MXPA98000760A - Methods for the treatment of asthma allergy - Google Patents
Methods for the treatment of asthma allergyInfo
- Publication number
- MXPA98000760A MXPA98000760A MXPA/A/1998/000760A MX9800760A MXPA98000760A MX PA98000760 A MXPA98000760 A MX PA98000760A MX 9800760 A MX9800760 A MX 9800760A MX PA98000760 A MXPA98000760 A MX PA98000760A
- Authority
- MX
- Mexico
- Prior art keywords
- ige
- patient
- dose
- antagonist
- administration
- Prior art date
Links
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Abstract
The present invention relates to a pharmaceutical composition for reducing the late asthmatic response, characterized in that it comprises an anti-IgE antibody in a pharmaceutically acceptable medium. A pharmaceutical composition characterized in that it is for reducing late bronchial hyperreactivity comprising an anti-IgE antibody in a pharmaceutically acceptable medium.
Description
METHODS FOR TREATMENT DB
FIELD OF THE INVENTION This invention relates to methods of treating allergic asthma with IgE antagonists, including IgE antibodies.
1MfiOiI? LiMT? RfS D »I * INVENTION Asthma is characterized by three components: airway inflammation; obstruction of airways, which is reversible; and increased sensitivity, referred to as hyperreactivity. The airflow obstruction is measured by a decrease in forced expired volume in one second (FEV) which is obtained by comparison of baseline spirometry. Airway hyperreactivity is recognized by a decrease in FEV in response to very low levels of histamine or methacholine. Hyperreactivity can be exacerbated by exposure of the airways to allergen.
People with allergic asthma who inhale an aerosolized allergen for which they develop immediate sensitivity "early asthma response" (EAR), and often delayed "late asthmatic response" (LAR), as measured by FEVi (Cockcroft et al., Clin. Allersv 7: 503-13 (1977); Hargreave et al., Allersv Clin. Immunol., 83: 525-7 (1989) .The EAR results from mast cell degranulation caused by cross-linking of
REF: 26549 an antigen with IgE linked to mast cells. Preformed mediators (such as histamine and triptase) and freshly formed lipid mediators (such as prostaglandins and leukotrienes) release mast cells causing bronchoconstriction, mucus hypersecretion, and changes in vascular permeability (Fick et al., J. Appl. Phys. : 1147-55 (1987) .The recovery of EAR occurs in 30-60 minutes.The LAR is associated with more pronounced airway inflammation characterized by eosinophilic and neutrophilic infiltration of the mucosa, longer changes in bronchovascular patency, and bronchial reactivity increased for non-specific stimulus (Hargreave et al., supra, Fick et al., Diaz et al., Am. Rev. Respir Dis. 139: 1383-9 (1989); Fhay et al., J. Allersy Clin.I Munol 93: 1031-9 (1994) The pathophysiological relationship between LAR and EAR remains unclear, but changes in the airway of the LAR could be caused by mast cell mediators (including cytokines) released during the EAR. The activ The characteristics of these mast cell mediators include the chemoattraction of inflammatory cells to the airway mucosa and the induction of more prolonged changes in the vascular permeability of the airway mucosa (Fick et al. J. Am. Rev. Respir. Dis. 135: 1204-9 (1987). It is thought that IgE is the central effector antibody in EAR due to inhaled allergen in people with allergic asthma, however its role in the LAR is unclear. Irogenic allergic asthma could result from continuous degranulation of airway mast cells in response to exposure to perennial bacteria (eg house dust, dog slag, and cat hair). This hypothesis is supported by studies which demonstrate a reduction of asthma symptoms and bronchial hyperresponsiveness in subjects who reduce their environmental exposure to aeroallergens (Platts-Mills et al., Lancet ii: 675-8 (1982); Murray et al. Pediatrics 71: 418-22 (1983) Reactions of airway hyperreactivity can be induced in the laboratory by subject exposure with allergic asthma to nebulized solutions of allergen extract, the concentration of which can be determined by airway hyperreactivity to methacholine and proven skin reactivity for the same allergen.This procedure is known as experimental aerosolized allergen change or bronchial provocation.Oronchial provocation is a useful and relevant model for the study of anti-asthma drugs (Ockcroft et al. al J. Alleray, Immunol 79: 734-40 (1987), Cresciolli et al Ann.Allersv f 6: 24-51 (1991), Ward et al. Am. Rev. Respir Dis. 147: 518- 3 (199 3) For example, it is known that beta agonists inhibit EAF but not LAR to allergen, and that a single dose of inhaled steroid inhibits LAR but not RAS (Cockcroft et al. J. Allersv. Imrnunol. 79: 734-40 (198"). Theophylline and rhoduoglycate of disodium attenuate the responses of EAR and LAR to allergen (Cresciolli et al., = Upra; Ward et al., Supra). The majority of drugs with proven efficiency in the management of donkeys have shown to attenuate the airway responses for inhaled antigens administered in bronchial challenge. If the IgE linked to the mast cell of the airway is central to the response of the airway for inhaled allergen,
Ic decreasing or eliminating then the circulation and the IgE bound to mast cell could result in significant attenuation of the EAR and possibly also of the LAR to inhaled aeroallergens. The concept of the use of anti-IgE antibodies as a
treatment for allergy has been widely exposed in the scientific literature. A few representative examples of the following. Baniyash and Eshhar (European Journal of Irrunolo and 14.-799-80 (1984) showed that an anti-IgE monoclonal antibody could specifically block
_0 passive cutaneous anaphylaxis reaction when irithraea was injected before testing the antigen; U.S. 4,714,759 discloses a product and process to treat allergy; using an antibody specific for IgE; and Rup and Ka n 'International Archives Allersy and Applied Immunology,
_5 89: 3 7-393 (1 ,: < 89) discuss the prevention of the development of allergic responses with monoclonal antibodies which block the sensitization of IgE mast cells. Anti-IgE antibodies are exposed which block the IgE binding to its basophil receptor and which is missing to bind to the IgE binding to the receptor, thus preventing the release of histamine, eg, Rup and Khan ( supra), by Eaniyash et al. (Molecular Immunolosv 25: 705-711, 1988), and by Hook et al. (Federation of American Societies for Experimental Biolosy / 71st Annual Meeting,? Abstract # 6008, 1987). IgE antagonists in the form of receptors, anti-IgE antibodies, binding factors, or fragments thereof have been discussed in the art. For example, U.S. 4,962,035 discloses the DNA encoding the alpha subunit or the IgE mast cell receptor or an IgE fragment linked thereto. Hook et al. (Federation Proceedings Vol. 40, No. 3, Abstract # 4177) exposes monoclonal antibodies, of the rils one type is anti-idiotypic, a second type binds to common determinants of IgE, and a third type is directed? towards hidden determinants when IgE is on the surface of the basophil. U.S. 4,940,782 exposes monoclonal antibodies that react with free IgE and thus inhibit the binding of IgE to mast cells, and react with IgE when bound to the 5 F: E receptor of the P cell, but do not bind to IgE when it binds to the FcE receptor of mast cell, nor block the link of IgE to the receiver of the cell BUS 4,496,788 discloses a purified IgE binding factor and fragments thereof, and monoclonal antibodies which react with IgE binding factor and lymphocyte cell receptors for IgE, and derivatives thereof. U.S. 5,091,313 discloses antigenic epitopes associated with the extracellular segment of the domain that binds immunoglobulins to the B cell membrane. Recognized epitopes occur in B cells that carry IgE but not basophils or in the secreted, soluble form of IgE. U.S. 5,252,467 discloses a method for producing antibodies specific for such antigenic epltopes. U.S. 5,523,026 discloses DNA encoding specific human-killed antibodies for such antigenic epitopes. U.S. 4,714,759 discloses an in unotoxin in the form of an antibody or an antibody fragment coupled to a toxin to treat allergy. Presta et al. (J. Immunol., 151: 2623 (1993) discloses a humanized anti-IgE antibody that prevents the binding of free IgE to Fc-Rl but does not bind to the Fc-Rl IgE link.Copending WO93 / 04173 discloses polypeptides which are linked Differentially to high and low IgE receptors US 5,428,133 disclose anti-IgE antibodies as an allergy therapy, especially antibodies that bind to IgE in B cells, but not IgE in basophils This publication mentions the possibility of treating asthma with such antibodies US 5,422,258 discloses a method for making such antibodies Tepper et al. ("The Role of Mast cells and IgE in Marine.
Asthma ", presented in" Asthma Theory to Treatment ", July 15-17, 1995) states that neither mast cells nor IgE greatly influence anaphylaxis, airway hyperreactivity, or airway inflammation in a dying asthma model .
BRIEF DESCRIPTION OF THE INVENTION One embodiment of the invention is a method of treating allergic asthma in a patient comprising administering to the patient a sustained dose of an IgE antagonist and, optionally, a loading dose of the IgE antagonist. A further embodiment of the invention is a method for treating allergic asthma in a patient comprising administration to the patient of a dose of IgE antagonist with an average of from 0.001 to 0.01 mg / kg / week IgE antagonists for each IU / ml baseline IgE in the patient's serum. A further embodiment of the invention is a method for eliciting the late asmati-a response in a patient comprising administering to the patient a sustained dose of a JgE antagonist and, optionally, a charged dose of the IgE antagonist. A further embodiment of the invention is a method for reducing the late asthmatic response in a patient comprising administration to the patient of a dose of IgE antagonist with an average of 0.001 to 0.01 mg / kg / week IgE antagonists for each IU / ml. IgE baseline in the patient's serum. A further embodiment of the invention is a method for reducing the early asthmatic response in a patient comprising administering to the patient a sustained dose of an IgE antagonist and, optionally, a dose of administration of the IgE antagonist. A further embodiment of the invention is a method for reducing the early asthmatic response in a patient comprising the administration to the patient of an IgE antagonist dose approximately ccn from 0.001 to 0.01 mg / kg / week IgE antagonists for each IU / ml. IgE baseline in the patient's serum. A further embodiment of the invention is a method for reducing bronchial hyperresponsiveness in a patient comprising administering to the patient a sustained dose of an IgE antagonist and, optionally, an aosis of administration of the IgE antagonist.
A further embodiment of the invention is a method for reducing hyperexcline bronchial reactivity in a patient that comprises administering to the patient a dose of IgE antagonist with an average of 0.001 to u.Ol mg / kg / week IgE antagonists for each IU / ml IgE base line in the patient's serum. A further embodiment of the invention is a method for reducing skin reactivity in a patient comprising administering to the patient a sustained dose of an IgE antagonist and, optionally, a dose of administration of the IgE antagonist. A further embodiment ie the invention is a method for reducing the reactivity of the skin in a patient comprising administering to the patient a dose of Ig antagonist? approximately with an average of 0.001 to 0.01 mg / kg / week antagonists IgE for each lU / rnl baseline IgE in the patient's serum. A further embodiment of the invention is a method for reducing pulmonary inflammation in a patient comprising the administration to the patient of a sustained dose of an IgE antagonist and, optionally, a ctosis of administration of the IgE antagonist. A further embodiment of the invention is a method for reducing pulmonary inflammation in a patient comprising administration to the patient of a dose of IgE antagonist with an average of from 0.001 to 0.01 mg / kg / week IgE antagonists for each IU / ml line Is base? in the patient's serum.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph representing the percentage change in baseline FEVX in a bronchial allergen change in patients treated with anti-IgE antibody and patients receiving placebo in the U.S. Figures 2 (U.S.) and 3 (Canada) represent the results of methacholine bronchial change in patients treated with anti-IgE antibody and patients receiving placebo). Figures 4 (U.S.) and 5 (Canada) represent the change of the case line in averages of total symptoms in patients treated with anti-IgE antibodies and patients receiving pía bait. Figures 6 (U.S.) and 7 (Canada) represent the endpoint of titration tested on the skin by allergens in patients receiving placeoo or anti-IgE antibody.
DETAILED DESCRIPTION OF THE INVENTION A. DEFINITIONS The term "asthma" is used herein to refer to a lung disease characterized by airway obstruction that is reversible (although not completely in some patients) either spontaneously or with treatment, airway inflammation. , and increased airway response for a variety of stimuli. "Allergic asthma" is used herein to refer to an asthmatic response by inhalation of an antigen for which the patient is sensitive. The term "early asthmatic response" (EAR) is used here to refer to an asthmatic response to an antigen with approximately two hours of exposure. The term "late asthmatic response" (LAR) is used herein to refer to an asthmatic response of an antigen with approximately two to eight hours after exposure. The term "IgE antagonist" is used herein to refer to a substance that inhibits the biological activity of IgE. Such antagonists include but are not limited to anti-IgE antibodies, IgE receptors, anti-IgE receptor antibodies, IgE antibody variants, ligands for IgE receptors, and fragments thereof. Antibody antagonists could be of the class IgA, IgD, IgG, IgE, or IgM. The variant IgE antibodies typically have amino acid substitutions or deletions in one or more amino acid residues. Ligands for IgE receptors include but are not limited to IgE and anti-receptor antibodies, and proteins thereof capable of binding to receptors, including amino acid substitution and deletion variants, and cyclized variants. In general, in some embodiments of the invention, the IgE antagonists act by blocking the binding of IgE to its receptors on B cells, mast cells, or basophils, either by blocking the binding site in the IgE molecule or by blocking its receptors. Additionally, in some embodiments of the invention, the IgE antagonists act by binding soluble IgE and thereby remove it from the circulation. The IgE antagonists of the invention can also act to bind IgE in B cells, thereby eliminating clonal populations of B cells. The IgE antagonists of the present invention can also act by inhibiting IgE production. Preferably, the IgE antagonists of the present invention do not result in the release of histamine from mast cells or basophils. The term "therapeutic amount" as used herein denotes an amount that prevents or ameliorates the symptoms of a disorder or response to the pathological physiological condition.
"Polypeptide" as used herein generally refers to peptides and proteins having at least about two amino acids. The term "free IgE" as used herein refers to non-complexed IgE) to a coupling standard, such as an anti-IgE antibody. The term "total IgE" as used herein refers to the measurement of free IgE and IgE complexed to a coupling standard, such as an anti-IgE antibody. The term "IgE baseline" as used herein refers to the level of free IgE in a patient's serum prior to treatment with an IgE antagonist. The term "polyol" as used herein denotes a hydrocarbon includes at least two hydroxyls attached to carbon atoms, such as polyethers (eg polyethylene glycol), trehalose and sugar alcohols (such as mannitol). The term "polyether" as used herein denotes a hydrocarbon containing at least three attached ethers.
The polyethers may include other functional groups. The polystyrenes useful in practicing the invention include polyethylene glycol (PEG).
B. GENERAL METHODS Polyclonal antibodies to IgE are generally cultured in animals by multiple subcutaneous (se) or intra peritoneal (ip) injections of IgE and an adjuvant. This may be useful for conjugating IgE or a fragment containing the amino acid receptor sequence of the Fc region of IgE to a protein that is immunogenic in the species to be immunized, p. ex. , mollusc hemocyanin, albumin serum, bovine triroglobulin, or soybean trypsin inhibitor using a bifunctional or derivatizing agent, eg, maleimidobenzoyl sulfosuccinimide ester or conjugation by means of cysteine residues), N-hydrC'Xisuccinimide ( by means of Usin residues), gluteraldehyde, succinic anhydride, SOCI2, or RN = NR, where R and R1 are different alkyl groups. Ordinarily the animals are immunized against the cells or immunogenic conjugates or derivatives by combination of 1 mg or 1 μg of IgE with complete Freund's adjuvant and injecting the intra dermal solution in multiple sites. One month later the animals are assisted with 1/5 to 1/10 the original amount of the incomplete Freund's adjuvant conjugate by subcutaneous injection at multiple sites. Seven to fourteen days later, the animals are mixed and the serum is analyzed to titrate the anti-IgE. The animals are assisted until the plates are titled. Preferably, the animal is assisted with a conjugate of the same IgE but conjugated to a different protein and / or through a cross-linking agent. The conjugates can also be made in recombinant cell culture as protein fusions. Similarly, aggregation agents such as alum can be used to improve the response i mun. The monoclonal antibodies are prepared by recovering spleen cells from immunized animals and immortalizing the cells in a conventional manner, e.g. ex. by fusion with myeloma cells or by virus transformation
Epstein-Barr (EB) and screening to express the desired antibody clones. The hybridoma technique originally described by Koehler and Milstein, Eur. J. Immunol. , 6: 511
(1976) and also described by Hmmeriing et al., In: Monoclonal
Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681
(1981) has been widely applied to produce lines of hybrid cells that secrete high levels of monoclonal antibodies against many specific antigens. Hybrid cell lines can be maintained in vitro in cell culture medium. The cell lines produce the antibodies that can be selected and / or maintained in a composition containing the cell line continuously in the medium of hypoxanthine-aminopterin thymidine (HAT). In fact, once the hybridoma cell line is established, it can be maintained in a variety of nutritionally adequate media. In addition, the lines of hybrid cells can be stored and preserved in any number of conventional ways, including freezing and storage in liquid nitrogen. Frozen cell lines can be revived and cultured indefinitely with summarized synthesis and secretion of monoclonal antibody. The secreted antibody is recovered from the tissue culture supernatant or conventional methods such as precipitation, ion exchange chromatography, affinity chromatography, or the like. The antibodies described herein are also recovered from culture of hybridoma cells by conventional methods for purification of IgG or IgM, as it might be the case, that the foregoing thereof has been used to purify these immunoglobulins from the plasma pool, e.g. ex. , ethanol or polyethylene glycol precipitation procedures. The purified antibodies are filtered in sterility. Since mouse monoclonal antibodies are used, the invention is not limited; in fact, human antibodies can be used. Such antibodies can be obtained, for example, using human hybridomas (Cote et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985)). In fact, according to the invention, techniques for the production of chimeric antibodies were developed (Cabilly et al., US 4,816,567, Morrison et al., Prcc Nati Acad.Sci. 81: 6851 (1984); Boulianne et al. ., Nature 314: 452 (1985), EP 184,187, EP 171,494, PCT WO 86/01533, Shaw et al., J. Nat. Cano, Inst. 80: 1553-1559 (1988), Morrison, Science 229: 1202. -1207 (1985); Oi et al., BioTechniques 4: 214 (1986) coupling a variable domain animal antigen binding can be used for a human constant domain, such antibodies are within the scope of this invention. "chimeric" is used herein to describe a polypeptide comprising at least the binding portion of the antigen of an antibody molecule linked to at least one part of another protein.
(tip i • amenté a constant immunoglobulin domain). In one embodiment, such chimeric antibodies contain about one third of the rodent sequence (or other non-human species) and thus are capable of obtaining a significant anti-globulin response in humans. For example, in the case of murine anti-CD3 antibody 0KT3, many of the results of the anti-globulin response are directed against the variable region rather than the constant region (Jaffers et al., Transplantation 41: 572-578 (1986)). Humanized antibodies are used to reduce or eliminate any anti-globulin immune response in humans In practice, humanized antibodies are typically human antibodies in which some amino acid residues of the complementarily determined regions (CDRs), the hypervariable regions. , in the variable domains that are directly involved with formation of the antigen binding site, and possibly some amino acids of the skeletal regions (FRs), the sequence regions that are retained some in the variable domains, are replaced by residues of analogous sites in rodent antibodies. The construction of humanized antibodies is described in Riechman et al., Nature 332: 323-327 (1988), Queen et al., Proc. Nati Acad. Sci. USA 86: 10029-10033 (1989), Co et al., Proc. Nati Acad. Sci. USA 88: 2869-2873 (1991), Gorman et al., Proc. Nati Acad. Sci. USA 88: 4181-4185 (1991), Daughert et al., Nucleic Acid Res. 19: 2471-2476 (1991), Brown et al., Proc. Nati Acad. Sci. USA 88: 2663-2667 (1991), Junghans et al., Cancer Res. 50: 1495-1502 (1990), Fendly et al., Cancer Res. 50: 1550-1558 (1990) and in PCT applications. WO 89/06692 and WO 92/22653. In some cases, the substituent CDRs of rodent antibodies to human CDRs in human structures are sufficient to transfer high affinity of the antigen binding (Jones et al., Nature 321: 522-525 (1986), Verhoeyen et al., Science 239: 1534-1536 (1988) considered in other cases that it is necessary to additionally replace one (Rie-hman et al., Supra) or several (Queen et al., Supra) FR residues See also Co et al., Supra The invention also encompasses the use of human antibodies produced in transgenic animals.In this system, the DNA encoding the antibody of interest is isolated and stably incorporated into the germ line of a host animal.The antibody is produced by the animal and harvesting the blood of the animal or other body fluid Alternatively, a cell line expressing the desired antibody can be isolated from the host animal and used to produce the antibody, in vitro, and the antibody can be harvested from the cell culture by m all standard. The anti-IgE antibody fragments can also be used in the methods of the invention. Any fragment of an anti-IgE antibody capable of blocking or breaking the interaction of IgE with this receptor is appropriate for use here. Appropriate anti-IgE antibody fragments can be obtained by screening the combinatorial variable domain libraries of DNA capable of expressing the desired antibody fragments. These techniques for creating recombinant DNA versions of the antigen binding regions of antibody molecules that bypass the generation of monoclonal antibodies are encompassed within the practice of this invention. One extract typically from the antibody-specific messenger RNA molecules of the immune system is taken from an immunized animal, transcribed into complementary DNA (cADM), and cloned the cDNA into a bacterial expression system. The libraries of "manifestation of the Phage" are an example of such techniques. You can quickly generate and screen a large number of candidates that link to the antigen of interest. Such IgE-binding molecules are specifically encompassed with the term "antibody" as defined, discussed, and claimed herein. In a further embodiment of the invention, the soluble IgE receptor can be used as the IgE antagonist. Suitable soluble receptors for use herein include, for example, molecules comprising the IgE binding site in the extracellular (exodomain) domain of the Fc ~ RI chain. The Fc Rl O chain can be genetically modified such that the exodominium is secreted as a soluble protein in a recombinant expression system according to the method of Blank et al., J. Biol. Chem., 266: 2639-2646 (1991 ) or Qu et al., J. Ex ?. Med., 167: 1195. The invention also encompasses the use of peptides that bind to IgE in addition to anti-IgE and soluble receptor antibodies. Any peptide linked to IgE capable of breaking or blocking the interaction between IgE and its receptors is suitable for use here. In addition IgE antagonists that interfere with the IgE / receptor binding to IgE, such as anti-IgE antibodies, fragments thereof, soluble IgE receptor and other IgE-linked peptides described above, the invention encompasses the use of IgE antagonists that breaks down the IgE / receptor interaction competing with IgE to bind to its receptor, thereby reducing the available IgE receptor. The IgE variants are an example of a competitor r ceptor-link orne is suitable for use in the methods of the invention. The IgE variants are ways that IgE possesses i. an alteration, such as a substitution of amino acid substitutions and / or an amino acid deletion or deletions, wherein the altered IgE molecule is able to compete with IgE to bind to its receptors. The fragments of IgE variants are also suitable for use here. Any fragment of an IgE variant capable of competing with IgE to bind to its receptors can be used in the methods of the invention. The invention also encompasses the use of peptides linked to the IgE receptor in addition to IgE variants and fragments of the same. Any peptide linked to IgE receptor capable of breaking or blocking the interaction between IgE and its receptors with suitable for use here. The amount of IgE antagonists considered for the patient to be used in therapy will be formulated and established in a manner consistent with good medical practice that takes into account the disorder to be treated, the individual patient's condition, the site of release, the method of administration and other factors known to physicians. Similarly, the dose of IgE antagonist administered will depend on the properties of the IgE antagonist employed, e.g. ex. its binding activity and half-life of the plasma ii, the concentration of IgE antagonist in the formulation, the route of administration, the site and locification ratio, the clinical tolerance of the patient involved, the pathological condition that afflicts the patient and the like, They are good for the expert in medicine. Typically IgE antagonists are administered by the intramuscular, intravenous, trabranchial, intraperitoneal, subcutaneous route or other suitable routes. Antagonists can be administered before and / or after the attack symptoms. In general, a "loaded" dose of an IgE antagonist is useful to obtain a rapid and sustained decrease in free IgE. A dose of administration is typically a first dose of IgE antagonist that is greater than a subsequent dose or "maintenance" of an IgE antagonist. However, patients can be administered by other routes. For example, patients may be given a dose of antagonist that is greater than or equal to the same mg / kg amount as the maintenance dose, but increasing the frequency of administration in a "administration regimen". Thus, for example, if the maintenance dose is 1 mg / kg biweekly, the patient can be administered 1 mg / kg weekly for two or more weeks in a treatment, then the maintenance dose of 1 mg is administered. / kg biweekly. In addition, patients can be administered during a period of treatment with a maintenance dose of IqE antagonist by administering higher or more frequent doses than the maintenance dose. The term "administration dose" is understood as used herein to include such simple administration doses, multiple administration doses, administration units, and combinations thereof. A decrease sustained in free IgE can be obtained by administration of a maintenance dose of the antagonist. Maintenance doses are given with a frequency from about every day to about every 90 days, more preferably weekly or biweekly, or depending on the severity of the patient's symptoms, the concentration and the in vivo properties of the given antagonists, and the formulation of the antagonist. For example, delayed-release formulations may allow for less frequent administration. Maintenance doses may
be adjusted up or down all the time, depending on the patient's response. Thus, for example, in one embodiment of the invention, the dose of IgE antagonist is sufficient to reduce free IgE in the patient's serum to less than about 40 μl / ml. In a further dosage strategy, about 0.05 to 10 mg / kg, more preferably about 0.1 to 1 mg / kg, more preferably about 0.5 mg / kg IgE antagonist may be administered.
-5 on a weekly basis to a patient who has approximately 40-200 IU / l IgE baseline. In another dosage strategy for individuals with large IgE baseline, patients are preferably "administered" with about 10 mg / kg, more preferably about 1 to 5 mg / kg, more preferably about 2 mg / kg, of IgE antagonist. , followed by weekly or biweekly administration of approximately 0.1 to 10 mg / kg, more preferably approximately 1 mg / kg. In a further dosage strategy, a maintenance dose of IgE antagonist is used by averaging approximately 0.0005 to 0.05 mg / kg / week for each Ul / ml baseline IgE, more preferably 0.001 to approximately 0.01 mg / kg / week for each Ul. / ml IgE base line. This maintenance regimen may follow an initial administration dose of about 1 to 10 mg / kg, more preferably about i to 5 mg / kg of IgE antagonist. In a further embodiment of the invention, sufficient IgE antagonist is provided by means of the maintenance dose, and optionally, the administration dose, to reach approximately 1 to 20 fold, fold back from 1 to 20, preferably about 3 to 5 times, more preferably about 5 times the highest serum concentration with the total IgE concentration in the patient's serum. IgE levels are typically assayed by standard ELISA techniques well known in the art. The total IgE serum can be measured by means of available assays, such as the Abbott Laboratories IgE Total Assay. "Free IgE, eg IgE not bound to antibody can be measured by a capture assay in which for example, the IgE receptor binds to a solid support.IgE complexed to an anti-IgE antibody that binds to or near the IgE site which binds to the receptor will be blocked from binding to the receptor, and thus only IgE free or unbound can react with the receptor bound to the solid support in this assay An anti-IgE antibody that recognizes IgE even when the IgE binds to its receptor can be used to detect the IgE captured by the receptor in the solid support. This anti-IgE antibody can be labeled with any of a variety of reported systems, such as alkaline phosphatase, etc. It is anticipated that the injections (intravenous, intramuscular or subcutaneous) will be the primary route for administration. of the IgE antagonist of this invention, although it is also used to deliver it by means of a catheter or other surgical conduit. Alternative routes include suspensions, tablets, capsules and the like for oral administration, commercially available nebulizers for liquefied formulations, and inhalation of lyophilized or aerosolized microcapsules, and suppositories for rectal or vaginal administration. The liquid formulations can be used after the restitution of powder formulations. Additional pharmaceutical methods could be employed to control the duration of action of the antagonists of this invention. Antagonists could also be entrapped in microcapsules prepared, for example, by coacervation techniques or by inter face facial polymerization (e.g., hydroxymethylcellulose or gelatin and poly- (methylmetacylate) microcapsules, respectively), in colloidal drug delivery systems (by example, liposomes, micro spheres of albumin, nanoparticles and nanocapsules), or in macroemulsions. Such techniques are set forth in Pemington's Pharmaceutical Sciences 1st edition, Osol A., ed. , 1980). In general, formulations of the subject matter of the invention may contain other components in non-decreasing amounts of the preparation of stable forms and in "suitable antigens for effective and pharmaceutically safe administration, For example, other pharmaceutically acceptable excipients well known to those skilled in the art. The art may form a part of the subject compositions, these include, for example, salts, various olume agents, additional buffering agents, agents, antioxidants, cosolvents and the like.; specific examples of these include salts of tris-hydroxymethyl) amino methane ("Tris buffer"), and disodium edetate. In one embodiment of the invention, the IgE antagonist formulations comprise a buffer, a salt, optionally, a polyol, and optionally, a condom. An example of a formulation of the invention is a liquid formulation of about 1-100 mg / ml of IgE antagonist in 10 mM acetate buffer, pH 5.0-6.5, 100-200 mM sodium chloride, and about 0.01% polysorbate 20 , more preferably about 5 mg / ml of IgE antagonist in 10 M acetate buffer, pH 5.2, 142 mM sodium chloride, and 0.01% polysorbate 20. In other embodiments of the invention, the formulation can be dried by cooling and reconstitute for administration. For example, anti-IgE antibody can be formulated at approximately 25 mg / ml mM histidine, pH 6.0, and 88 mM sucrose, dried by cooling, and reconstituted in water at 100 mg / ml in antibody for administration. The mixed sugars can also be used, such as a combination of sucrose and mannitol, etc. In general, unless otherwise specified, the abbreviations used for the designation of amino acids and the
The protective groups used for them are based on recommendations of the IUPAC-IUB Commission of the Biochemical Nomenclature (Biochemistry, 11: 1726-1732 (1972) .The nomenclature used to define the compounds of the invention is the same as that specified by IUPAC, published in? uropean Journal of Biochemistry 138: 9-37 (1984) .Allergic asthma therapy can be combined with other known therapies for allergy and / or asthma, including anti-histamines, theophylline, salbutamol, beclomethasone dipropionate , sodium cromoglycate, steroids, anti-inflammatory agents, etc. Further details of the invention can be found in the following examples, which further define the scope of the invention.All references cited herein are expressly incorporated by reference to their completeness. .
EXPERIMENTAL RESULTS
The objects of this double-blind, placebo-controlled, multi-center Phase II clinical trial were to determine whether an IgE antagonist in the form of an anti-IgE antibody inhibits EAP, and / or LAR to an inhaled aeroallergen in asthmatic patients. Parameters to cyclonal examined included inhibition of the increase in bronchial reactivity, inhibition of the increase in biological markers of inflammation and decrease in asthma symptoms in response to treatment with an anti-IgE antibody. The anti-IgE E25 antibody used in this study was the humanized version of the MaEll monoclonal antibody described in Presta et al., Supra. Two dosing protocols were used (it is the same for U.S. and Canada). In both protocols subjects endured the test of an initial provocation (control) of allergen diluent and then two bronchial allergen tests separated approximately eight weeks of drug study. 10 subjects of U.S. and 9 from Canada received anti-IgE antibody E25 and 9 subjects from U.S. and 9 from Canada received placebo therapy. The allergens used for the study were house dust, cat hair or grass. The allergen used for each individual patient was the first that contracted the most positive response in the test of C'.me ri of allergen in the patient. On day 0, the pot after the first bronchial allergen test (baseline), patients from U.S. received 0.5 mg / kg E25 or the; equivalent placebo intravenously. U.S. patients Subsequently they received 0.5 / kg E25 or the laceko ecjuvant intravenously a week. Subjects in Canada received 2.0 mg / kg E25 or placebo equjui on Day 0, mg lu / kg 5 or placebo equivalent on days 7/14, t-l.1"1 ms / kcj c In the studies of Canada and the US, a patient receiving E25 was withdrawn due to an asthma attack.The effects of the inhaled antigen solution on the airway were evaluated in three ways in the US protocol. and 5 two ways in the Canadian protocol In the US protocol, first, allergen-induced reductions in airflow during EAR and LAR were recorded by measuring baseline changes in FEVX. changes in LAR in bronchial reactivity for methacholine 3. Third, changes in inflammatory markers (percent and number of eosinophil and neutrophil, cationic eosinophilic protein, myeloperoxidase (MPO) and tryptase) in induced sputum were measured during LAR. Canadian protocol, they were quantified changes 5 in the amount of aeroallergen required to cause a decrease greater than or equal to 15% of FEVX (PD15). Second, the changes in methacholine concentration required to induce a fall greater than or equal to 20% in FEVX (PD20Mch) were assigned one day before the first and last | > bronchoprcvocación of aeroalérgeno and on Day 42. In the US, the main variable efficiency was the change in FEVX measured with one hour of allergen test (EAR) between Day 1 and Day 63. The baseline was defined oiiiO the difference observed in the percent change of 5 pre-tested levels in the FEVX response between Day 6 of the diluent allergen test and Day 1 of the allergen test. It was then defined as the difference between the allergen diluent test on Day 56 and the allergen diluent test on Day 63. In each case, two variables were derived: maximum observed decrease and aerial under the curve (AUC) as approximation by the trapeze method. The efficiency of the treatment was based between the comparison of the treatment of the baseline and that followed by AUC and maximum decrease. The differences between groups for the change between Day 1 and Day 63 were assigned by the ilcoxon Rank sum test. The LAR was calculated in a similar way as the main variable efficiency of change in FEV1 (AUC and dl3m? Nuc? On maximum) The initial dosage of allergen for inhalation were four double doses after calculating them from the prediction formula: y = 0.69x + 0.11, where y = log10 of PD20FEV1 of allergen (the dose of allergen causing a 20% decrease in FEVi) and x = logi0 PD10 of methacholine (the dose of methacholine causing a 10% decrease in FEV X sensitivity of the skin to the allergen (sensitivity of the skin to the allergen is defined as the smallest dilution of allergen with a diameter of 2 mm.) When the dose causes a fall in FEV of 20% or greater, no more When the dose causes a decrease in FEVX less than 10%, then the test goes to the next stage of doubling the dose, etc. The FEVX was measured at 20, 30, 45, 60, 90, and 110 minutes and at intervals of one hour to seven hours _pué3 of the inhale The allergen identification for the second bronchial test started at an allergen concentration of the four double doses more diluted than the dose that caused a 20% FEVX clearance during the first test. Dosing then proceeded in the higher concentration stages twice until the FEVX decreased 20% or until the allergen was given at a concentration of a double dose higher than that given in Day i. The results for percent change in FEVX of the baseline bronchial allergen test in the dosing protocol of U.S. they are shown in tabular form in Tables I and II and graphically in Figure 1. The numerical values were adjusted by means of the diluent test. One patient withdrew from the study, reducing the total number of enrollees to 19. These results indicate that this treatment protocol with an anti-IgE antibody effectively reduced EAR by 43% and LAR by 82%.
Table I. Percent of Change of EAR FEV, of Baseline in Allergen Test
Placebo E25 Total Number of Patients 9 9 Maximum Decrease Before Treatment 30% 25% After Treatment 34% 16% Improvement -15% 37% Value p 0.05 Area Under the Curve. Before Treatment 1320 1319 After Treatment 1506 752 Improvement -14% 43% Value p 0.02
Table II. Percent of Change of LAR FEV, of Baseline in Allergen Test
Placebo E25 Total Number of Patients 9 9 Maximum Decrease Before Treatment 15% 21% After Treatment 15% 5% Improvement 0% 76% Value p 0.05 area Under the Curve Before Treatment 2235 4928 After Treatment 2759 864 Improvement -23% 82% Value p 0.04
The effect of treatment with anti-IgE antibody was also evident in the evaluation of the allergen concentration released during the second allergen test. These results, shown in Table III, indicate that in 7/9 patients receiving E25 (as opposed to 2/9 patients receiving placebo), the dose of allergen needed to achieve a 20% reduction in FEVX was increased 100%.
Table III. Concentration of Allergen Released During the Second Allergen Test
Placebo E25 Total Number of Patients 9 9 Increase of 100% 2 7 No Change 1 1 Reduction of 50% 5 0 Reduction of 75% 0 1 Reduction of 80% 1 0
In Canada the main efficiency of the final pointer was the PC15 concentration of allergen for EAR (the allergen concentration needed to reach the 15% decrease in
EAR FEVX after the allergen test). Basically, those subjected to inhalation increased the doses twice in intervals of approximately 12 minutes until a measurement of the FEVX showed that a decrease of at least 15% or greater was obtained. PC15 was calculated using the final allergen concentration (C2), the second final allergen concentration (Cl), the percentage decrease in FEV1 after C2 (R2) and the percentage decrease in FEV after Cl (Rl) and the formula: log10 allergen PC15 = 0.3 (15-R1) (R2-R1) + log10 Cl. The baseline was defined as the PC15 concentration of allergen in Day 1. The main efficiency variable was the change in the PC15 concentration of allergen measured on Day 77. Among the group differences for the change between Day 1 and Day 77 were evaluated by the addition test of ilcoxon Rank. The PCi5 allergen log changes measured in one hour in the allergen test on days 27 and 55 of the baseline were also compared between the two groups using the Wilcoxon Rank test. The dosage for subsequent tests in the Canadian protocol was started on the same allergen test as the previous test. However, if the FEV: did not decrease more than or equal to 15% of the same concentration that caused a decrease greater than or equal to 15% during the first test, for three additional double doses it was released until a greater or equal to 15%. The results of the bronchial provocation test with allergen in the Canadian protocol are provided in tabular form in Table IV. The results show that patients receiving anti-IgE therapy require their most antigen (more double doses) to decrease their FEVX to less than 15% baseline.
Table IV. Change of Concentration PC15
Placebo E25 < 1 double or without 75% 10% mei oramiento > 1 25% 90% > 2 0% 60% 0% 36% Media < 0 2.4 double p = 0.0001 < 1 double or without 89% 20% improvement > 1 11% 80% > 2 0% 60% > 3 0% 48% Average 0 2.9 doubles p = 0.0008 < 1 double or no 67% 20% improvement X "±. 33% 80%> 2 11% 70%> 3 0% 45% Medium <0 2.9 doubles
P = 0.002 Figures 2 (U.S.) and 3 (Canada) represent the results of methacholine bronchial treatment in treated and untreated patients. Methacholine was provided in an initial dose of 0.03 mg / ml and a dose-response curve was constructed by administering serial double concentrations of methacholine until the worst maneuver of FEVq 1 or 3 minutes after inhalation of methacholine was recorded. equal to 80% of the FE'.q baseline. PC ^ FEMI (methacholine) was calculated by linear interpolation between the last two open points of the dose-response treatment. The results in Figures 2 and 3 indicate that opposite the patients who received placebo, a PC0FEVj was observed. (methacholine) increased in patients who received anti-IgE therapy. Thus, patients who received anti-IgE antibody have reduced their reactivity as a result of therapy. Figures 4 (U.S.) and 5 (Canada) represent the change of baseline in the total symptoms. The study subjects were asked to keep a symptom diary. The parameters included asthma symptoms such as decreased respiration, congested chest, wheezing, cough, and sputum (phlegm / mucus); nocturnal asthma symptoms such as the ole number v- ^ s the patient awakes with asthma, expiratory flow velocity peak AM (best of three attempts), number of inhaled beta agonist puffs in the past 12 hours; and symptoms of day asthma such as absence from work due to asthma; peak expiratory flow rate PM (the best of three attempts), and number of inhaled beta agonist puffs in the past 12 hours. These numbers were related on a scale of 0/10, with 10 being extremely severe. The results in Figures 4 and 5 show that patients receiving anti-IgE therapy show a tendency to reduce symptoms related to asthma as a result of treatment. Figures 6 (U.S.) and 7 (Canada) represent the allergen end-point titration skin test in patients receiving placebo or anti-IgE antibody. Basically, patients were injected intradermally with 10-fold serial dilutions of the allergen to which the patients were more reactive (house dust, cat hair, or grass) on Day 7 and Day 70 (after the end of treatment) for find the highest dilution that causes a skin reaction of 2 mm or less. The results demonstrate that subjects who received anti-IgE antibody had substantially a reduction in the reactivity of the allergen as a result of the treatment. In summary, the results of the two dosing protocols demonstrated that treatment with anti-IgE significantly improved early and late asthmatic responses to allergen, non-specific bronchial hyperreactivity, and allergen skin-skin reactivity test. Markers of airway inflammation also improved.
Claims (43)
1. A method of treating allergic asthma in a patient, characterized in that it comprises administration to the relative of a maintenance dose of an I jE antagonist and, optionally, a dose of administration of the IgE antagonist.
2. The method of claim 1, characterized in that the maintenance dose is repeated in intervals of approximately 1 to 90 days.
3. The method of claim 2, characterized in that the maintenance dose is repeated weekly.
4. The method of claim 2, characterized in that the maintenance oiosis is repeated biweekly.
5. The method of claim 1, characterized in that the IgE antagonist is an anti-IgE antibody.
F. The method of claim 5, characterized prqqie the antibody is chimeric.
7. The everything; 6. Claim 6, characterized in that the antibody is humanized.
8. The method of claim 5, characterized in that the antibody is a human antibody.
9. The method of claim 1, characterized in that the antagonist binds to soluble IgE and blocks the binding of IgE to the IgE receptor in basophils.
10. The method of claim 5, characterized in that the antibody binds to soluble IgE and blocks the binding of IgE to the IgE receptor in basophils.
11. The method of claim 1, characterized in that the administration dose is administered before the attack of asthma symptoms.
1_. The method of claim 1, characterized in that the dose of administration is administered after the attack of asthma symptoms.
13. The method of claim 1, characterized in that the administration dose is greater than the maintenance dose.
14. The method of claim 1, characterized in that the antagonist is administered in a formulation containing a buffer, a salt, optionally, a polyol, and optionally, a condom.
15. The method of claim 14, characterized in that the antagonist is freeze-dried, then reconstituted prior to administration.
16. The method of claim 1, characterized in that the maintenance dose, and optionally, the administration dose reduce the concentration of free IgE in the patient's serum to less than about 40 ng / ml.
17. The method of claim 1, characterized in that the maintenance dose of the agonist is approximately 0.001 to 0.01 mg / kg / week / baseline IgE lU / l.
18. The method of claim 1, characterized in that the maintenance dose, and optionally, the administration dose, results in a total serum antagonist concentration of about 1 to 10 times higher than the IgE concentration in the patient's total serum.
19. A method-- for treating allergic asin in a patient, characterized in that it comprises the administration to the patient of an IgE antagonist dose on average of about 0.001 to 0.01 mg / kg / week of IgE antagonist per lU / ml baseline IgE in the patient's serum.
20. A method for reducing the late asthmatic response in a patient, characterized in that it comprises administering to the patient a maintenance dose of an IgE antagonist and, optionally, a dose of administration of the IgE antagonist.
21. The method of claim 20, characterized in that the maintenance dose, and optionally, the administration dose reduce the concentration of free IgE in the patient's serum to less than 40 ng / ml.
22. The method of claim 20, characterized in that the maintenance dose, and optionally, the administration dose, results in a total serum antagonist concentration of about 1 to 10 times greater than the IgE concentration in the patient's total serum.
23. A method for reducing the late asthmatic response in a patient, characterized in that it comprises administering to the patient an IgE antagonist dose on average of about 0.001 to 0.01 mg / kg / week of IgE antagonist per each UI / ml baseline. IgE in the patient's serum.
24. A method for reducing the early asthmatic response in a patient, characterized in that it comprises administration to the patient of a maintenance dose of an IgE antagonist and, optionally, a dose of administration of the IgE antagonist.
2. The method of claim 24, characterized by c. { The maintenance dose, and optionally, the administration dose reduce the concentration of free IgE in the patient's serum to less than 40 ng / ml.
26 The method of claim 24, characterized in that the maintenance dose, and optionally, the dose of administration, results in a total serum concentration of antagonist of approximately 1 to 10 times greater than the concentration of IgE in the patient's total serum. .
27. A method for reducing the early asthmatic response in a patient, characterized in that it comprises the administration to the patient of an IgE antagonist dose on average of approximately 0.001 to 0.01 mg / kg / week of IgE antagonist per each UI / ml baseline. IgE in the patient's serum.
28. A method for reducing bronchial hyperreactivity in a patient, characterized in that it comprises administering to the patient a maintenance dose of an IgE antagonist and, optionally, a dose of administration of the IgE antagonist.
29. The method of claim 28, characterized in that the maintenance dose, and optionally, the administration dose reduce the concentration of free IgE in the patient's serum to less than 40 ng / ml. .
30. The method of claim 28, characterized in that the maintenance dose, and optionally, the administration dose, results in a total serum antagonist concentration of about 1 to 10 times greater than the IgE concentration in the patient's total serum.
31. A method for reducing bronchial hyperreactivity in a patient, characterized in that it comprises administering to the patient a dose of IgE antagonist i on average from about 0.001 to 0.01 mg / kg / week of IgE antagonist per each UI / ml baseline of IgE in the patient's serum.
32. A method for reducing skin reactivity in a patient, characterized in that it comprises administering to the patient a maintenance dose of an IgE antagonist and, optionally, a dose of administering the IgE antagonist.
33. The method of claim 32, characterized in that the maintenance dose, and optionally, the administration dose reduce the concentration of free IgE in the patient's serum to less than 40 ng / ml.
34. The method of claim 32, characterized in that the maintenance dose, and optionally, the administration dose, results in a total serum antagonist concentration of about 1 to 10 times greater than the IgE concentration in the patient's total serum.
35. A method for reducing skin reactivity in a patient, characterized in that it comprises administering to the patient a dose of IgE antagonist on average of about 0.001 to 0.01 mg / kg / week of IgE antagonist per each IU / ml line IgE base in the patient's serum.
36 A method for reducing pulmonary inflammation in a patient, characterized in that it comprises administering to the patient a maintenance dose of an IgE antagonist and, optionally, a dose of administration of the IgE antagonist.
37. The method of claim 36, characterized in that the maintenance dose, and optionally, the administration dose reduce the concentration of free IgE in the patient's serum to less than 40 ng / ml.
38. The method of claim 36, characterized in that the maintenance dose, and optionally, the administration dose, results in a total serum antagonist concentration of about 1 to 10 times greater than the IgE concentration in the patient's total serum.
39. A method for reducing pulmonary inflammation in a patient, characterized in that it comprises administering to the patient an IgE antagonist dose on average of approximately 0.001 to 0.01 mg / kg / week of IgE antagonist for each IU / ml IgE base line in the patient's serum.
40. The use of an IgE antagonist in the preparation of a pharmaceutical composition for the treatment of allergic asthma, comprising a maintenance dose, and optionally, a dose of administration of an IgE antagonist.
41. The use of claim 40, characterized in that it reduces the late asthmatic response in a patient.
42. The use of claim 40, characterized in that it reduces the early asthmatic response in a patient.
43. The use of an IgE antagonist in the preparation of a pharmaceutical composition for reducing bronchial hyperreactivity, to skin reactivity, or inflammation in a patient, characterized in that it comprises a maintenance dose, and optionally, a dose of administration of an antagonist of IgE
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US50801495A | 1995-07-27 | 1995-07-27 | |
US08/508,014 | 1995-07-27 | ||
PCT/US1996/012275 WO1997004807A1 (en) | 1995-07-27 | 1996-07-24 | Methods for treatment of allergic asthma |
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JP (1) | JP4153560B2 (en) |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6991790B1 (en) | 1997-06-13 | 2006-01-31 | Genentech, Inc. | Antibody formulation |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
WO1999045777A1 (en) * | 1998-03-10 | 1999-09-16 | The Children's Hospital Of Philadelphia | Compositions and methods for treatment of asthma |
US6299875B1 (en) | 1998-06-04 | 2001-10-09 | Panacea Pharmaceuticals, Llc | Methods to block IGE binding to cell surface receptors of mast cells |
US6913749B2 (en) | 1998-11-02 | 2005-07-05 | Resistentia Pharmaceuticals Ab | Immunogenic polypeptides for inducing anti-self IgE responses |
US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
IL155002A0 (en) * | 2000-10-12 | 2003-10-31 | Genentech Inc | Reduced-viscosity concentrated protein formulations |
EP2267032A3 (en) | 2002-11-08 | 2011-11-09 | Ablynx N.V. | Method of administering therapeutic polypeptides, and polypeptides therefor |
WO2004041865A2 (en) | 2002-11-08 | 2004-05-21 | Ablynx N.V. | Stabilized single domain antibodies |
JO3000B1 (en) | 2004-10-20 | 2016-09-05 | Genentech Inc | Antibody Formulations. |
DE202006020194U1 (en) * | 2006-03-01 | 2007-12-06 | Bioceuticals Arzneimittel Ag | G-CSF liquid formulation |
JP2010516747A (en) * | 2007-01-29 | 2010-05-20 | バルティオン テクニリーネン トゥトキムスケスクス | Method for producing a novel reagent mainly composed of IgE |
AR065368A1 (en) | 2007-02-15 | 2009-06-03 | Astrazeneca Ab | ANTIBODIES FOR IGE MOLECULES |
EP2052736A1 (en) * | 2007-10-26 | 2009-04-29 | Nycomed Danmark ApS | Parathyroid hormone formulations und uses thereof |
US20100316625A1 (en) * | 2007-12-21 | 2010-12-16 | Inspiration Biopharmaceuticals, Inc. | Stabilized factor ix formulations containing trehalose |
MX2010006395A (en) * | 2007-12-21 | 2010-07-01 | Hoffmann La Roche | Antibody formulation. |
WO2010056550A1 (en) | 2008-10-29 | 2010-05-20 | Wyeth Llc | Methods for purification of single domain antigen binding molecules |
CN102271707B (en) * | 2008-10-29 | 2015-04-08 | 阿布林克斯公司 | Formulations of single domain antigen binding molecules |
ES2667025T3 (en) | 2009-12-15 | 2018-05-09 | Ascendis Pharma Endocrinology Division A/S | Dry growth hormone composition transiently bound to a polymer carrier |
CN102533704A (en) * | 2010-12-30 | 2012-07-04 | 上海雅心生物技术有限公司 | Trypsin preparation prepared for immediate use |
TR201810298T4 (en) * | 2011-03-31 | 2018-08-27 | Merck Sharp & Dohme | Stable formulations of antibodies against human programmed death receptor PD-1 and related treatments. |
EA037797B1 (en) * | 2011-10-25 | 2021-05-21 | Протена Байосайенсиз Лимитед | Antibody formulation useful for prophylaxis and treatment of amyloidosis, variants thereof and method of making same |
TW201605468A (en) | 2013-09-27 | 2016-02-16 | 韓美藥品股份有限公司 | A formulation of long-acting human growth hormone conjugate |
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 |
GB201610198D0 (en) * | 2016-06-10 | 2016-07-27 | Ucb Biopharma Sprl | Anti-ige antibodies |
US11845798B2 (en) | 2017-05-02 | 2023-12-19 | Merck Sharp & Dohme Llc | Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies |
JOP20190260A1 (en) | 2017-05-02 | 2019-10-31 | Merck Sharp & Dohme | Stable formulations of programmed death receptor 1 (pd-1) antibodies and methods of use thereof |
RU2749342C1 (en) * | 2017-07-25 | 2021-06-08 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Pharmaceutical composition based on il-15 protein complex and applications thereof |
CN110732023B (en) * | 2018-07-18 | 2023-06-16 | 江苏恒瑞医药股份有限公司 | HER2 antibody pharmaceutical composition and application thereof |
US20230250191A1 (en) | 2020-07-10 | 2023-08-10 | Shanghai Jemincare Pharmaceutical Co., Ltd. | Anti-ige engineered antibody and application thereof |
WO2024017241A1 (en) * | 2022-07-18 | 2024-01-25 | Suzhou Transcenta Therapeutics Co., Ltd. | Stable pharmaceutical formulation comprising anti-gremlin1 antibody |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3729863A1 (en) * | 1987-09-05 | 1989-03-16 | Boehringer Mannheim Gmbh | STABILIZED ERYTHROPOIETIN LYOPHILISATES |
AU616916B2 (en) * | 1987-11-20 | 1991-11-14 | Kissei Pharmaceutical Co. Ltd. | 4h-quinolizin-4-one compounds exhibiting therapeutic activities |
JP2724625B2 (en) * | 1987-12-31 | 1998-03-09 | タノックス・バイオシステムズ・インコーポレーテッド | Unique antigenic determinants on IgE-producing B lymphocytes |
WO1993019197A1 (en) * | 1992-03-20 | 1993-09-30 | Immunet | Human monoclonal antibodies and methods for human monoclonal antibody production |
JPH07118168A (en) * | 1993-10-19 | 1995-05-09 | Tomoyasu Ra | Ige production suppressing agent |
DK0589840T3 (en) * | 1992-09-24 | 2004-07-26 | Novartis Ag | Converted monoclonal antibodies to an immunoglobulin isotype |
DE4344824C1 (en) * | 1993-12-28 | 1995-08-31 | Immuno Ag | Highly concentrated immunoglobulin preparation and process for its preparation |
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