EP0448632A1 - Analyse immunometrique anti-idiotopique - Google Patents

Analyse immunometrique anti-idiotopique

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Publication number
EP0448632A1
EP0448632A1 EP19900901337 EP90901337A EP0448632A1 EP 0448632 A1 EP0448632 A1 EP 0448632A1 EP 19900901337 EP19900901337 EP 19900901337 EP 90901337 A EP90901337 A EP 90901337A EP 0448632 A1 EP0448632 A1 EP 0448632A1
Authority
EP
European Patent Office
Prior art keywords
monoclonal antibody
preselected
antibody
idiotypic
amount
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Withdrawn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
EP19900901337
Other languages
German (de)
English (en)
Inventor
Albert F. Lobuglio
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.)
Janssen Biotech Inc
Original Assignee
Centocor Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Centocor Inc filed Critical Centocor Inc
Publication of EP0448632A1 publication Critical patent/EP0448632A1/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Withdrawn legal-status Critical Current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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • G01N33/686—Anti-idiotype
    • 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
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins

Definitions

  • Monoclonal antibodies such as these may be useful as therapeutic reagents.
  • they can have both safety and product standardization advantages as compared to the use of human pooled hyperimmune sera.
  • their use would have presumably fewer problems with immunogenicity than with use of murine monoclonal antibodies.
  • Radiolabeled antibodies have been used to determine the pharmacokinetics of monoclonal antibody products in man [Sears, et al., J. Biol. Resgonse Mod., 3:138 (1984) and Meeker, et a l . , Blood, 65:1349 (1985)], but this method has the disadvantage of requiring use of a radiolabeling procedure that might alter the molecule, thus resulting in alteration in pharmacokinetics.
  • the pharmacokinetics of an injected dose can also be measured by quantitation of the circulating antibody at various times following administration [Khazaeli et al., Clin. Res., 35:615A (1988)].
  • This approach would require a specific and sensitive assay capable of detecting the monoclonal antibody in the presence of a vast excess of normal human immunoglobulins in serum.
  • the present invention provides an immunometric assay for a preselected antibody in a biological fluid such as a blood sample.
  • the assay comprises forming a complex of a first monoclonal antibody that is labeled, the preselected antibody, and a second monoclonal antibody and detecting the amount of label associated with the complex as indicative of the presence or the amount of preselected antibody in the biological fluid.
  • the first and second monoclonal antibodies are specific for idiotopes of the preselected antibody.
  • the preferred assay is a solid phase assay where at least one of the antibody constituents of the complex is bound to a solid phase, either before or after formation of the complex.
  • the first antibody can be labeled before or after formation of the complex.
  • Figure 1 shows a HPLC profile of purified anti-idiotypic murine monoclonal antibody, 15B2.2.
  • Figure 2 shows cross reactivity of normal human immunoglobulins.
  • increasing concentrations of HA-1A normal human IgG, IgM, IgA, IgE and IgD were incubated in the assay as described in materials and methods.
  • Figure 3 shows a dose response curve of HA-1A in solid phase radiometric assay. Increasing concentrations of HA-1A were incubated with 9B5.5- coated beads for 2 hours, washed and incubation was continued for 1 hour with 125 I-15B2.2. Bead associated radioactivity was determined and a standard curve was constructed using logit-log transformati on regre s s ion analys is .
  • Figure 4 shows the serum concentrations of human IgM monoclonal antibody HA-1A in a patient who received 100 mg of the antibody. Serum samples obtained from the patient were assayed at appropriate dilution in the solid phase radiometric assay. The values are the mean of triplicate determinations ⁇ 1S.D. Detailed Description of the Invention
  • the present invention provides a novel immuno- assay for a preselected antibody in liquid sample.
  • a complex is formed comprising a first labelled monoclonal antibody, the antibody to be measured (the
  • an antibody a monoclonal antibody
  • the first and second monoclonal antibodies react with an idiotopic site on the antibody to be measured.
  • the immunoassay can be conducted in a reverse, simultaneous, or forward format.
  • the amount of preselected monoclonal antibody is quantified by detecting the amount of label associated with the complex.
  • Preferred assays are those where the complex is immobilized on the solid phase.
  • This invention is based on the recognition that antibodies are themselves antigenic. It is possible, therefore, to induce antibodies that will recognize antigenic determinants on both the constant and the variable regions of immunoglobulin chains. Antigenic determinants on the variable regions of L and H chains that are associated with the antigen-binding site of an antibody are called idiotopes. The set of idiotopes on an individual antibody molecule defines the idiotype of that antibody.
  • the first and second monoclonal antibodies of this invention are anti-idiotypic. That is, they will react solely with antigenic determinants
  • idiotopes associated with the antigen-binding site of a pre-selected antibody molecule.
  • these monoclonal antibodies are specific for a "private idiotope".
  • Antibodies useful in the invention can be any suitable antibodies.
  • Particularly preferred monoclonal anti- idiotypic antibodies of this invention are "private" anti-idiotypic antibodies, and are produced as described herein.
  • a p arti cular example of such a monoclonal anti-idiotypic antibody is one that specifically reacts with idiotopes of human monoclonal antibody HA-1A.
  • anti-idiotypic monoclonal antibodies of this invention are produced by hybridomas formed by fusion of: a) a mouse myeloma which does not secrete antibody with b) human lymph node spleen cells which secrete anti- idiotypic antibodies obtained from mice immunized against a preselected human monoclonal antibody (e.g., HA-1A).
  • a mouse myeloma which does not secrete antibody
  • human lymph node spleen cells which secrete anti- idiotypic antibodies obtained from mice immunized against a preselected human monoclonal antibody (e.g., HA-1A).
  • mice are immunized with a primary injection of monoclonal antibody followed by a number of boosting injections of the same antibody.
  • sera of the mice may be screened to identify those mice in which a substantial immune response to the antibody has been evoked.
  • the spleen cells are obtained and fusions are performed. Suitable fusion techniques are the Sendai virus technique. Kohler, G. and Milstein, C, Nature 256:495 (1975), or the polyethylene glycol method, Kennet, R.H. in "Monoclonal Antibodies, Hybridomas -- A New Dimension in Biological Analyses", ed. R.H. Kennet, T. J. McKearn and K.B. Bechtol, Plenum Press, N.Y., 1980. Also, electrofusing techniques may be employed. Zimmerman, U. and Vienken, J., J. Membrane Bio. 67:165 (1982).
  • hybridomas are then screened for production of anti-idiotypic antibody.
  • a suitable preliminary screening technique is an enzyme-linked immuno- sorbent assay (ELISA) using plates precoated with the monoclonal antibody of interest and control immunoglobulins. That is, solid phase immuno- adsorbent is prepared by coupling, for example
  • Monoclonal anti-idiotypic antibodies for use in the assays can be produced in large quantities by injecting anti-idiotype-producing hybridoma cells into the peritoneal cavity of mice and, after an appropriate time, harvesting ascites fluid from the mice which yields a very high titer of homogenous anti-idiotypic antibody.
  • the monoclonal antibodies are isolated therefrom.
  • the antibodies can be produced by culturing anti-idiotype producing cells in vitro and isolating secreted monoclonal anti-idiotype antibodies from the cell culture medium directly.
  • anti-idiotypic antibodies of this invention discriminate between the preselected antibody and the normal suite of human
  • immunoglobulins they permit a sensitive
  • immunochemical assay is a sandwich immunometric assay in which antigen (i.e., natural or recombinant the monoclonal antibody) is measured directly by reacting it with murine anti-idiotypic antibody that is labeled, or capable of being labeled.
  • antigen i.e., natural or recombinant the monoclonal antibody
  • the complex can be formed before it is immobilized onto a solid phase. In other embodiments, the complex can be immobilized on the solid phase at the same time that it is formed.
  • the antigen is immobilized on an immuno- adsorbent which specifically "captures” or binds the preselected antibody ("antigen").
  • This immuno- adsorbent is formed by affixing to it an antibody specific for an idiotope of the preselected mono- clonal antibody.
  • sandwich assays of this invention two anti-idiotypic antibodies which recognize identical idiotopes on the antigen can be used. Thus, for most purposes, the same anti- idiotypic antibody used to form the immunoadsorbent can be used as the lab eled antibody.
  • Sandwich assays may be performed in forward, reverse or simultaneous mode. In a forward sandwich assay for an antibody, a monoclonal antibody
  • a liquid sample to be tested is incubated with the immunoadsorbent.
  • Incubation is maintained for a sufficient period of time to allow the antibody in the liquid sample to bind to its immobilized anti-idiotypic antibody on the immunoadsorbent.
  • the solid phase immunoadsorbent is separated from the sample.
  • the immunoadsorbent is washed to remove unbound monoclonal antibody and interfering substances, such as non-specific binding proteins, which may also be present in the liquid sample.
  • the immunoadsorbent containing antibody bound to immobilized antibody is subsequently incubated with labeled anti-idiotypic antibody, specific for idiotope(s) on the monoclonal antibody.
  • the incubation is carried out for a period of time and under conditions sufficient to ensure binding of the labeled anti-idiotypic antibody to the antibody.
  • Another wash may be performed to remove unbound label from the solid phase immunoadsorbent.
  • the labeled anti-idiotypic antibody bound to the solid phase immunoadsorbent is then measured, and the amount of label detected serves as a direct measure of the amount of antibody present in the liquid sample.
  • the sandwich immunoassays may also be performed in reverse and simultaneous modes.
  • reverse modes an incubation mixture is formed of the liquid sample to be tested and a soluble labeled anti- idiotypic antibody directed against an idiotope of a preselected antibody such as HA-1A.
  • the mixture is incubated, then contacted with a solid phase immunoadsorbent containing an anti-idiotypic monoclonal antibody directed against the same or different idiotope of the preselected antibody.
  • the immunoadsorbent is separated from the mixture and the label bound to the immunoadsorbent is taken as an indication of the amount of preselected monoclonal antibody in the liquid sample.
  • an incubation mixture is formed of the liquid sample containing monoclonal antibody to be measured (e.g., HA-1A), labeled anti-idiotypic antibody and the solid phase immuno- adsorbent. After appropriate incubation, the solid phase immunoadsorbent is separated from the mixture and the label associated with the immunoadsorbent is measured to give an indication of the amount of monoclonal antibody in the liquid sample.
  • monoclonal antibody to be measured e.g., HA-1A
  • the immunoassays of this invention are used to detect and quantify monoclonal antibody in a liquid sample.
  • Liquid samples include essentially all biological fluids such as blood, or blood- derived fluids such as plasma or serum, as well as urine, lymph, etc.
  • the liquid sample may be a sample of a liquid medium in which lymphocytes or other mammalian cells have been cultured. They may also be extracts or supernatants of microbial cultures.
  • the assays of this invention can be used to detect any monoclonal antibody capable of forming a suitable complex with anti-idiotypic monoclonal antibodies (i.e., labeled anti-idiotypic antibody preselected monoclonal antibody: unlabeled anti-idiotypic antibody), mammalian, preferably human monoclonal antibodies. These monoclonal antibodies are generally useful as therapeutic reagents. Assay methods of this invention can be used to detect monoclonal antibodies raised against carcinoma cells, lymphoma cells, fibrin (e.g.,
  • platelet e.g., 7E3, European Patent
  • endotoxin e.g., HA-1A
  • monoclonal antibodies that are
  • anti-idiotypic monoclonal antibodies reactive with preselected monoclonal antibodies can first be immobilized by affixing them to a solid phase to create an "immunoadsorbent".
  • the anti- idiotypic antibody is therefore affixed to the solid phase before the three-part complex (i.e., labeled anti-idiotypic antibody: preselected monoclonal antibody: unlabeled anti-idiotypic antibody) is created.
  • This tripartate or ternary complex can also be attached to a solid phase after the complex is formed. This can be accomplished, for example, by affixing avidin to the solid phase and allowing the ternary complex to form in solution, one antibody of this complex being labeled with biotin.
  • solid-phases Many types may be employed.
  • Well-known solid phases include beads formed from glass, polystyrene, polypropylene, dextran, and other materials; tubes formed from or coated with such materials, etc.
  • the anti-idiotypic antibody can be either covalently or noncovalently bound to the solid-phase by techniques such as covalent bonding via an amide or ester linkage or adsorption.
  • suitable solid-phases and methods for immobilizing antibodies thereon or will be able to ascertain such using no more than routine experimentation.
  • monoclonal anti-idiotypic antibody directed against an idiotope of a preselected mammalian monoclonal antibody is also used as the labeled antibody
  • Such antibodies can be labeled directly with a radioactive material, such as 125 I; labeled with an optical label, such as fluorescent material; labeled with an enzyme; or labeled by some other technique.
  • a radioactive material such as 125 I
  • an optical label such as fluorescent material
  • labeled with an enzyme or labeled by some other technique.
  • These antibodies can also be labeled Indirectly (I.e., by complexation with another labeled antibody).
  • the amount of label associated with the immunoadsorbent or the amount of unbound label is measured.
  • the label bound to the immunoadsorbent because at very low concentration of monoclonal in the sample, only small amounts of labeled anti-idiotypic antibody bind the immunoadsorbent.
  • the label may be detected by a gamma counter, for example, if the label is a radioactive gamma emitter, of by a fluorimeter, if the label Is a fluorescent material. In the case of an enzyme label, detection may be done by
  • the measured amount of label detected is then compared to a quantitative relationship between the amount of preselected label and the amount of monoclonal antibody.
  • the quantitative relationship can be determined by performing the immunoassay with standards (i.e., liquid samples containing known amounts of monoclonal antibody). For several samples containing different amounts of preselected monoclonal antibody, the assay is conducted and the amount of label either bound or unbound to the immunoadsorbent is determined; a curve is con structed defining the quantitative relationship between the amount of label and the amount of monoclonal antibody. By reference to the curve, the amount of monoclonal antibody in a liquid sample containing an unknown amount of monoclonal antibody can be determined from the amount of label detected.
  • the immunoassays described provide rapid, highly sensitive, inexpensive and reproducible methods for detection and quantification of mono- clonal antibodies.
  • the assays provide a substitute for existing bioassays which are more time-consuming and variable and much less sensitive and specific.
  • the assay reagents may be provided conveniently in kits.
  • the assay may also be used to monitor the amount of monoclonal antibody during the course of antibody therapy. This will be of predictive value in managing the course of treatment in a variety of disease states.
  • kits for performing an immunoassay for HA-1A would comprise a solid phase immunoadsorbent containing an anti-idiotypic antibody specific for one idiotope of HA-1A, a labeled anti-idiotypic antibody specific for the same idiotope of HA-1A and, optionally, an HA-1A standard.
  • a kit for performing an immunoassay for HA-1A would comprise a solid phase immunoadsorbent containing an anti-idiotypic antibody specific for one idiotope of HA-1A, a labeled anti-idiotypic antibody specific for the same idiotope of HA-1A and, optionally, an HA-1A standard.
  • the invention is further described in the following examples wherein all parts and percentages are by weight degrees are celsius.
  • LPS Gram negative lipopolysaccharide
  • IgE and IgD was supplied by Behring Diagnostics, LaJolla, CA. 125 I was obtained from the DuPont
  • the HA-1A monoclonal antibody was produced by a hybridoma cell line generated by fusion of splenic lymphocytes with a heteromyeloma cell line (Teng, N.N.A., K.S. Lam, F.C. Rieva and J.S. Kaplan, Proc. Natl. Acad. Sci. USA, 80:7308-7312 (1983) and Bron, D., M.B. Feinberg, N.N.H. Teng and H.S. Kaplan,
  • the splenocytes were removed from a patient undergoing splenectomy during staging for Hodgkin's disease.
  • the patient had been immunized with the J5 mutant of Escherichia Coli (E. coli) which expresses the core oligosaccharide common to the lipopolysaccharide (LPS) of all Gram-negative bacteria.
  • E. coli Escherichia Coli
  • LPS lipopolysaccharide
  • the HA-1A monoclonal antibody cross-reacts with endotoxins from a wide range of unrelated species of Gram- negative bacteria and protects against lethal
  • mice Gram-negative bacteremia in mice (Teng, N.N.H., H.S. Kaplan, J.M. Herbert, C. Moore, H. Douglas, A.
  • HA-1A is a human IgM k
  • Lymph node cells from BALB/c mice immunized with HA-1A were fused with non-Ig producing cell line P3 -X63 -Ag8.653 (Kearney, J.F. et al., J.
  • the ascites fluid was purified by passage over a Bakerbond ABx HPLC column (10x250 mm) equilibrated with 25mM MES buffer pH 5.5. After the elution of unbound proteins, a gradient from 0 to 100% of 1M NaOAc pH 7.0 was used over 60 min to elute the monoclonal antibody. The recovered antibody was analyzed for purity using a Quick-check analysis (BioRad, Richmond, CA). This analytic column was a Blo-Sil TSK-250 (7.5 x 300mm). The eluting buffer was .01M phosphate, 0.3 M NaCI, 10% dimethyl- sulfoxide (v/v) eluting at 1 ml/min.
  • Polystyrene beads 6.4 mm diameter (Precision Plastic Ball, Inc., Chicago, IL), were coated with 200 ⁇ l anti-id 9B5.5 in phosphate buffered saline (PBS) at a concentration of 5 ⁇ g/ml. Beads were washed three times with PBS containing 2% bovine serum albumin (BSA) and .02% Tween 20 and allowed to stand in wash buffer for 1 hr at room temperature. The beads were air dried and stored at 4°C until used. Human monoclonal antibody HA-1A was diluted in normal human serum (NHS) at concentrations ranging from 12.5-6400 ng/ml. Standard, controls and patient serum at appropriate dilution were incubated (100 ⁇ l) for 2 hr in triplicate with coated beads on a laboratory rotator at room
  • the purified monoclonal antibodies were labeled with 125 I by a modified method of Greenwood, e t al . ,
  • radiolabeled monoclonal antibodies were analyzed using HPLC as described above, except that a radioisotope monitor was used to detect radio- activity in sequence with the U.V. monitor.
  • the protein was measured in final preparation by the method of Lowry, O.H. e t al., J . Biol . Chem .,
  • antibodies 9B5.5 and 15B2.5 were designated as
  • Polystyrene beads were carried with varying amounts of 9B5.5 from 0.1 ⁇ g to 1.6 ⁇ g/bead. Maximum binding occurred at 1.0 ⁇ g/bead.
  • the amount of radiolabeled 15B2.2 used in the assay was determined by incubating the 9B5.5 coated beads with HA-1A standards followed by incubation with varying amount of 125 I - 15B2.2.
  • the 0.1 ⁇ g of 125 I - 15B2.2 was sufficient to have an excess of 15B2.2 available at all concentrations of standard.
  • the two incubations were carried out, at intervals varying from 30 min to 18 hrs at both room temperature and 37°C. Greater than 90% of maximum binding occurred with 2 hour incubation with sera and one hour incubation with radioactive 15B2.2. Binding was comparable at room temperature and 37oC. For convenience, room
  • HA-1A assay as described above, increasing concentrations of HA-1A, normal human IgG, IgM, IgA, IgE and IgD were assayed (Fig. 2). The cross reactivity of these various immunoglobulin preparations was calculated as less than 0.1%. The sensitivity of the assay defined as 2 standard deviations above the nonspecific binding (normal human serum) was
  • the linearity of the assay is best seen by logit-log analysis (Fig. 3).
  • the assay is linear between 25 and 800 ng/ml.
  • the inter-assay variance was examined by assay of three concentrations of HA-1A (200, 1000 and 2500 ng/ml in human serum) as positive controls in 10 consecutive independent assays.
  • the means for the three HA-1A levels were 206 ⁇ 12, 981 ⁇ 65 and 2573 ⁇ 161 ng/ml, respectively (a coefficient of variation of between 5.8 and 6.6 percent).
  • HA-1A Since this antibody (HA-1A) is likely to be used In patients with gram negative sepsis, the effects of bacteria and LPS on the assay HA-1A in human serum was studied. Human sera containing 20 ⁇ g/ml HA-1A was Incubated with varying numbers of bacteria (E. coli) or varying concentrations) LPS at 37o for 20 minutes and then assayed for HA-1A content (Table 2). These additives had no adverse effects in detection of HA-1A.

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Abstract

On a mis au point une analyse immunométrique permettant de déterminer un anticorps monoclonal dans un échantillon biologique, consistant à former un complexe à partir d'un premier anticorps monoclonal anti-idiotypique marqué, l'anticorps monoclonal présélectionné, et d'un second anticorps monoclonal anti-idiotypique, que l'on peut lier à un substrat solide, et à détecter la quantité d'anticorps marqués associés au complexe. L'analyse est caractérisée par l'emploi de premier et second anticorps monoclonaux réagissant avec un site idiotypique sur l'anticorps monoclonal présélectionné.
EP19900901337 1988-12-09 1989-12-08 Analyse immunometrique anti-idiotopique Withdrawn EP0448632A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP1745288A2 (fr) * 2004-04-16 2007-01-24 Genentech, Inc. Dosage pour anticorps
BRPI0609439A2 (pt) * 2005-03-23 2010-04-06 Wyeth Corp detecção de uma resposta imunológica a agentes moduladores de gdf-8
CN101371140B (zh) * 2006-03-09 2013-11-13 弗·哈夫曼-拉罗切有限公司 抗药物抗体的测定
WO2008031532A1 (fr) 2006-09-12 2008-03-20 F. Hoffmann-La Roche Ag Essai d'anticorps anti-médicament
WO2009032128A1 (fr) * 2007-08-28 2009-03-12 Abbott Biotechnology Ltd. Compositions et procédés comprenant des protéines de liaison pour adalimumab
ES2407603T3 (es) 2007-12-15 2013-06-13 F. Hoffmann-La Roche Ag Ensayo de distinción
US8614297B2 (en) 2008-12-22 2013-12-24 Hoffmann-La Roche Inc. Anti-idiotype antibody against an antibody against the amyloid β peptide
EP2606362B1 (fr) 2010-08-19 2015-09-30 Roche Diagniostics GmbH Dosage pour la mesure d'anticorps se liant à un anticorps monoclonal thérapeutique
DK3105592T3 (en) 2014-02-11 2019-02-04 Genzyme Corp PROCEDURES FOR DETERMINING THE PRESENCE OR THE QUANTITY OF AN ANTI-MEDICINE ANTIBODY
US9958464B2 (en) 2015-03-03 2018-05-01 Ark Diagnostics, Inc. Pregabalin immunoassays

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5325300A (en) * 1976-08-20 1978-03-08 Nippon Crucible Co Process for preparing betaatype silicon carbide particle
US4217335A (en) * 1979-06-14 1980-08-12 Nippon Crucible Co., Ltd. Process for producing β-silicon carbide fine powder
JPS58183629A (ja) * 1982-04-21 1983-10-26 Eisai Co Ltd 非ａ非ｂ型肝炎関連モノクロナ−ル抗体および診断薬
US4828981A (en) * 1983-08-24 1989-05-09 Synbiotics Corporation Immunoassays for determining Dirofilaria immitis infection using antiidiotype monoclonal antibody reagents
JPS60141612A (ja) * 1983-12-28 1985-07-26 Nippon Cement Co Ltd 高純度炭化けい素粉末の製造方法
WO1988006293A2 (fr) * 1987-02-17 1988-08-25 Lewis Donald G Immunoanalyse liposomique pour detecter des antigenes et des immunoglobulines specifiques des antigenes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9006515A1 *

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WO1990006515A1 (fr) 1990-06-14

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