CN1268174A - Catalytic monoclonal antibodies for the vivo transformation of corticosteroid prodrugs - Google Patents
Catalytic monoclonal antibodies for the vivo transformation of corticosteroid prodrugs Download PDFInfo
- Publication number
- CN1268174A CN1268174A CN98808387A CN98808387A CN1268174A CN 1268174 A CN1268174 A CN 1268174A CN 98808387 A CN98808387 A CN 98808387A CN 98808387 A CN98808387 A CN 98808387A CN 1268174 A CN1268174 A CN 1268174A
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- CN
- China
- Prior art keywords
- abzyme
- prodrug
- hydrocortisone
- medicine
- corticosteroid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 125000001424 substituent group Chemical group 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
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- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0002—Antibodies with enzymatic activity, e.g. abzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
Catalytic monoclonal antibodies (abzymes) for the in vivo transformation of corticosteroid prodrugs ae herein disclosed. These abzymes are advantageously used in emergency therapy of acute adrenal insufficiency allowing a prompt pharmacological action of the corticosteroid. Haptens against which the abzymes are generated are also disclosed.
Description
The present invention relates to name and be called the catalytic monoclonal antibodies of " abzyme ", it can be used for transforming the corticosteroid prodrug in the body, also relates to described antibody and is used for the treatment of application in the medicine of acute adrenocortical insufficiency in preparation.The present invention also relates to be used to prepare the method for described abzyme.
Background of invention
Acute adrenocortical insufficiency is breakneck illness, and often has fatal consequence.It can be in Sepsis, the acute asthma crisis, wound, operation, shock and collapse behind hypovolemia illness and the burn, myocardial infarction, pulmonary infarction, serious oedema state (vasodilation, glottic edema, pulmonary edema), acute pancreatitis, the anaphylaxis behind the serum injection, transfer accident, drug anaphylaxis, serious atopic reaction, apoplexy, the Childhood acute poisoning and unexpected the poisoning, hepatitis and hepatic coma, Tiroidina toxicity and Addison crisis, occluding thrombus vasculitis.
The methods of treatment of using comprises the corticosteroid vein treatment with high dosage at present.But the clinical application of corticosteroid in such therepic use do not confirmed by suitable clinical study that also on the contrary, the clinical trial of the overwhelming majority does not provide clearly efficacy outcomes.The pharmacokinetic properties of employed product can determine this uncertainty, on the other hand this can not owing to methodological error can not owing in described therapy from the shortage of the pharmacological activity of steroid.Because corticosteroid is water-insoluble, they must be puted together with hydrophilic support, so that they can be injected.But their biologic activity only could keep after separating hydrophilic segment, thereby discharges corticosteroid, and by this way, they can pass cytolemma and be attached on the cytosol receptor.Fracture is very slow in the body of the key between cortisone molecule and the hydrophilic segment, because this molecule is middle equistability, and does not have the specificity esterase in blood flow.Therefore, the bioavailability of activeconstituents is not immediately, and only just can observe treatment and reply the danger that causes the patient to survive after several hrs.
Corticosteroid remains the selectable medicine that treatment needs the acute syndromes of emergency schedule, although the comparative study that its mechanism of action is not also clarified fully at present and do not obtained as yet his feel of its effect is found out.Be similar to acute adrenocortical insufficiency, anaphylactic shock, hypovolemia shock and cardiogenic shock, the situation of the laryngeal edema and other symptom uses the cortisone medicine (500 milligrams to 10 grams) of high dosage to treat by intravenous route usually, and in 24 hours processes,, produce clinical response up to the patient every 1-2 hour repeat administration.Several days after crisis further should treat prolongation than low dosage, up to the recovery of control that reaches symptom and life parameters.Subsequently, normally necessary with LDMT, even by oral route.And, well-known, also corticosteroid can be widely used for treatment and degenerate, subacute and the chronic disease of inflammatory and tumorigenesis type, glomerulonephritis for example, kidney changes, systemic lupus erythematous, sacroiliitis, rheumatoid myocarditis, bronchial asthma, allergic disease, enteron aisle and hepatic diseases, corium changes, lymphoma, Huo Qijin disease, pericarditis, pemphigus, erythroderma and other illness.Extended treatment and high dosage also are necessary for the suitable concentration that obtains activeconstituents at action site in these cases, and the result causes the typical side effect of corticosteroid.
The disadvantageous effect that produces after extended treatment mainly comprises the inhibition to pituitary gland and suprarenal gland function, hydrogen and electrolytic homeostatic disorder, and hypertension, hyperglycemia, glycosuria is to enhanced susceptibility, osteoporosis and the neuropathy that infects.Verified such untoward reaction is owing to medicine intrinsic activity, but the dynamics of corticosteroid also has intense influence to whole side reaction.Become these characteristics and make that such treatment plan is enforceable, as hereinafter explaining.
Prior art
In order to overcome the defective of carrying out emergence therapeutic with corticosteroid, several treatment plans have been attempted, for example at septic shock.In order to regulate acute systemic inflammatory, the inflammatory mediator or the endotoxic monoclonal antibody of deactivation that stop the cytokine type have been used.But these molecules that involve in acute process are many especially and abundant, and only to suppress in these molecules one or some be not enough in treatment to selectivity, therefore abandoned described treatment plan.The nearest pharmaceutical research that is used to clarify the mechanism of action of glucocorticosteroid shows by stimulating or suppressing DNA and transcribe the different aspect (cytokine that suppresses inflammatory process, nitrogen oxide, prostaglandin(PG), the generation of leukotriene, adhesion molecule is in expression of cell surface or the like), these medicines can control inflammation by the interaction of specificity cytosol receptor with them.According to these results, the use of corticosteroid in emergence therapeutic remains to be transvalued.On the other hand, some characteristics, particularly structural performance of this class medicine do not allow to make full use of its real treatment ability, and because its clinical efficacy of this reason is still doubtful.
As everyone knows, in order to produce its distinctive effect, medicine must reach suitable concentration at its action site, and described concentration depends on the amount of product of administration and degree of absorption and other kinetic parameter of this material.Particularly absorption process is subjected to for example form and the size of molecule, degree of ionization, the influence of factors such as the solvability in lipophilic solvent.
With regard to corticosteroid, they are lipophilic molecules, so they must pass cytolemma and are attached on its cytosol receptor so that utilize its pharmacological activity.This has constituted the subject matter that its treatment is used on the one hand.The lipotropy of described compound has obviously hindered the solvability in water-containing solvent, and the diffusion in blood flow, therefore makes their utilization ratio compromises at action site.In order to overcome this shortcoming, this quasi-molecule is conjugated on the specific hydrophilic molecules (carrier) by covalent linkage, allow its dissolving.For example,, used phosphoric acid for cortisone, sulfuric acid, succsinic acid, hemisuccinic acid or acetate, uncle's fourth acetate, acetonide, diacetic acid, six acetone groups are with position 11,17 or 21 esterifications.
Unfortunately, if on the one hand this ester bond makes this material become soluble and allows its administration and spread in blood circulation, hindered it simultaneously and passed through cytolemma.Therefore this product only could utilize its pharmacological activity at the ester linkage breaking of prodrug and after discharging the lipophilic activeconstituents.On the other hand, this organism do not have to rupture esterase of such key, so hydrolytic process be very slowly and the bioavailability of this activeconstituents be insufficient equally.Clearly, for the symptom that wherein needs the emergence therapeutic effect, such pharmacokinetic properties often produces negative test.
Therefore, the activeconstituents that need have certain form, described composition is dissolvable in water aqueous pharmaceutical preparations, for example in the injection formulations, and in case in blood flow, just can be utilized rapidly so that pass cytolemma fast and bring into play himself pharmacotoxicological effect with the lipophilic form.
Catalytic monoclonal antibodies and its purposes in the activation prodrug are known, and for example are disclosed in chemical abstracts (114) 610w, and (119) 210716q is among (121) 195943g and (122) 28553d.General scheme is based on the exploitation of catalytic monoclonal antibodies (abzyme), this antibody can at simulation participate in chemical reaction compound transition state molecular structure haptens and produce.Have wherein that the potential energy of constituting atom and all molecules reaches peaked intermediate configuration in arranging in that the initial sum of the molecule of participating in chemical reaction is final.This configuration is corresponding to transition state and trend towards guaranteeing the final arrangement of reacting so that make potential energy return to lower level.
The abzyme or derivatives thereof of anti-corticosteroid is unknown.
The problem that runs in the preparation of abzyme is to find out suitable haptenic chemical structure.
WO8910754 discloses the catalytic monoclonal antibodies of the ester bond that can rupture, and under any circumstance can activate prodrug in the body.The instruction that is provided in this piece prior art is intended to solve the problem of activation or deactivation peptide class biomolecules, and a series of peptide class haptens is provided.
WO9302703 relates to antineoplaston particularly, and wherein corticosteroid is not predicted before being.
WO9416734 relates to a kind of methods of treatment, wherein the drug release in the effector molecule is arrived predetermined cell site by a kind of composite structure, described structure provides the first kind of reagent that is connected on the cell site, pattern with amplification is connected to second kind of reagent on described first kind of reagent, effector molecule is connected to again on described second kind of reagent, after this discharges active ingredient.These reagents have antibody as the functional group that forms different keys, but also can liken them to antibody.This effector molecule can be medicine and can be connected to carrier molecule, for example on the protein.This medicine also can be a prodrug, because the enzymatic agent that discharges active part also is provided; Or this effector molecule can be the enzyme that the catalyged precursor medicine transforms.
The selectivity of active ingredient discharges near present acceptor site or its, and the effect that active medicine is directed to action site is under any circumstance all arranged.Should concrete instruction at the diagnosis of tumour or the effective guiding molecule in the treatment.
JP94220072 discloses the abzyme of antiviral antibiotic.
Designing a complete class medicine, rather than need have unique standard the suitable homologue of the effective transition state of one compound.And, also need to have such homologue, do not rely on the hydrophilic segment that is conjugated on the steroid quasi-molecule.
Concrete problem is the quick hydrolysis of ester function in the cortisone prodrug, because there is not the specificity esterase that can discharge the medicine of being discussed in organism.General term about the problem of the abzyme of the prodrug that obtains anti-ester-formin all comprises in the prior art: the phosphonic acids function is indicated as being the simulation transition state, has also described and carrier protein link coupled group.But, not to those skilled in the art indicate about how coupling group navigated to the steroid quasi-molecule and wherein with the such key issue of relation of the simulation group of transition state.
Therefore, employed haptenic type is very crucial, and the mutual alignment of the coupling of transition state and simulation group is more crucial.
WO8910754 has particularly at length said some protein except mentioning general computer modeling technique, human renin for example, the fracture of the selected peptide bond of HIV gp120 envelope protein.
WO9302703 has discussed immunosuppression; antiviral; the particular problem of the prodrug of antitumor and cytotoxic agent; the part of selecting the esterification medicine is so that protect possible prodrug to avoid the destruction of endogenous esterase; and only subsequently; in case reached appropriate level of treatment, just release of active ingredients.In one aspect, technical problem is the reverse side of problem solved by the invention, and wherein hydrolysis must be finished in the shortest possible time, because must be in the emergence therapeutic method, rather than works at chronic treatment.
Abstract of invention
The haptens that has been found that the abzyme that is suitable for producing anti-corticosteroid water-soluble prodrug now is the compound that carries the steroid class formation of phosphate group on hydroxyl, described group is conjugated on the hydrophilic support in corresponding corticosteroid, be suitable for the chemical group puted together with macromole with carrying on the position C-3 of steroid class skeleton, described chemical group may be farthest from described phosphate group.
Therefore, one of purpose of the present invention is the compound of general formula (I)
R-[A]-OR-PO
3X
2 (I)
Wherein: A is the steroid nucleoid of corticosteroid hormone; R is connected to the chemical group on the C-3 position of pregnane ring A and is suitable for puting together with the immunogen macromole; PO
3X
2It is the phosphate group (it is carrying hydrophilic molecules on corresponding corticosteroid hormone) that is connected on the hydroxyl of 21-or 17-position; X is hydrogen or pharmaceutically acceptable positively charged ion.
The compound of the general formula of suitably puting together by R and the molecule that is suitable in animal producing antibody response (I) has constituted haptens, will obtain the catalytic monoclonal antibodies (abzyme) of the different water-soluble prodrugs of the anti-corticosteroid of specificity from this haptens.
The fragment of described abzyme or its fragment or its through engineering approaches is another object of the present invention.
Another object of the present invention is the medicine of treatment acute adrenocortical insufficiency of application abzyme is applicable to to(for) preparation.
Because the higher bioavailability of activeconstituents is to obtain the possibility of instant result of treatment by the major advantage that the present invention obtained, under emergency situation, this successfully obtains than high viability the patient who is treated with allowing.
Owing to can obtain the pharmacotoxicological effect of corticosteroid immediately, so might use with low dosage.
Because the higher bioavailability of activeconstituents uses the possibility than low dosage with the chance that reduces treatment time chronic disease listed above is obtained the effective treatment, to avoid side effect.
These and other purpose of the present invention will be carried out in more detail open by means of embodiment.
Detailed Description Of The Invention
In the compound of general formula (I), (A) be natural or the steroid of synthetic corticosteroid is examined.
The example of adrenocortical hormone is: hydrocortisone, fluoro cortisone, triamcinolone, dexamethasone, prednisone, cortisone and Betamethasone Valerate.
The example that is suitable for the R chemical group puted together with the immunogen macromole is an azido-, right-phenylazo--β-D-lactoside (Lac), right-phenylazo--β-D-glucoside (Glu), right-phenylazo--arsonate (Ars), trinitrobenzene sulfonate (TNBS), dinitrobenzene sulfonic acid sodium (DNBS), dinitrophenyl (DNP) and S-acetyl-mercaptosuccinic acid acid anhydride.Wherein, azido group is preferred.
The example of water-soluble corticosteroid prodrug is to be used for those of injection formulations.Preferred example is a betamethasone sodium phosphate, betamethasone sodium phosphate and sodium acetate, acetate cortisone, the hydrocortisone sodium phosphate, hydrocortisone sodium succinate, acetate cortisone, the acetate dexamethasone, dexamethasone sodium phosphate, acetate prednisone, methyl prednisone sodium succinate, acetate prednisone, prednisone sodium phosphate, uncle's fourth acetate prednisone, the tramcinolone acetonide, oxalic acid tramcinolone, tramcinolone six acetonides.21-hemisuccinic acid hydrocortisone, 21-acetate hydrocortisone, the 21-Acticorton, 17-hemisuccinic acid hydrocortisone, 17-acetate hydrocortisone, 17-Acticorton are preferred embodiment.
From each activeconstituents, that is, and the compound that begins to prepare general formula (I) from steroid class or its commodity derivative of pharmacological activity.For example, the activeconstituents that has carried bound phosphate groups in the position of needs is that commodity maybe can be from the method preparation of knowing.Then, insert selected R group according to the ordinary method of document description.
In case obtained the compound (haptens) of general formula (I), it and immunogen macromole puted together.Macromolecular example like this is KLH, BSA, Protalbinic acid, thyroglobulin, chicken IG, polysaccharide.
Then the hapten-carrier conjugate is used for the immunization animal, utilizes ordinary method to obtain catalytic monoclonal antibodies (abzyme) from this animal.
One of purpose of the present invention is abzyme or its fragment or its through engineering approaches fragment of the water-soluble prodrug of anti-corticosteroid hormone.
Usually, with splenocyte and the myeloma cell line fusion of immunization animal, after selecting hybridoma and positive colony, the antibody purification enzyme.
The program that is used to obtain abzyme is not crucial and for selecting animal, immunization scheme, and specific myeloma cell line (or other immortalized cell) has no particular limits.
The purification process of abzyme of the present invention definitely is conventional and in those skilled in the art's normal motility scope.
First embodiment preferred of the present invention relates to the 21 cortisone haptens that replace in the position.It is compound 21 β, 17 α-21-trihydroxy--4-pregnene-20-ketone-3-hydrazono--4 '-azido benzoyl amine-21-phosphoric acid ester, the compound of general formula (I) just, wherein (A) is the steroid component of cortisone, R is 3-hydrazono--4 '-azido benzoyl amine groups, X
This compound has constituted haptens.
Can observe the molecular structure that is used as haptenic compound and not have side chain corresponding to the hydrophilic segment of any prodrug of cortisone.Replacement is for the analogue of the synthetic transition state of each existing cortisone prodrug, and the present invention allows to provide for each activeconstituents of determining the analogue of transition state of the cleavage reaction of the every kind of prodrug that does not rely on hydrophilic residue.
Therefore, this antibody will be discerned the part by the molecule of the representative of the breaking point except the steroid component, and can be hemisuccinic acid salt, and the hydrophilic segment of one of carrier that phosphoric acid salt or other are known is not too important.According to identical principle, also other cortisone derivative can be used as therapeutical agent, the methyl prednisone that for example is different from cortisone, there is methyl group in it at position 6-α, has only when being connected to hemisuccinic acid residue (hemisuccinic acid prednisone, URBASON (R) SOLUBILE, 8,20,40,250 milligrams) Shi Caineng is used for injection formulations.
For hapten molecule, phosphate group is present in-21 positions, and the transition state of the hydrolysis of simulation ester group is spatially similar with quaternary carbon.
The group that is intended for use to set up with carrier proteins key is connected to position 3, and there is hydrophilic substituent in its representative and position 21 or 17 carbon atom farthest on it in this molecule.
According to the present invention, catalytic antibody can be discerned the integral part near the steroid molecule of reactive center.In fact, macromolecular carrier is connected on the trinitride of position C3, makes this component of molecule can be used for immunity identification, wherein reaction must really take place.So the antibody that is excited just can be discerned the major portion of binding site and the steroid quasi-molecule of C21.
Obtained haptens by hydrazides condensation with commodity two hydrocortisones-21-phosphoric acid ester and 4-azidobenzoic acid; Begin to have prepared a back compound:, react to obtain the 4-azidobenzoic acid with sodium nitride subsequently with the nitric acid diazonium acidifying the water by following reactions steps from the 4-benzaminic acid; The latter uses the hydrochloric acid methanol esterification; In the methyl alcohol of intermediate methyl ester, carry out the hydrazinolysis reaction.The reagent of the equimolar amount (2 mmole) by will being dissolved in methyl alcohol (3 milliliters) in airtight phial is heated to 90 ℃, carried out the condensation of haptens and two hydrocortisones-21-phosphoric acid ester in 3 hours, up to obtaining clear soln, haptens is therefrom separated with solid form by solvent evaporation.Mobilely infer haptenic existence in reaction mixture according to what on RMN spectrum, be connected to vinyl signals on the C-4.
Because its lower molecular weight, lack the immunogen ability as analogue synthetic molecule, and the acquisition when they and macromolecular carrier are puted together of said immunogen ability.Under common experiment condition, the molecular vehicle of more frequent use is a protein.So, the steroid class (haptens) of modifying is conjugated on the protein so as the maximum of the molecular regime (antigenic determinant) that need to guarantee appear become essential.In preferred embodiments, KLH is the protein of selecting.
The pattern on the macromolecular carrier of being conjugated to depends on the type of available functional group on hapten molecule.Different methods with haptens chemistry modifying protein is obtainable, and generally can use, and selects the most effective then.Mol ratio by absorption spectrophotometry estimation replacement.
According to different treatment plans,, haptens-protein carrier conjugate is used for the immunization 8-10 Balb/c mouse in age in week by subcutaneous injection approach (with complete and incomplete Freund's adjuvant) with by the intraperitoneal approach.
When the treatment phase finished, the serum that extracts animal had produced at antigenic immunne response with checking, produced the catalytic activity that needs then.
In case selected to produce the animal of higher antibody response, carrying out MONOCLONAL ANTIBODIES SPECIFIC FOR according to the method for routine (merges splenocyte and myeloma cell, by disclosed radioactivity measurement method screening hybridoma family hereinafter, select positive colony, antibody purification).
In order to make the effectiveness maximization of catalytic antibody, can take different strategies to carry out: the analogue of-modification transition state;-select antibody (phage demonstration) from the merging library of expressing in phage;-by means of the catalytic monoclonal antibodies that obtains with standard method before the site-specific mutagenesis modification.
Abzyme of the present invention has the catalytic activity of the water-soluble prodrug of anti-corticosteroid hormone, so they can be used for treating Adrenal cortex function insufficiency, particularly emergence therapeutic, and wherein the fastest effect of this medicine is essential.
Therefore, one of purpose of the present invention is the medicine of the recoverable symptom of cortisone medicine of the application abzyme of the water-soluble prodrug of anti-corticosteroid hormone is used for the treatment of to(for) preparation.Specifically, application of the present invention is included in treatment acute adrenocortical insufficiency, Sepsis, the acute asthma crisis, wound, operation, shock and collapse behind hypovolemia illness and the burn, myocardial infarction, pulmonary infarction, serious oedema state (vasodilation, glottic edema, pulmonary edema), acute pancreatitis, the anaphylaxis behind the serum injection, transfer accident, drug anaphylaxis, serious atopic reaction, apoplexy, the Childhood acute poisoning and unexpected the poisoning, hepatitis and hepatic coma, Tiroidina toxicity and Addison crisis, the application in the occluding thrombus vasculitis.
Another object of the present invention is that the abzyme of the water-soluble prodrug of anti-corticosteroid hormone is used for the treatment of degeneration for preparation, the subacute and chronic disease of inflammatory and tumorigenesis type, for example glomerulonephritis, kidney changes, systemic lupus erythematous, sacroiliitis, rheumatoid myocarditis, bronchial asthma, allergic disease, enteron aisle and hepatic diseases, corium changes, lymphoma, the Huo Qijin disease, pericarditis, pemphigus, the application of the medicine of erythroderma and other illness.
The administration of abzyme will be by the type of doctor in charge according to symptom, and patient's state is determined number of times and dosage with the type of relevant prodrug.
Abzyme of the present invention can be with the administration simultaneously of corresponding prodrug or with the certain sequence administration by experienced doctor's establishment.
Be easily, abzyme of the present invention is formulated as pharmaceutical composition, described composition is also included within the scope of the present invention.Said composition contains the abzyme of significant quantity, and this significant quantity is determined according to the specific activity of described prodrug.
Composition of the present invention contain with medicine on can accept the abzyme of carrier and mixed with excipients, and the method preparation that can for example in Remington ' s pharmaceutical science handbook (publication of USA New York Mack press), describe with the method for knowing.
Injectable composition is preferred.
The present invention also comprises medicine box, and it contains the pharmaceutical composition of the water-soluble prodrug of a kind of pharmaceutical composition of the abzyme of the present invention that comprises appropriate amount and a kind of (antagonist enzyme) corticosteroid that comprises significant quantity on the medicine with isolating form.
The following examples further specify the present invention.Embodiment
A) haptens 21 β, the preparation of 17 α-21-trihydroxy--4-pregnene-20-ketone-3-hydrazono--4 '-azido benzoyl amine-21-phosphoric acid ester
Be evaporated to do by 21-Acticorton and obtain title compound the non-purifying of 50 milligrams of 3-azido benzoyl base hydrazines and 150 milligrams.
B) put together with KLH
20 milligrams of KLH (six aggressiveness, molecular weight 450000 gram/moles) are dissolved in the 10mM saleratus, pH7.4,5 milliliters to final concentration be 4 mg/ml.
Unpurified above-mentioned product is dissolved in identical solution, calculates the 21-Acticorton derivative of 200 molar excess.Calculate the amount of the product that uses, suppose that all steroid classes exist with the nitrine form of active replacement:
(consider such fact: 1 part of trinitride and 3 parts of 21-Acticortons are arranged in initial reaction mixture, and 4/3 is used for correction mass.
This solution is used cold light with unshielded 200W-mercury vapor light, and irradiation is 20 minutes under agitation condition.
Product is passed through with 5 centimetres of identical reaction buffer equilibrated Sephadex G 50 Zim Δs 2 cm x.
Collect the fraction of (A280) peak value by measurement volumes.For the content of the phosphoric acid ester of predicting every volume unit, suppose to have obtained maximum mole and replace than (200: 1), and by means of the amount of Ames test with suitable volume and extent of dilution estimation phosphoric acid ester.The value that the Ames test is used for the reaction KLH and the acquisition A280=0.981 of 10 microlitres.
Because the optical extinction coefficient of this test is the micromolar phosphoric acid ester of A280=0.240/0.01, so the result is:
Wherein replacing mol ratio is:
C) with the conjugate immunized mice and control antibody activity
According to different treatment plans,, haptens-protein carrier conjugate is used for the immunization 8-10 β alb/c mouse in age in week by subcutaneous injection approach (with complete and incomplete Freund's adjuvant) with by the intraperitoneal approach.
When the treatment phase finished, the serum that extracts animal had produced at antigenic immunne response with checking, produced the catalytic activity that needs then.
In order to carry out this control, carry out specific radioactivity measurement in order: from 37Mbq [1,2,6,7-
3H] hydrocortisone (Amersham) begin to have synthesized with tritium (
3H-C21-H) mark [1,2,6,7-
3H]-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone-21 hemisuccinic acid ester.
In order to obtain to have b
aThe analytical signal of the 50.000cpm of 60% counting efficiency, volume are that the working concentration of 100 microlitres is as follows:
The quality of possibility mark allows preparation to be equal in theory:
The volume of working solution.
Because the work with the real concentration of the substrate that is equal to 10 micro-molar concentrations (obtaining from document) is suitable, is necessary so prepare the substrate of following total amount:
2.664 * 10
-6Mol=2.664 * 10
-5Mole
Because the amount of marker is equal to 37 * 10
6Bq/2.11 * 10
15Bq/ mole=1.7 * 10
-8Mole, its contribution to total mass is insignificant.
From 2.664 * 10
-5Mole * 362 gram/moles=9.6 * 10
-3Gram can obtain the amount of cold carrier of the molecular weight=62.5 gram/moles of hydrocortisone.
The hydrocortisone of this quality is allocated in the reaction phial (React.Vial Pierce), and wherein the solvent of mark is at T
0Evaporate under the nitrogen gas stream that (maximum) is 30 ℃.
Hydrocortisone is dissolved in the anhydrous pyridine of 200 microlitres, so that react with basic catalyst with three moles of doubly excessive succinyl oxides
2.664 * 10
-5Mole * 3 * 100.1 gram/moles=8.0 * 10
-3Gram
Reaction mixture was at room temperature placed under the condition of constant agitation 15 hours.
When insulation finishes, this mixture is transferred in the separating funnel, use 200 microlitre pyridine washing reaction phials again.
Hydrochloric acid 37% with 400 microlitres solidifies pyridine.After dilute with water, with ethyl acetate extraction (3 times).
By this way, can obtain the hydrocortisone of mark, the crystallization of the product that the evaporation acquisition needs.
After the reaction substrate of preparation mark, set up the radioactivity enzymatic and measured.
Solubility change after this method is removed from the nuclear of tritiate hydrocortisone based on cold succsinic acid component.After with substrate and response matrix (damping fluid, clone's supernatant liquor or whole human serum) contact insulation, the water ether extraction, carry out subsequently solvent evaporation and
3Measurement in the extract of the radiated signal that the H hydrocortisone sends.By jumping dilution (16 *) in the termination insulation of the moment of needs with distilled water at its fusing point.If the catalysis speed dependent is in catalyst concn and temperature, and this program permission speed of response reduction by 16 * 2 is carried out in the consideration insulation under 38.5 ℃ (corresponding to inside of human body temperature)
4Doubly (remembeing 10 ℃ of the every reductions of T, AE=20hJ/ mole, speed) therefore can be considered to gratifying.
Used the extraction of ether in 10 seconds by vortex.During milking, in the so limited time, allow to be reflected at aqueous phase and still be in unbalanced state.
By the different volumetric molar concentration of utilizing five substrates that in human serum, are incubated in the different time this program is limited.
Compare with control sample, only detect the spontaneous esterase activity of the hydrocortisone-21-hemisuccinic acid ester in the human serum at concentration of substrate＞100mM with when being higher than 1 hour soaking time.
So the animal that this method has been used to identify immunization, described animal has produced positive immunne response, and this is owing to have the production of antibodies of the esterase activity of anti-hydrocortisone-21-hemisuccinic acid ester.Under being equal to the concentration of substrate of 10mM and in the result of this mensuration that insulation was carried out after 1 hour, provided following sign: in serum, found to be higher than the active esterase activity that exists in the serum of untreated animal and blank with the mouse of hapten-carrier conjugate immunization.
Claims (20)
1. the fragment of the abzyme of the water-soluble prodrug of anti-corticosteroid hormone or its fragment or its through engineering approaches.
2. the abzyme of the water-soluble prodrug of anti-corticosteroid hormone, it can be obtained by the method that comprises the following steps:
A) the haptens analogue of the transition state of described prodrug and immunogen macromole are puted together to produce conjugate, and described haptens has the structure of general formula (I)
R-[A]-OR-PO
3X
2 (I)
Wherein: A is the steroid nucleoid of corticosteroid hormone; R is the chemical group that is connected on the C-3 position of pregnane ring A and is suitable for puting together with the immunogen macromole; PO
3X
2It is the phosphate group (it is carrying hydrophilic molecules on corresponding corticosteroid hormone) that is connected on the hydroxyl of 21-or 17-position; X is hydrogen or pharmaceutically acceptable positively charged ion;
B) catalytic monoclonal antibodies of the anti-described conjugate of acquisition.
3. abzyme according to claim 1 and 2, wherein said prodrug is a hydrocortisone, fluoro cortisone, tramcinolone, dexamethasone, prednisone, cortisone, the soluble derivative of Betamethasone Valerate.
4. abzyme according to claim 3, wherein said prodrug are the soluble derivatives of hydrocortisone.
5. abzyme according to claim 4, wherein said prodrug are selected from following group: 21-hemisuccinic acid hydrocortisone, 21-acetate hydrocortisone, 21-Acticorton.
6. abzyme according to claim 4, wherein said prodrug are selected from following group: 17-hemisuccinic acid hydrocortisone, 17-acetate hydrocortisone, 17-Acticorton.
7. according to claim 1 or each described abzyme of 2-6, wherein said haptens is compound 21 β, 17 α-21-trihydroxy--4-pregnene-20-diketone-3-hydrazono--3 '-azido benzoyl amine-21-phosphoric acid ester.
8. according to each described abzyme of claim 2-7, wherein said macromole is a protein.
9. abzyme according to claim 8, wherein said protein is KLH.
10. according to each described abzyme of claim 2-8, wherein said monoclonal antibody is by obtaining with the described conjugate immunization animal that obtains in step a).
11. according to each described abzyme of claim 2-8, wherein said monoclonal antibody obtains by external immunization.
12. the abzyme of claim 1 or 2-10 is as the application of medicine.
13. the abzyme of claim 1 or 2-10 can be used for application with the medicine of the recoverable methods of treatment of hydrocortisone medicine for preparation.
14. the abzyme of claim 1 or 2-10 is for the application of the medicine of preparation treatment acute adrenocortical insufficiency.
15. contain the pharmaceutical composition that to accept carrier and mixed with excipients on the abzyme of the claim 1 of significant quantity or 2-10 and the medicine.
16. pharmaceutical composition according to claim 15, said composition are injectable forms.
17. comprise on the abzyme of at least a claim 1 that contains significant quantity or 2-10 and the medicine and can accept the pharmaceutical composition of carrier and mixed with excipients and the test kit of another kind of pharmaceutical composition that back one composition contains the water-soluble prodrug of corticosteroid hormone of the amount significant quantity of antagonist enzyme.
18. the compound of general formula (I)
R-[A]-O-PO
3X
2 (I)
Wherein: A is the steroid nucleoid of corticosteroid hormone; R is the chemical group that is connected on the C-3 position of pregnane ring A and is suitable for puting together with the immunogen macromole; PO
3X
2It is the phosphate group (it is carrying hydrophilic molecules on corresponding corticosteroid hormone) that is connected on the hydroxyl of 21-or 17-position; X is hydrogen or pharmaceutically acceptable positively charged ion.
19. compound according to claim 18, this compound are 11 β, 17 α-21-trihydroxy--4-pregnene-20-diketone-3-hydrazono--3 '-azido benzoyl amine-21-phosphoric acid ester.
20. the compound of claim 18 or 19 in the abzyme of preparation claim 1 or 2-10 as haptenic application.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI97A001825 | 1997-07-30 | ||
| IT97MI001825A IT1293510B1 (en) | 1997-07-30 | 1997-07-30 | MONOCLONAL CATALYTIC ANTIBODIES FOR THE IN VIVO TRANSFORMATION OF CORTICOSTEROID PROFARMACES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1268174A true CN1268174A (en) | 2000-09-27 |
Family
ID=11377677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98808387A Pending CN1268174A (en) | 1997-07-30 | 1998-07-27 | Catalytic monoclonal antibodies for the vivo transformation of corticosteroid prodrugs |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1003842A1 (en) |
| JP (1) | JP2001512006A (en) |
| CN (1) | CN1268174A (en) |
| AU (1) | AU736187B2 (en) |
| CA (1) | CA2299623A1 (en) |
| IT (1) | IT1293510B1 (en) |
| NO (1) | NO20000395L (en) |
| NZ (1) | NZ502526A (en) |
| WO (1) | WO1999006536A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6582945B1 (en) | 1999-06-16 | 2003-06-24 | Boston Biomedical Research Institute | Immunological control of β-amyloid levels in vivo |
| JO3076B1 (en) | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | Immunotherapy regimes dependent on apoe status |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4469689A (en) * | 1983-03-30 | 1984-09-04 | The Upjohn Company | Sulfonate containing ester prodrugs of corticosteroids |
| US4588718A (en) * | 1984-03-28 | 1986-05-13 | The Upjohn Company | Carboxy containing ester prodrugs of corticosteroids |
| GB9510830D0 (en) * | 1995-05-27 | 1995-07-19 | Zeneca Ltd | Proteins |
-
1997
- 1997-07-30 IT IT97MI001825A patent/IT1293510B1/en active IP Right Grant
-
1998
- 1998-07-27 AU AU87328/98A patent/AU736187B2/en not_active Ceased
- 1998-07-27 NZ NZ502526A patent/NZ502526A/en unknown
- 1998-07-27 WO PCT/EP1998/004682 patent/WO1999006536A1/en not_active Application Discontinuation
- 1998-07-27 EP EP98938707A patent/EP1003842A1/en not_active Withdrawn
- 1998-07-27 CA CA002299623A patent/CA2299623A1/en not_active Abandoned
- 1998-07-27 CN CN98808387A patent/CN1268174A/en active Pending
- 1998-07-27 JP JP2000505278A patent/JP2001512006A/en not_active Withdrawn
-
2000
- 2000-01-26 NO NO20000395A patent/NO20000395L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU736187B2 (en) | 2001-07-26 |
| AU8732898A (en) | 1999-02-22 |
| EP1003842A1 (en) | 2000-05-31 |
| NO20000395L (en) | 2000-03-28 |
| CA2299623A1 (en) | 1999-02-11 |
| NO20000395D0 (en) | 2000-01-26 |
| IT1293510B1 (en) | 1999-03-01 |
| NZ502526A (en) | 2002-09-27 |
| JP2001512006A (en) | 2001-08-21 |
| WO1999006536A1 (en) | 1999-02-11 |
| ITMI971825A1 (en) | 1999-01-30 |
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