR BRPI0709229-6A patent/BRPI0709229A2/en not_active IP Right Cessation
- 2007-03-26 AR ARP070101241A patent/AR060130A1/en not_active Application Discontinuation
- 2007-03-26 TW TW096110388A patent/TW200815029A/en unknown
- 2007-03-26 CL CL2007000797A patent/CL2007000797A1/en unknown
-
2008
- 2008-09-04 IL IL193904A patent/IL193904A0/en unknown
- 2008-09-11 NO NO20083895A patent/NO20083895L/en not_active Application Discontinuation
- 2008-09-17 CR CR10295A patent/CR10295A/en not_active Application Discontinuation
- 2008-09-26 EC EC2008008778A patent/ECSP088778A/en unknown
- 2008-10-20 MA MA31308A patent/MA30345B1/en unknown
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102905692A (en) * | 2010-05-28 | 2013-01-30 | 诺沃—诺迪斯克有限公司 | Stable multi-dose compositions comprising antibody and preservative |
| CN102905692B (en) * | 2010-05-28 | 2015-09-16 | 诺沃—诺迪斯克有限公司 | Comprise the stable multi-dose compositions of antibody and antiseptic |
| CN102363040A (en) * | 2011-10-21 | 2012-02-29 | 北京锐瑟科技有限公司 | Antimicrobial peptide preparation for mucosal tissues |
| CN102363040B (en) * | 2011-10-21 | 2013-05-01 | 北京锐瑟科技有限公司 | Antimicrobial peptide preparation for mucosal tissues |
| CN103505729A (en) * | 2013-05-24 | 2014-01-15 | 华北制药集团新药研究开发有限责任公司 | Stable rabies virus humanized antibody combined reagent |
| CN103505729B (en) * | 2013-05-24 | 2015-10-28 | 华北制药集团新药研究开发有限责任公司 | A kind of stable rabies virus human antibody combination preparation |
| CN104707146A (en) * | 2013-12-16 | 2015-06-17 | 浙江海正药业股份有限公司 | Adalimumab-containing pharmaceutical composition |
| CN104707146B (en) * | 2013-12-16 | 2019-04-16 | 浙江海正药业股份有限公司 | A kind of pharmaceutical composition containing adalimumab |
| CN106199007A (en) * | 2016-08-03 | 2016-12-07 | 烟台普罗吉生物科技发展有限公司 | Protein protective agent |
| CN106199007B (en) * | 2016-08-03 | 2017-04-05 | 烟台普罗吉生物科技发展有限公司 | Protein protective agent |
Also Published As
| Publication number | Publication date |
|---|---|
| ECSP088778A (en) | 2008-10-31 |
| TW200815029A (en) | 2008-04-01 |
| IL193904A0 (en) | 2011-08-01 |
| CA2647111A1 (en) | 2007-10-04 |
| KR20080104160A (en) | 2008-12-01 |
| RU2008142359A (en) | 2010-05-10 |
| NO20083895L (en) | 2008-10-24 |
| BRPI0709229A2 (en) | 2011-06-28 |
| EP1998806A1 (en) | 2008-12-10 |
| AR060130A1 (en) | 2008-05-28 |
| CR10295A (en) | 2008-10-06 |
| JP2009531371A (en) | 2009-09-03 |
| CL2007000797A1 (en) | 2008-01-25 |
| AU2007229554A1 (en) | 2007-10-04 |
| MA30345B1 (en) | 2009-04-01 |
| WO2007110339A1 (en) | 2007-10-04 |
| MX2008012295A (en) | 2008-10-09 |
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