EP0162896A1 - Matrices portant de multiples allergenes utiles pour un tamisage qualitatif d'allergies - Google Patents

Matrices portant de multiples allergenes utiles pour un tamisage qualitatif d'allergies

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Publication number
EP0162896A1
EP0162896A1 EP84904289A EP84904289A EP0162896A1 EP 0162896 A1 EP0162896 A1 EP 0162896A1 EP 84904289 A EP84904289 A EP 84904289A EP 84904289 A EP84904289 A EP 84904289A EP 0162896 A1 EP0162896 A1 EP 0162896A1
Authority
EP
European Patent Office
Prior art keywords
allergens
allergen
allergosorbent
screening device
discs
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.)
Withdrawn
Application number
EP84904289A
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German (de)
English (en)
Inventor
Anne Beatrice Jepson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ventrex Laboratories Inc
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Ventrex Laboratories Inc
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Filing date
Publication date
Application filed by Ventrex Laboratories Inc filed Critical Ventrex Laboratories Inc
Publication of EP0162896A1 publication Critical patent/EP0162896A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
    • G01N33/548—Carbohydrates, e.g. dextran

Definitions

  • This invention relates to allergen-bearing matrixes or supports, useful for qualitatively screening human sera, by means of the RAST test or modifications thereof, for allergic or atopic hypersensitivity.
  • immunoglobulin E IgE was isolated and identified as the blood serum component (reagin) that causes allergic or atopic hypersensitivity.
  • RIA radioimmunoassay
  • EIA fluorescent immunoassay procedures were also routinely adapted to provide in vitro tests for total IgE and allergen-specific IgE.
  • the allergosorbent used in such RAST or modified RAST assays generally has been prepared by binding an antigenic substance, or allergen — for example a grass allergen from Bermuda or timothy grass, a weed allergen from common ragweed or Russian thistle, a tree allergen from maple or birch trees, a food allergen from milk or chocolate, an allergen from house dust, dust mites, cat epithelium, dog dander or penicillium notatum, to mention only some of the more common examples — to a solid support, usually a paper disc.
  • allergen for example a grass allergen from Bermuda or timothy grass, a weed allergen from common ragweed or Russian thistle, a tree allergen from maple or birch trees, a food allergen from milk or chocolate, an allergen from house dust, dust mites, cat epithelium, dog dander or penicillium notatum, to mention only some of the more common examples — to a solid support, usually
  • the assay is run by taking a small sample of blood from a patient suspected of having allergic hypersensitivity because of such symptoms as rhinitis, itchy or watery eyes, asthma, eczema, hives or localized swelling, correlated in some cases tq particular times of year or particular episodes involving contact with known allergens, and incubating the blood serum with, the allergosorbent to enable allergen-specific IgE from the serum to bind to the allergen on the substrate. Following this incubation, the serum and all non-specific (unbound) IgE present are washed from the substrate, and a labeled anti-IgE is added which binds to the patient's IgE bound to the allergen on the substrate. The quantity of labeled anti-IgE which binds to the patient's IgE determines the patient's sensitivity to that particular allergen. The test is then repeated for each suspected allergen.
  • Each of these methods involves the use of a screen that in one way or another reduces the number of individual RAST tests required, thus reducing the cost to the patient.
  • the screen essentially "weeds out" those patients who are non-allergic with respect to IgE mediated allergies, thereby avoiding the need to perform many more tests on them.
  • Such a screen should detect those patients who are allergic or atopic, and individual RAST tests will then be run on them to determine the particular allergens causing the problem.
  • the screening RAST batteries disclosed by King employed 6-10 individual allergen-impregnated paper discs, each individually impregnated with an allergen indicator for major allergen fields (i.e., one weed, one grass, one tree, one mold, one animal epithelium allergen, etc.).
  • Nalebuff, Aid Service Corporation Consultants' Report, November, 1982 suggests a "mini screen profile" of six allergens for initial allergy diagnosis: "one grass, one weed, one mold, one animal dander, one tree and dust mite", with the suspected atopic patient's serum being subjected to these allergens in six individual RAST tests. And, in a paper presented at a public Section meeting of the Triological Society at Pebble Beach, California on January 8, 1983, Dr. Nalebuff indicated that such a mini screen profile, using five allergens, has a sensitivity level of 98%.
  • Each of the Marinkovich patents uses expressions such as "a large number of allergens", “a plurality of separate allergens", “various allergenic materials”, “specific identified allergen”, “separate identified allergen”, “the allergens to which a patient is hypersensitive”, “separate identified allergens” and “a different allergen”; see, for example, column 1, lines 46 and 48-49; column 2, lines 10 and 55; column 3, line 11; column 5, lines 23-24 and column 6, lines 15-16, respectively, of U.S. 3,941,876, and column 2, line 7 of U.S. 4,031,197.
  • neither of these patents explicitly discloses that different allergens from different allergen groups are bonded to the particular supports shown.
  • U.S. Patent No. 4,327,073, issued April 27, 1983 to Huang discloses an analytical method for quantitatively analyzing bodily fluids for a plurality of substances, each of which undergoes at least one reaction with a cognate compound.
  • Huang specifically teaches, at from column 10, line 54 to column 11, line 2, using a substrate carrier bearing "immobilized antibodies which conjugate with antigens of unknown quantities in the biological fluid" to analyze an immune system for the antibodies. No specific mention is made of allergens being bound to the immobilized antibodies, nor is there, once again, any disclosure by Huang that a plurality of different allergens from different allergen groups can be bound to the substrate carrier.
  • allergen-bearing (allergosorbent) screening devices can be prepared which are useful for screening human sera qualitatively, by means of the RAST test or modifications thereof, for allergic hypersensitivity to the entire range of known prevalent allergens responsible for IgE mediated allergies, i.e., to allergens represented by allergen indicators for major allergen fields across the known spectrum of allergens now employed in a full battery of individual RAST tests for IgE mediated allergies.
  • These screening devices comprise a monolithic matrix or support coated with allergens from a plurality of different allergen groups, e.g., weeds, grasses, trees, molds, animal epithelia or dander, dust, dust mites, etc.
  • the monolithic matrixes or supports which can be used in preparing the allergosorbents of the present invention can be any monolithic water-insoluble organic or inorganic matrix or support having surface properties which render it suitable to the adsorption of allergens.
  • a multifinned stick or similar device of the type disclosed in U.S. Patents Nos. 4,197,278 and 4,225,575, issued April 8 and September 30, 1980, respectively, to Piasio et al preferably one made of a thermoplastic polymer such as polystyrene, polyethylene, polypropylene, polyvinyl chloride, and the like, can be used, and can be coated with a mixture of all the different allergens making up the screen.
  • each of the fins in such a stick e.g., a stick having six or nine fins, can be coated with different allergens entirely or partly from different allergen groups.
  • six allergen screens can be prepared by coating each fin of a six finned molded polystyrene stick with a different allergen, such as one allergen from each of the following sets of six allergens:
  • a nine allergen screen can be prepared by coating each fin of a nine finned molded polyethylene stick with one of the following nine allergens: Screen NO. 3
  • Such multifinned sticks can be molded or otherwise formed as a unitary construction, i.e., with the chosen number of fins initially attached to the stick or shaft. If it is desired to coat each fin in such a stick with a different allergen from different allergen groups, this can be accomplished by dipping each fin into a different liquid allergen extract, painting a different allergen onto each fin, or by any other suitable means.
  • the central stick or shaft can also be constructed, if desired, to contain a multiplicity of receptacles (slots, holes or the like), or adapted to contain or receive any other suitable fastening means, to accommodate the attachment thereto of any chosen number of fins coated with different allergens from different allergen groups.
  • a batch of fins can be coated with the same allergen, another batch with another allergen from a different allergen group, and so on until the desired number of batches of fins coated with different allergens from different allergen groups has been prepared.
  • the thus-coated batches of fins can be shipped, together with sticks or shafts adapted to receive them, to the allergists, otolaryngologists or general practicioners (or their laboratory technicians) who will connect a desired number of fins bearing different allergens from different allergen groups to a stick and use it as an allergen screen.
  • allergen screens containing any chosen number of different allergens, including ones prevalent in particular sections of this or any other country, or ones to which particular populations of patients, e.g., children, are particularly susceptible, can easily be assembled.
  • Test tubes, beads, sheets, fibers, mats, microtiter plate wells, and the like, made from glass or a thermoplastic polymeric material, can also be used as the monolithic matrix or support, as can monolithic cellulosic substrates such as paper discs or strips.
  • allergens that can be bonded to the monolithic matrix or support are allergens from the following groups: I. Inhalant Allergens
  • At least six different allergens each from a different allergen group, will be employed to coat the monolithic matrix or support when practicing the present invention, although lesser numbers of different allergens from different allergen groups can be employed, if desired (for example, if for any reason the practitioner considers it preferable to use two or more screens, each bearing two or more different allergens from different allergen groups, to carry out a series of screens on patient's sera).
  • As many as 12 to 18 or more allergens from different groups can be used, with each of them being a different allergen from a different allergen group or, as illustrated above by Screen No.
  • the number of allergens includable is limited only by the purity of the allergen extracts employed and the surface area and properties of the monolithic matrix or support.
  • the allergens used in preparing the present invention's multiallergen screens are chosen, as indicated above, to represent the typical allergens to which a patient population manifesting the symptoms of allergic hypersensitivity is likely to be sensitive, e.g., those IgE mediated allergens in a particular geographic area to which significant numbers of allergic patients are sensitive, those to which children more commonly exhibit sensitivities, foods which frequently cause allergic reactions, etc.
  • the present invention's multiallergen screens permit an examining physician, oftentimes a general practitioner or an internist in the first instance, to obtain at least an initial indication of allergic hypersensitivity. This is valuable not only when the patient exhibits some or all of the common symptoms of allergies, and the results obtained using the screen will be used by a specialist in allergies to whom the patient will be referred as the basis on which to structure a battery of individual RAST tests, but also when the patient's reported symptoms and history, and the physician's physical examination, do not indicate a typical allergic patient. In such a case, the present invention's multiallergen screen either will rule out one more possibility, or perhaps find the hitherto hidden cause of the patient's complaint.
  • the matrix or support is a monolithic cellulosic support, such as a paper disc
  • the following procedure published by Ventrex Laboratories, Inc. for use in its Neuter Disc Program (by which individual customers are enabled to coat discs with allergen extracts of their own choosing, including extracts which may be commercially unavailable or difficult to obtain) can be used.
  • This procedure as given here allows 200 discs to be coated at one time. Adjustment of the volumes of reagents employed permits the coating of greater or lesser numbers of discs.
  • the procedure involves first presaturating the discs [typically APT (aminophenylthioether derivative) paper discs (Schleicher & Schuell, Inc., Keene, N.H.) having a diameter of approximately 6.12 mm, a weight/10 discs of 0.0269 gram and a basis weight of 92 grams/square meter] with 20 ml. of cold (4°C) IN HCl. Upon the addition of the 20 ml.
  • APT aminoophenylthioether derivative
  • HCl HCl
  • the discs and aqueous HCl are swirled for approximately 30-60 seconds, using the disc bottle as a reaction vessel.
  • the disc bottle is then aspirated thoroughly.
  • 20 ml. of cold IN HCl are again added to the disc bottle and swirled.
  • 0.6 ml. of a freshly prepared aqueous sodium nitrite solution (1 gram % w/v NaNO 2 in water) is added to the disc bottle, which then contains 200 discs, 20 ml. of cold IN HCl and 0.6 ml. of the aqueous sodium nitrite solution. Swirling of this combination is continued at 2-8°C for 30 minutes.
  • the swirling is carried out by hand, it should be done for five minutes initially and then once every five minutes thereafter for the full 30 minutes.
  • a flask swirling unit will be employed. After the full 30 minutes, the solution is aspirated from the disc bottle. The treated discs are then washed with 10 ml. of cold distilled water, aspirated, and washed again four times in the same manner, making sure that the disc bottle has been aspirated thoroughly after the final wash.
  • the desired amount of extract is measured and added to an equal amount of aqueous 0.1M phosphate buffer, then brought up to 10 ml. with aqueous 0.05M phosphate buffer.
  • the discs are suspended in the correct volume of diluted extract and 10 ml. of aqueous 0.05M phosphate buffer.
  • the combination is then swirled at 2-8°C for one hour, using the same instructions as stated above if swirling is carried out by hand. After one hour, the solution is aspirated and washed with 10 ml. of cold distilled water. This washing procedure is then repeated four times, with the discs being aspirated thoroughly after the final washing step.
  • aqueous ⁇ -naphthol solution prepared by adding 1 gram percent of ⁇ -naphthol, w/v, to water, treating with an aqueous solution containing 10 grams of potassium hydroxide per liter until no ⁇ - naphthol flakes are visible, and then back-titrating with aqueous 6N HCl to a slightly acidic pH, about 6, at which point a precipitate should just begin to form
  • the solution is aspirated off, the discs are washed with 10 ml. of distilled water, aspirated, and this washing step repeated three times, making sure again that the disc bottle has been aspirated thoroughly after the final wash.
  • the binding of the allergen to the diazonium salt site on the disc is a coupling reaction, in which nitrogen is retained in the product, rather than a replacement reaction, in which nitrogen is lost as N 2 and some other group becomes attached to the phenyl ring in place of nitrogen:
  • G must be a strongly electron-releasing group, such as hydroxyl, amino, monoalkylamino or dialkylamino.
  • the allergens coated on a monolithic support or matrix prepared according to the present invention can be coated onto said support as a mixture of allergens.
  • each allergen extract employed each of which extracts can contain, for example, from about 1 ng to about 10 ⁇ g, and preferably from about 1 ng to about 5 ⁇ g, of allergen per milliliter, in a liquid medium such as distilled water plus 0.4% phenol as a preservative, distilled water plus 50 volume percent glycerine, glycerine plus sodium bicarbonate buffer, or the like, can simply be mixed together at room temperature, then admixed with phosphate buffer, or the like, to a dilution of from about 1:2 to about 1:32, and preferably from about 1:4 to about 1:8.
  • the thus-obtained diluted allergen extract mixture is then coated on the monolithic matrix by any suitable procedure, such as those mentioned above.
  • allergosorbents of the present invention can be used in conjunction with the published standard Modified RAST Procedure of Fadal et al, "IgE in Investigation and Management of Atopic Disorders; Recent Advances", J.Cont.Ed. in O.R.L. and Allergy, 40, 47-59 (1978), which can be summarized as follows:
  • a blood sample is collected by venipuncture and the serum is separated by centrifugation.
  • the serum should be stored at 2-8°C until assayed, and repeated freezing and thawing of the serum should be avoided.
  • Time Control A 1:4 dilution of the 100 U/ml IgE standard in a total IgE kit is prepared using 0.9% saline. The resulting 25 U/ml IgE sample can then be used as the time control for the multiallergen RAST screens of the present invention. Alternatively, no time control need be run if, as is usually the case with the multiallergen screens of the present invention, a simple yes/no qualitative response will suffice.
  • Positive Control Serum is pooled from patients sensitive to one particular allergen (e.g., ragweed). When tested against the appropriate homologous RAST allergen disc, the positive control serum should give binding comparable to that obtained using time control, if one is used.
  • allergen e.g., ragweed
  • Negative Control One or more of the following can be used:
  • pooled fresh human cord serum (b) pooled serum samples (3-5) from non- atopic individuals with total IgE of less than 10 U/ml, with negative RAST scores and/or skin test results, (c) serum from an atopic individual (e.g., test such serum against an allergen disc to which patient is negative).
  • the tubes are labeled and arranged as shown in Table II below.
  • the tubes are then covered with aluminum foil or plastic film after all the serum has been pipetted, and let the covered tubes stand at room temperature (about 25 °C) overnight (16-24 hours).
  • step 14 The saline is removed completely; the rinsing procedure in step 14 is repeated two more times .
  • Tubes #1 and #2 are capped, all tubes are covered with aluminum foil or plastic film and allow to stand at room temperature overnight. 18. The washing procedure outlined in step #14 is repeated 3 times.
  • the discs are transferred to clean tubes with corresponding labeled numbers.
  • tube #3 is counted until the counter registers 25,000 counts. The amount of time required is recorded. The same procedure is repeated for tube #4. The average time to reach 25,000 for tubes #3 and #4 is calculated and recorded. (See example under Table II) .
  • Negative control tubes #7, 8 should count to 500 counts ⁇ 200 counts.
  • the patient's test results are expressed as counts or as % time control, and the results can be classified according to the breakdown given in Table I below:
  • the allergosorbents of the present invention can also be used in other recognized RAST procedures, e.g., ones involving the use of radioactive tags other than 1 25 I to label the anti-IgE, such as 131 I, 3 H, 14 C or any other conveniently measurable radioisotope, or ones involving anti-IgE tagged with an enzyme, such as horseradish peroxidase or ⁇ -galactosidase, or with a fluorogenic, chromophoric or luminescent tag.
  • radioactive tags other than 1 25 I to label the anti-IgE, such as 131 I, 3 H, 14 C or any other conveniently measurable radioisotope
  • an enzyme such as horseradish peroxidase or ⁇ -galactosidase, or with a fluorogenic, chromophoric or luminescent tag.
  • Teh ml. of cold (4°C) 1N hydrochloric acid were added to 100 APT (aminophenylthioether derivative) cellulosic paper discs (obtained from Schleicher & Schuell, Inc., Keene, N.H. and weighing a total of 0.28 gram), contained in a suitable vessel.
  • the aqueous hydrochloric acid-disc mixture was swirled, then decanted, and 10 ml. more of cold 1N hydrochloric acid were added, followed by 300 ⁇ l. of a mg./ml. dilution of sodium nitrite prepared by adding 0.020 grams of sodium nitrite to 2 ml. of distilled water.
  • the vessel containing the discs, the aqueous hydrochloric acid and the aqueous sodium nitrite solution was placed on a shaker-in-the-round in a walk-in cooler, shaken for 30 minutes, and the discs were then aspirated and washed 4 times with cold distilled water, with aspiration after each washing.
  • the discs were aspirated and washed 4 times with cold distilled water, with aspiration after each washing.
  • 10 ml. of an aqueous ⁇ -naphthol solution prepared by adding 1 gram of ⁇ -naphthol to 100 ml. of distilled water, then adding 10-12 potassium hydroxide pellets to aid in dissolving the ⁇ -naphthol, and then back-titrating the resulting solution to a pH of approximately 6.0 with 6 N hydrochloric acid, were added to the washed discs and shaking continued for 15 minutes. Following this reaction the discs were aspirated and washed 3 times with distilled water, with aspiration after each washing.
  • Example II The procedure of Example I was repeated in every respect but one, namely, 2 ml of extracts of each of the allergens identified hereinabove as being present in Screen No. 2, i.e., Bermuda grass, Cladosporioides, mountain cedar, American elm (Meridian: lot nos. 3A21, 2E2, 1L9 and 2K24, respectively), dog dander (Hollister- Stier: Code No. 4084) and false ragweed (Greer: Code No. 185), in a water-glycerine medium, were substituted for the allergen extracts used in Example I.
  • 2 ml of extracts of each of the allergens identified hereinabove as being present in Screen No. 2 i.e., Bermuda grass, Cladosporioides, mountain cedar, American elm (Meridian: lot nos. 3A21, 2E2, 1L9 and 2K24, respectively), dog dander (Hollister- Stier: Code No. 4084
  • Example III The procedure of Example I was again repeated in every respect but one, namely, 2 ml of extracts of each of the allergens identified hereinabove as being present in Screen No. 3, i.e., dog dander, June grass (Kentucky blue), cat epithelium (Hollister-Stier: Code Nos. 4084, 1190 and 4042, respectively), birch tree, dust mite, short ragweed, white oak, A. tenuis (Meridian: lot nos. 0G3B, 2F22, 2K1, 1T13 and 3D15, respectively) and timothy grass (Greer: Code No. 28) , in a water-glycerine medium, were substituted for the allergen extracts used in Example I.
  • Example IV The screen discs prepared as described in Examples I-III above were evaluated by using them to assay sera from 21 patients in side-by-side comparison with individual allergen-bearing cellulose paper discs.
  • the standard Fadal/Nalebuff Modified RAST assay procedure described above was used in this evaluation, and the scoring was done using the Fadal/ Nalebuff Modified RAST scoring system shown in Table I above.
  • Table III below records the results obtained in this evaluation using Screens Nos. 1, 2 and 3 and individual discs, both by Fadal/Nalebuff class and by individual counts bound in each test.
  • An allergen extract pool for coating cellulosic paper discs, the insides of plastic tubes and plastic multifinned sticks was prepared by mixing 13 ml. of each of the following Meridian allergen extracts, each in a water-50 volume % glycerine medium, in a clean vessel at 2-8°C:
  • the allergen extract pool was covered, labeled and stored at 2-8°C.
  • a 1:2 dilution of the above-prepared 15-allergen extract pool was prepared by adding 125 ml. of the pool to 125 ml. of 0.1M phosphate buffer. This 1:2 dilution was then added to the 5000 discs, which had been suspended in 250 ml. of 0.05M phosphate buffer in the round bottom flask, giving a 1:4 dilution of the mixed allergen pool in contact with the discs. The flask was then shaken in the walk-in cooler for 1 hour, following which the discs were aspirated and washed 4 times with cold distilled water, with aspiration after each washing.
  • the discs After soaking the discs in 500 ml. of the above-described storage buffer for 10 minutes, aspirating, and then adding 500 ml. more of the storage buffer, the discs were transferred, with the storage buffer, to a storage vessel, labeled, and kept at 2-8°C.
  • An allergen extract pool for coating cellulosic paper discs, the insides of plastic tubes and plastic multifinned sticks was prepared by mixing 2 ml. of each of the following twenty-four allergen extracts in a clean vessel at 2-8°C: Allergen Source and Extract Lot No.
  • this allergen extract pool was covered, labeled and stored at 2-8°C.
  • the discs After soaking the discs in 125 ml. of the above-described storage buffer for ten minutes, aspirating, and then adding 125 ml. more of the storage buffer, the discs were transferred, with the storage buffer, to a storage bottle, labeled, and stored at 2-8 °C.

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Abstract

Dispositif de tamisage allergosorbant permettant un titrage qualitatif des sérums humains pour une hypersensibilité allergique où une matrice monolithique, par exemple un disque de papier cellulosique ou un bâton à ailettes multiples, est enduite de deux ou de plusieurs allergènes différents provenant de différents groupes d'allergènes.
EP84904289A 1983-11-10 1984-11-09 Matrices portant de multiples allergenes utiles pour un tamisage qualitatif d'allergies Withdrawn EP0162896A1 (fr)

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US55053583A 1983-11-10 1983-11-10
US550535 1983-11-10

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EP (1) EP0162896A1 (fr)
AU (1) AU3616684A (fr)
WO (1) WO1985002262A1 (fr)
ZA (1) ZA848820B (fr)

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CN102539748A (zh) * 2011-12-30 2012-07-04 苏州浩欧博生物医药有限公司 一种利用酶联板进行多指标酶联免疫吸附检测的方法
CN109073645A (zh) * 2016-04-26 2018-12-21 拜尔梅里科有限公司 溃疡性结肠炎敏感测试的组合物、设备以及方法

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